<1. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27993090 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Koido S AU - Okamoto M AU - Shimodaira S AU - Sugiyama H FA - Koido, Shigeo FA - Okamoto, Masato FA - Shimodaira, Shigetaka FA - Sugiyama, Haruo IN - Koido, Shigeo. Division of Gastroenterology & Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, Kashiwa City, Chiba 277-8567, Japan. IN - Koido, Shigeo. Institute of Clinical Medicine & Research, The Jikei University School of Medicine, Kashiwa City, Chiba 277-8567, Japan. IN - Okamoto, Masato. Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Tokyo 108-8641, Japan. IN - Shimodaira, Shigetaka. Cell Processing Center, Shinshu University Hospital, Nagano 390-8621, Japan. IN - Sugiyama, Haruo. Department of Functional Diagnostic Science, Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan. TI - Wilms' tumor 1 (WT1)-targeted cancer vaccines to extend survival for patients with pancreatic cancer. [Review] SO - Immunotherapy. 8(11):1309-1320, 2016 Nov AS - Immunotherapy. 8(11):1309-1320, 2016 Nov NJ - Immunotherapy PI - Journal available in: Print PI - Citation processed from: Internet JC - 101485158 IO - Immunotherapy SB - Index Medicus CP - England MH - Animals MH - *Antigens, Neoplasm/im [Immunology] MH - *Cancer Vaccines/im [Immunology] MH - Carcinoma, Pancreatic Ductal/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/th [Therapy] MH - Clinical Trials as Topic MH - Dendritic Cells/im [Immunology] MH - *Dendritic Cells/tr [Transplantation] MH - Humans MH - Molecular Targeted Therapy MH - Vaccines, Subunit MH - *WT1 Proteins/im [Immunology] KW - WT1; cancer vaccine; dendritic cell; pancreatic cancer; peptide AB - Despite novel chemotherapy treatments, pancreatic ductal adenocarcinoma (PDA) remains a lethal disease. New targeted cancer vaccines may represent a viable option for patients with PDA. The Wilms' tumor 1 (WT1) antigen is one of the most widely expressed tumor-associated antigens in various types of tumors, including PDA. Recent reports have indicated that WT1-targeted cancer vaccines for patients with PDA mediated a potent antitumor effect when combined with chemotherapy in preclinical and clinical studies. This review summarizes the early-phase clinical trials of WT1-targeted cancer vaccines (peptide vaccines and dendritic cell-based vaccines) for PDA. Moreover, we will discuss future strategies for PDA treatments using WT1-specific cancer vaccines combined with immune checkpoint therapies to maximize the clinical effectiveness of PDA treatments. RN - 0 (Antigens, Neoplasm) RN - 0 (Cancer Vaccines) RN - 0 (Vaccines, Subunit) RN - 0 (WT1 Proteins) RN - 0 (WT1 protein, human) ES - 1750-7448 IL - 1750-743X DO - https://dx.doi.org/10.2217/imt-2016-0031 PT - Journal Article PT - Review ID - 10.2217/imt-2016-0031 [doi] PP - ppublish LG - English DP - 2016 Nov DC - 20161220 EZ - 2016/12/21 06:00 DA - 2017/07/06 06:00 DT - 2016/12/21 06:00 YR - 2016 ED - 20170705 RD - 20170705 UP - 20170706 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27993090 <2. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27892744 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Abdel-Rahman O FA - Abdel-Rahman, Omar IN - Abdel-Rahman, Omar. Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. TI - Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. [Review] SO - Immunotherapy. 8(12):1383-1391, 2016 Dec AS - Immunotherapy. 8(12):1383-1391, 2016 Dec NJ - Immunotherapy PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101485158 IO - Immunotherapy SB - Index Medicus CP - England MH - *Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Clinical Protocols MH - Clinical Trials as Topic MH - Drug-Related Side Effects and Adverse Reactions MH - Humans MH - *Melanoma/dh [Diet Therapy] MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Treatment Outcome KW - NSCLC; dose; melanoma; pembrolizumab AB - AIM: Pembrolizumab is a fully humanized anti-PD-1 agent currently approved for the treatment of advanced melanoma and pretreated non-small-cell lung cancer (NSCLC). AB - OBJECTIVE: To assess the efficacy and safety of different dose schedules of pembrolizumab in the treatment of patients with advanced NSCLC and melanoma. Search method: MEDLINE database has been searched. Reference lists of original studies and review articles were checked for other related articles. AB - SELECTION CRITERIA: Prospective clinical trials reporting the outcomes of more than one dose schedule of pembrolizumab in the treatment of advanced NSCLC and melanoma. AB - DATA COLLECTION & ANALYSIS: The review author extracted information on the outcomes of the study for this review, and presented the results. AB - MAIN RESULTS: Four trials with 3425 patients were included in this systematic review. Pooled analysis for the odds ratio of objective response rate comparing 2 versus 10 mg/kg every 3 weeks in advanced melanoma was 1.03 (95% CI: 0.71-1.49; p = 0.89), while for advanced NSCLC, it was 0.97 (95% CI: 0.66-1.43; p = 0.87). Moreover, odds ratio for selected side effects between the two doses was as follows: rash: 0.83 (95 CI: 0.58-1.18; p = 0.29); vitiligo: 1.27 (95% CI: 0.62-2.61; p = 0.52); diarrhea: 0.94 (95% CI: 0.63-1.42; p = 0.79); hypothyroidism: 0.97 (95% CI: 0.63-1.50; p = 0.90); hepatitis/elevated transaminases: 1.86 (95% CI: 0.91-3.79; p = 0.09); nephritis: 0.88 (95% CI: 0.32-2.44; p = 0.80); pneumonitis: 1.17 (95% CI: 0.62-2.23; p = 0.63). RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - DPT0O3T46P (pembrolizumab) ES - 1750-7448 IL - 1750-743X DO - https://dx.doi.org/10.2217/imt-2016-0075 PT - Journal Article PT - Meta-Analysis PT - Review ID - 10.2217/imt-2016-0075 [doi] PP - ppublish LG - English EP - 20161128 DP - 2016 Dec DC - 20161128 EZ - 2016/11/29 06:00 DA - 2017/07/06 06:00 DT - 2016/11/29 06:00 YR - 2016 ED - 20170705 RD - 20170705 UP - 20170706 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27892744 <3. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27045886 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bastman JJ AU - Serracino HS AU - Zhu Y AU - Koenig MR AU - Mateescu V AU - Sams SB AU - Davies KD AU - Raeburn CD AU - McIntyre RC Jr AU - Haugen BR AU - French JD FA - Bastman, Jill J FA - Serracino, Hilary S FA - Zhu, Yuwen FA - Koenig, Michelle R FA - Mateescu, Valerica FA - Sams, Sharon B FA - Davies, Kurtis D FA - Raeburn, Christopher D FA - McIntyre, Robert C Jr FA - Haugen, Bryan R FA - French, Jena D IN - Bastman, Jill J. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - Serracino, Hilary S. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - Zhu, Yuwen. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - Koenig, Michelle R. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - Mateescu, Valerica. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - Sams, Sharon B. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - Davies, Kurtis D. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - Raeburn, Christopher D. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - McIntyre, Robert C Jr. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - Haugen, Bryan R. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. IN - French, Jena D. Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045. TI - Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced Differentiated and Anaplastic Thyroid Cancer. SO - Journal of Clinical Endocrinology & Metabolism. 101(7):2863-73, 2016 Jul AS - J Clin Endocrinol Metab. 101(7):2863-73, 2016 Jul NJ - The Journal of clinical endocrinology and metabolism PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hrb, 0375362 IO - J. Clin. Endocrinol. Metab. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929840 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Biomarkers, Tumor/ge [Genetics] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - CD8-Positive T-Lymphocytes/pa [Pathology] MH - Cell Cycle Checkpoints/ge [Genetics] MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - *Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/pa [Pathology] MH - Male MH - Middle Aged MH - Neoplasm Invasiveness MH - Prognosis MH - *Programmed Cell Death 1 Receptor/ge [Genetics] MH - Programmed Cell Death 1 Receptor/ph [Physiology] MH - Signal Transduction/ge [Genetics] MH - Thyroid Carcinoma, Anaplastic/di [Diagnosis] MH - *Thyroid Carcinoma, Anaplastic/ge [Genetics] MH - *Thyroid Carcinoma, Anaplastic/im [Immunology] MH - Thyroid Carcinoma, Anaplastic/pa [Pathology] MH - Thyroid Neoplasms/di [Diagnosis] MH - *Thyroid Neoplasms/ge [Genetics] MH - *Thyroid Neoplasms/im [Immunology] MH - Thyroid Neoplasms/pa [Pathology] AB - CONTEXT: Five to 10% of patients with differentiated thyroid cancers (DTC) develop invasive and/or distant metastatic disease that is marginally improved with standard therapies. Prognosis is poor for patients with anaplastic thyroid cancer, with a median survival of 3-5 months. We suggest that a paradigm shift is necessary in the treatment of advanced cases. AB - OBJECTIVE: We hypothesized that a T-cell response is generated in advanced thyroid cancer and may be a viable therapeutic target. AB - DESIGN: Primary DTCs were analyzed by quantitative RT-PCR (n = 92) for expression of CD3, CD8, forkhead box (Fox)-P3, programmed death (PD)-1, PD-1 ligand-1, and PD-1 ligand-2 and biopsied for cellular analysis by flow cytometry (n = 11). Advanced pT4 cases (n = 22) and metastases (n = 5) were analyzed by immunohistochemistry. AB - SETTING: The study was conducted at the University of Colorado Hospital. AB - PATIENTS: Thyroid cancer patients undergoing thyroidectomy or completion surgery for advanced disease between 2002 and 2013 participated in the study. AB - INTERVENTION: There were no interventions. AB - MAIN OUTCOME MEASURE: Immune markers were analyzed for association with disease severity. AB - RESULTS: Immune markers were commonly expressed at the RNA level. PD-L1 was higher (P = .0443) in patients with nodal metastases. FoxP3(+) (P < .0001), PD-1(+)CD8(+) (P = .0058), and PD-1(+)CD4(+) (P = .0104) T cells were enriched in DTC biopsies. CD8(+) and FoxP3(+) T cells were detected by immunohistochemistry in all pT4 tumors and a subset of metastases. PD-1(+) lymphocytes were found in 50% of DTCs. PD-L1 was expressed by tumor and associated leukocytes in 13 of 22 cases, and expression was more diffuse in anaplastic thyroid cancer (P = .0373). BRAF(V600E) mutation was associated with higher frequencies of tumor-associated lymphocytes (P = .0095) but not PD-L1 expression. AB - CONCLUSIONS: PD-1 checkpoint blockades may have therapeutic efficacy in patients with aggressive forms of thyroid cancer. RN - 0 (Biomarkers, Tumor) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1945-7197 IL - 0021-972X DO - https://dx.doi.org/10.1210/jc.2015-4227 PT - Journal Article ID - 10.1210/jc.2015-4227 [doi] ID - PMC4929840 [pmc] PP - ppublish PH - 2017/07/01 [pmc-release] GI - No: P30 CA046934 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 RR025780 Organization: (RR) *NCRR NIH HHS* Country: United States LG - English EP - 20160405 DP - 2016 Jul DC - 20160706 EZ - 2016/04/06 06:00 DA - 2017/07/06 06:00 DT - 2016/04/06 06:00 YR - 2016 ED - 20170705 RD - 20170705 UP - 20170706 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27045886 <4. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28106152 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Byun DJ AU - Wolchok JD AU - Rosenberg LM AU - Girotra M FA - Byun, David J FA - Wolchok, Jedd D FA - Rosenberg, Lynne M FA - Girotra, Monica IN - Byun, David J. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065 New York, USA. IN - Byun, David J. Weill Cornell Medical College, 1300 York Avenue, New York, 10065 New York, USA. IN - Wolchok, Jedd D. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065 New York, USA. IN - Wolchok, Jedd D. Weill Cornell Medical College, 1300 York Avenue, New York, 10065 New York, USA. IN - Rosenberg, Lynne M. Weill Cornell Medical College, 1300 York Avenue, New York, 10065 New York, USA. IN - Girotra, Monica. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, 10065 New York, USA. IN - Girotra, Monica. Weill Cornell Medical College, 1300 York Avenue, New York, 10065 New York, USA. TI - Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. [Review] SO - Nature Reviews Endocrinology. 13(4):195-207, 2017 Apr AS - Nat Rev Endocrinol. 13(4):195-207, 2017 Apr NJ - Nature reviews. Endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101500078 IO - Nat Rev Endocrinol SB - Index Medicus CP - England MH - Animals MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - CTLA-4 Antigen/bi [Biosynthesis] MH - *Endocrine System Diseases/ci [Chemically Induced] MH - *Endocrine System Diseases/im [Immunology] MH - Endocrine System Diseases/me [Metabolism] MH - Humans MH - Immunotherapy/ae [Adverse Effects] MH - *Neoplasms/dt [Drug Therapy] MH - *Neoplasms/im [Immunology] MH - Neoplasms/me [Metabolism] MH - Programmed Cell Death 1 Receptor/bi [Biosynthesis] AB - Advances in cancer therapy in the past few years include the development of medications that modulate immune checkpoint proteins. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (IRAEs), which resemble autoimmune disease. In this Review, we describe the current data regarding immune-related endocrinopathies, including hypophysitis, thyroid dysfunction and diabetes mellitus. We discuss the clinical management of these endocrinopathies within the context of our current understanding of the mechanisms of IRAEs. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 6T8C155666 (ipilimumab) ES - 1759-5037 IL - 1759-5029 DI - nrendo.2016.205 DO - https://dx.doi.org/10.1038/nrendo.2016.205 PT - Journal Article PT - Review ID - nrendo.2016.205 [pii] ID - 10.1038/nrendo.2016.205 [doi] PP - ppublish GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20170120 DP - 2017 Apr DC - 20170120 EZ - 2017/01/21 06:00 DA - 2017/07/04 06:00 DT - 2017/01/21 06:00 YR - 2017 ED - 20170703 RD - 20170703 UP - 20170705 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28106152 <5. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27085692 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hofmann L AU - Forschner A AU - Loquai C AU - Goldinger SM AU - Zimmer L AU - Ugurel S AU - Schmidgen MI AU - Gutzmer R AU - Utikal JS AU - Goppner D AU - Hassel JC AU - Meier F AU - Tietze JK AU - Thomas I AU - Weishaupt C AU - Leverkus M AU - Wahl R AU - Dietrich U AU - Garbe C AU - Kirchberger MC AU - Eigentler T AU - Berking C AU - Gesierich A AU - Krackhardt AM AU - Schadendorf D AU - Schuler G AU - Dummer R AU - Heinzerling LM FA - Hofmann, Lars FA - Forschner, Andrea FA - Loquai, Carmen FA - Goldinger, Simone M FA - Zimmer, Lisa FA - Ugurel, Selma FA - Schmidgen, Maria I FA - Gutzmer, Ralf FA - Utikal, Jochen S FA - Goppner, Daniela FA - Hassel, Jessica C FA - Meier, Friedegund FA - Tietze, Julia K FA - Thomas, Ioannis FA - Weishaupt, Carsten FA - Leverkus, Martin FA - Wahl, Renate FA - Dietrich, Ursula FA - Garbe, Claus FA - Kirchberger, Michael C FA - Eigentler, Thomas FA - Berking, Carola FA - Gesierich, Anja FA - Krackhardt, Angela M FA - Schadendorf, Dirk FA - Schuler, Gerold FA - Dummer, Reinhard FA - Heinzerling, Lucie M IN - Hofmann, Lars. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. IN - Forschner, Andrea. Department of Dermatology, University Hospital Tubingen, Germany. IN - Loquai, Carmen. Department of Dermatology, University Hospital Mainz, Germany. IN - Goldinger, Simone M. Department of Dermatology, University Hospital Zurich, Switzerland. IN - Zimmer, Lisa. Department of Dermatology, University Hospital, University Duisburg-Essen, Germany. IN - Ugurel, Selma. Department of Dermatology, University Hospital, University Duisburg-Essen, Germany. IN - Schmidgen, Maria I. Department of Dermatology, University Hospital Mainz, Germany. IN - Gutzmer, Ralf. Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Germany. IN - Utikal, Jochen S. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. IN - Goppner, Daniela. Department of Dermatology, University Hospital Magdeburg, Germany. IN - Hassel, Jessica C. Department of Dermatology, University Hospital Heidelberg, Germany. IN - Meier, Friedegund. Department of Dermatology, University Hospital Dresden, Germany. IN - Tietze, Julia K. Department of Dermatology and Allergology, Ludwig-Maximilian-University (LMU) Munich, Germany. IN - Thomas, Ioannis. Department of Dermatology, University Hospital Tubingen, Germany. IN - Weishaupt, Carsten. Department of Dermatology, University Hospital Munster, Munster, Germany. IN - Leverkus, Martin. Department of Dermatology, University Hospital RWTH Aachen, Germany. IN - Wahl, Renate. Department of Dermatology, University Hospital RWTH Aachen, Germany. IN - Dietrich, Ursula. Department of Dermatology, University Hospital Dresden, Germany. IN - Garbe, Claus. Department of Dermatology, University Hospital Tubingen, Germany. IN - Kirchberger, Michael C. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. IN - Eigentler, Thomas. Department of Dermatology, University Hospital Tubingen, Germany. IN - Berking, Carola. Department of Dermatology and Allergology, Ludwig-Maximilian-University (LMU) Munich, Germany. IN - Gesierich, Anja. Department of Dermatology, University Hospital Wurzburg, Germany. IN - Krackhardt, Angela M. III. Medical Department, Technische Universitat Munchen (TUM), Munich, Germany. IN - Schadendorf, Dirk. Department of Dermatology, University Hospital, University Duisburg-Essen, Germany. IN - Schuler, Gerold. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. IN - Dummer, Reinhard. Department of Dermatology, University Hospital Zurich, Switzerland. IN - Heinzerling, Lucie M. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. Electronic address: Lucie.Heinzerling@uk-erlangen.de. TI - Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. SO - European Journal of Cancer. 60:190-209, 2016 Jun AS - Eur J Cancer. 60:190-209, 2016 Jun NJ - European journal of cancer (Oxford, England : 1990) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - arv, 9005373 IO - Eur. J. Cancer SB - Index Medicus CP - England MH - Adult MH - Aged MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Chemical and Drug Induced Liver Injury/et [Etiology] MH - Drug Eruptions/et [Etiology] MH - Endocrine System Diseases/ci [Chemically Induced] MH - Female MH - Gastrointestinal Diseases/ci [Chemically Induced] MH - Humans MH - Kidney Diseases/ci [Chemically Induced] MH - *Melanoma/dt [Drug Therapy] MH - Middle Aged MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Retrospective Studies MH - *Skin Neoplasms/dt [Drug Therapy] KW - Adverse event; Anti-PD-1; Checkpoint inhibitors; Immune-related; Nivolumab; Pembrolizumab; Side-effect; Tolerability; Toxicity AB - BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. AB - METHODS AND FINDINGS: In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. AB - CONCLUSION: Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity. Copyright © 2016 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RN - DPT0O3T46P (pembrolizumab) ES - 1879-0852 IL - 0959-8049 DI - S0959-8049(16)00151-9 DO - https://dx.doi.org/10.1016/j.ejca.2016.02.025 PT - Journal Article PT - Multicenter Study ID - S0959-8049(16)00151-9 [pii] ID - 10.1016/j.ejca.2016.02.025 [doi] PP - ppublish PH - 2016/02/22 [received] PH - 2016/02/25 [accepted] LG - English EP - 20160413 DP - 2016 Jun DC - 20160516 EZ - 2016/04/18 06:00 DA - 2017/07/04 06:00 DT - 2016/04/18 06:00 YR - 2016 ED - 20170703 RD - 20170703 UP - 20170705 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27085692 <6. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27084345 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Zimmer L AU - Goldinger SM AU - Hofmann L AU - Loquai C AU - Ugurel S AU - Thomas I AU - Schmidgen MI AU - Gutzmer R AU - Utikal JS AU - Goppner D AU - Hassel JC AU - Meier F AU - Tietze JK AU - Forschner A AU - Weishaupt C AU - Leverkus M AU - Wahl R AU - Dietrich U AU - Garbe C AU - Kirchberger MC AU - Eigentler T AU - Berking C AU - Gesierich A AU - Krackhardt AM AU - Schadendorf D AU - Schuler G AU - Dummer R AU - Heinzerling LM FA - Zimmer, Lisa FA - Goldinger, Simone M FA - Hofmann, Lars FA - Loquai, Carmen FA - Ugurel, Selma FA - Thomas, Ioannis FA - Schmidgen, Maria I FA - Gutzmer, Ralf FA - Utikal, Jochen S FA - Goppner, Daniela FA - Hassel, Jessica C FA - Meier, Friedegund FA - Tietze, Julia K FA - Forschner, Andrea FA - Weishaupt, Carsten FA - Leverkus, Martin FA - Wahl, Renate FA - Dietrich, Ursula FA - Garbe, Claus FA - Kirchberger, Michael C FA - Eigentler, Thomas FA - Berking, Carola FA - Gesierich, Anja FA - Krackhardt, Angela M FA - Schadendorf, Dirk FA - Schuler, Gerold FA - Dummer, Reinhard FA - Heinzerling, Lucie M IN - Zimmer, Lisa. Department of Dermatology, University Hospital, University Duisburg-Essen, Germany. IN - Goldinger, Simone M. Department of Dermatology, University Hospital Zurich, Switzerland. IN - Hofmann, Lars. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. IN - Loquai, Carmen. Department of Dermatology, University Hospital Mainz, Germany. IN - Ugurel, Selma. Department of Dermatology, University Hospital, University Duisburg-Essen, Germany. IN - Thomas, Ioannis. Department of Dermatology, University Hospital Tubingen, Germany. IN - Schmidgen, Maria I. Department of Dermatology, University Hospital Mainz, Germany. IN - Gutzmer, Ralf. Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Germany. IN - Utikal, Jochen S. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. IN - Goppner, Daniela. Department of Dermatology, University Hospital Magdeburg, Germany. IN - Hassel, Jessica C. Department of Dermatology, University Hospital Heidelberg, Germany. IN - Meier, Friedegund. Department of Dermatology, University Hospital Dresden, Germany. IN - Tietze, Julia K. Department of Dermatology and Allergology, University Hospital Munich (LMU), Germany. IN - Forschner, Andrea. Department of Dermatology, University Hospital Tubingen, Germany. IN - Weishaupt, Carsten. Department of Dermatology, University Hospital Munster, Germany. IN - Leverkus, Martin. Department of Dermatology, University Hospital RWTH Aachen, Germany. IN - Wahl, Renate. Department of Dermatology, University Hospital RWTH Aachen, Germany. IN - Dietrich, Ursula. Department of Dermatology, University Hospital Dresden, Germany. IN - Garbe, Claus. Department of Dermatology, University Hospital Tubingen, Germany. IN - Kirchberger, Michael C. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. IN - Eigentler, Thomas. Department of Dermatology, University Hospital Tubingen, Germany. IN - Berking, Carola. Department of Dermatology and Allergology, University Hospital Munich (LMU), Germany. IN - Gesierich, Anja. Department of Dermatology, University Hospital Wurzburg, Germany. IN - Krackhardt, Angela M. III. Medical Department, Technische Universitat Munchen (TUM) Munich, Germany. IN - Schadendorf, Dirk. Department of Dermatology, University Hospital, University Duisburg-Essen, Germany. IN - Schuler, Gerold. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. IN - Dummer, Reinhard. Department of Dermatology, University Hospital Zurich, Switzerland. IN - Heinzerling, Lucie M. Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nurnberg (FAU), Germany. Electronic address: Lucie.Heinzerling@uk-erlangen.de. TI - Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. SO - European Journal of Cancer. 60:210-25, 2016 Jun AS - Eur J Cancer. 60:210-25, 2016 Jun NJ - European journal of cancer (Oxford, England : 1990) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - arv, 9005373 IO - Eur. J. Cancer SB - Index Medicus CP - England MH - Adult MH - Aged MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Cell Cycle Checkpoints MH - Eye Diseases/ci [Chemically Induced] MH - Female MH - Heart Diseases/ci [Chemically Induced] MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Middle Aged MH - Musculoskeletal Diseases/ci [Chemically Induced] MH - Nervous System Diseases/ci [Chemically Induced] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Respiratory Tract Diseases/ci [Chemically Induced] MH - Retrospective Studies MH - *Skin Neoplasms/dt [Drug Therapy] KW - Adverse event; Anti-PD-1; Checkpoint inhibitors; Immune-related; Nivolumab; Pembrolizumab; Side-effect; Tolerability; Toxicity AB - BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. AB - METHODS AND FINDINGS: In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. AB - CONCLUSION: Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity. Copyright © 2016. Published by Elsevier Ltd. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RN - DPT0O3T46P (pembrolizumab) ES - 1879-0852 IL - 0959-8049 DI - S0959-8049(16)00150-7 DO - https://dx.doi.org/10.1016/j.ejca.2016.02.024 PT - Journal Article PT - Multicenter Study ID - S0959-8049(16)00150-7 [pii] ID - 10.1016/j.ejca.2016.02.024 [doi] PP - ppublish PH - 2016/02/22 [received] PH - 2016/02/25 [accepted] LG - English EP - 20160413 DP - 2016 Jun DC - 20160516 EZ - 2016/04/17 06:00 DA - 2017/07/04 06:00 DT - 2016/04/17 06:00 YR - 2016 ED - 20170703 RD - 20170703 UP - 20170705 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27084345 <7. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27571185 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - de Filette J AU - Jansen Y AU - Schreuer M AU - Everaert H AU - Velkeniers B AU - Neyns B AU - Bravenboer B FA - de Filette, Jeroen FA - Jansen, Yanina FA - Schreuer, Max FA - Everaert, Hendrik FA - Velkeniers, Brigitte FA - Neyns, Bart FA - Bravenboer, Bert IN - de Filette, Jeroen. Departments of Endocrinology (J.d.F., B.V., B.B.), Medical Oncology (Y.J., M.S., B.N.), and Nuclear Medicine (H.E.), Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium. IN - Jansen, Yanina. Departments of Endocrinology (J.d.F., B.V., B.B.), Medical Oncology (Y.J., M.S., B.N.), and Nuclear Medicine (H.E.), Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium. IN - Schreuer, Max. Departments of Endocrinology (J.d.F., B.V., B.B.), Medical Oncology (Y.J., M.S., B.N.), and Nuclear Medicine (H.E.), Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium. IN - Everaert, Hendrik. Departments of Endocrinology (J.d.F., B.V., B.B.), Medical Oncology (Y.J., M.S., B.N.), and Nuclear Medicine (H.E.), Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium. IN - Velkeniers, Brigitte. Departments of Endocrinology (J.d.F., B.V., B.B.), Medical Oncology (Y.J., M.S., B.N.), and Nuclear Medicine (H.E.), Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium. IN - Neyns, Bart. Departments of Endocrinology (J.d.F., B.V., B.B.), Medical Oncology (Y.J., M.S., B.N.), and Nuclear Medicine (H.E.), Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium. IN - Bravenboer, Bert. Departments of Endocrinology (J.d.F., B.V., B.B.), Medical Oncology (Y.J., M.S., B.N.), and Nuclear Medicine (H.E.), Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium. TI - Incidence of Thyroid-Related Adverse Events in Melanoma Patients Treated With Pembrolizumab. SO - Journal of Clinical Endocrinology & Metabolism. 101(11):4431-4439, 2016 Nov AS - J Clin Endocrinol Metab. 101(11):4431-4439, 2016 Nov NJ - The Journal of clinical endocrinology and metabolism PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hrb, 0375362 IO - J. Clin. Endocrinol. Metab. SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Female MH - Humans MH - Hypothyroidism/bl [Blood] MH - *Hypothyroidism/ci [Chemically Induced] MH - Hypothyroidism/dg [Diagnostic Imaging] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Middle Aged MH - Positron Emission Tomography Computed Tomography MH - *Thyroiditis/ci [Chemically Induced] MH - Thyroiditis/dg [Diagnostic Imaging] MH - Thyrotoxicosis/bl [Blood] MH - *Thyrotoxicosis/ci [Chemically Induced] MH - Thyrotoxicosis/dg [Diagnostic Imaging] AB - CONTEXT: Immune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 (PD-1) receptor monoclonal antibody, remains to be fully characterized. AB - OBJECTIVE: To assess the incidence and characteristics of pembrolizumab-associated thyroid dysfunction. AB - DESIGN AND SETTING: Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a referral oncology center. ¹⁸Fluorodeoxyglucose uptake on positron emission tomography/computed tomography (¹⁸FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis. AB - PATIENTS: Ninety-nine patients with advanced melanoma (age, 26.3-93.6 years; 63.6% females) who received at least one administration of pembrolizumab. AB - MAIN OUTCOME MEASURES: Patient characteristics, thyroid function (TSH, free T₄), thyroid autoantibodies, and ¹⁸FDG-PET/CT. AB - RESULTS: Eighteen adverse events of thyroid dysfunction were observed in 17 patients. Thyrotoxicosis occurred in 12 patients, of which nine evolved to hypothyroidism. Isolated hypothyroidism was present in six patients. Levothyroxine therapy was required in 10 of 15 hypothyroid patients. Thyroid autoantibodies were elevated during thyroid dysfunction in four of 10 cases. Diffuse increased ¹⁸FDG uptake by the thyroid gland was observed in all seven thyrotoxic patients who progressed to hypothyroidism. AB - CONCLUSIONS: Thyroid dysfunction is common in melanoma patients treated with pembrolizumab. Hypothyroidism and thyrotoxicosis related to inflammatory thyroiditis are the most frequent presentations. Serial measurements of thyroid function tests are indicated during anti-PD-1 monoclonal antibody therapy. Thyrotoxicosis compatible with inflammatory thyroiditis was associated with diffuse increased ¹⁸FDG uptake by the thyroid gland. The prospective role of thyroid autoantibodies should be further investigated, together with the histopathological correlates. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - DPT0O3T46P (pembrolizumab) ES - 1945-7197 IL - 0021-972X DO - https://dx.doi.org/10.1210/jc.2016-2300 PT - Journal Article ID - 10.1210/jc.2016-2300 [doi] ID - PMC5095250 [pmc] PP - ppublish LG - English EP - 20160829 DP - 2016 Nov DC - 20160829 EZ - 2016/08/30 06:00 DA - 2017/07/01 06:00 DT - 2016/11/05 06:00 YR - 2016 ED - 20170630 RD - 20170630 UP - 20170703 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27571185 <8. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27221508 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lin HY AU - Chin YT AU - Nana AW AU - Shih YJ AU - Lai HY AU - Tang HY AU - Leinung M AU - Mousa SA AU - Davis PJ FA - Lin, Hung-Yun FA - Chin, Yu-Tang FA - Nana, Andre Wendindonde FA - Shih, Ya-Jung FA - Lai, Hsuan-Yu FA - Tang, Heng-Yuan FA - Leinung, Matthew FA - Mousa, Shaker A FA - Davis, Paul J IN - Lin, Hung-Yun. PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. IN - Chin, Yu-Tang. Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan. IN - Nana, Andre Wendindonde. PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. IN - Shih, Ya-Jung. Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. IN - Lai, Hsuan-Yu. Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. IN - Tang, Heng-Yuan. Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; NanoPharmaceuticals LLC, Rensselaer, NY, USA. IN - Leinung, Matthew. Department of Medicine, Albany Medical College, Albany, NY, USA. IN - Mousa, Shaker A. Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; NanoPharmaceuticals LLC, Rensselaer, NY, USA. IN - Davis, Paul J. Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA; NanoPharmaceuticals LLC, Rensselaer, NY, USA; Department of Medicine, Albany Medical College, Albany, NY, USA. Electronic address: pdavis.ordwayst@gmail.com. TI - Actions of l-thyroxine and Nano-diamino-tetrac (Nanotetrac) on PD-L1 in cancer cells. SO - Steroids. 114:59-67, 2016 Oct AS - Steroids. 114:59-67, 2016 Oct NJ - Steroids PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - v10, 0404536 IO - Steroids SB - Index Medicus CP - United States MH - Antigens, CD274/ge [Genetics] MH - *Antigens, CD274/me [Metabolism] MH - Antineoplastic Agents/ch [Chemistry] MH - *Antineoplastic Agents/pd [Pharmacology] MH - Breast Neoplasms/me [Metabolism] MH - Cell Line, Tumor MH - HCT116 Cells MH - HT29 Cells MH - Humans MH - Phosphorylation/de [Drug Effects] MH - RNA, Messenger MH - Signal Transduction/de [Drug Effects] MH - Signal Transduction/ge [Genetics] MH - Thyroxine/aa [Analogs & Derivatives] MH - Thyroxine/ch [Chemistry] MH - *Thyroxine/pd [Pharmacology] KW - Breast carcinoma; Cancer immunotherapy; Colon carcinoma; Programmed death ligand 1; l-Thyroxine (T(4)) AB - The PD-1 (programmed death-1)/PD-L1 (PD-ligand 1) checkpoint is a critical regulator of activated T cell-cancer cell interactions, defending tumor cells against immune destruction. Nano-diamino-tetrac (NDAT; Nanotetrac) is an anticancer/anti-angiogenic agent targeted to the thyroid hormone-tetrac receptor on the extracellular domain of integrin alphavbeta3. NDAT inhibits the cancer cell PI3-K and MAPK signal transduction pathways that are critical to PD-L1 gene expression. We examined actions in vitro of thyroid hormone (l-thyroxine, T₄) and NDAT on PD-L1 mRNA abundance (qPCR) and PD-L1 protein content in human breast cancer (MDA-MB-231) cells and colon carcinoma (HCT116 and HT-29) cells. In MDA-MB-231 cells, a physiological concentration of T₄ (10^-7M total; 10^-10M free hormone) stimulated PD-L1 gene expression by 38% and increased PD-L1 protein by 2.7-fold (p<0.05, all changes). NDAT (10^-7M) reduced PD-L1 in T₄-exposed cells by 21% (mRNA) and 39% (protein) (p<0.05, all changes). In HCT116 cells, T₄ enhanced PD-L1 gene expression by 17% and protein content by 24% (p<0.05). NDAT reduced basal PD-L1 mRNA by 35% and protein by 31% and in T₄-treated cells lowered mRNA by 33% and protein by 66%. In HT-29 cells, T₄ increased PD-L1 mRNA by 62% and protein by 27%. NDAT lowered basal and T₄-stimulated responses in PD-L1 mRNA and protein by 35-40% (p<0.05). Activation of ERK1/2 was involved in T₄-induced PD-L1 accumulation. We propose that, by a nongenomic mechanism, endogenous T₄ may clinically support activity of the defensive PD-1/PD-L1 checkpoint in tumor cells. NDAT non-immunologically suppresses basal and T₄-induced PD-L1 gene expression and protein accumulation in cancer cells. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved. RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (CD274 protein, human) RN - 0 (RNA, Messenger) RN - PA7UX1FFYQ (tetraiodothyroacetic acid) RN - Q51BO43MG4 (Thyroxine) ES - 1878-5867 IL - 0039-128X DI - S0039-128X(16)30038-1 DO - https://dx.doi.org/10.1016/j.steroids.2016.05.006 PT - Journal Article ID - S0039-128X(16)30038-1 [pii] ID - 10.1016/j.steroids.2016.05.006 [doi] PP - ppublish PH - 2016/01/28 [received] PH - 2016/05/13 [revised] PH - 2016/05/19 [accepted] LG - English EP - 20160521 DP - 2016 Oct DC - 20160603 EZ - 2016/05/26 06:00 DA - 2017/06/27 06:00 DT - 2016/05/26 06:00 YR - 2016 ED - 20170626 RD - 20170626 UP - 20170627 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27221508 <9. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28564739 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Micheel A AU - Aigner F AU - Henke O FA - Micheel, Anita FA - Aigner, Felix FA - Henke, Oliver IN - Micheel, Anita. Bundeswehrkrankenhaus Berlin, Abteilung fur Innere Medizin, Berlin. IN - Aigner, Felix. Charite - Universitatsmedizin Berlin, Chirurgische Klinik, Campus Virchow Klinikum, Berlin. IN - Henke, Oliver. Bundeswehrkrankenhaus Berlin, Abteilung fur Innere Medizin, Berlin. TI - [Histologic Remission following Neoadjuvant Immunotherapy in a Patient with Lynch-Syndrome and Primarily Unresectable Relapse of Rectum Carcinoma]. [German] OT - Histologische Vollremission nach neoadjuvanter Immuntherapie bei einem Patienten mit Lynch-Syndrom und primar inoperablem Rezidiv eines Rektumkarzinoms. SO - Deutsche Medizinische Wochenschrift. 142(11):842-846, 2017 Jun AS - Dtsch Med Wochenschr. 142(11):842-846, 2017 Jun NJ - Deutsche medizinische Wochenschrift (1946) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ecl, 0006723 IO - Dtsch. Med. Wochenschr. SB - Index Medicus CP - Germany MH - Adult MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Colorectal Neoplasms, Hereditary Nonpolyposis/pa [Pathology] MH - Colorectal Neoplasms, Hereditary Nonpolyposis/th [Therapy] MH - *Colorectal Neoplasms, Hereditary Nonpolyposis MH - Humans MH - Immunotherapy MH - Male MH - Neoadjuvant Therapy MH - Neoplasm Recurrence, Local MH - Off-Label Use MH - Rectal Neoplasms/pa [Pathology] MH - Rectal Neoplasms/th [Therapy] MH - *Rectal Neoplasms MH - Recurrence AB - Clinical History A 43-year-old male patient was diagnosed to have rectum carcinoma cT4N2M0 with underlying Lynch-Syndrome. After initializing neoadjuvant radio-chemotherapy followed by operation, the patient presents with an extensive locoregional relapse within a short time. In order to achieve resectability, a second line treatment with FOLFOXIRI protocol in addition to Bevacizumab was conducted. However, after completing six cycles of this intensiv treatment protocol, the tumour showed further progression. Clinical Course Having no evidence of distance metastasis, we decided to initiate off-label use of Pembrolizumab, a PD-1-receptor inhibitor. Clinical symptoms decreased rapidly and after receiving six cycles, PET/CT imaging showed regression. The side effects were limited to subclinical autoimmune thyroiditis. After re-operation no evidence of malignancy were found in the resectates of exenteration of the pelvis. Currently the patient is capable of working with only limited symptoms. Conclusion Pembrolizumab offers new treatment options for patients with DNA-repair-deficiency mismatch, e. g. Lynch-Syndrome. A phase II study already showed effectiveness in this particular group of patients. The striking and unexpected histo-pathologic results showing full remission should draw attention to the use of Pembrolizumab in neoadjuvant settings. Copyright © Georg Thieme Verlag KG Stuttgart . New York. OA - Publisher: Anamnese Bei dem 43-jahrigen mannlichen Patienten wurde ein Rektumkarzinom mit zugrundeliegendem Lynch-Syndrom im Stadium cT4N2M0 diagnostiziert. Nach leitliniengerechter neoadjuvanter Radiochemotherapie und Rektumexstirpation entwickelte sich innerhalb weniger Monate ein ausgedehntes lokoregionares Rezidiv. Es erfolgte eine erneute Polychemotherapie nach dem FOLFOXIRI-Protokoll in Kombination mit Bevacizumab fur sechs Zyklen, um erneute Resektabilitat zu erreichen. Trotz dieser intensiven Therapie zeigte sich der Befund progredient. Weiterer Verlauf Angesichts fehlender Fernmetastasierung wurde ein Off-label-Therapieversuch mit dem PD-1-Rezeptor Inhibitor Pembrolizumab begonnen. Klinisch profitierte der Patient rasch, auch die Bildgebung zeigte nach sechs Zyklen eine Regression des Tumors, die Nebenwirkungen der Therapie beschrankten sich auf eine subklinische Autoimmunthyreoiditis. Die histopathologische Aufarbeitung der anschliesenden ausgedehnten operativen Beckenexenteration konnte keinen Malignitatsnachweis mehr erbringen. Mittlerweile ist der Patient wieder dienstfahig mit geringer Symptomenlast. Folgerung Die Therapie mit Pembrolizumab eroffnet fur Patienten mit einem DNA-repair-deficiency mismatch, wie z. B. dem Lynch-Syndrom, eine Therapiealternative, wie bereits eine Phase-II-Studie zeigen konnte. Bemerkenswert ist in dem vorliegenden Fall die komplette histopathologische Vollremission, die bislang in der Literatur nicht beschrieben wurde und ein besonderes Augenmerk auf die Verwendung des Antikorpers Pembrolizumab auf den neoadjuvanten Einsatz legt.; Language: German CI - Disclosure The authors report no conflicts of interest in this work. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - DPT0O3T46P (pembrolizumab) ES - 1439-4413 IL - 0012-0472 DO - https://dx.doi.org/10.1055/s-0043-101212 PT - Journal Article ID - 10.1055/s-0043-101212 [doi] PP - ppublish LG - German EP - 20170531 DP - 2017 Jun DC - 20170531 EZ - 2017/06/01 06:00 DA - 2017/06/01 06:00 DT - 2017/06/01 06:00 YR - 2017 ED - 20170622 RD - 20170622 UP - 20170623 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28564739 <10. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27734691 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Cap J FA - Cap, Jan TI - [Endocrine complications of modern cancer therapy]. [Czech] OT - Endokrinni komplikace moderni onkologicke lecby. SO - Vnitrni Lekarstvi. 62(9 Suppl 3):45-49, Fall 2016 AS - Vnitr Lek. 62(9 Suppl 3):45-49, Fall 2016 NJ - Vnitrni lekarstvi PI - Journal available in: Print PI - Citation processed from: Print JC - xfy, 0413602 IO - Vnitr Lek SB - Index Medicus CP - Czech Republic MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Anticarcinogenic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Humans MH - *Hypophysitis/ci [Chemically Induced] MH - *Hypothyroidism/ci [Chemically Induced] MH - Immunotherapy MH - *Neoplasms/dt [Drug Therapy] MH - *Protein Kinase Inhibitors/ae [Adverse Effects] MH - *Tetrahydronaphthalenes/ae [Adverse Effects] MH - Thyroid Diseases/ci [Chemically Induced] MH - *Thyroiditis, Autoimmune/ci [Chemically Induced] MH - Thyroxine/me [Metabolism] AB - Treatment with tyrosine kinase inhibitors leads to thyroid dysfunction in up to one half of treated patients, hypothyroidism being the most common. It is caused by destructive thyroiditis, impaired transport of T4 into the cell and deiodinase induction. Bexarotene is a nuclear retinoid X receptor agonist. Its application is accompanied with central hypothyroidism and hypertriglyceriaemia in virtually all patients and it also increases thyroxin metabolism. Autoimmune endocrine side effects are common in cancer immunotherapy. Cytokines (interpheron alpha and interleukin 2) cause autoimmune thyroiditis in 2-10 % of treated patients. Therapy with immune checkpoints inhibitors is connected with a variety of immune-related adverse events (irAE). Endocrine irAE include hypophysitis and thyroiditis during treatment with monoclonal antibodies against CTLA4 and thyroid dysfunction during therapy with antibody against CD1 receptor and its ligand. Knowledge, early recognition and management of these side effects is crucial.Key words: bexarotene - endocrine complication - hypophysitis - immune checkpoint inhibitors - immunotherapy. RN - 0 (Antibodies, Monoclonal) RN - 0 (Anticarcinogenic Agents) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Tetrahydronaphthalenes) RN - 6T8C155666 (ipilimumab) RN - A61RXM4375 (bexarotene) RN - Q51BO43MG4 (Thyroxine) IS - 0042-773X IL - 0042-773X DI - 59243 PT - Journal Article ID - 59243 [pii] PP - ppublish LG - Czech DP - Fall 2016 DC - 20161013 EZ - 2016/10/14 06:00 DA - 2016/10/14 06:00 DT - 2016/10/14 06:00 YR - Fall ED - 20170622 RD - 20170622 UP - 20170623 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27734691 <11. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28564739 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Micheel A AU - Aigner F AU - Henke O FA - Micheel, Anita FA - Aigner, Felix FA - Henke, Oliver IN - Micheel, Anita. Bundeswehrkrankenhaus Berlin, Abteilung fur Innere Medizin, Berlin. IN - Aigner, Felix. Charite - Universitatsmedizin Berlin, Chirurgische Klinik, Campus Virchow Klinikum, Berlin. IN - Henke, Oliver. Bundeswehrkrankenhaus Berlin, Abteilung fur Innere Medizin, Berlin. TI - [Histologic Remission following Neoadjuvant Immunotherapy in a Patient with Lynch-Syndrome and Primarily Unresectable Relapse of Rectum Carcinoma]. [German] OT - Histologische Vollremission nach neoadjuvanter Immuntherapie bei einem Patienten mit Lynch-Syndrom und primar inoperablem Rezidiv eines Rektumkarzinoms. SO - Deutsche Medizinische Wochenschrift. 142(11):842-846, 2017 Jun AS - Dtsch Med Wochenschr. 142(11):842-846, 2017 Jun NJ - Deutsche medizinische Wochenschrift (1946) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ecl, 0006723 IO - Dtsch. Med. Wochenschr. SB - Index Medicus CP - Germany MH - Adult MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Colorectal Neoplasms, Hereditary Nonpolyposis/pa [Pathology] MH - Colorectal Neoplasms, Hereditary Nonpolyposis/th [Therapy] MH - *Colorectal Neoplasms, Hereditary Nonpolyposis MH - Humans MH - Immunotherapy MH - Male MH - Neoadjuvant Therapy MH - Neoplasm Recurrence, Local MH - Off-Label Use MH - Rectal Neoplasms/pa [Pathology] MH - Rectal Neoplasms/th [Therapy] MH - *Rectal Neoplasms MH - Recurrence AB - Clinical History A 43-year-old male patient was diagnosed to have rectum carcinoma cT4N2M0 with underlying Lynch-Syndrome. After initializing neoadjuvant radio-chemotherapy followed by operation, the patient presents with an extensive locoregional relapse within a short time. In order to achieve resectability, a second line treatment with FOLFOXIRI protocol in addition to Bevacizumab was conducted. However, after completing six cycles of this intensiv treatment protocol, the tumour showed further progression. Clinical Course Having no evidence of distance metastasis, we decided to initiate off-label use of Pembrolizumab, a PD-1-receptor inhibitor. Clinical symptoms decreased rapidly and after receiving six cycles, PET/CT imaging showed regression. The side effects were limited to subclinical autoimmune thyroiditis. After re-operation no evidence of malignancy were found in the resectates of exenteration of the pelvis. Currently the patient is capable of working with only limited symptoms. Conclusion Pembrolizumab offers new treatment options for patients with DNA-repair-deficiency mismatch, e. g. Lynch-Syndrome. A phase II study already showed effectiveness in this particular group of patients. The striking and unexpected histo-pathologic results showing full remission should draw attention to the use of Pembrolizumab in neoadjuvant settings. Copyright © Georg Thieme Verlag KG Stuttgart . New York. OA - Publisher: Anamnese Bei dem 43-jahrigen mannlichen Patienten wurde ein Rektumkarzinom mit zugrundeliegendem Lynch-Syndrom im Stadium cT4N2M0 diagnostiziert. Nach leitliniengerechter neoadjuvanter Radiochemotherapie und Rektumexstirpation entwickelte sich innerhalb weniger Monate ein ausgedehntes lokoregionares Rezidiv. Es erfolgte eine erneute Polychemotherapie nach dem FOLFOXIRI-Protokoll in Kombination mit Bevacizumab fur sechs Zyklen, um erneute Resektabilitat zu erreichen. Trotz dieser intensiven Therapie zeigte sich der Befund progredient. Weiterer Verlauf Angesichts fehlender Fernmetastasierung wurde ein Off-label-Therapieversuch mit dem PD-1-Rezeptor Inhibitor Pembrolizumab begonnen. Klinisch profitierte der Patient rasch, auch die Bildgebung zeigte nach sechs Zyklen eine Regression des Tumors, die Nebenwirkungen der Therapie beschrankten sich auf eine subklinische Autoimmunthyreoiditis. Die histopathologische Aufarbeitung der anschliesenden ausgedehnten operativen Beckenexenteration konnte keinen Malignitatsnachweis mehr erbringen. Mittlerweile ist der Patient wieder dienstfahig mit geringer Symptomenlast. Folgerung Die Therapie mit Pembrolizumab eroffnet fur Patienten mit einem DNA-repair-deficiency mismatch, wie z. B. dem Lynch-Syndrom, eine Therapiealternative, wie bereits eine Phase-II-Studie zeigen konnte. Bemerkenswert ist in dem vorliegenden Fall die komplette histopathologische Vollremission, die bislang in der Literatur nicht beschrieben wurde und ein besonderes Augenmerk auf die Verwendung des Antikorpers Pembrolizumab auf den neoadjuvanten Einsatz legt.; Language: German CI - Disclosure The authors report no conflicts of interest in this work. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - DPT0O3T46P (pembrolizumab) ES - 1439-4413 IL - 0012-0472 DO - https://dx.doi.org/10.1055/s-0043-101212 PT - Journal Article ID - 10.1055/s-0043-101212 [doi] PP - ppublish LG - German EP - 20170531 DP - 2017 Jun DC - 20170531 EZ - 2017/06/01 06:00 DA - 2017/06/24 06:00 DT - 2017/06/01 06:00 YR - 2017 ED - 20170622 RD - 20170622 UP - 20170626 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=28564739 <12. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27734691 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Cap J FA - Cap, Jan TI - [Endocrine complications of modern cancer therapy]. [Czech] OT - Endokrinni komplikace moderni onkologicke lecby. SO - Vnitrni Lekarstvi. 62(9 Suppl 3):45-49, Fall 2016 AS - Vnitr Lek. 62(9 Suppl 3):45-49, Fall 2016 NJ - Vnitrni lekarstvi PI - Journal available in: Print PI - Citation processed from: Print JC - xfy, 0413602 IO - Vnitr Lek SB - Index Medicus CP - Czech Republic MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Anticarcinogenic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Humans MH - *Hypophysitis/ci [Chemically Induced] MH - *Hypothyroidism/ci [Chemically Induced] MH - Immunotherapy MH - *Neoplasms/dt [Drug Therapy] MH - *Protein Kinase Inhibitors/ae [Adverse Effects] MH - *Tetrahydronaphthalenes/ae [Adverse Effects] MH - Thyroid Diseases/ci [Chemically Induced] MH - *Thyroiditis, Autoimmune/ci [Chemically Induced] MH - Thyroxine/me [Metabolism] AB - Treatment with tyrosine kinase inhibitors leads to thyroid dysfunction in up to one half of treated patients, hypothyroidism being the most common. It is caused by destructive thyroiditis, impaired transport of T4 into the cell and deiodinase induction. Bexarotene is a nuclear retinoid X receptor agonist. Its application is accompanied with central hypothyroidism and hypertriglyceriaemia in virtually all patients and it also increases thyroxin metabolism. Autoimmune endocrine side effects are common in cancer immunotherapy. Cytokines (interpheron alpha and interleukin 2) cause autoimmune thyroiditis in 2-10 % of treated patients. Therapy with immune checkpoints inhibitors is connected with a variety of immune-related adverse events (irAE). Endocrine irAE include hypophysitis and thyroiditis during treatment with monoclonal antibodies against CTLA4 and thyroid dysfunction during therapy with antibody against CD1 receptor and its ligand. Knowledge, early recognition and management of these side effects is crucial.Key words: bexarotene - endocrine complication - hypophysitis - immune checkpoint inhibitors - immunotherapy. RN - 0 (Antibodies, Monoclonal) RN - 0 (Anticarcinogenic Agents) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Tetrahydronaphthalenes) RN - 6T8C155666 (ipilimumab) RN - A61RXM4375 (bexarotene) RN - Q51BO43MG4 (Thyroxine) IS - 0042-773X IL - 0042-773X DI - 59243 PT - Journal Article ID - 59243 [pii] PP - ppublish LG - Czech DP - Fall 2016 DC - 20161013 EZ - 2016/10/14 06:00 DA - 2017/06/24 06:00 DT - 2016/10/14 06:00 YR - Fall ED - 20170622 RD - 20170622 UP - 20170626 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27734691 <13. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28065619 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gottlieb CE AU - Mills AM AU - Cross JV AU - Ring KL FA - Gottlieb, Chelsea E FA - Mills, Anne M FA - Cross, Janet V FA - Ring, Kari L IN - Gottlieb, Chelsea E. Department of Pathology, University of Virginia Health System, PO Box 800712, Charlottesville, VA, United States. Electronic address: CEG2KC@hscmail.mcc.virginia.edu. IN - Mills, Anne M. Department of Pathology, University of Virginia Health System, PO Box 800712, Charlottesville, VA, United States. Electronic address: AMM7R@hscmail.mcc.virginia.edu. IN - Cross, Janet V. Department of Pathology, University of Virginia Health System, PO Box 800712, Charlottesville, VA, United States. Electronic address: jvc5b@eservices.virginia.edu. IN - Ring, Kari L. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Virginia Health System, PO Box 800712, Charlottesville, VA, United States. Electronic address: kel7j@hscmail.mcc.virginia.edu. TI - Tumor-associated macrophage expression of PD-L1 in implants of high grade serous ovarian carcinoma: A comparison of matched primary and metastatic tumors. SO - Gynecologic Oncology. 144(3):607-612, 2017 Mar AS - Gynecol Oncol. 144(3):607-612, 2017 Mar NJ - Gynecologic oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - fxc, 0365304 IO - Gynecol. Oncol. SB - Index Medicus CP - United States MH - *Antigens, CD274/bi [Biosynthesis] MH - Antigens, CD274/ge [Genetics] MH - Cystadenocarcinoma, Serous/ge [Genetics] MH - *Cystadenocarcinoma, Serous/me [Metabolism] MH - Female MH - Humans MH - Immunohistochemistry MH - *Macrophages/me [Metabolism] MH - Middle Aged MH - Neoplasm Grading MH - Ovarian Neoplasms/ge [Genetics] MH - *Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] KW - BRCA; High grade serous ovarian cancer; PD-L1; Treatment naive; Tumor-associated macrophages AB - OBJECTIVE: Data on PD-L1 expression in high grade serous ovarian carcinoma (HGSOC) is mixed. Some studies report robust tumor staining and others identify expression limited to tumor-associated macrophages (TAM). TAM PD-L1 expression is induced in HGSOC metastatic implants from patients who have undergone chemotherapy. However, it is unclear whether TAM acquisition of PD-L1 plays a role in treatment naive tumors. We investigated PD-L1 expression in primary ovarian tumors and matched metastatic implants from predominantly treatment-naive HGSOC. AB - METHODS: Sixty one primary HGSOC were evaluated with PD-L1 and CD68 IHC: 40 on TMA and 21 on whole section. Whole section cases were matched to a metastatic implant. TAM were delineated by CD68. Membranous PD-L1 staining was scored separately for tumor cells and TAM. AB - RESULTS: Eight percent of primary HGSOC demonstrated PD-L1 expression. In contrast, 74% showed PD-L1+ TAM. In the 16 treatment naive cases, 13 (81.3%) demonstrated fidelity in intratumoral PD-L1 expression between the primary and metastatic site. Of the 21 matched pairs, only one case (4.8%) did not exhibit PD-L1 positive TAM in the metastatic implant and 19 (90.5%) showed fidelity across both locations. Intratumoral and immune infiltrate PD-L1 expression was not different in cases who received neoadjuvant chemotherapy compared to treatment naive cases. AB - CONCLUSIONS: PD-L1+ TAM are common in both primary and metastatic HGSOC however tumoral PD-L1 staining is rare. There was high fidelity of PD-L1 expression when comparing primary tumors and metastatic implants in treatment naive specimens. Clinical trials are needed to determine whether tumor-associated staining correlates with clinical response to PD-1/PD-L1 inhibition. Copyright A© 2016 Elsevier Inc. All rights reserved. RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) ES - 1095-6859 IL - 0090-8258 DI - S0090-8258(16)31685-7 DO - https://dx.doi.org/10.1016/j.ygyno.2016.12.021 PT - Journal Article ID - S0090-8258(16)31685-7 [pii] ID - 10.1016/j.ygyno.2016.12.021 [doi] PP - ppublish PH - 2016/11/29 [received] PH - 2016/12/21 [revised] PH - 2016/12/22 [accepted] LG - English EP - 20170105 DP - 2017 Mar DC - 20170109 EZ - 2017/01/10 06:00 DA - 2017/06/22 06:00 DT - 2017/01/10 06:00 YR - 2017 ED - 20170621 RD - 20170621 UP - 20170622 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28065619 <14. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28253833 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Andrikou K AU - Peterle C AU - Pipitone S AU - Salati M AU - Cascinu S FA - Andrikou, Kalliopi FA - Peterle, Chiara FA - Pipitone, Stefania FA - Salati, Massimiliano FA - Cascinu, Stefano IN - Andrikou, Kalliopi. a Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults , University Hospital of Modena , Modena , Italy. IN - Peterle, Chiara. a Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults , University Hospital of Modena , Modena , Italy. IN - Pipitone, Stefania. a Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults , University Hospital of Modena , Modena , Italy. IN - Salati, Massimiliano. a Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults , University Hospital of Modena , Modena , Italy. IN - Cascinu, Stefano. a Division of Medical Oncology, Department of Medical and Surgical Sciences for Children & Adults , University Hospital of Modena , Modena , Italy. TI - Emerging antibodies for the treatment of pancreatic cancer. [Review] SO - Expert Opinion on Emerging Drugs. 22(1):39-51, 2017 Mar AS - Expert Opin Emerg Drugs. 22(1):39-51, 2017 Mar NJ - Expert opinion on emerging drugs PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101135662 IO - Expert Opin Emerg Drugs SB - Index Medicus CP - England MH - *Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/pa [Pathology] MH - Animals MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/pd [Pharmacology] MH - Antineoplastic Combined Chemotherapy Protocols/ad [Administration & Dosage] MH - Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] MH - Antineoplastic Combined Chemotherapy Protocols/pd [Pharmacology] MH - Biomarkers, Tumor/me [Metabolism] MH - *Carcinoma, Pancreatic Ductal/dt [Drug Therapy] MH - Carcinoma, Pancreatic Ductal/pa [Pathology] MH - Drug Design MH - Humans MH - Molecular Targeted Therapy MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/pa [Pathology] MH - Patient Selection MH - Tumor Microenvironment KW - Biomarkers; immunotherapy; monoclonal antibodies; pancreatic cancer; targeted therapies AB - INTRODUCTION: Pancreatic ductal adenocarcinoma cancer (PDAC) is the fourth leading cause of cancer death worldwide. Recently, two chemotherapy regimens have proven to improve median overall survival in comparison with gemcitabine. Based on better understanding of tumor molecular biology and of the role of tumor microenvironment, monoclonal antibodies (mAbs) could be an interesting and new type of targeted treatment of PDAC. Areas covered: Preclinical and clinical trials have evaluated the efficacy of several mAbs in pancreatic cancer treatment. This review will underline the most important targeted pathways by mAbs involved in this disease, including EGFR, HER-2, IGF-1 R, VEGF/VEGFR, NOTCH, WNT and immune checkpoints. Expert opinion: Despite the promising results of preclinical and phase I trials, the addition of mAbs to standard chemotherapy or in association with other target agents seems not to confirm these results in the following phase II and III trials in pancreatic cancer patients. However, an improved patient selection before treatment based on molecular characteristics in association with reliable predictive biomarkers can identified more efficacious treatment approaches, minimizing toxicity profile of these drugs. RN - 0 (Antibodies, Monoclonal) RN - 0 (Biomarkers, Tumor) ES - 1744-7623 IL - 1472-8214 DO - https://dx.doi.org/10.1080/14728214.2017.1293649 PT - Journal Article PT - Review ID - 10.1080/14728214.2017.1293649 [doi] PP - ppublish LG - English EP - 20170228 DP - 2017 Mar DC - 20170303 EZ - 2017/03/04 06:00 DA - 2017/06/20 06:00 DT - 2017/03/04 06:00 YR - 2017 ED - 20170619 RD - 20170619 UP - 20170620 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28253833 <15. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28283736 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Yamazaki N AU - Takenouchi T AU - Fujimoto M AU - Ihn H AU - Uchi H AU - Inozume T AU - Kiyohara Y AU - Uhara H AU - Nakagawa K AU - Furukawa H AU - Wada H AU - Noguchi K AU - Shimamoto T AU - Yokota K FA - Yamazaki, Naoya FA - Takenouchi, Tatsuya FA - Fujimoto, Manabu FA - Ihn, Hironobu FA - Uchi, Hiroshi FA - Inozume, Takashi FA - Kiyohara, Yoshio FA - Uhara, Hisashi FA - Nakagawa, Kazuhiko FA - Furukawa, Hiroshi FA - Wada, Hidefumi FA - Noguchi, Kazuo FA - Shimamoto, Takashi FA - Yokota, Kenji IN - Yamazaki, Naoya. Department of Dermatologic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. nyamazaki@ncc.go.jp. IN - Takenouchi, Tatsuya. Department of Dermatology, Niigata Cancer Center Hospital, Niigata, Japan. IN - Fujimoto, Manabu. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. IN - Ihn, Hironobu. Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. IN - Uchi, Hiroshi. Department of Dermatology, Kyushu University School of Medicine, Fukuoka, Japan. IN - Inozume, Takashi. Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan. IN - Kiyohara, Yoshio. Department of Dermatology, Shizuoka Cancer Center, Shizuoka, Japan. IN - Uhara, Hisashi. Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan. IN - Nakagawa, Kazuhiko. Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Japan. IN - Furukawa, Hiroshi. Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. IN - Wada, Hidefumi. Department of Dermatology, Yokohama City University School of Medicine, Yokohama, Japan. IN - Noguchi, Kazuo. MSD K.K., Tokyo, Japan. IN - Shimamoto, Takashi. MSD K.K., Tokyo, Japan. IN - Yokota, Kenji. Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan. TI - Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041). SO - Cancer Chemotherapy & Pharmacology. 79(4):651-660, 2017 Apr AS - Cancer Chemother Pharmacol. 79(4):651-660, 2017 Apr NJ - Cancer chemotherapy and pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c9s, 7806519 IO - Cancer Chemother. Pharmacol. SB - Index Medicus CP - Germany MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Asian Continental Ancestry Group MH - Disease-Free Survival MH - Female MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/ge [Genetics] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Skin/pa [Pathology] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/ge [Genetics] MH - Skin Neoplasms/pa [Pathology] MH - Survival Analysis KW - Anti-PD-1 therapy; Immunotherapy; Japanese patients; Melanoma; Pembrolizumab AB - PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. AB - METHODS: Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. AB - RESULTS: Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. AB - CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - DPT0O3T46P (pembrolizumab) RS - Melanoma, Cutaneous Malignant ES - 1432-0843 IL - 0344-5704 DI - 10.1007/s00280-016-3237-x DO - https://dx.doi.org/10.1007/s00280-016-3237-x PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study ID - 10.1007/s00280-016-3237-x [doi] ID - 10.1007/s00280-016-3237-x [pii] ID - PMC5364262 [pmc] PP - ppublish PH - 2016/12/02 [received] PH - 2016/12/28 [accepted] LG - English EP - 20170311 DP - 2017 Apr DC - 20170311 EZ - 2017/03/12 06:00 DA - 2017/06/14 06:00 DT - 2017/03/12 06:00 YR - 2017 ED - 20170613 RD - 20170613 UP - 20170614 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28283736 <16. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27932067 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hellmann MD AU - Rizvi NA AU - Goldman JW AU - Gettinger SN AU - Borghaei H AU - Brahmer JR AU - Ready NE AU - Gerber DE AU - Chow LQ AU - Juergens RA AU - Shepherd FA AU - Laurie SA AU - Geese WJ AU - Agrawal S AU - Young TC AU - Li X AU - Antonia SJ FA - Hellmann, Matthew D FA - Rizvi, Naiyer A FA - Goldman, Jonathan W FA - Gettinger, Scott N FA - Borghaei, Hossein FA - Brahmer, Julie R FA - Ready, Neal E FA - Gerber, David E FA - Chow, Laura Q FA - Juergens, Rosalyn A FA - Shepherd, Frances A FA - Laurie, Scott A FA - Geese, William J FA - Agrawal, Shruti FA - Young, Tina C FA - Li, Xuemei FA - Antonia, Scott J IN - Hellmann, Matthew D. Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: hellmanm@mskcc.org. IN - Rizvi, Naiyer A. Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Goldman, Jonathan W. UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. IN - Gettinger, Scott N. Yale Comprehensive Cancer Center, New Haven, CT, USA. IN - Borghaei, Hossein. Fox Chase Cancer Center, Philadelphia, PA, USA. IN - Brahmer, Julie R. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. IN - Ready, Neal E. Duke University Medical Center, Durham, NC, USA. IN - Gerber, David E. UT Southwestern Medical Center, Dallas, TX, USA. IN - Chow, Laura Q. University of Washington, Seattle, WA, USA. IN - Juergens, Rosalyn A. Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada. IN - Shepherd, Frances A. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. IN - Laurie, Scott A. Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada. IN - Geese, William J. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Agrawal, Shruti. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Young, Tina C. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Li, Xuemei. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Antonia, Scott J. H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. TI - Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. SO - Lancet Oncology. 18(1):31-41, 2017 Jan AS - Lancet Oncol. 18(1):31-41, 2017 Jan NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - *Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/pa [Pathology] MH - Aged MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - *Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/pa [Pathology] MH - *Carcinoma, Squamous Cell/dt [Drug Therapy] MH - Carcinoma, Squamous Cell/pa [Pathology] MH - Cohort Studies MH - Female MH - Follow-Up Studies MH - Humans MH - *Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/pa [Pathology] MH - Male MH - Middle Aged MH - Neoplasm Staging MH - Prognosis MH - Survival Rate AB - BACKGROUND: Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of combination nivolumab plus ipilimumab as first-line therapy for NSCLC. AB - METHODS: The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix. The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov, number NCT01454102. AB - FINDINGS: Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3-4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%] patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis (one [3%] and two [5%] patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% [95% CI 31-64]) patients in the ipilimumab every-12-weeks cohort and 15 (38% [95% CI 23-55]) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12.8 months (IQR 9.3-15.5) in the ipilimumab every-12-weeks cohort and 11.8 months (6.7-15.9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort. AB - INTERPRETATION: In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study. AB - FUNDING: Bristol-Myers Squibb. AB - Copyright © 2017 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(16)30624-6 DO - https://dx.doi.org/10.1016/S1470-2045(16)30624-6 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial ID - S1470-2045(16)30624-6 [pii] ID - 10.1016/S1470-2045(16)30624-6 [doi] PP - ppublish PH - 2016/09/07 [received] PH - 2016/10/01 [revised] PH - 2016/10/05 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01454102 SL - https://clinicaltrials.gov/search/term=NCT01454102 GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20161205 DP - 2017 Jan DC - 20161209 EZ - 2016/12/10 06:00 DA - 2017/06/14 06:00 DT - 2016/12/10 06:00 YR - 2017 ED - 20170613 RD - 20170613 UP - 20170614 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27932067 <17. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27856273 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Humphris JL AU - Patch AM AU - Nones K AU - Bailey PJ AU - Johns AL AU - McKay S AU - Chang DK AU - Miller DK AU - Pajic M AU - Kassahn KS AU - Quinn MC AU - Bruxner TJ AU - Christ AN AU - Harliwong I AU - Idrisoglu S AU - Manning S AU - Nourse C AU - Nourbakhsh E AU - Stone A AU - Wilson PJ AU - Anderson M AU - Fink JL AU - Holmes O AU - Kazakoff S AU - Leonard C AU - Newell F AU - Waddell N AU - Wood S AU - Mead RS AU - Xu Q AU - Wu J AU - Pinese M AU - Cowley MJ AU - Jones MD AU - Nagrial AM AU - Chin VT AU - Chantrill LA AU - Mawson A AU - Chou A AU - Scarlett CJ AU - Pinho AV AU - Rooman I AU - Giry-Laterriere M AU - Samra JS AU - Kench JG AU - Merrett ND AU - Toon CW AU - Epari K AU - Nguyen NQ AU - Barbour A AU - Zeps N AU - Jamieson NB AU - McKay CJ AU - Carter CR AU - Dickson EJ AU - Graham JS AU - Duthie F AU - Oien K AU - Hair J AU - Morton JP AU - Sansom OJ AU - Grutzmann R AU - Hruban RH AU - Maitra A AU - Iacobuzio-Donahue CA AU - Schulick RD AU - Wolfgang CL AU - Morgan RA AU - Lawlor RT AU - Rusev B AU - Corbo V AU - Salvia R AU - Cataldo I AU - Tortora G AU - Tempero MA AU - Australian Pancreatic Cancer Genome Initiative AU - Hofmann O AU - Eshleman JR AU - Pilarsky C AU - Scarpa A AU - Musgrove EA AU - Gill AJ AU - Pearson JV AU - Grimmond SM AU - Waddell N AU - Biankin AV FA - Humphris, Jeremy L FA - Patch, Ann-Marie FA - Nones, Katia FA - Bailey, Peter J FA - Johns, Amber L FA - McKay, Skye FA - Chang, David K FA - Miller, David K FA - Pajic, Marina FA - Kassahn, Karin S FA - Quinn, Michael C J FA - Bruxner, Timothy J C FA - Christ, Angelika N FA - Harliwong, Ivon FA - Idrisoglu, Senel FA - Manning, Suzanne FA - Nourse, Craig FA - Nourbakhsh, Ehsan FA - Stone, Andrew FA - Wilson, Peter J FA - Anderson, Matthew FA - Fink, J Lynn FA - Holmes, Oliver FA - Kazakoff, Stephen FA - Leonard, Conrad FA - Newell, Felicity FA - Waddell, Nick FA - Wood, Scott FA - Mead, Ronald S FA - Xu, Qinying FA - Wu, Jianmin FA - Pinese, Mark FA - Cowley, Mark J FA - Jones, Marc D FA - Nagrial, Adnan M FA - Chin, Venessa T FA - Chantrill, Lorraine A FA - Mawson, Amanda FA - Chou, Angela FA - Scarlett, Christopher J FA - Pinho, Andreia V FA - Rooman, Ilse FA - Giry-Laterriere, Marc FA - Samra, Jaswinder S FA - Kench, James G FA - Merrett, Neil D FA - Toon, Christopher W FA - Epari, Krishna FA - Nguyen, Nam Q FA - Barbour, Andrew FA - Zeps, Nikolajs FA - Jamieson, Nigel B FA - McKay, Colin J FA - Carter, C Ross FA - Dickson, Euan J FA - Graham, Janet S FA - Duthie, Fraser FA - Oien, Karin FA - Hair, Jane FA - Morton, Jennifer P FA - Sansom, Owen J FA - Grutzmann, Robert FA - Hruban, Ralph H FA - Maitra, Anirban FA - Iacobuzio-Donahue, Christine A FA - Schulick, Richard D FA - Wolfgang, Christopher L FA - Morgan, Richard A FA - Lawlor, Rita T FA - Rusev, Borislav FA - Corbo, Vincenzo FA - Salvia, Roberto FA - Cataldo, Ivana FA - Tortora, Giampaolo FA - Tempero, Margaret A FA - Australian Pancreatic Cancer Genome Initiative FA - Hofmann, Oliver FA - Eshleman, James R FA - Pilarsky, Christian FA - Scarpa, Aldo FA - Musgrove, Elizabeth A FA - Gill, Anthony J FA - Pearson, John V FA - Grimmond, Sean M FA - Waddell, Nicola FA - Biankin, Andrew V IN - Humphris, Jeremy L. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Patch, Ann-Marie. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Nones, Katia. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Bailey, Peter J. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. IN - Johns, Amber L. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - McKay, Skye. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Chang, David K. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. IN - Miller, David K. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Pajic, Marina. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. IN - Kassahn, Karin S. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia. IN - Quinn, Michael C J. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Bruxner, Timothy J C. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Christ, Angelika N. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Harliwong, Ivon. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Idrisoglu, Senel. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Manning, Suzanne. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Nourse, Craig. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. IN - Nourbakhsh, Ehsan. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Stone, Andrew. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Wilson, Peter J. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Anderson, Matthew. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Fink, J Lynn. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Holmes, Oliver. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Kazakoff, Stephen. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Leonard, Conrad. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Newell, Felicity. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Waddell, Nick. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Wood, Scott. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Mead, Ronald S. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia. IN - Xu, Qinying. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Wu, Jianmin. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Pinese, Mark. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Cowley, Mark J. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. IN - Jones, Marc D. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. IN - Nagrial, Adnan M. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Chin, Venessa T. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Chantrill, Lorraine A. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia. IN - Mawson, Amanda. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Chou, Angela. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia. IN - Scarlett, Christopher J. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. IN - Pinho, Andreia V. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Rooman, Ilse. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Giry-Laterriere, Marc. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Samra, Jaswinder S. Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia. IN - Kench, James G. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. IN - Merrett, Neil D. Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. IN - Toon, Christopher W. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. IN - Epari, Krishna. Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington. IN - Nguyen, Nam Q. Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. IN - Barbour, Andrew. Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia. IN - Zeps, Nikolajs. School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington. IN - Jamieson, Nigel B. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. IN - McKay, Colin J. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. IN - Carter, C Ross. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. IN - Dickson, Euan J. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. IN - Graham, Janet S. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. IN - Duthie, Fraser. Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. IN - Oien, Karin. Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. IN - Hair, Jane. Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. IN - Morton, Jennifer P. Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. IN - Sansom, Owen J. Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. IN - Grutzmann, Robert. Universitatsklinikum Erlangen, Erlangen, Germany. IN - Hruban, Ralph H. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Maitra, Anirban. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Iacobuzio-Donahue, Christine A. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Schulick, Richard D. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Wolfgang, Christopher L. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Morgan, Richard A. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Lawlor, Rita T. ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. IN - Rusev, Borislav. ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. IN - Corbo, Vincenzo. ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. IN - Salvia, Roberto. ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. IN - Cataldo, Ivana. ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. IN - Tortora, Giampaolo. Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. IN - Tempero, Margaret A. Division of Hematology and Oncology, University of California, San Francisco, California. IN - , . Australian Pancreatic Cancer Genome Initiative. IN - Hofmann, Oliver. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. IN - Eshleman, James R. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Pilarsky, Christian. Universitatsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany. IN - Scarpa, Aldo. ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. IN - Musgrove, Elizabeth A. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. IN - Gill, Anthony J. The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. IN - Pearson, John V. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. IN - Grimmond, Sean M. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia. IN - Waddell, Nicola. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au. IN - Biankin, Andrew V. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk. TI - Hypermutation In Pancreatic Cancer. SO - Gastroenterology. 152(1):68-74.e2, 2017 Jan AS - Gastroenterology. 152(1):68-74.e2, 2017 Jan NJ - Gastroenterology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - fh3, 0374630 IO - Gastroenterology SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - *Carcinoma, Pancreatic Ductal/ge [Genetics] MH - *DNA Mismatch Repair/ge [Genetics] MH - DNA Mutational Analysis MH - Female MH - Genome MH - Humans MH - Male MH - Middle Aged MH - MutL Protein Homolog 1/ge [Genetics] MH - MutS Homolog 2 Protein/ge [Genetics] MH - *Mutation MH - *Pancreatic Neoplasms/ge [Genetics] MH - Proto-Oncogene Proteins p21(ras)/ge [Genetics] MH - *Transcriptome KW - Cancer Genetics; Pancreatic Adenocarcinoma; Sequencing; Somatic Rearrangement AB - Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer. AB - Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved. RN - 0 (KRAS protein, human) RN - 0 (MLH1 protein, human) RN - EC 3-6-1-3 (MSH2 protein, human) RN - EC 3-6-1-3 (MutL Protein Homolog 1) RN - EC 3-6-1-3 (MutS Homolog 2 Protein) RN - EC 3-6-5-2 (Proto-Oncogene Proteins p21(ras)) ES - 1528-0012 IL - 0016-5085 DI - S0016-5085(16)35189-7 DO - https://dx.doi.org/10.1053/j.gastro.2016.09.060 PT - Journal Article ID - S0016-5085(16)35189-7 [pii] ID - 10.1053/j.gastro.2016.09.060 [doi] PP - ppublish PH - 2016/01/29 [received] PH - 2016/09/07 [revised] PH - 2016/09/21 [accepted] GI - No: 11650 Organization: *Cancer Research UK* Country: United Kingdom LG - English EP - 20161115 DP - 2017 Jan DC - 20161118 EZ - 2016/11/19 06:00 DA - 2017/06/14 06:00 DT - 2016/11/20 06:00 YR - 2017 ED - 20170613 RD - 20170613 UP - 20170614 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27856273 <18. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27912830 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kalemkerian GP AU - Schneider BJ FA - Kalemkerian, Gregory P FA - Schneider, Bryan J IN - Kalemkerian, Gregory P. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C350 Med Inn-SPC 5848, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5848, USA. Electronic address: kalemker@umich.edu. IN - Schneider, Bryan J. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C411 Med Inn-SPC 5848, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5848, USA. TI - Advances in Small Cell Lung Cancer. [Review] SO - Hematology - Oncology Clinics of North America. 31(1):143-156, 2017 Feb AS - Hematol Oncol Clin North Am. 31(1):143-156, 2017 Feb NJ - Hematology/oncology clinics of North America PI - Journal available in: Print PI - Citation processed from: Internet JC - heo, 8709473 IO - Hematol. Oncol. Clin. North Am. SB - Index Medicus CP - United States MH - *Chemoradiotherapy/mt [Methods] MH - Cranial Irradiation MH - Disease-Free Survival MH - Humans MH - Incidence MH - Lung Neoplasms/mo [Mortality] MH - Lung Neoplasms/pa [Pathology] MH - *Lung Neoplasms/th [Therapy] MH - Neoplasm Staging MH - Quality of Life MH - Small Cell Lung Carcinoma/mo [Mortality] MH - Small Cell Lung Carcinoma/pa [Pathology] MH - *Small Cell Lung Carcinoma/th [Therapy] MH - Smoking/ae [Adverse Effects] MH - Smoking/mo [Mortality] MH - Smoking/pa [Pathology] MH - Survival Rate KW - Chemotherapy; Genomics; Immunotherapy; Lung cancer; Radiation therapy; Small cell; Targeted therapy AB - Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by early metastatic spread and responsiveness to initial therapy. The incidence of SCLC has been declining in the United States in parallel with the decreasing prevalence of cigarette smoking. Limited stage disease is potentially curable with chemoradiotherapy followed by cranial irradiation. Extensive stage disease is incurable, but systemic chemotherapy can improve quality of life and prolong survival. Nearly all patients relapse with chemoresistant disease. Molecularly targeted therapy has failed to yield convincing clinical benefits. Nevertheless, many biologically rational strategies, including immune checkpoint inhibition, show promise in ongoing clinical trials. AB - Copyright A© 2016 Elsevier Inc. All rights reserved. ES - 1558-1977 IL - 0889-8588 DI - S0889-8588(16)30119-8 DO - https://dx.doi.org/10.1016/j.hoc.2016.08.005 PT - Journal Article PT - Review ID - S0889-8588(16)30119-8 [pii] ID - 10.1016/j.hoc.2016.08.005 [doi] PP - ppublish LG - English DP - 2017 Feb DC - 20161203 EZ - 2016/12/04 06:00 DA - 2017/06/10 06:00 DT - 2016/12/04 06:00 YR - 2017 ED - 20170609 RD - 20170609 UP - 20170612 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27912830 <19. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28223062 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Morris VK AU - Salem ME AU - Nimeiri H AU - Iqbal S AU - Singh P AU - Ciombor K AU - Polite B AU - Deming D AU - Chan E AU - Wade JL AU - Xiao L AU - Bekaii-Saab T AU - Vence L AU - Blando J AU - Mahvash A AU - Foo WC AU - Ohaji C AU - Pasia M AU - Bland G AU - Ohinata A AU - Rogers J AU - Mehdizadeh A AU - Banks K AU - Lanman R AU - Wolff RA AU - Streicher H AU - Allison J AU - Sharma P AU - Eng C FA - Morris, Van K FA - Salem, Mohamed E FA - Nimeiri, Halla FA - Iqbal, Syma FA - Singh, Preet FA - Ciombor, Kristen FA - Polite, Blase FA - Deming, Dustin FA - Chan, Emily FA - Wade, James L FA - Xiao, Lianchun FA - Bekaii-Saab, Tanios FA - Vence, Luis FA - Blando, Jorge FA - Mahvash, Armeen FA - Foo, Wai Chin FA - Ohaji, Chimela FA - Pasia, Manolo FA - Bland, Gail FA - Ohinata, Aki FA - Rogers, Jane FA - Mehdizadeh, Amir FA - Banks, Kimberly FA - Lanman, Richard FA - Wolff, Robert A FA - Streicher, Howard FA - Allison, James FA - Sharma, Padmanee FA - Eng, Cathy IN - Morris, Van K. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Salem, Mohamed E. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. IN - Nimeiri, Halla. Northwestern University, Chicago, IL, USA. IN - Iqbal, Syma. University of Southern California, Los Angeles, CA, USA. IN - Singh, Preet. Washington University, St Louis, MO, USA. IN - Ciombor, Kristen. The Ohio State University, Columbus, OH, USA. IN - Polite, Blase. University of Chicago, Chicago, IL, USA. IN - Deming, Dustin. University of Wisconsin, Madison, WI, USA. IN - Chan, Emily. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. IN - Wade, James L. Decatur Memorial Hospital, Decatur, IL, USA. IN - Xiao, Lianchun. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Bekaii-Saab, Tanios. The Ohio State University, Columbus, OH, USA. IN - Vence, Luis. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Blando, Jorge. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Mahvash, Armeen. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Foo, Wai Chin. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Ohaji, Chimela. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Pasia, Manolo. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Bland, Gail. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Ohinata, Aki. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Rogers, Jane. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Mehdizadeh, Amir. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Banks, Kimberly. Guardant Health, Redwood City, CA, USA. IN - Lanman, Richard. Guardant Health, Redwood City, CA, USA. IN - Wolff, Robert A. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Streicher, Howard. National Cancer Institute, Bethesda, MD, USA. IN - Allison, James. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Sharma, Padmanee. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. IN - Eng, Cathy. The University of Texas-MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ceng@mdanderson.org. TI - Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. SO - Lancet Oncology. 18(4):446-453, 2017 Apr AS - Lancet Oncol. 18(4):446-453, 2017 Apr NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - Aged MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Anus Neoplasms/dt [Drug Therapy] MH - Anus Neoplasms/pa [Pathology] MH - *Carcinoma, Squamous Cell/dt [Drug Therapy] MH - Carcinoma, Squamous Cell/sc [Secondary] MH - Case-Control Studies MH - *Drug Resistance, Neoplasm/de [Drug Effects] MH - Female MH - Follow-Up Studies MH - Humans MH - Lymphatic Metastasis MH - Male MH - Middle Aged MH - *Neoplasm Recurrence, Local/dt [Drug Therapy] MH - Neoplasm Recurrence, Local/pa [Pathology] MH - Neoplasm Staging MH - Prognosis MH - Prospective Studies MH - Response Evaluation Criteria in Solid Tumors MH - *Salvage Therapy MH - Survival Rate AB - BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. AB - METHODS: We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. AB - RESULTS: We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. AB - INTERPRETATION: To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. AB - FUNDING: National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor. AB - Copyright © 2017 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 31YO63LBSN (nivolumab) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(17)30104-3 DO - https://dx.doi.org/10.1016/S1470-2045(17)30104-3 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study ID - S1470-2045(17)30104-3 [pii] ID - 10.1016/S1470-2045(17)30104-3 [doi] PP - ppublish PH - 2016/11/01 [received] PH - 2016/12/16 [revised] PH - 2016/12/21 [accepted] LG - English EP - 20170218 DP - 2017 Apr DC - 20170222 EZ - 2017/02/23 06:00 DA - 2017/06/09 06:00 DT - 2017/02/23 06:00 YR - 2017 ED - 20170608 RD - 20170608 UP - 20170609 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28223062 <20. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28162999 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Coens C AU - Suciu S AU - Chiarion-Sileni V AU - Grob JJ AU - Dummer R AU - Wolchok JD AU - Schmidt H AU - Hamid O AU - Robert C AU - Ascierto PA AU - Richards JM AU - Lebbe C AU - Ferraresi V AU - Smylie M AU - Weber JS AU - Maio M AU - Bottomley A AU - Kotapati S AU - de Pril V AU - Testori A AU - Eggermont AM FA - Coens, Corneel FA - Suciu, Stefan FA - Chiarion-Sileni, Vanna FA - Grob, Jean-Jacques FA - Dummer, Reinhard FA - Wolchok, Jedd D FA - Schmidt, Henrik FA - Hamid, Omid FA - Robert, Caroline FA - Ascierto, Paolo A FA - Richards, Jon M FA - Lebbe, Celeste FA - Ferraresi, Virginia FA - Smylie, Michael FA - Weber, Jeffrey S FA - Maio, Michele FA - Bottomley, Andrew FA - Kotapati, Srividya FA - de Pril, Veerle FA - Testori, Alessandro FA - Eggermont, Alexander M M IN - Coens, Corneel. EORTC Headquarters, Brussels, Belgium. Electronic address: corneel.coens@eortc.be. IN - Suciu, Stefan. EORTC Headquarters, Brussels, Belgium. IN - Chiarion-Sileni, Vanna. IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. IN - Grob, Jean-Jacques. Hopital de la Timone, Marseille, France. IN - Dummer, Reinhard. University of Zurich Hospital, Zurich, Switzerland. IN - Wolchok, Jedd D. Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Schmidt, Henrik. Aarhus University Hospital, Aarhus, Denmark. IN - Hamid, Omid. The Angeles Clinic and Research Institute, Los Angeles, CA, USA. IN - Robert, Caroline. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. IN - Ascierto, Paolo A. Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. IN - Richards, Jon M. Oncology Specialists S C, Park Ridge, IL, USA. IN - Lebbe, Celeste. Assistance Publique des Hopitaux de Paris (AP-HP), Hopital Saint-Louis, Paris. IN - Ferraresi, Virginia. Istituti Fisioterapici Ospitalieri, Rome, Italy. IN - Smylie, Michael. Cross Cancer Institute, Edmonton, AB, Canada. IN - Weber, Jeffrey S. H Lee Moffitt Cancer Center, Tampa, FL, USA. IN - Maio, Michele. University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. IN - Bottomley, Andrew. EORTC Headquarters, Brussels, Belgium. IN - Kotapati, Srividya. Bristol-Myers Squibb, Wallingford, CT, USA. IN - de Pril, Veerle. Bristol-Myers Squibb, Braine-l'Alleud, Belgium. IN - Testori, Alessandro. European Institute of Oncology, Milan, Italy. IN - Eggermont, Alexander M M. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. TI - Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. SO - Lancet Oncology. 18(3):393-403, 2017 Mar AS - Lancet Oncol. 18(3):393-403, 2017 Mar NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - *Adjuvants, Immunologic/tu [Therapeutic Use] MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Double-Blind Method MH - Female MH - Follow-Up Studies MH - Humans MH - International Agencies MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Melanoma/su [Surgery] MH - Middle Aged MH - Neoplasm Staging MH - Prognosis MH - *Quality of Life MH - Young Adult AB - BACKGROUND: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial. Here, we report the results of the secondary endpoint, health-related quality of life (HRQoL), of this trial. AB - METHODS: EORTC 18071 was a multinational, double-blind, randomised, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis <=1 mm or in-transit metastasis) in 19 countries worldwide. Participants were randomly assigned (1:1) centrally by an interactive voice response system, to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. HRQoL was assessed with the EORTC QLQ-C30 quality-of-life instrument at baseline, weeks 4, 7, 10, and 24, and every 12 weeks thereafter up to 2 years, irrespective of disease progression. Results were summarised by timepoint and in a longitudinal manner in the intention-to-treat population. Two summary scores were calculated for each HRQoL scale: the average score reported during induction (ipilimumab or placebo at a dose of 10 mg/kg, administered as one single dose at the start of days 1, 22, 43, and 64-ie, four doses in 3 weeks), and the average score reported after induction. A predefined threshold of a 10 point difference between arms was considered clinically relevant. The primary HRQoL endpoint was the global health scale, with the predefined hypothesis of no clinically relevant differences after induction between groups. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. AB - FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to treatment: 475 in the ipilimumab group and 476 in the placebo group. Compliance with completing the HRQoL questionnaire was 893 (94%) of 951 patients at baseline, 693 (75%) of 924 at week 24, and 354 (51%) of 697 at week 108. Patient mean global health scores during (77.32 [SD 17.36] vs 72.96 [17.82]; p=0.00011) and after induction (76.48 [17.52] vs 72.32 [18.60]; p=0.00067) were statistically significantly different between groups but were not clinically relevant. Mean global health scores differed most between the groups at week 7 (77 [SD 19] in the placebo group vs 72 [22] in the ipilimumab group) and week 10 (77 [20] vs 70 [23]). Mean HRQoL scores differed by more than 10 points at week 10 between treatment groups for diarrhoea (7.67 [SD 17.05] for placebo vs 18.17 [28.35] for ipilimumab) and insomnia (15.17 [22.53] vs 25.60 [29.19]). AB - INTERPRETATION: Despite increased toxicity, which led to treatment discontinuation for most patients during the induction phase of ipilimumab administration, overall HRQoL, as measured by the EORTC QLQ-C30, was similar between groups, as no clinically relevant differences (10 points or more) in global health status scores were observed during or after induction. Clinically relevant deterioration for some symptoms was observed at week 10, but after induction, no clinically relevant differences remained. Together with the primary analysis, results from this trial show that treatment with ipilimumab results in longer recurrence-free survival compared with that for treatment with placebo, with little impairment in HRQoL despite grade 3-4 investigator-reported adverse events. AB - FUNDING: Bristol-Myers Squibb. AB - Copyright © 2017 Elsevier Ltd. All rights reserved. RN - 0 (Adjuvants, Immunologic) RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(17)30015-3 DO - https://dx.doi.org/10.1016/S1470-2045(17)30015-3 PT - Clinical Trial, Phase III PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial ID - S1470-2045(17)30015-3 [pii] ID - 10.1016/S1470-2045(17)30015-3 [doi] PP - ppublish PH - 2016/06/09 [received] PH - 2016/10/17 [revised] PH - 2016/10/24 [accepted] GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20170203 DP - 2017 Mar DC - 20170206 EZ - 2017/02/07 06:00 DA - 2017/06/09 06:00 DT - 2017/02/07 06:00 YR - 2017 ED - 20170608 RD - 20170609 UP - 20170609 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28162999 <21. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28161703 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Rinke A AU - Gress TM FA - Rinke, Anja FA - Gress, Thomas M IN - Rinke, Anja. Department of Gastroenterology, University Hospital Marburg, Marburg, Germany. TI - Neuroendocrine Cancer, Therapeutic Strategies in G3 Cancers. [Review] SO - Digestion. 95(2):109-114, 2017 AS - Digestion. 95(2):109-114, 2017 NJ - Digestion PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - e9a, 0150472 IO - Digestion SB - Index Medicus CP - Switzerland MH - Antineoplastic Agents/ad [Administration & Dosage] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols/ad [Administration & Dosage] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Camptothecin/ad [Administration & Dosage] MH - Camptothecin/aa [Analogs & Derivatives] MH - Camptothecin/tu [Therapeutic Use] MH - Carboplatin/ad [Administration & Dosage] MH - Carboplatin/tu [Therapeutic Use] MH - *Carcinoma, Neuroendocrine/dt [Drug Therapy] MH - Carcinoma, Neuroendocrine/mo [Mortality] MH - *Carcinoma, Neuroendocrine/pa [Pathology] MH - Cisplatin/ad [Administration & Dosage] MH - Cisplatin/tu [Therapeutic Use] MH - Etoposide/ad [Administration & Dosage] MH - Etoposide/tu [Therapeutic Use] MH - *Gastrointestinal Neoplasms/dt [Drug Therapy] MH - Gastrointestinal Neoplasms/mo [Mortality] MH - *Gastrointestinal Neoplasms/pa [Pathology] MH - Humans MH - Ki-67 Antigen/an [Analysis] MH - Neoplasm Grading MH - *Neuroendocrine Tumors/dt [Drug Therapy] MH - Neuroendocrine Tumors/mo [Mortality] MH - *Neuroendocrine Tumors/pa [Pathology] MH - Practice Guidelines as Topic MH - Prognosis MH - Treatment Outcome AB - BACKGROUND: According to the latest WHO classification, neuroendocrine neoplasm (NEN) G3 of the gastrointestinal tract is defined by a proliferation index Ki67 above 20%. Gastrointestinal neuroendocrine carcinoma (NEC) is a rare and highly aggressive malignancy and despite responsiveness to chemotherapy, overall survival is poor. In the last 3-4 years, the heterogeneity of the NEN G3 group has become evident. AB - SUMMARY: In addition to the proliferative activity, the tumour differentiation seems to play a major role, further dividing the NEN G3 group into neuroendocrine tumour (NET) G3 and NEC. NET G3 often arise in the pancreas, and their median proliferation rate is lower and prognosis is better as compared to NEC. However, NET G3 show a limited response to platinum-based chemotherapy. Lack of specific data for NET G3 hampers clear therapeutic recommendations. Cisplatin combined with etoposide is the established standard regimen for advanced gastrointestinal NEC. Substituting carboplatin for cisplatin or irinotecan for etoposide is considered alternative first-line regimen. There is no standard second-line treatment; options are discussed within this review. AB - KEY POINTS: (1) In NEN G3, the distinction between NET G3 and NEC G3 is clinically and prognostically meaningful. (2) Platinum-based chemotherapy remains the recommended first-line treatment in metastasized NEC patients. (3) There is no established standard for NET G3; treatments established for NET G2 such as temozolomide-based chemotherapy or peptide receptor radiotherapy may be considered. (4) Specific trials for NET G3 are necessary. (5) New therapies for NEC are urgently needed. Checkpoint inhibitors should be evaluated. AB - Copyright © 2017 S. Karger AG, Basel. RN - 0 (Antineoplastic Agents) RN - 0 (Ki-67 Antigen) RN - 0H43101T0J (irinotecan) RN - 6PLQ3CP4P3 (Etoposide) RN - BG3F62OND5 (Carboplatin) RN - Q20Q21Q62J (Cisplatin) RN - XT3Z54Z28A (Camptothecin) ES - 1421-9867 IL - 0012-2823 DI - 000454761 DO - https://dx.doi.org/10.1159/000454761 PT - Journal Article PT - Review ID - 000454761 [pii] ID - 10.1159/000454761 [doi] PP - ppublish PH - 2016/09/26 [received] PH - 2016/11/25 [accepted] LG - English EP - 20170204 DP - 2017 DC - 20170205 EZ - 2017/02/06 06:00 DA - 2017/06/07 06:00 DT - 2017/02/06 06:00 YR - 2017 ED - 20170606 RD - 20170606 UP - 20170608 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28161703 <22. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27307501 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Cappelli LC AU - Gutierrez AK AU - Baer AN AU - Albayda J AU - Manno RL AU - Haque U AU - Lipson EJ AU - Bleich KB AU - Shah AA AU - Naidoo J AU - Brahmer JR AU - Le D AU - Bingham CO 3rd FA - Cappelli, Laura C FA - Gutierrez, Anna Kristina FA - Baer, Alan N FA - Albayda, Jemima FA - Manno, Rebecca L FA - Haque, Uzma FA - Lipson, Evan J FA - Bleich, Karen B FA - Shah, Ami A FA - Naidoo, Jarushka FA - Brahmer, Julie R FA - Le, Dung FA - Bingham, Clifton O 3rd IN - Cappelli, Laura C. Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. IN - Gutierrez, Anna Kristina. Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. IN - Baer, Alan N. Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. IN - Albayda, Jemima. Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. IN - Manno, Rebecca L. Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. IN - Haque, Uzma. Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. IN - Lipson, Evan J. Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA. IN - Bleich, Karen B. Department of Radiology, Johns Hopkins University, Baltimore, Maryland, USA. IN - Shah, Ami A. Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. IN - Naidoo, Jarushka. Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA. IN - Brahmer, Julie R. Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA. IN - Le, Dung. Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA. IN - Bingham, Clifton O 3rd. Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. TI - Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. SO - Annals of the Rheumatic Diseases. 76(1):43-50, 2017 Jan AS - Ann Rheum Dis. 76(1):43-50, 2017 Jan NJ - Annals of the rheumatic diseases PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0372355, 62w IO - Ann. Rheum. Dis. SB - Index Medicus CP - England MH - Adult MH - Aged MH - Antibodies, Antinuclear/bl [Blood] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *Arthritis/ci [Chemically Induced] MH - Arthritis/dt [Drug Therapy] MH - Female MH - Humans MH - Male MH - Middle Aged MH - *Sjogren's Syndrome/ci [Chemically Induced] MH - Sjogren's Syndrome/dt [Drug Therapy] MH - *Synovitis/ci [Chemically Induced] MH - Synovitis/dt [Drug Therapy] KW - *Arthritis; *Autoimmune Diseases; *Inflammation; *Sjogren's Syndrome AB - OBJECTIVES: Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. AB - METHODS: We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. AB - RESULTS: We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. AB - CONCLUSIONS: As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs. AB - Copyright Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/. RN - 0 (Antibodies, Antinuclear) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) ES - 1468-2060 IL - 0003-4967 DI - annrheumdis-2016-209595 DO - https://dx.doi.org/10.1136/annrheumdis-2016-209595 PT - Journal Article ID - annrheumdis-2016-209595 [pii] ID - 10.1136/annrheumdis-2016-209595 [doi] ID - PMC5333990 [pmc] ID - NIHMS848643 [mid] PP - ppublish PH - 2016/03/22 [received] PH - 2016/05/16 [revised] PH - 2016/05/27 [accepted] PH - 2018/01/01 [pmc-release] GI - No: K23 AR061439 Organization: (AR) *NIAMS NIH HHS* Country: United States No: P30 AR053503 Organization: (AR) *NIAMS NIH HHS* Country: United States No: P30 AR070254 Organization: (AR) *NIAMS NIH HHS* Country: United States No: T35 AG026758 Organization: (AG) *NIA NIH HHS* Country: United States LG - English EP - 20160615 DP - 2017 Jan DC - 20160623 EZ - 2016/06/17 06:00 DA - 2017/06/07 06:00 DT - 2016/06/17 06:00 YR - 2017 ED - 20170606 RD - 20170606 UP - 20170608 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27307501 <23. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28292987 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Horio Y FA - Horio, Yoshitsugu IN - Horio, Yoshitsugu. Dept. of Outpatient Services, Aichi Cancer Center Hospital. TI - [Management of Toxicities of Immune Checkpoint Inhibitors]. [Review] [Japanese] SO - Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy]. 44(3):185-190, 2017 Mar AS - Gan To Kagaku Ryoho. 44(3):185-190, 2017 Mar NJ - Gan to kagaku ryoho. Cancer & chemotherapy PI - Journal available in: Print PI - Citation processed from: Print JC - 7810034, 6t8 IO - Gan To Kagaku Ryoho SB - Index Medicus CP - Japan MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Humans MH - *Immune System/de [Drug Effects] MH - *Molecular Targeted Therapy/ae [Adverse Effects] MH - Neoplasms/dt [Drug Therapy] MH - *Neoplasms/im [Immunology] AB - Immune checkpoint inhibitors, including the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibodies nivolumab and pembrolizumab, and the anti-PD-L1 antibody atezolizumab had produced long-lasting tumor responses in several malignancies. Immune-related Adverse Events(irAEs)which are different from adverse events of conventional chemotherapy and molecular targeted therapy, occur as a consequence of impaired self-tolerance from loss of T-cell inhibition. The main irAEs of immune checkpoint inhibitors include dermatological, gastrointestinal, pulmonary, hepatic, endocrine, renal toxicities. Every organ system can be potentially involved, but nivolumab, pembrolizumab and atezolizumab have a different toxicity profile with fewer high grade events compared with ipilimumab. In this article, we provide an approach to appropriate management for each class of irAEs. RN - 0 (Antineoplastic Agents) IS - 0385-0684 IL - 0385-0684 PT - Journal Article PT - Review PP - ppublish LG - Japanese DP - 2017 Mar DC - 20170315 EZ - 2017/03/16 06:00 DA - 2017/03/16 06:00 DT - 2017/03/16 06:00 YR - 2017 ED - 20170605 RD - 20170605 UP - 20170607 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28292987 <24. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27157491 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Muro K AU - Chung HC AU - Shankaran V AU - Geva R AU - Catenacci D AU - Gupta S AU - Eder JP AU - Golan T AU - Le DT AU - Burtness B AU - McRee AJ AU - Lin CC AU - Pathiraja K AU - Lunceford J AU - Emancipator K AU - Juco J AU - Koshiji M AU - Bang YJ FA - Muro, Kei FA - Chung, Hyun Cheol FA - Shankaran, Veena FA - Geva, Ravit FA - Catenacci, Daniel FA - Gupta, Shilpa FA - Eder, Joseph Paul FA - Golan, Talia FA - Le, Dung T FA - Burtness, Barbara FA - McRee, Autumn J FA - Lin, Chia-Chi FA - Pathiraja, Kumudu FA - Lunceford, Jared FA - Emancipator, Kenneth FA - Juco, Jonathan FA - Koshiji, Minori FA - Bang, Yung-Jue IN - Muro, Kei. Aichi Cancer Center Hospital, Nagoya, Japan. Electronic address: kmuro@aichi-cc.jp. IN - Chung, Hyun Cheol. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. IN - Shankaran, Veena. University of Washington, Seattle, WA, USA. IN - Geva, Ravit. Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. IN - Catenacci, Daniel. University of Chicago, Chicago, IL, USA. IN - Gupta, Shilpa. University of Minnesota, Minneapolis, MN, USA. IN - Eder, Joseph Paul. Yale University, New Haven, CT, USA. IN - Golan, Talia. Sheba Medical Center, Ramat Gan, Israel. IN - Le, Dung T. Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA. IN - Burtness, Barbara. Fox Chase Cancer Center, Philadelphia, PA, USA. IN - McRee, Autumn J. University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. IN - Lin, Chia-Chi. National Taiwan University Hospital, Taipei, Taiwan. IN - Pathiraja, Kumudu. Merck & Co, Kenilworth, NJ, USA. IN - Lunceford, Jared. Merck & Co, Kenilworth, NJ, USA. IN - Emancipator, Kenneth. Merck & Co, Kenilworth, NJ, USA. IN - Juco, Jonathan. Merck & Co, Kenilworth, NJ, USA. IN - Koshiji, Minori. Merck & Co, Kenilworth, NJ, USA. IN - Bang, Yung-Jue. Seoul National University College of Medicine, Seoul, South Korea. TI - Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. SO - Lancet Oncology. 17(6):717-26, 2016 Jun AS - Lancet Oncol. 17(6):717-26, 2016 Jun NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - *Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/me [Metabolism] MH - Adenocarcinoma/sc [Secondary] MH - Adult MH - Aged MH - *Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - *Antigens, CD274/me [Metabolism] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Biomarkers, Tumor/me [Metabolism] MH - Female MH - Follow-Up Studies MH - Humans MH - Male MH - Middle Aged MH - *Neoplasm Recurrence, Local/dt [Drug Therapy] MH - Neoplasm Recurrence, Local/me [Metabolism] MH - Neoplasm Recurrence, Local/pa [Pathology] MH - Neoplasm Staging MH - Prognosis MH - *Stomach Neoplasms/dt [Drug Therapy] MH - Stomach Neoplasms/me [Metabolism] MH - Stomach Neoplasms/pa [Pathology] MH - Survival Rate AB - BACKGROUND: Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer. As part of the phase 1b KEYNOTE-012 study, we aimed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. AB - METHODS: This study was a multicentre, open-label, phase 1b trial done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan. We enrolled patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Patients received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred. Response was assessed every 8 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary objectives were safety in patients who received at least one dose of pembrolizumab and the proportion of patients achieving overall responses in patients who received at least one pembrolizumab dose and who either had a post-baseline scan or who discontinued therapy because of clinical disease progression or a treatment-related adverse event before the first post-baseline scan. The study is registered with ClinicalTrials.gov, number NCT01848834, and is ongoing but no longer enrolling patients. AB - FINDINGS: From Oct 23, 2013, to May 5, 2014, 39 patients were enrolled. 36 were evaluable for response by central assessment. Eight (22%, 95% CI 10-39) patients were judged to have had an overall response at central review; all responses were partial. All 39 patients were included in the safety analyses. Five (13%) patients had a total of six grade 3 or 4 treatment-related adverse events, consisting of two cases of grade 3 fatigue, one case each of grade 3 pemphigoid, grade 3 hypothyroidism, and grade 3 peripheral sensory neuropathy, and one case of grade 4 pneumonitis. No treatment-related deaths occurred. AB - INTERPRETATION: In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 trials. AB - FUNDING: Merck & Co. AB - Copyright © 2016 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - DPT0O3T46P (pembrolizumab) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(16)00175-3 DO - https://dx.doi.org/10.1016/S1470-2045(16)00175-3 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study ID - S1470-2045(16)00175-3 [pii] ID - 10.1016/S1470-2045(16)00175-3 [doi] PP - ppublish PH - 2015/12/30 [received] PH - 2016/02/17 [revised] PH - 2016/03/11 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01848834 SL - https://clinicaltrials.gov/search/term=NCT01848834 LG - English EP - 20160503 DP - 2016 Jun DC - 20160615 EZ - 2016/05/10 06:00 DA - 2016/05/10 06:00 DT - 2016/05/10 06:00 YR - 2016 ED - 20170605 RD - 20170605 UP - 20170607 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27157491 <25. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28292987 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Horio Y FA - Horio, Yoshitsugu IN - Horio, Yoshitsugu. Dept. of Outpatient Services, Aichi Cancer Center Hospital. TI - [Management of Toxicities of Immune Checkpoint Inhibitors]. [Review] [Japanese] SO - Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy]. 44(3):185-190, 2017 Mar AS - Gan To Kagaku Ryoho. 44(3):185-190, 2017 Mar NJ - Gan to kagaku ryoho. Cancer & chemotherapy PI - Journal available in: Print PI - Citation processed from: Print JC - 7810034, 6t8 IO - Gan To Kagaku Ryoho SB - Index Medicus CP - Japan MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Humans MH - *Immune System/de [Drug Effects] MH - *Molecular Targeted Therapy/ae [Adverse Effects] MH - Neoplasms/dt [Drug Therapy] MH - *Neoplasms/im [Immunology] AB - Immune checkpoint inhibitors, including the anti-CTLA-4 antibody ipilimumab, the anti-PD-1 antibodies nivolumab and pembrolizumab, and the anti-PD-L1 antibody atezolizumab had produced long-lasting tumor responses in several malignancies. Immune-related Adverse Events(irAEs)which are different from adverse events of conventional chemotherapy and molecular targeted therapy, occur as a consequence of impaired self-tolerance from loss of T-cell inhibition. The main irAEs of immune checkpoint inhibitors include dermatological, gastrointestinal, pulmonary, hepatic, endocrine, renal toxicities. Every organ system can be potentially involved, but nivolumab, pembrolizumab and atezolizumab have a different toxicity profile with fewer high grade events compared with ipilimumab. In this article, we provide an approach to appropriate management for each class of irAEs. RN - 0 (Antineoplastic Agents) IS - 0385-0684 IL - 0385-0684 PT - Journal Article PT - Review PP - ppublish LG - Japanese DP - 2017 Mar DC - 20170315 EZ - 2017/03/16 06:00 DA - 2017/06/06 06:00 DT - 2017/03/16 06:00 YR - 2017 ED - 20170605 RD - 20170605 UP - 20170608 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=28292987 <26. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27157491 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Muro K AU - Chung HC AU - Shankaran V AU - Geva R AU - Catenacci D AU - Gupta S AU - Eder JP AU - Golan T AU - Le DT AU - Burtness B AU - McRee AJ AU - Lin CC AU - Pathiraja K AU - Lunceford J AU - Emancipator K AU - Juco J AU - Koshiji M AU - Bang YJ FA - Muro, Kei FA - Chung, Hyun Cheol FA - Shankaran, Veena FA - Geva, Ravit FA - Catenacci, Daniel FA - Gupta, Shilpa FA - Eder, Joseph Paul FA - Golan, Talia FA - Le, Dung T FA - Burtness, Barbara FA - McRee, Autumn J FA - Lin, Chia-Chi FA - Pathiraja, Kumudu FA - Lunceford, Jared FA - Emancipator, Kenneth FA - Juco, Jonathan FA - Koshiji, Minori FA - Bang, Yung-Jue IN - Muro, Kei. Aichi Cancer Center Hospital, Nagoya, Japan. Electronic address: kmuro@aichi-cc.jp. IN - Chung, Hyun Cheol. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea. IN - Shankaran, Veena. University of Washington, Seattle, WA, USA. IN - Geva, Ravit. Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. IN - Catenacci, Daniel. University of Chicago, Chicago, IL, USA. IN - Gupta, Shilpa. University of Minnesota, Minneapolis, MN, USA. IN - Eder, Joseph Paul. Yale University, New Haven, CT, USA. IN - Golan, Talia. Sheba Medical Center, Ramat Gan, Israel. IN - Le, Dung T. Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA. IN - Burtness, Barbara. Fox Chase Cancer Center, Philadelphia, PA, USA. IN - McRee, Autumn J. University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. IN - Lin, Chia-Chi. National Taiwan University Hospital, Taipei, Taiwan. IN - Pathiraja, Kumudu. Merck & Co, Kenilworth, NJ, USA. IN - Lunceford, Jared. Merck & Co, Kenilworth, NJ, USA. IN - Emancipator, Kenneth. Merck & Co, Kenilworth, NJ, USA. IN - Juco, Jonathan. Merck & Co, Kenilworth, NJ, USA. IN - Koshiji, Minori. Merck & Co, Kenilworth, NJ, USA. IN - Bang, Yung-Jue. Seoul National University College of Medicine, Seoul, South Korea. TI - Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. SO - Lancet Oncology. 17(6):717-26, 2016 Jun AS - Lancet Oncol. 17(6):717-26, 2016 Jun NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - *Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/me [Metabolism] MH - Adenocarcinoma/sc [Secondary] MH - Adult MH - Aged MH - *Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - *Antigens, CD274/me [Metabolism] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Biomarkers, Tumor/me [Metabolism] MH - Female MH - Follow-Up Studies MH - Humans MH - Male MH - Middle Aged MH - *Neoplasm Recurrence, Local/dt [Drug Therapy] MH - Neoplasm Recurrence, Local/me [Metabolism] MH - Neoplasm Recurrence, Local/pa [Pathology] MH - Neoplasm Staging MH - Prognosis MH - *Stomach Neoplasms/dt [Drug Therapy] MH - Stomach Neoplasms/me [Metabolism] MH - Stomach Neoplasms/pa [Pathology] MH - Survival Rate AB - BACKGROUND: Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer. As part of the phase 1b KEYNOTE-012 study, we aimed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. AB - METHODS: This study was a multicentre, open-label, phase 1b trial done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan. We enrolled patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Patients received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred. Response was assessed every 8 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary objectives were safety in patients who received at least one dose of pembrolizumab and the proportion of patients achieving overall responses in patients who received at least one pembrolizumab dose and who either had a post-baseline scan or who discontinued therapy because of clinical disease progression or a treatment-related adverse event before the first post-baseline scan. The study is registered with ClinicalTrials.gov, number NCT01848834, and is ongoing but no longer enrolling patients. AB - FINDINGS: From Oct 23, 2013, to May 5, 2014, 39 patients were enrolled. 36 were evaluable for response by central assessment. Eight (22%, 95% CI 10-39) patients were judged to have had an overall response at central review; all responses were partial. All 39 patients were included in the safety analyses. Five (13%) patients had a total of six grade 3 or 4 treatment-related adverse events, consisting of two cases of grade 3 fatigue, one case each of grade 3 pemphigoid, grade 3 hypothyroidism, and grade 3 peripheral sensory neuropathy, and one case of grade 4 pneumonitis. No treatment-related deaths occurred. AB - INTERPRETATION: In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 trials. AB - FUNDING: Merck & Co. AB - Copyright © 2016 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - DPT0O3T46P (pembrolizumab) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(16)00175-3 DO - https://dx.doi.org/10.1016/S1470-2045(16)00175-3 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study ID - S1470-2045(16)00175-3 [pii] ID - 10.1016/S1470-2045(16)00175-3 [doi] PP - ppublish PH - 2015/12/30 [received] PH - 2016/02/17 [revised] PH - 2016/03/11 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01848834 SL - https://clinicaltrials.gov/search/term=NCT01848834 LG - English EP - 20160503 DP - 2016 Jun DC - 20160615 EZ - 2016/05/10 06:00 DA - 2017/06/06 06:00 DT - 2016/05/10 06:00 YR - 2016 ED - 20170605 RD - 20170605 UP - 20170608 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27157491 <27. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27271951 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Williams TJ AU - Benavides DR AU - Patrice KA AU - Dalmau JO AU - de Avila AL AU - Le DT AU - Lipson EJ AU - Probasco JC AU - Mowry EM FA - Williams, Tanya J FA - Benavides, David R FA - Patrice, Kelly-Ann FA - Dalmau, Josep O FA - de Avila, Alexandre Leon Ribeiro FA - Le, Dung T FA - Lipson, Evan J FA - Probasco, John C FA - Mowry, Ellen M IN - Williams, Tanya J. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Benavides, David R. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Patrice, Kelly-Ann. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Dalmau, Josep O. Department of Neurology, Hospital Clinic/Institut d'Investigacio Biomedica August Pi i Sunyer, University of Barcelona, Barcelona, Spain3Institucio Catalana de Recerca i Estudis Avancats, University of Barcelona, Barcelona, Spain. IN - de Avila, Alexandre Leon Ribeiro. Bristol-Myers Squibb, Plainsboro, New Jersey. IN - Le, Dung T. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Lipson, Evan J. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Probasco, John C. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. IN - Mowry, Ellen M. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. TI - Association of Autoimmune Encephalitis With Combined Immune Checkpoint Inhibitor Treatment for Metastatic Cancer. SO - JAMA Neurology. 73(8):928-33, 2016 Aug 01 AS - JAMA Neurol. 73(8):928-33, 2016 Aug 01 NJ - JAMA neurology PI - Journal available in: Print PI - Citation processed from: Internet JC - 101589536 IO - JAMA Neurol SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Drug Therapy, Combination/ae [Adverse Effects] MH - *Encephalitis/ci [Chemically Induced] MH - Female MH - *Hashimoto Disease/ci [Chemically Induced] MH - Humans MH - *Immunologic Factors/ae [Adverse Effects] MH - Male MH - Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - Retrospective Studies MH - Small Cell Lung Carcinoma/dt [Drug Therapy] MH - Small Cell Lung Carcinoma/sc [Secondary] AB - IMPORTANCE: Paraneoplastic encephalitides usually precede a diagnosis of cancer and are often refractory to immunosuppressive therapy. Conversely, autoimmune encephalitides are reversible conditions that can occur in the presence or absence of cancer. AB - OBJECTIVE: To report the induction of autoimmune encephalitis in 2 patients after treatment of metastatic cancer with a combination of the immune checkpoint inhibitors nivolumab and ipilimumab. AB - DESIGN, SETTING, AND PARTICIPANTS: A retrospective case study was conducted of the clinical and management course of 2 patients with progressive, treatment-refractory metastatic cancer who were treated with a single dose each (concomitantly) of the immune checkpoint inhibitors nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg. AB - EXPOSURES: Nivolumab and ipilimumab. AB - MAIN OUTCOMES AND MEASURES: The clinical response to immunosuppressive therapy in suspected autoimmune encephalitis in the setting of immune checkpoint inhibitor use. AB - RESULTS: Autoantibody testing confirmed identification of anti-N-methyl-D-aspartate receptor antibodies in the cerebrospinal fluid of 1 patient. Withdrawal of immune checkpoint inhibitors and initiation of immunosuppressive therapy, consisting of intravenous methylprednisolone sodium succinate equivalent to 1000 mg of methylprednisolone for 5 days, 0.4 mg/kg/d of intravenous immunoglobulin for 5 days, and 2 doses of rituximab, 1000 mg, in 1 patient and oral prednisone, 60 mg/d, in the other patient, resulted in improved neurologic symptoms. AB - CONCLUSIONS AND RELEVANCE: Immune checkpoint inhibition may favor the development of immune responses against neuronal antigens, leading to autoimmune encephalitis. Early recognition and treatment of autoimmune encephalitis in patients receiving immune checkpoint blockade therapy will likely be essential for maximizing clinical recovery and minimizing the effect of drug-related toxic effects. The mechanisms by which immune checkpoint inhibition may contribute to autoimmune encephalitis require further study. RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunologic Factors) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RS - Hashimoto's encephalitis ES - 2168-6157 IL - 2168-6149 DI - 2526493 DO - https://dx.doi.org/10.1001/jamaneurol.2016.1399 PT - Case Reports PT - Journal Article ID - 2526493 [pii] ID - 10.1001/jamaneurol.2016.1399 [doi] PP - ppublish LG - English DP - 2016 Aug 01 DC - 20160809 EZ - 2016/06/09 06:00 DA - 2017/05/31 06:00 DT - 2016/06/09 06:00 YR - 2016 ED - 20170530 RD - 20170530 UP - 20170601 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27271951 <28. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27622997 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hodi FS AU - Chesney J AU - Pavlick AC AU - Robert C AU - Grossmann KF AU - McDermott DF AU - Linette GP AU - Meyer N AU - Giguere JK AU - Agarwala SS AU - Shaheen M AU - Ernstoff MS AU - Minor DR AU - Salama AK AU - Taylor MH AU - Ott PA AU - Horak C AU - Gagnier P AU - Jiang J AU - Wolchok JD AU - Postow MA FA - Hodi, F Stephen FA - Chesney, Jason FA - Pavlick, Anna C FA - Robert, Caroline FA - Grossmann, Kenneth F FA - McDermott, David F FA - Linette, Gerald P FA - Meyer, Nicolas FA - Giguere, Jeffrey K FA - Agarwala, Sanjiv S FA - Shaheen, Montaser FA - Ernstoff, Marc S FA - Minor, David R FA - Salama, April K FA - Taylor, Matthew H FA - Ott, Patrick A FA - Horak, Christine FA - Gagnier, Paul FA - Jiang, Joel FA - Wolchok, Jedd D FA - Postow, Michael A IN - Hodi, F Stephen. Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. IN - Chesney, Jason. University of Louisville, Louisville, KY, USA. IN - Pavlick, Anna C. New York University, New York, NY, USA. IN - Robert, Caroline. Gustave Roussy, INSERM U981, Paris, France. IN - Grossmann, Kenneth F. Huntsman Cancer Institute, Salt Lake City, UT, USA. IN - McDermott, David F. Beth Israel Deaconess Medical Center, Boston, MA, USA. IN - Linette, Gerald P. Washington University School of Medicine, St Louis, MO, USA. IN - Meyer, Nicolas. Institut Universitaire du Cancer, Toulouse, France. IN - Giguere, Jeffrey K. Greenville Health System Cancer Institute, Greenville, SC, USA. IN - Agarwala, Sanjiv S. St Luke's Cancer Center and Temple University, Bethlehem, PA, USA. IN - Shaheen, Montaser. University of New Mexico, Albuquerque, NM, USA. IN - Ernstoff, Marc S. Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. IN - Minor, David R. California Pacific Center for Melanoma Research, San Francisco, CA, USA. IN - Salama, April K. Duke University Medical Center, Durham, NC, USA. IN - Taylor, Matthew H. Oregon Health & Science University, Portland, OR, USA. IN - Ott, Patrick A. Dana-Farber Cancer Institute, Boston, MA, USA. IN - Horak, Christine. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Gagnier, Paul. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Jiang, Joel. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Wolchok, Jedd D. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. IN - Postow, Michael A. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. TI - Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. SO - Lancet Oncology. 17(11):1558-1568, 2016 Nov AS - Lancet Oncol. 17(11):1558-1568, 2016 Nov NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Double-Blind Method MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/ge [Genetics] MH - Melanoma/mo [Mortality] MH - Mutation MH - Proto-Oncogene Proteins B-raf/ge [Genetics] AB - BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. AB - METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF^V600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. AB - FINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24.5 months (IQR 9.1-25.7), 2-year overall survival was 63.8% (95% CI 53.3-72.6) for those assigned to nivolumab plus ipilimumab and 53.6% (95% CI 38.1-66.8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0.74, 95% CI 0.43-1.26; p=0.26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. AB - INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. AB - FUNDING: Bristol-Myers Squibb. AB - Copyright © 2016 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RN - EC 2-7-11-1 (BRAF protein, human) RN - EC 2-7-11-1 (Proto-Oncogene Proteins B-raf) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(16)30366-7 DO - https://dx.doi.org/10.1016/S1470-2045(16)30366-7 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial ID - S1470-2045(16)30366-7 [pii] ID - 10.1016/S1470-2045(16)30366-7 [doi] PP - ppublish PH - 2016/05/26 [received] PH - 2016/07/07 [revised] PH - 2016/07/12 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01927419 SL - https://clinicaltrials.gov/search/term=NCT01927419 LG - English EP - 20160909 DP - 2016 Nov DC - 20160913 EZ - 2016/09/14 06:00 DA - 2017/05/27 06:00 DT - 2016/09/14 06:00 YR - 2016 ED - 20170526 RD - 20170526 UP - 20170530 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27622997 <29. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27141885 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Boutros C AU - Tarhini A AU - Routier E AU - Lambotte O AU - Ladurie FL AU - Carbonnel F AU - Izzeddine H AU - Marabelle A AU - Champiat S AU - Berdelou A AU - Lanoy E AU - Texier M AU - Libenciuc C AU - Eggermont AM AU - Soria JC AU - Mateus C AU - Robert C FA - Boutros, Celine FA - Tarhini, Ahmad FA - Routier, Emilie FA - Lambotte, Olivier FA - Ladurie, Francois Leroy FA - Carbonnel, Franck FA - Izzeddine, Hassane FA - Marabelle, Aurelien FA - Champiat, Stephane FA - Berdelou, Armandine FA - Lanoy, Emilie FA - Texier, Matthieu FA - Libenciuc, Cristina FA - Eggermont, Alexander M M FA - Soria, Jean-Charles FA - Mateus, Christine FA - Robert, Caroline IN - Boutros, Celine. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Tarhini, Ahmad. University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA. IN - Routier, Emilie. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Lambotte, Olivier. AP-HP, Internal Medicine Department, University Hospital of Bicetre, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. IN - Lambotte, Olivier. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Lambotte, Olivier. INSERM Unit U1184, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Ladurie, Francois Leroy. Thoracic and Vascular Surgery Service, Centre Chirurgical Marie Lannelongue, 133 Avenue de la Resistance, 92350 Le Plessis-Robinson, France. IN - Carbonnel, Franck. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Carbonnel, Franck. AP-HP, Department of Gastroenterology, University Hospital of Bicetre, Paris Sud University, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. IN - Izzeddine, Hassane. Department of Nephrology, Pitie-Salpetriere Hospital, 47-83 Boulevard de l'hopital, 75013 Paris, France. IN - Marabelle, Aurelien. Drug Development Department (DITEP), Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Champiat, Stephane. INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Berdelou, Armandine. Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Lanoy, Emilie. Biostatistic and Epidemiology Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Texier, Matthieu. Biostatistic and Epidemiology Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Libenciuc, Cristina. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Eggermont, Alexander M M. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Eggermont, Alexander M M. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Soria, Jean-Charles. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Soria, Jean-Charles. Drug Development Department (DITEP), Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Soria, Jean-Charles. INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Mateus, Christine. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Robert, Caroline. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Robert, Caroline. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Robert, Caroline. INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. TI - Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. [Review] SO - Nature Reviews Clinical Oncology. 13(8):473-86, 2016 Aug AS - Nat Rev Clin Oncol. 13(8):473-86, 2016 Aug NJ - Nature reviews. Clinical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101500077 IO - Nat Rev Clin Oncol SB - Index Medicus CP - England MH - *Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Humans MH - Immunotherapy/mt [Methods] MH - Lymphocyte Activation/im [Immunology] MH - *Melanoma/dt [Drug Therapy] MH - Molecular Targeted Therapy/mt [Methods] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - *Skin Neoplasms/dt [Drug Therapy] AB - Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1759-4782 IL - 1759-4774 DI - nrclinonc.2016.58 DO - https://dx.doi.org/10.1038/nrclinonc.2016.58 PT - Journal Article PT - Review ID - nrclinonc.2016.58 [pii] ID - 10.1038/nrclinonc.2016.58 [doi] PP - ppublish LG - English EP - 20160504 DP - 2016 Aug DC - 20160720 EZ - 2016/05/05 06:00 DA - 2017/05/23 06:00 DT - 2016/05/05 06:00 YR - 2016 ED - 20170522 RD - 20170522 UP - 20170524 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27141885 <30. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27141885 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Boutros C AU - Tarhini A AU - Routier E AU - Lambotte O AU - Ladurie FL AU - Carbonnel F AU - Izzeddine H AU - Marabelle A AU - Champiat S AU - Berdelou A AU - Lanoy E AU - Texier M AU - Libenciuc C AU - Eggermont AM AU - Soria JC AU - Mateus C AU - Robert C FA - Boutros, Celine FA - Tarhini, Ahmad FA - Routier, Emilie FA - Lambotte, Olivier FA - Ladurie, Francois Leroy FA - Carbonnel, Franck FA - Izzeddine, Hassane FA - Marabelle, Aurelien FA - Champiat, Stephane FA - Berdelou, Armandine FA - Lanoy, Emilie FA - Texier, Matthieu FA - Libenciuc, Cristina FA - Eggermont, Alexander M M FA - Soria, Jean-Charles FA - Mateus, Christine FA - Robert, Caroline IN - Boutros, Celine. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Tarhini, Ahmad. University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA. IN - Routier, Emilie. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Lambotte, Olivier. AP-HP, Internal Medicine Department, University Hospital of Bicetre, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. IN - Lambotte, Olivier. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Lambotte, Olivier. INSERM Unit U1184, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Ladurie, Francois Leroy. Thoracic and Vascular Surgery Service, Centre Chirurgical Marie Lannelongue, 133 Avenue de la Resistance, 92350 Le Plessis-Robinson, France. IN - Carbonnel, Franck. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Carbonnel, Franck. AP-HP, Department of Gastroenterology, University Hospital of Bicetre, Paris Sud University, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. IN - Izzeddine, Hassane. Department of Nephrology, Pitie-Salpetriere Hospital, 47-83 Boulevard de l'hopital, 75013 Paris, France. IN - Marabelle, Aurelien. Drug Development Department (DITEP), Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Champiat, Stephane. INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Berdelou, Armandine. Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Lanoy, Emilie. Biostatistic and Epidemiology Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Texier, Matthieu. Biostatistic and Epidemiology Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Libenciuc, Cristina. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Eggermont, Alexander M M. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Eggermont, Alexander M M. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Soria, Jean-Charles. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Soria, Jean-Charles. Drug Development Department (DITEP), Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Soria, Jean-Charles. INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Mateus, Christine. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Robert, Caroline. Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. IN - Robert, Caroline. Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicetre, France. IN - Robert, Caroline. INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. TI - Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. [Review] SO - Nature Reviews Clinical Oncology. 13(8):473-86, 2016 Aug AS - Nat Rev Clin Oncol. 13(8):473-86, 2016 Aug NJ - Nature reviews. Clinical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101500077 IO - Nat Rev Clin Oncol SB - Index Medicus CP - England MH - *Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Humans MH - Immunotherapy/mt [Methods] MH - Lymphocyte Activation/im [Immunology] MH - *Melanoma/dt [Drug Therapy] MH - Molecular Targeted Therapy/mt [Methods] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - *Skin Neoplasms/dt [Drug Therapy] AB - Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1759-4782 IL - 1759-4774 DI - nrclinonc.2016.58 DO - https://dx.doi.org/10.1038/nrclinonc.2016.58 PT - Journal Article PT - Review ID - nrclinonc.2016.58 [pii] ID - 10.1038/nrclinonc.2016.58 [doi] PP - ppublish LG - English EP - 20160504 DP - 2016 Aug DC - 20160720 EZ - 2016/05/05 06:00 DA - 2017/05/23 06:00 DT - 2016/05/05 06:00 YR - 2016 ED - 20170522 RD - 20170606 UP - 20170608 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27141885 <31. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27672267 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kimbara S AU - Kondo S FA - Kimbara, Shiro FA - Kondo, Shunsuke IN - Kimbara, Shiro. Shiro Kimbara, Shunsuke Kondo, Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo 104-0045, Japan. IN - Kondo, Shunsuke. Shiro Kimbara, Shunsuke Kondo, Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo 104-0045, Japan. TI - Immune checkpoint and inflammation as therapeutic targets in pancreatic carcinoma. [Review] SO - World Journal of Gastroenterology. 22(33):7440-52, 2016 Sep 07 AS - World J Gastroenterol. 22(33):7440-52, 2016 Sep 07 NJ - World journal of gastroenterology PI - Journal available in: Print PI - Citation processed from: Internet JC - 100883448 IO - World J. Gastroenterol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011660 SB - Index Medicus CP - United States MH - Adenocarcinoma/im [Immunology] MH - *Adenocarcinoma/th [Therapy] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Cancer Vaccines/me [Metabolism] MH - Combined Modality Therapy MH - Humans MH - *Immunotherapy/mt [Methods] MH - Inflammation/dt [Drug Therapy] MH - Interleukin-6/me [Metabolism] MH - Janus Kinases/me [Metabolism] MH - NF-kappa B/me [Metabolism] MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Randomized Controlled Trials as Topic MH - Receptors, Interleukin-8B/me [Metabolism] MH - Signal Transduction MH - T-Lymphocytes, Cytotoxic/me [Metabolism] KW - Immune checkpoint; Inflammation; Pancreatic adenocarcinoma; Randomized clinical trial; Therapeutic anticancer target AB - Pancreatic adenocarcinoma (PAC) is one of the most deadly malignant neoplasms, and the efficacy of conventional cytotoxic chemotherapy is far from satisfactory. Recent research studies have revealed that immunosuppression and inflammation are associated with oncogenesis, as well as tumor development, invasion, and metastasis in PAC. Thus, immunosuppression-related signaling, especially that involving immune checkpoint and inflammation, has emerged as novel treatment targets for PAC. However, PAC is an immune-resistant tumor, and it is still unclear whether immune checkpoint or anti-inflammation therapies would be an ideal strategy. In this article, we will review immune checkpoint and inflammation as potential targets, as well as clinical trials and the prospects for immunotherapy in PAC. CI - Conflict-of-interest statement: Shiro Kimbara have no conflict of interest associated with this manuscript. Shunsuke Kondo received research funding from AstraZeneca, Eli Lilly and Company, and Bayer AG. RN - 0 (Antibodies, Monoclonal) RN - 0 (Cancer Vaccines) RN - 0 (IL6 protein, human) RN - 0 (Interleukin-6) RN - 0 (NF-kappa B) RN - 0 (Receptors, Interleukin-8B) RN - EC 2-7-10-2 (Janus Kinases) RS - Pancreatic Carcinoma ES - 2219-2840 IL - 1007-9327 DO - https://dx.doi.org/10.3748/wjg.v22.i33.7440 PT - Journal Article PT - Review ID - 10.3748/wjg.v22.i33.7440 [doi] ID - PMC5011660 [pmc] PP - ppublish PH - 2016/03/26 [received] PH - 2016/06/30 [revised] PH - 2016/08/01 [accepted] LG - English DP - 2016 Sep 07 DC - 20160927 EZ - 2016/09/28 06:00 DA - 2017/05/20 06:00 DT - 2016/09/28 06:00 YR - 2016 ED - 20170519 RD - 20170519 UP - 20170522 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27672267 <32. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27753448 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Rodrigues DN AU - Boysen G AU - Sumanasuriya S AU - Seed G AU - Marzo AM AU - de Bono J FA - Rodrigues, Daniel Nava FA - Boysen, Gunther FA - Sumanasuriya, Semini FA - Seed, George FA - Marzo, Angelo M De FA - de Bono, Johann IN - Rodrigues, Daniel Nava. The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK. IN - Rodrigues, Daniel Nava. Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK. IN - Boysen, Gunther. The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK. IN - Boysen, Gunther. Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK. IN - Sumanasuriya, Semini. The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK. IN - Sumanasuriya, Semini. Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK. IN - Seed, George. The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK. IN - Marzo, Angelo M De. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. IN - de Bono, Johann. The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK. IN - de Bono, Johann. Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK. TI - The molecular underpinnings of prostate cancer: impacts on management and pathology practice. [Review] SO - Journal of Pathology. 241(2):173-182, 2017 Jan AS - J Pathol. 241(2):173-182, 2017 Jan NJ - The Journal of pathology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - jlb, 0204634 IO - J. Pathol. SB - Index Medicus CP - England MH - Androstenes/tu [Therapeutic Use] MH - Animals MH - *Biomarkers/an [Analysis] MH - Humans MH - Male MH - Phosphatidylinositol 3-Kinases/me [Metabolism] MH - *Prostatic Neoplasms/dt [Drug Therapy] MH - Prostatic Neoplasms/me [Metabolism] MH - *Prostatic Neoplasms/pa [Pathology] MH - *Receptors, Androgen/me [Metabolism] MH - *Signal Transduction/de [Drug Effects] KW - *DNA sequencing; *FISH; *neoplasia; *prostate AB - Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognised as biomarkers of resistance to AR-targeted therapies such as abiraterone or enzalutamide. Genomic aberrations of the PI3K-AKT axis, in particular affecting PTEN, are common in PCa, and compounds targeting different kinases in this pathway are showing promise in clinical trials. Both germline and somatic defects in DNA repair genes have been shown to sensitise some patients to therapy with PARP inhibition. In addition, abnormalities in mismatch-repair genes are associated with response to immune checkpoint inhibition in other solid tumours and present a tantalising therapeutic avenue to be pursued. Aberrations in CDK4/6-RB1 pathway genes occur in a subset of PCas, may associate with differential sensitivity to treatment, and are likely to have clinical implications beyond prognostication. Inhibitors of CDK4/6 are already being tested in prostate cancer clinical trials. Furthermore, deletions of RB1 are strongly associated with a neuroendocrine phenotype, a rare condition characterized by a non-AR-driven transcriptomic profile. Finally, aberrations in genes involved in regulating the chromatin structure are an emerging area of interest. Deletions of CHD1 are not infrequent in PCa and may associate with increased AR activity and genomic instability, and these tumours could benefit from DNA-damaging therapies. This review summarises how genomic discoveries in PCa are changing the treatment landscape of advanced CRPC, both by identifying biomarkers of resistance and by identifying vulnerabilities to be targeted. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. AB - Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. RN - 0 (Androstenes) RN - 0 (Biomarkers) RN - 0 (Receptors, Androgen) RN - EC 2-7-1 (Phosphatidylinositol 3-Kinases) RN - G819A456D0 (abiraterone) ES - 1096-9896 IL - 0022-3417 DO - https://dx.doi.org/10.1002/path.4826 PT - Journal Article PT - Review ID - 10.1002/path.4826 [doi] PP - ppublish PH - 2016/09/14 [received] PH - 2016/09/29 [revised] PH - 2016/10/01 [accepted] LG - English EP - 20161201 DP - 2017 Jan DC - 20161018 EZ - 2016/10/19 06:00 DA - 2017/05/17 06:00 DT - 2016/10/19 06:00 YR - 2017 ED - 20170516 RD - 20170516 UP - 20170518 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27753448 <33. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27170616 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Marrone KA AU - Ying W AU - Naidoo J FA - Marrone, K A FA - Ying, W FA - Naidoo, J IN - Marrone, K A. Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland, USA. IN - Ying, W. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. IN - Naidoo, J. Department of Oncology, Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, Maryland, USA. TI - Immune-Related Adverse Events From Immune Checkpoint Inhibitors. [Review] SO - Clinical Pharmacology & Therapeutics. 100(3):242-51, 2016 Sep AS - Clin Pharmacol Ther. 100(3):242-51, 2016 Sep NJ - Clinical pharmacology and therapeutics PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dhr, 0372741 IO - Clin. Pharmacol. Ther. SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigens, CD/im [Immunology] MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Drug Therapy, Combination MH - Endocrine System Diseases/im [Immunology] MH - Gastrointestinal Diseases/im [Immunology] MH - Humans MH - Immunotherapy, Adoptive/ae [Adverse Effects] MH - Immunotherapy, Adoptive/mt [Methods] MH - Molecular Targeted Therapy MH - *Neoplasms/dt [Drug Therapy] MH - Programmed Cell Death 1 Receptor MH - Receptors, KIR/im [Immunology] MH - Receptors, OX40/im [Immunology] MH - Skin Diseases/im [Immunology] MH - Time Factors AB - Immunotherapy for cancer treatment has come of age, specifically with the use of immune checkpoint antibodies directed against molecules such as CTLA-4, PD-1, and PD-L1. Single-agent and combinatorial approaches utilizing these agents and other immunotherapies that may enhance antitumor effects are under investigation. With increasing clinical use of these agents, an appreciation for their toxicities comes to the fore. Adverse events that occur as a result of the immunologic effects of these therapies are termed "immune-related adverse events" (irAEs), and range in both frequency and severity in reported single-agent and combination studies. Improvements in our understanding of how and why irAEs develop and how to effectively manage them are needed. Herein we provide a state-of-the-art synopsis of the incidence, clinical features, mechanisms, and management of selected irAEs with immune checkpoint inhibitors currently in use. AB - Copyright © 2016 American Society for Clinical Pharmacology and Therapeutics. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (CD223 antigen) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Receptors, KIR) RN - 0 (Receptors, OX40) RN - 0 (TNFRSF4 protein, human) ES - 1532-6535 IL - 0009-9236 DO - https://dx.doi.org/10.1002/cpt.394 PT - Journal Article PT - Review ID - 10.1002/cpt.394 [doi] PP - ppublish PH - 2016/03/21 [received] PH - 2016/05/06 [revised] PH - 2016/05/07 [accepted] LG - English EP - 20160729 DP - 2016 Sep DC - 20160812 EZ - 2016/05/13 06:00 DA - 2017/05/16 06:00 DT - 2016/05/14 06:00 YR - 2016 ED - 20170515 RD - 20170515 UP - 20170517 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27170616 <34. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28094061 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Larsabal M AU - Marti A AU - Jacquemin C AU - Rambert J AU - Thiolat D AU - Dousset L AU - Taieb A AU - Dutriaux C AU - Prey S AU - Boniface K AU - Seneschal J FA - Larsabal, Maiana FA - Marti, Aurelie FA - Jacquemin, Clement FA - Rambert, Jerome FA - Thiolat, Denis FA - Dousset, Lea FA - Taieb, Alain FA - Dutriaux, Caroline FA - Prey, Sorilla FA - Boniface, Katia FA - Seneschal, Julien IN - Larsabal, Maiana. Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hopital Saint-Andre, Bordeaux, France. IN - Marti, Aurelie. Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hopital Saint-Andre, Bordeaux, France. IN - Jacquemin, Clement. Institut National de la Sante Et de la Recherche Medicale (INSERM) U1035, Biotherapies de Maladies Genetiques, Inflammatoires et Cancers (BMGIC), Immuno-dermatology ATIP-AVENIR, University of Bordeaux, Bordeaux, France. IN - Rambert, Jerome. Institut National de la Sante Et de la Recherche Medicale (INSERM) U1035, Biotherapies de Maladies Genetiques, Inflammatoires et Cancers (BMGIC), Immuno-dermatology ATIP-AVENIR, University of Bordeaux, Bordeaux, France. IN - Thiolat, Denis. Institut National de la Sante Et de la Recherche Medicale (INSERM) U1035, Biotherapies de Maladies Genetiques, Inflammatoires et Cancers (BMGIC), Immuno-dermatology ATIP-AVENIR, University of Bordeaux, Bordeaux, France. IN - Dousset, Lea. Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hopital Saint-Andre, Bordeaux, France. IN - Taieb, Alain. Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hopital Saint-Andre, Bordeaux, France; Institut National de la Sante Et de la Recherche Medicale (INSERM) U1035, Biotherapies de Maladies Genetiques, Inflammatoires et Cancers (BMGIC), Immuno-dermatology ATIP-AVENIR, University of Bordeaux, Bordeaux, France. IN - Dutriaux, Caroline. Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hopital Saint-Andre, Bordeaux, France. IN - Prey, Sorilla. Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hopital Saint-Andre, Bordeaux, France. IN - Boniface, Katia. Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hopital Saint-Andre, Bordeaux, France; Institut National de la Sante Et de la Recherche Medicale (INSERM) U1035, Biotherapies de Maladies Genetiques, Inflammatoires et Cancers (BMGIC), Immuno-dermatology ATIP-AVENIR, University of Bordeaux, Bordeaux, France. IN - Seneschal, Julien. Department of Dermatology and Pediatric Dermatology, National Reference Center for Rare Skin Disorders, Hopital Saint-Andre, Bordeaux, France; Institut National de la Sante Et de la Recherche Medicale (INSERM) U1035, Biotherapies de Maladies Genetiques, Inflammatoires et Cancers (BMGIC), Immuno-dermatology ATIP-AVENIR, University of Bordeaux, Bordeaux, France. Electronic address: julien.seneschal@chu-bordeaux.fr. TI - Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo. SO - Journal of the American Academy of Dermatology. 76(5):863-870, 2017 May AS - J Am Acad Dermatol. 76(5):863-870, 2017 May NJ - Journal of the American Academy of Dermatology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hvg, 7907132 IO - J. Am. Acad. Dermatol. SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antineoplastic Agents/ae [Adverse Effects] MH - CD8-Positive T-Lymphocytes MH - Case-Control Studies MH - *Chemokine CXCL10/bl [Blood] MH - Drug Eruptions/et [Etiology] MH - *Drug Eruptions/me [Metabolism] MH - *Drug Eruptions/pa [Pathology] MH - Female MH - Humans MH - Interferon-gamma/me [Metabolism] MH - Male MH - Middle Aged MH - Photography MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Prospective Studies MH - Receptors, CXCR3/me [Metabolism] MH - Tumor Necrosis Factor-alpha/me [Metabolism] MH - Vitiligo/ge [Genetics] MH - *Vitiligo/me [Metabolism] MH - *Vitiligo/pa [Pathology] MH - Young Adult KW - anti-programmed cell death-1 therapy; nivolumab; pembrolizumab; vitiligo; vitiligo-like lesions AB - BACKGROUND: The use of anti-programmed cell death (PD)-1 therapies in metastatic tumors is associated with cutaneous side effects including vitiligo-like lesions. AB - OBJECTIVE: We sought to characterize clinically and biologically vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies by studying a case series of 8 patients with metastatic tumors and 30 control subjects with vitiligo. AB - METHODS: Eight patients receiving anti-PD-1 therapies with features of vitiligo-like lesions seen in our department were recruited. Clinical features and photographs were analyzed. For some patients, skin and blood samples were obtained. Results were compared with the vitiligo group. AB - RESULTS: All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T-cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon-gamma and tumor necrosis factor-alfa. AB - LIMITATIONS: This cross-sectional study concerned a single center. AB - CONCLUSIONS: Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism. AB - Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (CXCL10 protein, human) RN - 0 (CXCR3 protein, human) RN - 0 (Chemokine CXCL10) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Receptors, CXCR3) RN - 0 (Tumor Necrosis Factor-alpha) RN - 31YO63LBSN (nivolumab) RN - 82115-62-6 (Interferon-gamma) RN - DPT0O3T46P (pembrolizumab) ES - 1097-6787 IL - 0190-9622 DI - S0190-9622(16)31020-9 DO - https://dx.doi.org/10.1016/j.jaad.2016.10.044 PT - Journal Article ID - S0190-9622(16)31020-9 [pii] ID - 10.1016/j.jaad.2016.10.044 [doi] PP - ppublish PH - 2016/07/26 [received] PH - 2016/10/27 [revised] PH - 2016/10/31 [accepted] LG - English EP - 20170113 DP - 2017 May DC - 20170117 EZ - 2017/01/18 06:00 DA - 2017/05/04 06:00 DT - 2017/01/18 06:00 YR - 2017 ED - 20170503 RD - 20170503 UP - 20170505 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28094061 <35. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27920468 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Johansson H AU - Andersson R AU - Bauden M AU - Hammes S AU - Holdenrieder S AU - Ansari D FA - Johansson, Henrik FA - Andersson, Roland FA - Bauden, Monika FA - Hammes, Sarah FA - Holdenrieder, Stefan FA - Ansari, Daniel IN - Johansson, Henrik. Henrik Johansson, Roland Andersson, Monika Bauden, Daniel Ansari, Department of Surgery, Clinical Sciences Lund, Lund University, and Skane University Hospital, SE-221 85 Lund, Sweden. IN - Andersson, Roland. Henrik Johansson, Roland Andersson, Monika Bauden, Daniel Ansari, Department of Surgery, Clinical Sciences Lund, Lund University, and Skane University Hospital, SE-221 85 Lund, Sweden. IN - Bauden, Monika. Henrik Johansson, Roland Andersson, Monika Bauden, Daniel Ansari, Department of Surgery, Clinical Sciences Lund, Lund University, and Skane University Hospital, SE-221 85 Lund, Sweden. IN - Hammes, Sarah. Henrik Johansson, Roland Andersson, Monika Bauden, Daniel Ansari, Department of Surgery, Clinical Sciences Lund, Lund University, and Skane University Hospital, SE-221 85 Lund, Sweden. IN - Holdenrieder, Stefan. Henrik Johansson, Roland Andersson, Monika Bauden, Daniel Ansari, Department of Surgery, Clinical Sciences Lund, Lund University, and Skane University Hospital, SE-221 85 Lund, Sweden. IN - Ansari, Daniel. Henrik Johansson, Roland Andersson, Monika Bauden, Daniel Ansari, Department of Surgery, Clinical Sciences Lund, Lund University, and Skane University Hospital, SE-221 85 Lund, Sweden. TI - Immune checkpoint therapy for pancreatic cancer. [Review] SO - World Journal of Gastroenterology. 22(43):9457-9476, 2016 Nov 21 AS - World J Gastroenterol. 22(43):9457-9476, 2016 Nov 21 NJ - World journal of gastroenterology PI - Journal available in: Print PI - Citation processed from: Internet JC - 100883448 IO - World J. Gastroenterol. SB - Index Medicus CP - United States MH - Animals MH - *Antibodies/tu [Therapeutic Use] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antigens, CD274/im [Immunology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Clinical Trials as Topic MH - Humans MH - *Immunotherapy/mt [Methods] MH - Molecular Targeted Therapy MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/pa [Pathology] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Signal Transduction/de [Drug Effects] KW - *Clinical trials; *Immune checkpoint inhibitors; *Pancreatic cancer AB - Novel treatment modalities are necessary for pancreatic cancer. Immunotherapy with immune checkpoint inhibition has shown effect in other solid tumors, and could have a place in pancreatic cancer treatment. Most available clinical studies on immune checkpoint inhibitors for pancreatic cancer are not yet completed and are still recruiting patients. Among the completed trials, there have been findings of a preliminary nature such as delayed disease progression and enhanced overall survival after treatment with immune checkpoint inhibitors in mono- or combination therapy. However, due to small sample sizes, major results are not yet identifiable. The present article provides a clinical overview of immune checkpoint inhibition in pancreatic cancer. PubMed, ClinicalTrials.gov and American Society of Clinical Oncology's meeting abstracts were systematically searched for relevant clinical studies. Four articles, five abstracts and 25 clinical trials were identified and analyzed in detail. CI - Conflict-of-interest statement: No potential conflicts of interest. No financial support. RN - 0 (Antibodies) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (CD274 protein, human) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 2219-2840 IL - 1007-9327 DO - https://dx.doi.org/10.3748/wjg.v22.i43.9457 PT - Journal Article PT - Review ID - 10.3748/wjg.v22.i43.9457 [doi] ID - PMC5116591 [pmc] PP - ppublish PH - 2016/07/24 [received] PH - 2016/09/18 [revised] PH - 2016/10/19 [accepted] LG - English DP - 2016 Nov 21 DC - 20161206 EZ - 2016/12/07 06:00 DA - 2017/05/04 06:00 DT - 2016/12/07 06:00 YR - 2016 ED - 20170503 RD - 20170503 UP - 20170505 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27920468 <36. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28230773 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Botti G AU - Collina F AU - Scognamiglio G AU - Rao F AU - Peluso V AU - De Cecio R AU - Piezzo M AU - Landi G AU - De Laurentiis M AU - Cantile M AU - Di Bonito M FA - Botti, Gerardo FA - Collina, Francesca FA - Scognamiglio, Giosue FA - Rao, Federica FA - Peluso, Valentina FA - De Cecio, Rossella FA - Piezzo, Michela FA - Landi, Gabriella FA - De Laurentiis, Michelino FA - Cantile, Monica FA - Di Bonito, Maurizio IN - Botti, Gerardo. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. g.botti@istitutotumori.na.it. IN - Collina, Francesca. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. francescacollina84@gmail.com. IN - Scognamiglio, Giosue. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. giosco80@gmail.com. IN - Rao, Federica. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. federica.rao@gmail.com. IN - Peluso, Valentina. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. valent.peluso@gmail.com. IN - De Cecio, Rossella. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. r.dececio@istitutotumori.na.it. IN - Piezzo, Michela. Department of Breast Surgery and Cancer Prevention, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. m.piezzo@breastunit.org. IN - Landi, Gabriella. Department of Breast Surgery and Cancer Prevention, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. g.landi@istitutotumori.na.it. IN - De Laurentiis, Michelino. Department of Breast Surgery and Cancer Prevention, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. m.delaurentiis@istitutotumori.na.it. IN - Cantile, Monica. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. m.cantile@istitutotumori.na.it. IN - Di Bonito, Maurizio. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. mauriziodibonito@libero.it. TI - Programmed Death Ligand 1 (PD-L1) Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients. SO - International Journal of Molecular Sciences. 18(2), 2017 Feb 21 AS - Int. j. mol. sci.. 18(2), 2017 Feb 21 NJ - International journal of molecular sciences PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101092791 IO - Int J Mol Sci SB - Index Medicus CP - Switzerland MH - Adult MH - Aged MH - Aged, 80 and over MH - Antigens, CD274/ge [Genetics] MH - *Antigens, CD274/me [Metabolism] MH - Biomarkers, Tumor MH - *Diabetes Mellitus/me [Metabolism] MH - Female MH - Humans MH - Immunohistochemistry MH - Kaplan-Meier Estimate MH - Ki-67 Antigen/me [Metabolism] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/me [Metabolism] MH - Middle Aged MH - Neoplasm Grading MH - Neoplasm Metastasis MH - Neoplasm Staging MH - Prognosis MH - Risk Factors MH - *Triple Negative Breast Neoplasms/me [Metabolism] MH - *Triple Negative Breast Neoplasms/mo [Mortality] MH - Triple Negative Breast Neoplasms/pa [Pathology] MH - Tumor Burden MH - Young Adult KW - PD-L1; TNBC; diabetes AB - Triple Negative Breast Cancers (TNBC) subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1) is a trans-membrane protein expressed on a wide variety of cells including immune cells, epithelial and vascular endothelial cells. Recently, PD-1/PD-L1 pathway signaling was described as an adaptive immune resistance mechanism enacted by the tumor cells to evade the immune response. Its presence on tumor cell membranes, acquired for this reason, through time, is an important prognostic value. However, data available in the literature about PD-L1 immunohistochemical expression in breast cancer are often discordant and not uniform, probably for the use of different antibodies clones and the high molecular heterogeneity of the different tumor types. The absence of target therapies, in particular for TNBC, has shifted the clinical attention mainly on the role of PD-L1 in this subtype of breast cancer. In this study, we evaluated tumor and TIL (tumor infiltrating lymphocytes) PDL-1 expression in a series of TNBC, included in Tissue Micro Arrays (TMAs), to define its real prognostic value, optimizing immunohistochemistry method with an "approved for diagnostic assay" antibody. PD-L1 expression directly correlated with proliferation index (Ki-67), glycemia, the presence of diabetes and indirectly with menopausal status, presence of lymph node metastasis and relapse. The analysis of Kaplan-Meier showed that an increased PD-L1 expression was strongly associated with better disease-free survival (DFS) but not correlated with overall survival (OS). Our data confirmed that PD-L1 could be an important marker for prognostic stratification and for planning immune checkpoint inhibitors therapies in patients with TNBC. RN - 0 (Antigens, CD274) RN - 0 (Biomarkers, Tumor) RN - 0 (Ki-67 Antigen) ES - 1422-0067 IL - 1422-0067 DI - E459 DI - ijms18020459 DO - https://dx.doi.org/10.3390/ijms18020459 PT - Journal Article ID - ijms18020459 [pii] ID - 10.3390/ijms18020459 [doi] ID - PMC5343992 [pmc] PP - epublish PH - 2016/12/28 [received] PH - 2017/02/06 [revised] PH - 2017/02/15 [accepted] LG - English EP - 20170221 DP - 2017 Feb 21 DC - 20170223 EZ - 2017/02/24 06:00 DA - 2017/02/24 06:00 DT - 2017/02/24 06:00 YR - 2017 ED - 20170428 RD - 20170428 UP - 20170501 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28230773 <37. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28230773 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Botti G AU - Collina F AU - Scognamiglio G AU - Rao F AU - Peluso V AU - De Cecio R AU - Piezzo M AU - Landi G AU - De Laurentiis M AU - Cantile M AU - Di Bonito M FA - Botti, Gerardo FA - Collina, Francesca FA - Scognamiglio, Giosue FA - Rao, Federica FA - Peluso, Valentina FA - De Cecio, Rossella FA - Piezzo, Michela FA - Landi, Gabriella FA - De Laurentiis, Michelino FA - Cantile, Monica FA - Di Bonito, Maurizio IN - Botti, Gerardo. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. g.botti@istitutotumori.na.it. IN - Collina, Francesca. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. francescacollina84@gmail.com. IN - Scognamiglio, Giosue. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. giosco80@gmail.com. IN - Rao, Federica. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. federica.rao@gmail.com. IN - Peluso, Valentina. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. valent.peluso@gmail.com. IN - De Cecio, Rossella. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. r.dececio@istitutotumori.na.it. IN - Piezzo, Michela. Department of Breast Surgery and Cancer Prevention, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. m.piezzo@breastunit.org. IN - Landi, Gabriella. Department of Breast Surgery and Cancer Prevention, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. g.landi@istitutotumori.na.it. IN - De Laurentiis, Michelino. Department of Breast Surgery and Cancer Prevention, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. m.delaurentiis@istitutotumori.na.it. IN - Cantile, Monica. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. m.cantile@istitutotumori.na.it. IN - Di Bonito, Maurizio. Pathology Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", via Mariano Semmola, 80131 Napoli, Italy. mauriziodibonito@libero.it. TI - Programmed Death Ligand 1 (PD-L1) Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients. SO - International Journal of Molecular Sciences. 18(2), 2017 Feb 21 AS - Int. j. mol. sci.. 18(2), 2017 Feb 21 NJ - International journal of molecular sciences PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101092791 IO - Int J Mol Sci SB - Index Medicus CP - Switzerland MH - Adult MH - Aged MH - Aged, 80 and over MH - Antigens, CD274/ge [Genetics] MH - *Antigens, CD274/me [Metabolism] MH - Biomarkers, Tumor MH - *Diabetes Mellitus/me [Metabolism] MH - Female MH - Humans MH - Immunohistochemistry MH - Kaplan-Meier Estimate MH - Ki-67 Antigen/me [Metabolism] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/me [Metabolism] MH - Middle Aged MH - Neoplasm Grading MH - Neoplasm Metastasis MH - Neoplasm Staging MH - Prognosis MH - Risk Factors MH - *Triple Negative Breast Neoplasms/me [Metabolism] MH - *Triple Negative Breast Neoplasms/mo [Mortality] MH - Triple Negative Breast Neoplasms/pa [Pathology] MH - Tumor Burden MH - Young Adult KW - PD-L1; TNBC; diabetes AB - Triple Negative Breast Cancers (TNBC) subtype is an aggressive disease with poor clinical outcome. The only treatment available is surgery followed by chemotherapy or radiotherapy. Programmed death-ligand 1 (PD-L1) is a trans-membrane protein expressed on a wide variety of cells including immune cells, epithelial and vascular endothelial cells. Recently, PD-1/PD-L1 pathway signaling was described as an adaptive immune resistance mechanism enacted by the tumor cells to evade the immune response. Its presence on tumor cell membranes, acquired for this reason, through time, is an important prognostic value. However, data available in the literature about PD-L1 immunohistochemical expression in breast cancer are often discordant and not uniform, probably for the use of different antibodies clones and the high molecular heterogeneity of the different tumor types. The absence of target therapies, in particular for TNBC, has shifted the clinical attention mainly on the role of PD-L1 in this subtype of breast cancer. In this study, we evaluated tumor and TIL (tumor infiltrating lymphocytes) PDL-1 expression in a series of TNBC, included in Tissue Micro Arrays (TMAs), to define its real prognostic value, optimizing immunohistochemistry method with an "approved for diagnostic assay" antibody. PD-L1 expression directly correlated with proliferation index (Ki-67), glycemia, the presence of diabetes and indirectly with menopausal status, presence of lymph node metastasis and relapse. The analysis of Kaplan-Meier showed that an increased PD-L1 expression was strongly associated with better disease-free survival (DFS) but not correlated with overall survival (OS). Our data confirmed that PD-L1 could be an important marker for prognostic stratification and for planning immune checkpoint inhibitors therapies in patients with TNBC. RN - 0 (Antigens, CD274) RN - 0 (Biomarkers, Tumor) RN - 0 (Ki-67 Antigen) ES - 1422-0067 IL - 1422-0067 DI - E459 DI - ijms18020459 DO - https://dx.doi.org/10.3390/ijms18020459 PT - Journal Article ID - ijms18020459 [pii] ID - 10.3390/ijms18020459 [doi] ID - PMC5343992 [pmc] PP - epublish PH - 2016/12/28 [received] PH - 2017/02/06 [revised] PH - 2017/02/15 [accepted] LG - English EP - 20170221 DP - 2017 Feb 21 DC - 20170223 EZ - 2017/02/24 06:00 DA - 2017/04/30 06:00 DT - 2017/02/24 06:00 YR - 2017 ED - 20170428 RD - 20170428 UP - 20170502 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=28230773 <38. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27696192 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Munakata W AU - Ohashi K AU - Yamauchi N AU - Tobinai K AI - Munakata, Wataru; ORCID: http://orcid.org/0000-0002-4679-0656 FA - Munakata, Wataru FA - Ohashi, Ken FA - Yamauchi, Nobuhiko FA - Tobinai, Kensei IN - Munakata, Wataru. Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. wmunakat@ncc.go.jp. IN - Ohashi, Ken. Department of General Internal Medicine, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. IN - Yamauchi, Nobuhiko. Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. IN - Tobinai, Kensei. Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. TI - Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma. SO - International Journal of Hematology. 105(3):383-386, 2017 Mar AS - Int J Hematol. 105(3):383-386, 2017 Mar NJ - International journal of hematology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - a7f, 9111627 IO - Int. J. Hematol. SB - Index Medicus CP - Japan MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Diabetes Mellitus, Type 1/ci [Chemically Induced] MH - Diabetes Mellitus, Type 1/di [Diagnosis] MH - Diabetes Mellitus, Type 1/ge [Genetics] MH - Genetic Predisposition to Disease MH - HLA-B Antigens/an [Analysis] MH - HLA-B Antigens/ge [Genetics] MH - *Hodgkin Disease/co [Complications] MH - Hodgkin Disease/dt [Drug Therapy] MH - Humans MH - Male MH - Recurrence KW - *Anti-PD-1 antibody; *Fulminant type I diabetes mellitus; *Immune-related adverse events; *Nivolumab AB - We report the case of a patient with relapsed classical Hodgkin lymphoma who developed fulminant type I diabetes mellitus as a severe adverse event of treatment with the anti-programmed cell death-1 (PD-1) antibody, nivolumab. On the first day of the sixth cycle, the blood glucose level was markedly elevated (375 mg/dL). Although neither ketoacidosis nor ketonuria was detected, the markedly acute onset of the hyperglycemia was consistent with the typical clinical course of fulminant type I diabetes mellitus, and this diagnosis was supported by clinical data. All autoantibodies associated with type I diabetes mellitus were negative. The endogenous insulin secretion ceased completely within 2 weeks. After the blood glucose level was brought under control, nivolumab was resumed and continued without other major adverse events. Human leukocyte antigen (HLA) analysis revealed that the patient carried the HLA-B*4002 haplotype, a susceptibility allele for this type of diabetes mellitus. This case suggests that fulminant type I diabetes mellitus may be triggered by nivolumab in patients with a genetic background associated with the condition, warranting careful future consideration of this particular adverse event. RN - 0 (Antibodies, Monoclonal) RN - 0 (HLA-B Antigens) RN - 31YO63LBSN (nivolumab) ES - 1865-3774 IL - 0925-5710 DI - 10.1007/s12185-016-2101-4 DO - https://dx.doi.org/10.1007/s12185-016-2101-4 PT - Case Reports PT - Journal Article ID - 10.1007/s12185-016-2101-4 [doi] ID - 10.1007/s12185-016-2101-4 [pii] PP - ppublish PH - 2016/07/11 [received] PH - 2016/09/26 [accepted] PH - 2016/09/20 [revised] LG - English EP - 20161001 DP - 2017 Mar DC - 20161003 EZ - 2016/10/04 06:00 DA - 2017/04/27 06:00 DT - 2016/10/04 06:00 YR - 2017 ED - 20170426 RD - 20170426 UP - 20170428 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27696192 <39. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28112370 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Doi T AU - Ishikawa T AU - Okayama T AU - Oka K AU - Mizushima K AU - Yasuda T AU - Sakamoto N AU - Katada K AU - Kamada K AU - Uchiyama K AU - Handa O AU - Takagi T AU - Naito Y AU - Itoh Y FA - Doi, Toshifumi FA - Ishikawa, Takeshi FA - Okayama, Tetsuya FA - Oka, Kaname FA - Mizushima, Katsura FA - Yasuda, Tomoyo FA - Sakamoto, Naoyuki FA - Katada, Kazuhiro FA - Kamada, Kazuhiro FA - Uchiyama, Kazuhiko FA - Handa, Osamu FA - Takagi, Tomohisa FA - Naito, Yuji FA - Itoh, Yoshito IN - Doi, Toshifumi. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Ishikawa, Takeshi. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Okayama, Tetsuya. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Oka, Kaname. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Mizushima, Katsura. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Yasuda, Tomoyo. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Sakamoto, Naoyuki. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Katada, Kazuhiro. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Kamada, Kazuhiro. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Uchiyama, Kazuhiko. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Handa, Osamu. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Takagi, Tomohisa. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Naito, Yuji. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. IN - Itoh, Yoshito. Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. TI - The JAK/STAT pathway is involved in the upregulation of PD-L1 expression in pancreatic cancer cell lines. SO - Oncology Reports. 37(3):1545-1554, 2017 Mar AS - Oncol Rep. 37(3):1545-1554, 2017 Mar NJ - Oncology reports PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c1f, 9422756 IO - Oncol. Rep. SB - Index Medicus CP - Greece MH - Antigens, CD274/ge [Genetics] MH - *Antigens, CD274/me [Metabolism] MH - *Antineoplastic Agents/pd [Pharmacology] MH - Apoptosis/de [Drug Effects] MH - Blotting, Western MH - Cell Proliferation/de [Drug Effects] MH - Flow Cytometry MH - *Gene Expression Regulation, Neoplastic/de [Drug Effects] MH - Humans MH - Janus Kinase 2/ge [Genetics] MH - *Janus Kinase 2/me [Metabolism] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - *Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - RNA, Messenger/ge [Genetics] MH - Real-Time Polymerase Chain Reaction MH - Reverse Transcriptase Polymerase Chain Reaction MH - STAT1 Transcription Factor/ge [Genetics] MH - *STAT1 Transcription Factor/me [Metabolism] MH - Signal Transduction MH - Tumor Cells, Cultured AB - Although improvements in the chemotherapy modalities for pancreatic cancer have been realized, pancreatic cancer remains one of the most lethal malignancies. New-generation cancer immunotherapy methods, such as blocking of the PD-1/PD-L1 pathway, are consistently being investigated to improve the survival of pancreatic cancer patients. In the present study, we evaluated the influence of anticancer agents 5-fluorouracil, gemcitabine and paclitaxel on PD-L1 expression in human pancreatic cancer cell lines MIA PaCa-2 and AsPC-1 and in murine pancreatic cancer cell line Pan02. Additionally, we analyzed the molecular mechanisms that facilitated the regulation of PD-L1 expression in these cell lines. We observed that when AsPC-1, MIA PaCa-2 and Pan02 cells were stimulated by 5-fluorouracil, gemcitabine or paclitaxel, PD-L1 surface protein expression was enhanced. Similarly, the mRNA level of PD-L1 was upregulated in the AsPC-1 and Pan02 cells when stimulated by each of the three anticancer agents. The phosphorylation of STAT1 and an increase in total STAT1 were also observed in the AsPC-1 cells when stimulated by each anticancer agent. In response to JAK2 inhibitor treatment, PD-L1 upregulation induced by the anticancer agents was reduced in a dose-dependent manner. These results suggest that i) the JAK2/STAT1 pathway is involved in the anticancer agent-mediated PD-L1 transcription; and ii) the anticancer agents altered the tumor immune response which may induce tumor immune escape. These findings can have an influence on the design of treatments that combine chemotherapy and immunotherapy. RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (CD274 protein, human) RN - 0 (RNA, Messenger) RN - 0 (STAT1 Transcription Factor) RN - 0 (STAT1 protein, human) RN - EC 2-7-10-2 (JAK2 protein, human) RN - EC 2-7-10-2 (Janus Kinase 2) ES - 1791-2431 IL - 1021-335X DO - https://dx.doi.org/10.3892/or.2017.5399 PT - Journal Article ID - 10.3892/or.2017.5399 [doi] PP - ppublish PH - 2016/03/28 [received] PH - 2016/12/28 [accepted] LG - English EP - 20170123 DP - 2017 Mar DC - 20170123 EZ - 2017/01/24 06:00 DA - 2017/04/26 06:00 DT - 2017/01/24 06:00 YR - 2017 ED - 20170425 RD - 20170425 UP - 20170427 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28112370 <40. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27416087 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gonzalez N AU - Ratner D FA - Gonzalez, Noelani FA - Ratner, Desiree IN - Gonzalez, Noelani. Icahn School of Medicine at Mount Sinai, New York, New York, USA. IN - Ratner, Desiree. Icahn School of Medicine at Mount Sinai and Mount Sinai Beth Israel, New York, New York, USA. TI - Novel melanoma therapies and their side effects. [Review] SO - Cutis. 97(6):426-8, 2016 Jun AS - Cutis. 97(6):426-8, 2016 Jun NJ - Cutis PI - Journal available in: Print PI - Citation processed from: Internet JC - dxb, 0006440 IO - Cutis SB - Index Medicus CP - United States MH - Adrenal Cortex Hormones/tu [Therapeutic Use] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Chemical and Drug Induced Liver Injury/dt [Drug Therapy] MH - Chemical and Drug Induced Liver Injury/et [Etiology] MH - Drug Eruptions/et [Etiology] MH - Gastrointestinal Diseases/ci [Chemically Induced] MH - Gastrointestinal Diseases/dt [Drug Therapy] MH - Humans MH - Hypophysitis/ci [Chemically Induced] MH - Hypophysitis/dt [Drug Therapy] MH - Hypothyroidism/ci [Chemically Induced] MH - Hypothyroidism/dt [Drug Therapy] MH - Imidazoles/ae [Adverse Effects] MH - Immunosuppressive Agents/tu [Therapeutic Use] MH - Indoles/ae [Adverse Effects] MH - *Melanoma/dt [Drug Therapy] MH - Mycophenolic Acid/tu [Therapeutic Use] MH - Oximes/ae [Adverse Effects] MH - Pyridones/ae [Adverse Effects] MH - Pyrimidinones/ae [Adverse Effects] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Sulfonamides/ae [Adverse Effects] MH - Sweet Syndrome/ci [Chemically Induced] MH - Thyrotoxicosis/ci [Chemically Induced] MH - Thyrotoxicosis/dt [Drug Therapy] MH - Tumor Necrosis Factor-alpha/ai [Antagonists & Inhibitors] MH - Vitiligo/ci [Chemically Induced] AB - In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint-blocking antibodies or immune checkpoint inhibitors including ipilimumab, vemurafenib, dabrafenib, trametinib, nivolumab, and pembrolizumab. Although they have shown promising results, they also have caused multiple adverse events (AEs), particularly immune-related AEs (irAEs). Specialists should be familiar with these AEs. RN - 0 (Adrenal Cortex Hormones) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Imidazoles) RN - 0 (Immunosuppressive Agents) RN - 0 (Indoles) RN - 0 (Oximes) RN - 0 (Pyridones) RN - 0 (Pyrimidinones) RN - 0 (Sulfonamides) RN - 0 (Tumor Necrosis Factor-alpha) RN - 207SMY3FQT (vemurafenib) RN - 31YO63LBSN (nivolumab) RN - 33E86K87QN (trametinib) RN - 6T8C155666 (ipilimumab) RN - DPT0O3T46P (pembrolizumab) RN - HU9DX48N0T (Mycophenolic Acid) RN - QGP4HA4G1B (dabrafenib) ES - 2326-6929 IL - 0011-4162 PT - Journal Article PT - Review PP - ppublish LG - English DP - 2016 Jun DC - 20160715 EZ - 2016/07/15 06:00 DA - 2017/04/19 06:00 DT - 2016/07/16 06:00 YR - 2016 ED - 20170418 RD - 20170418 UP - 20170420 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27416087 <41. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27809739 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bourke JM AU - O'Sullivan M AU - Khattak MA FA - Bourke, Jack M FA - O'Sullivan, Michael FA - Khattak, Muhammad A IN - Bourke, Jack M. Fiona Stanley Hospital, Perth, WA Jack.Bourke@health.wa.gov.au. IN - O'Sullivan, Michael. Fiona Stanley Hospital, Perth, WA. IN - Khattak, Muhammad A. Fiona Stanley Hospital, Perth, WA. TI - Management of adverse events related to new cancer immunotherapy (immune checkpoint inhibitors). [Review] SO - Medical Journal of Australia. 205(9):418-424, 2016 Nov 07 AS - Med J Aust. 205(9):418-424, 2016 Nov 07 NJ - The Medical journal of Australia PI - Journal available in: Print PI - Citation processed from: Internet JC - 0400714, m26 IO - Med. J. Aust. SB - Index Medicus CP - Australia MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/ad [Administration & Dosage] MH - *Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Cell Cycle Checkpoints MH - Drug Eruptions/et [Etiology] MH - Humans MH - Immunosuppressive Agents/ad [Administration & Dosage] MH - *Immunosuppressive Agents/ae [Adverse Effects] MH - *Lung Neoplasms/dt [Drug Therapy] MH - *Melanoma/dt [Drug Therapy] MH - Pituitary Diseases/et [Etiology] AB - New immunotherapies have significantly improved survival in certain advanced cancers in recent years, particularly metastatic melanoma and lung cancer. The most effective of these therapies are the immune checkpoint inhibitors (ICIs) such as ipilimumab, nivolumab and pembrolizumab. The use of ICIs will continue to increase in the coming years as evidence of their benefit in a range of other cancers builds. ICIs are associated with novel immune-related adverse events (irAEs), which can involve a wide range of organs. The most common irAEs involve the skin (rash, pruritus), gastrointestinal tract (diarrhoea, colitis) and endocrine system (thyroid, pituitary). While severity is generally mild, life-threatening complications can occur if not recognised and treated promptly. Due to the diverse manifestations of irAEs, patients may present to doctors who are not familiar with these drugs, which creates the potential for delays in management. Management of irAEs depends on severity and the organ affected. Systemic steroids are often required and ICI therapy may be withheld or discontinued. Additional immunosuppressive medications may be necessary in steroid-refractory cases. This review provides an overview of the potential toxicities and their management for general clinicians. Broader awareness of these issues among medical professionals will hopefully reduce unnecessary delays in diagnosis and treatment. Patient and carer education regarding irAEs is extremely important; patients and carers should be advised to seek urgent medical attention if required. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Immunosuppressive Agents) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RN - DPT0O3T46P (pembrolizumab) ES - 1326-5377 IL - 0025-729X DI - 10.5694/mja16.00586 PT - Journal Article PT - Review ID - 10.5694/mja16.00586 [pii] PP - ppublish PH - 2016/05/17 [received] PH - 2016/07/20 [accepted] LG - English DP - 2016 Nov 07 DC - 20161104 EZ - 2016/11/05 06:00 DA - 2017/04/13 06:00 DT - 2016/11/05 06:00 YR - 2016 ED - 20170412 RD - 20170412 UP - 20170414 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27809739 <42. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27297738 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Miyoshi Y AU - Ogawa O AU - Oyama Y FA - Miyoshi, Yuka FA - Ogawa, Osamu FA - Oyama, Yu IN - Miyoshi, Yuka. Department of Diabetes and Endocrinology, Kameda Medical Center. TI - Nivolumab, an Anti-Programmed Cell Death-1 Antibody, Induces Fulminant Type 1 Diabetes. SO - Tohoku Journal of Experimental Medicine. 239(2):155-8, 2016 AS - Tohoku J Exp Med. 239(2):155-8, 2016 NJ - The Tohoku journal of experimental medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - vtf, 0417355 IO - Tohoku J. Exp. Med. SB - Index Medicus CP - Japan MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Diabetes Mellitus, Type 1/ci [Chemically Induced] MH - Diabetes Mellitus, Type 1/dt [Drug Therapy] MH - Female MH - Hemoglobin A, Glycosylated/me [Metabolism] MH - Humans MH - Insulin/me [Metabolism] MH - *Programmed Cell Death 1 Receptor/im [Immunology] AB - Programmed cell death-1 (PD-1), an immunoreceptor, is located on T cells and pro-B cells and interacts with its ligands to inhibit T cell activation and proliferation, thereby promoting immunological self-tolerance. Nivolumab, an anti-PD1 antibody, blocks PD-1 and can restore anticancer immune responses by abrogating PD-1 pathway-mediated T-cell inhibition. Autoimmune adverse events are expected with PD-1 therapy. Fulminant type 1 diabetes is the subtype of type 1 diabetes. The clinical feature is the extremely rapid progression of hyperglycemia and ketoacidosis. Here we describe a 66-year-old woman with advanced melanoma who was treated with nivolumab. After 4 months and six doses of the medicine, the patient was admitted to the hospital with complaints of nausea and vomiting. The laboratory data showed ketonuria, hyperglycemia (531 mg/dl), high anion gap metabolic acidosis, HbA1c (7.3%), and absence of insulin-secreting capacity. These data are compatible with the criteria of fulminant type 1 diabetes. The patient was diagnosed with diabetic ketoacidosis because of fulminant type 1 diabetes. The findings of this case indicated that nivolumab can cause fulminant type 1 diabetes. Diabetic ketoacidosis due to fulminant type 1 diabetes is potentially fatal condition. Thus, diabetic ketoacidosis due to fulminant type 1 diabetes should be considered in the differential diagnosis when patients treated with nivolumab complain of gastrointestinal symptoms. RN - 0 (Antibodies, Monoclonal) RN - 0 (Hemoglobin A, Glycosylated) RN - 0 (Insulin) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) ES - 1349-3329 IL - 0040-8727 DO - https://dx.doi.org/10.1620/tjem.239.155 PT - Case Reports PT - Journal Article ID - 10.1620/tjem.239.155 [doi] PP - ppublish LG - English DP - 2016 DC - 20160614 EZ - 2016/06/15 06:00 DA - 2017/04/04 06:00 DT - 2016/06/15 06:00 YR - 2016 ED - 20170403 RD - 20170403 UP - 20170405 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27297738 <43. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27447625 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Mittica G AU - Genta S AU - Aglietta M AU - Valabrega G FA - Mittica, Gloria FA - Genta, Sofia FA - Aglietta, Massimo FA - Valabrega, Giorgio IN - Mittica, Gloria. Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy. gloria.mittica@ircc.it. IN - Mittica, Gloria. Department of Oncology, University of Torino, Turin 10060, Italy. gloria.mittica@ircc.it. IN - Genta, Sofia. Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy. sofia.genta@ircc.it. IN - Genta, Sofia. Department of Oncology, University of Torino, Turin 10060, Italy. sofia.genta@ircc.it. IN - Aglietta, Massimo. Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy. massimo.aglietta@ircc.it. IN - Aglietta, Massimo. Department of Oncology, University of Torino, Turin 10060, Italy. massimo.aglietta@ircc.it. IN - Valabrega, Giorgio. Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy. giorgio.valabrega@ircc.it. IN - Valabrega, Giorgio. Department of Oncology, University of Torino, Turin 10060, Italy. giorgio.valabrega@ircc.it. TI - Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?. [Review] SO - International Journal of Molecular Sciences. 17(7), 2016 Jul 20 AS - Int. j. mol. sci.. 17(7), 2016 Jul 20 NJ - International journal of molecular sciences PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101092791 IO - Int J Mol Sci PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964540 SB - Index Medicus CP - Switzerland MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Cell Cycle Checkpoints/de [Drug Effects] MH - Female MH - Humans MH - *Immunotherapy MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/im [Immunology] KW - cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); immune checkpoint inhibitor; ipilimumab; nivolumab; ovarian cancer; pembrolizumab; programmed cell death ligand-1 (PD-L1); programmed cell death-1 (PD-1); tumor infiltrating lymphocytes (TILs) AB - Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the "turn off" signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC. RN - 0 (Antineoplastic Agents) ES - 1422-0067 IL - 1422-0067 DI - E1169 DI - ijms17071169 DO - https://dx.doi.org/10.3390/ijms17071169 PT - Journal Article PT - Review ID - ijms17071169 [pii] ID - 10.3390/ijms17071169 [doi] ID - PMC4964540 [pmc] PP - epublish PH - 2016/06/20 [received] PH - 2016/07/08 [revised] PH - 2016/07/14 [accepted] LG - English EP - 20160720 DP - 2016 Jul 20 DC - 20160724 EZ - 2016/07/23 06:00 DA - 2016/07/23 06:00 DT - 2016/07/23 06:00 YR - 2016 ED - 20170328 RD - 20170328 UP - 20170330 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27447625 <44. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27012985 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Tanaka R AU - Fujisawa Y AU - Maruyama H AU - Nakamura Y AU - Yoshino K AU - Ohtsuka M AU - Fujimoto M FA - Tanaka, Ryota FA - Fujisawa, Yasuhiro FA - Maruyama, Hiroshi FA - Nakamura, Yasuhiro FA - Yoshino, Koji FA - Ohtsuka, Mikio FA - Fujimoto, Manabu IN - Tanaka, Ryota. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki ryota621@hotmail.co.jp. IN - Fujisawa, Yasuhiro. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki. IN - Maruyama, Hiroshi. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki. IN - Nakamura, Yasuhiro. Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama. IN - Yoshino, Koji. Department of Dermatology, Tokyo Metropolitan Komagome Hospital, Tokyo. IN - Ohtsuka, Mikio. Department of Dermatology, Fukushima Medical University School of Medicine, Fukushima, Japan. IN - Fujimoto, Manabu. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki. TI - Nivolumab-induced thyroid dysfunction. SO - Japanese Journal of Clinical Oncology. 46(6):575-9, 2016 Jun AS - Jpn J Clin Oncol. 46(6):575-9, 2016 Jun NJ - Japanese journal of clinical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - kin, 0313225 IO - Jpn. J. Clin. Oncol. SB - Index Medicus CP - England MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Female MH - Hormone Replacement Therapy MH - Humans MH - *Hypothyroidism/et [Etiology] MH - Hypothyroidism/th [Therapy] MH - Male MH - Melanoma/dt [Drug Therapy] MH - Middle Aged MH - Quality of Life MH - Thyrotropin/an [Analysis] MH - Thyroxine/an [Analysis] MH - Triiodothyronine/an [Analysis] KW - *endocrine-med; *immunotherapy; *skin AB - Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody, which has become a standard treatment for metastatic malignant melanoma. Nivolumab induces autoimmune adverse events, defined as immune-related adverse events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the clinical setting. Fourteen patients were treated with nivolumab at our institute, of which three developed thyroid dysfunction, an incidence higher than previously reported in the initial clinical trials. Interestingly, one patient achieved complete remission; suggesting that in some patients, the occurrence of immune-related adverse events, including thyroid dysfunction, might reflect the drug's antitumour efficacy. No patient died or discontinued nivolumab treatment owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be asymptomatic, two of the three patients developed symptoms related to hypothyroidism soon after, requiring hormone replacement therapy. Another patient developed hyperthyroidism that was initially asymptomatic; the patient subsequently developed myalgia with fever >39.5degreeC after two additional courses of nivolumab. Treatment with nivolumab was therefore discontinued, and treatment with prednisolone was initiated. Symptoms resolved within a few days, and thyroid function normalized. Thyroid dysfunction is sometimes difficult to diagnose because its symptoms similar to those of many other diseases. In addition, thyroid-related immune-related adverse events may present with unique symptoms such as myalgia with high fever, abruptly worsening patients' quality of life. Consequently, thyroid dysfunction should be considered as a possible immune-related adverse event. Thus, it is important to test for thyroid dysfunction at baseline and before the administration of each nivolumab dose if possible. AB - Copyright © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 06LU7C9H1V (Triiodothyronine) RN - 31YO63LBSN (nivolumab) RN - 9002-71-5 (Thyrotropin) RN - Q51BO43MG4 (Thyroxine) ES - 1465-3621 IL - 0368-2811 DI - hyw036 DO - https://dx.doi.org/10.1093/jjco/hyw036 PT - Case Reports PT - Journal Article ID - hyw036 [pii] ID - 10.1093/jjco/hyw036 [doi] PP - ppublish PH - 2015/08/31 [received] PH - 2016/02/20 [accepted] LG - English EP - 20160323 DP - 2016 Jun DC - 20160702 EZ - 2016/03/26 06:00 DA - 2016/03/26 06:00 DT - 2016/03/26 06:00 YR - 2016 ED - 20170328 RD - 20170328 UP - 20170330 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27012985 <45. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27447625 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Mittica G AU - Genta S AU - Aglietta M AU - Valabrega G FA - Mittica, Gloria FA - Genta, Sofia FA - Aglietta, Massimo FA - Valabrega, Giorgio IN - Mittica, Gloria. Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy. gloria.mittica@ircc.it. IN - Mittica, Gloria. Department of Oncology, University of Torino, Turin 10060, Italy. gloria.mittica@ircc.it. IN - Genta, Sofia. Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy. sofia.genta@ircc.it. IN - Genta, Sofia. Department of Oncology, University of Torino, Turin 10060, Italy. sofia.genta@ircc.it. IN - Aglietta, Massimo. Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy. massimo.aglietta@ircc.it. IN - Aglietta, Massimo. Department of Oncology, University of Torino, Turin 10060, Italy. massimo.aglietta@ircc.it. IN - Valabrega, Giorgio. Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy. giorgio.valabrega@ircc.it. IN - Valabrega, Giorgio. Department of Oncology, University of Torino, Turin 10060, Italy. giorgio.valabrega@ircc.it. TI - Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?. [Review] SO - International Journal of Molecular Sciences. 17(7), 2016 Jul 20 AS - Int. j. mol. sci.. 17(7), 2016 Jul 20 NJ - International journal of molecular sciences PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101092791 IO - Int J Mol Sci PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964540 SB - Index Medicus CP - Switzerland MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Cell Cycle Checkpoints/de [Drug Effects] MH - Female MH - Humans MH - *Immunotherapy MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/im [Immunology] KW - cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); immune checkpoint inhibitor; ipilimumab; nivolumab; ovarian cancer; pembrolizumab; programmed cell death ligand-1 (PD-L1); programmed cell death-1 (PD-1); tumor infiltrating lymphocytes (TILs) AB - Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the "turn off" signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC. RN - 0 (Antineoplastic Agents) ES - 1422-0067 IL - 1422-0067 DI - E1169 DI - ijms17071169 DO - https://dx.doi.org/10.3390/ijms17071169 PT - Journal Article PT - Review ID - ijms17071169 [pii] ID - 10.3390/ijms17071169 [doi] ID - PMC4964540 [pmc] PP - epublish PH - 2016/06/20 [received] PH - 2016/07/08 [revised] PH - 2016/07/14 [accepted] LG - English EP - 20160720 DP - 2016 Jul 20 DC - 20160724 EZ - 2016/07/23 06:00 DA - 2017/03/30 06:00 DT - 2016/07/23 06:00 YR - 2016 ED - 20170328 RD - 20170328 UP - 20170331 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27447625 <46. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27012985 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Tanaka R AU - Fujisawa Y AU - Maruyama H AU - Nakamura Y AU - Yoshino K AU - Ohtsuka M AU - Fujimoto M FA - Tanaka, Ryota FA - Fujisawa, Yasuhiro FA - Maruyama, Hiroshi FA - Nakamura, Yasuhiro FA - Yoshino, Koji FA - Ohtsuka, Mikio FA - Fujimoto, Manabu IN - Tanaka, Ryota. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki ryota621@hotmail.co.jp. IN - Fujisawa, Yasuhiro. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki. IN - Maruyama, Hiroshi. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki. IN - Nakamura, Yasuhiro. Department of Skin Oncology/Dermatology, Saitama Medical University International Medical Center, Saitama. IN - Yoshino, Koji. Department of Dermatology, Tokyo Metropolitan Komagome Hospital, Tokyo. IN - Ohtsuka, Mikio. Department of Dermatology, Fukushima Medical University School of Medicine, Fukushima, Japan. IN - Fujimoto, Manabu. Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki. TI - Nivolumab-induced thyroid dysfunction. SO - Japanese Journal of Clinical Oncology. 46(6):575-9, 2016 Jun AS - Jpn J Clin Oncol. 46(6):575-9, 2016 Jun NJ - Japanese journal of clinical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - kin, 0313225 IO - Jpn. J. Clin. Oncol. SB - Index Medicus CP - England MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Female MH - Hormone Replacement Therapy MH - Humans MH - *Hypothyroidism/et [Etiology] MH - Hypothyroidism/th [Therapy] MH - Male MH - Melanoma/dt [Drug Therapy] MH - Middle Aged MH - Quality of Life MH - Thyrotropin/an [Analysis] MH - Thyroxine/an [Analysis] MH - Triiodothyronine/an [Analysis] KW - *endocrine-med; *immunotherapy; *skin AB - Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody, which has become a standard treatment for metastatic malignant melanoma. Nivolumab induces autoimmune adverse events, defined as immune-related adverse events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the clinical setting. Fourteen patients were treated with nivolumab at our institute, of which three developed thyroid dysfunction, an incidence higher than previously reported in the initial clinical trials. Interestingly, one patient achieved complete remission; suggesting that in some patients, the occurrence of immune-related adverse events, including thyroid dysfunction, might reflect the drug's antitumour efficacy. No patient died or discontinued nivolumab treatment owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be asymptomatic, two of the three patients developed symptoms related to hypothyroidism soon after, requiring hormone replacement therapy. Another patient developed hyperthyroidism that was initially asymptomatic; the patient subsequently developed myalgia with fever >39.5degreeC after two additional courses of nivolumab. Treatment with nivolumab was therefore discontinued, and treatment with prednisolone was initiated. Symptoms resolved within a few days, and thyroid function normalized. Thyroid dysfunction is sometimes difficult to diagnose because its symptoms similar to those of many other diseases. In addition, thyroid-related immune-related adverse events may present with unique symptoms such as myalgia with high fever, abruptly worsening patients' quality of life. Consequently, thyroid dysfunction should be considered as a possible immune-related adverse event. Thus, it is important to test for thyroid dysfunction at baseline and before the administration of each nivolumab dose if possible. AB - Copyright © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 06LU7C9H1V (Triiodothyronine) RN - 31YO63LBSN (nivolumab) RN - 9002-71-5 (Thyrotropin) RN - Q51BO43MG4 (Thyroxine) ES - 1465-3621 IL - 0368-2811 DI - hyw036 DO - https://dx.doi.org/10.1093/jjco/hyw036 PT - Case Reports PT - Journal Article ID - hyw036 [pii] ID - 10.1093/jjco/hyw036 [doi] PP - ppublish PH - 2015/08/31 [received] PH - 2016/02/20 [accepted] LG - English EP - 20160323 DP - 2016 Jun DC - 20160702 EZ - 2016/03/26 06:00 DA - 2017/03/30 06:00 DT - 2016/03/26 06:00 YR - 2016 ED - 20170328 RD - 20170328 UP - 20170331 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27012985 <47. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27881588 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Aleksova J AU - Lau PK AU - Soldatos G AU - McArthur G FA - Aleksova, Jasna FA - Lau, Peter K H FA - Soldatos, Georgia FA - McArthur, Grant IN - Aleksova, Jasna. Monash Health, Clayton, Victoria, Australia. IN - Lau, Peter K H. Peter MacCallum Cancer Institute, Cancer Medicine, East Melbourne, Victoria, Australia. IN - Soldatos, Georgia. Peter MacCallum Cancer Institute, Cancer Medicine, East Melbourne, Victoria, Australia. IN - Soldatos, Georgia. Monash Centre for Health Research and Implementation, Melbourne, Victoria, Australia. IN - McArthur, Grant. Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. IN - McArthur, Grant. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia. TI - Glucocorticoids did not reverse type 1 diabetes mellitus secondary to pembrolizumab in a patient with metastatic melanoma. SO - BMJ Case Reports. 2016, 2016 Nov 23 AS - BMJ Case Rep. 2016, 2016 Nov 23 NJ - BMJ case reports PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101526291 IO - BMJ Case Rep SB - Index Medicus CP - England MH - *Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - *Diabetes Mellitus, Type 1/ci [Chemically Induced] MH - *Diabetes Mellitus, Type 1/dt [Drug Therapy] MH - *Glucocorticoids/tu [Therapeutic Use] MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/pa [Pathology] MH - Middle Aged MH - Treatment Outcome AB - Immune checkpoint inhibitors offer patients with advanced melanoma substantial improvements in survival. Unlike chemotherapy, immune checkpoint inhibitors such as ipilimumab and pembrolizumab cause unique immune-related adverse events (irAEs), including the development of endocrinopathies. We report a case of a man aged 60 years who developed diabetic ketoacidosis (DKA) following the use of pembrolizumab for the treatment of metastatic melanoma. He received four cycles of ipilimumab, before proceeding to pembrolizumab. Five weeks after initiating pembrolizumab, he presented in DKA with a pH of 7.0, bicarbonate of 7 mmol/L, blood glucose of 27 mmol/L and serum ketones of 5.9 mmol/L. Antibodies to glutamic acid decarboxylase (anti-GAD) and Islet antigen 2 (IA-2) were negative and C-peptide was low at 57 pmol/L (300-2350 pmol/L). There was no personal or family history of autoimmune conditions. Standard immunosuppression for irAEs was started using prednisolone in an attempt to salvage beta cell function but was unsuccessful. To the best of our knowledge, this is the first reported attempt at reversing pembrolizumab-induced type 1 diabetes using glucocorticoids. AB - Copyright 2016 BMJ Publishing Group Ltd. CI - PL has received honoraria and travel funding from Bristol Myers Squibb. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Glucocorticoids) RN - DPT0O3T46P (pembrolizumab) ES - 1757-790X IL - 1757-790X DI - bcr2016217454 DI - bcr-2016-217454 DO - https://dx.doi.org/10.1136/bcr-2016-217454 PT - Case Reports PT - Journal Article ID - bcr-2016-217454 [pii] ID - 10.1136/bcr-2016-217454 [doi] PP - epublish LG - English EP - 20161123 DP - 2016 Nov 23 DC - 20161124 EZ - 2016/11/25 06:00 DA - 2017/03/18 06:00 DT - 2016/11/25 06:00 YR - 2016 ED - 20170317 RD - 20170317 UP - 20170320 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27881588 <48. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27181232 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Fukushima S FA - Fukushima, Satoshi IN - Fukushima, Satoshi. Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University. TI - A review of adverse events caused by immune checkpoint inhibitors. [Review] SO - Nihon Rinsho Meneki Gakkai Kaishi. 39(1):30-6, 2016 AS - Nihon Rinsho Meneki Gakkai Kaishi. 39(1):30-6, 2016 NJ - Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology PI - Journal available in: Print PI - Citation processed from: Internet JC - ccm, 9505992 IO - Nihon Rinsho Meneki Gakkai Kaishi SB - Index Medicus CP - Japan MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Autoimmune Diseases/ci [Chemically Induced] MH - Chemical and Drug Induced Liver Injury/et [Etiology] MH - Colitis/ci [Chemically Induced] MH - Endocrine System Diseases/ci [Chemically Induced] MH - Humans MH - Lung Diseases, Interstitial/ci [Chemically Induced] MH - Melanoma/dt [Drug Therapy] MH - *Membrane Transport Proteins/im [Immunology] MH - Myasthenia Gravis/ci [Chemically Induced] MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Skin Diseases/ci [Chemically Induced] AB - There has been no effective therapy in the unresectable melanoma for more than 40 years. Anti-PD-1 antibody and anti-CTLA-4 antibody have totally changed the situation. They have clearly shown the survival benefits of the patients with metastatic melanoma. However, immune checkpoint inhibitors sometimes induce various kinds of immune-related adverse events (irAEs). It is very important for the clinicians to know the reported cases of irAEs and to keep in mind the symptoms of irAEs for the early detection. This review describes the previously reported irAEs and adequate managements for irAEs induced by immune checkpoint inhibitors. RN - 0 (Antibodies, Monoclonal) RN - 0 (Membrane Transport Proteins) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (choline transporter-like protein 4, human) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) ES - 1349-7413 IL - 0911-4300 DO - https://dx.doi.org/10.2177/jsci.39.30 PT - Journal Article PT - Review ID - 10.2177/jsci.39.30 [doi] PP - ppublish LG - English DP - 2016 DC - 20160516 EZ - 2016/05/17 06:00 DA - 2017/03/17 06:00 DT - 2016/05/18 06:00 YR - 2016 ED - 20170316 RD - 20170316 UP - 20170320 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27181232 <49. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27286362 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Oing C AU - Kollmannsberger C AU - Oechsle K AU - Bokemeyer C FA - Oing, Christoph FA - Kollmannsberger, Christian FA - Oechsle, Karin FA - Bokemeyer, Carsten IN - Oing, Christoph. a Department of Oncology, Hematology and Bone Marrow Transplantation , University Medical Center Hamburg-Eppendorf , Hamburg , Germany. IN - Kollmannsberger, Christian. b Division of Medical Oncology, British Columbia Cancer Agency Vancouver Cancer Center , University of British Columbia , Vancouver , Canada. IN - Oechsle, Karin. a Department of Oncology, Hematology and Bone Marrow Transplantation , University Medical Center Hamburg-Eppendorf , Hamburg , Germany. IN - Bokemeyer, Carsten. a Department of Oncology, Hematology and Bone Marrow Transplantation , University Medical Center Hamburg-Eppendorf , Hamburg , Germany. TI - Investigational targeted therapies for the treatment of testicular germ cell tumors. [Review] SO - Expert Opinion on Investigational Drugs. 25(9):1033-43, 2016 Sep AS - Expert Opin Investig Drugs. 25(9):1033-43, 2016 Sep NJ - Expert opinion on investigational drugs PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9434197 IO - Expert Opin Investig Drugs SB - Index Medicus CP - England MH - Antineoplastic Agents/ad [Administration & Dosage] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Clinical Trials as Topic MH - Drug Resistance, Neoplasm/de [Drug Effects] MH - Humans MH - Male MH - *Molecular Targeted Therapy/mt [Methods] MH - *Neoplasms, Germ Cell and Embryonal/dt [Drug Therapy] MH - Neoplasms, Germ Cell and Embryonal/ge [Genetics] MH - Neoplasms, Germ Cell and Embryonal/me [Metabolism] MH - Neoplasms, Germ Cell and Embryonal/pa [Pathology] MH - Taxoids/ad [Administration & Dosage] MH - *Taxoids/tu [Therapeutic Use] MH - *Testicular Neoplasms/dt [Drug Therapy] MH - Testicular Neoplasms/ge [Genetics] MH - Testicular Neoplasms/me [Metabolism] MH - Testicular Neoplasms/pa [Pathology] MH - Treatment Outcome KW - *Germ cell tumor; *platinum-refractory disease; *targeted therapy; *testicular cancer AB - INTRODUCTION: Germ cell tumors (GCTs) are the most common malignancy among men aged between 15 to 45. Despite high cure rates of >90% over all GCTs, 3 to 5% of patients will still die of platinum-refractory disease. New systemic treatment options are needed to improve treatment success in this challenging setting. AB - AREAS COVERED: To review targeted treatment options and preclinical developments in platinum-refractory GCTs, a comprehensive literature search of PubMed, Medline and scientific meeting abstracts on published clinical trials and reports on molecularly targeted approaches was conducted. Outcomes of platinum-refractory disease and of patients failing high-dose chemotherapy remain poor. Currently, no molecularly targeted treatment has shown clinically meaningful activity in unselected patient populations in clinical trials, but individual patients may achieve short-lived objective responses by treatment with sunitinib, brentuximab vedotin or imatinib. Targeted trials based on molecular selection of patients have not yet been performed. AB - EXPERT OPINION: The limited activity of targeted agents in refractory GCT is disappointing. Assessment of druggable biomarkers and marker-stratified treatment may help individual patients, but is largely lacking. The low incidence and high curability of GCTs make the design of larger clinical trials difficult. The potential of novel agents, i.e. immune-checkpoint inhibitors, remains to be elucidated. RN - 0 (Antineoplastic Agents) RN - 0 (Taxoids) RN - 51F690397J (cabazitaxel) ES - 1744-7658 IL - 1354-3784 DO - https://dx.doi.org/10.1080/13543784.2016.1195808 PT - Journal Article PT - Review ID - 10.1080/13543784.2016.1195808 [doi] PP - ppublish LG - English EP - 20160610 DP - 2016 Sep DC - 20160819 EZ - 2016/06/11 06:00 DA - 2016/06/11 06:00 DT - 2016/06/11 06:00 YR - 2016 ED - 20170314 RD - 20170314 UP - 20170316 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27286362 <50. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27286362 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Oing C AU - Kollmannsberger C AU - Oechsle K AU - Bokemeyer C FA - Oing, Christoph FA - Kollmannsberger, Christian FA - Oechsle, Karin FA - Bokemeyer, Carsten IN - Oing, Christoph. a Department of Oncology, Hematology and Bone Marrow Transplantation , University Medical Center Hamburg-Eppendorf , Hamburg , Germany. IN - Kollmannsberger, Christian. b Division of Medical Oncology, British Columbia Cancer Agency Vancouver Cancer Center , University of British Columbia , Vancouver , Canada. IN - Oechsle, Karin. a Department of Oncology, Hematology and Bone Marrow Transplantation , University Medical Center Hamburg-Eppendorf , Hamburg , Germany. IN - Bokemeyer, Carsten. a Department of Oncology, Hematology and Bone Marrow Transplantation , University Medical Center Hamburg-Eppendorf , Hamburg , Germany. TI - Investigational targeted therapies for the treatment of testicular germ cell tumors. [Review] SO - Expert Opinion on Investigational Drugs. 25(9):1033-43, 2016 Sep AS - Expert Opin Investig Drugs. 25(9):1033-43, 2016 Sep NJ - Expert opinion on investigational drugs PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9434197 IO - Expert Opin Investig Drugs SB - Index Medicus CP - England MH - Antineoplastic Agents/ad [Administration & Dosage] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Clinical Trials as Topic MH - Drug Resistance, Neoplasm/de [Drug Effects] MH - Humans MH - Male MH - *Molecular Targeted Therapy/mt [Methods] MH - *Neoplasms, Germ Cell and Embryonal/dt [Drug Therapy] MH - Neoplasms, Germ Cell and Embryonal/ge [Genetics] MH - Neoplasms, Germ Cell and Embryonal/me [Metabolism] MH - Neoplasms, Germ Cell and Embryonal/pa [Pathology] MH - Taxoids/ad [Administration & Dosage] MH - *Taxoids/tu [Therapeutic Use] MH - *Testicular Neoplasms/dt [Drug Therapy] MH - Testicular Neoplasms/ge [Genetics] MH - Testicular Neoplasms/me [Metabolism] MH - Testicular Neoplasms/pa [Pathology] MH - Treatment Outcome KW - *Germ cell tumor; *platinum-refractory disease; *targeted therapy; *testicular cancer AB - INTRODUCTION: Germ cell tumors (GCTs) are the most common malignancy among men aged between 15 to 45. Despite high cure rates of >90% over all GCTs, 3 to 5% of patients will still die of platinum-refractory disease. New systemic treatment options are needed to improve treatment success in this challenging setting. AB - AREAS COVERED: To review targeted treatment options and preclinical developments in platinum-refractory GCTs, a comprehensive literature search of PubMed, Medline and scientific meeting abstracts on published clinical trials and reports on molecularly targeted approaches was conducted. Outcomes of platinum-refractory disease and of patients failing high-dose chemotherapy remain poor. Currently, no molecularly targeted treatment has shown clinically meaningful activity in unselected patient populations in clinical trials, but individual patients may achieve short-lived objective responses by treatment with sunitinib, brentuximab vedotin or imatinib. Targeted trials based on molecular selection of patients have not yet been performed. AB - EXPERT OPINION: The limited activity of targeted agents in refractory GCT is disappointing. Assessment of druggable biomarkers and marker-stratified treatment may help individual patients, but is largely lacking. The low incidence and high curability of GCTs make the design of larger clinical trials difficult. The potential of novel agents, i.e. immune-checkpoint inhibitors, remains to be elucidated. RN - 0 (Antineoplastic Agents) RN - 0 (Taxoids) RN - 51F690397J (cabazitaxel) ES - 1744-7658 IL - 1354-3784 DO - https://dx.doi.org/10.1080/13543784.2016.1195808 PT - Journal Article PT - Review ID - 10.1080/13543784.2016.1195808 [doi] PP - ppublish LG - English EP - 20160610 DP - 2016 Sep DC - 20160819 EZ - 2016/06/11 06:00 DA - 2017/03/16 06:00 DT - 2016/06/11 06:00 YR - 2016 ED - 20170314 RD - 20170314 UP - 20170317 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27286362 <51. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27438590 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ellenrieder V AU - Konig A AU - Seufferlein T FA - Ellenrieder, Volker FA - Konig, Alexander FA - Seufferlein, Thomas IN - Ellenrieder, Volker. Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Gottingen, Gottingen, Germany. TI - Current Standard and Future Perspectives in First- and Second-Line Treatment of Metastatic Pancreatic Adenocarcinoma. [Review] SO - Digestion. 94(1):44-9, 2016 AS - Digestion. 94(1):44-9, 2016 NJ - Digestion PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - e9a, 0150472 IO - Digestion SB - Index Medicus CP - Switzerland MH - Aged MH - Albumins/ad [Administration & Dosage] MH - Albumins/tu [Therapeutic Use] MH - *Antineoplastic Combined Chemotherapy Protocols/st [Standards] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Camptothecin/ad [Administration & Dosage] MH - Camptothecin/aa [Analogs & Derivatives] MH - Camptothecin/tu [Therapeutic Use] MH - *Carcinoma, Pancreatic Ductal/dt [Drug Therapy] MH - Carcinoma, Pancreatic Ductal/mo [Mortality] MH - Clinical Trials as Topic MH - Deoxycytidine/ad [Administration & Dosage] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/tu [Therapeutic Use] MH - Disease-Free Survival MH - Fluorouracil/ad [Administration & Dosage] MH - Fluorouracil/tu [Therapeutic Use] MH - Humans MH - Leucovorin/ad [Administration & Dosage] MH - Leucovorin/tu [Therapeutic Use] MH - Male MH - Middle Aged MH - Nanoparticles/ad [Administration & Dosage] MH - Nanoparticles/tu [Therapeutic Use] MH - Organoplatinum Compounds/ad [Administration & Dosage] MH - Organoplatinum Compounds/tu [Therapeutic Use] MH - Paclitaxel/ad [Administration & Dosage] MH - Paclitaxel/tu [Therapeutic Use] MH - Palliative Care/mt [Methods] MH - *Pancreatic Neoplasms/dt [Drug Therapy] AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a median 5-year survival of <8%. At the time of diagnosis, a vast majority of pancreatic cancer patients were found to be with either metastatic spread of the disease or locally advanced tumors. Despite relatively low efficacy, gemcitabine administration was the first choice chemotherapeutic strategy in advanced PDAC for many years. In the last 5 years, however, our understanding of pancreatic carcinogenesis has improved dramatically and with this our therapeutic options have expanded significantly. AB - SUMMARY: With the FOLFIRINOX protocol or the combination of gemcitabine and nab-paclitaxel, 2 novel and more effective chemotherapeutic regimens have been introduced in clinical routine, which increased the overall survival by 4-5 months in the palliative situation. Most recently, we learned that both regimens can be modified and dosages can be adapted in older patients without significant loss of efficacy. Additionally, novel application strategies such as nanoparticle fused liposomal irinotecan along with 5-FU/LV provided convincing results in patients previously treated with gemcitabine. Current preclinical and clinical trials investigate efficacy and tolerability of novel drugs aiming at the inhibition of key inflammatory pathways, for example, JAK-STAT signaling, or the tumor surrounding desmoplasia. Prospectively, immunovaccination approaches or immune checkpoint inhibition appears as promising strategies in the near future, particularly when combined with epigenetic drugs in advanced PDAC patients. In this 'to-the-point' article, we review the current standard and summarize the most recent and encouraging advances in cytostatic PDAC treatment. AB - KEY POINTS: (1) FOLFIRINOX and nab-paclitaxel/gemcitabine as first-line treatment regime significantly increase survival in patients with advanced PDAC; (2) Selection of appropriate treatment regime depends on patient performance, comorbidity, and toxicity; (3) PDAC patients will benefit from second-line chemotherapy and selection of appropriate regimes depends on first line therapy and patient criteria; (4) Future therapeutic strategies in advanced PDAC will respect molecular tumor profiling and other biomarkers. AB - Copyright © 2016 S. Karger AG, Basel. RN - 0 (130-nm albumin-bound paclitaxel) RN - 0 (Albumins) RN - 0 (Organoplatinum Compounds) RN - 04ZR38536J (oxaliplatin) RN - 0H43101T0J (irinotecan) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - P88XT4IS4D (Paclitaxel) RN - Q573I9DVLP (Leucovorin) RN - U3P01618RT (Fluorouracil) RN - XT3Z54Z28A (Camptothecin) ES - 1421-9867 IL - 0012-2823 DI - 000447739 DO - https://dx.doi.org/10.1159/000447739 PT - Journal Article PT - Review ID - 000447739 [pii] ID - 10.1159/000447739 [doi] PP - ppublish PH - 2016/03/17 [received] PH - 2016/06/11 [accepted] LG - English EP - 20160721 DP - 2016 DC - 20160831 EZ - 2016/07/21 06:00 DA - 2017/03/08 06:00 DT - 2016/07/21 06:00 YR - 2016 ED - 20170307 RD - 20170307 UP - 20170309 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27438590 <52. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28148549 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hsieh AH AU - Faithfull S AU - Brown MP FA - Hsieh, Amy Hsin-Chieh FA - Faithfull, Sarah FA - Brown, Michael P IN - Hsieh, Amy Hsin-Chieh. Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia. IN - Faithfull, Sarah. Radiology Department, Royal Adelaide Hospital, Adelaide, South Australia, Australia. IN - Brown, Michael P. Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia. TI - Risk of cumulative toxicity after complete melanoma response with pembrolizumab. SO - BMJ Case Reports. 2017, 2017 Feb 01 AS - BMJ Case Rep. 2017, 2017 Feb 01 NJ - BMJ case reports PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101526291 IO - BMJ Case Rep SB - Index Medicus CP - England MH - Aged MH - *Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *Drug Eruptions/et [Etiology] MH - Groin MH - Hormone Replacement Therapy MH - Humans MH - Hydrocortisone/tu [Therapeutic Use] MH - *Hypopituitarism/ci [Chemically Induced] MH - Hypopituitarism/dt [Drug Therapy] MH - *Limbic Encephalitis/ci [Chemically Induced] MH - Limbic Encephalitis/dg [Diagnostic Imaging] MH - Lymphatic Metastasis MH - Magnetic Resonance Imaging MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Pelvis MH - Thyroxine/tu [Therapeutic Use] AB - Pembrolizumab is an approved first-line systemic therapy for unresectable metastatic melanoma. Despite the achievement of complete and durable responses in a small subgroup of patients, it is standard practice that pembrolizumab therapy continues beyond complete response. Nevertheless, the incidence of immune-related toxicities gradually increases with continuing pembrolizumab therapy. We report a case highlighting the occurrence of serious induced immune-related adverse events, which were attributed to pembrolizumab in a patient with metastatic melanoma who obtained a complete response (CR) after receiving pembrolizumab for a total of 6.5 months. Although mild pembrolizumab-related toxicity persists, the patient remains disease-free 5.5 months after discontinuation of pembrolizumab. Accordingly, we believe that cessation of pembrolizumab should be considered in patients who achieve a CR because of the ongoing risk of toxicity with extended pembrolizumab administration. AB - Copyright 2017 BMJ Publishing Group Ltd. CI - Competing interests: None declared. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - DPT0O3T46P (pembrolizumab) RN - Q51BO43MG4 (Thyroxine) RN - WI4X0X7BPJ (Hydrocortisone) RS - Combined Pituitary Hormone Deficiency ES - 1757-790X IL - 1757-790X DI - bcr2016218308 DI - bcr-2016-218308 DO - https://dx.doi.org/10.1136/bcr-2016-218308 PT - Case Reports PT - Journal Article ID - 28148549 [pubmed] ID - bcr-2016-218308 [pii] ID - 10.1136/bcr-2016-218308 [doi] PP - epublish LG - English EP - 20170201 DP - 2017 Feb 01 DC - 20170202 EZ - 2017/02/03 06:00 DA - 2017/03/07 06:00 DT - 2017/02/06 06:00 YR - 2017 ED - 20170306 RD - 20170306 UP - 20170308 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28148549 <53. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27245147 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Katoh M FA - Katoh, Masaru IN - Katoh, Masaru. Department of Omics Network, National Cancer Center, Tokyo 104-0045, Japan. TI - FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). [Review] SO - International Journal of Molecular Medicine. 38(1):3-15, 2016 Jul AS - Int J Mol Med. 38(1):3-15, 2016 Jul NJ - International journal of molecular medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c8h, 9810955 IO - Int. J. Mol. Med. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899036 SB - Index Medicus CP - Greece MH - Animals MH - Drug Delivery Systems MH - *Homeostasis/de [Drug Effects] MH - Humans MH - *Neoplasms/pa [Pathology] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - *Receptor Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - Receptor Protein-Tyrosine Kinases/ge [Genetics] MH - Receptor Protein-Tyrosine Kinases/me [Metabolism] MH - *Tumor Microenvironment/de [Drug Effects] AB - Fibroblast growth factor (FGF)2, FGF4, FGF7 and FGF20 are representative paracrine FGFs binding to heparan-sulfate proteoglycan and fibroblast growth factor receptors (FGFRs), whereas FGF19, FGF21 and FGF23 are endocrine FGFs binding to Klotho and FGFRs. FGFR1 is relatively frequently amplified and overexpressed in breast and lung cancer, and FGFR2 in gastric cancer. BCR-FGFR1, CNTRL-FGFR1, CUX1-FGFR1, FGFR1OP-FGFR1, MYO18A-FGFR1 and ZMYM2-FGFR1 fusions in myeloproliferative neoplasms are non-receptor-type FGFR kinases, whereas FGFR1-TACC1, FGFR2-AFF3, FGFR2-BICC1, FGFR2-PPHLN1, FGFR3-BAIAP2L1 and FGFR3-TACC3 fusions in solid tumors are transmembrane-type FGFRs with C-terminal alterations. AZD4547, BGJ398 (infigratinib), Debio-1347 and dovitinib are FGFR1/2/3 inhibitors; BLU9931 is a selective FGFR4 inhibitor; FIIN-2, JNJ-42756493, LY2874455 and ponatinib are pan-FGFR inhibitors. AZD4547, dovitinib and ponatinib are multi-kinase inhibitors targeting FGFRs, colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF)R2, and others. The tumor microenvironment consists of cancer cells and stromal/immune cells, such as cancer-associated fibroblasts (CAFs), endothelial cells, M2-type tumor-associating macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells. FGFR inhibitors elicit antitumor effects directly on cancer cells, as well as indirectly through the blockade of paracrine signaling. The dual inhibition of FGF and CSF1 or VEGF signaling is expected to enhance the antitumor effects through the targeting of immune evasion and angiogenesis in the tumor microenvironment. Combination therapy using tyrosine kinase inhibitors (FGFR or CSF1R inhibitors) and immune checkpoint blockers (anti-PD-1 or anti-CTLA-4 monoclonal antibodies) may be a promising choice for cancer patients. The inhibition of FGF19-FGFR4 signaling is associated with a risk of liver toxicity, whereas the activation of FGF23-FGFR4 signaling is associated with a risk of heart toxicity. Endocrine FGF signaling affects the pathophysiology of cancer patients who are prescribed FGFR inhibitors. Whole-genome sequencing is necessary for the detection of promoter/enhancer alterations of FGFR genes and rare alterations of other genes causing FGFR overexpression. To sustain the health care system in an aging society, a benefit-cost analysis should be performed with a focus on disease-free survival and the total medical cost before implementing genome-based precision medicine for cancer patients. RN - 0 (Protein Kinase Inhibitors) RN - EC 2-7-10-1 (Receptor Protein-Tyrosine Kinases) ES - 1791-244X IL - 1107-3756 DO - https://dx.doi.org/10.3892/ijmm.2016.2620 PT - Journal Article PT - Review ID - 27245147 [pubmed] ID - 10.3892/ijmm.2016.2620 [doi] ID - PMC4899036 [pmc] PP - ppublish PH - 2016/02/29 [received] PH - 2016/05/23 [accepted] LG - English EP - 20160531 DP - 2016 Jul DC - 20160618 EZ - 2016/06/02 06:00 DA - 2017/03/07 06:00 DT - 2016/06/02 06:00 YR - 2016 ED - 20170306 RD - 20170306 UP - 20170308 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27245147 <54. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28174381 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Daido W AU - Yamasaki M AU - Saito N AU - Ishiyama S AU - Deguchi N AU - Taniwaki M AU - Daga H AU - Ohashi N FA - Daido, Wakako FA - Yamasaki, Masahiro FA - Saito, Naomi FA - Ishiyama, Sayaka FA - Deguchi, Naoko FA - Taniwaki, Masaya FA - Daga, Haruko FA - Ohashi, Nobuyuki IN - Daido, Wakako. Dept. of Respiratory Disease, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital. TI - [Effectiveness of Nivolumab in Large-Cell Neuroendocrine Carcinoma of the Lung - A Report of Two Cases]. [Review] [Japanese] SO - Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy]. 44(1):59-62, 2017 Jan AS - Gan To Kagaku Ryoho. 44(1):59-62, 2017 Jan NJ - Gan to kagaku ryoho. Cancer & chemotherapy PI - Journal available in: Print PI - Citation processed from: Print JC - 7810034, 6t8 IO - Gan To Kagaku Ryoho SB - Index Medicus CP - Japan MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Biomarkers, Tumor/bl [Blood] MH - Carcinoma, Large Cell/ch [Chemistry] MH - Carcinoma, Large Cell/dg [Diagnostic Imaging] MH - *Carcinoma, Large Cell/dt [Drug Therapy] MH - Carcinoma, Neuroendocrine/ch [Chemistry] MH - Carcinoma, Neuroendocrine/dg [Diagnostic Imaging] MH - *Carcinoma, Neuroendocrine/dt [Drug Therapy] MH - Humans MH - Lung Neoplasms/ch [Chemistry] MH - Lung Neoplasms/dg [Diagnostic Imaging] MH - *Lung Neoplasms/dt [Drug Therapy] MH - Male MH - Middle Aged MH - Tomography, X-Ray Computed MH - Treatment Outcome AB - BACKGROUND: The anti-programmed death-1 antibody nivolumab is an important treatment option for non-small-cell lung carcinoma.However, its effectiveness for large-cell neuroendocrine carcinomas(LCNEC)is still controversial.Here, we report 2 cases of LCNECs that responded to nivolumab.Case 1: A 62-year-old man received chemotherapy and radiotherapy for stage III A lung adenocarcinoma.One year later, another lung lesion was observed and diagnosed as LCNEC using surgical lung biopsy.Although he subsequently received some chemotherapy regimens, the patient developed new brain metastasis, expanded mediastinal lesion, and increased levels of the tumor marker pro-gastrin releasing peptide(ProGRP).We started nivolumab as the sixth-line treatment.In response, ProGRP levels significantly decreased and the mediastinal lesion became smaller.Case 2: A 55-year-old man was diagnosed with stage III A LCNEC and received chemotherapy and radiotherapy.The primary lesion was controlled; however, lung metastases developed and chemotherapy was unable to control them.We provided treatment with nivolumab as the third-line therapy.The tumor marker ProGRP decreased and the lung metastases became smaller. AB - CONCLUSION: Nivolumab can be a valuable treatment option for LCNEC. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 31YO63LBSN (nivolumab) IS - 0385-0684 IL - 0385-0684 PT - Case Reports PT - Journal Article PT - Review ID - 28174381 [pubmed] PP - ppublish LG - Japanese DP - 2017 Jan DC - 20170208 EZ - 2017/02/09 06:00 DA - 2017/02/09 06:00 DT - 2017/02/09 06:00 YR - 2017 ED - 20170301 RD - 20170302 UP - 20170303 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28174381 <55. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28174381 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Daido W AU - Yamasaki M AU - Saito N AU - Ishiyama S AU - Deguchi N AU - Taniwaki M AU - Daga H AU - Ohashi N FA - Daido, Wakako FA - Yamasaki, Masahiro FA - Saito, Naomi FA - Ishiyama, Sayaka FA - Deguchi, Naoko FA - Taniwaki, Masaya FA - Daga, Haruko FA - Ohashi, Nobuyuki IN - Daido, Wakako. Dept. of Respiratory Disease, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital. TI - [Effectiveness of Nivolumab in Large-Cell Neuroendocrine Carcinoma of the Lung - A Report of Two Cases]. [Review] [Japanese] SO - Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy]. 44(1):59-62, 2017 Jan AS - Gan To Kagaku Ryoho. 44(1):59-62, 2017 Jan NJ - Gan to kagaku ryoho. Cancer & chemotherapy PI - Journal available in: Print PI - Citation processed from: Print JC - 7810034, 6t8 IO - Gan To Kagaku Ryoho SB - Index Medicus CP - Japan MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Biomarkers, Tumor/bl [Blood] MH - Carcinoma, Large Cell/ch [Chemistry] MH - Carcinoma, Large Cell/dg [Diagnostic Imaging] MH - *Carcinoma, Large Cell/dt [Drug Therapy] MH - Carcinoma, Neuroendocrine/ch [Chemistry] MH - Carcinoma, Neuroendocrine/dg [Diagnostic Imaging] MH - *Carcinoma, Neuroendocrine/dt [Drug Therapy] MH - Humans MH - Lung Neoplasms/ch [Chemistry] MH - Lung Neoplasms/dg [Diagnostic Imaging] MH - *Lung Neoplasms/dt [Drug Therapy] MH - Male MH - Middle Aged MH - Tomography, X-Ray Computed MH - Treatment Outcome AB - BACKGROUND: The anti-programmed death-1 antibody nivolumab is an important treatment option for non-small-cell lung carcinoma.However, its effectiveness for large-cell neuroendocrine carcinomas(LCNEC)is still controversial.Here, we report 2 cases of LCNECs that responded to nivolumab.Case 1: A 62-year-old man received chemotherapy and radiotherapy for stage III A lung adenocarcinoma.One year later, another lung lesion was observed and diagnosed as LCNEC using surgical lung biopsy.Although he subsequently received some chemotherapy regimens, the patient developed new brain metastasis, expanded mediastinal lesion, and increased levels of the tumor marker pro-gastrin releasing peptide(ProGRP).We started nivolumab as the sixth-line treatment.In response, ProGRP levels significantly decreased and the mediastinal lesion became smaller.Case 2: A 55-year-old man was diagnosed with stage III A LCNEC and received chemotherapy and radiotherapy.The primary lesion was controlled; however, lung metastases developed and chemotherapy was unable to control them.We provided treatment with nivolumab as the third-line therapy.The tumor marker ProGRP decreased and the lung metastases became smaller. AB - CONCLUSION: Nivolumab can be a valuable treatment option for LCNEC. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 31YO63LBSN (nivolumab) IS - 0385-0684 IL - 0385-0684 PT - Case Reports PT - Journal Article PT - Review ID - 28174381 [pubmed] PP - ppublish LG - Japanese DP - 2017 Jan DC - 20170208 EZ - 2017/02/09 06:00 DA - 2017/03/03 06:00 DT - 2017/02/09 06:00 YR - 2017 ED - 20170301 RD - 20170302 UP - 20170306 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=28174381 <56. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27367787 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Friedman CF AU - Proverbs-Singh TA AU - Postow MA FA - Friedman, Claire F FA - Proverbs-Singh, Tracy A FA - Postow, Michael A IN - Friedman, Claire F. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York2Weill Cornell Medical College, New York, New York. IN - Proverbs-Singh, Tracy A. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York2Weill Cornell Medical College, New York, New York. IN - Postow, Michael A. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York2Weill Cornell Medical College, New York, New York. TI - Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. [Review] SO - JAMA Oncology. 2(10):1346-1353, 2016 Oct 01 AS - JAMA Oncol. 2(10):1346-1353, 2016 Oct 01 NJ - JAMA oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - 101652861 IO - JAMA Oncol SB - Index Medicus CP - United States MH - Adrenal Cortex Hormones/tu [Therapeutic Use] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Chemical and Drug Induced Liver Injury/et [Etiology] MH - Colitis/ci [Chemically Induced] MH - Colitis/dt [Drug Therapy] MH - Exanthema/ci [Chemically Induced] MH - Exanthema/dt [Drug Therapy] MH - Humans MH - Immunosuppressive Agents/tu [Therapeutic Use] MH - Pneumonia/ci [Chemically Induced] MH - Pneumonia/dt [Drug Therapy] AB - Importance: The development of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) has significantly improved the treatment of a variety of cancers and led to US Food and Drug Administration approvals for patients with a variety of malignant neoplasms. Immune checkpoint inhibitors enhance antitumor immunity by blocking negative regulators of T-cell function that exist both on immune cells and on tumor cells. Although these agents can lead to remarkable responses, their use can also be associated with unique immune-related adverse effects (irAEs). AB - Observations: In general, use of PD-1 inhibitors such as nivolumab and pembrolizumab has a lower incidence of irAEs compared with those that block CTLA-4 such as ipilimumab. The combination of nivolumab and ipilimumab has a higher rate of irAEs than either approach as monotherapy. Consensus guidelines regarding the treatment of the most common irAEs including rash, colitis, hepatitis, endocrinopathies, and pneumonitis have been established. The mainstay of irAE treatment consists of immunosuppression with corticosteroids or other immunosuppressant agents such as infliximab; most irAEs will resolve with appropriate management. AB - Conclusions and Relevance: The clinical use of immune checkpoint inhibitors is expanding rapidly. Oncology practitioners will therefore be required to recognize and manage irAEs in a growing patient population. Early recognition and treatment are essential to prevent patient morbidity and mortality, and adherence to established algorithms is recommended. RN - 0 (Adrenal Cortex Hormones) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Immunosuppressive Agents) RN - 6T8C155666 (ipilimumab) RN - DPT0O3T46P (pembrolizumab) ES - 2374-2445 IL - 2374-2437 DI - 2531472 DO - https://dx.doi.org/10.1001/jamaoncol.2016.1051 PT - Journal Article PT - Review ID - 27367787 [pubmed] ID - 2531472 [pii] ID - 10.1001/jamaoncol.2016.1051 [doi] PP - ppublish LG - English DP - 2016 Oct 01 DC - 20160701 EZ - 2016/07/02 06:00 DA - 2017/02/22 06:00 DT - 2016/07/02 06:00 YR - 2016 ED - 20170221 RD - 20170221 UP - 20170222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27367787 <57. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27305306 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Besemer B AU - Mussig K FA - Besemer, Britta FA - Mussig, Karsten TI - [Rare differential diagnosis of hyperthyroidism]. [German] OT - Seltene Ursache einer Hyperthyreose - Fall 4 / 2016. SO - Deutsche Medizinische Wochenschrift. 141(12):889, 2016 Jun AS - Dtsch Med Wochenschr. 141(12):889, 2016 Jun NJ - Deutsche medizinische Wochenschrift (1946) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ecl, 0006723 IO - Dtsch. Med. Wochenschr. SB - Index Medicus CP - Germany MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Diagnosis, Differential MH - Female MH - Humans MH - *Hyperthyroidism/ci [Chemically Induced] MH - *Hyperthyroidism/di [Diagnosis] MH - *Lung Neoplasms/dt [Drug Therapy] MH - *Lung Neoplasms/sc [Secondary] MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/sc [Secondary] MH - *Membrane Transport Proteins/de [Drug Effects] MH - Middle Aged MH - *Skin Neoplasms/dt [Drug Therapy] MH - Thyroid Function Tests MH - *Thyroiditis, Autoimmune/ci [Chemically Induced] MH - *Thyroiditis, Autoimmune/di [Diagnosis] AB - HISTORY AND ADMISSION FINDINGS: A 54-year-old female patient is admitted for evaluation of her thyroid function after two cycles of ipilimumab therapy. The decision for the anti-cytotoxic-T-lymphocyte-antigen-4-therapy (anti-CTLA-4) was made two months earlier because of malignant melanoma with pulmonary metastases. The patient was euthyroid before initiation of treatment and without known thyroid disease. AB - INVESTIGATIONS: The laboratory reveals thyrotoxicosis with elevated anti-thyroid peroxidase and anti-thyroglobulin antibody levels. The anti-thyroid stimulating hormone receptor antibody levels are within the normal range. Thyroid ultrasound shows a normal-sized, inhomogenous, hypoechogenic thyroid gland, consistent with autoimmune thyroiditis. AB - DIAGNOSIS, TREATMENT AND COURSE: Diagnosis of hyperthyroidism due to ipilimumab-induced autoimmune thyroiditis is made. The patient does not receive any thyroid-specific medication, with regular control of the thyroid hormone levels. When the patient becomes euthyroid, the ipilimumab therapy is continued. Three weeks later, the patient develops hypothyroidism and a supplementation with L-thyroxine is initiated. AB - CONCLUSIONS: An anti-CTLA-4 therapy may cause thyroid dysfunction. Therefore, before initiation and in the course of the treatment, regular controls of the thyroid hormone levels are required. AB - Copyright © Georg Thieme Verlag KG Stuttgart . New York. RN - 0 (Antibodies, Monoclonal) RN - 0 (Membrane Transport Proteins) RN - 0 (choline transporter-like protein 4, human) RN - 6T8C155666 (ipilimumab) ES - 1439-4413 IL - 0012-0472 DO - https://dx.doi.org/10.1055/s-0041-104686 PT - Case Reports PT - Journal Article ID - 27305306 [pubmed] ID - 10.1055/s-0041-104686 [doi] PP - ppublish LG - German EP - 20160615 DP - 2016 Jun DC - 20160616 EZ - 2016/06/16 06:00 DA - 2017/02/22 06:00 DT - 2016/06/16 06:00 YR - 2016 ED - 20170221 RD - 20170221 UP - 20170222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27305306 <58. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27440480 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Okano Y AU - Satoh T AU - Horiguchi K AU - Toyoda M AU - Osaki A AU - Matsumoto S AU - Tomaru T AU - Nakajima Y AU - Ishii S AU - Ozawa A AU - Shibusawa N AU - Shimada T AU - Higuchi T AU - Chikamatsu K AU - Yamada M FA - Okano, Yudai FA - Satoh, Tetsurou FA - Horiguchi, Kazuhiko FA - Toyoda, Minoru FA - Osaki, Aya FA - Matsumoto, Shunichi FA - Tomaru, Takuya FA - Nakajima, Yasuyo FA - Ishii, Sumiyasu FA - Ozawa, Atsushi FA - Shibusawa, Nobuyuki FA - Shimada, Takehiro FA - Higuchi, Tetsuya FA - Chikamatsu, Kazuaki FA - Yamada, Masanobu IN - Okano, Yudai. Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan. TI - Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma. SO - Endocrine Journal. 63(10):905-912, 2016 Oct 29 AS - Endocr J. 63(10):905-912, 2016 Oct 29 NJ - Endocrine journal PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bt5, 9313485 IO - Endocr. J. SB - Index Medicus CP - Japan MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Disease Progression MH - Humans MH - *Hypophysitis/ci [Chemically Induced] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - *Oropharyngeal Neoplasms/dt [Drug Therapy] MH - Oropharyngeal Neoplasms/pa [Pathology] AB - The anti-programmed cell death-1 monoclonal antibody (mab), nivolumab has recently been approved for the treatment of unresectable or metastatic malignant melanoma and non-small-cell lung cancers in Japan. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 mab for malignant melanoma that was approved earlier than nivolumab in Western countries, is known to frequently cause endocrine immune-related adverse events such as hypophysitis and thyroid dysfunction. We herein report a patient with advanced melanoma who appeared to develop hypophysitis as a consequence of the inhibition of PD-1 by nivolumab. One week after the 6^th administration of nivolumab, the patient developed progressive fatigue and appetite loss. Laboratory data on admission for the 7^th administration of nivolumab showed eosinophilia and hyponatremia. Since ACTH and cortisol levels were low, nivolumab was discontinued and a large dose of hydrocortisone (100 mg/d) was promptly administered intravenously. A magnetic resonance imaging scan revealed the mild enlargement of the anterior pituitary gland and thickening of the stalk with homogenous contrast. A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges showed that hormonal secretions other than ACTH and TSH were normal. With a replacement dose of hydrocortisone (20 mg/d), the 7^th administration of nivolumab was completed without exacerbating the patient's general condition. The present report provides the first detailed endocrinological presentation of nivolumab-induced hypophysitis showing the enlargement of the pituitary gland and stalk in a malignant melanoma patient in Japan. Oncologists and endocrinologists need to be familiar with potentially life-threatening hypophysitis induced by immune-checkpoint inhibitors. RN - 0 (Antibodies, Monoclonal) RN - 31YO63LBSN (nivolumab) ES - 1348-4540 IL - 0918-8959 DO - https://dx.doi.org/10.1507/endocrj.EJ16-0161 PT - Case Reports PT - Journal Article ID - 27440480 [pubmed] ID - 10.1507/endocrj.EJ16-0161 [doi] PP - ppublish LG - English EP - 20160720 DP - 2016 Oct 29 DC - 20160721 EZ - 2016/07/22 06:00 DA - 2017/02/18 06:00 DT - 2016/11/01 06:00 YR - 2016 ED - 20170217 RD - 20170217 UP - 20170221 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27440480 <59. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27930550 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Chang JH AU - Jiang Y AU - Pillarisetty VG FA - Chang, Jae Hyuck FA - Jiang, Yongjian FA - Pillarisetty, Venu G IN - Chang, Jae Hyuck. aDepartment of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea bDepartment of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China cDepartment of Surgery, University of Washington Medical Center, Seattle, University of Washington, Seattle, WA. TI - Role of immune cells in pancreatic cancer from bench to clinical application: An updated review. [Review] SO - Medicine. 95(49):e5541, 2016 Dec AS - Medicine (Baltimore). 95(49):e5541, 2016 Dec NJ - Medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - mny, 2985248r IO - Medicine (Baltimore) SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Cancer Vaccines/tu [Therapeutic Use] MH - Humans MH - Immune Tolerance MH - Immunotherapy MH - *Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/th [Therapy] AB - BACKGROUND: Pancreatic cancer (PC) remains difficult to treat, despite the recent advances in various anticancer therapies. Immuno-inflammatory response is considered to be a major risk factor for the development of PC in addition to a combination of genetic background and environmental factors. Although patients with PC exhibit evidence of systemic immune dysfunction, the PC microenvironment is replete with immune cells. AB - METHODS: We searched PubMed for all relevant English language articles published up to March 2016. They included clinical trials, experimental studies, observational studies, and reviews. Trials enrolled at Clinical trial.gov were also searched. AB - RESULTS: PC induces an immunosuppressive microenvironment, and intratumoral activation of immunity in PC is attenuated by inhibitory signals that limit immune effector function. Multiple types of immune responses can promote an immunosuppressive microenvironment; key regulators of the host tumor immune response are dendritic cells, natural killer cells, macrophages, myeloid derived suppressor cells, and T cells. The function of these immune cells in PC is also influenced by chemotherapeutic agents and the components in tumor microenvironment such as pancreatic stellate cells. Immunotherapy of PC employs monoclonal antibodies/effector cells generated in vitro or vaccination to stimulate antitumor response. Immune therapy in PC has failed to improve overall survival; however, combination therapies comprising immune checkpoint inhibitors and vaccines have been attempted to increase the response. AB - CONCLUSION: A number of studies have begun to elucidate the roles of immune cell subtypes and their capacity to function or dysfunction in the tumor microenvironment of PC. It will not be long before immune therapy for PC becomes a clinical reality. RN - 0 (Cancer Vaccines) ES - 1536-5964 IL - 0025-7974 DI - 00005792-201612060-00047 DO - https://dx.doi.org/10.1097/MD.0000000000005541 PT - Journal Article PT - Review ID - 27930550 [pubmed] ID - 10.1097/MD.0000000000005541 [doi] ID - 00005792-201612060-00047 [pii] ID - PMC5266022 [pmc] PP - ppublish LG - English DP - 2016 Dec DC - 20161208 EZ - 2016/12/09 06:00 DA - 2017/02/16 06:00 DT - 2016/12/09 06:00 YR - 2016 ED - 20170215 RD - 20170215 UP - 20170217 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27930550 <60. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27181090 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Okamoto M AU - Okamoto M AU - Gotoh K AU - Masaki T AU - Ozeki Y AU - Ando H AU - Anai M AU - Sato A AU - Yoshida Y AU - Ueda S AU - Kakuma T AU - Shibata H FA - Okamoto, Masahide FA - Okamoto, Mitsuhiro FA - Gotoh, Koro FA - Masaki, Takayuki FA - Ozeki, Yoshinori FA - Ando, Hisae FA - Anai, Manabu FA - Sato, Asami FA - Yoshida, Yuichi FA - Ueda, So FA - Kakuma, Tetsuya FA - Shibata, Hirotaka IN - Okamoto, Masahide. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Okamoto, Mitsuhiro. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Gotoh, Koro. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Masaki, Takayuki. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Ozeki, Yoshinori. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Ando, Hisae. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Anai, Manabu. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Sato, Asami. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Yoshida, Yuichi. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Ueda, So. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Kakuma, Tetsuya. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. IN - Shibata, Hirotaka. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, Japan. hiro-405@cb3.so-net.ne.jp. TI - Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. SO - Journal of Diabetes Investigation. 7(6):915-918, 2016 Nov AS - J. diabetes investig.. 7(6):915-918, 2016 Nov NJ - Journal of diabetes investigation PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101520702 IO - J Diabetes Investig SB - Index Medicus CP - Japan MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *Diabetes Mellitus, Type 1/ci [Chemically Induced] MH - Diabetes Mellitus, Type 1/im [Immunology] MH - Female MH - Humans MH - Melanoma/dt [Drug Therapy] MH - Middle Aged MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Treatment Outcome KW - Anti-programmed cell death-1 antibodies; Fulminant type 1 diabetes; Nivolumab AB - Anti-programmed cell death-1 (PD-1) antibodies are regarded as a risk factor for insulin-dependent diabetes mellitus as a side-effect. While a small number of cases have been reported, evidence remains limited. This is the first report of an Asian patient developing insulin-dependent diabetes during anti-PD-1 therapy. A 55-year-old euglycemic woman receiving nivolumab for malignant melanoma showed abrupt onset of ketonuria, and elevated levels of plasma glucose (580 mg/dL) and hemoglobin A1c (7.0%). Over the next 2 weeks, serum C-peptide levels fell below the limit of detection. Islet autoantibodies were negative, and the patient showed a human leukocyte antigen haplotype associated with type 1 diabetes. Anti-PD-1 therapy can cause rapid onset of insulin-dependent diabetes, possibly because of inappropriate activation of T cells. Human leukocyte antigen haplotypes might be related to the onset of this disease. Physicians should be aware of this serious adverse event and carry out routine blood glucose testing during anti-PD-1 therapy. AB - Copyright © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) ES - 2040-1124 IL - 2040-1116 DO - https://dx.doi.org/10.1111/jdi.12531 PT - Case Reports ID - 27181090 [pubmed] ID - 10.1111/jdi.12531 [doi] ID - PMC5089956 [pmc] PP - ppublish PH - 2015/12/16 [received] PH - 2016/03/14 [revised] PH - 2016/04/11 [accepted] LG - English EP - 20160531 DP - 2016 Nov DC - 20160516 EZ - 2016/05/17 06:00 DA - 2017/02/16 06:00 DT - 2016/11/03 06:00 YR - 2016 ED - 20170215 RD - 20170215 UP - 20170217 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27181090 <61. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27930550 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Chang JH AU - Jiang Y AU - Pillarisetty VG FA - Chang, Jae Hyuck FA - Jiang, Yongjian FA - Pillarisetty, Venu G IN - Chang, Jae Hyuck. aDepartment of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea bDepartment of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China cDepartment of Surgery, University of Washington Medical Center, Seattle, University of Washington, Seattle, WA. TI - Role of immune cells in pancreatic cancer from bench to clinical application: An updated review. [Review] SO - Medicine. 95(49):e5541, 2016 Dec AS - Medicine (Baltimore). 95(49):e5541, 2016 Dec NJ - Medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - mny, 2985248r IO - Medicine (Baltimore) SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Cancer Vaccines/tu [Therapeutic Use] MH - Humans MH - Immune Tolerance MH - Immunotherapy MH - *Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/th [Therapy] AB - BACKGROUND: Pancreatic cancer (PC) remains difficult to treat, despite the recent advances in various anticancer therapies. Immuno-inflammatory response is considered to be a major risk factor for the development of PC in addition to a combination of genetic background and environmental factors. Although patients with PC exhibit evidence of systemic immune dysfunction, the PC microenvironment is replete with immune cells. AB - METHODS: We searched PubMed for all relevant English language articles published up to March 2016. They included clinical trials, experimental studies, observational studies, and reviews. Trials enrolled at Clinical trial.gov were also searched. AB - RESULTS: PC induces an immunosuppressive microenvironment, and intratumoral activation of immunity in PC is attenuated by inhibitory signals that limit immune effector function. Multiple types of immune responses can promote an immunosuppressive microenvironment; key regulators of the host tumor immune response are dendritic cells, natural killer cells, macrophages, myeloid derived suppressor cells, and T cells. The function of these immune cells in PC is also influenced by chemotherapeutic agents and the components in tumor microenvironment such as pancreatic stellate cells. Immunotherapy of PC employs monoclonal antibodies/effector cells generated in vitro or vaccination to stimulate antitumor response. Immune therapy in PC has failed to improve overall survival; however, combination therapies comprising immune checkpoint inhibitors and vaccines have been attempted to increase the response. AB - CONCLUSION: A number of studies have begun to elucidate the roles of immune cell subtypes and their capacity to function or dysfunction in the tumor microenvironment of PC. It will not be long before immune therapy for PC becomes a clinical reality. CI - The authors have no conflicts of interest to disclose. RN - 0 (Cancer Vaccines) ES - 1536-5964 IL - 0025-7974 DI - 00005792-201612060-00047 DO - https://dx.doi.org/10.1097/MD.0000000000005541 PT - Journal Article PT - Review ID - 27930550 [pubmed] ID - 10.1097/MD.0000000000005541 [doi] ID - 00005792-201612060-00047 [pii] ID - PMC5266022 [pmc] PP - ppublish LG - English DP - 2016 Dec DC - 20161208 EZ - 2016/12/09 06:00 DA - 2017/02/16 06:00 DT - 2016/12/09 06:00 YR - 2016 ED - 20170215 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27930550 <62. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28113097 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Solinas C AU - Chanza NM AU - Awada A AU - Scartozzi M FA - Solinas, Cinzia FA - Chanza, Nieves Martinez FA - Awada, Ahmad FA - Scartozzi, Mario IN - Solinas, Cinzia. Molecular Immunology Unit, Universite Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium. Electronic address: czsolinas@gmail.com. IN - Chanza, Nieves Martinez. Medical Oncology, Universite Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium; Medical Oncology, Universite Libre de Bruxelles, Erasme Hospital, Brussels, Belgium. Electronic address: nieves.martinez-chanza@bordet.be. IN - Awada, Ahmad. Medical Oncology, Universite Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium. Electronic address: ahmad.awada@bordet.be. IN - Scartozzi, Mario. Medical Oncology, University of Cagliari, Cagliari, Italy. Electronic address: marioscartozzi@gmail.com. TI - The immune infiltrate in prostate, bladder and testicular tumors: An old friend for new challenges. [Review] SO - Cancer Treatment Reviews. 53:138-145, 2017 Feb AS - Cancer Treat Rev. 53:138-145, 2017 Feb NJ - Cancer treatment reviews PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnn, 7502030 IO - Cancer Treat. Rev. SB - Index Medicus CP - Netherlands MH - Humans MH - Immunotherapy/mt [Methods] MH - Lymphocytes, Tumor-Infiltrating MH - Male MH - Prostatic Neoplasms/im [Immunology] MH - *Prostatic Neoplasms/th [Therapy] MH - Prostatic Neoplasms, Castration-Resistant/im [Immunology] MH - Prostatic Neoplasms, Castration-Resistant/th [Therapy] MH - Testicular Neoplasms/im [Immunology] MH - *Testicular Neoplasms/th [Therapy] MH - Urinary Bladder Neoplasms/im [Immunology] MH - Urinary Bladder Neoplasms/pa [Pathology] MH - *Urinary Bladder Neoplasms/th [Therapy] KW - Bladder cancer; Immune checkpoint molecules; Immunotherapy; Prostate cancer; TIL; Testicular tumors AB - In genito-urinary tumors immunotherapy has been administered for a long time: Calmette-Guerin Bacillus as adjuvant treatment in high risk patients with non muscle invasive urothelial bladder cancer and interleukin-2 and interferon-alpha in metastatic kidney cancer. The vaccine Sipuleucel-T has been approved by United States Food and Drug Administration for the treatment of castration resistant prostate cancer patients with asymptomatic or minimally symptomatic disease, given the 22% reduction of mortality risk in this group. Recently immunotherapeutic agents targeting inhibitory immune checkpoint molecules lead to improved outcomes and lasting anti-tumor effects in a variety of hematological and solid malignancies, including urogenital tumors. The benefit from these treatments has been observed only in a proportion of subjects, raising a need in optimizing patients' selection for immune checkpoint blockade. The composition and activity of a pre-existing immune infiltrate may aid in identifying ideal candidates to immunotherapy, with possible implications for the clinical management of neoplastic diseases from earlier to later stages. AB - Copyright © 2017 Elsevier Ltd. All rights reserved. ES - 1532-1967 IL - 0305-7372 DI - S0305-7372(16)30152-9 DO - https://dx.doi.org/10.1016/j.ctrv.2016.12.004 PT - Journal Article PT - Review ID - 28113097 [pubmed] ID - S0305-7372(16)30152-9 [pii] ID - 10.1016/j.ctrv.2016.12.004 [doi] PP - ppublish PH - 2016/12/09 [received] PH - 2016/12/16 [revised] PH - 2016/12/18 [accepted] LG - English EP - 20161230 DP - 2017 Feb DC - 20170123 EZ - 2017/01/24 06:00 DA - 2017/02/12 06:00 DT - 2017/01/24 06:00 YR - 2017 ED - 20170210 RD - 20170210 UP - 20170214 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=28113097 <63. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27583876 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Zhou GW AU - Xiong Y AU - Chen S AU - Xia F AU - Li Q AU - Hu J FA - Zhou, Guo-Wu FA - Xiong, Ye FA - Chen, Si FA - Xia, Fan FA - Li, Qiang FA - Hu, Jia IN - Zhou, Guo-Wu. aDepartment of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University bDepartment of Pulmonary Medicine, Medicine, 85 Hospital of People's Liberation Army, Shanghai cDepartment of Oncology, The First Affiliated Hospital to PLA General Hospital, Beijing, P.R. China. TI - Anti-PD-1/PD-L1 antibody therapy for pretreated advanced nonsmall-cell lung cancer: A meta-analysis of randomized clinical trials. [Review] SO - Medicine. 95(35):e4611, 2016 Aug AS - Medicine (Baltimore). 95(35):e4611, 2016 Aug NJ - Medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - mny, 2985248r IO - Medicine (Baltimore) PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008560 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antigens, CD274/an [Analysis] MH - Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Carcinoma, Non-Small-Cell Lung/ch [Chemistry] MH - *Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Disease-Free Survival MH - Humans MH - Lung Neoplasms/ch [Chemistry] MH - *Lung Neoplasms/dt [Drug Therapy] MH - *Programmed Cell Death 1 Receptor/an [Analysis] MH - Randomized Controlled Trials as Topic MH - Retreatment MH - Survival Rate MH - Taxoids/ad [Administration & Dosage] AB - BACKGROUND: Anti-PD-1/PD-L1 antibody therapy is a promising clinical treatment for nonsmall-cell lung cancer (NSCLC). However, whether anti-PD-1/PD-L1 antibody therapy can provide added benefits for heavily pretreated patients with advanced NSCLC and whether the efficacy of anti-PD-1/PD-L1 antibody therapy relates to the tumor PD-L1 expression level remain controversial. Thus, this meta-analysis evaluated the efficacy and safety of anti-PD-1/PD-L1 antibody therapy for pretreated patients with advanced NSCLC. AB - METHODS: Randomized clinical trials were retrieved by searching the PubMed, EMBASE, ASCO meeting abstract, clinicaltrial.gov, and Cochrane library databases. The pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios for the overall response rate and adverse events (AEs) were calculated by STATA software. AB - RESULTS: Three randomized clinical trials involving 1141 pretreated patients with advanced NSCLC were included. These trials all compared the efficacy and safety of anti-PD-1/PD-L1 antibodies (nivolumab and MPDL3280A) with docetaxel. The results suggested that, for all patients, anti-PD-1/PD-L1 therapy could acquire a greater overall response (odds ratio = 1.50, 95% CI: 1.08-2.07, P = 0.015, P for heterogeneity [Ph] = 0.620) and longer OS (HR = 0.71, 95% CI: 0.61-0.81, P < 0.001, Ph = 0.361) than docetaxel, but not PFS (HR = 0.83, 95% CI: 0.65-1.06, P = 0.134; Ph = 0.031). Subgroup analyses according to the tumor PD-L1 expression level showed that anti-PD-1/PD-L1 therapy could significantly improve both OS and PFS in patients with high expressions of PD-L1, but not in those with low expressions. Generally, the rates of grade 3 or 4 AEs of anti-PD-1/PD-L1 therapy were significantly lower than that of docetaxel. However, the risks of pneumonitis and hypothyroidism were significantly higher. AB - CONCLUSION: Anti-PD-1/PD-L1 antibody therapy may significantly improve the outcomes for pretreated advanced NSCLC patients, with a better safety profile than docetaxel. CI - The authors have no conflicts of interest to disclose. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Taxoids) RN - 15H5577CQD (docetaxel) RN - 31YO63LBSN (nivolumab) RN - 52CMI0WC3Y (atezolizumab) ES - 1536-5964 IL - 0025-7974 DI - 00005792-201608300-00036 DO - https://dx.doi.org/10.1097/MD.0000000000004611 PT - Journal Article PT - Meta-Analysis PT - Review ID - 27583876 [pubmed] ID - 10.1097/MD.0000000000004611 [doi] ID - 00005792-201608300-00036 [pii] ID - PMC5008560 [pmc] PP - ppublish LG - English DP - 2016 Aug DC - 20160902 EZ - 2016/09/02 06:00 DA - 2017/02/09 06:00 DT - 2016/09/02 06:00 YR - 2016 ED - 20170208 RD - 20170224 UP - 20170227 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27583876 <64. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26843405 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kotteas E AU - Saif MW AU - Syrigos K FA - Kotteas, Elias FA - Saif, Muhammad Wasif FA - Syrigos, Konstantinos IN - Kotteas, Elias. Oncology Unit, 3rd Department of Internal Medicine, Sotiria General Hospital, Athens University School of Medicine, 152 Mesogeion Avenue, Athens, Greece. ilkotteas@hotmail.com. IN - Saif, Muhammad Wasif. Section of GI and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA. IN - Syrigos, Konstantinos. Oncology Unit, 3rd Department of Internal Medicine, Sotiria General Hospital, Athens University School of Medicine, 152 Mesogeion Avenue, Athens, Greece. IN - Syrigos, Konstantinos. Yale School of Medicine, New Haven, CT, USA. TI - Immunotherapy for pancreatic cancer. [Review] SO - Journal of Cancer Research & Clinical Oncology. 142(8):1795-805, 2016 Aug AS - J Cancer Res Clin Oncol. 142(8):1795-805, 2016 Aug NJ - Journal of cancer research and clinical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hl5, 7902060 IO - J. Cancer Res. Clin. Oncol. SB - Index Medicus CP - Germany MH - Cancer Vaccines/tu [Therapeutic Use] MH - Cell Transplantation MH - Humans MH - Immunotherapy/ae [Adverse Effects] MH - *Immunotherapy MH - Male MH - *Pancreatic Neoplasms/th [Therapy] KW - Antibodies; Checkpoint inhibitors; Cytokines; Immunotherapy; Pancreatic cancer; Vaccines AB - INTRODUCTION: Pancreatic cancer is among the most lethal malignancies resistant to conventional therapies. The vast majority of patients is diagnosed with advanced/metastatic disease and consequently has grim prognosis. Despite the available options with nab-paclitaxel and gemcitabine or 5-fluorouracil/leucovorin/oxaliplatin, chemotherapy offers a modest survival benefit. Targeted therapy in combination with chemotherapy has not shown significant improvement in treatment outcomes. The urgent need for new therapies has turned the spotlights on immunotherapy. Immunotherapy in pancreatic cancer recruits and activates T cells which recognize tumor-specific antigens. AB - RESULTS: Preclinical models have demonstrated that chemotherapy or targeted therapy works synergistically with immunotherapy. A growing body of evidence has already been gathered regarding the efficacy of checkpoint inhibitors, vaccines, adoptive T cell therapy, monoclonal antibodies, and cytokines in patients with pancreatic cancer. AB - CONCLUSIONS: Many ongoing trials are aiming to identify treatments which could combine efficacy with limited toxicity. In this article, we review the available data concerning multiple aspects of immunotherapy in pancreatic cancer. RN - 0 (Cancer Vaccines) ES - 1432-1335 IL - 0171-5216 DI - 10.1007/s00432-016-2119-2 DO - https://dx.doi.org/10.1007/s00432-016-2119-2 PT - Journal Article PT - Review ID - 26843405 [pubmed] ID - 10.1007/s00432-016-2119-2 [doi] ID - 10.1007/s00432-016-2119-2 [pii] PP - ppublish PH - 2015/12/23 [received] PH - 2016/01/18 [accepted] LG - English EP - 20160203 DP - 2016 Aug DC - 20160721 EZ - 2016/02/05 06:00 DA - 2017/02/09 06:00 DT - 2016/02/05 06:00 YR - 2016 ED - 20170208 RD - 20170208 UP - 20170210 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26843405 <65. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27583876 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Zhou GW AU - Xiong Y AU - Chen S AU - Xia F AU - Li Q AU - Hu J FA - Zhou, Guo-Wu FA - Xiong, Ye FA - Chen, Si FA - Xia, Fan FA - Li, Qiang FA - Hu, Jia IN - Zhou, Guo-Wu. aDepartment of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University bDepartment of Pulmonary Medicine, Medicine, 85 Hospital of People's Liberation Army, Shanghai cDepartment of Oncology, The First Affiliated Hospital to PLA General Hospital, Beijing, P.R. China. TI - Anti-PD-1/PD-L1 antibody therapy for pretreated advanced nonsmall-cell lung cancer: A meta-analysis of randomized clinical trials. [Review] SO - Medicine. 95(35):e4611, 2016 Aug AS - Medicine (Baltimore). 95(35):e4611, 2016 Aug NJ - Medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - mny, 2985248r IO - Medicine (Baltimore) PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008560 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antigens, CD274/an [Analysis] MH - Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Carcinoma, Non-Small-Cell Lung/ch [Chemistry] MH - *Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Disease-Free Survival MH - Humans MH - Lung Neoplasms/ch [Chemistry] MH - *Lung Neoplasms/dt [Drug Therapy] MH - *Programmed Cell Death 1 Receptor/an [Analysis] MH - Randomized Controlled Trials as Topic MH - Retreatment MH - Survival Rate MH - Taxoids/ad [Administration & Dosage] AB - BACKGROUND: Anti-PD-1/PD-L1 antibody therapy is a promising clinical treatment for nonsmall-cell lung cancer (NSCLC). However, whether anti-PD-1/PD-L1 antibody therapy can provide added benefits for heavily pretreated patients with advanced NSCLC and whether the efficacy of anti-PD-1/PD-L1 antibody therapy relates to the tumor PD-L1 expression level remain controversial. Thus, this meta-analysis evaluated the efficacy and safety of anti-PD-1/PD-L1 antibody therapy for pretreated patients with advanced NSCLC. AB - METHODS: Randomized clinical trials were retrieved by searching the PubMed, EMBASE, ASCO meeting abstract, clinicaltrial.gov, and Cochrane library databases. The pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios for the overall response rate and adverse events (AEs) were calculated by STATA software. AB - RESULTS: Three randomized clinical trials involving 1141 pretreated patients with advanced NSCLC were included. These trials all compared the efficacy and safety of anti-PD-1/PD-L1 antibodies (nivolumab and MPDL3280A) with docetaxel. The results suggested that, for all patients, anti-PD-1/PD-L1 therapy could acquire a greater overall response (odds ratio = 1.50, 95% CI: 1.08-2.07, P = 0.015, P for heterogeneity [Ph] = 0.620) and longer OS (HR = 0.71, 95% CI: 0.61-0.81, P < 0.001, Ph = 0.361) than docetaxel, but not PFS (HR = 0.83, 95% CI: 0.65-1.06, P = 0.134; Ph = 0.031). Subgroup analyses according to the tumor PD-L1 expression level showed that anti-PD-1/PD-L1 therapy could significantly improve both OS and PFS in patients with high expressions of PD-L1, but not in those with low expressions. Generally, the rates of grade 3 or 4 AEs of anti-PD-1/PD-L1 therapy were significantly lower than that of docetaxel. However, the risks of pneumonitis and hypothyroidism were significantly higher. AB - CONCLUSION: Anti-PD-1/PD-L1 antibody therapy may significantly improve the outcomes for pretreated advanced NSCLC patients, with a better safety profile than docetaxel. CI - The authors have no conflicts of interest to disclose. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Taxoids) RN - 15H5577CQD (docetaxel) RN - 31YO63LBSN (nivolumab) RN - 52CMI0WC3Y (atezolizumab) ES - 1536-5964 IL - 0025-7974 DI - 00005792-201608300-00036 DO - https://dx.doi.org/10.1097/MD.0000000000004611 PT - Journal Article PT - Meta-Analysis PT - Review ID - 27583876 [pubmed] ID - 10.1097/MD.0000000000004611 [doi] ID - 00005792-201608300-00036 [pii] ID - PMC5008560 [pmc] PP - ppublish LG - English DP - 2016 Aug DC - 20160902 EZ - 2016/09/02 06:00 DA - 2017/02/09 06:00 DT - 2016/09/02 06:00 YR - 2016 ED - 20170208 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27583876 <66. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27229364 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bonnet C AU - Beinse G AU - Cabel L AU - Cochereau D AU - Lavaud P AU - Rochefort P AU - Tabouret E AU - Turpin A AU - Verlingue L AU - Vicier C AU - Massard C FA - Bonnet, Clement FA - Beinse, Guillaume FA - Cabel, Luc FA - Cochereau, Delphine FA - Lavaud, Pernelle FA - Rochefort, Pauline FA - Tabouret, Emeline FA - Turpin, Anthony FA - Verlingue, Loic FA - Vicier, Cecile FA - Massard, Christophe IN - Bonnet, Clement. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Beinse, Guillaume. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Cabel, Luc. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Cochereau, Delphine. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Lavaud, Pernelle. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Rochefort, Pauline. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Tabouret, Emeline. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Turpin, Anthony. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Verlingue, Loic. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Vicier, Cecile. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Massard, Christophe. AERIO, 149, avenue du Maine, 75014 Paris, France; DITEP, Gustave-Roussy, 94805 Villejuif, France. Electronic address: christophe.massard@gustaveroussy.fr. TI - [ESMO ECCO 2015: The highlights of immunotherapy and targeted therapies]. [French] OT - ESMO ECCO 2015 : les temps forts de l'immunotherapie et des therapies ciblees. SO - Bulletin du Cancer. 103(6):594-603, 2016 Jun AS - Bull Cancer. 103(6):594-603, 2016 Jun NJ - Bulletin du cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0072416 IO - Bull Cancer SB - Index Medicus CP - France MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Austria MH - Europe MH - Humans MH - *Immunotherapy MH - Medical Oncology MH - *Molecular Targeted Therapy MH - *Neoplasms/th [Therapy] KW - Early phase studies; Essai de phases precoces; Immunotherapies; Immunotherapies; Medecine personnalisee; Personalized medicine; Targeted therapies; Therapies ciblees AB - The ESMO/ECC congress (European Society for Medical Oncology/European Cancer Congress) took place in Vienna, Austria, September 25-29. The main topic of the conference was immunotherapies especially in advanced kidney cancer with nivolumab in phase III and in metastatic lung cancer with atezolizumab in phase II. Targeted therapies were also highlighted with cabozantinib proposed in advanced renal cancer or everolimus in differenciated neuroendocrine tumors grade 1 or 2. Furthermore the current challenges remain unchanged: improving patients' care through better selection and finding biomarkers using simple samples (blood or urine). Also early phases and personalized medicine found their place in the different presentations and were highlighted largely bringing new approaches in the treatment of metastatic patients. AB - Copyright © 2016. RN - 0 (Antineoplastic Agents) ES - 1769-6917 IL - 0007-4551 DI - S0007-4551(16)30039-X DO - https://dx.doi.org/10.1016/j.bulcan.2016.04.001 PT - Congresses ID - 27229364 [pubmed] ID - S0007-4551(16)30039-X [pii] ID - 10.1016/j.bulcan.2016.04.001 [doi] PP - ppublish PH - 2016/04/01 [received] PH - 2016/04/09 [accepted] LG - French EP - 20160524 DP - 2016 Jun DC - 20160617 EZ - 2016/05/28 06:00 DA - 2017/01/26 06:00 DT - 2016/05/28 06:00 YR - 2016 ED - 20170125 RD - 20170125 UP - 20170127 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27229364 <67. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26811622 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ibrahim AM AU - Wang YH FA - Ibrahim, Andrea Marie FA - Wang, Yao-He IN - Ibrahim, Andrea Marie. Andrea Marie Ibrahim, Yao-He Wang, Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, EC1M6BQ London, United Kingdom. IN - Wang, Yao-He. Andrea Marie Ibrahim, Yao-He Wang, Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, EC1M6BQ London, United Kingdom. TI - Viro-immune therapy: A new strategy for treatment of pancreatic cancer. [Review] SO - World Journal of Gastroenterology. 22(2):748-63, 2016 Jan 14 AS - World J Gastroenterol. 22(2):748-63, 2016 Jan 14 NJ - World journal of gastroenterology PI - Journal available in: Print PI - Citation processed from: Internet JC - 100883448 IO - World J. Gastroenterol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716074 SB - Index Medicus CP - United States MH - Animals MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Cancer Vaccines/tu [Therapeutic Use] MH - Carcinoma, Pancreatic Ductal/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/th [Therapy] MH - Carcinoma, Pancreatic Ductal/vi [Virology] MH - Combined Modality Therapy MH - Host-Pathogen Interactions MH - Humans MH - *Immunotherapy/mt [Methods] MH - Molecular Targeted Therapy MH - *Oncolytic Virotherapy MH - Oncolytic Viruses/im [Immunology] MH - *Oncolytic Viruses/py [Pathogenicity] MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/th [Therapy] MH - *Pancreatic Neoplasms/vi [Virology] MH - Treatment Outcome MH - Tumor Escape MH - Tumor Microenvironment KW - Anti-cytotoxic T-lymphocyte-associate protein 4; Anti-programmed death receptor 1; Anti-programmed death receptor ligand 1; Cancer vaccine; Immune checkpoint blockade inhibitors; Immunotherapy; Oncolytic viruses; Pancreatic cancer; Pancreatic ductal adenocarcinoma AB - Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses (TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1 (PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer. RN - 0 (Antineoplastic Agents) RN - 0 (Cancer Vaccines) ES - 2219-2840 IL - 1007-9327 DO - https://dx.doi.org/10.3748/wjg.v22.i2.748 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 26811622 [pubmed] ID - 10.3748/wjg.v22.i2.748 [doi] ID - PMC4716074 [pmc] PP - ppublish PH - 2015/07/29 [received] PH - 2015/10/26 [revised] PH - 2015/12/12 [accepted] LG - English DP - 2016 Jan 14 DC - 20160126 EZ - 2016/01/27 06:00 DA - 2016/01/27 06:00 DT - 2016/01/27 06:00 YR - 2016 ED - 20170117 RD - 20170117 UP - 20170119 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26811622 <68. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26198822 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Narita T AU - Oiso N AU - Taketomo Y AU - Okahashi K AU - Yamauchi K AU - Sato M AU - Uchida S AU - Matsuda H AU - Kawada A FA - Narita, Tomohiko FA - Oiso, Naoki FA - Taketomo, Yasunori FA - Okahashi, Kazunori FA - Yamauchi, Kohei FA - Sato, Masako FA - Uchida, Shusuke FA - Matsuda, Hiromasa FA - Kawada, Akira IN - Narita, Tomohiko. Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. IN - Oiso, Naoki. Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. IN - Taketomo, Yasunori. Department of Endocrinology, Metabolism and Diabetes, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. IN - Okahashi, Kazunori. Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. IN - Yamauchi, Kohei. Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. IN - Sato, Masako. Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. IN - Uchida, Shusuke. Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. IN - Matsuda, Hiromasa. Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. IN - Kawada, Akira. Department of Dermatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. TI - Serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab. SO - Journal of Dermatology. 43(2):210-4, 2016 Feb AS - J Dermatol. 43(2):210-4, 2016 Feb NJ - The Journal of dermatology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hz7, 7600545 IO - J. Dermatol. SB - Index Medicus CP - England MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Female MH - Hashimoto Disease/bl [Blood] MH - *Hashimoto Disease/et [Etiology] MH - Hashimoto Disease/im [Immunology] MH - Humans MH - Male MH - Melanoma/sc [Secondary] MH - Melanoma/th [Therapy] MH - Thyroid Gland/dg [Diagnostic Imaging] MH - Thyroid Hormones/bl [Blood] MH - Ultrasonography KW - Hashimoto disease; insulin-dependent diabetes; malignant melanoma; nivolumab; ultrasonography; vitiligo AB - Nivolumab, a blockade of programmed cell death 1, is now administrated for advanced malignant melanomas. Nivolumab-associated adverse events include organ-specific autoimmune disorders; autoimmune thyroid disease, vitiligo and insulin-dependent diabetes. However, predisposed persons are currently unknown. Here, we report serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab: one with Hashimoto disease and another with probable subclinical Hashimoto disease. We should verify if nivolumab-related hypothyroidism and hyperthyroidism are predisposed to occur in euthyroid individuals with subclinical autoimmune thyroid disease. AB - Copyright © 2015 Japanese Dermatological Association. RN - 0 (Antibodies, Monoclonal) RN - 0 (Thyroid Hormones) RN - 31YO63LBSN (nivolumab) ES - 1346-8138 IL - 0385-2407 DO - https://dx.doi.org/10.1111/1346-8138.13028 PT - Case Reports PT - Journal Article ID - 26198822 [pubmed] ID - 10.1111/1346-8138.13028 [doi] PP - ppublish PH - 2015/04/22 [received] PH - 2015/06/12 [accepted] LG - English EP - 20150722 DP - 2016 Feb DC - 20160127 EZ - 2015/07/23 06:00 DA - 2015/07/23 06:00 DT - 2015/07/23 06:00 YR - 2016 ED - 20170117 RD - 20170117 UP - 20170119 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26198822 <69. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26968587 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Mandai M AU - Hamanishi J AU - Abiko K AU - Matsumura N AU - Baba T AU - Konishi I FA - Mandai, Masaki FA - Hamanishi, Junzo FA - Abiko, Kaoru FA - Matsumura, Noriomi FA - Baba, Tsukasa FA - Konishi, Ikuo IN - Mandai, Masaki. Department of Obstetrics and Gynecology, Faculty of Medicine, Kinki University, Osaka-Sayama, Japan. mandai@med.kindai.ac.jp. IN - Hamanishi, Junzo. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Abiko, Kaoru. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Matsumura, Noriomi. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Baba, Tsukasa. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Konishi, Ikuo. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. TI - Anti-PD-L1/PD-1 immune therapies in ovarian cancer: basic mechanism and future clinical application. [Review] SO - International Journal of Clinical Oncology. 21(3):456-61, 2016 Jun AS - Int J Clin Oncol. 21(3):456-61, 2016 Jun NJ - International journal of clinical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9616295 IO - Int. J. Clin. Oncol. SB - Index Medicus CP - Japan MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antigens, CD274/im [Immunology] MH - Antigens, CD274/me [Metabolism] MH - Female MH - Humans MH - *Immunotherapy MH - *Ovarian Neoplasms/th [Therapy] MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - Signal Transduction MH - Tumor Escape/im [Immunology] MH - Tumor Microenvironment/im [Immunology] KW - Immune checkpoint inhibitor; Immunotherapy; Ovarian cancer; PD-L1/PD-1 AB - Tumor immune therapy, especially anti-programmed cell death ligand-1/programmed cell death-1 (PD-L1/PD-1) treatment, is currently the focus of substantial attention. Ovarian cancer is the leading cause of mortality from gynecological malignancies, and novel treatment modalities, including immune therapy, are needed. However, a basic understanding of tumor immunity associated with the PD-L1/PD-1 signal has only recently emerged. In this review, we first discuss the importance of local tumor immunity, which affects the clinical outcome of ovarian cancer. We subsequently provide an overview of the basic findings regarding how the PD-L1/PD-1 signal influences local tumor immunity in ovarian cancer. Finally, we discuss what is needed to apply immune therapy in future clinical medicine. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1437-7772 IL - 1341-9625 DI - 10.1007/s10147-016-0968-y DO - https://dx.doi.org/10.1007/s10147-016-0968-y PT - Journal Article PT - Review ID - 26968587 [pubmed] ID - 10.1007/s10147-016-0968-y [doi] ID - 10.1007/s10147-016-0968-y [pii] PP - ppublish PH - 2016/02/02 [received] PH - 2016/02/22 [accepted] LG - English EP - 20160311 DP - 2016 Jun DC - 20160610 EZ - 2016/03/13 06:00 DA - 2017/01/12 06:00 DT - 2016/03/13 06:00 YR - 2016 ED - 20170111 RD - 20170112 UP - 20170113 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26968587 <70. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27090545 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - McMillen B AU - Dhillon MS AU - Yong-Yow S FA - McMillen, Brock FA - Dhillon, Manvinder Shelley FA - Yong-Yow, Sabrina IN - McMillen, Brock. Department of Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. IN - Dhillon, Manvinder Shelley. Department of Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. IN - Yong-Yow, Sabrina. Department of Family Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. TI - A rare case of thyroid storm. SO - BMJ Case Reports. 2016:10.1136/bcr-2016-214603, 2016 Apr 18 AS - BMJ Case Rep. 2016:10.1136/bcr-2016-214603, 2016 Apr 18 NJ - BMJ case reports PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101526291 IO - BMJ Case Rep SB - Index Medicus CP - England MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] MH - Female MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - *Thyroid Crisis/ci [Chemically Induced] MH - Young Adult AB - Thyroid storm is a rare and life-threatening state of thyroid hormone excess. Rapid recognition of thyroid storm is key to decreasing the morbidity and mortality of this condition. Clinical manifestations of thyroid storm include unexplained weight loss, hyperactivity and irritability. The most common causes of thyrotoxicosis are Graves' disease, toxic multinodular goitre and toxic adenoma. We present a rare case of thyroid storm induced by dual nivolumab and ipilimumab immunotherapy in a patient receiving treatment for advanced melanoma. In this case, our patient was admitted for thyroid storm 1 month after initiating treatment with nivolumab and ipilimumab immunotherapy. The patient was treated with beta-blockers, antithyroid medications and systemic steroids resulting in an improvement in thyroid function testing and symptoms. AB - Copyright 2016 BMJ Publishing Group Ltd. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) ES - 1757-790X IL - 1757-790X DI - bcr2016214603 DI - bcr-2016-214603 DO - https://dx.doi.org/10.1136/bcr-2016-214603 PT - Case Reports PT - Journal Article ID - 27090545 [pubmed] ID - bcr-2016-214603 [pii] ID - 10.1136/bcr-2016-214603 [doi] PP - epublish LG - English EP - 20160418 DP - 2016 Apr 18 DC - 20160419 EZ - 2016/04/20 06:00 DA - 2017/01/05 06:00 DT - 2016/04/20 06:00 YR - 2016 ED - 20170104 RD - 20170105 UP - 20170106 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27090545 <71. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27628544 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Nakamura Y AU - Teramoto Y AU - Asami Y AU - Matsuya T AU - Yamamoto A FA - Nakamura, Yasuhiro FA - Teramoto, Yukiko FA - Asami, Yuri FA - Matsuya, Taisuke FA - Yamamoto, Akifumi IN - Nakamura, Yasuhiro. Dept. of Skin Oncology/Dermatology, Saitama Medical University International Medical Center. TI - [Immune Checkpoint Inhibitors for Advanced Melanoma - Evidences and Future Perspectives]. [Japanese] SO - Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy]. 43(9):1036-40, 2016 Sep AS - Gan To Kagaku Ryoho. 43(9):1036-40, 2016 Sep NJ - Gan to kagaku ryoho. Cancer & chemotherapy PI - Journal available in: Print PI - Citation processed from: Print JC - 7810034, 6t8 IO - Gan To Kagaku Ryoho SB - Index Medicus CP - Japan MH - Antigens, CD274/im [Immunology] MH - Clinical Trials as Topic MH - Humans MH - *Melanoma/im [Immunology] MH - Molecular Targeted Therapy MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Signal Transduction AB - Recently developed immune checkpoint inhibitors, such as anti-PD-1 antibodies, have shown a clear improvement in clinical efficacy compared with conventional cytotoxic chemotherapy in the treatment of patients with advanced melanoma. Treatment with anti-PD-1 antibodies has resulted in improved objective response rates, longer durations of response, and longer overall survival rates. Although the incidence rate of adverse events associated with anti-PD-1 antibodies is lower than that associated with cytotoxic agents, characteristic severe adverse events such as pneumonia, endocrinopathy, and colitis can occur. A recent clinical trial that evaluated the utility of an anti-PD-1 antibody in combination with an anti-CTLA-4 antibody reported that the treatment enhanced clinical efficacy in terms of response rate and progression-free survival. However, the incidence of adverse events and treatment discontinuation also increased. For optimal selection of immune checkpoint inhibitors for treating patients with advanced melanoma, biomarkers capable of predicting clinical efficacy, prognosis, and adverse events in each patient need to be identified. In addition, novel combination therapies, including immune checkpoint inhibitors and MAP kinase pathway-targeting agents, should result in more favorable clinical responses and prolonged overall survival rates. RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) IS - 0385-0684 IL - 0385-0684 PT - Journal Article ID - 27628544 [pubmed] PP - ppublish LG - Japanese DP - 2016 Sep DC - 20160916 EZ - 2016/09/16 06:00 DA - 2016/12/17 06:00 DT - 2016/09/16 06:00 YR - 2016 ED - 20161216 RD - 20161217 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27628544 <72. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26892612 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Antonilli M AU - Rahimi H AU - Visconti V AU - Napoletano C AU - Ruscito I AU - Zizzari IG AU - Caponnetto S AU - Barchiesi G AU - Iadarola R AU - Pierelli L AU - Rughetti A AU - Bellati F AU - Panici PB AU - Nuti M FA - Antonilli, Morena FA - Rahimi, Hassan FA - Visconti, Valeria FA - Napoletano, Chiara FA - Ruscito, Ilary FA - Zizzari, Ilaria Grazia FA - Caponnetto, Salvatore FA - Barchiesi, Giacomo FA - Iadarola, Roberta FA - Pierelli, Luca FA - Rughetti, Aurelia FA - Bellati, Filippo FA - Panici, Pierluigi Benedetti FA - Nuti, Marianna IN - Antonilli, Morena. Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Rahimi, Hassan. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Visconti, Valeria. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Napoletano, Chiara. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Ruscito, Ilary. Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Zizzari, Ilaria Grazia. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Caponnetto, Salvatore. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Barchiesi, Giacomo. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Iadarola, Roberta. Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Pierelli, Luca. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Rughetti, Aurelia. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Bellati, Filippo. Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Panici, Pierluigi Benedetti. Department of Gynecology, Obstetrics and Urology, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. IN - Nuti, Marianna. Department of Experimental Medicine, 'Sapienza' University of Rome, Policlinico Umberto I, 00161 Rome, Italy. TI - Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial. SO - International Journal of Oncology. 48(4):1369-78, 2016 Apr AS - Int J Oncol. 48(4):1369-78, 2016 Apr NJ - International journal of oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cx5, 9306042 IO - Int. J. Oncol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777599 SB - Index Medicus CP - Greece MH - Adult MH - Aged MH - *Breast Neoplasms/dt [Drug Therapy] MH - Breast Neoplasms/im [Immunology] MH - Breast Neoplasms/pa [Pathology] MH - Cancer Vaccines/ad [Administration & Dosage] MH - Cancer Vaccines/im [Immunology] MH - *Carcinoembryonic Antigen/ad [Administration & Dosage] MH - Carcinoembryonic Antigen/im [Immunology] MH - Disease-Free Survival MH - Female MH - Flow Cytometry MH - HLA-A2 Antigen/ge [Genetics] MH - HLA-A2 Antigen/im [Immunology] MH - Humans MH - Immunotherapy/mt [Methods] MH - Lymph Nodes/im [Immunology] MH - Lymph Nodes/pa [Pathology] MH - Middle Aged MH - *Mucin-1/ad [Administration & Dosage] MH - Mucin-1/im [Immunology] MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/pa [Pathology] MH - Peptide Fragments/ad [Administration & Dosage] MH - Peptide Fragments/im [Immunology] MH - *Receptor, ErbB-2/ad [Administration & Dosage] MH - Receptor, ErbB-2/im [Immunology] MH - T-Lymphocytes/im [Immunology] AB - Vaccination with priming and expansion of tumour reacting T cells is an important therapeutic option to be used in combination with novel checkpoint inhibitors to increase the specificity of the T cell infiltrate and the efficacy of the treatment. In this phase I/II study, 14 high-risk disease-free ovarian (OC) and breast cancer (BC) patients after completion of standard therapies were vaccinated with MUC1, ErbB2 and carcinoembryonic antigen (CEA) HLA-A2+-restricted peptides and Montanide. Patients were subjected to 6 doses of vaccine every two weeks and a recall dose after 3 months. ECOG grade 2 toxicity was observed at the injection site. Eight out of 14 patients showed specific CD8+ T cells to at least one antigen. None of 4 patients vaccinated for compassionate use showed a CD8 activation. An OC patient who suffered from a lymph nodal recurrence, showed specific anti-ErbB2 CD8+ T cells in the bulky aortic lymph nodes suggesting homing of the activated T cells. Results confirm that peptide vaccination strategy is feasible, safe and well tolerated. In particular OC patients appear to show a higher response rate compared to BC patients. Vaccination generates a long-lasting immune response, which is strongly enhanced by recall administrations. The clinical outcome of patients enrolled in the trial appears favourable, having registered no deceased patients with a minimum follow-up of 8 years. These promising data, in line with the results of similar studies, the high compliance of patients observed and the favourable toxicity profile, support future trials of peptide vaccination in clinically disease-free patients who have completed standard treatments. RN - 0 (Cancer Vaccines) RN - 0 (Carcinoembryonic Antigen) RN - 0 (HLA-A2 Antigen) RN - 0 (MUC1 protein, human) RN - 0 (Mucin-1) RN - 0 (Peptide Fragments) RN - EC 2-7-10-1 (ERBB2 protein, human) RN - EC 2-7-10-1 (Receptor, ErbB-2) ES - 1791-2423 IL - 1019-6439 DO - https://dx.doi.org/10.3892/ijo.2016.3386 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26892612 [pubmed] ID - 10.3892/ijo.2016.3386 [doi] ID - PMC4777599 [pmc] PP - ppublish PH - 2015/11/05 [received] PH - 2016/01/13 [accepted] LG - English EP - 20160208 DP - 2016 Apr DC - 20160407 EZ - 2016/02/20 06:00 DA - 2016/12/17 06:00 DT - 2016/02/20 06:00 YR - 2016 ED - 20161216 RD - 20161217 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26892612 <73. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26890478 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Parsels LA AU - Tanska DM AU - Parsels JD AU - Zabludoff SD AU - Cuneo KC AU - Lawrence TS AU - Maybaum J AU - Morgan MA FA - Parsels, Leslie A FA - Tanska, Daria M FA - Parsels, Joshua D FA - Zabludoff, Sonya D FA - Cuneo, Kyle C FA - Lawrence, Theodore S FA - Maybaum, Jonathan FA - Morgan, Meredith A IN - Parsels, Leslie A. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Parsels, Leslie A. b Department of Pharmacology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Tanska, Daria M. b Department of Pharmacology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Parsels, Joshua D. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Parsels, Joshua D. b Department of Pharmacology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Zabludoff, Sonya D. c AstraZeneca R&D Boston , Waltham , MA , USA. IN - Zabludoff, Sonya D. d Zabludoff Consulting San Diego , CA , USA. IN - Cuneo, Kyle C. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Lawrence, Theodore S. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Maybaum, Jonathan. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Maybaum, Jonathan. b Department of Pharmacology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Morgan, Meredith A. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. TI - Dissociation of gemcitabine chemosensitization by CHK1 inhibition from cell cycle checkpoint abrogation and aberrant mitotic entry. SO - Cell Cycle. 15(5):730-9, 2016 AS - Cell Cycle. 15(5):730-9, 2016 NJ - Cell cycle (Georgetown, Tex.) PI - Journal available in: Print PI - Citation processed from: Internet JC - 101137841 IO - Cell Cycle PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845922 SB - Index Medicus CP - United States MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - Cell Cycle Checkpoints MH - Cell Line, Tumor MH - *Checkpoint Kinase 1/ai [Antagonists & Inhibitors] MH - Cyclin B1/me [Metabolism] MH - DNA Damage MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Drug Screening Assays, Antitumor MH - G2 Phase Cell Cycle Checkpoints MH - Humans MH - Mitosis MH - Nocodazole/pd [Pharmacology] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - *Thiophenes/pd [Pharmacology] MH - *Urea/aa [Analogs & Derivatives] MH - Urea/pd [Pharmacology] KW - AZD7762; CHK1; aberrant mitotic entry; checkpoint abrogation; gemcitabine; pancreatic cancer AB - In order to determine the relative contribution of checkpoint abrogation and subsequent aberrant mitotic entry to gemcitabine chemosensitization by CHK1 inhibition, we established a model utilizing the CDK inhibitors roscovitine or purvalanol A to re-establish cell cycle arrest and prevent aberrant mitotic entry in pancreatic cancer cells treated with gemcitabine and the CHK inhibitor AZD7762. In this study, we report that the extent of aberrant mitotic entry, as determined by flow cytometry for the mitotic marker phospho-Histone H3 (Ser10), did not reflect the relative sensitivities of pancreatic cancer cell lines to gemcitabine chemosensitization by AZD7762. In addition, re-establishing gemcitabine-induced cell cycle arrest either pharmacologically, with roscovitine or purvalanol A, or genetically, with cyclin B1 siRNA, did not inhibit chemosensitization uniformly across the cell lines. Furthermore, we found that AZD7762 augmented high-intensity gammaH2AX signaling in gemcitabine-treated cells, suggesting the presence of replication stress when CHK1 is inhibited. Finally, the ability of roscovitine to prevent chemosensitization correlated with its ability to inhibit AZD7762-induced high-intensity gammaH2AX, but not aberrant pHH3, suggesting that the effects of AZD7762 on DNA replication or repair rather than aberrant mitotic entry determine gemcitabine chemosensitization in pancreatic cancer cells. RN - 0 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (CCNB1 protein, human) RN - 0 (Cyclin B1) RN - 0 (Thiophenes) RN - 0W860991D6 (Deoxycytidine) RN - 8W8T17847W (Urea) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - SH1WY3R615 (Nocodazole) ES - 1551-4005 IL - 1551-4005 DO - https://dx.doi.org/10.1080/15384101.2016.1148841 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26890478 [pubmed] ID - 10.1080/15384101.2016.1148841 [doi] ID - PMC4845922 [pmc] PP - ppublish PH - 2017/02/18 [pmc-release] GI - No: R01 CA163895 Organization: (CA) *NCI NIH HHS* Country: United States No: P50CA130810 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA163895 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2016 DC - 20160331 EZ - 2016/02/19 06:00 DA - 2016/12/16 06:00 DT - 2016/02/19 06:00 YR - 2016 ED - 20161215 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26890478 <74. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26890478 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Parsels LA AU - Tanska DM AU - Parsels JD AU - Zabludoff SD AU - Cuneo KC AU - Lawrence TS AU - Maybaum J AU - Morgan MA FA - Parsels, Leslie A FA - Tanska, Daria M FA - Parsels, Joshua D FA - Zabludoff, Sonya D FA - Cuneo, Kyle C FA - Lawrence, Theodore S FA - Maybaum, Jonathan FA - Morgan, Meredith A IN - Parsels, Leslie A. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Parsels, Leslie A. b Department of Pharmacology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Tanska, Daria M. b Department of Pharmacology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Parsels, Joshua D. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Parsels, Joshua D. b Department of Pharmacology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Zabludoff, Sonya D. c AstraZeneca R&D Boston , Waltham , MA , USA. IN - Zabludoff, Sonya D. d Zabludoff Consulting San Diego , CA , USA. IN - Cuneo, Kyle C. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Lawrence, Theodore S. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Maybaum, Jonathan. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Maybaum, Jonathan. b Department of Pharmacology , University of Michigan Medical School , Ann Arbor , MI , USA. IN - Morgan, Meredith A. a Department of Radiation Oncology , University of Michigan Medical School , Ann Arbor , MI , USA. TI - Dissociation of gemcitabine chemosensitization by CHK1 inhibition from cell cycle checkpoint abrogation and aberrant mitotic entry. SO - Cell Cycle. 15(5):730-9, 2016 AS - Cell Cycle. 15(5):730-9, 2016 NJ - Cell cycle (Georgetown, Tex.) PI - Journal available in: Print PI - Citation processed from: Internet JC - 101137841 IO - Cell Cycle PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845922 SB - Index Medicus CP - United States MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - Cell Cycle Checkpoints MH - Cell Line, Tumor MH - *Checkpoint Kinase 1/ai [Antagonists & Inhibitors] MH - Cyclin B1/me [Metabolism] MH - DNA Damage MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Drug Screening Assays, Antitumor MH - G2 Phase Cell Cycle Checkpoints MH - Humans MH - Mitosis MH - Nocodazole/pd [Pharmacology] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - *Thiophenes/pd [Pharmacology] MH - *Urea/aa [Analogs & Derivatives] MH - Urea/pd [Pharmacology] KW - AZD7762; CHK1; aberrant mitotic entry; checkpoint abrogation; gemcitabine; pancreatic cancer AB - In order to determine the relative contribution of checkpoint abrogation and subsequent aberrant mitotic entry to gemcitabine chemosensitization by CHK1 inhibition, we established a model utilizing the CDK inhibitors roscovitine or purvalanol A to re-establish cell cycle arrest and prevent aberrant mitotic entry in pancreatic cancer cells treated with gemcitabine and the CHK inhibitor AZD7762. In this study, we report that the extent of aberrant mitotic entry, as determined by flow cytometry for the mitotic marker phospho-Histone H3 (Ser10), did not reflect the relative sensitivities of pancreatic cancer cell lines to gemcitabine chemosensitization by AZD7762. In addition, re-establishing gemcitabine-induced cell cycle arrest either pharmacologically, with roscovitine or purvalanol A, or genetically, with cyclin B1 siRNA, did not inhibit chemosensitization uniformly across the cell lines. Furthermore, we found that AZD7762 augmented high-intensity gammaH2AX signaling in gemcitabine-treated cells, suggesting the presence of replication stress when CHK1 is inhibited. Finally, the ability of roscovitine to prevent chemosensitization correlated with its ability to inhibit AZD7762-induced high-intensity gammaH2AX, but not aberrant pHH3, suggesting that the effects of AZD7762 on DNA replication or repair rather than aberrant mitotic entry determine gemcitabine chemosensitization in pancreatic cancer cells. RN - 0 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (CCNB1 protein, human) RN - 0 (Cyclin B1) RN - 0 (Thiophenes) RN - 0W860991D6 (Deoxycytidine) RN - 8W8T17847W (Urea) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - SH1WY3R615 (Nocodazole) ES - 1551-4005 IL - 1551-4005 DO - https://dx.doi.org/10.1080/15384101.2016.1148841 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26890478 [pubmed] ID - 10.1080/15384101.2016.1148841 [doi] ID - PMC4845922 [pmc] PP - ppublish GI - No: R01 CA163895 Organization: (CA) *NCI NIH HHS* Country: United States No: P50CA130810 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA163895 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2016 DC - 20160331 EZ - 2016/02/19 06:00 DA - 2016/12/16 06:00 DT - 2016/02/19 06:00 YR - 2016 ED - 20161215 RD - 20170218 UP - 20170221 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26890478 <75. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25760920 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Papavasileiou E AU - Prasad S AU - Freitag SK AU - Sobrin L AU - Lobo AM FA - Papavasileiou, Evangelia FA - Prasad, Sashank FA - Freitag, Suzanne K FA - Sobrin, Lucia FA - Lobo, Ann-Marie IN - Papavasileiou, Evangelia. a Department of Ophthalmology , Harvard Medical School, Massachusetts Eye and Ear Infirmary , Boston , Massachusetts , USA and. IN - Prasad, Sashank. b Department of Neurology , Harvard Medical School, Brigham and Women's Hospital , Boston , Massachusetts , USA. IN - Freitag, Suzanne K. a Department of Ophthalmology , Harvard Medical School, Massachusetts Eye and Ear Infirmary , Boston , Massachusetts , USA and. IN - Sobrin, Lucia. a Department of Ophthalmology , Harvard Medical School, Massachusetts Eye and Ear Infirmary , Boston , Massachusetts , USA and. IN - Lobo, Ann-Marie. a Department of Ophthalmology , Harvard Medical School, Massachusetts Eye and Ear Infirmary , Boston , Massachusetts , USA and. TI - Ipilimumab-induced Ocular and Orbital Inflammation--A Case Series and Review of the Literature. [Review] SO - Ocular Immunology & Inflammation. 24(2):140-6, 2016 AS - Ocul Immunol Inflamm. 24(2):140-6, 2016 NJ - Ocular immunology and inflammation PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cq1, 9312169 IO - Ocul. Immunol. Inflamm. SB - Index Medicus CP - England MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - CTLA-4 Antigen/im [Immunology] MH - *Corneal Ulcer/ci [Chemically Induced] MH - Corneal Ulcer/di [Diagnosis] MH - Corneal Ulcer/dt [Drug Therapy] MH - Female MH - Glucocorticoids/tu [Therapeutic Use] MH - Humans MH - Male MH - Middle Aged MH - *Orbital Cellulitis/ci [Chemically Induced] MH - Orbital Cellulitis/di [Diagnosis] MH - Orbital Cellulitis/dt [Drug Therapy] MH - Retrospective Studies MH - Tomography, X-Ray Computed MH - *Uveitis/ci [Chemically Induced] MH - Uveitis/di [Diagnosis] MH - Uveitis/dt [Drug Therapy] KW - Autoimmune adverse events; CTLA-4 inhibitors; eye and orbit complications; ipilimumab; melanoma AB - PURPOSE: Ipilimumab, a monoclonal antibody directed against the immune protein cytotoxic T-lymphocyte antigen-4 (CTLA-4), characteristically induces side effects called "immune-related adverse events" (IRAE). Although ophthalmic involvement is rare, we report 7 cases of eye and orbit complications related to ipilimumab therapy. AB - METHODS: We performed a retrospective review of patients with metastatic melanoma who developed ipilimumab-related ocular or orbital inflammation who were seen at our institutions. AB - RESULTS: Seven patients were identified: 4 patients had orbital inflammation, 2 had uveitis, and 1 had peripheral ulcerative keratitis. Four patients developed inflammation after the second ipilimumab infusion, 2 after the third infusion and 1 after the first infusion. All 4 patients with orbital inflammation were treated with systemic corticosteroids. Two patients with uveitis were treated with topical steroids, but were also treated with systemic corticosteroids for other IRAE, including colitis and hypophysitis. The patient with keratitis was treated with topical corticosteroids alone with resolution of inflammation. All 7 patients discontinued ipilimumab therapy, 5 due to systemic IRAE and 2 due to tumor progression. Five of 7 patients had tumor progression on ipilimumab therapy. AB - CONCLUSIONS: Ocular and orbital inflammation may occur in patients with metastatic melanoma receiving ipilimumab, is frequently accompanied by other IRAEs, and resolves with corticosteroid treatment, often leaving no long-term sequelae. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Glucocorticoids) RN - 6T8C155666 (ipilimumab) ES - 1744-5078 IL - 0927-3948 DO - https://dx.doi.org/10.3109/09273948.2014.1001858 PT - Case Reports PT - Journal Article PT - Review ID - 25760920 [pubmed] ID - 10.3109/09273948.2014.1001858 [doi] PP - ppublish LG - English EP - 20150311 DP - 2016 DC - 20160414 EZ - 2015/03/12 06:00 DA - 2016/12/15 06:00 DT - 2015/03/12 06:00 YR - 2016 ED - 20161214 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25760920 <76. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26186958 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Faje A FA - Faje, Alexander IN - Faje, Alexander. BUL 457, Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. afaje@partners.org. TI - Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. [Review] SO - Pituitary. 19(1):82-92, 2016 Feb AS - Pituitary. 19(1):82-92, 2016 Feb NJ - Pituitary PI - Journal available in: Print PI - Citation processed from: Internet JC - dsi, 9814578 IO - Pituitary SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - CTLA-4 Antigen/me [Metabolism] MH - Humans MH - *Hypophysitis/me [Metabolism] MH - *Hypophysitis/th [Therapy] MH - *Immunotherapy/mt [Methods] KW - CTLA-4; Hypophysitis; Hypopituitarism; Ipilimumab AB - INTRODUCTION: Advances in immunotherapy have transformed the management of metastatic melanoma and generated encouraging results in the treatment of other malignancies. Autoimmune side effects from these agents, termed immune-related adverse events (IRAEs), are diverse and can include multiple endocrinopathies. Ipilimumab-induced hypophysitis (IH) is a recently recognized endocrine IRAE. AB - METHODS: This review summarizes published data and experience from our center on the incidence, presentation and management, and proposed mechanisms for immunotherapy-related hypophysitis, with a focus on patients treated with ipilimumab (Ipi). AB - CONCLUSION: Hypophysitis occurs in a significant minority of patients treated with Ipi, in contrast to the relative rarity of idiopathic autoimmune hypophysitis or hypophysitis after treatment with other immunotherapies. Recently published cohorts have described the clinical presentation and management of IH and longitudinal outcomes in these patients. Additional studies with Ipi and other emerging agents have helped identify potential risk factors for the development of immunotherapy-related hypophysitis and possible underlying mechanisms for IH. Clarification of the mechanism(s) for IH may enhance our understanding of idiopathic autoimmune hypophysitis and could have potential therapeutic applications. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) ES - 1573-7403 IL - 1386-341X DI - 10.1007/s11102-015-0671-4 DO - https://dx.doi.org/10.1007/s11102-015-0671-4 PT - Journal Article PT - Review ID - 26186958 [pubmed] ID - 10.1007/s11102-015-0671-4 [doi] ID - 10.1007/s11102-015-0671-4 [pii] PP - ppublish LG - English DP - 2016 Feb DC - 20160113 EZ - 2015/07/19 06:00 DA - 2016/12/15 06:00 DT - 2015/07/19 06:00 YR - 2016 ED - 20161213 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26186958 <77. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26942589 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hardwick N AU - Frankel PH AU - Cristea M FA - Hardwick, Nicola FA - Frankel, Paul H FA - Cristea, Mihaela IN - Hardwick, Nicola. Department of Experimental Therapeutics, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA. IN - Frankel, Paul H. Division of Biostatistics, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA. IN - Cristea, Mihaela. Department of Medical Oncology, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA. mcristea@coh.org. TI - New Approaches for Immune Directed Treatment for Ovarian Cancer. [Review] SO - Current Treatment Options in Oncology. 17(3):14, 2016 Mar AS - Curr Treat Options Oncol. 17(3):14, 2016 Mar NJ - Current treatment options in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - 100900946 IO - Curr Treat Options Oncol SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antigens, CD274/im [Immunology] MH - Cancer Vaccines/im [Immunology] MH - *Cancer Vaccines/tu [Therapeutic Use] MH - Clinical Trials as Topic MH - Disease-Free Survival MH - Female MH - Humans MH - Immunosuppression MH - *Immunotherapy MH - Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/pa [Pathology] MH - *Ovarian Neoplasms/th [Therapy] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - T-Lymphocytes/de [Drug Effects] MH - T-Lymphocytes/im [Immunology] KW - Adoptive T cell transfer; Cancer vaccine; Immunotherapy; Monoclonal antibodies check point inhibitors; Ovarian cancer AB - OPINION STATEMENT: The immune system plays an active role in the pathogenesis of ovarian cancer (OC), as well as in the mechanisms of disease progression and overall survival (OS). Immunotherapy in gynecological cancers could help to revert immunosuppression and lymphocyte depletion due to prior treatments. Current immunotherapies for ovarian cancer, like all cancer immunotherapy, are based on either stimulating the immune system or reverting immune suppression. Several approaches have been used, including therapeutic vaccines, monoclonal antibodies; checkpoint inhibitors and adoptive T cell transfer. Most of these therapies are still in early-phase testing (phase I and II) for ovarian cancer, but the initial data in ovarian cancer and successful use in other types of cancers suggests some of these approaches may ultimately prove useful for ovarian cancer as well. Ovarian cancer vaccines have shown only a modest benefit in ovarian cancer when used as monotherapy, but these agents may be able to enhance antitumor activity when combined with chemotherapy, checkpoint inhibitors, or other immunotherapies. Monoclonal antibodies have been explored in ovarian cancer but despite encouraging phase II data, randomized studies failed to demonstrate significant clinical benefit. Check point inhibitors have promising activity in several solid tumors and have demonstrated a favorable toxicity profile. Data from early clinical trials utilizing PD1 and PD-L1 inhibitors showed encouraging results. Ongoing clinical trials are evaluating the role of check point inhibitors in combination with chemotherapy. Adoptive T cell transfer involves the infusion of ex vivo activated and expanded tumor specific T cells, using various sources and types of T cells. While this approach has been explored in several hematologic malignancies, it constitutes early research in ovarian cancer. Immunotherapy remains investigational in ovarian cancer and the benefit of this approach in improving progression-free survival (PFS) or OS is unknown. Previous clinical trials have not selected patients based on biomarkers and this may explain the negative results. We expect to discover that tumor response will relate to the patient's immune features and specific tumor characteristics. We are only beginning to realize the potential of immunotherapy for ovarian cancer patients, and one goal of future clinical trials will be to identify subsets of patient based on histologic, molecular, and immune characteristics. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (Cancer Vaccines) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1534-6277 IL - 1534-6277 DI - 10.1007/s11864-016-0389-1 DO - https://dx.doi.org/10.1007/s11864-016-0389-1 PT - Journal Article PT - Review ID - 26942589 [pubmed] ID - 10.1007/s11864-016-0389-1 [doi] ID - 10.1007/s11864-016-0389-1 [pii] PP - ppublish LG - English DP - 2016 Mar DC - 20160305 EZ - 2016/03/05 06:00 DA - 2016/12/15 06:00 DT - 2016/03/05 06:00 YR - 2016 ED - 20161213 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26942589 <78. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26534966 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Merchant MS AU - Wright M AU - Baird K AU - Wexler LH AU - Rodriguez-Galindo C AU - Bernstein D AU - Delbrook C AU - Lodish M AU - Bishop R AU - Wolchok JD AU - Streicher H AU - Mackall CL FA - Merchant, Melinda S FA - Wright, Matthew FA - Baird, Kristin FA - Wexler, Leonard H FA - Rodriguez-Galindo, Carlos FA - Bernstein, Donna FA - Delbrook, Cindy FA - Lodish, Maya FA - Bishop, Rachel FA - Wolchok, Jedd D FA - Streicher, Howard FA - Mackall, Crystal L IN - Merchant, Melinda S. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. mackallc@mail.nih.gov. IN - Wright, Matthew. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. IN - Baird, Kristin. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. IN - Wexler, Leonard H. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY and Weill-Cornell Medical College, New York, NY. IN - Rodriguez-Galindo, Carlos. Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA. IN - Bernstein, Donna. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. IN - Delbrook, Cindy. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. IN - Lodish, Maya. National Institute of Child Health and Human Development, NIH, Bethesda, MD. IN - Bishop, Rachel. National Eye Institute, NIH, Bethesda, MD. IN - Wolchok, Jedd D. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Weill-Cornell Medical College, New York, NY. IN - Streicher, Howard. Investigational Drug Branch, National Cancer Institute, NIH, Bethesda, MD. IN - Mackall, Crystal L. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. TI - Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. SO - Clinical Cancer Research. 22(6):1364-70, 2016 Mar 15 AS - Clin Cancer Res. 22(6):1364-70, 2016 Mar 15 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. SB - Index Medicus CP - United States MH - Adolescent MH - Adult MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Brain/pa [Pathology] MH - Child MH - Child, Preschool MH - Combined Modality Therapy MH - Drug Monitoring MH - Female MH - Humans MH - Immunomodulation MH - Magnetic Resonance Imaging MH - Male MH - Neoplasms/di [Diagnosis] MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/im [Immunology] MH - Neoplasms/me [Metabolism] MH - Retreatment MH - Treatment Outcome MH - Young Adult AB - PURPOSE: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol. AB - EXPERIMENTAL DESIGN: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects <=21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. AB - RESULTS: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). AB - CONCLUSIONS: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-15-0491 DO - https://dx.doi.org/10.1158/1078-0432.CCR-15-0491 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Intramural ID - 26534966 [pubmed] ID - 1078-0432.CCR-15-0491 [pii] ID - 10.1158/1078-0432.CCR-15-0491 [doi] ID - PMC5027962 [pmc] ID - NIHMS735794 [mid] PP - ppublish PH - 2015/03/02 [received] PH - 2015/10/14 [accepted] PH - 2017/03/15 [pmc-release] GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States No: Z99 CA999999 Organization: *Intramural NIH HHS* Country: United States LG - English EP - 20151103 DP - 2016 Mar 15 DC - 20160316 EZ - 2015/11/05 06:00 DA - 2016/12/15 06:00 DT - 2015/11/05 06:00 YR - 2016 ED - 20161213 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26534966 <79. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26655088 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Goh G AU - Walradt T AU - Markarov V AU - Blom A AU - Riaz N AU - Doumani R AU - Stafstrom K AU - Moshiri A AU - Yelistratova L AU - Levinsohn J AU - Chan TA AU - Nghiem P AU - Lifton RP AU - Choi J FA - Goh, Gerald FA - Walradt, Trent FA - Markarov, Vladimir FA - Blom, Astrid FA - Riaz, Nadeem FA - Doumani, Ryan FA - Stafstrom, Krista FA - Moshiri, Ata FA - Yelistratova, Lola FA - Levinsohn, Jonathan FA - Chan, Timothy A FA - Nghiem, Paul FA - Lifton, Richard P FA - Choi, Jaehyuk IN - Goh, Gerald. Department of Genetics, Yale School of Medicine, New Haven, CT, USA. IN - Goh, Gerald. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA. IN - Walradt, Trent. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. IN - Markarov, Vladimir. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Blom, Astrid. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Riaz, Nadeem. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Riaz, Nadeem. Department of Pathology, University of Washington, Seattle, WA, USA. IN - Doumani, Ryan. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Stafstrom, Krista. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Moshiri, Ata. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Yelistratova, Lola. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Levinsohn, Jonathan. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. IN - Chan, Timothy A. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Chan, Timothy A. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Nghiem, Paul. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Nghiem, Paul. Department of Pathology, University of Washington, Seattle, WA, USA. IN - Nghiem, Paul. Fred Hutchinson Cancer Center, Seattle, WA, USA. IN - Lifton, Richard P. Department of Genetics, Yale School of Medicine, New Haven, CT, USA. IN - Lifton, Richard P. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA. IN - Choi, Jaehyuk. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. IN - Choi, Jaehyuk. Department of Dermatology, Veterans Affairs Healthcare, West Haven, CT, USA. IN - Choi, Jaehyuk. Current address: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. TI - Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. SO - Oncotarget. 7(3):3403-15, 2016 Jan 19 AS - Oncotarget. 7(3):3403-15, 2016 Jan 19 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823115 SB - Index Medicus CP - United States MH - *Biomarkers, Tumor/ge [Genetics] MH - *Carcinoma, Merkel Cell/ge [Genetics] MH - Carcinoma, Merkel Cell/im [Immunology] MH - Carcinoma, Merkel Cell/vi [Virology] MH - Exome/ge [Genetics] MH - Genes, Tumor Suppressor MH - Humans MH - Immunotherapy MH - *Merkel cell polyomavirus/im [Immunology] MH - *Mutation/ge [Genetics] MH - Oncogenes/ge [Genetics] MH - RNA, Messenger/ge [Genetics] MH - Real-Time Polymerase Chain Reaction MH - Reverse Transcriptase Polymerase Chain Reaction MH - *Skin Neoplasms/ge [Genetics] MH - Skin Neoplasms/im [Immunology] MH - Skin Neoplasms/vi [Virology] MH - *Tumor Virus Infections/ge [Genetics] MH - Tumor Virus Infections/im [Immunology] MH - Tumor Virus Infections/vi [Virology] KW - Merkel cell carcinoma; Merkel cell polyomavirus; TP53; cancer genetics; tumor neoantigens AB - Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs. RN - 0 (Biomarkers, Tumor) RN - 0 (RNA, Messenger) ES - 1949-2553 IL - 1949-2553 DI - 6494 DO - https://dx.doi.org/10.18632/oncotarget.6494 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26655088 [pubmed] ID - 6494 [pii] ID - 10.18632/oncotarget.6494 [doi] ID - PMC4823115 [pmc] PP - ppublish PH - 2015/08/27 [received] PH - 2015/11/20 [accepted] GI - No: K08 CA191019 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA162522 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 AR007016 Organization: (AR) *NIAMS NIH HHS* Country: United States No: K24 CA139052 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA060553 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA176841 Organization: (CA) *NCI NIH HHS* Country: United States Organization: *Howard Hughes Medical Institute* Country: United States LG - English DP - 2016 Jan 19 DC - 20160216 EZ - 2015/12/15 06:00 DA - 2016/12/15 06:00 DT - 2015/12/15 06:00 YR - 2016 ED - 20161213 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26655088 <80. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26881392 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Emens LA AU - Kok M AU - Ojalvo LS FA - Emens, Leisha A FA - Kok, Marleen FA - Ojalvo, Laureen S IN - Emens, Leisha A. aDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA bThe Netherlands Cancer Institute, Amsterdam, the Netherlands cThe Kelly Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. TI - Targeting the programmed cell death-1 pathway in breast and ovarian cancer. SO - Current Opinion in Obstetrics & Gynecology. 28(2):142-7, 2016 Apr AS - Curr Opin Obstet Gynecol. 28(2):142-7, 2016 Apr NJ - Current opinion in obstetrics & gynecology PI - Journal available in: Print PI - Citation processed from: Internet JC - a50, 9007264 IO - Curr. Opin. Obstet. Gynecol. SB - Index Medicus CP - England MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Apoptosis MH - Breast Neoplasms/im [Immunology] MH - *Breast Neoplasms/th [Therapy] MH - Female MH - Humans MH - *Immunotherapy MH - Ovarian Neoplasms/im [Immunology] MH - *Ovarian Neoplasms/th [Therapy] AB - PURPOSE OF REVIEW: Immune checkpoint blockade is changing cancer therapy. Targeting the programmed cell death-1 (PD-1) pathway releases T cells from inhibitory signals within the tumor microenvironment, thereby activating a latent antitumor immune response. Here, we review the biology underlying the activity of PD-1/programmed cell death-ligand 1 (PD-L1) antagonists, and data describing their clinical activity in breast and ovarian cancer. AB - RECENT FINDINGS: Several antagonists of PD-1 and PD-L1 have been tested in breast and ovarian cancer. These drugs are generally well tolerated, with some immune-related adverse events that are typically easily managed. Objective response rates generally range from about 10 to 20% in both breast cancer and ovarian cancer, with durable responses noted in multiple trials. Selecting patients with PD-L1 expression by cells within the tumor microenvironment appears to enrich for responses. These agents are under accelerated development based on these promising early data. AB - SUMMARY: Monoclonal antibody-based blockade of the PD-1 pathway results in objective and durable clinical responses in a subset of patients with breast or ovarian cancers, particularly those with PD-L1-positive cells within the tumor microenvironment. Current priorities are to refine biomarkers of therapeutic response, and to develop combination immunotherapy strategies that integrate PD-1/PD-L1 antagonists with both standard and immune-based cancer therapies to increase efficacy. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) ES - 1473-656X IL - 1040-872X DO - https://dx.doi.org/10.1097/GCO.0000000000000257 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26881392 [pubmed] ID - 10.1097/GCO.0000000000000257 [doi] PP - ppublish LG - English DP - 2016 Apr DC - 20160304 EZ - 2016/02/17 06:00 DA - 2016/12/15 06:00 DT - 2016/02/18 06:00 YR - 2016 ED - 20161213 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26881392 <81. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26625204 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Darb-Esfahani S AU - Kunze CA AU - Kulbe H AU - Sehouli J AU - Wienert S AU - Lindner J AU - Budczies J AU - Bockmayr M AU - Dietel M AU - Denkert C AU - Braicu I AU - Johrens K FA - Darb-Esfahani, Silvia FA - Kunze, Catarina Alisa FA - Kulbe, Hagen FA - Sehouli, Jalid FA - Wienert, Stephan FA - Lindner, Judith FA - Budczies, Jan FA - Bockmayr, Michael FA - Dietel, Manfred FA - Denkert, Carsten FA - Braicu, Ioana FA - Johrens, Korinna IN - Darb-Esfahani, Silvia. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Darb-Esfahani, Silvia. Tumorbank Ovarian Cancer Network, Department of Gynecology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Kunze, Catarina Alisa. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Kulbe, Hagen. Tumorbank Ovarian Cancer Network, Department of Gynecology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Kulbe, Hagen. Department of Gynecology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Sehouli, Jalid. Tumorbank Ovarian Cancer Network, Department of Gynecology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Sehouli, Jalid. Department of Gynecology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Wienert, Stephan. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Wienert, Stephan. VM Scope GmbH, Berlin, Germany. IN - Lindner, Judith. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Budczies, Jan. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Bockmayr, Michael. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Dietel, Manfred. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Denkert, Carsten. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Denkert, Carsten. Tumorbank Ovarian Cancer Network, Department of Gynecology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Braicu, Ioana. Tumorbank Ovarian Cancer Network, Department of Gynecology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Braicu, Ioana. Department of Gynecology, Charite Universitatsmedizin Berlin, Berlin, Germany. IN - Johrens, Korinna. Institute of Pathology, Charite Universitatsmedizin Berlin, Berlin, Germany. TI - Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. SO - Oncotarget. 7(2):1486-99, 2016 Jan 12 AS - Oncotarget. 7(2):1486-99, 2016 Jan 12 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811475 SB - Index Medicus CP - United States MH - *Antigens, CD274/an [Analysis] MH - Antigens, CD274/ge [Genetics] MH - *Biomarkers, Tumor/an [Analysis] MH - Biomarkers, Tumor/ge [Genetics] MH - *Carcinoma/ch [Chemistry] MH - Carcinoma/ge [Genetics] MH - Carcinoma/im [Immunology] MH - Carcinoma/th [Therapy] MH - Databases, Genetic MH - Disease-Free Survival MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Immunohistochemistry MH - Kaplan-Meier Estimate MH - *Lymphocytes, Tumor-Infiltrating/ch [Chemistry] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/pa [Pathology] MH - Middle Aged MH - Neoplasm Grading MH - *Neoplasms, Cystic, Mucinous, and Serous/ch [Chemistry] MH - Neoplasms, Cystic, Mucinous, and Serous/ge [Genetics] MH - Neoplasms, Cystic, Mucinous, and Serous/im [Immunology] MH - Neoplasms, Cystic, Mucinous, and Serous/th [Therapy] MH - *Ovarian Neoplasms/ch [Chemistry] MH - Ovarian Neoplasms/ge [Genetics] MH - Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/th [Therapy] MH - *Programmed Cell Death 1 Receptor/an [Analysis] MH - Programmed Cell Death 1 Receptor/ge [Genetics] MH - RNA, Messenger/ge [Genetics] MH - Reverse Transcriptase Polymerase Chain Reaction MH - Time Factors MH - Tissue Array Analysis KW - PD-1; PD-L1; high grade serous carcinoma; ovarian; tumor-infiltrating lymphocytes AB - AIMS: Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. AB - METHODS: PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset. AB - RESULTS: PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively). AB - CONCLUSIONS: Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity. RN - 0 (Antigens, CD274) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (RNA, Messenger) ES - 1949-2553 IL - 1949-2553 DI - 6429 DO - https://dx.doi.org/10.18632/oncotarget.6429 PT - Journal Article ID - 26625204 [pubmed] ID - 6429 [pii] ID - 10.18632/oncotarget.6429 [doi] ID - PMC4811475 [pmc] PP - ppublish PH - 2015/06/12 [received] PH - 2015/11/15 [accepted] LG - English DP - 2016 Jan 12 DC - 20160216 EZ - 2015/12/02 06:00 DA - 2016/12/15 06:00 DT - 2015/12/02 06:00 YR - 2016 ED - 20161213 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26625204 <82. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26655088 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Goh G AU - Walradt T AU - Markarov V AU - Blom A AU - Riaz N AU - Doumani R AU - Stafstrom K AU - Moshiri A AU - Yelistratova L AU - Levinsohn J AU - Chan TA AU - Nghiem P AU - Lifton RP AU - Choi J FA - Goh, Gerald FA - Walradt, Trent FA - Markarov, Vladimir FA - Blom, Astrid FA - Riaz, Nadeem FA - Doumani, Ryan FA - Stafstrom, Krista FA - Moshiri, Ata FA - Yelistratova, Lola FA - Levinsohn, Jonathan FA - Chan, Timothy A FA - Nghiem, Paul FA - Lifton, Richard P FA - Choi, Jaehyuk IN - Goh, Gerald. Department of Genetics, Yale School of Medicine, New Haven, CT, USA. IN - Goh, Gerald. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA. IN - Walradt, Trent. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. IN - Markarov, Vladimir. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Blom, Astrid. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Riaz, Nadeem. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Riaz, Nadeem. Department of Pathology, University of Washington, Seattle, WA, USA. IN - Doumani, Ryan. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Stafstrom, Krista. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Moshiri, Ata. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Yelistratova, Lola. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Levinsohn, Jonathan. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. IN - Chan, Timothy A. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Chan, Timothy A. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. IN - Nghiem, Paul. Department of Dermatology, University of Washington, Seattle, WA, USA. IN - Nghiem, Paul. Department of Pathology, University of Washington, Seattle, WA, USA. IN - Nghiem, Paul. Fred Hutchinson Cancer Center, Seattle, WA, USA. IN - Lifton, Richard P. Department of Genetics, Yale School of Medicine, New Haven, CT, USA. IN - Lifton, Richard P. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA. IN - Choi, Jaehyuk. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. IN - Choi, Jaehyuk. Department of Dermatology, Veterans Affairs Healthcare, West Haven, CT, USA. IN - Choi, Jaehyuk. Current address: Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. TI - Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. SO - Oncotarget. 7(3):3403-15, 2016 Jan 19 AS - Oncotarget. 7(3):3403-15, 2016 Jan 19 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823115 SB - Index Medicus CP - United States MH - *Biomarkers, Tumor/ge [Genetics] MH - *Carcinoma, Merkel Cell/ge [Genetics] MH - Carcinoma, Merkel Cell/im [Immunology] MH - Carcinoma, Merkel Cell/vi [Virology] MH - Exome/ge [Genetics] MH - Genes, Tumor Suppressor MH - Humans MH - Immunotherapy MH - *Merkel cell polyomavirus/im [Immunology] MH - *Mutation/ge [Genetics] MH - Oncogenes/ge [Genetics] MH - RNA, Messenger/ge [Genetics] MH - Real-Time Polymerase Chain Reaction MH - Reverse Transcriptase Polymerase Chain Reaction MH - *Skin Neoplasms/ge [Genetics] MH - Skin Neoplasms/im [Immunology] MH - Skin Neoplasms/vi [Virology] MH - *Tumor Virus Infections/ge [Genetics] MH - Tumor Virus Infections/im [Immunology] MH - Tumor Virus Infections/vi [Virology] KW - Merkel cell carcinoma; Merkel cell polyomavirus; TP53; cancer genetics; tumor neoantigens AB - Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs. RN - 0 (Biomarkers, Tumor) RN - 0 (RNA, Messenger) ES - 1949-2553 IL - 1949-2553 DI - 6494 DO - https://dx.doi.org/10.18632/oncotarget.6494 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 6494 [pii] ID - 10.18632/oncotarget.6494 [doi] ID - PMC4823115 [pmc] PP - ppublish PH - 2015/08/27 [received] PH - 2015/11/20 [accepted] GI - No: K08 CA191019 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 TR001863 Organization: (TR) *NCATS NIH HHS* Country: United States No: R01 CA162522 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 AR007016 Organization: (AR) *NIAMS NIH HHS* Country: United States No: K24 CA139052 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA060553 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA176841 Organization: (CA) *NCI NIH HHS* Country: United States Organization: *Howard Hughes Medical Institute* Country: United States LG - English DP - 2016 Jan 19 DC - 20160216 EZ - 2015/12/15 06:00 DA - 2016/12/15 06:00 DT - 2015/12/15 06:00 YR - 2016 ED - 20161213 RD - 20170412 UP - 20170414 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26655088 <83. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26534966 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Merchant MS AU - Wright M AU - Baird K AU - Wexler LH AU - Rodriguez-Galindo C AU - Bernstein D AU - Delbrook C AU - Lodish M AU - Bishop R AU - Wolchok JD AU - Streicher H AU - Mackall CL FA - Merchant, Melinda S FA - Wright, Matthew FA - Baird, Kristin FA - Wexler, Leonard H FA - Rodriguez-Galindo, Carlos FA - Bernstein, Donna FA - Delbrook, Cindy FA - Lodish, Maya FA - Bishop, Rachel FA - Wolchok, Jedd D FA - Streicher, Howard FA - Mackall, Crystal L IN - Merchant, Melinda S. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. mackallc@mail.nih.gov. IN - Wright, Matthew. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. IN - Baird, Kristin. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. IN - Wexler, Leonard H. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY and Weill-Cornell Medical College, New York, NY. IN - Rodriguez-Galindo, Carlos. Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA. IN - Bernstein, Donna. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. IN - Delbrook, Cindy. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. IN - Lodish, Maya. National Institute of Child Health and Human Development, NIH, Bethesda, MD. IN - Bishop, Rachel. National Eye Institute, NIH, Bethesda, MD. IN - Wolchok, Jedd D. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Weill-Cornell Medical College, New York, NY. IN - Streicher, Howard. Investigational Drug Branch, National Cancer Institute, NIH, Bethesda, MD. IN - Mackall, Crystal L. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. TI - Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. SO - Clinical Cancer Research. 22(6):1364-70, 2016 Mar 15 AS - Clin Cancer Res. 22(6):1364-70, 2016 Mar 15 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. SB - Index Medicus CP - United States MH - Adolescent MH - Adult MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Brain/pa [Pathology] MH - Child MH - Child, Preschool MH - Combined Modality Therapy MH - Drug Monitoring MH - Female MH - Humans MH - Immunomodulation MH - Magnetic Resonance Imaging MH - Male MH - Neoplasms/di [Diagnosis] MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/im [Immunology] MH - Neoplasms/me [Metabolism] MH - Retreatment MH - Treatment Outcome MH - Young Adult AB - PURPOSE: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol. AB - EXPERIMENTAL DESIGN: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects <=21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. AB - RESULTS: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). AB - CONCLUSIONS: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-15-0491 DO - https://dx.doi.org/10.1158/1078-0432.CCR-15-0491 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Intramural ID - 1078-0432.CCR-15-0491 [pii] ID - 10.1158/1078-0432.CCR-15-0491 [doi] ID - PMC5027962 [pmc] ID - NIHMS735794 [mid] PP - ppublish PH - 2015/03/02 [received] PH - 2015/10/14 [accepted] GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States No: Z99 CA999999 Organization: *Intramural NIH HHS* Country: United States LG - English EP - 20151103 DP - 2016 Mar 15 DC - 20160316 EZ - 2015/11/05 06:00 DA - 2016/12/15 06:00 DT - 2015/11/05 06:00 YR - 2016 ED - 20161213 RD - 20170315 UP - 20170317 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26534966 <84. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26598537 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Cierna Z AU - Mego M AU - Miskovska V AU - Machalekova K AU - Chovanec M AU - Svetlovska D AU - Hainova K AU - Rejlekova K AU - Macak D AU - Spanik S AU - Ondrus D AU - Kajo K AU - Mardiak J AU - Babal P FA - Cierna, Z FA - Mego, M FA - Miskovska, V FA - Machalekova, K FA - Chovanec, M FA - Svetlovska, D FA - Hainova, K FA - Rejlekova, K FA - Macak, D FA - Spanik, S FA - Ondrus, D FA - Kajo, K FA - Mardiak, J FA - Babal, P IN - Cierna, Z. Department of Pathology, Faculty of Medicine. IN - Mego, M. 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute Translational Research Unit, 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute 1st Department of Oncology, Comenius University, Bratislava misomego@gmail.com. IN - Miskovska, V. Faculty of Medicine, St Elisabeth Cancer Institute, Bratislava. IN - Machalekova, K. Department of Pathology, Slovak Medical University and St Elisabeth Cancer Institute, Bratislava. IN - Chovanec, M. 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute 1st Department of Oncology, Comenius University, Bratislava. IN - Svetlovska, D. Translational Research Unit, 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute. IN - Hainova, K. Translational Research Unit, 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute Cancer Research Institute, Slovak, Academy of Sciences, Bratislava. IN - Rejlekova, K. 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute 1st Department of Oncology, Comenius University, Bratislava. IN - Macak, D. Department of Pathology, National Cancer Institute, Bratislava. IN - Spanik, S. Faculty of Medicine, St Elisabeth Cancer Institute, Bratislava. IN - Ondrus, D. Faculty of Medicine, St Elisabeth Cancer Institute, Bratislava. IN - Kajo, K. Department of Pathology, Slovak Medical University and St Elisabeth Cancer Institute, Bratislava. IN - Mardiak, J. 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute Translational Research Unit, 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute 1st Department of Oncology, Comenius University, Bratislava. IN - Babal, P. Department of Pathology, Faculty of Medicine Faculty Hospital with Policlinics Skalica, a.s., Skalica, Slovak Republic. TI - Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors. CM - Comment in: Nat Rev Urol. 2016 Feb;13(2):62; PMID: 26666362 SO - Annals of Oncology. 27(2):300-5, 2016 Feb AS - Ann Oncol. 27(2):300-5, 2016 Feb NJ - Annals of oncology : official journal of the European Society for Medical Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ayf, 9007735 IO - Ann. Oncol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751222 SB - Index Medicus CP - England MH - Adolescent MH - Adult MH - Aged MH - Antibodies, Monoclonal/im [Immunology] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Antigens, CD274/me [Metabolism] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *Biomarkers, Tumor/bl [Blood] MH - *Choriocarcinoma/pa [Pathology] MH - Cisplatin/tu [Therapeutic Use] MH - Disease-Free Survival MH - Humans MH - Immunotherapy/mt [Methods] MH - Male MH - Middle Aged MH - Neoplasms, Germ Cell and Embryonal/dt [Drug Therapy] MH - Neoplasms, Germ Cell and Embryonal/mo [Mortality] MH - *Neoplasms, Germ Cell and Embryonal/pa [Pathology] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - *Programmed Cell Death 1 Receptor/me [Metabolism] MH - Testicular Neoplasms/dt [Drug Therapy] MH - Testicular Neoplasms/mo [Mortality] MH - *Testicular Neoplasms/pa [Pathology] MH - Translational Medical Research MH - Young Adult KW - immunotherapy; prognosis; programmed death receptor 1; programmed death-ligand 1; testicular germ cell tumors AB - BACKGROUND: Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs. AB - PATIENTS AND METHODS: Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome. AB - RESULTS: None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including >=3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression. AB - CONCLUSIONS: In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs. AB - Copyright © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - Q20Q21Q62J (Cisplatin) RS - Testicular Germ Cell Tumor ES - 1569-8041 IL - 0923-7534 DI - mdv574 DO - https://dx.doi.org/10.1093/annonc/mdv574 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26598537 [pubmed] ID - mdv574 [pii] ID - 10.1093/annonc/mdv574 [doi] ID - PMC4751222 [pmc] PP - ppublish PH - 2015/09/06 [received] PH - 2015/11/09 [accepted] PH - 2017/02/01 [pmc-release] LG - English EP - 20151123 DP - 2016 Feb DC - 20160123 EZ - 2015/11/25 06:00 DA - 2016/11/12 06:00 DT - 2015/11/26 06:00 YR - 2016 ED - 20161111 RD - 20161112 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26598537 <85. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26598537 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Cierna Z AU - Mego M AU - Miskovska V AU - Machalekova K AU - Chovanec M AU - Svetlovska D AU - Hainova K AU - Rejlekova K AU - Macak D AU - Spanik S AU - Ondrus D AU - Kajo K AU - Mardiak J AU - Babal P FA - Cierna, Z FA - Mego, M FA - Miskovska, V FA - Machalekova, K FA - Chovanec, M FA - Svetlovska, D FA - Hainova, K FA - Rejlekova, K FA - Macak, D FA - Spanik, S FA - Ondrus, D FA - Kajo, K FA - Mardiak, J FA - Babal, P IN - Cierna, Z. Department of Pathology, Faculty of Medicine. IN - Mego, M. 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute Translational Research Unit, 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute 1st Department of Oncology, Comenius University, Bratislava misomego@gmail.com. IN - Miskovska, V. Faculty of Medicine, St Elisabeth Cancer Institute, Bratislava. IN - Machalekova, K. Department of Pathology, Slovak Medical University and St Elisabeth Cancer Institute, Bratislava. IN - Chovanec, M. 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute 1st Department of Oncology, Comenius University, Bratislava. IN - Svetlovska, D. Translational Research Unit, 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute. IN - Hainova, K. Translational Research Unit, 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute Cancer Research Institute, Slovak, Academy of Sciences, Bratislava. IN - Rejlekova, K. 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute 1st Department of Oncology, Comenius University, Bratislava. IN - Macak, D. Department of Pathology, National Cancer Institute, Bratislava. IN - Spanik, S. Faculty of Medicine, St Elisabeth Cancer Institute, Bratislava. IN - Ondrus, D. Faculty of Medicine, St Elisabeth Cancer Institute, Bratislava. IN - Kajo, K. Department of Pathology, Slovak Medical University and St Elisabeth Cancer Institute, Bratislava. IN - Mardiak, J. 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute Translational Research Unit, 2nd Department of Oncology, Faculty of Medicine and National Cancer Institute 1st Department of Oncology, Comenius University, Bratislava. IN - Babal, P. Department of Pathology, Faculty of Medicine Faculty Hospital with Policlinics Skalica, a.s., Skalica, Slovak Republic. TI - Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors. CM - Comment in: Nat Rev Urol. 2016 Feb;13(2):62; PMID: 26666362 SO - Annals of Oncology. 27(2):300-5, 2016 Feb AS - Ann Oncol. 27(2):300-5, 2016 Feb NJ - Annals of oncology : official journal of the European Society for Medical Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ayf, 9007735 IO - Ann. Oncol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751222 SB - Index Medicus CP - England MH - Adolescent MH - Adult MH - Aged MH - Antibodies, Monoclonal/im [Immunology] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Antigens, CD274/me [Metabolism] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *Biomarkers, Tumor/bl [Blood] MH - *Choriocarcinoma/pa [Pathology] MH - Cisplatin/tu [Therapeutic Use] MH - Disease-Free Survival MH - Humans MH - Immunotherapy/mt [Methods] MH - Male MH - Middle Aged MH - Neoplasms, Germ Cell and Embryonal/dt [Drug Therapy] MH - Neoplasms, Germ Cell and Embryonal/mo [Mortality] MH - *Neoplasms, Germ Cell and Embryonal/pa [Pathology] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - *Programmed Cell Death 1 Receptor/me [Metabolism] MH - Testicular Neoplasms/dt [Drug Therapy] MH - Testicular Neoplasms/mo [Mortality] MH - *Testicular Neoplasms/pa [Pathology] MH - Translational Medical Research MH - Young Adult KW - immunotherapy; prognosis; programmed death receptor 1; programmed death-ligand 1; testicular germ cell tumors AB - BACKGROUND: Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs. AB - PATIENTS AND METHODS: Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome. AB - RESULTS: None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including >=3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression. AB - CONCLUSIONS: In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs. AB - Copyright © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - Q20Q21Q62J (Cisplatin) RS - Testicular Germ Cell Tumor ES - 1569-8041 IL - 0923-7534 DI - mdv574 DO - https://dx.doi.org/10.1093/annonc/mdv574 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26598537 [pubmed] ID - mdv574 [pii] ID - 10.1093/annonc/mdv574 [doi] ID - PMC4751222 [pmc] PP - ppublish PH - 2015/09/06 [received] PH - 2015/11/09 [accepted] LG - English EP - 20151123 DP - 2016 Feb DC - 20160123 EZ - 2015/11/25 06:00 DA - 2016/11/12 06:00 DT - 2015/11/26 06:00 YR - 2016 ED - 20161111 RD - 20170201 UP - 20170202 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26598537 <86. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27569912 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Daley D AU - Zambirinis CP AU - Seifert L AU - Akkad N AU - Mohan N AU - Werba G AU - Barilla R AU - Torres-Hernandez A AU - Hundeyin M AU - Mani VR AU - Avanzi A AU - Tippens D AU - Narayanan R AU - Jang JE AU - Newman E AU - Pillarisetty VG AU - Dustin ML AU - Bar-Sagi D AU - Hajdu C AU - Miller G FA - Daley, Donnele FA - Zambirinis, Constantinos Pantelis FA - Seifert, Lena FA - Akkad, Neha FA - Mohan, Navyatha FA - Werba, Gregor FA - Barilla, Rocky FA - Torres-Hernandez, Alejandro FA - Hundeyin, Mautin FA - Mani, Vishnu Raj Kumar FA - Avanzi, Antonina FA - Tippens, Daniel FA - Narayanan, Rajkishen FA - Jang, Jung-Eun FA - Newman, Elliot FA - Pillarisetty, Venu Gopal FA - Dustin, Michael Loran FA - Bar-Sagi, Dafna FA - Hajdu, Cristina FA - Miller, George IN - Daley, Donnele. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Zambirinis, Constantinos Pantelis. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Seifert, Lena. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Akkad, Neha. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Mohan, Navyatha. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Werba, Gregor. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Barilla, Rocky. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Torres-Hernandez, Alejandro. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Hundeyin, Mautin. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Mani, Vishnu Raj Kumar. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Avanzi, Antonina. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Tippens, Daniel. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Narayanan, Rajkishen. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Jang, Jung-Eun. Department of Biochemistry, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Newman, Elliot. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Pillarisetty, Venu Gopal. Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA. IN - Dustin, Michael Loran. Department of Pathology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; The Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington Oxford OX3 7FY, UK. IN - Bar-Sagi, Dafna. Department of Biochemistry, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Hajdu, Cristina. Department of Pathology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Miller, George. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. Electronic address: george.miller@nyumc.org. TI - gammadelta T Cells Support Pancreatic Oncogenesis by Restraining alphabeta T Cell Activation. SO - Cell. 166(6):1485-1499.e15, 2016 Sep 08 AS - Cell. 166(6):1485-1499.e15, 2016 Sep 08 NJ - Cell PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cq4, 0413066 IO - Cell PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017923 OI - Source: NLM. NIHMS812937 [Available on 09/08/17] SB - Index Medicus CP - United States MH - Adaptive Immunity MH - Animals MH - *Carcinogenesis/im [Immunology] MH - Carcinogenesis/pa [Pathology] MH - *Carcinoma, Pancreatic Ductal/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/pp [Physiopathology] MH - Cells, Cultured MH - Chemokines/im [Immunology] MH - Epithelial Cells/ph [Physiology] MH - Female MH - Humans MH - Ligands MH - *Lymphocyte Activation/im [Immunology] MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Signal Transduction/im [Immunology] MH - *T-Lymphocytes/im [Immunology] MH - Tumor Microenvironment/im [Immunology] KW - Kras; cancer; checkpoint ligands AB - Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated gammadeltaT cell population, which constituted ~40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of gammadeltaT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of gammadeltaT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of alphabetaT cells. Although alphabetaT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon gammadeltaT cell ablation. PDA-infiltrating gammadeltaT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in gammadeltaT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that gammadeltaT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe gammadeltaT cells as central regulators of effector T cell activation in cancer via novel cross-talk. AB - Copyright © 2016 Elsevier Inc. All rights reserved. RN - 0 (Chemokines) RN - 0 (Ligands) ES - 1097-4172 IL - 0092-8674 DI - S0092-8674(16)30996-5 DO - https://dx.doi.org/10.1016/j.cell.2016.07.046 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 27569912 [pubmed] ID - S0092-8674(16)30996-5 [pii] ID - 10.1016/j.cell.2016.07.046 [doi] ID - PMC5017923 [pmc] ID - NIHMS812937 [mid] PP - ppublish PH - 2015/07/16 [received] PH - 2016/02/16 [revised] PH - 2016/07/27 [accepted] PH - 2017/09/08 [pmc-release] GI - Organization: (PCAN) *Pancreatic Cancer Action Network* Country: United States No: P30 CA016087 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA168611 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 CA193111 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA155649 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 TR000038 Organization: (TR) *NCATS NIH HHS* Country: United States LG - English EP - 20160825 DP - 2016 Sep 08 DC - 20160910 EZ - 2016/08/30 06:00 DA - 2016/11/05 06:00 DT - 2016/08/30 06:00 YR - 2016 ED - 20161104 RD - 20161202 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27569912 <87. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27569912 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Daley D AU - Zambirinis CP AU - Seifert L AU - Akkad N AU - Mohan N AU - Werba G AU - Barilla R AU - Torres-Hernandez A AU - Hundeyin M AU - Mani VR AU - Avanzi A AU - Tippens D AU - Narayanan R AU - Jang JE AU - Newman E AU - Pillarisetty VG AU - Dustin ML AU - Bar-Sagi D AU - Hajdu C AU - Miller G FA - Daley, Donnele FA - Zambirinis, Constantinos Pantelis FA - Seifert, Lena FA - Akkad, Neha FA - Mohan, Navyatha FA - Werba, Gregor FA - Barilla, Rocky FA - Torres-Hernandez, Alejandro FA - Hundeyin, Mautin FA - Mani, Vishnu Raj Kumar FA - Avanzi, Antonina FA - Tippens, Daniel FA - Narayanan, Rajkishen FA - Jang, Jung-Eun FA - Newman, Elliot FA - Pillarisetty, Venu Gopal FA - Dustin, Michael Loran FA - Bar-Sagi, Dafna FA - Hajdu, Cristina FA - Miller, George IN - Daley, Donnele. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Zambirinis, Constantinos Pantelis. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Seifert, Lena. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Akkad, Neha. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Mohan, Navyatha. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Werba, Gregor. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Barilla, Rocky. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Torres-Hernandez, Alejandro. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Hundeyin, Mautin. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Mani, Vishnu Raj Kumar. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Avanzi, Antonina. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Tippens, Daniel. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Narayanan, Rajkishen. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Jang, Jung-Eun. Department of Biochemistry, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Newman, Elliot. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Pillarisetty, Venu Gopal. Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA. IN - Dustin, Michael Loran. Department of Pathology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; The Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington Oxford OX3 7FY, UK. IN - Bar-Sagi, Dafna. Department of Biochemistry, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Hajdu, Cristina. Department of Pathology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. IN - Miller, George. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 430 East 29th Street, New York, NY 10016, USA. Electronic address: george.miller@nyumc.org. TI - gammadelta T Cells Support Pancreatic Oncogenesis by Restraining alphabeta T Cell Activation. SO - Cell. 166(6):1485-1499.e15, 2016 Sep 08 AS - Cell. 166(6):1485-1499.e15, 2016 Sep 08 NJ - Cell PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cq4, 0413066 IO - Cell PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017923 OI - Source: NLM. NIHMS812937 [Available on 09/08/17] SB - Index Medicus CP - United States MH - Adaptive Immunity MH - Animals MH - *Carcinogenesis/im [Immunology] MH - Carcinogenesis/pa [Pathology] MH - *Carcinoma, Pancreatic Ductal/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/pp [Physiopathology] MH - Cells, Cultured MH - Chemokines/im [Immunology] MH - Epithelial Cells/ph [Physiology] MH - Female MH - Humans MH - Ligands MH - *Lymphocyte Activation/im [Immunology] MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Signal Transduction/im [Immunology] MH - *T-Lymphocytes/im [Immunology] MH - Tumor Microenvironment/im [Immunology] KW - Kras; cancer; checkpoint ligands AB - Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated gammadeltaT cell population, which constituted ~40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of gammadeltaT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of gammadeltaT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of alphabetaT cells. Although alphabetaT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon gammadeltaT cell ablation. PDA-infiltrating gammadeltaT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in gammadeltaT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that gammadeltaT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe gammadeltaT cells as central regulators of effector T cell activation in cancer via novel cross-talk. AB - Copyright © 2016 Elsevier Inc. All rights reserved. RN - 0 (Chemokines) RN - 0 (Ligands) ES - 1097-4172 IL - 0092-8674 DI - S0092-8674(16)30996-5 DO - https://dx.doi.org/10.1016/j.cell.2016.07.046 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 27569912 [pubmed] ID - S0092-8674(16)30996-5 [pii] ID - 10.1016/j.cell.2016.07.046 [doi] ID - PMC5017923 [pmc] ID - NIHMS812937 [mid] PP - ppublish PH - 2015/07/16 [received] PH - 2016/02/16 [revised] PH - 2016/07/27 [accepted] PH - 2017/09/08 [pmc-release] GI - No: UL1 TR001445 Organization: (TR) *NCATS NIH HHS* Country: United States Organization: (PCAN) *Pancreatic Cancer Action Network* Country: United States No: P30 CA016087 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA168611 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 CA193111 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA155649 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 TR000038 Organization: (TR) *NCATS NIH HHS* Country: United States LG - English EP - 20160825 DP - 2016 Sep 08 DC - 20160910 EZ - 2016/08/30 06:00 DA - 2016/11/05 06:00 DT - 2016/08/30 06:00 YR - 2016 ED - 20161104 RD - 20170125 UP - 20170126 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=27569912 <88. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26446948 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Freeman-Keller M AU - Kim Y AU - Cronin H AU - Richards A AU - Gibney G AU - Weber JS FA - Freeman-Keller, Morganna FA - Kim, Youngchul FA - Cronin, Heather FA - Richards, Allison FA - Gibney, Geoffrey FA - Weber, Jeffrey S IN - Freeman-Keller, Morganna. Department of Graduate Medical Education, University of South Florida, Tampa, Florida. morganna.freemankeller@moffitt.org. IN - Kim, Youngchul. Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida. IN - Cronin, Heather. Clinical Trials Office, Moffitt Cancer Center, Tampa, Florida. IN - Richards, Allison. Clinical Trials Office, Moffitt Cancer Center, Tampa, Florida. IN - Gibney, Geoffrey. Department of Cutaneous Oncology, Lombardi Comprehensive Cancer Center, Washington, DC. IN - Weber, Jeffrey S. Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida. TI - Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. SO - Clinical Cancer Research. 22(4):886-94, 2016 Feb 15 AS - Clin Cancer Res. 22(4):886-94, 2016 Feb 15 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755809 OI - Source: NLM. NIHMS729897 [Available on 02/15/17] SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Exanthema/ci [Chemically Induced] MH - Humans MH - Hypothyroidism/ci [Chemically Induced] MH - Kaplan-Meier Estimate MH - Melanoma/im [Immunology] MH - Melanoma/mo [Mortality] MH - *Melanoma/th [Therapy] MH - Mucositis/ci [Chemically Induced] MH - Multivariate Analysis MH - Pneumonia/ci [Chemically Induced] MH - Proportional Hazards Models MH - Skin Neoplasms/im [Immunology] MH - Skin Neoplasms/mo [Mortality] MH - *Skin Neoplasms/th [Therapy] MH - Treatment Outcome AB - PURPOSE: Retrospective analysis of irAEs in melanoma patients treated with nivolumab. AB - EXPERIMENTAL DESIGN: Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of immune-related adverse events (irAE) were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in overall survival (OS) in the presence or absence of irAEs. AB - RESULTS: IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically significant OS difference was noted among patients with any grade of irAE versus those without (P <= 0.001), and OS benefit was noted in patients who reported three or more irAE events (P <= 0.001). Subset analyses showed statistically significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence interval (CI), 0.243-0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI, 0.036-0.94). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (P = 0.004 and P = 0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis). AB - CONCLUSIONS: Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 31YO63LBSN (nivolumab) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-15-1136 DO - https://dx.doi.org/10.1158/1078-0432.CCR-15-1136 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, P.H.S. ID - 26446948 [pubmed] ID - 1078-0432.CCR-15-1136 [pii] ID - 10.1158/1078-0432.CCR-15-1136 [doi] ID - PMC4755809 [pmc] ID - NIHMS729897 [mid] PP - ppublish PH - 2015/06/05 [received] PH - 2015/09/28 [accepted] PH - 2017/02/15 [pmc-release] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01176461 SA - ClinicalTrials.gov/NCT01176474 SL - https://clinicaltrials.gov/search/term=NCT01176461 SL - https://clinicaltrials.gov/search/term=NCT01176474 GI - No: FDA RO1 FD-003511 Organization: *PHS HHS* Country: United States No: R01 FD003511 Organization: (FD) *FDA HHS* Country: United States No: NCI P30 CA076292 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA076292 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA129594 Organization: (CA) *NCI NIH HHS* Country: United States No: NCI RO1 CA129594 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA168536 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20151007 DP - 2016 Feb 15 DC - 20160216 EZ - 2015/10/09 06:00 DA - 2016/11/04 06:00 DT - 2015/10/09 06:00 YR - 2016 ED - 20161103 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26446948 <89. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26446948 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Freeman-Keller M AU - Kim Y AU - Cronin H AU - Richards A AU - Gibney G AU - Weber JS FA - Freeman-Keller, Morganna FA - Kim, Youngchul FA - Cronin, Heather FA - Richards, Allison FA - Gibney, Geoffrey FA - Weber, Jeffrey S IN - Freeman-Keller, Morganna. Department of Graduate Medical Education, University of South Florida, Tampa, Florida. morganna.freemankeller@moffitt.org. IN - Kim, Youngchul. Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida. IN - Cronin, Heather. Clinical Trials Office, Moffitt Cancer Center, Tampa, Florida. IN - Richards, Allison. Clinical Trials Office, Moffitt Cancer Center, Tampa, Florida. IN - Gibney, Geoffrey. Department of Cutaneous Oncology, Lombardi Comprehensive Cancer Center, Washington, DC. IN - Weber, Jeffrey S. Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, Florida. TI - Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. SO - Clinical Cancer Research. 22(4):886-94, 2016 Feb 15 AS - Clin Cancer Res. 22(4):886-94, 2016 Feb 15 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755809 OI - Source: NLM. NIHMS729897 [Available on 02/15/17] SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Exanthema/ci [Chemically Induced] MH - Humans MH - Hypothyroidism/ci [Chemically Induced] MH - Kaplan-Meier Estimate MH - Melanoma/im [Immunology] MH - Melanoma/mo [Mortality] MH - *Melanoma/th [Therapy] MH - Mucositis/ci [Chemically Induced] MH - Multivariate Analysis MH - Pneumonia/ci [Chemically Induced] MH - Proportional Hazards Models MH - Skin Neoplasms/im [Immunology] MH - Skin Neoplasms/mo [Mortality] MH - *Skin Neoplasms/th [Therapy] MH - Treatment Outcome AB - PURPOSE: Retrospective analysis of irAEs in melanoma patients treated with nivolumab. AB - EXPERIMENTAL DESIGN: Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of immune-related adverse events (irAE) were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in overall survival (OS) in the presence or absence of irAEs. AB - RESULTS: IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically significant OS difference was noted among patients with any grade of irAE versus those without (P <= 0.001), and OS benefit was noted in patients who reported three or more irAE events (P <= 0.001). Subset analyses showed statistically significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence interval (CI), 0.243-0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI, 0.036-0.94). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (P = 0.004 and P = 0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis). AB - CONCLUSIONS: Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 31YO63LBSN (nivolumab) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-15-1136 DO - https://dx.doi.org/10.1158/1078-0432.CCR-15-1136 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, P.H.S. ID - 26446948 [pubmed] ID - 1078-0432.CCR-15-1136 [pii] ID - 10.1158/1078-0432.CCR-15-1136 [doi] ID - PMC4755809 [pmc] ID - NIHMS729897 [mid] PP - ppublish PH - 2015/06/05 [received] PH - 2015/09/28 [accepted] GI - No: FDA RO1 FD-003511 Organization: *PHS HHS* Country: United States No: R01 FD003511 Organization: (FD) *FDA HHS* Country: United States No: NCI P30 CA076292 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA076292 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA129594 Organization: (CA) *NCI NIH HHS* Country: United States No: NCI RO1 CA129594 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA168536 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20151007 DP - 2016 Feb 15 DC - 20160216 EZ - 2015/10/09 06:00 DA - 2016/11/04 06:00 DT - 2015/10/09 06:00 YR - 2016 ED - 20161103 RD - 20170215 UP - 20170216 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26446948 <90. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26775673 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Abdel-Rahman O AU - ElHalawani H AU - Fouad M FA - Abdel-Rahman, Omar FA - ElHalawani, Hesham FA - Fouad, Mona IN - Abdel-Rahman, Omar. Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. IN - ElHalawani, Hesham. Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. IN - Fouad, Mona. Medical Microbiology & Immunology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. TI - Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis. [Review] SO - Future Oncology. 12(3):413-25, 2016 Feb AS - Fut Oncol. 12(3):413-25, 2016 Feb NJ - Future oncology (London, England) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101256629 IO - Future Oncol SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *Endocrine System Diseases/ci [Chemically Induced] MH - Humans MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/im [Immunology] MH - Randomized Controlled Trials as Topic MH - Risk KW - adrenal insufficiency; hypothyroidism; ipilimumab; nivolumab AB - BACKGROUND: We performed a meta-analysis of the risk of endocrine adverse events associated with immune check point inhibitors. AB - METHODS: Eligible studies included randomized trials of cancer patients on immune checkpoint inhibitors; describing events of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency. AB - RESULTS: A total of ten clinical trials were eligible for the meta-analysis. The relative risk of all-grade hypothyroidism, hyperthyroidism, hypophyisitis and adrenal insufficiency were 8.26 (95% CI: 4.67-14.62; p < 0.00001), 5.48 (95% CI: 1.33-22.53; p = 0.02); 22.03 (95% CI: 8.52-56.94; p < 0.00001), 3.87 (95% CI: 1.12-13.41; p = 0.03), respectively. AB - CONCLUSION: Our meta-analysis has demonstrated that the use of immune check point inhibitors is associated with an increased risk of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency compared with control. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (pidilizumab) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RN - DPT0O3T46P (pembrolizumab) RN - QEN1X95CIX (tremelimumab) ES - 1744-8301 IL - 1479-6694 DO - https://dx.doi.org/10.2217/fon.15.222 PT - Journal Article PT - Meta-Analysis PT - Review ID - 26775673 [pubmed] ID - 10.2217/fon.15.222 [doi] PP - ppublish LG - English EP - 20160118 DP - 2016 Feb DC - 20160128 EZ - 2016/01/19 06:00 DA - 2016/11/27 06:00 DT - 2016/01/19 06:00 YR - 2016 ED - 20161019 RD - 20161127 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26775673 <91. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26775673 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Abdel-Rahman O AU - ElHalawani H AU - Fouad M FA - Abdel-Rahman, Omar FA - ElHalawani, Hesham FA - Fouad, Mona IN - Abdel-Rahman, Omar. Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. IN - ElHalawani, Hesham. Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. IN - Fouad, Mona. Medical Microbiology & Immunology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt. TI - Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis. [Review] SO - Future Oncology. 12(3):413-25, 2016 Feb AS - Fut Oncol. 12(3):413-25, 2016 Feb NJ - Future oncology (London, England) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101256629 IO - Future Oncol SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *Endocrine System Diseases/ci [Chemically Induced] MH - Humans MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/im [Immunology] MH - Randomized Controlled Trials as Topic MH - Risk KW - adrenal insufficiency; hypothyroidism; ipilimumab; nivolumab AB - BACKGROUND: We performed a meta-analysis of the risk of endocrine adverse events associated with immune check point inhibitors. AB - METHODS: Eligible studies included randomized trials of cancer patients on immune checkpoint inhibitors; describing events of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency. AB - RESULTS: A total of ten clinical trials were eligible for the meta-analysis. The relative risk of all-grade hypothyroidism, hyperthyroidism, hypophyisitis and adrenal insufficiency were 8.26 (95% CI: 4.67-14.62; p < 0.00001), 5.48 (95% CI: 1.33-22.53; p = 0.02); 22.03 (95% CI: 8.52-56.94; p < 0.00001), 3.87 (95% CI: 1.12-13.41; p = 0.03), respectively. AB - CONCLUSION: Our meta-analysis has demonstrated that the use of immune check point inhibitors is associated with an increased risk of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency compared with control. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (pidilizumab) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RN - DPT0O3T46P (pembrolizumab) RN - QEN1X95CIX (tremelimumab) ES - 1744-8301 IL - 1479-6694 DO - https://dx.doi.org/10.2217/fon.15.222 PT - Journal Article PT - Meta-Analysis PT - Review ID - 26775673 [pubmed] ID - 10.2217/fon.15.222 [doi] PP - ppublish LG - English EP - 20160118 DP - 2016 Feb DC - 20160128 EZ - 2016/01/19 06:00 DA - 2016/11/27 06:00 DT - 2016/01/19 06:00 YR - 2016 ED - 20161019 RD - 20170103 UP - 20170103 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26775673 <92. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26733436 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Verma I AU - Modi A AU - Tripathi H AU - Agrawal A AI - Agrawal, Abhinav; ORCID: http://orcid.org/0000-0003-1080-6449 FA - Verma, Isha FA - Modi, Anar FA - Tripathi, Hemantkumar FA - Agrawal, Abhinav IN - Verma, Isha. Department of Medicine, Monmouth Medical Center, Long Branch, New Jersey, USA. IN - Modi, Anar. Division of Endocrinology, Diabetes & Metabolism, Cooper University Hospital, Camden, New Jersey, USA. IN - Tripathi, Hemantkumar. Mower Central Research Lab, Sinai Hospital of Baltimore, Baltimore, Maryland, USA. IN - Agrawal, Abhinav. Department of Medicine, Monmouth Medical Center, Long Branch, New Jersey, USA. TI - Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of the lung. SO - BMJ Case Reports. 2016, 2016 Jan 05 AS - BMJ Case Rep. 2016, 2016 Jan 05 NJ - BMJ case reports PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101526291 IO - BMJ Case Rep SB - Index Medicus CP - England MH - *Adenocarcinoma/co [Complications] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Female MH - Humans MH - *Lung Neoplasms/co [Complications] MH - Middle Aged MH - *Thyroiditis/ci [Chemically Induced] MH - Thyrotoxicosis/et [Etiology] AB - Thyroiditis is characterised by transient hyperthyroidism, followed sometimes by hypothyroidism, and then recovery. We report a case of painless drug-induced thyroiditis-in a patient with no history of any thyroid disorder-treated with Nivolumab (an IgG4 monoclonal antibody against Programmed Death Receptor 1). The purpose of this case report is to increase awareness among clinicians regarding this possible adverse effect from Nivolumab, and discuss the possible pathophysiology and management strategies in such patients. AB - Copyright 2016 BMJ Publishing Group Ltd. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 31YO63LBSN (nivolumab) ES - 1757-790X IL - 1757-790X DI - bcr2015213692 DI - bcr-2015-213692 DO - https://dx.doi.org/10.1136/bcr-2015-213692 PT - Case Reports PT - Journal Article ID - 26733436 [pubmed] ID - bcr-2015-213692 [pii] ID - 10.1136/bcr-2015-213692 [doi] PP - epublish LG - English EP - 20160105 DP - 2016 Jan 05 DC - 20160106 EZ - 2016/01/07 06:00 DA - 2016/10/11 06:00 DT - 2016/01/07 06:00 YR - 2016 ED - 20161010 RD - 20161117 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26733436 <93. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26733436 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Verma I AU - Modi A AU - Tripathi H AU - Agrawal A AI - Agrawal, Abhinav; ORCID: http://orcid.org/0000-0003-1080-6449 FA - Verma, Isha FA - Modi, Anar FA - Tripathi, Hemantkumar FA - Agrawal, Abhinav IN - Verma, Isha. Department of Medicine, Monmouth Medical Center, Long Branch, New Jersey, USA. IN - Modi, Anar. Division of Endocrinology, Diabetes & Metabolism, Cooper University Hospital, Camden, New Jersey, USA. IN - Tripathi, Hemantkumar. Mower Central Research Lab, Sinai Hospital of Baltimore, Baltimore, Maryland, USA. IN - Agrawal, Abhinav. Department of Medicine, Monmouth Medical Center, Long Branch, New Jersey, USA. TI - Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of the lung. SO - BMJ Case Reports. 2016, 2016 Jan 05 AS - BMJ Case Rep. 2016, 2016 Jan 05 NJ - BMJ case reports PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101526291 IO - BMJ Case Rep SB - Index Medicus CP - England MH - *Adenocarcinoma/co [Complications] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Female MH - Humans MH - *Lung Neoplasms/co [Complications] MH - Middle Aged MH - *Thyroiditis/ci [Chemically Induced] MH - Thyrotoxicosis/et [Etiology] AB - Thyroiditis is characterised by transient hyperthyroidism, followed sometimes by hypothyroidism, and then recovery. We report a case of painless drug-induced thyroiditis-in a patient with no history of any thyroid disorder-treated with Nivolumab (an IgG4 monoclonal antibody against Programmed Death Receptor 1). The purpose of this case report is to increase awareness among clinicians regarding this possible adverse effect from Nivolumab, and discuss the possible pathophysiology and management strategies in such patients. AB - Copyright 2016 BMJ Publishing Group Ltd. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 31YO63LBSN (nivolumab) ES - 1757-790X IL - 1757-790X DI - bcr2015213692 DI - bcr-2015-213692 DO - https://dx.doi.org/10.1136/bcr-2015-213692 PT - Case Reports PT - Journal Article ID - 26733436 [pubmed] ID - bcr-2015-213692 [pii] ID - 10.1136/bcr-2015-213692 [doi] PP - epublish LG - English EP - 20160105 DP - 2016 Jan 05 DC - 20160106 EZ - 2016/01/07 06:00 DA - 2016/10/11 06:00 DT - 2016/01/07 06:00 YR - 2016 ED - 20161010 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26733436 <94. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26681547 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Rossi E AU - Sgambato A AU - De Chiara G AU - Casaluce F AU - Losanno T AU - Sacco PC AU - Santabarbara G AU - Gridelli C FA - Rossi, Emanuela FA - Sgambato, Assunta FA - De Chiara, Giovanni FA - Casaluce, Francesca FA - Losanno, Tania FA - Sacco, Paola Claudia FA - Santabarbara, Giuseppe FA - Gridelli, Cesare IN - Rossi, Emanuela. a Division of Medical Oncology , "S. G. Moscati" Hospital , Avellino , Italy. IN - Sgambato, Assunta. b Department of Clinical and Experimental Medicine , Second University of Naples , Naples , Italy. IN - De Chiara, Giovanni. c Division of Pathologic Anatomy , "S. G. Moscati" Hospital , Avellino , Italy. IN - Casaluce, Francesca. b Department of Clinical and Experimental Medicine , Second University of Naples , Naples , Italy. IN - Losanno, Tania. d Department of Experimental Medicine , "Sapienza" University , Rome , Italy. IN - Sacco, Paola Claudia. a Division of Medical Oncology , "S. G. Moscati" Hospital , Avellino , Italy. IN - Santabarbara, Giuseppe. a Division of Medical Oncology , "S. G. Moscati" Hospital , Avellino , Italy. IN - Gridelli, Cesare. a Division of Medical Oncology , "S. G. Moscati" Hospital , Avellino , Italy. TI - Endocrinopathies induced by immune-checkpoint inhibitors in advanced non-small cell lung cancer. [Review] SO - Expert Review of Clinical Pharmacology. 9(3):419-28, 2016 AS - Expert Rev Clin Pharmacol. 9(3):419-28, 2016 NJ - Expert review of clinical pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101278296 IO - Expert Rev Clin Pharmacol SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/pd [Pharmacology] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/pd [Pharmacology] MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/pd [Pharmacology] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/im [Immunology] MH - Carcinoma, Non-Small-Cell Lung/pa [Pathology] MH - *Endocrine System Diseases/ci [Chemically Induced] MH - Endocrine System Diseases/di [Diagnosis] MH - Endocrine System Diseases/th [Therapy] MH - Humans MH - *Immunotherapy/ae [Adverse Effects] MH - Immunotherapy/mt [Methods] MH - Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/im [Immunology] MH - Lung Neoplasms/pa [Pathology] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] KW - CTLA-4; NSCLC; PD-1; PD-L1; endocrine toxicities; immunotherapy AB - The advent of immunotherapy has recently expanded the therapeutic options in advanced non-small cell lung cancer (NSCLC). In these patients, the recent efficacy demonstration of antibodies against immune checkpoints: the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1), has led to approval of nivolumab and pembrolizumab (anti-PD-1) in the treatment of advanced NSCLC. The mechanism of action of checkpoint inhibitors explains the development of autoimmune diseases as a side-effect of these medications. Among these, a spectrum of endocrine disorders has been also reported. This manuscript focuses particularly on endocrine disorders induced by immuno-checkpoint inhibitors employed in NSCLC, in order to suggest the strategies for their diagnosis and effective management. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (CD274 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) RN - DPT0O3T46P (pembrolizumab) ES - 1751-2441 IL - 1751-2433 DO - https://dx.doi.org/10.1586/17512433.2016.1133289 PT - Journal Article PT - Review ID - 26681547 [pubmed] ID - 10.1586/17512433.2016.1133289 [doi] PP - ppublish LG - English EP - 20160206 DP - 2016 DC - 20160225 EZ - 2015/12/19 06:00 DA - 2016/10/08 06:00 DT - 2015/12/19 06:00 YR - 2016 ED - 20161007 RD - 20161008 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26681547 <95. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26681547 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Rossi E AU - Sgambato A AU - De Chiara G AU - Casaluce F AU - Losanno T AU - Sacco PC AU - Santabarbara G AU - Gridelli C FA - Rossi, Emanuela FA - Sgambato, Assunta FA - De Chiara, Giovanni FA - Casaluce, Francesca FA - Losanno, Tania FA - Sacco, Paola Claudia FA - Santabarbara, Giuseppe FA - Gridelli, Cesare IN - Rossi, Emanuela. a Division of Medical Oncology , "S. G. Moscati" Hospital , Avellino , Italy. IN - Sgambato, Assunta. b Department of Clinical and Experimental Medicine , Second University of Naples , Naples , Italy. IN - De Chiara, Giovanni. c Division of Pathologic Anatomy , "S. G. Moscati" Hospital , Avellino , Italy. IN - Casaluce, Francesca. b Department of Clinical and Experimental Medicine , Second University of Naples , Naples , Italy. IN - Losanno, Tania. d Department of Experimental Medicine , "Sapienza" University , Rome , Italy. IN - Sacco, Paola Claudia. a Division of Medical Oncology , "S. G. Moscati" Hospital , Avellino , Italy. IN - Santabarbara, Giuseppe. a Division of Medical Oncology , "S. G. Moscati" Hospital , Avellino , Italy. IN - Gridelli, Cesare. a Division of Medical Oncology , "S. G. Moscati" Hospital , Avellino , Italy. TI - Endocrinopathies induced by immune-checkpoint inhibitors in advanced non-small cell lung cancer. [Review] SO - Expert Review of Clinical Pharmacology. 9(3):419-28, 2016 AS - Expert Rev Clin Pharmacol. 9(3):419-28, 2016 NJ - Expert review of clinical pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101278296 IO - Expert Rev Clin Pharmacol SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/pd [Pharmacology] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/pd [Pharmacology] MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/pd [Pharmacology] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/im [Immunology] MH - Carcinoma, Non-Small-Cell Lung/pa [Pathology] MH - *Endocrine System Diseases/ci [Chemically Induced] MH - Endocrine System Diseases/di [Diagnosis] MH - Endocrine System Diseases/th [Therapy] MH - Humans MH - *Immunotherapy/ae [Adverse Effects] MH - Immunotherapy/mt [Methods] MH - Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/im [Immunology] MH - Lung Neoplasms/pa [Pathology] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] KW - CTLA-4; NSCLC; PD-1; PD-L1; endocrine toxicities; immunotherapy AB - The advent of immunotherapy has recently expanded the therapeutic options in advanced non-small cell lung cancer (NSCLC). In these patients, the recent efficacy demonstration of antibodies against immune checkpoints: the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1), has led to approval of nivolumab and pembrolizumab (anti-PD-1) in the treatment of advanced NSCLC. The mechanism of action of checkpoint inhibitors explains the development of autoimmune diseases as a side-effect of these medications. Among these, a spectrum of endocrine disorders has been also reported. This manuscript focuses particularly on endocrine disorders induced by immuno-checkpoint inhibitors employed in NSCLC, in order to suggest the strategies for their diagnosis and effective management. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (CD274 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) RN - DPT0O3T46P (pembrolizumab) ES - 1751-2441 IL - 1751-2433 DO - https://dx.doi.org/10.1586/17512433.2016.1133289 PT - Journal Article PT - Review ID - 26681547 [pubmed] ID - 10.1586/17512433.2016.1133289 [doi] PP - ppublish LG - English EP - 20160206 DP - 2016 DC - 20160225 EZ - 2015/12/19 06:00 DA - 2016/10/08 06:00 DT - 2015/12/19 06:00 YR - 2016 ED - 20161007 RD - 20161230 UP - 20161230 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26681547 <96. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27688833 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Bilir SP AU - Ma Q AU - Zhao Z AU - Wehler E AU - Munakata J AU - Barber B FA - Bilir, S Pinar FA - Ma, Qiufei FA - Zhao, Zhongyun FA - Wehler, Elizabeth FA - Munakata, Julie FA - Barber, Beth IN - Bilir, S Pinar. Director, Health Economics and Outcomes Research, IMS Health, San Francisco, CA. IN - Ma, Qiufei. Senior Manager, Amgen, Thousand Oaks, CA. IN - Zhao, Zhongyun. Director, Amgen. IN - Wehler, Elizabeth. Senior Consultant, Health Economics and Outcomes Research, IMS Health, Plymouth Meeting, PA. IN - Munakata, Julie. General Manager, Medical and Scientific Services, Health Economics and Outcomes Research, IMS Health, San Francisco. IN - Barber, Beth. Executive Director, Amgen. TI - Economic Burden of Toxicities Associated with Treating Metastatic Melanoma in the United States. SO - American Health & Drug Benefits. 9(4):203-13, 2016 Jun AS - Am. health drug benefits. 9(4):203-13, 2016 Jun NJ - American health & drug benefits PI - Journal available in: Print PI - Citation processed from: Print JC - 101479877 IO - Am Health Drug Benefits CP - United States KW - adverse events; chemotherapy; cost analysis; cost of illness; dabrafenib; dacarbazine; drug-related side effects; interleukin-2; ipilimumab; metastatic melanoma; talimogene laherparepvec; temozolomide; toxicities; trametinib; vemurafenib AB - BACKGROUND: Little has been reported on the costs of managing the adverse events (AEs) associated with current therapies for patients with regional or distant metastatic melanoma. AB - OBJECTIVES: To identify treatment-related AEs in patients with metastatic melanoma and to estimate the associated costs of treating these AEs in the United States. AB - METHODS: A cost-estimation study for AEs associated with treatment of metastatic melanoma was conducted from 2012 to 2013 by identifying grades 3 and 4 AEs through the use of a comprehensive search of drug labels and English-language, published phase 2/3 studies in PubMed, conference abstracts, and the National Comprehensive Cancer Network guidelines. Resource utilization for the management of each type of AE in the outpatient setting was obtained via interviews with 5 melanoma specialists in the United States. Unit costs for an AE associated with melanoma treatment in the outpatient setting were assigned using Medicare reimbursement rates to obtain these costs. Hospitalization and length-of-stay costs were estimated for each associated AE using the large national claims database Optum Clinformatics Data Mart for the period of July 1, 2004, to November 30, 2012. AB - RESULTS: The most common AEs associated with chemotherapies used for melanoma were neutropenia, vomiting, and anemia. The most common AEs associated with vemurafenib were cutaneous squamous-cell carcinoma or keratoacanthoma, rash, and elevated liver enzymes; the most common AEs associated with dabrafenib were cutaneous squamous-cell carcinoma and pyrexia. Trametinib was most often associated with hypertension and rash. The most common AEs with ipilimumab were immune-related diarrhea or colitis, dyspnea, anemia, vomiting, and, less frequently, hypophysitis. The most common grade 3/4 AE with talimogene laherparepvec was cellulitis. The highest treatment costs for an AE in the outpatient setting were for neutropenia ($2092), headache ($609), and peripheral neuropathy ($539). The highest mean inpatient costs for an AE were for acute myocardial infarction, sepsis, and coma, which ranged from $31,682 to $47,069. Colitis or diarrhea, cutaneous squamous-cell carcinoma, thrombocytopenia, hyponatremia, oliguria or anuria, hypertension, anemia, and elevated liver enzymes were associated with mean costs for hospitalization ranging from $19,122 to $26,861. AB - CONCLUSION: The costs of managing treatment-related AEs in patients with metastatic melanoma are substantial. Effective treatments with improved safety profiles may help to reduce these costs. Until real-world evidence for the costs associated with treatment toxicity is available in the outpatient and inpatient settings, the costs estimated in this study can help inform decision makers about the cost-effectiveness of managing patients with metastatic melanoma. IS - 1942-2962 IL - 1942-2962 PT - Journal Article ID - 27688833 [pubmed] ID - PMC5004818 [pmc] PP - ppublish LG - English DP - 2016 Jun DC - 20160930 EZ - 2016/10/01 06:00 DA - 2016/10/01 06:01 DT - 2016/10/01 06:00 YR - 2016 ED - 20160930 RD - 20161011 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27688833 <97. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26691441 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Katsuta E AU - Tanaka S AU - Mogushi K AU - Shimada S AU - Akiyama Y AU - Aihara A AU - Matsumura S AU - Mitsunori Y AU - Ban D AU - Ochiai T AU - Kudo A AU - Fukamachi H AU - Tanaka H AU - Nakayama K AU - Arii S AU - Tanabe M FA - Katsuta, Eriko FA - Tanaka, Shinji FA - Mogushi, Kaoru FA - Shimada, Shu FA - Akiyama, Yoshimitsu FA - Aihara, Arihiro FA - Matsumura, Satoshi FA - Mitsunori, Yusuke FA - Ban, Daisuke FA - Ochiai, Takanori FA - Kudo, Atsushi FA - Fukamachi, Hiroshi FA - Tanaka, Hiroshi FA - Nakayama, Koh FA - Arii, Shigeki FA - Tanabe, Minoru IN - Katsuta, Eriko. Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Tanaka, Shinji. Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Mogushi, Kaoru. Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. IN - Shimada, Shu. Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Akiyama, Yoshimitsu. Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Aihara, Arihiro. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Matsumura, Satoshi. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Mitsunori, Yusuke. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Ban, Daisuke. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Ochiai, Takanori. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Kudo, Atsushi. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Fukamachi, Hiroshi. Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Tanaka, Hiroshi. Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. IN - Nakayama, Koh. Oxygen Biology Unit, Frontier Research Laboratory, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. IN - Arii, Shigeki. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. IN - Tanabe, Minoru. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. TI - CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells. SO - International Journal of Oncology. 48(2):657-69, 2016 Feb AS - Int J Oncol. 48(2):657-69, 2016 Feb NJ - International journal of oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cx5, 9306042 IO - Int. J. Oncol. SB - Index Medicus CP - Greece MH - *5'-Nucleotidase/me [Metabolism] MH - Animals MH - Biomarkers, Tumor/me [Metabolism] MH - Cell Line, Tumor MH - Cell Movement/ph [Physiology] MH - Female MH - GPI-Linked Proteins/me [Metabolism] MH - Gene Expression/ph [Physiology] MH - Humans MH - Mice MH - *Neoplastic Stem Cells/me [Metabolism] MH - *Neuroendocrine Tumors/me [Metabolism] MH - *Pancreatic Neoplasms/me [Metabolism] AB - Identification and purification of cancer stem cells (CSCs) lead to the discovery of novel therapeutic targets; however, there has been no study on isolation of the CSC population among pancreatic neuroendocrine tumors (pNETs). This study aimed to identify pNET CSCs and to characterize a therapeutic candidate for pNET CSCs. We identified CSCs by aldehyde dehydrogenase (ALDH) activity in pNET clinical specimens and cell lines. We verified whether or not these cells have the stemness property in vivo and in vitro. ALDHhigh cells, but not control bulk cells, formed spheres, proliferated under hypoxic condition as well as normoxic condition and promoted cell motility, which are features of CSCs. Injection of as few as 10 ALDHhigh cells led to subcutaneous tumor formation, and 105 ALDHhigh cells, but not control bulk cells, established metastases in mice. Comprehensive gene expression analysis revealed that genes associated with mesenchymal stem cells, including CD73, were overexpressed in ALDHhigh cells. Additionally, the in vitro and in vivo effects of an inhibitor of CD73 were investigated. The CD73 inhibitor APCP significantly attenuated in vitro sphere formation and cell motility, as well as in vivo tumor growth observed for ALDHhigh cells. Finally, its expression was evaluated using clinical pNET tissue samples. Immunohistochemical analysis of clinical tissue samples demonstrated CD73 expression was significantly correlated with the invasion into adjacent organs. Since recent studies revealed CD73 as a potential biomarker of anti-PD-1 immune checkpoint therapy, CD73 might be a promising therapeutic target for pNET CSCs. RN - 0 (Biomarkers, Tumor) RN - 0 (GPI-Linked Proteins) RN - EC 3-1-3-5 (5'-Nucleotidase) RN - EC 3-1-3-5 (NT5E protein, human) ES - 1791-2423 IL - 1019-6439 DO - https://dx.doi.org/10.3892/ijo.2015.3299 PT - Journal Article ID - 26691441 [pubmed] ID - 10.3892/ijo.2015.3299 [doi] PP - ppublish PH - 2015/09/26 [received] PH - 2015/11/05 [accepted] LG - English EP - 20151218 DP - 2016 Feb DC - 20151228 EZ - 2015/12/23 06:00 DA - 2016/09/28 06:00 DT - 2015/12/23 06:00 YR - 2016 ED - 20160927 RD - 20151228 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26691441 <98. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26926680 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wilgenhof S AU - Corthals J AU - Heirman C AU - van Baren N AU - Lucas S AU - Kvistborg P AU - Thielemans K AU - Neyns B FA - Wilgenhof, Sofie FA - Corthals, Jurgen FA - Heirman, Carlo FA - van Baren, Nicolas FA - Lucas, Sophie FA - Kvistborg, Pia FA - Thielemans, Kris FA - Neyns, Bart IN - Wilgenhof, Sofie. Sofie Wilgenhof, Kris Thielemans, and Bart Neyns, Universitair Ziekenhuis Brussel; Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans, and Bart Neyns, Vrije Universiteit Brussel; Nicolas van Baren, Ludwig Institute for Cancer Research; Sophie Lucas, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium; and Pia Kvistborg, The Netherlands Cancer Institute, Amsterdam, the Netherlands. IN - Corthals, Jurgen. Sofie Wilgenhof, Kris Thielemans, and Bart Neyns, Universitair Ziekenhuis Brussel; Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans, and Bart Neyns, Vrije Universiteit Brussel; Nicolas van Baren, Ludwig Institute for Cancer Research; Sophie Lucas, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium; and Pia Kvistborg, The Netherlands Cancer Institute, Amsterdam, the Netherlands. IN - Heirman, Carlo. Sofie Wilgenhof, Kris Thielemans, and Bart Neyns, Universitair Ziekenhuis Brussel; Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans, and Bart Neyns, Vrije Universiteit Brussel; Nicolas van Baren, Ludwig Institute for Cancer Research; Sophie Lucas, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium; and Pia Kvistborg, The Netherlands Cancer Institute, Amsterdam, the Netherlands. IN - van Baren, Nicolas. Sofie Wilgenhof, Kris Thielemans, and Bart Neyns, Universitair Ziekenhuis Brussel; Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans, and Bart Neyns, Vrije Universiteit Brussel; Nicolas van Baren, Ludwig Institute for Cancer Research; Sophie Lucas, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium; and Pia Kvistborg, The Netherlands Cancer Institute, Amsterdam, the Netherlands. IN - Lucas, Sophie. Sofie Wilgenhof, Kris Thielemans, and Bart Neyns, Universitair Ziekenhuis Brussel; Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans, and Bart Neyns, Vrije Universiteit Brussel; Nicolas van Baren, Ludwig Institute for Cancer Research; Sophie Lucas, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium; and Pia Kvistborg, The Netherlands Cancer Institute, Amsterdam, the Netherlands. IN - Kvistborg, Pia. Sofie Wilgenhof, Kris Thielemans, and Bart Neyns, Universitair Ziekenhuis Brussel; Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans, and Bart Neyns, Vrije Universiteit Brussel; Nicolas van Baren, Ludwig Institute for Cancer Research; Sophie Lucas, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium; and Pia Kvistborg, The Netherlands Cancer Institute, Amsterdam, the Netherlands. IN - Thielemans, Kris. Sofie Wilgenhof, Kris Thielemans, and Bart Neyns, Universitair Ziekenhuis Brussel; Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans, and Bart Neyns, Vrije Universiteit Brussel; Nicolas van Baren, Ludwig Institute for Cancer Research; Sophie Lucas, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium; and Pia Kvistborg, The Netherlands Cancer Institute, Amsterdam, the Netherlands. IN - Neyns, Bart. Sofie Wilgenhof, Kris Thielemans, and Bart Neyns, Universitair Ziekenhuis Brussel; Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Kris Thielemans, and Bart Neyns, Vrije Universiteit Brussel; Nicolas van Baren, Ludwig Institute for Cancer Research; Sophie Lucas, de Duve Institute, Universite Catholique de Louvain, Brussels, Belgium; and Pia Kvistborg, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Bart.Neyns@uzbrussel.be. TI - Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells (TriMixDC-MEL) Plus Ipilimumab in Patients With Pretreated Advanced Melanoma. SO - Journal of Clinical Oncology. 34(12):1330-8, 2016 Apr 20 AS - J Clin Oncol. 34(12):1330-8, 2016 Apr 20 NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Cells, Cultured MH - Chemotherapy, Adjuvant MH - Dendritic Cells/im [Immunology] MH - Dendritic Cells/me [Metabolism] MH - *Dendritic Cells/tr [Transplantation] MH - Disease Progression MH - Disease-Free Survival MH - Drug Administration Schedule MH - *Electroporation MH - Female MH - Genetic Therapy/ae [Adverse Effects] MH - *Genetic Therapy/mt [Methods] MH - Genetic Therapy/mo [Mortality] MH - Humans MH - Kaplan-Meier Estimate MH - Male MH - Melanoma/ge [Genetics] MH - Melanoma/im [Immunology] MH - Melanoma/mo [Mortality] MH - *Melanoma/th [Therapy] MH - Middle Aged MH - Proportional Hazards Models MH - *RNA, Messenger/ge [Genetics] MH - RNA, Messenger/me [Metabolism] MH - Skin Neoplasms/ge [Genetics] MH - Skin Neoplasms/im [Immunology] MH - Skin Neoplasms/mo [Mortality] MH - *Skin Neoplasms/th [Therapy] MH - Time Factors MH - Transplantation, Autologous MH - Treatment Outcome MH - Young Adult AB - PURPOSE: Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic mRNA (TriMixDC-MEL) are immunogenic and have antitumor activity as a monotherapy in patients with pretreated advanced melanoma. Ipilimumab, an immunoglobulin G1 monoclonal antibody directed against the cytotoxic T-lymphocyte-associated protein 4 receptor that counteracts physiologic suppression of T-cell function, improves the overall survival of patients with advanced melanoma. This phase II study investigated the combination of TriMixDC-MEL and ipilimumab in patients with pretreated advanced melanoma. AB - PATIENTS AND METHODS: Thirty-nine patients were treated with TriMixDC-MEL (4 x 10(6) cells administered intradermally and 20 x 10(6) cells administered intravenously) plus ipilimumab (10 mg/kg every 3 weeks for a total of four administrations, followed by maintenance therapy every 12 weeks in patients who remained progression free). Six-month disease control rate according to the immune-related response criteria served as the primary end point. AB - RESULTS: The 6-month disease control rate was 51% (95% CI, 36% to 67%), and the overall tumor response rate was 38% (including eight complete and seven partial responses). Seven complete responses and one partial tumor response are ongoing after a median follow-up time of 36 months (range, 22 to 43 months). The most common treatment-related adverse events (all grades) consisted of local DC injection site skin reactions (100%), transient post-DC infusion chills (38%) and flu-like symptoms (84%), dermatitis (64%), hepatitis (13%), hypophysitis (15%), and diarrhea/colitis (15%). Grade 3 or 4 immune-related adverse events occurred in 36% of patients. There was no grade 5 adverse event. AB - CONCLUSION: The combination of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of highly durable tumor responses in patients with pretreated advanced melanoma. AB - Copyright © 2016 by American Society of Clinical Oncology. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (RNA, Messenger) RN - 6T8C155666 (ipilimumab) ES - 1527-7755 IL - 0732-183X DI - JCO.2015.63.4121 DO - https://dx.doi.org/10.1200/JCO.2015.63.4121 PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26926680 [pubmed] ID - JCO.2015.63.4121 [pii] ID - 10.1200/JCO.2015.63.4121 [doi] PP - ppublish LG - English EP - 20160229 DP - 2016 Apr 20 DC - 20160414 EZ - 2016/03/02 06:00 DA - 2016/09/07 06:00 DT - 2016/03/02 06:00 YR - 2016 ED - 20160906 RD - 20161126 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26926680 <99. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27555886 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Iyevleva AG AU - Imyanitov EN FA - Iyevleva, Aglaya G FA - Imyanitov, Evgeny N IN - Iyevleva, Aglaya G. N.N. Petrov Institute of Oncology, Pesochny-2, St. Petersburg, 197758 Russia ; St. Petersburg Pediatric Medical University, St. Petersburg, 194100 Russia. IN - Imyanitov, Evgeny N. N.N. Petrov Institute of Oncology, Pesochny-2, St. Petersburg, 197758 Russia ; St. Petersburg Pediatric Medical University, St. Petersburg, 194100 Russia ; I.I. Mechnikov North-Western Medical University, St. Petersburg, 191015 Russia ; St. Petersburg State University, St. Petersburg, 199034 Russia. TI - Cytotoxic and targeted therapy for hereditary cancers. [Review] SO - Hereditary Cancer in Clinical Practice. 14(1):17, 2016 AS - Hered. Cancer Clin. Pract.. 14(1):17, 2016 NJ - Hereditary cancer in clinical practice PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101231179 IO - Hered Cancer Clin Pract PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994296 CP - Poland KW - BRCA1; BRCA2; Breast cancer; Colorectal cancer; Cytotoxic therapy; Familial cancer; Hereditary cancer syndromes; Ovarian cancer; Predictive markers; Targeted therapy AB - There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning. IS - 1731-2302 IL - 1731-2302 DI - 57 DO - https://dx.doi.org/10.1186/s13053-016-0057-2 PT - Journal Article PT - Review ID - 27555886 [pubmed] ID - 10.1186/s13053-016-0057-2 [doi] ID - 57 [pii] ID - PMC4994296 [pmc] PP - epublish PH - 2016/05/12 [received] PH - 2016/06/27 [accepted] LG - English EP - 20160823 DP - 2016 DC - 20160824 EZ - 2016/08/25 06:00 DA - 2016/08/25 06:01 DT - 2016/08/25 06:00 YR - 2016 ED - 20160824 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27555886 <100. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26585231 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kausar T AU - Schreiber JS AU - Karnak D AU - Parsels LA AU - Parsels JD AU - Davis MA AU - Zhao L AU - Maybaum J AU - Lawrence TS AU - Morgan MA FA - Kausar, Tasneem FA - Schreiber, Jason S FA - Karnak, David FA - Parsels, Leslie A FA - Parsels, Joshua D FA - Davis, Mary A FA - Zhao, Lili FA - Maybaum, Jonathan FA - Lawrence, Theodore S FA - Morgan, Meredith A IN - Kausar, Tasneem. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Schreiber, Jason S. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Karnak, David. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Parsels, Leslie A. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Parsels, Joshua D. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Davis, Mary A. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Zhao, Lili. Biostatistics Unit, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109. IN - Maybaum, Jonathan. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Lawrence, Theodore S. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Morgan, Meredith A. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. Electronic address: mmccrack@med.umich.edu. TI - Sensitization of Pancreatic Cancers to Gemcitabine Chemoradiation by WEE1 Kinase Inhibition Depends on Homologous Recombination Repair. SO - Neoplasia (New York). 17(10):757-66, 2015 Oct AS - Neoplasia. 17(10):757-66, 2015 Oct NJ - Neoplasia (New York, N.Y.) PI - Journal available in: Print PI - Citation processed from: Internet JC - dru, 100886622 IO - Neoplasia PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4656803 SB - Index Medicus CP - United States MH - Animals MH - Apoptosis/de [Drug Effects] MH - Blotting, Western MH - *Cell Cycle Proteins/ai [Antagonists & Inhibitors] MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Proliferation/de [Drug Effects] MH - Chemoradiotherapy MH - DNA Damage/de [Drug Effects] MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Female MH - Flow Cytometry MH - Fluorescent Antibody Technique MH - Humans MH - Immunoenzyme Techniques MH - Mice MH - Mice, Nude MH - *Nuclear Proteins/ai [Antagonists & Inhibitors] MH - Nuclear Proteins/me [Metabolism] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/pa [Pathology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Phosphorylation/de [Drug Effects] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - *Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Tyrosine Kinases/me [Metabolism] MH - *Radiation-Sensitizing Agents/pd [Pharmacology] MH - *Recombinational DNA Repair/de [Drug Effects] MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays AB - To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR) repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by gammaH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively. We found that AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type but not BRCA2 mutant pancreatic cancer cells. In all cells, AZD1775 caused inhibition of CDK1 phosphorylation and G2 checkpoint abrogation. However, sensitization by AZD1775 was associated with persistent gammaH2AX and inhibition of RAD51 focus formation. In HR-proficient (BRCA2 wild-type) or -deficient (BRAC2 null) isogenic cells, AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type, but not in BRCA2 null cells, despite significant G2 checkpoint abrogation. In patient-derived pancreatic tumor xenografts, AZD1775 significantly inhibited tumor growth and impaired RAD51 focus formation in response to gemcitabine-radiation. In conclusion, WEE1 inhibition by AZD1775 is an effective strategy for sensitizing pancreatic cancers to gemcitabine chemoradiation. Although this sensitization is accompanied by inhibition of CDK1 phosphorylation and G2 checkpoint abrogation, this mechanism is not sufficient for sensitization. Our findings demonstrate that sensitization to chemoradiation by WEE1 inhibition results from inhibition of HR repair and suggest that patient tumors without underlying HR defects would benefit most from this therapy. AB - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. RN - 0 (Cell Cycle Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Radiation-Sensitizing Agents) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7-10-1 (Protein-Tyrosine Kinases) RN - EC 2-7-10-2 (WEE1 protein, human) ES - 1476-5586 IL - 1476-5586 DI - S1476-5586(15)00119-0 DO - https://dx.doi.org/10.1016/j.neo.2015.09.006 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26585231 [pubmed] ID - S1476-5586(15)00119-0 [pii] ID - 10.1016/j.neo.2015.09.006 [doi] ID - PMC4656803 [pmc] PP - ppublish PH - 2015/08/14 [received] PH - 2015/09/18 [revised] PH - 2015/09/24 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT02037230 SL - https://clinicaltrials.gov/search/term=NCT02037230 GI - No: R01CA163895 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA046592 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA130810 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA163895 Organization: (CA) *NCI NIH HHS* Country: United States No: P50CA130810 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2015 Oct DC - 20151120 EZ - 2015/11/21 06:00 DA - 2016/08/24 06:00 DT - 2015/11/21 06:00 YR - 2015 ED - 20160823 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26585231 <101. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26585231 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kausar T AU - Schreiber JS AU - Karnak D AU - Parsels LA AU - Parsels JD AU - Davis MA AU - Zhao L AU - Maybaum J AU - Lawrence TS AU - Morgan MA FA - Kausar, Tasneem FA - Schreiber, Jason S FA - Karnak, David FA - Parsels, Leslie A FA - Parsels, Joshua D FA - Davis, Mary A FA - Zhao, Lili FA - Maybaum, Jonathan FA - Lawrence, Theodore S FA - Morgan, Meredith A IN - Kausar, Tasneem. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Schreiber, Jason S. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Karnak, David. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Parsels, Leslie A. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Parsels, Joshua D. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Davis, Mary A. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Zhao, Lili. Biostatistics Unit, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109. IN - Maybaum, Jonathan. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Lawrence, Theodore S. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. IN - Morgan, Meredith A. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109. Electronic address: mmccrack@med.umich.edu. TI - Sensitization of Pancreatic Cancers to Gemcitabine Chemoradiation by WEE1 Kinase Inhibition Depends on Homologous Recombination Repair. SO - Neoplasia (New York). 17(10):757-66, 2015 Oct AS - Neoplasia. 17(10):757-66, 2015 Oct NJ - Neoplasia (New York, N.Y.) PI - Journal available in: Print PI - Citation processed from: Internet JC - dru, 100886622 IO - Neoplasia PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4656803 SB - Index Medicus CP - United States MH - Animals MH - Apoptosis/de [Drug Effects] MH - Blotting, Western MH - *Cell Cycle Proteins/ai [Antagonists & Inhibitors] MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Proliferation/de [Drug Effects] MH - Chemoradiotherapy MH - DNA Damage/de [Drug Effects] MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Female MH - Flow Cytometry MH - Fluorescent Antibody Technique MH - Humans MH - Immunoenzyme Techniques MH - Mice MH - Mice, Nude MH - *Nuclear Proteins/ai [Antagonists & Inhibitors] MH - Nuclear Proteins/me [Metabolism] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/pa [Pathology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Phosphorylation/de [Drug Effects] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - *Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Tyrosine Kinases/me [Metabolism] MH - *Radiation-Sensitizing Agents/pd [Pharmacology] MH - *Recombinational DNA Repair/de [Drug Effects] MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays AB - To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR) repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by gammaH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively. We found that AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type but not BRCA2 mutant pancreatic cancer cells. In all cells, AZD1775 caused inhibition of CDK1 phosphorylation and G2 checkpoint abrogation. However, sensitization by AZD1775 was associated with persistent gammaH2AX and inhibition of RAD51 focus formation. In HR-proficient (BRCA2 wild-type) or -deficient (BRAC2 null) isogenic cells, AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type, but not in BRCA2 null cells, despite significant G2 checkpoint abrogation. In patient-derived pancreatic tumor xenografts, AZD1775 significantly inhibited tumor growth and impaired RAD51 focus formation in response to gemcitabine-radiation. In conclusion, WEE1 inhibition by AZD1775 is an effective strategy for sensitizing pancreatic cancers to gemcitabine chemoradiation. Although this sensitization is accompanied by inhibition of CDK1 phosphorylation and G2 checkpoint abrogation, this mechanism is not sufficient for sensitization. Our findings demonstrate that sensitization to chemoradiation by WEE1 inhibition results from inhibition of HR repair and suggest that patient tumors without underlying HR defects would benefit most from this therapy. AB - Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. RN - 0 (Cell Cycle Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Radiation-Sensitizing Agents) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7-10-1 (Protein-Tyrosine Kinases) RN - EC 2-7-10-2 (WEE1 protein, human) ES - 1476-5586 IL - 1476-5586 DI - S1476-5586(15)00119-0 DO - https://dx.doi.org/10.1016/j.neo.2015.09.006 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26585231 [pubmed] ID - S1476-5586(15)00119-0 [pii] ID - 10.1016/j.neo.2015.09.006 [doi] ID - PMC4656803 [pmc] PP - ppublish PH - 2015/08/14 [received] PH - 2015/09/18 [revised] PH - 2015/09/24 [accepted] GI - No: R01CA163895 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA046592 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA130810 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA163895 Organization: (CA) *NCI NIH HHS* Country: United States No: P50CA130810 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2015 Oct DC - 20151120 EZ - 2015/11/21 06:00 DA - 2016/08/24 06:00 DT - 2015/11/21 06:00 YR - 2015 ED - 20160823 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26585231 <102. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26561720 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Awuah SG AU - Zheng YR AU - Bruno PM AU - Hemann MT AU - Lippard SJ FA - Awuah, Samuel G FA - Zheng, Yao-Rong FA - Bruno, Peter M FA - Hemann, Michael T FA - Lippard, Stephen J IN - Awuah, Samuel G. Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States. IN - Zheng, Yao-Rong. Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States. IN - Bruno, Peter M. The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States. IN - Hemann, Michael T. The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States. IN - Lippard, Stephen J. Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States. IN - Lippard, Stephen J. The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States. TI - A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy.[Erratum appears in J Am Chem Soc. 2016 Mar 9;138(9):3250; PMID: 26916820] SO - Journal of the American Chemical Society. 137(47):14854-7, 2015 Dec 02 AS - J Am Chem Soc. 137(47):14854-7, 2015 Dec 02 NJ - Journal of the American Chemical Society PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - h59, 7503056 IO - J. Am. Chem. Soc. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772771 OI - Source: NLM. NIHMS757395 SB - Index Medicus CP - United States MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Female MH - Humans MH - *Immunotherapy MH - *Indoleamine-Pyrrole 2,3,-Dioxygenase/me [Metabolism] MH - Ovarian Neoplasms/dt [Drug Therapy] MH - *Ovarian Neoplasms/th [Therapy] AB - Expression of indoleamine-2,3-dioxygenase (IDO), an immunosuppressive enzyme in human tumors, leads to immune evasion and tumor tolerance. IDO is therefore a tumor immunotherapeutic target, and several IDO inhibitors are currently undergoing clinical trials. IDO inhibitors can enhance the efficacy of common cancer chemotherapeutics. Here we investigate Pt(IV)-(D)-1-methyltryptophan conjugates 1 and 2 for combined immunomodulation and DNA cross-link-triggered apoptosis for cancer "immuno-chemotherapy". Compound 2 effectively kills hormone-dependent, cisplatin-resistant human ovarian cancer cells, inhibiting IDO by transcriptional deregulation of the autocrine-signaling loop IDO-AHR-IL6, which blocks kynurenine production and promotes T-cell proliferation. Additionally, 1 and 2 display low toxicity in mice and are stable in blood. To our knowledge, this construct is the first Pt drug candidate with immune checkpoint blockade properties. RN - 0 (Antineoplastic Agents) RN - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) ES - 1520-5126 IL - 0002-7863 DO - https://dx.doi.org/10.1021/jacs.5b10182 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 26561720 [pubmed] ID - 10.1021/jacs.5b10182 [doi] ID - PMC4772771 [pmc] ID - NIHMS757395 [mid] PP - ppublish GI - No: R01 CA034992 Organization: (CA) *NCI NIH HHS* Country: United States No: R37 CA034992 Organization: (CA) *NCI NIH HHS* Country: United States No: CA034992 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20151118 DP - 2015 Dec 02 DC - 20151202 EZ - 2015/11/13 06:00 DA - 2016/08/23 06:00 DT - 2015/11/13 06:00 YR - 2015 ED - 20160822 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26561720 <103. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26922661 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Eigentler TK AU - Hassel JC AU - Berking C AU - Aberle J AU - Bachmann O AU - Grunwald V AU - Kahler KC AU - Loquai C AU - Reinmuth N AU - Steins M AU - Zimmer L AU - Sendl A AU - Gutzmer R FA - Eigentler, Thomas K FA - Hassel, Jessica C FA - Berking, Carola FA - Aberle, Jens FA - Bachmann, Oliver FA - Grunwald, Viktor FA - Kahler, Katharina C FA - Loquai, Carmen FA - Reinmuth, Niels FA - Steins, Martin FA - Zimmer, Lisa FA - Sendl, Anna FA - Gutzmer, Ralf IN - Eigentler, Thomas K. Department of Dermatology, Center for Dermatooncology, University Medical Center Tubingen, Germany. Electronic address: thomas.eigentler@med.uni-tuebingen.de. IN - Hassel, Jessica C. Department of Dermatology, University Hospital Heidelberg, Germany. Electronic address: jessica.hassel@med.uni-heidelberg.de. IN - Berking, Carola. Department of Dermatology and Allergy, University Hospital Munich, Munich, Germany. Electronic address: carola.berking@med.uni-muenchen.de. IN - Aberle, Jens. Department of Internal Medicine III, University Hospital Hamburg Eppendorf, Germany. Electronic address: aberle@uke.de. IN - Bachmann, Oliver. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany. Electronic address: bachmann.oliver@mh-hannover.de. IN - Grunwald, Viktor. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany. Electronic address: Gruenwald.Victor@mh-hannover.de. IN - Kahler, Katharina C. Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Germany. Electronic address: kckaehler@dermatology.uni-kiel.de. IN - Loquai, Carmen. Department of Dermatology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany. Electronic address: Carmen.Loquai@unimedizin-mainz.de. IN - Reinmuth, Niels. Department of Thoracic Oncology, LungenClinic Grosshansdorf, Germany. Electronic address: n.reinmuth@lungenclinic.de. IN - Steins, Martin. Department of Thoracic Oncology, Thoraxklinik, University of Heidelberg, Germany. Electronic address: martin.steins@med.uni-heidelberg.de. IN - Zimmer, Lisa. Department of Dermatology, University Hospital, University Essen-Duisburg, Germany. Electronic address: lisa.zimmer@uk-essen.de. IN - Sendl, Anna. Bristol-Myers Squibb GmbH&KGaA, Munich, Germany. Electronic address: anna.sendl@bms.com. IN - Gutzmer, Ralf. Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Germany. Electronic address: gutzmer.ralf@mh-hannover.de. TI - Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. [Review] SO - Cancer Treatment Reviews. 45:7-18, 2016 Apr AS - Cancer Treat Rev. 45:7-18, 2016 Apr NJ - Cancer treatment reviews PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnn, 7502030 IO - Cancer Treat. Rev. SB - Index Medicus CP - Netherlands MH - Antibodies, Monoclonal/im [Immunology] MH - Antibodies, Monoclonal/pd [Pharmacology] MH - *Antibodies, Monoclonal MH - Antibodies, Monoclonal, Humanized/im [Immunology] MH - Antibodies, Monoclonal, Humanized/pd [Pharmacology] MH - *Antibodies, Monoclonal, Humanized MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antineoplastic Agents/im [Immunology] MH - Antineoplastic Agents/pd [Pharmacology] MH - Disease Management MH - Drug-Related Side Effects and Adverse Reactions/dt [Drug Therapy] MH - Drug-Related Side Effects and Adverse Reactions/et [Etiology] MH - Drug-Related Side Effects and Adverse Reactions/im [Immunology] MH - *Drug-Related Side Effects and Adverse Reactions MH - Early Diagnosis MH - Humans MH - *Immunosuppressive Agents/tu [Therapeutic Use] MH - Monitoring, Immunologic MH - *Neoplasms/dt [Drug Therapy] MH - *Programmed Cell Death 1 Receptor/im [Immunology] KW - Adverse drug reaction; Immune-related adverse events; Immunotherapy; Nivolumab; PD-1; Pembrolizumab AB - PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events. This spectrum is different from toxicities known for kinase inhibitors or cytotoxic drugs. Since PD-1 directed therapies show effectivity in an increasing number of malignant diseases, their clinical usage will increase rapidly. Therefore clinicians from different specialities such as medical oncology, internal medicine, family doctors and emergency unit staff should be aware of the adverse effects of PD-1 checkpoint inhibitors to avoid delays in diagnosis and treatment. Based on pooled data from pivotal trials as reported by the European Medicines Agency, the present paper reviews incidences and kinetics of onset and resolution of immune-mediated "adverse events of specific interest" (AEOSI) of both approved PD-1 inhibitors nivolumab and pembrolizumab. In general, the severity of AEOSI is mild to moderate (grade 1-2); the frequency of immune-mediated but also idiopathic grade 3-4 adverse drug reactions is 2% for any event term. Recommendations for the diagnosis, monitoring and management of the relevant dermatological, gastrointestinal, pulmonary, endocrine, renal and hepatic toxicities are convened by an expert panel that consolidated and clarified treatment recommendations after the onset of AEOSI. Although the time of onset is not predictable - the medians range from 1 to 6months - the huge majority of events is reversible, with no impact of the time of onset. By the systemic use of glucocorticoids, notably methylprednisolone or equivalents, most AEOSI are well manageable. Non-steroidal immunosuppressants may be used in certain cases of refractory/recalcitrant, long-lasting immune toxicities. With regard to the outstanding clinical activity of the anti-PD-1 antibodies, therapy restart is the principal therapeutic option after recovery of grade 2 AEOSI, or diminution of higher grade skin or endocrine events to mild severity. Early diagnosis and close clinical monitoring are essential for successful management of immune-related adverse events. AB - Copyright © 2016 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (Immunosuppressive Agents) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) RN - DPT0O3T46P (pembrolizumab) ES - 1532-1967 IL - 0305-7372 DI - S0305-7372(16)00018-9 DO - https://dx.doi.org/10.1016/j.ctrv.2016.02.003 PT - Journal Article PT - Review ID - 26922661 [pubmed] ID - S0305-7372(16)00018-9 [pii] ID - 10.1016/j.ctrv.2016.02.003 [doi] PP - ppublish PH - 2015/12/17 [received] PH - 2016/02/12 [revised] PH - 2016/02/13 [accepted] LG - English EP - 20160218 DP - 2016 Apr DC - 20160409 EZ - 2016/02/29 06:00 DA - 2016/08/20 06:00 DT - 2016/02/29 06:00 YR - 2016 ED - 20160819 RD - 20160409 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26922661 <104. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26374557 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Zhang Y AU - Choi M FA - Zhang, Yue FA - Choi, Minsig IN - Choi, Minsig. Stony Brook University, HSC 15-053C, 101 Nicholls Rd. Stony Brook, New York 11794-8151. TI - Immune Therapy in Pancreatic Cancer: Now and the Future?. [Review] SO - Reviews on Recent Clinical Trials. 10(4):317-25, 2015 AS - Rev Recent Clin Trials. 10(4):317-25, 2015 NJ - Reviews on recent clinical trials PI - Journal available in: Print PI - Citation processed from: Internet JC - 101270873 IO - Rev Recent Clin Trials SB - Index Medicus CP - United Arab Emirates MH - Adult MH - Aged MH - *Cancer Vaccines/tu [Therapeutic Use] MH - Clinical Trials, Phase III as Topic MH - Disease-Free Survival MH - Female MH - Forecasting MH - Humans MH - *Immunotherapy/st [Standards] MH - *Immunotherapy/td [Trends] MH - Male MH - Middle Aged MH - Neoplasm Invasiveness/pa [Pathology] MH - Neoplasm Recurrence, Local/mo [Mortality] MH - *Neoplasm Recurrence, Local/pa [Pathology] MH - Neoplasm Staging MH - Pancreatic Neoplasms/mo [Mortality] MH - *Pancreatic Neoplasms/pa [Pathology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Risk Assessment MH - Survival Analysis MH - Treatment Outcome AB - Pancreatic cancer continues to be the most lethal malignancy with rising incidence. Traditional chemotherapy remains the standard treatment for advanced pancreatic cancer. Regimens like FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) or gemcitabine and nab-paclitaxel have been used to palliate symptoms and prolong survival. Immune therapy is changing the current treatment paradigm for malignancy, especially with the recent development of antibodies that can modulate immune checkpoint pathways. Immunotherapy to treat pancreatic cancer is a promising approach due to its low toxicity and potential for creating life- long immune response. Multiple large phase III trials using simple vaccination strategies have failed to modulate the immune response in pancreatic cancer. However novel strategies with whole cell vaccines using hyperacute rejections (Algenpantucel- L) immunotherapy demonstrated 62% and 86% 12-month disease free survival and overall survival in resected pancreatic cancer patients. Combination of whole cell vaccine GVAX and mesothelin-secreting vaccine CRS-207 demonstrated an overall survival benefit in metastatic refractory pancreatic cancer patients. In the paper, we review the recently published and ongoing clinical trials using immune based treatment for pancreatic cancer. RN - 0 (Cancer Vaccines) ES - 1876-1038 IL - 1574-8871 DI - RRCT-EPUB-70454 PT - Journal Article PT - Review ID - 26374557 [pubmed] ID - RRCT-EPUB-70454 [pii] PP - ppublish PH - 2015/06/05 [received] PH - 2015/07/28 [revised] PH - 2015/07/31 [accepted] LG - English DP - 2015 DC - 20151103 EZ - 2015/09/17 06:00 DA - 2016/08/19 06:00 DT - 2015/09/17 06:00 YR - 2015 ED - 20160818 RD - 20151103 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26374557 <105. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24917416 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lu J AU - Lee-Gabel L AU - Nadeau MC AU - Ferencz TM AU - Soefje SA FA - Lu, Jing FA - Lee-Gabel, Linda FA - Nadeau, Michelle C FA - Ferencz, Thomas M FA - Soefje, Scott A IN - Lu, Jing. Department of Pharmacy, Smilow Cancer Hospital at Yale-New Haven, New Haven, USA jing.lu@ynhh.org. IN - Lee-Gabel, Linda. Department of Pharmacy, Smilow Cancer Hospital at Yale-New Haven, New Haven, USA. IN - Nadeau, Michelle C. Department of Pharmacy, Smilow Cancer Hospital at Yale-New Haven, New Haven, USA. IN - Ferencz, Thomas M. Department of Pharmacy, Smilow Cancer Hospital at Yale-New Haven, New Haven, USA. IN - Soefje, Scott A. Department of Pharmacy, University Medical Center Brackenridge, Seton Healthcare Family, Austin, USA. TI - Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy. [Review] SO - Journal of Oncology Pharmacy Practice. 21(6):451-67, 2015 Dec AS - J Oncol Pharm Pract. 21(6):451-67, 2015 Dec NJ - Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9511372 IO - J Oncol Pharm Pract SB - Index Medicus CP - England MH - Animals MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Humans MH - *Immunotherapy/mt [Methods] MH - Immunotherapy/td [Trends] MH - *Neoplasms/th [Therapy] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - *Signal Transduction/de [Drug Effects] MH - T-Lymphocytes/de [Drug Effects] KW - Antiprogrammed death-1/programmed death-ligand 1; BMS-936559; CTLA-4 blockade; MEDI4736; MK-3475; MPDL3280A; MSB0010718C; immune-related adverse event; ipilimumab; management of adverse events; nivolumab; pidilizumab AB - Significant enthusiasm currently exists for new immunotherapeutic strategies: blocking the interaction between programmed death-1 receptor on T-cells and programmed death-ligand 1 on tumor cells to boost immune system stimulation to fight cancer. Immunomodulation with the antiprogrammed death-1/programmed death-ligand 1 monoclonal antibodies has shown to mediate tumor shrinkage and extend overall survival from several pivotal phase I/II studies in melanoma, renal cell carcinoma, and non-small cell lung cancer. This has prompted multiple large ongoing phase III trials with the expectation for fast-track FDA approvals to satisfy unmet medical needs. Compounds targeting the programmed death-1 pathway that are in clinical trials fall into two major categories, namely antiprogrammed death-1 antibodies: Nivolumab, MK-3475, and pidilizumab; and antiprogrammed death-ligand 1 antibodies: MPDL3280A, BMS-936559, MEDI4736, and MSB0010718C. We reviewed the clinical efficacy and safety of each compound based upon major registered clinical trials and published clinical data. Overall, response rate of more than 20% is consistently seen across all these trials, with maximal response of approximately 50% achieved by certain single antiprogrammed death-1 agents or when used in combination with cytotoxic T-lymphocyte antigen-4 blockade. The responses seen are early, durable, and have continued after treatment discontinuation. Immune-related adverse events are the most common side effects seen in these clinical trials. Overall, the skin and gastrointestinal tract are the most common organ systems affected by these compounds while hepatic, endocrine, and neurologic events are less frequent. These side effects are low grade, manageable, and typically resolve within a relatively short time frame with a predictable resolution pattern given proper management. We therefore propose detailed guidelines for management of major immune-related adverse events that are anticipated with antiprogrammed death-1/programmed death-ligand 1 therapies based on general experience with other monoclonal antibodies and the established management algorithms for immune-related adverse events for cytotoxic T-lymphocyte antigen-4 blockade with ipilimumab. We anticipate that the antiprogrammed death-1 strategy will become a viable and crucial clinical strategy for cancer therapy. AB - Copyright © The Author(s) 2014. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1477-092X IL - 1078-1552 DI - 1078155214538087 DO - https://dx.doi.org/10.1177/1078155214538087 PT - Journal Article PT - Review ID - 24917416 [pubmed] ID - 1078155214538087 [pii] ID - 10.1177/1078155214538087 [doi] PP - ppublish LG - English EP - 20140609 DP - 2015 Dec DC - 20151027 EZ - 2014/06/12 06:00 DA - 2016/08/17 06:00 DT - 2014/06/12 06:00 YR - 2015 ED - 20160816 RD - 20151027 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24917416 <106. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26463091 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ojalvo LS AU - Nichols PE AU - Jelovac D AU - Emens LA FA - Ojalvo, Laureen S FA - Nichols, Paige E FA - Jelovac, Danijela FA - Emens, Leisha A IN - Ojalvo, Laureen S. The Kelly Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, MD 21202, USA. IN - Nichols, Paige E. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21202, USA. IN - Jelovac, Danijela. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21202, USA. IN - Emens, Leisha A. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21202, USA. TI - Emerging immunotherapies in ovarian cancer. [Review] SO - Discovery Medicine. 20(109):97-109, 2015 Sep AS - Discov. medicin.. 20(109):97-109, 2015 Sep NJ - Discovery medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - 101250006 IO - Discov Med SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ch [Chemistry] MH - Antigens, CD274/ch [Chemistry] MH - Antigens, Neoplasm/ch [Chemistry] MH - Antineoplastic Agents/ch [Chemistry] MH - Cancer Vaccines/ch [Chemistry] MH - Clinical Trials as Topic MH - Dendritic Cells/cy [Cytology] MH - Epitopes/ch [Chemistry] MH - Female MH - Humans MH - Immune System MH - *Immunotherapy/mt [Methods] MH - *Immunotherapy/td [Trends] MH - *Ovarian Neoplasms/im [Immunology] MH - *Ovarian Neoplasms/th [Therapy] MH - T-Lymphocytes/im [Immunology] MH - Treatment Outcome MH - Tumor Microenvironment MH - United States AB - Despite a global effort to significantly reduce mortality, ovarian cancer remains the fifth leading cause of cancer death among American women, and five-year survival rates remain discouragingly low at 45%. Novel therapies are urgently needed. Notably, higher infiltration of activated immune cells into the tumor microenvironment correlates with improved ovarian cancer survival, suggesting that promoting their activity could favorably impact clinical outcomes. Immunotherapy has recently demonstrated impressive clinical benefit in a variety of solid tumors. Immunotherapy strategies tested in ovarian cancer include vaccines, adoptive T cell therapy, and immune checkpoint blockade. Ultimately, a combination immunotherapy approach that integrates immunotherapy with other cancer treatment modalities in additive or synergistic ways will most effectively improve survival. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (Antigens, Neoplasm) RN - 0 (Antineoplastic Agents) RN - 0 (CD274 protein, human) RN - 0 (Cancer Vaccines) RN - 0 (Epitopes) ES - 1944-7930 IL - 1539-6509 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 26463091 [pubmed] PP - ppublish LG - English DP - 2015 Sep DC - 20151014 EZ - 2015/10/15 06:00 DA - 2016/08/12 06:00 DT - 2015/10/16 06:00 YR - 2015 ED - 20160811 RD - 20151014 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26463091 <107. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26138335 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Higuchi T AU - Flies DB AU - Marjon NA AU - Mantia-Smaldone G AU - Ronner L AU - Gimotty PA AU - Adams SF FA - Higuchi, Tomoe FA - Flies, Dallas B FA - Marjon, Nicole A FA - Mantia-Smaldone, Gina FA - Ronner, Lukas FA - Gimotty, Phyllis A FA - Adams, Sarah F IN - Higuchi, Tomoe. The University of New Mexico Cancer Center, Albuquerque, New Mexico. IN - Flies, Dallas B. The University of New Mexico Cancer Center, Albuquerque, New Mexico. IN - Marjon, Nicole A. The University of New Mexico Cancer Center, Albuquerque, New Mexico. IN - Mantia-Smaldone, Gina. Fox Chase Cancer Center, Philadelphia, Pennsylvania. IN - Ronner, Lukas. Carnegie Mellon University, Pittsburgh, Pennsylvania. IN - Gimotty, Phyllis A. The University of Pennsylvania, Philadelphia, Pennsylvania. IN - Adams, Sarah F. The University of New Mexico Cancer Center, Albuquerque, New Mexico. SAdams@salud.unm.edu. TI - CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer. SO - Cancer Immunology Research. 3(11):1257-68, 2015 Nov AS - Cancer Immunol Res. 3(11):1257-68, 2015 Nov NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984269 OI - Source: NLM. NIHMS807483 [Available on 11/01/16] SB - Index Medicus CP - United States MH - Animals MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Combined Modality Therapy MH - Cytotoxicity, Immunologic MH - Dose-Response Relationship, Drug MH - Drug Evaluation, Preclinical/mt [Methods] MH - Female MH - Humans MH - Immunologic Memory MH - Immunotherapy/mt [Methods] MH - Interferon-gamma/bi [Biosynthesis] MH - Interferon-gamma/im [Immunology] MH - Mice, Inbred C57BL MH - Neoplasm Transplantation MH - Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - *Ovarian Neoplasms/th [Therapy] MH - Poly(ADP-ribose) Polymerase Inhibitors/ad [Administration & Dosage] MH - *Poly(ADP-ribose) Polymerase Inhibitors/tu [Therapeutic Use] MH - T-Lymphocyte Subsets/im [Immunology] MH - Tumor Cells, Cultured MH - *Ubiquitin-Protein Ligases/df [Deficiency] AB - Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA(-) ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1(-) cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNgamma production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNgamma in human BRCA1(-) cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1(-) tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 82115-62-6 (Interferon-gamma) RN - EC 2-3-2-27 (Brap protein, mouse) RN - EC 2-3-2-27 (Ubiquitin-Protein Ligases) ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-15-0044 DO - https://dx.doi.org/10.1158/2326-6066.CIR-15-0044 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26138335 [pubmed] ID - 2326-6066.CIR-15-0044 [pii] ID - 10.1158/2326-6066.CIR-15-0044 [doi] ID - PMC4984269 [pmc] ID - NIHMS807483 [mid] PP - ppublish PH - 2015/02/10 [received] PH - 2015/06/13 [accepted] GI - No: P30 CA016520 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 AI007538 Organization: (AI) *NIAID NIH HHS* Country: United States LG - English EP - 20150702 DP - 2015 Nov DC - 20151106 EZ - 2015/07/04 06:00 DA - 2016/08/11 06:00 DT - 2015/07/04 06:00 YR - 2015 ED - 20160810 RD - 20161126 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26138335 <108. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27306803 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Miyauchi E AU - Inoue A FA - Miyauchi, Eisaku FA - Inoue, Akira IN - Miyauchi, Eisaku. Dept. of Respiratory Medicine, Tohoku University Hospital. TI - [Immune Checkpoint Therapy for Non-Small-Cell Lung Cancer]. [Japanese] SO - Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy]. 43(6):666-71, 2016 Jun AS - Gan To Kagaku Ryoho. 43(6):666-71, 2016 Jun NJ - Gan to kagaku ryoho. Cancer & chemotherapy PI - Journal available in: Print PI - Citation processed from: Print JC - 7810034, 6t8 IO - Gan To Kagaku Ryoho SB - Index Medicus CP - Japan MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - CTLA-4 Antigen/im [Immunology] MH - *Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/im [Immunology] MH - Humans MH - *Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/im [Immunology] MH - Molecular Targeted Therapy MH - Neoplasm Proteins/im [Immunology] MH - Transcription Factors/im [Immunology] AB - Nivolumab is an anti-PD-1 antibody that has recently been approved in Japan, and has shown high response rates and more favorable safety profiles in 2 phase III clinical trials. Accordingly, immune checkpoint therapy has now been included as a new standard treatment for non-small-cell lung cancer. These immune checkpoints are receptors expressed on T cells that regulate the immune response. The PD-1/PD-L1 signal inhibits cytotoxic T lymphocyte proliferation and survival, induces apoptosis of infiltrative T cells, and increases the amount of regulatory T cells in the tumor microenvironment. Therefore, severe immune-related adverse event(irAE)have been observed, including enterocolitis, neuropathies, and endocrinopathies. There are different management approaches to irAEs with conventional cytotoxic drugs. This article reviews the available data regarding immune checkpoint therapy for patients with non-small-cell lung cancer. RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (Neoplasm Proteins) RN - 0 (PCD1 protein, human) RN - 0 (Transcription Factors) IS - 0385-0684 IL - 0385-0684 PT - English Abstract PT - Journal Article ID - 27306803 [pubmed] PP - ppublish LG - Japanese DP - 2016 Jun DC - 20160616 EZ - 2016/06/17 06:00 DA - 2016/08/06 06:00 DT - 2016/06/17 06:00 YR - 2016 ED - 20160805 RD - 20160616 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27306803 <109. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27467964 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Karydis I AU - Chan PY AU - Wheater M AU - Arriola E AU - Szlosarek PW AU - Ottensmeier CH FA - Karydis, Ioannis FA - Chan, Pui Ying FA - Wheater, Matthew FA - Arriola, Edurne FA - Szlosarek, Peter W FA - Ottensmeier, Christian H IN - Karydis, Ioannis. Cancer Sciences Academic Unit, University of Southampton , Southampton, United Kingdom. IN - Chan, Pui Ying. Department of Medical Oncology, St Bartholomew's Hospital , London. IN - Wheater, Matthew. Medical Oncology, University Hospital Southampton , Southampton, United Kingdom. IN - Arriola, Edurne. Medical Oncology, University Hospital Southampton , Southampton, United Kingdom. IN - Szlosarek, Peter W. Department of Medical Oncology, St Bartholomew's Hospital, London; Barts Cancer Institute, Queen Mary University of London, London. IN - Ottensmeier, Christian H. Cancer Sciences Academic Unit, University of Southampton , Southampton, United Kingdom. TI - Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma. SO - Oncoimmunology. 5(5):e1143997, 2016 May AS - Oncoimmunology. 5(5):e1143997, 2016 May NJ - Oncoimmunology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101570526 IO - Oncoimmunology PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910726 CP - United States KW - Anti-PD-1; Pembrolizumab; immuno-oncology; metastases; uveal melanoma AB - BACKGROUND: Untreated metastatic uveal melanoma (UM) carries a grave prognosis. Unlike cutaneous melanoma (CM), there are no established treatments known to significantly improve outcomes for a meaningful proportion of patients. Inhibition of the PD1-PDL1 axis has shown promise in the management of CM and we here report a two center experience of UM patients receiving pembrolizumab. AB - METHODS: To assess the efficacy and safety of pembrolizumab, we retrospectively analyzed outcome data of 25 consecutive UM patients participating in the MK3475 expanded access program (EAP) who received pembrolizumab at 2 mg/kg 3 weekly. Tumor assessment was evaluated using RECIST 1.1 and immune-related Response Criteria (irRC) by CT scanning. Toxicity was recorded utilizing Common Terminology Criteria for Adverse Events ("CTCAE") v4.03. AB - RESULTS: Twenty-five patients were identified receiving a median of six cycles of treatment. Two patients achieved a partial response and six patients stable disease. After a median follow-up of 225 d median progression free survival (PFS) was 91 d and overall survival (OS) was not reached. There was a significant trend for improved outcomes in patients with extrahepatic disease progression as opposed to liver only progression at the outset. Five patients experienced grade 3 or 4 adverse events (AEs); there were no treatment related deaths. AB - CONCLUSIONS: Pembrolizumab 2mg/kg q3w is a safe option in UM patients. Disease control rates, particularly in the subgroup of patients without progressive liver disease at the outset are promising; these results merit further investigation in clinical trials possibly incorporating liver targeted treatment modalities. IS - 2162-4011 IL - 2162-4011 DI - 1143997 DO - https://dx.doi.org/10.1080/2162402X.2016.1143997 PT - Journal Article ID - 27467964 [pubmed] ID - 10.1080/2162402X.2016.1143997 [doi] ID - 1143997 [pii] ID - PMC4910726 [pmc] PP - epublish PH - 2015/10/02 [received] PH - 2016/01/12 [revised] PH - 2016/01/14 [accepted] LG - English EP - 20160218 DP - 2016 May DC - 20160729 EZ - 2016/07/29 06:00 DA - 2016/07/29 06:01 DT - 2016/07/29 06:00 YR - 2016 ED - 20160729 RD - 20160730 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27467964 <110. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26574148 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Guibert N AU - Mazieres J FA - Guibert, Nicolas FA - Mazieres, Julien IN - Guibert, Nicolas. a Centre Hospitalier Universitaire, Thoracic Oncology Unit, Respiratory Disease Department , Hopital Larrey, Universite Paul Sabatier , CHU Toulouse, Chemin de Pouvourville, Toulouse , Toulouse Cedex 31059 , France. IN - Mazieres, Julien. a Centre Hospitalier Universitaire, Thoracic Oncology Unit, Respiratory Disease Department , Hopital Larrey, Universite Paul Sabatier , CHU Toulouse, Chemin de Pouvourville, Toulouse , Toulouse Cedex 31059 , France. IN - Mazieres, Julien. b Hopital Larrey , Institut Universitaire du Cancer , Toulouse , Toulouse Cedex 31059 , France. TI - Nivolumab for treating non-small cell lung cancer. [Review] SO - Expert Opinion on Biological Therapy. 15(12):1789-97, 2015 AS - Expert Opin Biol Ther. 15(12):1789-97, 2015 NJ - Expert opinion on biological therapy PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101125414 IO - Expert Opin Biol Ther SB - Index Medicus CP - England MH - Animals MH - Antibodies, Monoclonal/pd [Pharmacology] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antigens, CD274/im [Immunology] MH - Antineoplastic Agents/pd [Pharmacology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Biomarkers MH - *Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/im [Immunology] MH - Clinical Trials as Topic/mt [Methods] MH - Humans MH - *Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/im [Immunology] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Treatment Outcome KW - PD-1; PD-1 inhibitor; PD-L1; antitumor immunotherapy; immune checkpoint inhibitors; nivolumab AB - INTRODUCTION: Diversion of the immune checkpoint PD-1/PD-L1 by a tumor in order to escape antitumor immunity is a hallmark of NSCLC, but offers promising new strategies. Nivolumab, a fully human monoclonal antibody, is the first PD-1 inhibitor to be approved to treat metastatic NSCLC after exciting results obtained from clinical trials. AB - AREAS COVERED: This review aims to:) clarify the mechanism of action and toxicities of PD-1 inhibitors; recapitulate the results from various clinical trials that have evaluated nivolumab as a monotherapy for metastatic NSCLC; discuss the clinical and translational research axes to better use this molecule; and summarize the therapeutic combinations currently under evaluation. AB - EXPERT OPINION: The contribution of this molecule to treat NSCLC is undeniable, making it a new standard of care after prior chemotherapy. Its toxicity profile is favorable but a good knowledge of new and potentially severe immune-related adverse effects such as endocrinopathy or interstitial pneumonitis is essential for its early detection and management. Better selection of patients is needed, particularly based on the discovery of predictive biomarkers, such as PD-L1 expression. Multiple associations with other checkpoint inhibitors, chemotherapy and targeted therapies are currently being studied and should pave the way toward new uses for this drug. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) ES - 1744-7682 IL - 1471-2598 DO - https://dx.doi.org/10.1517/14712598.2015.1114097 PT - Journal Article PT - Review ID - 26574148 [pubmed] ID - 10.1517/14712598.2015.1114097 [doi] PP - ppublish LG - English EP - 20151116 DP - 2015 DC - 20151215 EZ - 2015/11/18 06:00 DA - 2016/07/29 06:00 DT - 2015/11/18 06:00 YR - 2015 ED - 20160728 RD - 20151215 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26574148 <111. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26317899 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Barrett MT AU - Anderson KS AU - Lenkiewicz E AU - Andreozzi M AU - Cunliffe HE AU - Klassen CL AU - Dueck AC AU - McCullough AE AU - Reddy SK AU - Ramanathan RK AU - Northfelt DW AU - Pockaj BA FA - Barrett, Michael T FA - Anderson, Karen S FA - Lenkiewicz, Elizabeth FA - Andreozzi, Mariacarla FA - Cunliffe, Heather E FA - Klassen, Christine L FA - Dueck, Amylou C FA - McCullough, Ann E FA - Reddy, Srikanth K FA - Ramanathan, Ramesh K FA - Northfelt, Donald W FA - Pockaj, Barbara A IN - Barrett, Michael T. Department of Research, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. IN - Anderson, Karen S. Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America. IN - Lenkiewicz, Elizabeth. Department of Research, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. IN - Andreozzi, Mariacarla. Department of Research, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. IN - Cunliffe, Heather E. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. IN - Klassen, Christine L. Division of General Surgery, Section of Surgical Oncology, Mayo Clinic in Arizona, Phoenix, Arizona, United States of America. IN - Dueck, Amylou C. Section of Biostatistics, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. IN - McCullough, Ann E. Department of Pathology and Laboratory Medicine, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. IN - Reddy, Srikanth K. Vanderbilt University, Nashville, Tennessee, United States of America. IN - Ramanathan, Ramesh K. Division of Hematology-Oncology, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. IN - Northfelt, Donald W. Division of Hematology-Oncology, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America. IN - Pockaj, Barbara A. Division of General Surgery, Section of Surgical Oncology, Mayo Clinic in Arizona, Phoenix, Arizona, United States of America. TI - Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer. SO - Oncotarget. 6(28):26483-93, 2015 Sep 22 AS - Oncotarget. 6(28):26483-93, 2015 Sep 22 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694916 SB - Index Medicus CP - United States MH - Adult MH - Aged MH - *Antigens, CD274/ge [Genetics] MH - *Biomarkers, Tumor/ge [Genetics] MH - Carcinoma, Pancreatic Ductal/ge [Genetics] MH - *Chromosomes, Human, Pair 9 MH - Colorectal Neoplasms/ge [Genetics] MH - Comparative Genomic Hybridization MH - Disease-Free Survival MH - Female MH - Flow Cytometry MH - Gene Dosage MH - Gene Expression Profiling MH - Gene Expression Regulation, Enzymologic MH - Gene Expression Regulation, Neoplastic MH - *Genetic Loci MH - Genetic Predisposition to Disease MH - Glioblastoma/ge [Genetics] MH - Humans MH - *Janus Kinase 2/ge [Genetics] MH - Kaplan-Meier Estimate MH - Male MH - Middle Aged MH - Oligonucleotide Array Sequence Analysis MH - Pancreatic Neoplasms/ge [Genetics] MH - Phenotype MH - *Programmed Cell Death 1 Ligand 2 Protein/ge [Genetics] MH - Time Factors MH - Treatment Outcome MH - Triple Negative Breast Neoplasms/en [Enzymology] MH - *Triple Negative Breast Neoplasms/ge [Genetics] MH - Triple Negative Breast Neoplasms/mo [Mortality] MH - Triple Negative Breast Neoplasms/pa [Pathology] MH - Triple Negative Breast Neoplasms/th [Therapy] MH - Up-Regulation KW - 9p24.1 amplicon; JAK2; PD-L1; flow sorting; triple negative breast cancer AB - We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio >= 1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis. RN - 0 (Antigens, CD274) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - 0 (PDCD1LG2 protein, human) RN - 0 (Programmed Cell Death 1 Ligand 2 Protein) RN - EC 2-7-10-2 (JAK2 protein, human) RN - EC 2-7-10-2 (Janus Kinase 2) ES - 1949-2553 IL - 1949-2553 DI - 4494 DO - https://dx.doi.org/10.18632/oncotarget.4494 PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26317899 [pubmed] ID - 4494 [pii] ID - 10.18632/oncotarget.4494 [doi] ID - PMC4694916 [pmc] PP - ppublish PH - 2015/05/05 [received] PH - 2015/06/22 [accepted] LG - English DP - 2015 Sep 22 DC - 20151005 EZ - 2015/08/29 06:00 DA - 2016/07/23 06:00 DT - 2015/09/01 06:00 YR - 2015 ED - 20160722 RD - 20160122 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26317899 <112. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26010858 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lam T AU - Chan MM AU - Sweeting AN AU - De Sousa SM AU - Clements A AU - Carlino MS AU - Long GV AU - Tonks K AU - Chua E AU - Kefford RF AU - Chipps DR AI - De Sousa, S M C; ORCID: http://orcid.org/0000-0003-0127-6482 FA - Lam, T FA - Chan, M M K FA - Sweeting, A N FA - De Sousa, S M C FA - Clements, A FA - Carlino, M S FA - Long, G V FA - Tonks, K FA - Chua, E FA - Kefford, R F FA - Chipps, D R IN - Lam, T. Department of Diabetes and Endocrinology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. IN - Chan, M M K. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. IN - Chan, M M K. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. IN - Chan, M M K. Central Coast Cancer Centre, Gosford Hospital, Gosford, New South Wales, Australia. IN - Sweeting, A N. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. IN - Sweeting, A N. Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. IN - De Sousa, S M C. Department of Endocrinology, St Vincent's Hospital, Sydney, New South Wales, Australia. IN - De Sousa, S M C. Hormones and Cancer Group, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. IN - Clements, A. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. IN - Clements, A. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. IN - Carlino, M S. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. IN - Carlino, M S. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. IN - Carlino, M S. Melanoma Institute of Australia, Sydney, New South Wales, Australia. IN - Long, G V. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. IN - Long, G V. Melanoma Institute of Australia, Sydney, New South Wales, Australia. IN - Tonks, K. Department of Endocrinology, St Vincent's Hospital, Sydney, New South Wales, Australia. IN - Tonks, K. Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. IN - Chua, E. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. IN - Chua, E. Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. IN - Kefford, R F. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. IN - Kefford, R F. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. IN - Kefford, R F. Melanoma Institute of Australia, Sydney, New South Wales, Australia. IN - Kefford, R F. Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia. IN - Chipps, D R. Department of Diabetes and Endocrinology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. IN - Chipps, D R. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. TI - Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series.[Erratum appears in Intern Med J. 2015 Dec;45(12):1318; PMID: 26648200] SO - Internal Medicine Journal. 45(10):1066-73, 2015 Oct AS - Intern Med J. 45(10):1066-73, 2015 Oct NJ - Internal medicine journal PI - Journal available in: Print PI - Citation processed from: Internet JC - d20, 101092952 IO - Intern Med J SB - Index Medicus CP - Australia MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Australia MH - CTLA-4 Antigen/im [Immunology] MH - Female MH - Hormone Replacement Therapy MH - Humans MH - *Hypopituitarism/ci [Chemically Induced] MH - Hypopituitarism/di [Diagnosis] MH - Hypopituitarism/dt [Drug Therapy] MH - Immunotherapy MH - Magnetic Resonance Imaging MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Middle Aged MH - *Skin Neoplasms/dt [Drug Therapy] KW - hypophysitis; hypopituitarism; immune-related adverse event; immunotherapy; ipilimumab; melanoma AB - BACKGROUND: Ipilimumab (Yervoy; Bristol-Myers Squibb) is a novel fully humanised monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4, an immune checkpoint molecule, to augment anti-tumour T-cell responses. It is associated with significant immune-related side-effects including hypophysitis. AB - AIM: We reviewed the clinical and biochemical characteristics of 10 patients with ipilimumab-induced hypophysitis (IH), and developed guidelines for the early detection and management of IH based on our experiences at three major teaching hospitals in Sydney. AB - METHODS: All patients were evaluated at the Crown Princess Mary Cancer Centre and Department of Endocrinology, Westmead Hospital, Department of Endocrinology, Royal Prince Alfred Hospital, the Melanoma Institute Australia and Macarthur Cancer Therapy Centre, Campbelltown Hospital from 2010 to 2014. Relevant data were extracted by review of medical records. Main outcome measures included clinical features, hormone profile and radiological findings associated with IH, and presence of pituitary recovery. AB - RESULTS: Ten patients were identified with IH. In four patients who underwent monitoring of plasma cortisol, there was a fall in levels in the weeks prior to presentation. The pituitary-adrenal and pituitary-thyroid axes were affected in the majority of patients, with the need for physiological hormone replacement. Imaging abnormalities were identified in five of 10 patients, and resolved without high-dose glucocorticoid therapy. To date, all patients remain on levothyroxine and hydrocortisone replacement, where appropriate. AB - CONCLUSIONS: There is significant morbidity associated with development of IH. We suggest guidelines to assist with early recognition and therapeutic intervention. AB - Copyright © 2015 Royal Australasian College of Physicians. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) ES - 1445-5994 IL - 1444-0903 DO - https://dx.doi.org/10.1111/imj.12819 PT - Journal Article PT - Multicenter Study ID - 26010858 [pubmed] ID - 10.1111/imj.12819 [doi] PP - ppublish PH - 2015/01/10 [received] PH - 2015/05/12 [accepted] LG - English DP - 2015 Oct DC - 20151002 EZ - 2015/05/27 06:00 DA - 2016/07/22 06:00 DT - 2015/05/27 06:00 YR - 2015 ED - 20160721 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26010858 <113. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25957829 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Araujo PB AU - Coelho MC AU - Arruda M AU - Gadelha MR AU - Neto LV FA - Araujo, P B FA - Coelho, M C A FA - Arruda, M FA - Gadelha, M R FA - Neto, L V IN - Araujo, P B. Department of Internal Medicine and Endocrine Unit, Medical School and Hospital Universitario Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255 9degree andar, Servico de Endocrinologia, 21941-913, Rio de Janeiro, RJ, Brazil. paulabruna@gmail.com. IN - Coelho, M C A. Department of Internal Medicine and Endocrine Unit, Medical School and Hospital Universitario Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255 9degree andar, Servico de Endocrinologia, 21941-913, Rio de Janeiro, RJ, Brazil. carolinealvescoelho@yahoo.com.br. IN - Coelho, M C A. Endocrinology Unit, Hospital Universitario Pedro Ernesto, Universidade Estadual do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. carolinealvescoelho@yahoo.com.br. IN - Coelho, M C A. Instituto Estadual de Diabetes e Endocrinologia, Rio de Janeiro, RJ, Brazil. carolinealvescoelho@yahoo.com.br. IN - Arruda, M. Department of Internal Medicine and Endocrine Unit, Medical School and Hospital Universitario Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255 9degree andar, Servico de Endocrinologia, 21941-913, Rio de Janeiro, RJ, Brazil. mariana.arruda.silva@gmail.com. IN - Gadelha, M R. Department of Internal Medicine and Endocrine Unit, Medical School and Hospital Universitario Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255 9degree andar, Servico de Endocrinologia, 21941-913, Rio de Janeiro, RJ, Brazil. mgadelha@hucff.ufrj.br. IN - Neto, L V. Department of Internal Medicine and Endocrine Unit, Medical School and Hospital Universitario Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255 9degree andar, Servico de Endocrinologia, 21941-913, Rio de Janeiro, RJ, Brazil. netolv@gmail.com. IN - Neto, L V. Endocrinology Unit, Hospital Federal da Lagoa, Rio De Janeiro, RJ, Brazil. netolv@gmail.com. TI - Ipilimumab-induced hypophysitis: review of the literature. [Review] SO - Journal of Endocrinological Investigation. 38(11):1159-66, 2015 Nov AS - J Endocrinol Invest. 38(11):1159-66, 2015 Nov NJ - Journal of endocrinological investigation PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - iam, 7806594 IO - J. Endocrinol. Invest. SB - Index Medicus CP - Italy MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Female MH - Humans MH - *Hypopituitarism/ci [Chemically Induced] MH - *Immunologic Factors/ae [Adverse Effects] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Middle Aged MH - *Pituitary Diseases/ci [Chemically Induced] KW - Hypophysitis; Hypopituitarism; Ipilimumab AB - PURPOSE: Ipilimumab is a human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 available as an immunotherapy mainly for advanced melanoma. It induces an activation of T cells, resulting in an immune-mediated anti-tumor response and also immune-related adverse events, including hypophysitis. The aim of this review is to identify and discuss features concerning ipilimumab-induced hypophysitis (IIH). AB - DESIGN: A MEDLINE research of all years of publication of IIH was conducted. We gathered information regarding clinical, radiologic and laboratory features of 71 cases recorded in the literature. AB - RESULTS: In our review, IIH was more frequent among older and male patients. Fatigue and headache were the most frequent initial clinical manifestations of IIH and enlargement of the pituitary gland at MRI was present in the majority of patients. Those who received more than 3 cycles of ipilimumab had more fatigue (p = 0.04) and arthritis (p = 0.04). Adrenal insufficiency was more prevalent in men (p = 0.007). Glucocorticoid therapy and hormone replacement were required in most patients and pituitary function recovery was uncommon. Low prolactin at diagnosis tended to predict permanent pituitary dysfunction (p = 0.07). AB - CONCLUSION: Hypopituitarism as a consequence of IIH, if not promptly recognized, can lead to potentially fatal events, such as adrenal insufficiency. IIH can be easily managed with glucocorticoids and hormonal replacement; therefore, physicians should be familiar with the key aspects of this condition. More studies to develop screening protocols and therapeutic intervention algorithms should be performed to decrease morbidity related to IIH. RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunologic Factors) RN - 6T8C155666 (ipilimumab) ES - 1720-8386 IL - 0391-4097 DI - 10.1007/s40618-015-0301-z DO - https://dx.doi.org/10.1007/s40618-015-0301-z PT - Case Reports PT - Journal Article PT - Meta-Analysis PT - Review ID - 25957829 [pubmed] ID - 10.1007/s40618-015-0301-z [doi] ID - 10.1007/s40618-015-0301-z [pii] PP - ppublish PH - 2015/02/12 [received] PH - 2015/04/24 [accepted] LG - English EP - 20150510 DP - 2015 Nov DC - 20151012 EZ - 2015/05/11 06:00 DA - 2016/07/21 06:00 DT - 2015/05/11 06:00 YR - 2015 ED - 20160720 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25957829 <114. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26970135 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wojtowicz ME AU - Dunn BK AU - Umar A FA - Wojtowicz, Malgorzata E FA - Dunn, Barbara K FA - Umar, Asad IN - Wojtowicz, Malgorzata E. Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: wojtowim@mail.nih.gov. IN - Dunn, Barbara K. Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. IN - Umar, Asad. Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. TI - Immunologic approaches to cancer prevention-current status, challenges, and future perspectives. [Review] SO - Seminars in Oncology. 43(1):161-72, 2016 Feb AS - Semin Oncol. 43(1):161-72, 2016 Feb NJ - Seminars in oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - un5, 0420432 IO - Semin. Oncol. SB - Index Medicus CP - United States MH - Adaptive Immunity MH - Animals MH - *Antigens, Neoplasm/im [Immunology] MH - Autoantigens/im [Immunology] MH - *Breast Neoplasms/im [Immunology] MH - *Breast Neoplasms/pc [Prevention & Control] MH - Colorectal Neoplasms/ge [Genetics] MH - *Colorectal Neoplasms/im [Immunology] MH - *Colorectal Neoplasms/pc [Prevention & Control] MH - Female MH - Frameshift Mutation MH - Hepatitis B Vaccines/tu [Therapeutic Use] MH - Humans MH - Immunity, Innate MH - Immunologic Surveillance MH - *Immunotherapy MH - Lactalbumin/im [Immunology] MH - Mammaglobin A/im [Immunology] MH - *Pancreatic Neoplasms/im [Immunology] MH - Papillomavirus Vaccines/tu [Therapeutic Use] MH - Receptor, ErbB-2/im [Immunology] MH - Telomerase/ai [Antagonists & Inhibitors] MH - Telomerase/im [Immunology] KW - Cancer immunoprevention; Cancer vaccines; Tumor antigens; Tumor immunity AB - The potential of the immune system to recognize and reject tumors has been investigated for more than a century. However, only recently impressive breakthroughs in cancer immunotherapy have been seen with the use of checkpoint inhibitors. The experience with various immune-based strategies in the treatment of late cancer highlighted the importance of negative impact advanced disease has on immunity. Consequently, use of immune modulation for cancer prevention rather than therapy has gained considerable attention, with many promising results seen already in preclinical and early clinical studies. Although not without challenges, these results provide much excitement and optimism that successful cancer immunoprevention could be within our reach. In this review we will discuss the current state of predominantly primary and secondary cancer immunoprevention, relevant research, potential barriers, and future directions. AB - Copyright Published by Elsevier Inc. RN - 0 (Antigens, Neoplasm) RN - 0 (Autoantigens) RN - 0 (Hepatitis B Vaccines) RN - 0 (Mammaglobin A) RN - 0 (Papillomavirus Vaccines) RN - 9013-90-5 (Lactalbumin) RN - EC 2-7-10-1 (ERBB2 protein, human) RN - EC 2-7-10-1 (Receptor, ErbB-2) RN - EC 2-7-7-49 (TERT protein, human) RN - EC 2-7-7-49 (Telomerase) ES - 1532-8708 IL - 0093-7754 DI - S0093-7754(15)00243-2 DO - https://dx.doi.org/10.1053/j.seminoncol.2015.11.001 PT - Journal Article PT - Review ID - 26970135 [pubmed] ID - S0093-7754(15)00243-2 [pii] ID - 10.1053/j.seminoncol.2015.11.001 [doi] PP - ppublish LG - English EP - 20151114 DP - 2016 Feb DC - 20160313 EZ - 2016/03/13 06:00 DA - 2016/07/20 06:00 DT - 2016/03/13 06:00 YR - 2016 ED - 20160719 RD - 20160313 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26970135 <115. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26100356 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Tirumani SH AU - Ramaiya NH AU - Keraliya A AU - Bailey ND AU - Ott PA AU - Hodi FS AU - Nishino M FA - Tirumani, Sree Harsha FA - Ramaiya, Nikhil H FA - Keraliya, Abhishek FA - Bailey, Nancy D FA - Ott, Patrick A FA - Hodi, F Stephen FA - Nishino, Mizuki IN - Tirumani, Sree Harsha. Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Ramaiya, Nikhil H. Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Keraliya, Abhishek. Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Bailey, Nancy D. Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Ott, Patrick A. Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Hodi, F Stephen. Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Nishino, Mizuki. Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. Mizuki_Nishino@dfci.harvard.edu. TI - Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab. SO - Cancer Immunology Research. 3(10):1185-92, 2015 Oct AS - Cancer Immunol Res. 3(10):1185-92, 2015 Oct NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596761 OI - Source: NLM. NIHMS703148 [Available on 10/01/16] SB - Index Medicus CP - United States MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Colitis/di [Diagnosis] MH - Colitis/et [Etiology] MH - *Drug-Related Side Effects and Adverse Reactions/di [Diagnosis] MH - Female MH - Fluorodeoxyglucose F18 MH - Hepatitis/di [Diagnosis] MH - Hepatitis/et [Etiology] MH - Humans MH - Lymphatic Diseases/di [Diagnosis] MH - Lymphatic Diseases/et [Etiology] MH - Male MH - *Melanoma/co [Complications] MH - Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Neoplasm Staging MH - Organ Specificity MH - Pancreatitis/di [Diagnosis] MH - Pancreatitis/et [Etiology] MH - Pneumonia/di [Diagnosis] MH - Pneumonia/et [Etiology] MH - Positron-Emission Tomography MH - Thyroiditis/di [Diagnosis] MH - Thyroiditis/et [Etiology] MH - Tomography, X-Ray Computed MH - Treatment Outcome AB - Ipilimumab is a promising novel immunotherapy agent and is associated with a variety of immune-related adverse events (irAE). The purpose of this study was to investigate the manifestations of irAEs on body imaging in patients with advanced melanoma treated with ipilimumab. One-hundred forty-seven patients with advanced melanoma (59 women, 88 men; median age, 64.5 years) treated with ipilimumab were studied. All patients had the baseline and at least one follow-up chest/abdomen/pelvis CT or PET/CT during therapy, which were reviewed by a consensus of two radiologists blinded to the clinical data. Findings indicative of individual types of irAEs were assessed, including thyroiditis, sarcoid-like lymphadenopathy, pneumonitis, hepatitis, pancreatitis, and colitis. Among the 147 patients, 46 (31%) had radiologically identified irAEs. The time interval from the initiation of therapy to the development of irAEs was less than 3 months in 76% (35 of 46) of the patients (range, 0.2-9.1 months). Clinical characteristics did not differ between patients with and without irAEs (P > 0.18). Among the individual types of irAEs, colitis was most common (n = 28; 19%), followed by sarcoid-like lymphadenopathy (n = 8; 5%) and pneumonitis (n = 8; 5%). Hepatitis (n = 3), thyroiditis (n = 2), and pancreatitis (n = 1) were less common. The resolution of irAEs was noted in 32 of 36 patients (89%) with further follow-up scans, with a median time of 2.3 months after the detection of irAE. In conclusion, irAEs were noted on body imaging in 31% of patients with melanoma treated with ipilimumab. Colitis was the most common, followed by sarcoid-like lymphadenopathy and pneumonitis. The results call for an increased awareness of irAEs, given the expanding role of cancer immunotherapy. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0Z5B2CJX4D (Fluorodeoxyglucose F18) RN - 6T8C155666 (ipilimumab) ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-15-0102 DO - https://dx.doi.org/10.1158/2326-6066.CIR-15-0102 PT - Journal Article ID - 26100356 [pubmed] ID - 2326-6066.CIR-15-0102 [pii] ID - 10.1158/2326-6066.CIR-15-0102 [doi] ID - PMC4596761 [pmc] ID - NIHMS703148 [mid] PP - ppublish PH - 2015/04/13 [received] PH - 2015/06/11 [accepted] GI - No: K23 CA157631 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20150622 DP - 2015 Oct DC - 20151006 EZ - 2015/06/24 06:00 DA - 2016/07/20 06:00 DT - 2015/06/24 06:00 YR - 2015 ED - 20160719 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26100356 <116. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26429981 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kurose K AU - Ohue Y AU - Wada H AU - Iida S AU - Ishida T AU - Kojima T AU - Doi T AU - Suzuki S AU - Isobe M AU - Funakoshi T AU - Kakimi K AU - Nishikawa H AU - Udono H AU - Oka M AU - Ueda R AU - Nakayama E FA - Kurose, Koji FA - Ohue, Yoshihiro FA - Wada, Hisashi FA - Iida, Shinsuke FA - Ishida, Takashi FA - Kojima, Takashi FA - Doi, Toshihiko FA - Suzuki, Susumu FA - Isobe, Midori FA - Funakoshi, Takeru FA - Kakimi, Kazuhiro FA - Nishikawa, Hiroyoshi FA - Udono, Heiichiro FA - Oka, Mikio FA - Ueda, Ryuzo FA - Nakayama, Eiichi IN - Kurose, Koji. Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan. IN - Ohue, Yoshihiro. Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan. IN - Wada, Hisashi. Department of Clinical Research in Tumor Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. IN - Iida, Shinsuke. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan. IN - Ishida, Takashi. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan. IN - Kojima, Takashi. Exploratory Oncology Research & Clinical Trial Center, Kashiwa, Chiba, Japan. IN - Doi, Toshihiko. Exploratory Oncology Research & Clinical Trial Center, Kashiwa, Chiba, Japan. IN - Suzuki, Susumu. Department of Tumor Immunology, Aichi Medical University, Nagakute, Aichi, Japan. IN - Isobe, Midori. Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan. IN - Funakoshi, Takeru. Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. IN - Kakimi, Kazuhiro. Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-Ku, Tokyo, Japan. IN - Nishikawa, Hiroyoshi. Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan. IN - Udono, Heiichiro. Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan. IN - Oka, Mikio. Department of Respiratory Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan. IN - Ueda, Ryuzo. Department of Tumor Immunology, Aichi Medical University, Nagakute, Aichi, Japan. nakayama@mw.kawasaki-m.ac.jp uedaryu@aichi-med-u.ac.jp. IN - Nakayama, Eiichi. Faculty of Health and Welfare, Kawasaki University of Medical Welfare, Kurashiki, Okayama, Japan. nakayama@mw.kawasaki-m.ac.jp uedaryu@aichi-med-u.ac.jp. TI - Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. SO - Clinical Cancer Research. 21(19):4327-36, 2015 Oct 01 AS - Clin Cancer Res. 21(19):4327-36, 2015 Oct 01 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. SB - Index Medicus CP - United States MH - Antibodies, Monoclonal, Humanized/pd [Pharmacology] MH - *Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - Antineoplastic Agents/pd [Pharmacology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/im [Immunology] MH - Carcinoma, Non-Small-Cell Lung/me [Metabolism] MH - Female MH - Forkhead Transcription Factors/me [Metabolism] MH - Granulocytes/im [Immunology] MH - Granulocytes/me [Metabolism] MH - Humans MH - Immunophenotyping MH - Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/im [Immunology] MH - Lung Neoplasms/me [Metabolism] MH - *Lymphocyte Depletion MH - Male MH - *Neoplasms/dt [Drug Therapy] MH - *Neoplasms/im [Immunology] MH - Neoplasms/me [Metabolism] MH - Phenotype MH - *Receptors, CCR4/ai [Antagonists & Inhibitors] MH - T-Lymphocyte Subsets/im [Immunology] MH - T-Lymphocyte Subsets/me [Metabolism] MH - *T-Lymphocytes, Regulatory/im [Immunology] MH - T-Lymphocytes, Regulatory/me [Metabolism] MH - Treatment Outcome AB - PURPOSE: FoxP3(+) Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3(+) CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. AB - EXPERIMENTAL DESIGN: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, including Tregs, and induction of immune responses were analyzed. AB - RESULTS: The results showed that KW-0761 infusion in a dose range between 0.1 mg/kg and 1.0 mg/kg was safe and well tolerated. No dose-limiting toxicity was observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3(+) Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. AB - CONCLUSIONS: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3(+) Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (FOXP3 protein, human) RN - 0 (Forkhead Transcription Factors) RN - 0 (Receptors, CCR4) RN - 0 (mogamulizumab) IS - 1078-0432 IL - 1078-0432 DI - 21/19/4327 DO - https://dx.doi.org/10.1158/1078-0432.CCR-15-0357 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26429981 [pubmed] ID - 21/19/4327 [pii] ID - 10.1158/1078-0432.CCR-15-0357 [doi] PP - ppublish LG - English DP - 2015 Oct 01 DC - 20151002 EZ - 2015/10/03 06:00 DA - 2016/07/12 06:00 DT - 2015/10/03 06:00 YR - 2015 ED - 20160711 RD - 20151002 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26429981 <117. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26924195 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Javle M AU - Golan T AU - Maitra A FA - Javle, Milind FA - Golan, Talia FA - Maitra, Anirban IN - Javle, Milind. MD Anderson Cancer Center, 1515, Holcombe Blvd, Unit 426, Houston, TX 77030, USA. IN - Golan, Talia. Sheba Medical Center, Tel Hashomer 52621, Israel. IN - Maitra, Anirban. MD Anderson Cancer Center, 1515, Holcombe Blvd, Unit 426, Houston, TX 77030, USA. TI - Changing the course of pancreatic cancer--Focus on recent translational advances. [Review] SO - Cancer Treatment Reviews. 44:17-25, 2016 Mar AS - Cancer Treat Rev. 44:17-25, 2016 Mar NJ - Cancer treatment reviews PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnn, 7502030 IO - Cancer Treat. Rev. SB - Index Medicus CP - Netherlands MH - Cancer Vaccines/tu [Therapeutic Use] MH - Carcinoma, Pancreatic Ductal/dt [Drug Therapy] MH - *Carcinoma, Pancreatic Ductal/ge [Genetics] MH - Carcinoma, Pancreatic Ductal/im [Immunology] MH - DNA Repair/ge [Genetics] MH - *Genes, BRCA1 MH - *Genes, BRCA2 MH - Humans MH - Immunotherapy MH - Immunotherapy, Adoptive MH - Molecular Targeted Therapy MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - *Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/im [Immunology] MH - Poly(ADP-ribose) Polymerase Inhibitors MH - *Proto-Oncogene Proteins p21(ras)/ge [Genetics] MH - T-Lymphocytes/im [Immunology] MH - T-Lymphocytes, Regulatory/im [Immunology] MH - Translational Medical Research MH - Tumor Microenvironment KW - Carcinoma; Pancreatic ductal; Translational medical research AB - In the past decade, insightful preclinical research has led to important breakthroughs in our understanding of pancreatic cancer. Even though the vast majority of pancreatic cancers are KRAS mutated, not all pancreatic cancer tumors are "KRAS equal"; there seems to be varying dependencies on the KRAS pathway. While KRAS-targeting therapies have been disappointing in the clinic, 'synthetic lethal' approaches hold promise in this setting. The pancreatic cancer stromal microenvironment appears to have contradictory roles. While there is evidence to suggest that stromal barrier prevents drug delivery, in other circumstances, stroma can play a protective role and its disruption enhances tumor dissemination. Clinical trials aimed at manipulating the various stromal components are in progress. BRCA mutation-related pancreatic tumors illustrate a unique subtype with enhanced susceptibility to DNA damaging agents and PARP-inhibition. DNA repair defects in cancer extend beyond germ line BRCA mutation and may extend the indications for DNA repair-targeting agents. Immune strategies are an area of active investigation in pancreatic cancer. Although the initial trials of single-agent checkpoint inhibitors have been negative, combinational approaches using immune-modifying agents and vaccines appear promising and goal is to identify an 'immune-therapy responsive' profile in pancreatic cancer. AB - Copyright © 2016 Elsevier Ltd. All rights reserved. RN - 0 (Cancer Vaccines) RN - 0 (KRAS protein, human) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - EC 3-6-5-2 (Proto-Oncogene Proteins p21(ras)) ES - 1532-1967 IL - 0305-7372 DI - S0305-7372(16)00012-8 DO - https://dx.doi.org/10.1016/j.ctrv.2016.01.004 PT - Journal Article PT - Review ID - 26924195 [pubmed] ID - S0305-7372(16)00012-8 [pii] ID - 10.1016/j.ctrv.2016.01.004 [doi] PP - ppublish PH - 2015/12/11 [received] PH - 2016/01/18 [revised] PH - 2016/01/19 [accepted] GI - No: P30 CA016672 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20160125 DP - 2016 Mar DC - 20160229 EZ - 2016/03/01 06:00 DA - 2016/07/07 06:00 DT - 2016/03/01 06:00 YR - 2016 ED - 20160706 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26924195 <118. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26874776 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Spain L AU - Diem S AU - Larkin J FA - Spain, Lavinia FA - Diem, Stefan FA - Larkin, James IN - Spain, Lavinia. Melanoma Unit, Royal Marsden Foundation Trust, Fulham Road, London SW3 6JJ, United Kingdom. IN - Diem, Stefan. Melanoma Unit, Royal Marsden Foundation Trust, Fulham Road, London SW3 6JJ, United Kingdom. IN - Larkin, James. Melanoma Unit, Royal Marsden Foundation Trust, Fulham Road, London SW3 6JJ, United Kingdom. Electronic address: james.larkin@rmh.nhs.uk. TI - Management of toxicities of immune checkpoint inhibitors. [Review] SO - Cancer Treatment Reviews. 44:51-60, 2016 Mar AS - Cancer Treat Rev. 44:51-60, 2016 Mar NJ - Cancer treatment reviews PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnn, 7502030 IO - Cancer Treat. Rev. SB - Index Medicus CP - Netherlands MH - Adrenal Cortex Hormones/tu [Therapeutic Use] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antilymphocyte Serum/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Carcinoma, Renal Cell/dt [Drug Therapy] MH - Chemical and Drug Induced Liver Injury/dt [Drug Therapy] MH - *Chemical and Drug Induced Liver Injury/et [Etiology] MH - *Colitis/ci [Chemically Induced] MH - Colitis/dt [Drug Therapy] MH - Cyclosporine/tu [Therapeutic Use] MH - *Diarrhea/ci [Chemically Induced] MH - Diarrhea/dt [Drug Therapy] MH - Drug Eruptions/dt [Drug Therapy] MH - *Drug Eruptions/et [Etiology] MH - Humans MH - *Immunosuppressive Agents/tu [Therapeutic Use] MH - Infliximab/tu [Therapeutic Use] MH - Kidney Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/dt [Drug Therapy] MH - Melanoma/dt [Drug Therapy] MH - Mycophenolic Acid/aa [Analogs & Derivatives] MH - Mycophenolic Acid/tu [Therapeutic Use] MH - *Neoplasms/dt [Drug Therapy] MH - *Pituitary Diseases/ci [Chemically Induced] MH - Pituitary Diseases/dt [Drug Therapy] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Skin Neoplasms/dt [Drug Therapy] MH - Tacrolimus/tu [Therapeutic Use] MH - *Thyroiditis/ci [Chemically Induced] MH - Thyroiditis/dt [Drug Therapy] KW - Immune-checkpoint inhibitors; Immune-related adverse events; Ipilimumab; Lung cancer; Melanoma; Nivolumab; Pembrolizumab; Renal cancer AB - Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided. AB - Copyright © 2016 Elsevier Ltd. All rights reserved. RN - 0 (Adrenal Cortex Hormones) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antilymphocyte Serum) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (Immunosuppressive Agents) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RN - 83HN0GTJ6D (Cyclosporine) RN - B72HH48FLU (Infliximab) RN - DPT0O3T46P (pembrolizumab) RN - HU9DX48N0T (Mycophenolic Acid) RN - WM0HAQ4WNM (Tacrolimus) ES - 1532-1967 IL - 0305-7372 DI - S0305-7372(16)00016-5 DO - https://dx.doi.org/10.1016/j.ctrv.2016.02.001 PT - Journal Article PT - Review ID - 26874776 [pubmed] ID - S0305-7372(16)00016-5 [pii] ID - 10.1016/j.ctrv.2016.02.001 [doi] PP - ppublish PH - 2015/07/22 [received] PH - 2016/01/27 [revised] PH - 2016/02/01 [accepted] LG - English EP - 20160206 DP - 2016 Mar DC - 20160229 EZ - 2016/02/15 06:00 DA - 2016/07/07 06:00 DT - 2016/02/15 06:00 YR - 2016 ED - 20160706 RD - 20161126 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26874776 <119. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26633184 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Johnson DB AU - Sullivan RJ AU - Ott PA AU - Carlino MS AU - Khushalani NI AU - Ye F AU - Guminski A AU - Puzanov I AU - Lawrence DP AU - Buchbinder EI AU - Mudigonda T AU - Spencer K AU - Bender C AU - Lee J AU - Kaufman HL AU - Menzies AM AU - Hassel JC AU - Mehnert JM AU - Sosman JA AU - Long GV AU - Clark JI FA - Johnson, Douglas B FA - Sullivan, Ryan J FA - Ott, Patrick A FA - Carlino, Matteo S FA - Khushalani, Nikhil I FA - Ye, Fei FA - Guminski, Alexander FA - Puzanov, Igor FA - Lawrence, Donald P FA - Buchbinder, Elizabeth I FA - Mudigonda, Tejaswi FA - Spencer, Kristen FA - Bender, Carolin FA - Lee, Jenny FA - Kaufman, Howard L FA - Menzies, Alexander M FA - Hassel, Jessica C FA - Mehnert, Janice M FA - Sosman, Jeffrey A FA - Long, Georgina V FA - Clark, Joseph I IN - Johnson, Douglas B. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Sullivan, Ryan J. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. IN - Ott, Patrick A. Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Carlino, Matteo S. Department of Medicine, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia5Department of Medicine, University of Sydney, Sydney, New South Wales, Australia. IN - Khushalani, Nikhil I. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York. IN - Ye, Fei. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Guminski, Alexander. Department of Medicine, University of Sydney, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. IN - Puzanov, Igor. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Lawrence, Donald P. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. IN - Buchbinder, Elizabeth I. Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Mudigonda, Tejaswi. medical student at School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Spencer, Kristen. Department of Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick. IN - Bender, Carolin. Department of Medicine, Heidelberg University Hospital, Heidelberg, Germany. IN - Lee, Jenny. Department of Medicine, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. IN - Kaufman, Howard L. Department of Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick. IN - Menzies, Alexander M. Department of Medicine, University of Sydney, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. IN - Hassel, Jessica C. Department of Medicine, Heidelberg University Hospital, Heidelberg, Germany. IN - Mehnert, Janice M. Department of Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick. IN - Sosman, Jeffrey A. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Long, Georgina V. Department of Medicine, University of Sydney, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. IN - Clark, Joseph I. Department of Medicine, Loyola University Medical Center, Maywood, Illinois. TI - Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. CM - Comment in: JAMA Oncol. 2016 Feb;2(2):241; PMID: 26632762 SO - JAMA Oncology. 2(2):234-40, 2016 Feb AS - JAMA Oncol. 2(2):234-40, 2016 Feb NJ - JAMA oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - 101652861 IO - JAMA Oncol SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Autoimmune Diseases/co [Complications] MH - Autoimmune Diseases/di [Diagnosis] MH - Autoimmune Diseases/im [Immunology] MH - *Autoimmunity MH - Female MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Patient Selection MH - Retrospective Studies MH - Risk Assessment MH - Risk Factors MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] MH - Skin Neoplasms/pa [Pathology] MH - Tertiary Care Centers MH - Time Factors MH - Treatment Outcome AB - IMPORTANCE: Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. AB - OBJECTIVE: To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. AB - DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. AB - EXPOSURE: Ipilimumab therapy. AB - MAIN OUTCOMES AND MEASURES: Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. AB - RESULTS: Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. AB - CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 2374-2445 IL - 2374-2437 DI - 2473508 DO - https://dx.doi.org/10.1001/jamaoncol.2015.4368 PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural ID - 26633184 [pubmed] ID - 2473508 [pii] ID - 10.1001/jamaoncol.2015.4368 [doi] PP - ppublish GI - No: K12 CA0906525 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2016 Feb DC - 20160212 EZ - 2015/12/04 06:00 DA - 2016/06/30 06:00 DT - 2015/12/04 06:00 YR - 2016 ED - 20160629 RD - 20161126 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26633184 <120. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26633184 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Johnson DB AU - Sullivan RJ AU - Ott PA AU - Carlino MS AU - Khushalani NI AU - Ye F AU - Guminski A AU - Puzanov I AU - Lawrence DP AU - Buchbinder EI AU - Mudigonda T AU - Spencer K AU - Bender C AU - Lee J AU - Kaufman HL AU - Menzies AM AU - Hassel JC AU - Mehnert JM AU - Sosman JA AU - Long GV AU - Clark JI FA - Johnson, Douglas B FA - Sullivan, Ryan J FA - Ott, Patrick A FA - Carlino, Matteo S FA - Khushalani, Nikhil I FA - Ye, Fei FA - Guminski, Alexander FA - Puzanov, Igor FA - Lawrence, Donald P FA - Buchbinder, Elizabeth I FA - Mudigonda, Tejaswi FA - Spencer, Kristen FA - Bender, Carolin FA - Lee, Jenny FA - Kaufman, Howard L FA - Menzies, Alexander M FA - Hassel, Jessica C FA - Mehnert, Janice M FA - Sosman, Jeffrey A FA - Long, Georgina V FA - Clark, Joseph I IN - Johnson, Douglas B. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Sullivan, Ryan J. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. IN - Ott, Patrick A. Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Carlino, Matteo S. Department of Medicine, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia5Department of Medicine, University of Sydney, Sydney, New South Wales, Australia. IN - Khushalani, Nikhil I. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York. IN - Ye, Fei. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Guminski, Alexander. Department of Medicine, University of Sydney, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. IN - Puzanov, Igor. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Lawrence, Donald P. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. IN - Buchbinder, Elizabeth I. Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Mudigonda, Tejaswi. medical student at School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Spencer, Kristen. Department of Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick. IN - Bender, Carolin. Department of Medicine, Heidelberg University Hospital, Heidelberg, Germany. IN - Lee, Jenny. Department of Medicine, Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. IN - Kaufman, Howard L. Department of Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick. IN - Menzies, Alexander M. Department of Medicine, University of Sydney, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. IN - Hassel, Jessica C. Department of Medicine, Heidelberg University Hospital, Heidelberg, Germany. IN - Mehnert, Janice M. Department of Medicine, Rutgers Cancer Institute of New Jersey, New Brunswick. IN - Sosman, Jeffrey A. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Long, Georgina V. Department of Medicine, University of Sydney, Sydney, New South Wales, Australia8Department of Medicine, Melanoma Institute Australia, Sydney, New South Wales, Australia. IN - Clark, Joseph I. Department of Medicine, Loyola University Medical Center, Maywood, Illinois. TI - Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. CM - Comment in: JAMA Oncol. 2016 Feb;2(2):241; PMID: 26632762 SO - JAMA Oncology. 2(2):234-40, 2016 Feb AS - JAMA Oncol. 2(2):234-40, 2016 Feb NJ - JAMA oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - 101652861 IO - JAMA Oncol SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Autoimmune Diseases/co [Complications] MH - Autoimmune Diseases/di [Diagnosis] MH - Autoimmune Diseases/im [Immunology] MH - *Autoimmunity MH - Female MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Patient Selection MH - Retrospective Studies MH - Risk Assessment MH - Risk Factors MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] MH - Skin Neoplasms/pa [Pathology] MH - Tertiary Care Centers MH - Time Factors MH - Treatment Outcome AB - IMPORTANCE: Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. AB - OBJECTIVE: To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. AB - DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. AB - EXPOSURE: Ipilimumab therapy. AB - MAIN OUTCOMES AND MEASURES: Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. AB - RESULTS: Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. AB - CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 2374-2445 IL - 2374-2437 DI - 2473508 DO - https://dx.doi.org/10.1001/jamaoncol.2015.4368 PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural ID - 26633184 [pubmed] ID - 2473508 [pii] ID - 10.1001/jamaoncol.2015.4368 [doi] PP - ppublish GI - No: P30 CA072720 Organization: (CA) *NCI NIH HHS* Country: United States No: K12 CA0906525 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2016 Feb DC - 20160212 EZ - 2015/12/04 06:00 DA - 2016/06/30 06:00 DT - 2015/12/04 06:00 YR - 2016 ED - 20160629 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26633184 <121. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26567141 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Karyampudi L AU - Lamichhane P AU - Krempski J AU - Kalli KR AU - Behrens MD AU - Vargas DM AU - Hartmann LC AU - Janco JM AU - Dong H AU - Hedin KE AU - Dietz AB AU - Goode EL AU - Knutson KL FA - Karyampudi, Lavakumar FA - Lamichhane, Purushottam FA - Krempski, James FA - Kalli, Kimberly R FA - Behrens, Marshall D FA - Vargas, Doris M FA - Hartmann, Lynn C FA - Janco, Jo Marie T FA - Dong, Haidong FA - Hedin, Karen E FA - Dietz, Allan B FA - Goode, Ellen L FA - Knutson, Keith L IN - Karyampudi, Lavakumar. Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. IN - Lamichhane, Purushottam. Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Krempski, James. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Kalli, Kimberly R. Department of Oncology, Mayo Clinic, Rochester, Minnesota. IN - Behrens, Marshall D. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Vargas, Doris M. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Hartmann, Lynn C. Department of Oncology, Mayo Clinic, Rochester, Minnesota. IN - Janco, Jo Marie T. Department of Gynecologic Surgery Mayo Clinic, Mayo Clinic, Rochester, Minnesota. IN - Dong, Haidong. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Hedin, Karen E. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Dietz, Allan B. Human Cell Therapy Lab, Mayo Clinic, Rochester, Minnesota. IN - Goode, Ellen L. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. IN - Knutson, Keith L. Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. Department of Immunology, Mayo Clinic, Rochester, Minnesota. knutson.keith@mayo.edu. TI - PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-kappaB. SO - Cancer Research. 76(2):239-50, 2016 Jan 15 AS - Cancer Res. 76(2):239-50, 2016 Jan 15 NJ - Cancer research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnf, 2984705r IO - Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715980 OI - Source: NLM. NIHMS737606 [Available on 01/15/17] SB - Index Medicus CP - United States MH - Animals MH - *Dendritic Cells/im [Immunology] MH - Female MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - *NF-kappa B/me [Metabolism] MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/pa [Pathology] MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Signal Transduction AB - The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c(+)CD11b(+)CD8(-)CD209a(+)) and human (CD1c(+)CD19(-)) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-kappaB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-kappaB activation. Further mechanistic investigations showed that PD-1 blocked NF-kappaB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-kappaB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (NF-kappa B) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1538-7445 IL - 0008-5472 DI - 0008-5472.CAN-15-0748 DO - https://dx.doi.org/10.1158/0008-5472.CAN-15-0748 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26567141 [pubmed] ID - 0008-5472.CAN-15-0748 [pii] ID - 10.1158/0008-5472.CAN-15-0748 [doi] ID - PMC4715980 [pmc] ID - NIHMS737606 [mid] PP - ppublish PH - 2015/03/17 [received] PH - 2015/10/13 [accepted] PH - 2017/01/15 [pmc-release] GI - No: P30 CA015083 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA136393 Organization: (CA) *NCI NIH HHS* Country: United States No: P30-CA015083-25 Organization: (CA) *NCI NIH HHS* Country: United States No: P50-CA136393 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20151113 DP - 2016 Jan 15 DC - 20160116 EZ - 2015/11/15 06:00 DA - 2016/06/29 06:00 DT - 2015/11/15 06:00 YR - 2016 ED - 20160628 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26567141 <122. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26567141 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Karyampudi L AU - Lamichhane P AU - Krempski J AU - Kalli KR AU - Behrens MD AU - Vargas DM AU - Hartmann LC AU - Janco JM AU - Dong H AU - Hedin KE AU - Dietz AB AU - Goode EL AU - Knutson KL FA - Karyampudi, Lavakumar FA - Lamichhane, Purushottam FA - Krempski, James FA - Kalli, Kimberly R FA - Behrens, Marshall D FA - Vargas, Doris M FA - Hartmann, Lynn C FA - Janco, Jo Marie T FA - Dong, Haidong FA - Hedin, Karen E FA - Dietz, Allan B FA - Goode, Ellen L FA - Knutson, Keith L IN - Karyampudi, Lavakumar. Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. IN - Lamichhane, Purushottam. Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Krempski, James. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Kalli, Kimberly R. Department of Oncology, Mayo Clinic, Rochester, Minnesota. IN - Behrens, Marshall D. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Vargas, Doris M. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Hartmann, Lynn C. Department of Oncology, Mayo Clinic, Rochester, Minnesota. IN - Janco, Jo Marie T. Department of Gynecologic Surgery Mayo Clinic, Mayo Clinic, Rochester, Minnesota. IN - Dong, Haidong. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Hedin, Karen E. Department of Immunology, Mayo Clinic, Rochester, Minnesota. IN - Dietz, Allan B. Human Cell Therapy Lab, Mayo Clinic, Rochester, Minnesota. IN - Goode, Ellen L. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. IN - Knutson, Keith L. Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. Department of Immunology, Mayo Clinic, Rochester, Minnesota. knutson.keith@mayo.edu. TI - PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-kappaB. SO - Cancer Research. 76(2):239-50, 2016 Jan 15 AS - Cancer Res. 76(2):239-50, 2016 Jan 15 NJ - Cancer research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnf, 2984705r IO - Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715980 OI - Source: NLM. NIHMS737606 [Available on 01/15/17] SB - Index Medicus CP - United States MH - Animals MH - *Dendritic Cells/im [Immunology] MH - Female MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - *NF-kappa B/me [Metabolism] MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/pa [Pathology] MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Signal Transduction AB - The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c(+)CD11b(+)CD8(-)CD209a(+)) and human (CD1c(+)CD19(-)) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-kappaB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-kappaB activation. Further mechanistic investigations showed that PD-1 blocked NF-kappaB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-kappaB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (NF-kappa B) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1538-7445 IL - 0008-5472 DI - 0008-5472.CAN-15-0748 DO - https://dx.doi.org/10.1158/0008-5472.CAN-15-0748 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26567141 [pubmed] ID - 0008-5472.CAN-15-0748 [pii] ID - 10.1158/0008-5472.CAN-15-0748 [doi] ID - PMC4715980 [pmc] ID - NIHMS737606 [mid] PP - ppublish PH - 2015/03/17 [received] PH - 2015/10/13 [accepted] GI - No: P30 CA015083 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA136393 Organization: (CA) *NCI NIH HHS* Country: United States No: P30-CA015083-25 Organization: (CA) *NCI NIH HHS* Country: United States No: P50-CA136393 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20151113 DP - 2016 Jan 15 DC - 20160116 EZ - 2015/11/15 06:00 DA - 2016/06/29 06:00 DT - 2015/11/15 06:00 YR - 2016 ED - 20160628 RD - 20170118 UP - 20170119 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26567141 <123. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26642366 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Chamberlain N AU - Massad C AU - Oe T AU - Cantaert T AU - Herold KC AU - Meffre E FA - Chamberlain, Nicolas FA - Massad, Christopher FA - Oe, Tyler FA - Cantaert, Tineke FA - Herold, Kevan C FA - Meffre, Eric TI - Rituximab does not reset defective early B cell tolerance checkpoints. SO - Journal of Clinical Investigation. 126(1):282-7, 2016 Jan AS - J Clin Invest. 126(1):282-7, 2016 Jan NJ - The Journal of clinical investigation PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hs7, 7802877 IO - J. Clin. Invest. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701568 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - *B-Lymphocytes/de [Drug Effects] MH - B-Lymphocytes/im [Immunology] MH - Diabetes Mellitus, Type 1/im [Immunology] MH - Humans MH - *Immune Tolerance/de [Drug Effects] MH - Lymphocyte Depletion MH - Receptors, Antigen, B-Cell/ph [Physiology] MH - *Rituximab/pd [Pharmacology] AB - Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve beta cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti-B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti-B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti-B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti-B cell therapy. RN - 0 (Receptors, Antigen, B-Cell) RN - 4F4X42SYQ6 (Rituximab) ES - 1558-8238 IL - 0021-9738 DI - 83840 DO - https://dx.doi.org/10.1172/JCI83840 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 26642366 [pubmed] ID - 83840 [pii] ID - 10.1172/JCI83840 [doi] ID - PMC4701568 [pmc] PP - ppublish PH - 2015/07/20 [received] PH - 2015/11/03 [accepted] GI - No: AI095848 Organization: (AI) *NIAID NIH HHS* Country: United States No: U01 DK061010 Organization: (DK) *NIDDK NIH HHS* Country: United States No: U01 DK103153 Organization: (DK) *NIDDK NIH HHS* Country: United States No: R01 AI071087 Organization: (AI) *NIAID NIH HHS* Country: United States No: AI071087 Organization: (AI) *NIAID NIH HHS* Country: United States No: U01 DK085499 Organization: (DK) *NIDDK NIH HHS* Country: United States No: U01 DK103266 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P01 AI061093 Organization: (AI) *NIAID NIH HHS* Country: United States No: U01 DK107014 Organization: (DK) *NIDDK NIH HHS* Country: United States No: AI082713 Organization: (AI) *NIAID NIH HHS* Country: United States No: U19 AI082713 Organization: (AI) *NIAID NIH HHS* Country: United States No: R21 AI095848 Organization: (AI) *NIAID NIH HHS* Country: United States No: AI061093 Organization: (AI) *NIAID NIH HHS* Country: United States LG - English EP - 20151207 DP - 2016 Jan DC - 20160105 EZ - 2015/12/08 06:00 DA - 2016/06/18 06:00 DT - 2015/12/08 06:00 YR - 2016 ED - 20160617 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26642366 <124. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26164177 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bacanovic S AU - Burger IA AU - Stolzmann P AU - Hafner J AU - Huellner MW FA - Bacanovic, Sara FA - Burger, Irene A FA - Stolzmann, Paul FA - Hafner, Jurg FA - Huellner, Martin W IN - Bacanovic, Sara. From the *Department of Medical Radiology, Division of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland; +Department of Medical Radiology, Divisions of Nuclear Medicine and Neuroradiology, University Hospital Zurich, Zurich, Switzerland; and ++Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. TI - Ipilimumab-Induced Adrenalitis: A Possible Pitfall in 18F-FDG-PET/CT. SO - Clinical Nuclear Medicine. 40(11):e518-9, 2015 Nov AS - Clin Nucl Med. 40(11):e518-9, 2015 Nov NJ - Clinical nuclear medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - df6, 7611109 IO - Clin Nucl Med SB - Index Medicus CP - United States MH - Adrenocortical Hyperfunction/ci [Chemically Induced] MH - *Adrenocortical Hyperfunction/dg [Diagnostic Imaging] MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - False Positive Reactions MH - Fluorodeoxyglucose F18 MH - Humans MH - Male MH - *Melanoma/dg [Diagnostic Imaging] MH - Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Multimodal Imaging MH - Neoplasm Metastasis MH - *Positron-Emission Tomography MH - Radiopharmaceuticals MH - *Tomography, X-Ray Computed AB - Ipilimumab is a monoclonal antibody against the inhibitory CTLA-4 receptor expressed on T cells. It provokes an upregulation of the immune system. This substance was approved by the US Food and Drug Administration in 2011 and is since increasingly used as a targeted therapeutic approach for metastasized melanoma. Ipilimumab is known to cause neuroendocrine disorders, such as hypophysitis and adrenal insufficiency. Our case of a 79-year-old patient represents an important imaging pitfall. Imaging findings of newly symmetrically and smoothly enlarged, hypermetabolic adrenal glands in the setting of previous ipilimumab therapy represent drug-induced adrenalitis and not metastatic disease. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Radiopharmaceuticals) RN - 0Z5B2CJX4D (Fluorodeoxyglucose F18) RN - 6T8C155666 (ipilimumab) ES - 1536-0229 IL - 0363-9762 DO - https://dx.doi.org/10.1097/RLU.0000000000000887 PT - Case Reports PT - Journal Article ID - 26164177 [pubmed] ID - 10.1097/RLU.0000000000000887 [doi] PP - ppublish LG - English DP - 2015 Nov DC - 20151007 EZ - 2015/07/13 06:00 DA - 2016/06/18 06:00 DT - 2015/07/15 06:00 YR - 2015 ED - 20160617 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26164177 <125. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26642366 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Chamberlain N AU - Massad C AU - Oe T AU - Cantaert T AU - Herold KC AU - Meffre E FA - Chamberlain, Nicolas FA - Massad, Christopher FA - Oe, Tyler FA - Cantaert, Tineke FA - Herold, Kevan C FA - Meffre, Eric TI - Rituximab does not reset defective early B cell tolerance checkpoints. SO - Journal of Clinical Investigation. 126(1):282-7, 2016 Jan AS - J Clin Invest. 126(1):282-7, 2016 Jan NJ - The Journal of clinical investigation PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hs7, 7802877 IO - J. Clin. Invest. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701568 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - *B-Lymphocytes/de [Drug Effects] MH - B-Lymphocytes/im [Immunology] MH - Diabetes Mellitus, Type 1/im [Immunology] MH - Humans MH - *Immune Tolerance/de [Drug Effects] MH - Lymphocyte Depletion MH - Receptors, Antigen, B-Cell/ph [Physiology] MH - *Rituximab/pd [Pharmacology] AB - Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve beta cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti-B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti-B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti-B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti-B cell therapy. RN - 0 (Receptors, Antigen, B-Cell) RN - 4F4X42SYQ6 (Rituximab) ES - 1558-8238 IL - 0021-9738 DI - 83840 DO - https://dx.doi.org/10.1172/JCI83840 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 26642366 [pubmed] ID - 83840 [pii] ID - 10.1172/JCI83840 [doi] ID - PMC4701568 [pmc] PP - ppublish PH - 2015/07/20 [received] PH - 2015/11/03 [accepted] GI - No: U01 DK085476 Organization: (DK) *NIDDK NIH HHS* Country: United States No: AI095848 Organization: (AI) *NIAID NIH HHS* Country: United States No: U01 DK061010 Organization: (DK) *NIDDK NIH HHS* Country: United States No: U01 DK103153 Organization: (DK) *NIDDK NIH HHS* Country: United States No: U01 DK061058 Organization: (DK) *NIDDK NIH HHS* Country: United States No: R01 AI071087 Organization: (AI) *NIAID NIH HHS* Country: United States No: AI071087 Organization: (AI) *NIAID NIH HHS* Country: United States No: U01 DK106984 Organization: (DK) *NIDDK NIH HHS* Country: United States No: U01 DK085499 Organization: (DK) *NIDDK NIH HHS* Country: United States No: U01 DK103266 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P01 AI061093 Organization: (AI) *NIAID NIH HHS* Country: United States No: U01 DK107014 Organization: (DK) *NIDDK NIH HHS* Country: United States No: AI082713 Organization: (AI) *NIAID NIH HHS* Country: United States No: U19 AI082713 Organization: (AI) *NIAID NIH HHS* Country: United States No: R21 AI095848 Organization: (AI) *NIAID NIH HHS* Country: United States No: AI061093 Organization: (AI) *NIAID NIH HHS* Country: United States No: U01 DK085465 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English EP - 20151207 DP - 2016 Jan DC - 20160105 EZ - 2015/12/08 06:00 DA - 2016/06/18 06:00 DT - 2015/12/08 06:00 YR - 2016 ED - 20160617 RD - 20170302 UP - 20170303 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26642366 <126. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27274826 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Murakami N AU - Borges TJ AU - Yamashita M AU - Riella LV FA - Murakami, Naoka FA - Borges, Thiago J FA - Yamashita, Michifumi FA - Riella, Leonardo V IN - Murakami, Naoka. Renal Division, Brigham & Women's Hospital , Harvard Medical School , Boston, MA , USA. IN - Borges, Thiago J. Renal Division, Brigham & Women's Hospital , Harvard Medical School , Boston, MA , USA. IN - Yamashita, Michifumi. Department of Pathology, Brigham and Women's Hospital , Harvard Medical School , Boston, MA , USA. IN - Riella, Leonardo V. Renal Division, Brigham& Women's Hospital, Harvard Medical School, Boston, MA, USA; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, USA. TI - Severe acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma.[Erratum appears in Clin Kidney J. 2016 Aug;9(4):649; PMID: 27478613] SO - Clinical Kidney Journal. 9(3):411-7, 2016 Jun AS - Clin Kidney J. 9(3):411-7, 2016 Jun NJ - Clinical kidney journal PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101579321 IO - Clin Kidney J PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886917 CP - England KW - acute kidney injury; immune-checkpoint blockade; interstitial nephritis AB - Immune-checkpoint inhibitors are emerging as revolutionary drugs for certain malignancies. However, blocking the co-inhibitory signals may lead to immune-related adverse events, mainly in the spectrum of autoimmune diseases including colitis, endocrinopathies and nephritis. Here, we report a case of a 75-year-old man with metastatic malignant melanoma treated with a combination of nivolumab (anti-PD1-antibody) and ipilimumab (anti-CTLA-4 antibody) who developed systemic rash along with severe acute tubulointerstitial nephritis after two doses of combination therapy. Kidney biopsy and peripheral blood immune profile revealed highly proliferative and cytotoxic T cell features. Herein, we discuss the pathophysiology and management of immune checkpoint blockade-related adverse events. IS - 2048-8505 IL - 2048-8505 DI - sfw024 DO - https://dx.doi.org/10.1093/ckj/sfw024 PT - Journal Article ID - 27274826 [pubmed] ID - 10.1093/ckj/sfw024 [doi] ID - sfw024 [pii] ID - PMC4886917 [pmc] PP - ppublish PH - 2016/02/16 [received] PH - 2016/03/08 [accepted] GI - No: T32 DK007527 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English EP - 20160504 DP - 2016 Jun DC - 20160609 EZ - 2016/06/09 06:00 DA - 2016/06/09 06:01 DT - 2016/06/09 06:00 YR - 2016 ED - 20160609 RD - 20161025 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27274826 <127. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26765102 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Michot JM AU - Bigenwald C AU - Champiat S AU - Collins M AU - Carbonnel F AU - Postel-Vinay S AU - Berdelou A AU - Varga A AU - Bahleda R AU - Hollebecque A AU - Massard C AU - Fuerea A AU - Ribrag V AU - Gazzah A AU - Armand JP AU - Amellal N AU - Angevin E AU - Noel N AU - Boutros C AU - Mateus C AU - Robert C AU - Soria JC AU - Marabelle A AU - Lambotte O FA - Michot, J M FA - Bigenwald, C FA - Champiat, S FA - Collins, M FA - Carbonnel, F FA - Postel-Vinay, S FA - Berdelou, A FA - Varga, A FA - Bahleda, R FA - Hollebecque, A FA - Massard, C FA - Fuerea, A FA - Ribrag, V FA - Gazzah, A FA - Armand, J P FA - Amellal, N FA - Angevin, E FA - Noel, N FA - Boutros, C FA - Mateus, C FA - Robert, C FA - Soria, J C FA - Marabelle, A FA - Lambotte, O IN - Michot, J M. Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hopitaux de Paris, Hopital Universitaire Bicetre, F-94275 Le Kremlin Bicetre, France. Electronic address: jean-marie.michot@gustaveroussy.fr. IN - Bigenwald, C. Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Champiat, S. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Collins, M. Gastroenterology Department, Assistance Publique-Hopitaux de Paris, Hopital Universitaire Bicetre, F-94275 Le Kremlin Bicetre, France; Universite Paris Sud 11, F-94275 Le Kremlin-Bicetre, France. IN - Carbonnel, F. Gastroenterology Department, Assistance Publique-Hopitaux de Paris, Hopital Universitaire Bicetre, F-94275 Le Kremlin Bicetre, France; Universite Paris Sud 11, F-94275 Le Kremlin-Bicetre, France. IN - Postel-Vinay, S. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Berdelou, A. Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Varga, A. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Bahleda, R. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Hollebecque, A. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Massard, C. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Fuerea, A. Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Ribrag, V. Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Gazzah, A. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Armand, J P. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Amellal, N. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Angevin, E. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Noel, N. Internal Medicine and Clinical Immunology Department, Assistance Publique-Hopitaux de Paris, Hopital Universitaire Bicetre, F-94275 Le Kremlin Bicetre, France; Universite Paris Sud 11, F-94275 Le Kremlin-Bicetre, France; CEA, DSV/iMETI, Division of Immunovirology, IDMIT, F-92265 Fontenay-aux-Roses, France; INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, F-94276 Le Kremlin-Bicetre, France. IN - Boutros, C. Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hopitaux de Paris, Hopital Universitaire Bicetre, F-94275 Le Kremlin Bicetre, France. IN - Mateus, C. Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hopitaux de Paris, Hopital Universitaire Bicetre, F-94275 Le Kremlin Bicetre, France. IN - Robert, C. Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hopitaux de Paris, Hopital Universitaire Bicetre, F-94275 Le Kremlin Bicetre, France. IN - Soria, J C. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Marabelle, A. Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France. IN - Lambotte, O. Internal Medicine and Clinical Immunology Department, Assistance Publique-Hopitaux de Paris, Hopital Universitaire Bicetre, F-94275 Le Kremlin Bicetre, France; Universite Paris Sud 11, F-94275 Le Kremlin-Bicetre, France; CEA, DSV/iMETI, Division of Immunovirology, IDMIT, F-92265 Fontenay-aux-Roses, France; INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, F-94276 Le Kremlin-Bicetre, France. TI - Immune-related adverse events with immune checkpoint blockade: a comprehensive review. [Review] SO - European Journal of Cancer. 54:139-48, 2016 Feb AS - Eur J Cancer. 54:139-48, 2016 Feb NJ - European journal of cancer (Oxford, England : 1990) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - arv, 9005373 IO - Eur. J. Cancer SB - Index Medicus CP - England MH - Abatacept/ae [Adverse Effects] MH - Animals MH - *Antibodies/ae [Adverse Effects] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antigens, CD274/im [Immunology] MH - Antigens, CD274/me [Metabolism] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - CTLA-4 Antigen/me [Metabolism] MH - Drug-Related Side Effects and Adverse Reactions/di [Diagnosis] MH - *Drug-Related Side Effects and Adverse Reactions/im [Immunology] MH - Humans MH - *Immunotherapy/ae [Adverse Effects] MH - Immunotherapy/mt [Methods] MH - Molecular Targeted Therapy MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/im [Immunology] MH - Neoplasms/me [Metabolism] MH - Neoplasms/pa [Pathology] MH - Risk Factors MH - Signal Transduction/de [Drug Effects] MH - Treatment Outcome KW - Anti-PD-1 antibody; Cytotoxic T-lymphocyte-associated antigen 4; Immune checkpoint blockade; Immune-related adverse events; Tumour neoantigen AB - Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines. AB - Copyright © 2015 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (CD274 protein, human) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 7D0YB67S97 (Abatacept) ES - 1879-0852 IL - 0959-8049 DI - S0959-8049(15)01112-0 DO - https://dx.doi.org/10.1016/j.ejca.2015.11.016 PT - Journal Article PT - Review ID - 26765102 [pubmed] ID - S0959-8049(15)01112-0 [pii] ID - 10.1016/j.ejca.2015.11.016 [doi] PP - ppublish PH - 2015/11/11 [received] PH - 2015/11/15 [accepted] LG - English EP - 20160105 DP - 2016 Feb DC - 20160202 EZ - 2016/01/15 06:00 DA - 2016/06/09 06:00 DT - 2016/01/15 06:00 YR - 2016 ED - 20160606 RD - 20160202 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26765102 <128. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26056145 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wang L AU - Amoozgar Z AU - Huang J AU - Saleh MH AU - Xing D AU - Orsulic S AU - Goldberg MS FA - Wang, Lei FA - Amoozgar, Zohreh FA - Huang, Jing FA - Saleh, Mohammad H FA - Xing, Deyin FA - Orsulic, Sandra FA - Goldberg, Michael S IN - Wang, Lei. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Amoozgar, Zohreh. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Huang, Jing. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Saleh, Mohammad H. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Xing, Deyin. Department of Pathology, Johns Hopkins University, Baltimore, Maryland. IN - Orsulic, Sandra. Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. IN - Goldberg, Michael S. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts. Michael_Goldberg1@dfci.harvard.edu. TI - Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model. SO - Cancer Immunology Research. 3(9):1030-41, 2015 Sep AS - Cancer Immunol Res. 3(9):1030-41, 2015 Sep NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res SB - Index Medicus CP - United States MH - Animals MH - Antineoplastic Agents/pd [Pharmacology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Ascitic Fluid/im [Immunology] MH - Azacitidine/ad [Administration & Dosage] MH - *Azacitidine/aa [Analogs & Derivatives] MH - Azacitidine/pd [Pharmacology] MH - Azacitidine/tu [Therapeutic Use] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Cell Movement/de [Drug Effects] MH - Cell Transformation, Neoplastic/de [Drug Effects] MH - Cell Transformation, Neoplastic/im [Immunology] MH - Cytokines/bi [Biosynthesis] MH - Female MH - Gene Expression Regulation, Neoplastic/de [Drug Effects] MH - Gene Expression Regulation, Neoplastic/im [Immunology] MH - Humans MH - Immunotherapy/mt [Methods] MH - Killer Cells, Natural/de [Drug Effects] MH - Killer Cells, Natural/im [Immunology] MH - Lymph Nodes/im [Immunology] MH - *Lymphocytes, Tumor-Infiltrating/de [Drug Effects] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Mice MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/im [Immunology] MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays/mt [Methods] AB - The lack of second-line treatment for relapsed ovarian cancer necessitates the development of improved combination therapies. Targeted therapy and immunotherapy each confer clinical benefit, albeit limited as monotherapies. Ovarian cancer is not particularly responsive to immune checkpoint blockade, so combination with a complementary therapy may be beneficial. Recent studies have revealed that a DNA methyl transferase inhibitor, azacytidine, alters expression of immunoregulatory genes in ovarian cancer. In this study, the antitumor effects of a related DNA methyl transferase inhibitor, decitabine (DAC), were demonstrated in a syngeneic murine ovarian cancer model. Low-dose DAC treatment increases the expression of chemokines that recruit NK cells and CD8(+) T cells, promotes their production of IFNgamma and TNFalpha, and extends the survival of mice bearing subcutaneous or orthotopic tumors. While neither DAC nor immune checkpoint blockade confers durable responses as a monotherapy in this model, the efficacy of anti-CTLA-4 was potentiated by combination with DAC. This combination promotes differentiation of naive T cells into effector T cells and prolongs cytotoxic lymphocyte responses as well as mouse survival. These results suggest that this combination therapy may be worthy of further consideration for improved treatment of drug-resistant ovarian cancer. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (Cytokines) RN - 776B62CQ27 (decitabine) RN - M801H13NRU (Azacitidine) ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-15-0073 DO - https://dx.doi.org/10.1158/2326-6066.CIR-15-0073 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26056145 [pubmed] ID - 2326-6066.CIR-15-0073 [pii] ID - 10.1158/2326-6066.CIR-15-0073 [doi] PP - ppublish PH - 2015/03/16 [received] PH - 2015/05/26 [accepted] LG - English EP - 20150608 DP - 2015 Sep DC - 20150905 EZ - 2015/06/10 06:00 DA - 2016/05/26 06:00 DT - 2015/06/10 06:00 YR - 2015 ED - 20160525 RD - 20150905 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26056145 <129. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25943534 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Stewart R AU - Morrow M AU - Hammond SA AU - Mulgrew K AU - Marcus D AU - Poon E AU - Watkins A AU - Mullins S AU - Chodorge M AU - Andrews J AU - Bannister D AU - Dick E AU - Crawford N AU - Parmentier J AU - Alimzhanov M AU - Babcook JS AU - Foltz IN AU - Buchanan A AU - Bedian V AU - Wilkinson RW AU - McCourt M FA - Stewart, Ross FA - Morrow, Michelle FA - Hammond, Scott A FA - Mulgrew, Kathy FA - Marcus, Danielle FA - Poon, Edmund FA - Watkins, Amanda FA - Mullins, Stefanie FA - Chodorge, Matthieu FA - Andrews, John FA - Bannister, David FA - Dick, Emily FA - Crawford, Nicola FA - Parmentier, Julie FA - Alimzhanov, Marat FA - Babcook, John S FA - Foltz, Ian N FA - Buchanan, Andrew FA - Bedian, Vahe FA - Wilkinson, Robert W FA - McCourt, Matthew IN - Stewart, Ross. MedImmune Ltd, Cambridge, United Kingdom. StewartR@medimmune.com. IN - Morrow, Michelle. MedImmune Ltd, Cambridge, United Kingdom. IN - Hammond, Scott A. MedImmune LLC, Gaithersburg, Maryland. IN - Mulgrew, Kathy. MedImmune LLC, Gaithersburg, Maryland. IN - Marcus, Danielle. MedImmune Ltd, Cambridge, United Kingdom. IN - Poon, Edmund. MedImmune Ltd, Cambridge, United Kingdom. IN - Watkins, Amanda. MedImmune Ltd, Cambridge, United Kingdom. IN - Mullins, Stefanie. MedImmune Ltd, Cambridge, United Kingdom. IN - Chodorge, Matthieu. MedImmune Ltd, Cambridge, United Kingdom. IN - Andrews, John. MedImmune Ltd, Cambridge, United Kingdom. IN - Bannister, David. MedImmune Ltd, Cambridge, United Kingdom. IN - Dick, Emily. MedImmune Ltd, Cambridge, United Kingdom. IN - Crawford, Nicola. MedImmune Ltd, Cambridge, United Kingdom. IN - Parmentier, Julie. Abbvie Inc, Worcester, Massachusetts. Previously AstraZeneca Ltd. IN - Alimzhanov, Marat. Acceleron Pharma, Inc, Cambridge, Massachusetts. Previously Astrazeneca Ltd. IN - Babcook, John S. CDRD, University of British Columbia, Vancouver, British Columbia, Canada. Previously Amgen Inc. IN - Foltz, Ian N. Amgen Inc, Burnaby, British Columbia, Canada. IN - Buchanan, Andrew. MedImmune Ltd, Cambridge, United Kingdom. IN - Bedian, Vahe. AstraZeneca Ltd, Waltham, Massachusetts. IN - Wilkinson, Robert W. MedImmune Ltd, Cambridge, United Kingdom. IN - McCourt, Matthew. Kymab Ltd, The Bennet Building, Babraham Research Campus, Cambridge, United Kingdom. Previously MedImmune Ltd. TI - Identification and Characterization of MEDI4736, an Antagonistic Anti-PD-L1 Monoclonal Antibody. SO - Cancer Immunology Research. 3(9):1052-62, 2015 Sep AS - Cancer Immunol Res. 3(9):1052-62, 2015 Sep NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res SB - Index Medicus CP - United States MH - Animals MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/me [Metabolism] MH - *Antibodies, Monoclonal/pd [Pharmacology] MH - Antibody-Dependent Cell Cytotoxicity/de [Drug Effects] MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antigens, CD274/me [Metabolism] MH - Antigens, CD80/me [Metabolism] MH - Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Binding, Competitive MH - Colorectal Neoplasms/dt [Drug Therapy] MH - Colorectal Neoplasms/pa [Pathology] MH - Female MH - Humans MH - Lymphocyte Activation/de [Drug Effects] MH - Lymphocyte Culture Test, Mixed MH - Melanoma/im [Immunology] MH - Melanoma/pa [Pathology] MH - Melanoma/pc [Prevention & Control] MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mice, Inbred NOD MH - Organoplatinum Compounds/ad [Administration & Dosage] MH - Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/pa [Pathology] MH - Pancreatic Neoplasms/pc [Prevention & Control] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - T-Lymphocytes/de [Drug Effects] MH - T-Lymphocytes/im [Immunology] MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays AB - Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti-PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti-CTLA-4, anti-PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (Antigens, CD80) RN - 0 (CD274 protein, human) RN - 0 (Cd274 protein, mouse) RN - 0 (MEDI4736) RN - 0 (Organoplatinum Compounds) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 04ZR38536J (oxaliplatin) ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-14-0191 DO - https://dx.doi.org/10.1158/2326-6066.CIR-14-0191 PT - Journal Article ID - 25943534 [pubmed] ID - 2326-6066.CIR-14-0191 [pii] ID - 10.1158/2326-6066.CIR-14-0191 [doi] PP - ppublish PH - 2014/11/20 [received] PH - 2015/04/07 [accepted] LG - English EP - 20150505 DP - 2015 Sep DC - 20150905 EZ - 2015/05/07 06:00 DA - 2016/05/26 06:00 DT - 2015/05/07 06:00 YR - 2015 ED - 20160525 RD - 20150905 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25943534 <130. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27093728 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hamanishi J AU - Mandai M AU - Konishi I FA - Hamanishi, Junzo FA - Mandai, Masaki FA - Konishi, Ikuo TI - [Future Prospects of Anit-PD-1 or Anti-PD-L1 Antibody Therapy]. [Japanese] SO - Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy]. 43(2):182-8, 2016 Feb AS - Gan To Kagaku Ryoho. 43(2):182-8, 2016 Feb NJ - Gan to kagaku ryoho. Cancer & chemotherapy PI - Journal available in: Print PI - Citation processed from: Print JC - 7810034, 6t8 IO - Gan To Kagaku Ryoho SB - Index Medicus CP - Japan MH - *Antibodies/tu [Therapeutic Use] MH - *Antigens, CD274/im [Immunology] MH - Clinical Trials as Topic MH - Female MH - Humans MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Recurrence MH - Signal Transduction/de [Drug Effects] RN - 0 (Antibodies) RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) IS - 0385-0684 IL - 0385-0684 PT - Journal Article ID - 27093728 [pubmed] PP - ppublish LG - Japanese DP - 2016 Feb DC - 20160419 EZ - 2016/04/21 06:00 DA - 2016/04/29 06:00 DT - 2016/04/21 06:00 YR - 2016 ED - 20160428 RD - 20160419 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=27093728 <131. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26573793 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Peng J AU - Hamanishi J AU - Matsumura N AU - Abiko K AU - Murat K AU - Baba T AU - Yamaguchi K AU - Horikawa N AU - Hosoe Y AU - Murphy SK AU - Konishi I AU - Mandai M FA - Peng, Jin FA - Hamanishi, Junzo FA - Matsumura, Noriomi FA - Abiko, Kaoru FA - Murat, Kumuruz FA - Baba, Tsukasa FA - Yamaguchi, Ken FA - Horikawa, Naoki FA - Hosoe, Yuko FA - Murphy, Susan K FA - Konishi, Ikuo FA - Mandai, Masaki IN - Peng, Jin. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Hamanishi, Junzo. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. jnkhmns@kuhp.kyoto-u.ac.jp. IN - Matsumura, Noriomi. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Abiko, Kaoru. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Murat, Kumuruz. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Baba, Tsukasa. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Yamaguchi, Ken. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Horikawa, Naoki. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Hosoe, Yuko. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Murphy, Susan K. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina. IN - Konishi, Ikuo. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. IN - Mandai, Masaki. Department of Obstetrics and Gynecology, Kinki University, Osaka, Japan. TI - Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-kappaB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer. SO - Cancer Research. 75(23):5034-45, 2015 Dec 01 AS - Cancer Res. 75(23):5034-45, 2015 Dec 01 NJ - Cancer research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnf, 2984705r IO - Cancer Res. SB - Index Medicus CP - United States MH - Animals MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Antigens, CD274/bi [Biosynthesis] MH - Antigens, CD274/ge [Genetics] MH - Antigens, CD274/im [Immunology] MH - *Antineoplastic Combined Chemotherapy Protocols/pd [Pharmacology] MH - Capecitabine/ad [Administration & Dosage] MH - Capecitabine/pd [Pharmacology] MH - Cell Line, Tumor MH - Female MH - Humans MH - Mice MH - NF-kappa B/im [Immunology] MH - *NF-kappa B/me [Metabolism] MH - Organoplatinum Compounds/ad [Administration & Dosage] MH - Organoplatinum Compounds/pd [Pharmacology] MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/ge [Genetics] MH - Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/me [Metabolism] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Taxoids/ad [Administration & Dosage] MH - Taxoids/pd [Pharmacology] MH - Transcriptome/de [Drug Effects] MH - Tumor Microenvironment/de [Drug Effects] MH - *Tumor Microenvironment/im [Immunology] MH - Xenograft Model Antitumor Assays AB - Emerging evidence has highlighted the host immune system in modulating the patient response to chemotherapy, but the mechanism of this modulation remains unclear. The aim of this study was to analyze the effect of chemotherapy on antitumor immunity in the tumor microenvironment of ovarian cancer. Treatment of ovarian cancer cell lines with various chemotherapeutic agents resulted in upregulated expression of MHC class I and programmed cell death 1 ligand 1 (PD-L1) in a NF-kappaB-dependent manner and suppression of antigen-specific T-cell function in vitro. In a mouse model of ovarian cancer, treatment with paclitaxel increased CD8(+) T-cell infiltration into the tumor site, upregulated PD-L1 expression, and activated NF-kappaB signaling. In particular, tumor-bearing mice treated with a combination of paclitaxel and a PD-L1/PD-1 signal blockade survived longer than mice treated with paclitaxel alone. In summary, we found that chemotherapy induces local immune suppression in ovarian cancer through NF-kappaB-mediated PD-L1 upregulation. Thus, a combination of chemotherapy and immunotherapy targeting the PD-L1/PD-1 signaling axis may improve the antitumor response and offers a promising new treatment modality against ovarian cancer. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (Cd274 protein, mouse) RN - 0 (NF-kappa B) RN - 0 (Organoplatinum Compounds) RN - 0 (PDCD1 protein, human) RN - 0 (Pdcd1 protein, mouse) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Taxoids) RN - 15H5577CQD (docetaxel) RN - 6804DJ8Z9U (Capecitabine) ES - 1538-7445 IL - 0008-5472 DI - 0008-5472.CAN-14-3098 DO - https://dx.doi.org/10.1158/0008-5472.CAN-14-3098 PT - Journal Article ID - 26573793 [pubmed] ID - 0008-5472.CAN-14-3098 [pii] ID - 10.1158/0008-5472.CAN-14-3098 [doi] PP - ppublish PH - 2014/10/20 [received] PH - 2015/09/01 [accepted] LG - English EP - 20151116 DP - 2015 Dec 01 DC - 20151202 EZ - 2015/11/18 06:00 DA - 2016/04/27 06:00 DT - 2015/11/18 06:00 YR - 2015 ED - 20160426 RD - 20151202 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26573793 <132. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26615135 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Mills TA AU - Orloff M AU - Domingo-Vidal M AU - Cotzia P AU - Birbe RC AU - Draganova-Tacheva R AU - Martinez Cantarin MP AU - Tuluc M AU - Martinez-Outschoorn U FA - Mills, Teresa Anne FA - Orloff, Marlana FA - Domingo-Vidal, Marina FA - Cotzia, Paolo FA - Birbe, Ruth C FA - Draganova-Tacheva, Rossitza FA - Martinez Cantarin, Maria P FA - Tuluc, Madalina FA - Martinez-Outschoorn, Ubaldo IN - Mills, Teresa Anne. Sidney Kimmel College of Medicine Thomas Jefferson University, Philadelphia, PA. IN - Orloff, Marlana. Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA. IN - Domingo-Vidal, Marina. Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA. IN - Cotzia, Paolo. Department of Pathology Thomas Jefferson University, Philadelphia, PA. IN - Birbe, Ruth C. Department of Pathology Thomas Jefferson University, Philadelphia, PA. IN - Draganova-Tacheva, Rossitza. Department of Pathology Thomas Jefferson University, Philadelphia, PA. IN - Martinez Cantarin, Maria P. Department of Medicine Thomas Jefferson University, Philadelphia, PA. IN - Tuluc, Madalina. Department of Pathology Thomas Jefferson University, Philadelphia, PA. IN - Martinez-Outschoorn, Ubaldo. Department of Medical Oncology Thomas Jefferson University, Philadelphia, PA. Electronic address: ubaldo.martinezoutschoorn@jefferson.edu. TI - Parathyroid Hormone-Related Peptide-Linked Hypercalcemia in a Melanoma Patient Treated With Ipilimumab: Hormone Source and Clinical and Metabolic Correlates. SO - Seminars in Oncology. 42(6):909-14, 2015 Dec AS - Semin Oncol. 42(6):909-14, 2015 Dec NJ - Seminars in oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - un5, 0420432 IO - Semin. Oncol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663680 OI - Source: NLM. NIHMS721618 [Available on 12/01/16] SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Cachexia/ci [Chemically Induced] MH - Female MH - Humans MH - Hypercalcemia/ci [Chemically Induced] MH - *Hypercalcemia/me [Metabolism] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Monocarboxylic Acid Transporters/me [Metabolism] MH - Paraneoplastic Syndromes/ci [Chemically Induced] MH - *Parathyroid Hormone-Related Protein/me [Metabolism] MH - Symporters/me [Metabolism] AB - A patient diagnosed with metastatic melanoma developed the paraneoplastic syndrome of humoral hypercalcemia of malignancy and cachexia after receiving ipilumumab. The cause of the hypercalcemia was thought to be secondary to parathyroid hormone-related peptide (PTHrP) as plasma levels were found to be elevated. The patient underwent two tumor biopsies: at diagnosis (when calcium levels were normal) and upon development of hypercalcemia and cachexia. PTHrP expression was higher in melanoma cells when hypercalcemia had occurred than prior to its onset. Metabolic characterization of melanoma cells revealed that, with development of hypercalcemia, there was high expression of monocarboxylate transporter 1 (MCT1), which is the main importer of lactate and ketone bodies into cells. MCT1 is associated with high mitochondrial metabolism. Beta-galactosidase (beta-GAL), a marker of senescence, had reduced expression in melanoma cells upon development of hypercalcemia compared to pre-hypercalcemia. In conclusion, PTHrP expression in melanoma is associated with cachexia, increased cancer cell lactate and ketone body import, high mitochondrial metabolism, and reduced senescence. Further studies are required to determine if PTHrP regulates cachexia, lactate and ketone body import, mitochondrial metabolism, and senescence in cancer cells. AB - Copyright © 2015 Elsevier Inc. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Monocarboxylic Acid Transporters) RN - 0 (PTHLH protein, human) RN - 0 (Parathyroid Hormone-Related Protein) RN - 0 (Symporters) RN - 0 (monocarboxylate transport protein 1) RN - 6T8C155666 (ipilimumab) ES - 1532-8708 IL - 0093-7754 DI - S0093-7754(15)00171-2 DO - https://dx.doi.org/10.1053/j.seminoncol.2015.09.006 PT - Case Reports PT - Journal Article ID - 26615135 [pubmed] ID - S0093-7754(15)00171-2 [pii] ID - 10.1053/j.seminoncol.2015.09.006 [doi] ID - PMC4663680 [pmc] ID - NIHMS721618 [mid] PP - ppublish GI - No: K08 CA175193 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA056036 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20150908 DP - 2015 Dec DC - 20151129 EZ - 2015/11/29 06:00 DA - 2016/04/26 06:00 DT - 2015/11/29 06:00 YR - 2015 ED - 20160425 RD - 20161201 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26615135 <133. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27110415 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Collins DC AU - Yela R AU - Horgan N AU - Power DG FA - Collins, Dearbhaile Catherine FA - Yela, Ruben FA - Horgan, Noel FA - Power, Derek Gerard IN - Collins, Dearbhaile Catherine. Department of Medical Oncology, Cork University Hospital, Wilton, Co. Cork, Ireland. IN - Yela, Ruben. Department of Histopathology, Cork University Hospital, Wilton, Co. Cork, Ireland. IN - Horgan, Noel. Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland. IN - Power, Derek Gerard. Department of Medical Oncology, Cork University Hospital, Wilton, Co. Cork, Ireland. TI - A Rare Thyroid Metastasis from Uveal Melanoma and Response to Immunotherapy Agents. SO - Case Reports in Oncological Medicine. 2016:6564094, 2016 AS - Case Rep Oncol Med. 2016:6564094, 2016 NJ - Case reports in oncological medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101581035 IO - Case Rep Oncol Med PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823504 CP - United States AB - Thyroid metastasis is a rare occurrence with cutaneous melanoma and even more uncommon with uveal melanoma. The management of such metastasis is uncertain due to its infrequency and, in the era of immunotherapy, the effect of these novel drugs on uncommon metastasis, such as to the thyroid, is unknown. We report the rare case of a thyroid metastasis in a patient diagnosed with ocular melanoma initially managed with enucleation. Metastatic disease developed in the lung and thyroid gland. The case patient received the immunotherapy ipilimumab with stable disease in the thyroid and progressive disease elsewhere. The patient was then further treated with a second immunotherapy agent, pembrolizumab, and remains with stable disease one year later. We discuss the current literature on thyroid metastases from all causes and the optimal known management strategies. Furthermore, we provide an original report on the response of this disease to the novel immunomodulators, ipilimumab, and pembrolizumab with stable disease four years after initial diagnosis of ocular melanoma. IS - 2090-6706 DO - https://dx.doi.org/10.1155/2016/6564094 PT - Journal Article ID - 27110415 [pubmed] ID - 10.1155/2016/6564094 [doi] ID - PMC4823504 [pmc] PP - ppublish PH - 2015/10/15 [received] PH - 2016/03/01 [accepted] LG - English EP - 20160324 DP - 2016 DC - 20160425 EZ - 2016/04/26 06:00 DA - 2016/04/26 06:01 DT - 2016/04/26 06:00 YR - 2016 ED - 20160425 RD - 20160427 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27110415 <134. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24451730 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Weber JS FA - Weber, Jeffrey S IN - Weber, Jeffrey S. From the Moffitt Cancer Center, Tampa, FL. TI - Practical management of immune-related adverse events from immune checkpoint protein antibodies for the oncologist. SO - American Society of Clinical Oncology Educational Book. :174-7, 2012 AS - Am. Soc. Clin. Oncol. educ. book. :174-7, 2012 NJ - American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting PI - Journal available in: Print PI - Citation processed from: Print JC - 101233985 IO - Am Soc Clin Oncol Educ Book CP - United States AB - Monoclonal antibodies directed against immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1), can boost endogenous immune responses directed against tumor cells. Recently, ipilimumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma, and the anti-PD-1 antibody BMS-936558 has shown promising results in patients with melanoma, non-small cell lung cancer, and renal cell cancer. During treatment with these antibodies, a unique set of toxicities occur called immune-related adverse events (irAEs). These irAEs may occur at any time during treatment and include colitis characterized by a mild to moderate but occasionally severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab, and a subset of those side effects has also been observed with BMS-936558. Patient and physician education as well as good patient-caretaker communication are keys to limiting the morbidity of irAEs. Early recognition of these irAEs and initiation of treatment are critical to reduce the risk of complications, since virtually all irAEs are reversible with the use of steroids and other immune suppressants. The onset of grade 3 to 4 irAEs correlated with treatment response in some ipilimumab studies. This article provides detailed description and recommendations for practicing oncologists to manage the common irAEs associated with antibodies against immune checkpoint blockade. IS - 1548-8748 IL - 1548-8748 DI - 79 DO - https://dx.doi.org/10.14694/EdBook_AM.2012.32.174 PT - Journal Article ID - 24451730 [pubmed] ID - 79 [pii] ID - 10.14694/EdBook_AM.2012.32.174 [doi] PP - ppublish LG - English DP - 2012 DC - 20140612 EZ - 2014/01/24 06:00 DA - 2012/01/01 00:01 DT - 2012/01/01 00:00 YR - 2012 ED - 20160415 RD - 20161021 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=24451730 <135. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25855890 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Tiu C AU - Pezaro C AU - Davis ID AU - Grossmann M AU - Parente P FA - Tiu, Crescens FA - Pezaro, Carmel FA - Davis, Ian D FA - Grossmann, Mathis FA - Parente, Phillip IN - Tiu, Crescens. Department of Medical Oncology, Eastern Health, Box Hill, Victoria, Australia. TI - Early recognition of ipilimumab-related autoimmune hypophysitis in patients with metastatic melanoma: Case studies and recommendations for management. SO - Asia-Pacific Journal of Clinical Oncology. 11(2):190-4, 2015 Jun AS - Asia Pac J Clin Oncol. 11(2):190-4, 2015 Jun NJ - Asia-Pacific journal of clinical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101241430 IO - Asia Pac J Clin Oncol SB - Index Medicus CP - Australia MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Autoimmune Hypophysitis/ci [Chemically Induced] MH - Humans MH - Male MH - *Melanoma/co [Complications] MH - Melanoma/pa [Pathology] MH - Middle Aged KW - CTLA-4; autoimmune hypophysitis; ipilimumab; melanoma AB - Ipilimumab is a human anti-CTLA-4 monoclonal antibody recently approved for the treatment of advanced melanoma. Stimulation of T-cell activity unmasks antitumor activity, but can cause immune-related adverse events. Autoimmune hypophysitis is of particular importance because its presentation can be subtle but life threatening. We present two cases where early recognition of ipilimumab-related autoimmune hypophysitis led to timely intervention and low subsequent morbidity, without compromise of antitumor effects. We provide recommendations for detection and management of this potentially life-threatening complication of ipilimumab. AB - Copyright © 2015 Wiley Publishing Asia Pty Ltd. RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 1743-7563 IL - 1743-7555 DO - https://dx.doi.org/10.1111/ajco.12348 PT - Case Reports PT - Journal Article ID - 25855890 [pubmed] ID - 10.1111/ajco.12348 [doi] PP - ppublish PH - 2015/01/11 [accepted] LG - English EP - 20150409 DP - 2015 Jun DC - 20150507 EZ - 2015/04/10 06:00 DA - 2016/04/15 06:00 DT - 2015/04/10 06:00 YR - 2015 ED - 20160414 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25855890 <136. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25965828 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Saini P AU - Li Y AU - Dobbelstein M FA - Saini, Priyanka FA - Li, Yizhu FA - Dobbelstein, Matthias IN - Saini, Priyanka. Institute of Molecular Oncology, Gottingen Centre of Molecular Biosciences (GZMB), Faculty of Medicine, University of Gottingen, Gottingen, Germany. IN - Li, Yizhu. Institute of Molecular Oncology, Gottingen Centre of Molecular Biosciences (GZMB), Faculty of Medicine, University of Gottingen, Gottingen, Germany. IN - Dobbelstein, Matthias. Institute of Molecular Oncology, Gottingen Centre of Molecular Biosciences (GZMB), Faculty of Medicine, University of Gottingen, Gottingen, Germany. TI - Wee1 is required to sustain ATR/Chk1 signaling upon replicative stress. SO - Oncotarget. 6(15):13072-87, 2015 May 30 AS - Oncotarget. 6(15):13072-87, 2015 May 30 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537000 SB - Index Medicus CP - United States MH - Antimetabolites, Antineoplastic/ad [Administration & Dosage] MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - *Antineoplastic Combined Chemotherapy Protocols/pd [Pharmacology] MH - Ataxia Telangiectasia Mutated Proteins/me [Metabolism] MH - *Cell Cycle Proteins/ai [Antagonists & Inhibitors] MH - *Cell Cycle Proteins/me [Metabolism] MH - Cell Line, Tumor MH - Checkpoint Kinase 1 MH - Deoxycytidine/ad [Administration & Dosage] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Drug Synergism MH - Humans MH - *Nuclear Proteins/ai [Antagonists & Inhibitors] MH - *Nuclear Proteins/me [Metabolism] MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/en [Enzymology] MH - *Pancreatic Neoplasms/me [Metabolism] MH - Protein Kinase Inhibitors/ad [Administration & Dosage] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - *Protein Kinases/me [Metabolism] MH - *Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - *Protein-Tyrosine Kinases/me [Metabolism] MH - Signal Transduction KW - ATR signaling pathway; Wee1; checkpoint kinases; gemcitabine; replicative stress AB - The therapeutic efficacy of nucleoside analogues, e.g. gemcitabine, against cancer cells can be augmented by inhibitors of checkpoint kinases, including Wee1, ATR, and Chk1. We have compared the chemosensitizing effect of these inhibitors in cells derived from pancreatic cancer, a tumor entity where gemcitabine is part of the first-line therapeutic regimens, and in osteosarcoma-derived cells. As expected, all three inhibitors rendered cancer cells more sensitive to gemcitabine, but Wee1 inhibition proved to be particularly efficient in this context. Investigating the reasons for this potent sensitizing effect, we found that Wee1 inhibition or knockdown not only blocked Wee1 activity, but also reduced the activation of ATR/Chk1 in gemcitabine-treated cells. Combination of several inhibitors revealed that Wee1 inhibition requires Cyclin-dependent kinases 1 and 2 (Cdk1/2) and Polo-like kinase 1 (Plk1) to reduce ATR/Chk1 activity. Through activation of Cdks and Plk1, Wee1 inhibition reduces Claspin and CtIP levels, explaining the impairment in ATR/Chk1 activity. Taken together, these results confer a consistent signaling pathway reaching from Wee1 inhibition to impaired Chk1 activity, mechanistically dissecting how Wee1 inhibitors not only dysregulate cell cycle progression, but also enhance replicative stress and chemosensitivity towards nucleoside analogues. RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Cell Cycle Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Protein Kinase Inhibitors) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-10-1 (Protein-Tyrosine Kinases) RN - EC 2-7-10-2 (WEE1 protein, human) RN - EC 2-7-11-1 (ATR protein, human) RN - EC 2-7-11-1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) ES - 1949-2553 IL - 1949-2553 DI - 3865 DO - https://dx.doi.org/10.18632/oncotarget.3865 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25965828 [pubmed] ID - 3865 [pii] ID - PMC4537000 [pmc] ID - 10.18632/oncotarget.3865 [doi] PP - ppublish PH - 2014/12/05 [received] PH - 2015/03/31 [accepted] LG - English DP - 2015 May 30 DC - 20150617 EZ - 2015/05/13 06:00 DA - 2016/04/14 06:00 DT - 2015/05/13 06:00 YR - 2015 ED - 20160412 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25965828 <137. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25444021 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gedye C AU - van der Westhuizen A AU - John T FA - Gedye, C FA - van der Westhuizen, A FA - John, T IN - Gedye, C. School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia. IN - Gedye, C. Department of Medical Oncology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia. IN - van der Westhuizen, A. Department of Medical Oncology, Calvary Mater Newcastle, Newcastle, New South Wales, Australia. IN - John, T. Department of Medical Oncology, Olivia Newton John Cancer and Wellness Centre, Austin Hospital, Melbourne, Victoria, Australia. TI - Checkpoint immunotherapy for cancer: superior survival, unaccustomed toxicities. [Review] SO - Internal Medicine Journal. 45(7):696-701, 2015 Jul AS - Intern Med J. 45(7):696-701, 2015 Jul NJ - Internal medicine journal PI - Journal available in: Print PI - Citation processed from: Internet JC - d20, 101092952 IO - Intern Med J SB - Index Medicus CP - Australia MH - *Genes, cdc/im [Immunology] MH - Humans MH - Immunotherapy/ae [Adverse Effects] MH - *Immunotherapy/mt [Methods] MH - *Neoplasms/mo [Mortality] MH - *Neoplasms/th [Therapy] MH - Survival Rate KW - cancer; checkpoint protein; immune-related side-effect; immunotherapy; lung cancer; melanoma AB - Novel cancer immunotherapy antibodies are moving from clinical trials into routine practice, delivering sustained benefits and prolonged survival to patients with melanoma, lung, kidney and other cancers. These immunostimulatory antibodies non-specifically activate the patient's own immune system by inhibiting immune system checkpoint proteins. This mechanism of action is entirely different to traditional cancer treatments, such as chemotherapy. While there are virtually no immediate toxicities, serious life-threatening autoimmune side-effects such as colitis, dermatitis, hypophysitis, pneumonitis and hepatitis can occur, sometimes starting long after the treatment has been given. Recognition, referral and prompt treatment with immunosuppressive drugs like corticosteroids can control these immune-related side-effects without compromising efficacy. This exciting new class of drugs is defining a new paradigm in cancer therapy. AB - Copyright © 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians. ES - 1445-5994 IL - 1444-0903 DO - https://dx.doi.org/10.1111/imj.12653 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 25444021 [pubmed] ID - 10.1111/imj.12653 [doi] PP - ppublish PH - 2014/09/14 [received] PH - 2014/11/26 [accepted] LG - English DP - 2015 Jul DC - 20150703 EZ - 2014/12/03 06:00 DA - 2016/04/06 06:00 DT - 2014/12/03 06:00 YR - 2015 ED - 20160405 RD - 20150703 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25444021 <138. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25866054 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Teo PY AU - Yang C AU - Whilding LM AU - Parente-Pereira AC AU - Maher J AU - George AJ AU - Hedrick JL AU - Yang YY AU - Ghaem-Maghami S FA - Teo, Pei Yun FA - Yang, Chuan FA - Whilding, Lynsey M FA - Parente-Pereira, Ana C FA - Maher, John FA - George, Andrew J T FA - Hedrick, James L FA - Yang, Yi Yan FA - Ghaem-Maghami, Sadaf IN - Teo, Pei Yun. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669, Singapore. IN - Teo, Pei Yun. Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK. IN - Yang, Chuan. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669, Singapore. IN - Whilding, Lynsey M. Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK. IN - Whilding, Lynsey M. King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT, UK. IN - Parente-Pereira, Ana C. King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT, UK. IN - Maher, John. King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT, UK. IN - George, Andrew J T. Brunel University, Kingston Lane, Uxbridge, Middlesex, UB8 3PH, UK. IN - Hedrick, James L. IBM Almaden Research Center, 650 Harry Road, San Jose, CA, 95120, USA. IN - Yang, Yi Yan. Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore, 138669, Singapore. IN - Ghaem-Maghami, Sadaf. Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK. TI - Ovarian cancer immunotherapy using PD-L1 siRNA targeted delivery from folic acid-functionalized polyethylenimine: strategies to enhance T cell killing. SO - Advanced Healthcare Materials. 4(8):1180-9, 2015 Jun 03 AS - Ad. healthc. mater.. 4(8):1180-9, 2015 Jun 03 NJ - Advanced healthcare materials PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101581613 IO - Adv Healthc Mater SB - Index Medicus CP - Germany MH - *Antigens, CD274/ge [Genetics] MH - Antigens, CD274/me [Metabolism] MH - Cell Line, Tumor MH - Down-Regulation MH - Female MH - *Folic Acid/me [Metabolism] MH - *Gene Expression Regulation, Neoplastic MH - Genetic Therapy MH - Humans MH - Immunotherapy/mt [Methods] MH - Lysosomal-Associated Membrane Protein 1/ge [Genetics] MH - Lysosomal-Associated Membrane Protein 1/me [Metabolism] MH - Nanoparticles/ch [Chemistry] MH - *Neoplasms, Glandular and Epithelial/ge [Genetics] MH - Neoplasms, Glandular and Epithelial/th [Therapy] MH - *Ovarian Neoplasms/ge [Genetics] MH - Ovarian Neoplasms/th [Therapy] MH - Particle Size MH - Polyethylene Glycols/ch [Chemistry] MH - *Polyethyleneimine/me [Metabolism] MH - Polymers/ch [Chemistry] MH - *RNA, Small Interfering/ge [Genetics] MH - T-Lymphocytes/me [Metabolism] KW - PD-L1 knock-down; T cells; ovarian cancer; polyethylenimine; siRNA delivery AB - Adoptive T cell immunotherapy is a promising treatment strategy for epithelial ovarian cancer (EOC). However, programmed death ligand-1 (PD-L1), highly expressed on EOC cells, interacts with programmed death-1 (PD-1), expressed on T cells, causing immunosuppression. This study aims to block PD-1/PD-L1 interactions by delivering PD-L1 siRNA, using various folic acid (FA)-functionalized polyethylenimine (PEI) polymers, to SKOV-3-Luc EOC cells, and investigate the sensitization of the EOC cells to T cell killing. To enhance siRNA uptake into EOC cells, which over express folate receptors, PEI is modified with FA or PEG-FA so that siRNA is complexed into nanoparticles with folate molecules on the surface. PEI modification with a single functional group lowers the polymer cytotoxicity compared to unmodified PEI. FA-conjugated polymers increase siRNA uptake into SKOV-3-luc cells and decrease unspecific uptake into monocytes. All polymers result in 40% to 50% PD-L1 protein knockdown. Importantly, SKOV-3-Luc cells treated with either PEI-FA or PEI- polyethylene glycol (PEG)-FA/PD-L1 siRNA complexes are up to twofold more sensitive to T cell killing compared to scrambled siRNA treated controls. These findings are the first to demonstrate that PD-L1 knockdown in EOC cells, via siRNA/FA-targeted delivery, are able to sensitize cancer cells to T cell killing. AB - Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (Lysosomal-Associated Membrane Protein 1) RN - 0 (Polymers) RN - 0 (RNA, Small Interfering) RN - 30IQX730WE (Polyethylene Glycols) RN - 9002-98-6 (Polyethyleneimine) RN - 935E97BOY8 (Folic Acid) RS - Ovarian epithelial cancer ES - 2192-2659 IL - 2192-2640 DO - https://dx.doi.org/10.1002/adhm.201500089 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25866054 [pubmed] ID - 10.1002/adhm.201500089 [doi] PP - ppublish PH - 2015/02/07 [received] PH - 2015/03/17 [revised] LG - English EP - 20150411 DP - 2015 Jun 03 DC - 20150604 EZ - 2015/04/14 06:00 DA - 2016/03/26 06:00 DT - 2015/04/14 06:00 YR - 2015 ED - 20160325 RD - 20150604 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25866054 <139. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26236750 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - De Felice F AU - Marchetti C AU - Palaia I AU - Musio D AU - Muzii L AU - Tombolini V AU - Panici PB FA - De Felice, Francesca FA - Marchetti, Claudia FA - Palaia, Innocenza FA - Musio, Daniela FA - Muzii, Ludovico FA - Tombolini, Vincenzo FA - Panici, Pierluigi Benedetti IN - De Felice, Francesca. Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Viale Regina Elena 326, 00161 Rome, Italy. IN - Marchetti, Claudia. Department of Gynecological and Obstetrical Sciences and Urological Sciences, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. IN - Palaia, Innocenza. Department of Gynecological and Obstetrical Sciences and Urological Sciences, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. IN - Musio, Daniela. Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Viale Regina Elena 326, 00161 Rome, Italy. IN - Muzii, Ludovico. Department of Gynecological and Obstetrical Sciences and Urological Sciences, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. IN - Tombolini, Vincenzo. Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Viale Regina Elena 326, 00161 Rome, Italy. IN - Panici, Pierluigi Benedetti. Department of Gynecological and Obstetrical Sciences and Urological Sciences, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. TI - Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors. [Review] SO - Journal of Immunological Research. 2015:191832, 2015 AS - J. immunol. res.. 2015:191832, 2015 NJ - Journal of immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101627166 IO - J Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508475 SB - Index Medicus CP - Egypt MH - Antibodies, Monoclonal/pd [Pharmacology] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Clinical Trials as Topic MH - Female MH - Humans MH - Immune System MH - Immunologic Factors/pd [Pharmacology] MH - Immunologic Factors/tu [Therapeutic Use] MH - Immunomodulation MH - Immunotherapy/mt [Methods] MH - *Immunotherapy MH - Molecular Targeted Therapy MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/me [Metabolism] MH - *Ovarian Neoplasms/th [Therapy] MH - Treatment Outcome AB - Ovarian cancer is the most important cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies to improve the outcomes. Advances in understanding the role of immune system in the pathogenesis of cancer have led to the rapid evolvement of immunotherapy, which might establish a sustained immune system response against recurring cancer cells. Recently, it has emerged that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints," which turn off the immune system. Similarly, cancer cells are able to use these checkpoints to avoid immune control and rejection. Inhibition of these inhibitory pathways represents a potent strategy in the fight against cancer and is currently under investigation with encouraging results in some cancers, such as melanoma. In ovarian cancer researches are still in an early phase, but with promising results. In this review we will explore the rationale of immunotherapy in ovarian cancer with a special focus on these emerging molecules. RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunologic Factors) ES - 2314-7156 IL - 2314-7156 DO - https://dx.doi.org/10.1155/2015/191832 PT - Journal Article PT - Review ID - 26236750 [pubmed] ID - 10.1155/2015/191832 [doi] ID - PMC4508475 [pmc] PP - ppublish PH - 2015/03/22 [received] PH - 2015/06/23 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01611558 SL - https://clinicaltrials.gov/search/term=NCT01611558 LG - English EP - 20150707 DP - 2015 DC - 20150803 EZ - 2015/08/04 06:00 DA - 2016/03/25 06:00 DT - 2015/08/04 06:00 YR - 2015 ED - 20160324 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26236750 <140. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26236750 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - De Felice F AU - Marchetti C AU - Palaia I AU - Musio D AU - Muzii L AU - Tombolini V AU - Panici PB FA - De Felice, Francesca FA - Marchetti, Claudia FA - Palaia, Innocenza FA - Musio, Daniela FA - Muzii, Ludovico FA - Tombolini, Vincenzo FA - Panici, Pierluigi Benedetti IN - De Felice, Francesca. Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Viale Regina Elena 326, 00161 Rome, Italy. IN - Marchetti, Claudia. Department of Gynecological and Obstetrical Sciences and Urological Sciences, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. IN - Palaia, Innocenza. Department of Gynecological and Obstetrical Sciences and Urological Sciences, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. IN - Musio, Daniela. Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Viale Regina Elena 326, 00161 Rome, Italy. IN - Muzii, Ludovico. Department of Gynecological and Obstetrical Sciences and Urological Sciences, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. IN - Tombolini, Vincenzo. Department of Radiotherapy, Policlinico Umberto I, "Sapienza" University of Rome, Viale Regina Elena 326, 00161 Rome, Italy. IN - Panici, Pierluigi Benedetti. Department of Gynecological and Obstetrical Sciences and Urological Sciences, "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. TI - Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors. [Review] SO - Journal of Immunological Research. 2015:191832, 2015 AS - J. immunol. res.. 2015:191832, 2015 NJ - Journal of immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101627166 IO - J Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508475 SB - Index Medicus CP - Egypt MH - Antibodies, Monoclonal/pd [Pharmacology] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Clinical Trials as Topic MH - Female MH - Humans MH - Immune System MH - Immunologic Factors/pd [Pharmacology] MH - Immunologic Factors/tu [Therapeutic Use] MH - Immunomodulation MH - Immunotherapy/mt [Methods] MH - *Immunotherapy MH - Molecular Targeted Therapy MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/me [Metabolism] MH - *Ovarian Neoplasms/th [Therapy] MH - Treatment Outcome AB - Ovarian cancer is the most important cause of gynecological cancer-related mortality, with the majority of women presenting with advanced disease. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies to improve the outcomes. Advances in understanding the role of immune system in the pathogenesis of cancer have led to the rapid evolvement of immunotherapy, which might establish a sustained immune system response against recurring cancer cells. Recently, it has emerged that powerful immunologic effector cells may be blocked by inhibitory regulatory pathways controlled by specific molecules often called "immune checkpoints," which turn off the immune system. Similarly, cancer cells are able to use these checkpoints to avoid immune control and rejection. Inhibition of these inhibitory pathways represents a potent strategy in the fight against cancer and is currently under investigation with encouraging results in some cancers, such as melanoma. In ovarian cancer researches are still in an early phase, but with promising results. In this review we will explore the rationale of immunotherapy in ovarian cancer with a special focus on these emerging molecules. RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunologic Factors) ES - 2314-7156 IL - 2314-7156 DO - https://dx.doi.org/10.1155/2015/191832 PT - Journal Article PT - Review ID - 26236750 [pubmed] ID - 10.1155/2015/191832 [doi] ID - PMC4508475 [pmc] PP - ppublish PH - 2015/03/22 [received] PH - 2015/06/23 [accepted] LG - English EP - 20150707 DP - 2015 DC - 20150803 EZ - 2015/08/04 06:00 DA - 2016/03/25 06:00 DT - 2015/08/04 06:00 YR - 2015 ED - 20160324 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26236750 <141. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26209970 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Carl D AU - Grullich C AU - Hering S AU - Schabet M FA - Carl, David FA - Grullich, Carsten FA - Hering, Steffen FA - Schabet, Martin IN - Carl, David. Department of Neurology, Klinikum Ludwigsburg, Posilipostrase 4, Ludwigsburg, Germany. david.carl@mail.klinikum-darmstadt.de. IN - Grullich, Carsten. National Cent Tumor Diseases (NCT), Heidelberg, Germany. carsten.gruellich@nct-heidelberg.de. IN - Hering, Steffen. Department of Internal Medicine, Klinikum Bietigheim, Bietigheim-Bissingen, Germany. steffen.hering@kliniken-lb.de. IN - Schabet, Martin. Department of Neurology, Klinikum Ludwigsburg, Posilipostrase 4, Ludwigsburg, Germany. martin.schabet@kliniken-lb.de. TI - Steroid responsive encephalopathy associated with autoimmune thyroiditis following ipilimumab therapy: a case report. SO - BMC Research Notes. 8:316, 2015 Jul 26 AS - BMC Res Notes. 8:316, 2015 Jul 26 NJ - BMC research notes PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101462768 IO - BMC Res Notes PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514969 SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Autoantibodies/bi [Biosynthesis] MH - *Brain Diseases/ci [Chemically Induced] MH - Brain Diseases/dt [Drug Therapy] MH - Brain Diseases/pa [Pathology] MH - Humans MH - Male MH - Methylprednisolone/tu [Therapeutic Use] MH - Middle Aged MH - Prostatic Neoplasms/dt [Drug Therapy] MH - Prostatic Neoplasms/pa [Pathology] MH - *Thyroiditis, Autoimmune/ci [Chemically Induced] MH - Thyroiditis, Autoimmune/dt [Drug Therapy] MH - Thyroiditis, Autoimmune/pa [Pathology] AB - BACKGROUND: Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 receptor antibody used for immunotherapy in cancer. Several immune-related adverse events are known. Steroid responsive encephalopathy associated with autoimmune thyroiditis is an autoimmune encephalopathy associated with Hashimoto's Disease and elevated serum levels of the related antibodies (anti-thyroid-peroxidase antibody or anti-thyroglobulin antibody). Our case implies that steroid responsive encephalopathy associated with autoimmune thyroiditis may be another previously unreported side effect of ipilimumab therapy. AB - CASE PRESENTATION: We report the case of a 64 years old caucasian patient with prostatic cancer who received ipilimumab therapy in a clinical trial. He presented with aphasia, tremor and ataxia, myocloni, hallucinations, anxiety and agitation in turns with somnolence. Cranial nerves, deep tendon reflexes, motor and sensory functions were normal. Electroencephalography showed background slowing but no epileptic discharges. Brain magnetic resonance imaging was normal and showed no signs of hypophysitis. Cerebrospinal fluid findings ruled out infection and neoplastic meningitis. Anti-thyroid antibodies (anti-thyroid-peroxidase antibody and anti-thyroglobulin antibody) were heavily increased. Assuming steroid responsive encephalopathy associated with autoimmune thyroiditis the patient was treated with 1,000 mg methylprednisolone i.v. for 3 days and continued with 1 mg/kg orally. On the 3rd day of treatment the patient's condition started to improve. Within the next few days he gradually returned to his previous state, and electroencephalography eventually showed only slight slowing. Seven months later the patient's condition was stable, and anti-thyroid antibodies were no more detectable. AB - CONCLUSION: Steroid responsive encephalopathy associated with autoimmune thyroiditis may be a hitherto unrecognized complication of ipililumab treatment and should be taken into consideration in patients developing central nervous symptoms undergoing this treatment. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Autoantibodies) RN - 0 (anti-thyroglobulin) RN - 6T8C155666 (ipilimumab) RN - X4W7ZR7023 (Methylprednisolone) ES - 1756-0500 IL - 1756-0500 DI - 10.1186/s13104-015-1283-9 DO - https://dx.doi.org/10.1186/s13104-015-1283-9 PT - Case Reports PT - Journal Article ID - 26209970 [pubmed] ID - 10.1186/s13104-015-1283-9 [doi] ID - 10.1186/s13104-015-1283-9 [pii] ID - PMC4514969 [pmc] PP - epublish PH - 2014/10/11 [received] PH - 2015/07/16 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01057810 SL - https://clinicaltrials.gov/search/term=NCT01057810 LG - English EP - 20150726 DP - 2015 Jul 26 DC - 20150727 EZ - 2015/07/27 06:00 DA - 2016/03/18 06:00 DT - 2015/07/27 06:00 YR - 2015 ED - 20160317 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26209970 <142. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26209970 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Carl D AU - Grullich C AU - Hering S AU - Schabet M FA - Carl, David FA - Grullich, Carsten FA - Hering, Steffen FA - Schabet, Martin IN - Carl, David. Department of Neurology, Klinikum Ludwigsburg, Posilipostrase 4, Ludwigsburg, Germany. david.carl@mail.klinikum-darmstadt.de. IN - Grullich, Carsten. National Cent Tumor Diseases (NCT), Heidelberg, Germany. carsten.gruellich@nct-heidelberg.de. IN - Hering, Steffen. Department of Internal Medicine, Klinikum Bietigheim, Bietigheim-Bissingen, Germany. steffen.hering@kliniken-lb.de. IN - Schabet, Martin. Department of Neurology, Klinikum Ludwigsburg, Posilipostrase 4, Ludwigsburg, Germany. martin.schabet@kliniken-lb.de. TI - Steroid responsive encephalopathy associated with autoimmune thyroiditis following ipilimumab therapy: a case report. SO - BMC Research Notes. 8:316, 2015 Jul 26 AS - BMC Res Notes. 8:316, 2015 Jul 26 NJ - BMC research notes PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101462768 IO - BMC Res Notes PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514969 SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Autoantibodies/bi [Biosynthesis] MH - *Brain Diseases/ci [Chemically Induced] MH - Brain Diseases/dt [Drug Therapy] MH - Brain Diseases/pa [Pathology] MH - Humans MH - Male MH - Methylprednisolone/tu [Therapeutic Use] MH - Middle Aged MH - Prostatic Neoplasms/dt [Drug Therapy] MH - Prostatic Neoplasms/pa [Pathology] MH - *Thyroiditis, Autoimmune/ci [Chemically Induced] MH - Thyroiditis, Autoimmune/dt [Drug Therapy] MH - Thyroiditis, Autoimmune/pa [Pathology] AB - BACKGROUND: Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 receptor antibody used for immunotherapy in cancer. Several immune-related adverse events are known. Steroid responsive encephalopathy associated with autoimmune thyroiditis is an autoimmune encephalopathy associated with Hashimoto's Disease and elevated serum levels of the related antibodies (anti-thyroid-peroxidase antibody or anti-thyroglobulin antibody). Our case implies that steroid responsive encephalopathy associated with autoimmune thyroiditis may be another previously unreported side effect of ipilimumab therapy. AB - CASE PRESENTATION: We report the case of a 64 years old caucasian patient with prostatic cancer who received ipilimumab therapy in a clinical trial. He presented with aphasia, tremor and ataxia, myocloni, hallucinations, anxiety and agitation in turns with somnolence. Cranial nerves, deep tendon reflexes, motor and sensory functions were normal. Electroencephalography showed background slowing but no epileptic discharges. Brain magnetic resonance imaging was normal and showed no signs of hypophysitis. Cerebrospinal fluid findings ruled out infection and neoplastic meningitis. Anti-thyroid antibodies (anti-thyroid-peroxidase antibody and anti-thyroglobulin antibody) were heavily increased. Assuming steroid responsive encephalopathy associated with autoimmune thyroiditis the patient was treated with 1,000 mg methylprednisolone i.v. for 3 days and continued with 1 mg/kg orally. On the 3rd day of treatment the patient's condition started to improve. Within the next few days he gradually returned to his previous state, and electroencephalography eventually showed only slight slowing. Seven months later the patient's condition was stable, and anti-thyroid antibodies were no more detectable. AB - CONCLUSION: Steroid responsive encephalopathy associated with autoimmune thyroiditis may be a hitherto unrecognized complication of ipililumab treatment and should be taken into consideration in patients developing central nervous symptoms undergoing this treatment. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Autoantibodies) RN - 0 (anti-thyroglobulin) RN - 6T8C155666 (ipilimumab) RN - X4W7ZR7023 (Methylprednisolone) ES - 1756-0500 IL - 1756-0500 DI - 10.1186/s13104-015-1283-9 DO - https://dx.doi.org/10.1186/s13104-015-1283-9 PT - Case Reports PT - Journal Article ID - 26209970 [pubmed] ID - 10.1186/s13104-015-1283-9 [doi] ID - 10.1186/s13104-015-1283-9 [pii] ID - PMC4514969 [pmc] PP - epublish PH - 2014/10/11 [received] PH - 2015/07/16 [accepted] LG - English EP - 20150726 DP - 2015 Jul 26 DC - 20150727 EZ - 2015/07/27 06:00 DA - 2016/03/18 06:00 DT - 2015/07/27 06:00 YR - 2015 ED - 20160317 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26209970 <143. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26060068 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Dangaj D AU - Scholler N FA - Dangaj, Denarda FA - Scholler, Nathalie IN - Dangaj, Denarda. Department of Oncology, Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland. TI - Isolation and Validation of Anti-B7-H4 scFvs from an Ovarian Cancer scFv Yeast-Display Library. SO - Methods in Molecular Biology. 1319:37-49, 2015 AS - Methods Mol Biol. 1319:37-49, 2015 NJ - Methods in molecular biology (Clifton, N.J.) PI - Journal available in: Print PI - Citation processed from: Internet JC - bu3, 9214969 IO - Methods Mol. Biol. SB - Index Medicus CP - United States MH - Animals MH - Antigen Presentation MH - B-Lymphocytes/im [Immunology] MH - Female MH - Gene Library MH - Humans MH - Mice MH - Ovarian Neoplasms/bl [Blood] MH - *Ovarian Neoplasms/im [Immunology] MH - *Saccharomyces cerevisiae/ge [Genetics] MH - Saccharomyces cerevisiae/me [Metabolism] MH - Single-Chain Antibodies/ge [Genetics] MH - *Single-Chain Antibodies/ip [Isolation & Purification] MH - T-Lymphocytes/im [Immunology] MH - *V-Set Domain-Containing T-Cell Activation Inhibitor 1/me [Metabolism] MH - Xenograft Model Antitumor Assays AB - B7-H4 (VTCN1, B7x, B7s) is an inhibitory modulator of T-cell response implicated in antigen tolerization. As such, B7-H4 is an immune checkpoint of potential therapeutic interest. To generate anti-B7-H4 targeting reagents, we isolated antibodies by differential cell screening of a yeast-display library of recombinant antibodies (scFvs) derived from ovarian cancer patients and we screened for functional scFvs capable to interfere with B7-H4-mediated inhibition of antitumor responses. We found one antibody binding to B7-H4 that could restore antitumor T cell responses. This chapter gives an overview of the methods we developed to isolate a functional anti-B7-H4 antibody fragment. RN - 0 (Single-Chain Antibodies) RN - 0 (V-Set Domain-Containing T-Cell Activation Inhibitor 1) RN - 0 (VTCN1 protein, human) ES - 1940-6029 IL - 1064-3745 DO - https://dx.doi.org/10.1007/978-1-4939-2748-7_2 PT - Journal Article ID - 26060068 [pubmed] ID - 10.1007/978-1-4939-2748-7_2 [doi] PP - ppublish LG - English DP - 2015 DC - 20150610 EZ - 2015/06/11 06:00 DA - 2016/03/16 06:00 DT - 2015/06/11 06:00 YR - 2015 ED - 20160315 RD - 20150610 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26060068 <144. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25588542 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wu H AU - Sun Y AU - Ye H AU - Yang S AU - Lee SL AU - de las Morenas A FA - Wu, Hao FA - Sun, Yue FA - Ye, Huihui FA - Yang, Shi FA - Lee, Stephanie L FA - de las Morenas, Antonio IN - Wu, Hao. Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, AB190.11, 6621 Fannin Street, Houston, TX, 77030, USA, hao.wu@bcm.edu. TI - Anaplastic thyroid cancer: outcome and the mutation/expression profiles of potential targets. SO - Pathology Oncology Research. 21(3):695-701, 2015 Jul AS - Pathol Oncol Res. 21(3):695-701, 2015 Jul NJ - Pathology oncology research : POR PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c3s, 9706087 IO - Pathol. Oncol. Res. SB - Index Medicus CP - Netherlands MH - Adenocarcinoma, Follicular/ge [Genetics] MH - Adenocarcinoma, Follicular/me [Metabolism] MH - Adenocarcinoma, Follicular/mo [Mortality] MH - Adenocarcinoma, Follicular/sc [Secondary] MH - Adult MH - Aged MH - *Antigens, CD274/me [Metabolism] MH - Biomarkers, Tumor/ge [Genetics] MH - Biomarkers, Tumor/me [Metabolism] MH - Female MH - Follow-Up Studies MH - Humans MH - Male MH - Middle Aged MH - *Mutation/ge [Genetics] MH - Neoplasm Metastasis MH - Neoplasm Staging MH - Prognosis MH - *Proto-Oncogene Proteins B-raf/ge [Genetics] MH - *Proto-Oncogene Proteins c-kit/me [Metabolism] MH - *Proto-Oncogene Proteins p21(ras)/ge [Genetics] MH - *Receptor, Epidermal Growth Factor/ge [Genetics] MH - Retrospective Studies MH - Survival Rate MH - Thyroid Carcinoma, Anaplastic/ge [Genetics] MH - Thyroid Carcinoma, Anaplastic/me [Metabolism] MH - Thyroid Carcinoma, Anaplastic/mo [Mortality] MH - *Thyroid Carcinoma, Anaplastic/pa [Pathology] MH - Thyroid Neoplasms/ge [Genetics] MH - Thyroid Neoplasms/me [Metabolism] MH - Thyroid Neoplasms/mo [Mortality] MH - Thyroid Neoplasms/pa [Pathology] AB - Anaplastic thyroid cancer (ATC) is a rare but aggressive malignancy of the thyroid. No effective treatment modalities are currently available. Targeted therapy against protein kinases showed promising results in preclinical studies. Our goal was to assess the mutational status of potential therapeutic targets, as well as the biomarker for immunotherapy in the clinical context. Using allele specific PCR, Sanger sequencing, fragment analysis and immunohistochemistry, we assessed BRAF, KRAS, EGFR mutations and protein overexpression of C-KIT and PDL1 in anaplastic thyroid cancer specimens. Results were compared to clinical information and patient outcome to assess the utility of these biomarkers. There were 13 patients in our study with a median overall survival of 19 weeks. Of the 13 ATC patients, 3 (23 %) had BRAF V600E mutation. C-KIT overexpression was found in 1 (8 %) patient who responded well to a tyrosine kinase inhibitor. PDL1 expression was seen in 3 (23 %) patients, none of them were surgical candidates due to unresectability and poor performance status. KRAS codon 12/13 and EGFR exon 18, 19, 20 and 21 were all wild type in our patients. Protein kinase inhibitors and immunotherapy may be useful adjuvant therapies for ATC. RN - 0 (Antigens, CD274) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - 0 (KRAS protein, human) RN - EC 2-7-10-1 (EGFR protein, human) RN - EC 2-7-10-1 (Proto-Oncogene Proteins c-kit) RN - EC 2-7-10-1 (Receptor, Epidermal Growth Factor) RN - EC 2-7-11-1 (BRAF protein, human) RN - EC 2-7-11-1 (Proto-Oncogene Proteins B-raf) RN - EC 3-6-5-2 (Proto-Oncogene Proteins p21(ras)) ES - 1532-2807 IL - 1219-4956 DO - https://dx.doi.org/10.1007/s12253-014-9876-5 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25588542 [pubmed] ID - 10.1007/s12253-014-9876-5 [doi] PP - ppublish PH - 2014/10/17 [received] PH - 2014/12/05 [accepted] LG - English EP - 20150115 DP - 2015 Jul DC - 20150603 EZ - 2015/01/16 06:00 DA - 2016/03/11 06:00 DT - 2015/01/16 06:00 YR - 2015 ED - 20160310 RD - 20150603 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25588542 <145. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26958083 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Kim ST AU - Ha SY AU - Lee S AU - Ahn S AU - Lee J AU - Park SH AU - Park JO AU - Lim HY AU - Kang WK AU - Kim KM AU - Park YS FA - Kim, Seung Tae FA - Ha, Sang Yun FA - Lee, Sujin FA - Ahn, Soomin FA - Lee, Jeeyun FA - Park, Se Hoon FA - Park, Joon Oh FA - Lim, Ho Yeong FA - Kang, Won Ki FA - Kim, Kyoung-Mee FA - Park, Young Suk IN - Kim, Seung Tae. 1. Division of Hematology-Oncology, Department of Medicine. IN - Ha, Sang Yun. 2. Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Lee, Sujin. 1. Division of Hematology-Oncology, Department of Medicine. IN - Ahn, Soomin. 2. Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Lee, Jeeyun. 1. Division of Hematology-Oncology, Department of Medicine. IN - Park, Se Hoon. 1. Division of Hematology-Oncology, Department of Medicine. IN - Park, Joon Oh. 1. Division of Hematology-Oncology, Department of Medicine. IN - Lim, Ho Yeong. 1. Division of Hematology-Oncology, Department of Medicine. IN - Kang, Won Ki. 1. Division of Hematology-Oncology, Department of Medicine. IN - Kim, Kyoung-Mee. 2. Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Park, Young Suk. 1. Division of Hematology-Oncology, Department of Medicine. TI - The Impact of PD-L1 Expression in Patients with Metastatic GEP-NETs. SO - Journal of Cancer. 7(5):484-9, 2016 AS - J. cancer. 7(5):484-9, 2016 NJ - Journal of Cancer PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101535920 IO - J Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780123 CP - Australia KW - Gastroenteropancreatic neuroendocrine tumor (GEP-NET); Programmed death-ligand 1 (PD-L1); WHO classification. AB - Programmed death-ligand 1 (PD-L1), which is expressed on many cancer cells, interacts with PD1 expressed on the surface of T cells, inhibiting the T cells and blocking the antitumor immune response. Expression of PD-L1 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has not been studied. We investigated the impact of PD-L1 expression in 32 patients with metastatic GEP-NET. The expression of PD-L1 was evaluated using an anti-PD-L1 immunohistochemistry (IHC) antibody optimized for staining of formalin-fixed paraffin-embedded (FFPE) tissue samples. The correlation between PD-L1 and clinicopathological data including survival and response to systemic treatments was analyzed. Primary sites were 24 foregut-derived GEP-NETs, including stomach (n=1), duodenum (n=2), biliary tract (n=7), and pancreas (n=14), and 8 hindgut-derived GEP-NETs of the distal colon and rectum. Among the 32 patients with metastatic GEP-NET analyzed in this study, 7 (21.9%) had expression of PD-L1 in tumor tissues. Expression of PD-L1 was significantly associated with high-grade WHO classification (grade 3) (p=0.008) but not with gender, primary site, and number of metastatic sites (p>0.05). The status of PD-L1 expression was statistically associated with progression-free survival (PFS) for first-line systemic treatment (p=0.047). Moreover, the status of PD-L1 expression could significantly predict overall survival (p=0.037). The expression of PD-L1 was associated with higher WHO tumor grade (grade 3) in metastatic GEP-NETs. PD-L1 expression had both predictive and prognostic value for survival of patients with metastatic GEP-NETs. IL - 1837-9664 DI - jcav07p0484 DO - https://dx.doi.org/10.7150/jca.13711 PT - Journal Article ID - 26958083 [pubmed] ID - 10.7150/jca.13711 [doi] ID - jcav07p0484 [pii] ID - PMC4780123 [pmc] PP - epublish PH - 2015/09/01 [received] PH - 2015/12/08 [accepted] LG - English EP - 20160205 DP - 2016 DC - 20160309 EZ - 2016/03/10 06:00 DA - 2016/03/10 06:01 DT - 2016/03/10 06:00 YR - 2016 ED - 20160309 RD - 20160311 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26958083 <146. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26598057 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Daud A FA - Daud, Adil IN - Daud, Adil. HS Clinical Professor, Department of Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, CA; Director, Melanoma Clinical Research, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA. Electronic address: Adil.Daud@ucsf.edu. TI - Current and Emerging Perspectives on Immunotherapy for Melanoma. [Review] SO - Seminars in Oncology. 42 Suppl 3:S3-S11, 2015 Dec AS - Semin Oncol. 42 Suppl 3:S3-S11, 2015 Dec NJ - Seminars in oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - un5, 0420432 IO - Semin. Oncol. SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Combined Modality Therapy MH - Humans MH - Immunotherapy/ae [Adverse Effects] MH - *Immunotherapy/mt [Methods] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Signal Transduction AB - Novel immunotherapeutic treatments are aimed at reversing the action of inhibitory pathways that restrain the T-cell-dominated immune-mediated defense against cancer. The first immune-inhibitory protein to be discovered was cytotoxic T-lymphocyte antigen-4 (CTLA-4). The effectiveness of a CTLA-targeted antibody in treating melanoma was an impetus for the use of programmed cell death-1 (PD-1) inhibitors in cancer treatment. Important differences between the use of CTLA-4 inhibitors and PD-1 inhibitors in treatment include the patterns of expression of each receptor and its ligands and sites of action, as CTLA-4 blockade has been noted to provide more global effects, whereas those of PD-1 inhibition are observed at the tumor site. Although each treatment has been associated with impressive benefits in advanced melanoma, recent comparative studies suggest that PD-1 inhibitors may be more effective than CTLA-4 inhibition and that the most optimal results may be observed using both agents in those who can tolerate the increased toxicity that accompanies combination treatment. The most common adverse reactions include skin effects using either CTLA-4-blocking antibody or PD-1 inhibitors, colitis using CTLA-4 blockade, or thyroid disease using PD-1 inhibitors. AB - Copyright © 2015 Elsevier Inc. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1532-8708 IL - 0093-7754 DI - S0093-7754(15)00216-X DO - https://dx.doi.org/10.1053/j.seminoncol.2015.10.003 PT - Journal Article PT - Review ID - 26598057 [pubmed] ID - S0093-7754(15)00216-X [pii] ID - 10.1053/j.seminoncol.2015.10.003 [doi] PP - ppublish LG - English EP - 20151023 DP - 2015 Dec DC - 20151124 EZ - 2015/11/25 06:00 DA - 2016/03/10 06:00 DT - 2015/11/26 06:00 YR - 2015 ED - 20160308 RD - 20151124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26598057 <147. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26351349 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hamanishi J AU - Mandai M AU - Ikeda T AU - Minami M AU - Kawaguchi A AU - Murayama T AU - Kanai M AU - Mori Y AU - Matsumoto S AU - Chikuma S AU - Matsumura N AU - Abiko K AU - Baba T AU - Yamaguchi K AU - Ueda A AU - Hosoe Y AU - Morita S AU - Yokode M AU - Shimizu A AU - Honjo T AU - Konishi I FA - Hamanishi, Junzo FA - Mandai, Masaki FA - Ikeda, Takafumi FA - Minami, Manabu FA - Kawaguchi, Atsushi FA - Murayama, Toshinori FA - Kanai, Masashi FA - Mori, Yukiko FA - Matsumoto, Shigemi FA - Chikuma, Shunsuke FA - Matsumura, Noriomi FA - Abiko, Kaoru FA - Baba, Tsukasa FA - Yamaguchi, Ken FA - Ueda, Akihiko FA - Hosoe, Yuko FA - Morita, Satoshi FA - Yokode, Masayuki FA - Shimizu, Akira FA - Honjo, Tasuku FA - Konishi, Ikuo IN - Hamanishi, Junzo. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. jnkhmns@kuhp.kyoto-u.ac.jp. IN - Mandai, Masaki. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Ikeda, Takafumi. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Minami, Manabu. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Kawaguchi, Atsushi. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Murayama, Toshinori. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Kanai, Masashi. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Mori, Yukiko. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Matsumoto, Shigemi. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Chikuma, Shunsuke. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Matsumura, Noriomi. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Abiko, Kaoru. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Baba, Tsukasa. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Yamaguchi, Ken. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Ueda, Akihiko. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Hosoe, Yuko. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Morita, Satoshi. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Yokode, Masayuki. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Shimizu, Akira. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Honjo, Tasuku. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. IN - Konishi, Ikuo. Junzo Hamanishi, Masashi Kanai, Yukiko Mori, Shigemi Matsumoto, Shunsuke Chikuma, Noriomi Matsumura, Kaoru Abiko, Tsukasa Baba, Ken Yamaguchi, Akihiko Ueda, Yuko Hosoe, Tasuku Honjo, and Ikuo Konishi, Kyoto University Graduate School of Medicine, Kyoto, Japan; Masaki Mandai, Kinki University Faculty of Medicine, Osaka, Japan; and Takafumi Ikeda, Manabu Minami, Atsushi Kawaguchi, Toshinori Murayama, Satoshi Morita, Masayuki Yokode, and Akira Shimizu, Kyoto University Hospital, Kyoto, Japan. TI - Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. CM - Comment in: J Clin Oncol. 2015 Dec 1;33(34):3987-9; PMID: 26503205 SO - Journal of Clinical Oncology. 33(34):4015-22, 2015 Dec 01 AS - J Clin Oncol. 33(34):4015-22, 2015 Dec 01 NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. SB - Index Medicus CP - United States MH - Adenocarcinoma, Clear Cell/dt [Drug Therapy] MH - Adenocarcinoma, Clear Cell/mo [Mortality] MH - Adenocarcinoma, Clear Cell/sc [Secondary] MH - Aged MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Cohort Studies MH - Cystadenocarcinoma, Serous/dt [Drug Therapy] MH - Cystadenocarcinoma, Serous/mo [Mortality] MH - Cystadenocarcinoma, Serous/sc [Secondary] MH - *Drug Resistance, Neoplasm/de [Drug Effects] MH - Endometrial Neoplasms/dt [Drug Therapy] MH - Endometrial Neoplasms/mo [Mortality] MH - Endometrial Neoplasms/sc [Secondary] MH - Female MH - Follow-Up Studies MH - Humans MH - Lymphatic Metastasis MH - Middle Aged MH - Neoplasm Invasiveness MH - *Neoplasm Recurrence, Local/dt [Drug Therapy] MH - Neoplasm Recurrence, Local/mo [Mortality] MH - Neoplasm Recurrence, Local/pa [Pathology] MH - Neoplasm Staging MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/mo [Mortality] MH - Ovarian Neoplasms/pa [Pathology] MH - Peritoneal Neoplasms/dt [Drug Therapy] MH - Peritoneal Neoplasms/mo [Mortality] MH - Peritoneal Neoplasms/sc [Secondary] MH - Platinum/pd [Pharmacology] MH - Prognosis MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - *Salvage Therapy MH - Survival Rate AB - PURPOSE: Programmed death-1 (PD-1), a coinhibitory immune signal receptor expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity. Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer. AB - PATIENTS AND METHODS: Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from October 21, 2011. This phase II trial defined the primary end point as the best overall response. Patients received up to six cycles (four doses per cycle) of nivolumab treatment or received doses until disease progression occurred. Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7, 2014. AB - RESULTS: Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, which included two patients who had a durable complete response (in the 3-mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and the median overall survival time was 20.0 months (95% CI, 7.0 months to not reached) at study termination. AB - CONCLUSION: This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714). AB - Copyright © 2015 by American Society of Clinical Oncology. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) RN - 49DFR088MY (Platinum) ES - 1527-7755 IL - 0732-183X DI - JCO.2015.62.3397 DO - https://dx.doi.org/10.1200/JCO.2015.62.3397 PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26351349 [pubmed] ID - JCO.2015.62.3397 [pii] ID - 10.1200/JCO.2015.62.3397 [doi] PP - ppublish SI - JPRN SA - JPRN/UMIN000005714 LG - English EP - 20150908 DP - 2015 Dec 01 DC - 20151126 EZ - 2015/09/10 06:00 DA - 2016/03/10 06:00 DT - 2015/09/10 06:00 YR - 2015 ED - 20160308 RD - 20151126 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26351349 <148. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25894333 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Santoiemma PP AU - Powell DJ Jr FA - Santoiemma, Phillip P FA - Powell, Daniel J Jr IN - Santoiemma, Phillip P. a Ovarian Cancer Research Center ; Department of Obstetrics and Gynecology ; Perelman School of Medicine; University of Pennsylvania ; Philadelphia , PA USA. TI - Tumor infiltrating lymphocytes in ovarian cancer. [Review] SO - Cancer Biology & Therapy. 16(6):807-20, 2015 AS - Cancer Biol Ther. 16(6):807-20, 2015 NJ - Cancer biology & therapy PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101137842 IO - Cancer Biol. Ther. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622931 SB - Index Medicus CP - United States MH - Animals MH - Cancer Vaccines/im [Immunology] MH - Clinical Trials as Topic MH - Female MH - Humans MH - Immunomodulation MH - Immunotherapy, Adoptive MH - *Lymphocyte Subsets/im [Immunology] MH - Lymphocyte Subsets/me [Metabolism] MH - Lymphocyte Subsets/pa [Pathology] MH - *Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/me [Metabolism] MH - Lymphocytes, Tumor-Infiltrating/pa [Pathology] MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/mo [Mortality] MH - *Ovarian Neoplasms/pa [Pathology] MH - Ovarian Neoplasms/th [Therapy] MH - Prognosis MH - Treatment Outcome MH - Tumor Microenvironment/im [Immunology] KW - CAR, chimeric antigen receptor; IDO, indoleamine 2,3-dioxygenase; TIL, tumor infiltrating lymphocyte; Tregs, regulatory T-cell; immunosuppression; immunotherapy; ovarian cancer; prognostic factors; regulatory T-cells; tumor infiltrating lymphocytes AB - The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment. RN - 0 (Cancer Vaccines) ES - 1555-8576 IL - 1538-4047 DO - https://dx.doi.org/10.1080/15384047.2015.1040960 PT - Journal Article PT - Review ID - 25894333 [pubmed] ID - 10.1080/15384047.2015.1040960 [doi] ID - PMC4622931 [pmc] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01982487 SA - ClinicalTrials.gov/NCT02042430 SL - https://clinicaltrials.gov/search/term=NCT01982487 SL - https://clinicaltrials.gov/search/term=NCT02042430 LG - English EP - 20150420 DP - 2015 DC - 20150613 EZ - 2015/04/21 06:00 DA - 2016/03/10 06:00 DT - 2015/04/22 06:00 YR - 2015 ED - 20160308 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25894333 <149. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25894333 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Santoiemma PP AU - Powell DJ Jr FA - Santoiemma, Phillip P FA - Powell, Daniel J Jr IN - Santoiemma, Phillip P. a Ovarian Cancer Research Center ; Department of Obstetrics and Gynecology ; Perelman School of Medicine; University of Pennsylvania ; Philadelphia , PA USA. TI - Tumor infiltrating lymphocytes in ovarian cancer. [Review] SO - Cancer Biology & Therapy. 16(6):807-20, 2015 AS - Cancer Biol Ther. 16(6):807-20, 2015 NJ - Cancer biology & therapy PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101137842 IO - Cancer Biol. Ther. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622931 SB - Index Medicus CP - United States MH - Animals MH - Cancer Vaccines/im [Immunology] MH - Clinical Trials as Topic MH - Female MH - Humans MH - Immunomodulation MH - Immunotherapy, Adoptive MH - *Lymphocyte Subsets/im [Immunology] MH - Lymphocyte Subsets/me [Metabolism] MH - Lymphocyte Subsets/pa [Pathology] MH - *Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/me [Metabolism] MH - Lymphocytes, Tumor-Infiltrating/pa [Pathology] MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/mo [Mortality] MH - *Ovarian Neoplasms/pa [Pathology] MH - Ovarian Neoplasms/th [Therapy] MH - Prognosis MH - Treatment Outcome MH - Tumor Microenvironment/im [Immunology] KW - CAR, chimeric antigen receptor; IDO, indoleamine 2,3-dioxygenase; TIL, tumor infiltrating lymphocyte; Tregs, regulatory T-cell; immunosuppression; immunotherapy; ovarian cancer; prognostic factors; regulatory T-cells; tumor infiltrating lymphocytes AB - The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment. RN - 0 (Cancer Vaccines) ES - 1555-8576 IL - 1538-4047 DO - https://dx.doi.org/10.1080/15384047.2015.1040960 PT - Journal Article PT - Review ID - 25894333 [pubmed] ID - 10.1080/15384047.2015.1040960 [doi] ID - PMC4622931 [pmc] PP - ppublish LG - English EP - 20150420 DP - 2015 DC - 20150613 EZ - 2015/04/21 06:00 DA - 2016/03/10 06:00 DT - 2015/04/22 06:00 YR - 2015 ED - 20160308 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=25894333 <150. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25806780 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wyluda EJ AU - Cheng J AU - Schell TD AU - Haley JS AU - Mallon C AU - Neves RI AU - Robertson G AU - Sivik J AU - Mackley H AU - Talamo G AU - Drabick JJ FA - Wyluda, Edward J FA - Cheng, Jihua FA - Schell, Todd D FA - Haley, Jeremy S FA - Mallon, Carol FA - Neves, Rogerio I FA - Robertson, Gavin FA - Sivik, Jeffrey FA - Mackley, Heath FA - Talamo, Giampaolo FA - Drabick, Joseph J IN - Wyluda, Edward J. a Division of Hematology Oncology; Penn State Milton S Hershey Medical Center ; Hershey , PA , USA. TI - Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy. SO - Cancer Biology & Therapy. 16(5):662-70, 2015 AS - Cancer Biol Ther. 16(5):662-70, 2015 NJ - Cancer biology & therapy PI - Journal available in: Print PI - Citation processed from: Internet JC - 101137842 IO - Cancer Biol. Ther. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622667 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Female MH - Humans MH - *Immunotherapy/mt [Methods] MH - *Interleukin-2/me [Metabolism] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/im [Immunology] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Neoplasm Metastasis MH - *Proto-Oncogene Proteins B-raf/ge [Genetics] MH - Proto-Oncogene Proteins B-raf/me [Metabolism] KW - BRAF inhibitor; CBC, complete blood count; CR, complete response; CRP, c-reactive protein; CT, computed tomography; CTL, cytotoxic lymphocyte; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GrzB, granzyme B; HD, high dose; IFN, interferon; IL-2, interleukin 2; LDH, lactate dehydrogenase; M6P, manose 6 phosphate; MAPK, mitogen-activated protein kinase pathway; PD-1, programmed death 1; PDL-1, programmed death ligand 1; PDL-2, programmed death ligand 2; PET, positron emission tomography; PR, partial response; RT, radiation therapy; SLE, systemic lupus erythematosus; WBC, white blood cell count; cytotoxic therapy, immunotherapy, treatment of melanoma; interleukin-2; ipilimumab; metastatic melanoma AB - We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment. RN - 0 (Antibodies, Monoclonal) RN - 0 (Interleukin-2) RN - 6T8C155666 (ipilimumab) RN - EC 2-7-11-1 (BRAF protein, human) RN - EC 2-7-11-1 (Proto-Oncogene Proteins B-raf) ES - 1555-8576 IL - 1538-4047 DO - https://dx.doi.org/10.1080/15384047.2015.1026507 PT - Case Reports PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25806780 [pubmed] ID - 10.1080/15384047.2015.1026507 [doi] ID - PMC4622667 [pmc] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT 01124734 SA - ClinicalTrials.gov/NCT01124734 SL - https://clinicaltrials.gov/search/term=NCT 01124734 SL - https://clinicaltrials.gov/search/term=NCT01124734 LG - English DP - 2015 DC - 20150522 EZ - 2015/03/26 06:00 DA - 2016/03/02 06:00 DT - 2015/03/26 06:00 YR - 2015 ED - 20160301 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25806780 <151. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25806780 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wyluda EJ AU - Cheng J AU - Schell TD AU - Haley JS AU - Mallon C AU - Neves RI AU - Robertson G AU - Sivik J AU - Mackley H AU - Talamo G AU - Drabick JJ FA - Wyluda, Edward J FA - Cheng, Jihua FA - Schell, Todd D FA - Haley, Jeremy S FA - Mallon, Carol FA - Neves, Rogerio I FA - Robertson, Gavin FA - Sivik, Jeffrey FA - Mackley, Heath FA - Talamo, Giampaolo FA - Drabick, Joseph J IN - Wyluda, Edward J. a Division of Hematology Oncology; Penn State Milton S Hershey Medical Center ; Hershey , PA , USA. TI - Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy. SO - Cancer Biology & Therapy. 16(5):662-70, 2015 AS - Cancer Biol Ther. 16(5):662-70, 2015 NJ - Cancer biology & therapy PI - Journal available in: Print PI - Citation processed from: Internet JC - 101137842 IO - Cancer Biol. Ther. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622667 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Female MH - Humans MH - *Immunotherapy/mt [Methods] MH - *Interleukin-2/me [Metabolism] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/im [Immunology] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Neoplasm Metastasis MH - *Proto-Oncogene Proteins B-raf/ge [Genetics] MH - Proto-Oncogene Proteins B-raf/me [Metabolism] KW - BRAF inhibitor; CBC, complete blood count; CR, complete response; CRP, c-reactive protein; CT, computed tomography; CTL, cytotoxic lymphocyte; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GrzB, granzyme B; HD, high dose; IFN, interferon; IL-2, interleukin 2; LDH, lactate dehydrogenase; M6P, manose 6 phosphate; MAPK, mitogen-activated protein kinase pathway; PD-1, programmed death 1; PDL-1, programmed death ligand 1; PDL-2, programmed death ligand 2; PET, positron emission tomography; PR, partial response; RT, radiation therapy; SLE, systemic lupus erythematosus; WBC, white blood cell count; cytotoxic therapy, immunotherapy, treatment of melanoma; interleukin-2; ipilimumab; metastatic melanoma AB - We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment. RN - 0 (Antibodies, Monoclonal) RN - 0 (Interleukin-2) RN - 6T8C155666 (ipilimumab) RN - EC 2-7-11-1 (BRAF protein, human) RN - EC 2-7-11-1 (Proto-Oncogene Proteins B-raf) ES - 1555-8576 IL - 1538-4047 DO - https://dx.doi.org/10.1080/15384047.2015.1026507 PT - Case Reports PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25806780 [pubmed] ID - 10.1080/15384047.2015.1026507 [doi] ID - PMC4622667 [pmc] PP - ppublish LG - English DP - 2015 DC - 20150522 EZ - 2015/03/26 06:00 DA - 2016/03/02 06:00 DT - 2015/03/26 06:00 YR - 2015 ED - 20160301 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=25806780 <152. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26423423 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Delitto D AU - Perez C AU - Han S AU - Gonzalo DH AU - Pham K AU - Knowlton AE AU - Graves CL AU - Behrns KE AU - Moldawer LL AU - Thomas RM AU - Liu C AU - George TJ Jr AU - Trevino JG AU - Wallet SM AU - Hughes SJ FA - Delitto, Daniel FA - Perez, Chelsey FA - Han, Song FA - Gonzalo, David H FA - Pham, Kien FA - Knowlton, Andrea E FA - Graves, Christina L FA - Behrns, Kevin E FA - Moldawer, Lyle L FA - Thomas, Ryan M FA - Liu, Chen FA - George, Thomas J Jr FA - Trevino, Jose G FA - Wallet, Shannon M FA - Hughes, Steven J IN - Delitto, Daniel. Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. IN - Perez, Chelsey. Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. IN - Han, Song. Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. IN - Gonzalo, David H. Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA. IN - Pham, Kien. Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA. IN - Knowlton, Andrea E. Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA. IN - Graves, Christina L. Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA. IN - Behrns, Kevin E. Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. IN - Moldawer, Lyle L. Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. IN - Thomas, Ryan M. Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. IN - Liu, Chen. Department of Pathology, Immunology, Laboratory Medicine, University of Florida, Gainesville, FL, USA. IN - George, Thomas J Jr. Department of Medicine, University of Florida, Gainesville, FL, USA. IN - Trevino, Jose G. Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. IN - Wallet, Shannon M. Department of Oral Biology, College of Dentistry, University of Florida, PO BOX 100434, Gainesville, FL, 32610, USA. swallet@dental.ufl.edu. IN - Hughes, Steven J. Department of Surgery, College of Medicine, University of Florida, PO BOX 100109, Gainesville, FL, 32610, USA. steven.hughes@surgery.ufl.edu. TI - Downstream mediators of the intratumoral interferon response suppress antitumor immunity, induce gemcitabine resistance and associate with poor survival in human pancreatic cancer. SO - Cancer Immunology, Immunotherapy. 64(12):1553-63, 2015 Dec AS - Cancer Immunol Immunother. 64(12):1553-63, 2015 Dec NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. SB - Index Medicus CP - Germany MH - Adaptive Immunity/ge [Genetics] MH - Adaptive Immunity/im [Immunology] MH - Cell Line, Tumor MH - Chemokine CXCL10/ge [Genetics] MH - Chemokine CXCL10/me [Metabolism] MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Drug Resistance, Neoplasm/ge [Genetics] MH - Enzyme-Linked Immunosorbent Assay MH - Flow Cytometry MH - Gene Expression Regulation, Neoplastic/de [Drug Effects] MH - HLA Antigens/ge [Genetics] MH - Humans MH - Interferon-gamma/pd [Pharmacology] MH - *Interferons/im [Immunology] MH - Pancreatic Neoplasms/di [Diagnosis] MH - *Pancreatic Neoplasms/pp [Physiopathology] MH - Receptors, CXCR3/ge [Genetics] MH - Tumor Cells, Cultured MH - *Tumor Microenvironment/ph [Physiology] KW - CXCL10; Epithelial cell; Immuno-oncology; Interferon-gamma; Pancreatic cancer; Tumor-associated stroma AB - The cancer microenvironment allows tumor cells to evade immune surveillance through a variety of mechanisms. While interferon-gamma (IFNgamma) is central to effective antitumor immunity, its effects on the microenvironment are not as clear and have in some cancers been shown to induce immune checkpoint ligands. The heterogeneity of these responses to IFNgamma remains poorly characterized in desmoplastic malignancies with minimal inflammatory cell infiltration, such as pancreatic cancer (PC). Thus, the IFNgamma response within and on key cells of the PC microenvironment was evaluated. IFNgamma induced expression of human leukocyte antigen (HLA) class I and II on PC cell lines, primary pancreatic cancer epithelial cells (PPCE) and patient-derived tumor-associated stroma, concomitant with an upregulation of PDL1 in the absence of CD80 and CD86 expression. As expected, IFNgamma also induced high levels of CXCL10 from all cell types. In addition, significantly higher levels of CXCL10 were observed in PC specimens compared to those from chronic pancreatitis, whereby intratumoral CXCL10 concentration was an independent predictor of poor survival. Immunohistochemical analysis revealed a subset of CXCR3-positive cancer cells in over 90 % of PC specimens, as well as on a subset of cultured PC cell lines and PPCE, whereby exposure to CXCL10 induced resistance to the chemotherapeutic gemcitabine. These findings suggest that IFNgamma has multiple effects on many cell types within the PC microenvironment that may lead to immune evasion, chemoresistance and shortened survival. RN - 0 (Chemokine CXCL10) RN - 0 (HLA Antigens) RN - 0 (Receptors, CXCR3) RN - 0W860991D6 (Deoxycytidine) RN - 82115-62-6 (Interferon-gamma) RN - 9008-11-1 (Interferons) RN - B76N6SBZ8R (gemcitabine) ES - 1432-0851 IL - 0340-7004 DI - 10.1007/s00262-015-1760-y DO - https://dx.doi.org/10.1007/s00262-015-1760-y PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26423423 [pubmed] ID - 10.1007/s00262-015-1760-y [doi] ID - 10.1007/s00262-015-1760-y [pii] ID - PMC5129167 [pmc] ID - NIHMS830192 [mid] PP - ppublish PH - 2015/06/26 [received] PH - 2015/09/17 [accepted] GI - No: T90 DE021990 Organization: (DE) *NIDCR NIH HHS* Country: United States No: 5T32 CA106493-09 Organization: (CA) *NCI NIH HHS* Country: United States No: F31 DK104492-01A Organization: (DK) *NIDDK NIH HHS* Country: United States No: T32 CA106493 Organization: (CA) *NCI NIH HHS* Country: United States No: T90 DE021990-02 Organization: (DE) *NIDCR NIH HHS* Country: United States No: F31 DK104492 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English EP - 20150930 DP - 2015 Dec DC - 20151113 EZ - 2015/10/02 06:00 DA - 2016/03/02 06:00 DT - 2015/10/02 06:00 YR - 2015 ED - 20160229 RD - 20161201 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26423423 <153. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26337719 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bertrand A AU - Kostine M AU - Barnetche T AU - Truchetet ME AU - Schaeverbeke T FA - Bertrand, Anne FA - Kostine, Marie FA - Barnetche, Thomas FA - Truchetet, Marie-Elise FA - Schaeverbeke, Thierry IN - Bertrand, Anne. Departement de Rhumatologie, Hopital Pellegrin, CHU de Bordeaux, Bordeaux, France. anne.bertrand87@gmail.com. IN - Kostine, Marie. Departement de Rhumatologie, Hopital Pellegrin, CHU de Bordeaux, Bordeaux, France. mariekostine@hotmail.fr. IN - Barnetche, Thomas. Departement de Rhumatologie, Hopital Pellegrin, CHU de Bordeaux, Bordeaux, France. thomas.barnetche@chu-bordeaux.fr. IN - Truchetet, Marie-Elise. Departement de Rhumatologie, Hopital Pellegrin, CHU de Bordeaux, Bordeaux, France. marie-elise.truchetet@chu-bordeaux.fr. IN - Truchetet, Marie-Elise. Laboratoire d'Immunologie, UMR-CNRS 5164, Universite de Bordeaux, Bordeaux, France. marie-elise.truchetet@chu-bordeaux.fr. IN - Schaeverbeke, Thierry. Departement de Rhumatologie, Hopital Pellegrin, CHU de Bordeaux, Bordeaux, France. thierry.schaeverbeke@chu-bordeaux.fr. IN - Schaeverbeke, Thierry. Unite sous Contrat, Infections a Mycoplasmes et a Chlamydia chez l'Homme, Universite de Bordeaux, Bordeaux, France. thierry.schaeverbeke@chu-bordeaux.fr. TI - Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. [Review] SO - BMC Medicine. 13:211, 2015 Sep 04 AS - BMC Med. 13:211, 2015 Sep 04 NJ - BMC medicine PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101190723 IO - BMC Med PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559965 SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *CTLA-4 Antigen/im [Immunology] MH - Humans MH - *Immunologic Factors/ae [Adverse Effects] MH - Immunotherapy/ae [Adverse Effects] MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/im [Immunology] AB - BACKGROUND: Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab). AB - METHODS: A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R(©), package meta. AB - RESULTS: Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barre syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65-79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18-30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56-66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69-89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients. The median time of onset of irAEs was about 10 weeks (IQR, 6-12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients. AB - CONCLUSION: The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Immunologic Factors) RN - 6T8C155666 (ipilimumab) RN - QEN1X95CIX (tremelimumab) ES - 1741-7015 IL - 1741-7015 DI - 10.1186/s12916-015-0455-8 DO - https://dx.doi.org/10.1186/s12916-015-0455-8 PT - Journal Article PT - Meta-Analysis PT - Review ID - 26337719 [pubmed] ID - 10.1186/s12916-015-0455-8 [doi] ID - 10.1186/s12916-015-0455-8 [pii] ID - PMC4559965 [pmc] PP - epublish PH - 2015/04/22 [received] PH - 2015/08/18 [accepted] LG - English EP - 20150904 DP - 2015 Sep 04 DC - 20150904 EZ - 2015/09/05 06:00 DA - 2016/03/02 06:00 DT - 2015/09/05 06:00 YR - 2015 ED - 20160229 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26337719 <154. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25770731 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Schmutz JL FA - Schmutz, J-L IN - Schmutz, J-L. Departement de dermatologie et allergologie, batiment des specialites medicales, 6, rue du Morvan, 54500 Vandoeuvre-les-Nancy, France. Electronic address: jl.schmutz@chu-nancy.fr. TI - [A new form of hypophisitis following ipilimumab therapy]. [French] OT - Une nouvelle forme d'hypophysite secondaire a l'ipilimumab. SO - Annales de Dermatologie et de Venereologie. 142(4):307-8, 2015 Apr AS - Ann Dermatol Venereol. 142(4):307-8, 2015 Apr NJ - Annales de dermatologie et de venereologie PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 5rc, 7702013 IO - Ann Dermatol Venereol SB - Index Medicus CP - France MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *Autoimmune Hypophysitis/ci [Chemically Induced] MH - Autoimmune Hypophysitis/co [Complications] MH - Autoimmune Hypophysitis/dt [Drug Therapy] MH - Autoimmune Hypophysitis/ep [Epidemiology] MH - Female MH - Glucocorticoids/tu [Therapeutic Use] MH - Humans MH - Hypopituitarism/et [Etiology] MH - Incidence MH - Male MH - Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Prognosis MH - Retrospective Studies MH - Skin Neoplasms/dt [Drug Therapy] RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Glucocorticoids) RN - 6T8C155666 (ipilimumab) IS - 0151-9638 IL - 0151-9638 DI - S0151-9638(15)00052-6 DO - https://dx.doi.org/10.1016/j.annder.2015.02.001 PT - Journal Article ID - 25770731 [pubmed] ID - S0151-9638(15)00052-6 [pii] ID - 10.1016/j.annder.2015.02.001 [doi] PP - ppublish LG - French EP - 20150312 DP - 2015 Apr DC - 20150406 EZ - 2015/03/16 06:00 DA - 2016/03/02 06:00 DT - 2015/03/17 06:00 YR - 2015 ED - 20160229 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25770731 <155. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24814274 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Henderson AD AU - Thomas DA FA - Henderson, Amanda D FA - Thomas, Dilip A IN - Henderson, Amanda D. Department of Ophthalmology, Georgia Regents University, Augusta, Georgia, U.S.A. TI - A case report of orbital inflammatory syndrome secondary to ipilimumab. SO - Ophthalmic Plastic & Reconstructive Surgery. 31(3):e68-70, 2015 May-Jun AS - Ophthal Plast Reconstr Surg. 31(3):e68-70, 2015 May-Jun NJ - Ophthalmic plastic and reconstructive surgery PI - Journal available in: Print PI - Citation processed from: Internet JC - ay2, 8508431 IO - Ophthal Plast Reconstr Surg SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - CTLA-4 Antigen/im [Immunology] MH - Humans MH - *Immunotherapy/ae [Adverse Effects] MH - Lymphatic Metastasis MH - Magnetic Resonance Imaging MH - Male MH - Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - *Orbital Pseudotumor/ci [Chemically Induced] MH - Orbital Pseudotumor/di [Diagnosis] MH - Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/pa [Pathology] AB - Ipilimumab is a monoclonal antibody to cytotoxic T-lymphocyte antigen-4, a negative regulator of T-cell-mediated immune response. Ipilimumab is approved by the US Food and Drug Administration for the treatment of advanced melanoma. However, its use frequently has been associated with immune-related side effects, which can be explained by its mechanism of action. More common adverse effects include dermatitis, colitis, hepatitis, and endocrinopathies, but many less common immune-related adverse effects that involve various tissues and organ systems have been reported with more widespread use of ipilimumab since its approval in 2011. A case of bilateral orbital inflammatory syndrome secondary to ipilimumab, in a patient undergoing adjuvant treatment for metastatic melanoma, is reported. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) ES - 1537-2677 IL - 0740-9303 DO - https://dx.doi.org/10.1097/IOP.0000000000000081 PT - Case Reports PT - Journal Article ID - 24814274 [pubmed] ID - 10.1097/IOP.0000000000000081 [doi] PP - ppublish LG - English DP - 2015 May-Jun DC - 20150507 EZ - 2014/05/13 06:00 DA - 2016/02/27 06:00 DT - 2014/05/13 06:00 YR - 2015 ED - 20160226 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24814274 <156. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25938471 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Longoria TC AU - Eskander RN FA - Longoria, Teresa C FA - Eskander, Ramez N IN - Eskander, Ramez N. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California, Irvine-Medical Center, 101 The City Drive, Bldg 56, Ste 800, ZC 3200, Orange, CA 92868 USA. Eskander@uci.edu. TI - Immune checkpoint inhibition: therapeutic implications in epithelial ovarian cancer. [Review] SO - Recent Patents on Anti-Cancer Drug Discovery. 10(2):133-44, 2015 AS - Recent Patents Anticancer Drug Discov. 10(2):133-44, 2015 NJ - Recent patents on anti-cancer drug discovery PI - Journal available in: Print PI - Citation processed from: Internet JC - 101266081 IO - Recent Pat Anticancer Drug Discov SB - Index Medicus CP - United Arab Emirates MH - Animals MH - Antibodies, Monoclonal/pd [Pharmacology] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/pd [Pharmacology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Female MH - Humans MH - Immunotherapy/mt [Methods] MH - Neoplasm Staging MH - *Neoplasms, Glandular and Epithelial/dt [Drug Therapy] MH - Neoplasms, Glandular and Epithelial/im [Immunology] MH - Neoplasms, Glandular and Epithelial/pa [Pathology] MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/pa [Pathology] MH - Patents as Topic MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] AB - Ovarian cancer accounts for more deaths than any other gynecologic malignancy. According to the Ovarian Cancer National Alliance, overall mortality rates due to ovarian cancer have not significantly improved in 40 years, a statistic that highlights the need for innovative treatment strategies. Immune checkpoint inhibitors are part of an emerging immunotherapeutic model that seeks to "inhibit the inhibitors" of adequate cancer immunosurveillance. Immune checkpoints encompass a variety of inhibitory pathways that downregulate an immune response, which allows them to assume an important physiologic role in maintaining homeostasis. While cancer cells are adept at utilizing these pathways to their advantage, basic scientists, translational researchers, and clinical trialists are making great strides in this area of investigation. This review article will focus on the development of anti-CTLA-4 and anti-PD1 monoclonal antibodies, their current role in the treatment of advanced stage EOC, and recently published patents that incorporate the use of immune checkpoint inhibition in the treatment of cancer. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (Programmed Cell Death 1 Receptor) RS - Ovarian epithelial cancer ES - 2212-3970 IL - 1574-8928 DI - PRA-EPUB-67005 PT - Journal Article PT - Review ID - 25938471 [pubmed] ID - PRA-EPUB-67005 [pii] PP - ppublish PH - 2015/01/19 [received] PH - 2015/04/28 [revised] PH - 2015/04/02 [accepted] LG - English DP - 2015 DC - 20150518 EZ - 2015/05/05 06:00 DA - 2016/02/19 06:00 DT - 2015/05/06 06:00 YR - 2015 ED - 20160218 RD - 20150518 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25938471 <157. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25993145 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Postow MA FA - Postow, Michael A IN - Postow, Michael A. From the Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medical College, New York, NY. TI - Managing immune checkpoint-blocking antibody side effects. [Review] SO - American Society of Clinical Oncology Educational Book. :76-83, 2015 AS - Am. Soc. Clin. Oncol. educ. book. :76-83, 2015 NJ - American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting PI - Journal available in: Print PI - Citation processed from: Internet JC - 101233985 IO - Am Soc Clin Oncol Educ Book SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Chemical and Drug Induced Liver Injury/dt [Drug Therapy] MH - Chemical and Drug Induced Liver Injury/et [Etiology] MH - Colitis/ci [Chemically Induced] MH - Colitis/dt [Drug Therapy] MH - Diarrhea/ci [Chemically Induced] MH - Diarrhea/dt [Drug Therapy] MH - Granulocyte-Macrophage Colony-Stimulating Factor/tu [Therapeutic Use] MH - Humans MH - Opportunistic Infections/dt [Drug Therapy] MH - Opportunistic Infections/et [Etiology] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Recombinant Proteins/tu [Therapeutic Use] AB - Immune checkpoint-blocking antibodies that enhance the immune system's ability to fight cancer are becoming important components of treatment for patients with a variety of malignancies. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) was the first immune checkpoint to be clinically targeted, and ipilimumab, an inhibitor of CTLA-4, was approved by the U.S. Food and Drug Administration (FDA) for patients with advanced melanoma. The programmed cell death-1 (PD-1) receptor and one of its ligands, PD-L1, more recently have shown great promise as therapeutic targets in a variety of malignancies. Nivolumab and pembrolizumab recently have been FDA- approved for patients with melanoma and additional approvals within this therapeutic class are expected. The use of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies is associated with side effects known as immune-related adverse events (irAEs). Immune-related adverse events affect the dermatologic, gastrointestinal, hepatic, endocrine, and other organ systems. Temporary immunosuppression with corticosteroids, tumor necrosis factor-alpha antagonists, mycophenolate mofetil, or other agents can be effective treatment. This article describes the side-effect profile of the checkpoint-blocking antibodies that target CTLA-4 and PD-1/PD-L1 and provides suggestions on how to manage specific irAEs. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Recombinant Proteins) RN - 123774-72-1 (sargramostim) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) ES - 1548-8756 IL - 1548-8748 DI - 00115000076 DO - https://dx.doi.org/10.14694/EdBook_AM.2015.35.76 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 25993145 [pubmed] ID - 00115000076 [pii] ID - 10.14694/EdBook_AM.2015.35.76 [doi] PP - ppublish LG - English DP - 2015 DC - 20150521 EZ - 2015/05/21 06:00 DA - 2016/02/18 06:00 DT - 2015/05/21 06:00 YR - 2015 ED - 20160217 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25993145 <158. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25811348 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Su D AU - Singer EA AU - Srinivasan R FA - Su, Daniel FA - Singer, Eric A FA - Srinivasan, Ramaprasad IN - Su, Daniel. aUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland bSection of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. TI - Molecular pathways in renal cell carcinoma: recent advances in genetics and molecular biology. [Review] SO - Current Opinion in Oncology. 27(3):217-23, 2015 May AS - Curr Opin Oncol. 27(3):217-23, 2015 May NJ - Current opinion in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - a1v, 9007265 IO - Curr Opin Oncol SB - Index Medicus CP - United States MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Carcinoma, Renal Cell/dt [Drug Therapy] MH - Carcinoma, Renal Cell/ge [Genetics] MH - Carcinoma, Renal Cell/mo [Mortality] MH - Carcinoma, Renal Cell/pa [Pathology] MH - Carrier Proteins MH - Disease-Free Survival MH - Humans MH - *Kidney Neoplasms/dt [Drug Therapy] MH - Kidney Neoplasms/ge [Genetics] MH - Kidney Neoplasms/mo [Mortality] MH - Kidney Neoplasms/pa [Pathology] MH - Molecular Targeted Therapy/mt [Methods] MH - *Molecular Targeted Therapy MH - Vascular Endothelial Growth Factor A AB - PURPOSE OF REVIEW: Advanced renal cell carcinoma (RCC) remains a largely incurable disease with a grave prognosis despite the availability of a multiplicity of systemic therapies targeted against vascular endothelial growth factor, its receptors, and the mammalian target of rapamycin. Although immune 'checkpoint inhibitors' appear to have activity in clear cell RCC based on recent early phase trials, the true magnitude of the benefit conferred by these agents remains to be fully understood. Given the limitations of existing treatment paradigms, ongoing research into new targetable pathways is critical. This review will highlight some of the more promising avenues of investigation into the molecular biology of RCC. AB - RECENT FINDINGS: The hypoxia-inducible factor and mammalian target of rapamycin pathways remain critical targets in clear cell RCC. In addition, genes involved in chromatin remodeling such as polybromo 1 (PBRM1), SET domain containing 2 (SETD2), and BRCA-1-associated protein-1 (BAP1) have been shown to influence tumor biology and predict survival. MET alterations and the Krebs cycle enzyme fumarate hydratase are associated with familial type 1 and type 2 papillary RCC (PRCC), respectively. Alterations in nuclear factor (erythroid-derived 2)-like 2, Kelch-like erythroid-derived cap-n-collar homology-associated protein 1, and cullin 3, components of an oxidative stress response pathway, have been recently recognized in some sporadic papillary tumors as well as in fumarate hydratase-deficient tumor and may serve as additional therapeutic targets. In addition, whole-genome sequencing and integrated genomic analysis strategies are beginning to uncover unique molecular signatures associated with distinct subtypes of RCC, laying the foundation for a molecular classification of RCC and more precise, mechanism-based therapeutic intervention. AB - SUMMARY: The complex molecular changes underlying individual RCC variants are yet to be fully elucidated and remain the subject of ongoing investigation. The findings summarized here further exemplify the diversity of RCC and the need to tailor our therapeutic approaches to the unique genetic alterations specific to individual subtypes of RCC. RN - 0 (Antineoplastic Agents) RN - 0 (Carrier Proteins) RN - 0 (Vascular Endothelial Growth Factor A) ES - 1531-703X IL - 1040-8746 DO - https://dx.doi.org/10.1097/CCO.0000000000000186 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Review ID - 25811348 [pubmed] ID - 10.1097/CCO.0000000000000186 [doi] PP - ppublish GI - No: P30CA072720 Organization: (CA) *NCI NIH HHS* Country: United States Organization: *Intramural NIH HHS* Country: United States LG - English DP - 2015 May DC - 20150408 EZ - 2015/03/27 06:00 DA - 2016/02/18 06:00 DT - 2015/03/27 06:00 YR - 2015 ED - 20160217 RD - 20150408 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25811348 <159. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25811348 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Su D AU - Singer EA AU - Srinivasan R FA - Su, Daniel FA - Singer, Eric A FA - Srinivasan, Ramaprasad IN - Su, Daniel. aUrologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland bSection of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA. TI - Molecular pathways in renal cell carcinoma: recent advances in genetics and molecular biology. [Review] SO - Current Opinion in Oncology. 27(3):217-23, 2015 May AS - Curr Opin Oncol. 27(3):217-23, 2015 May NJ - Current opinion in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - a1v, 9007265 IO - Curr Opin Oncol SB - Index Medicus CP - United States MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Carcinoma, Renal Cell/dt [Drug Therapy] MH - Carcinoma, Renal Cell/ge [Genetics] MH - Carcinoma, Renal Cell/mo [Mortality] MH - Carcinoma, Renal Cell/pa [Pathology] MH - Carrier Proteins MH - Disease-Free Survival MH - Humans MH - *Kidney Neoplasms/dt [Drug Therapy] MH - Kidney Neoplasms/ge [Genetics] MH - Kidney Neoplasms/mo [Mortality] MH - Kidney Neoplasms/pa [Pathology] MH - Molecular Targeted Therapy/mt [Methods] MH - *Molecular Targeted Therapy MH - Vascular Endothelial Growth Factor A AB - PURPOSE OF REVIEW: Advanced renal cell carcinoma (RCC) remains a largely incurable disease with a grave prognosis despite the availability of a multiplicity of systemic therapies targeted against vascular endothelial growth factor, its receptors, and the mammalian target of rapamycin. Although immune 'checkpoint inhibitors' appear to have activity in clear cell RCC based on recent early phase trials, the true magnitude of the benefit conferred by these agents remains to be fully understood. Given the limitations of existing treatment paradigms, ongoing research into new targetable pathways is critical. This review will highlight some of the more promising avenues of investigation into the molecular biology of RCC. AB - RECENT FINDINGS: The hypoxia-inducible factor and mammalian target of rapamycin pathways remain critical targets in clear cell RCC. In addition, genes involved in chromatin remodeling such as polybromo 1 (PBRM1), SET domain containing 2 (SETD2), and BRCA-1-associated protein-1 (BAP1) have been shown to influence tumor biology and predict survival. MET alterations and the Krebs cycle enzyme fumarate hydratase are associated with familial type 1 and type 2 papillary RCC (PRCC), respectively. Alterations in nuclear factor (erythroid-derived 2)-like 2, Kelch-like erythroid-derived cap-n-collar homology-associated protein 1, and cullin 3, components of an oxidative stress response pathway, have been recently recognized in some sporadic papillary tumors as well as in fumarate hydratase-deficient tumor and may serve as additional therapeutic targets. In addition, whole-genome sequencing and integrated genomic analysis strategies are beginning to uncover unique molecular signatures associated with distinct subtypes of RCC, laying the foundation for a molecular classification of RCC and more precise, mechanism-based therapeutic intervention. AB - SUMMARY: The complex molecular changes underlying individual RCC variants are yet to be fully elucidated and remain the subject of ongoing investigation. The findings summarized here further exemplify the diversity of RCC and the need to tailor our therapeutic approaches to the unique genetic alterations specific to individual subtypes of RCC. RN - 0 (Antineoplastic Agents) RN - 0 (Carrier Proteins) RN - 0 (Vascular Endothelial Growth Factor A) ES - 1531-703X IL - 1040-8746 DO - https://dx.doi.org/10.1097/CCO.0000000000000186 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Review ID - 25811348 [pubmed] ID - 10.1097/CCO.0000000000000186 [doi] PP - ppublish GI - No: P30 CA072720 Organization: (CA) *NCI NIH HHS* Country: United States No: P30CA072720 Organization: (CA) *NCI NIH HHS* Country: United States Organization: *Intramural NIH HHS* Country: United States LG - English DP - 2015 May DC - 20150408 EZ - 2015/03/27 06:00 DA - 2016/02/18 06:00 DT - 2015/03/27 06:00 YR - 2015 ED - 20160217 RD - 20161214 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=25811348 <160. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26881150 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Azmat U AU - Liebner D AU - Joehlin-Price A AU - Agrawal A AU - Nabhan F AI - Agrawal, Amit; ORCID: https://orcid.org/0000-0003-4047-5708 FA - Azmat, Umal FA - Liebner, David FA - Joehlin-Price, Amy FA - Agrawal, Amit FA - Nabhan, Fadi IN - Azmat, Umal. Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Columbus, OH, USA. IN - Liebner, David. Division of Medical Oncology and Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA. IN - Joehlin-Price, Amy. Department of Pathology, The Ohio State University, Columbus, OH, USA. IN - Agrawal, Amit. Department of Otolaryngology, Head and Neck Surgery, The Ohio State University, Columbus, OH, USA. IN - Nabhan, Fadi. Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Columbus, OH, USA. TI - Treatment of Ipilimumab Induced Graves' Disease in a Patient with Metastatic Melanoma. SO - Case Reports in Endocrinology Print. 2016:2087525, 2016 AS - case report. endocrinol.. 2016:2087525, 2016 NJ - Case reports in endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101576457 IO - Case Rep Endocrinol PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737013 CP - United States AB - Objective. Thyroid disease has been reported among the endocrinopathies that can occur after treatment with ipilimumab. Graves' disease, however, has been rarely reported with this medication. Here we report a case of Graves' disease diagnosed after initiation of ipilimumab in a patient with melanoma. Methods. We present the clinical presentation and management course of this patient followed by a related literature review. Results. A 67-year-old male with metastatic melanoma was started on ipilimumab. He developed hyperthyroidism after two doses of ipilimumab. The cause of hyperthyroidism was determined to be Graves' disease. Ipilimumab was held and the patient was started on methimazole with return to euthyroid status. Ipilimumab was resumed and the patient continued methimazole during the course of ipilimumab therapy, with controlled hyperthyroidism. Restaging studies following four cycles of ipilimumab showed complete response in the lungs, with residual melanoma in the neck. The patient then underwent total thyroidectomy and left neck dissection as a definitive treatment for both hyperthyroidism and residual melanoma. Conclusion. Graves' disease can develop after starting ipilimumab and methimazole can be an effective treatment. For patients whose hyperthyroidism is well-controlled on methimazole, ipilimumab may be resumed with close monitoring. IS - 2090-6501 IL - 2090-651X DO - https://dx.doi.org/10.1155/2016/2087525 PT - Journal Article ID - 26881150 [pubmed] ID - 10.1155/2016/2087525 [doi] ID - PMC4737013 [pmc] PP - ppublish PH - 2015/09/24 [received] PH - 2015/12/20 [accepted] LG - English EP - 20160111 DP - 2016 DC - 20160216 EZ - 2016/02/17 06:00 DA - 2016/02/18 06:01 DT - 2016/02/18 06:00 YR - 2016 ED - 20160216 RD - 20160219 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26881150 <161. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26673995 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kopecky J AU - Kubecek O AU - Gabalec F AU - Hoffmann P AU - Svilias I FA - Kopecky, J FA - Kubecek, O FA - Gabalec, F FA - Hoffmann, P FA - Svilias, I TI - [Possible Pitfalls of Ipilimumab Therapy in Malignant Melanoma - a Case Report]. [Czech] OT - Mozna uskali lecby ipilimumabem u maligniho melanomu - kazuistika. SO - Klinicka Onkologie. 28(6):444-9, 2015 AS - KLIN. ONKOL.. 28(6):444-9, 2015 NJ - Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti PI - Journal available in: Print PI - Citation processed from: Print JC - 9425213 IO - Klin Onkol SB - Index Medicus CP - Czech Republic MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Female MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - *Skin Neoplasms/dt [Drug Therapy] AB - BACKGROUND: Metastatic melanoma is a malignancy with one of the highest mortality rates. However, with the introduction of new drugs during the last decade, the prognosis of patients began to improve. Ipilimumab is one of the first so called modern drugs in melanoma treatment. The therapy is often complicated by adverse effects which are referred as immunerelated adverse events due to its mechanism of action. AB - CASE: We present a case of 68-year- old women with metastatic melanoma who underwent treatment with ipilimumab. The patient encountered several adverse events during the treatment. Some of them are quite common (e.g. skin affections), others (e.g. endocrinopathies) are less frequent. AB - CONCLUSION: This case study highlights the need for close observation not only during the actual treatment with ipilimumab, but also several weeks or months after the last dose. This case study also demonstrates further need of education of doctors who do not usually come in to contact with such patients. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) IS - 0862-495X IL - 0862-495X DI - 56839 PT - Case Reports PT - Journal Article ID - 26673995 [pubmed] ID - 56839 [pii] PP - ppublish LG - Czech DP - 2015 DC - 20151217 EZ - 2015/12/18 06:00 DA - 2016/02/13 06:00 DT - 2015/12/18 06:00 YR - 2015 ED - 20160211 RD - 20161126 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26673995 <162. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26855529 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Dawood S FA - Dawood, Shaheenah IN - Dawood, Shaheenah. Department of Medical Oncology, Dubai Hospital, Dubai, UAE. TI - Breast and gastrointestinal cancer updates from ASCO 2015. SO - Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology. 36(3):189-92, 2015 Jul-Sep AS - Indian J Med Paediatr Oncol. 36(3):189-92, 2015 Jul-Sep NJ - Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology PI - Journal available in: Print PI - Citation processed from: Print JC - 9604571 IO - Indian J Med Paediatr Oncol PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743179 CP - India KW - ASCO; breast cancer; colorectal cancer; immunotherapy AB - This review focuses on the updates presented at the ASCO 2015 symposium in breast and gastrointestinal malignancies. Some were practice changing while others gave us an exciting glimpse into what's to come in the very near future. Immunotherapy was the buzz word this year with data presented on every tumor site. Data on the efficacy of anti PD-1 agents in colorectal, hepatocellular and gastric cancer were presented. In breast cancer we saw data on a new and exciting therapeutic target in the form of androgen receptor among triple receptor negative breast tumors presented. Positive results of the PALOMA 3 trial were presented that has given women with hormone receptor positive metastatic breast cancer another therapeutic option. Furthermore data on strategies to further improve anti her2 therapy, optimizing of chemotherapy in the early and advanced stage and various strategies to improve endocrine therapy among patients with breast cancer were presented. IS - 0971-5851 IL - 0971-5851 DI - IJMPO-36-189 DO - https://dx.doi.org/10.4103/0971-5851.166757 PT - Journal Article ID - 26855529 [pubmed] ID - 10.4103/0971-5851.166757 [doi] ID - IJMPO-36-189 [pii] ID - PMC4743179 [pmc] PP - ppublish LG - English DP - 2015 Jul-Sep DC - 20160209 EZ - 2016/02/09 06:00 DA - 2016/02/09 06:01 DT - 2016/02/09 06:00 YR - 2015 ED - 20160209 RD - 20160210 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26855529 <163. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25649350 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Johnson DB AU - Friedman DL AU - Berry E AU - Decker I AU - Ye F AU - Zhao S AU - Morgans AK AU - Puzanov I AU - Sosman JA AU - Lovly CM FA - Johnson, Douglas B FA - Friedman, Debra L FA - Berry, Elizabeth FA - Decker, Ilka FA - Ye, Fei FA - Zhao, Shilin FA - Morgans, Alicia K FA - Puzanov, Igor FA - Sosman, Jeffrey A FA - Lovly, Christine M IN - Johnson, Douglas B. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. douglas.b.johnson@vanderbilt.edu. IN - Friedman, Debra L. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Berry, Elizabeth. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Decker, Ilka. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Ye, Fei. Department of Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Zhao, Shilin. Department of Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Morgans, Alicia K. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Puzanov, Igor. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Sosman, Jeffrey A. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Lovly, Christine M. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. TI - Survivorship in Immune Therapy: Assessing Chronic Immune Toxicities, Health Outcomes, and Functional Status among Long-term Ipilimumab Survivors at a Single Referral Center. SO - Cancer Immunology Research. 3(5):464-9, 2015 May AS - Cancer Immunol Res. 3(5):464-9, 2015 May NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420706 OI - Source: NLM. NIHMS661215 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Colitis/ci [Chemically Induced] MH - Diarrhea/ci [Chemically Induced] MH - Disease-Free Survival MH - Exanthema/ci [Chemically Induced] MH - Humans MH - Immunotherapy MH - *Melanoma/dt [Drug Therapy] MH - Neuralgia/ci [Chemically Induced] MH - Pituitary Diseases/ci [Chemically Induced] MH - Pruritus/ci [Chemically Induced] MH - Treatment Outcome AB - Ipilimumab, a novel immune checkpoint inhibitor, is associated with long-term survival in approximately 20% of patients with advanced melanoma and is also being evaluated in the adjuvant setting. With this growing cohort of survivors, long-term health outcomes, chronic toxicities, and functional outcomes among survivors treated with ipilimumab need to be defined. Using retrospective medical record abstraction, we evaluated disease status, chronic immune- and non-immune-related health events, pharmacologic management of symptoms, and functional status in patients with melanoma, with overall survival >=2 years following ipilimumab treatment at Vanderbilt University. Ninety patients received ipilimumab for metastatic disease or as adjuvant therapy between January 2006 and September 2012, and 33 patients survived >=2 years, with a median overall survival of 60.1 months. Of these, 24 patients were alive at the last follow-up (73%), with 14 patients free of disease (42%). Gastrointestinal and dermatologic adverse events were frequent but largely transient. By contrast, patients with hypophysitis universally required ongoing corticosteroids, although largely remained asymptomatic with appropriate hormone replacement. Surviving patients generally had excellent performance status (ECOG 0-1 in 23 of 24). Chronic neurologic toxicities caused substantial morbidity and mortality in 2 patients who received whole-brain radiotherapy >5 years before analysis, and in one patient with chronic, painful peripheral neuropathy. No previously undescribed cardiac, pulmonary, gastrointestinal, hematologic, or neoplastic safety signals were identified. In conclusion, ipilimumab was associated with largely excellent functional outcomes among long-term survivors. Chronic endocrine dysfunction and occasional neurologic toxicity (primarily associated with whole-brain radiation) were observed in a small number of patients. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-14-0217 DO - https://dx.doi.org/10.1158/2326-6066.CIR-14-0217 PT - Clinical Trial PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 25649350 [pubmed] ID - 2326-6066.CIR-14-0217 [pii] ID - 10.1158/2326-6066.CIR-14-0217 [doi] ID - PMC4420706 [pmc] ID - NIHMS661215 [mid] PP - ppublish PH - 2014/11/18 [received] PH - 2015/01/26 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00094653 SA - ClinicalTrials.gov/NCT00495066 SA - ClinicalTrials.gov/NCT00623766 SA - ClinicalTrials.gov/NCT01274338 SA - ClinicalTrials.gov/NCT00094653 SA - ClinicalTrials.gov/NCT00495066 SA - ClinicalTrials.gov/NCT00623766 SA - ClinicalTrials.gov/NCT01274338 SL - https://clinicaltrials.gov/search/term=NCT00094653 SL - https://clinicaltrials.gov/search/term=NCT00495066 SL - https://clinicaltrials.gov/search/term=NCT00623766 SL - https://clinicaltrials.gov/search/term=NCT01274338 SL - https://clinicaltrials.gov/search/term=NCT00094653 SL - https://clinicaltrials.gov/search/term=NCT00495066 SL - https://clinicaltrials.gov/search/term=NCT00623766 SL - https://clinicaltrials.gov/search/term=NCT01274338 GI - No: K12 CA090625 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 TR000445 Organization: (TR) *NCATS NIH HHS* Country: United States No: K12 CA 0906525 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20150203 DP - 2015 May DC - 20150505 EZ - 2015/02/05 06:00 DA - 2016/02/09 06:00 DT - 2015/02/05 06:00 YR - 2015 ED - 20160208 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25649350 <164. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25649350 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Johnson DB AU - Friedman DL AU - Berry E AU - Decker I AU - Ye F AU - Zhao S AU - Morgans AK AU - Puzanov I AU - Sosman JA AU - Lovly CM FA - Johnson, Douglas B FA - Friedman, Debra L FA - Berry, Elizabeth FA - Decker, Ilka FA - Ye, Fei FA - Zhao, Shilin FA - Morgans, Alicia K FA - Puzanov, Igor FA - Sosman, Jeffrey A FA - Lovly, Christine M IN - Johnson, Douglas B. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. douglas.b.johnson@vanderbilt.edu. IN - Friedman, Debra L. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Berry, Elizabeth. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Decker, Ilka. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Ye, Fei. Department of Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Zhao, Shilin. Department of Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Morgans, Alicia K. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Puzanov, Igor. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Sosman, Jeffrey A. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. IN - Lovly, Christine M. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee. TI - Survivorship in Immune Therapy: Assessing Chronic Immune Toxicities, Health Outcomes, and Functional Status among Long-term Ipilimumab Survivors at a Single Referral Center. SO - Cancer Immunology Research. 3(5):464-9, 2015 May AS - Cancer Immunol Res. 3(5):464-9, 2015 May NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420706 OI - Source: NLM. NIHMS661215 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Colitis/ci [Chemically Induced] MH - Diarrhea/ci [Chemically Induced] MH - Disease-Free Survival MH - Exanthema/ci [Chemically Induced] MH - Humans MH - Immunotherapy MH - *Melanoma/dt [Drug Therapy] MH - Neuralgia/ci [Chemically Induced] MH - Pituitary Diseases/ci [Chemically Induced] MH - Pruritus/ci [Chemically Induced] MH - Treatment Outcome AB - Ipilimumab, a novel immune checkpoint inhibitor, is associated with long-term survival in approximately 20% of patients with advanced melanoma and is also being evaluated in the adjuvant setting. With this growing cohort of survivors, long-term health outcomes, chronic toxicities, and functional outcomes among survivors treated with ipilimumab need to be defined. Using retrospective medical record abstraction, we evaluated disease status, chronic immune- and non-immune-related health events, pharmacologic management of symptoms, and functional status in patients with melanoma, with overall survival >=2 years following ipilimumab treatment at Vanderbilt University. Ninety patients received ipilimumab for metastatic disease or as adjuvant therapy between January 2006 and September 2012, and 33 patients survived >=2 years, with a median overall survival of 60.1 months. Of these, 24 patients were alive at the last follow-up (73%), with 14 patients free of disease (42%). Gastrointestinal and dermatologic adverse events were frequent but largely transient. By contrast, patients with hypophysitis universally required ongoing corticosteroids, although largely remained asymptomatic with appropriate hormone replacement. Surviving patients generally had excellent performance status (ECOG 0-1 in 23 of 24). Chronic neurologic toxicities caused substantial morbidity and mortality in 2 patients who received whole-brain radiotherapy >5 years before analysis, and in one patient with chronic, painful peripheral neuropathy. No previously undescribed cardiac, pulmonary, gastrointestinal, hematologic, or neoplastic safety signals were identified. In conclusion, ipilimumab was associated with largely excellent functional outcomes among long-term survivors. Chronic endocrine dysfunction and occasional neurologic toxicity (primarily associated with whole-brain radiation) were observed in a small number of patients. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-14-0217 DO - https://dx.doi.org/10.1158/2326-6066.CIR-14-0217 PT - Clinical Trial PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 25649350 [pubmed] ID - 2326-6066.CIR-14-0217 [pii] ID - 10.1158/2326-6066.CIR-14-0217 [doi] ID - PMC4420706 [pmc] ID - NIHMS661215 [mid] PP - ppublish PH - 2014/11/18 [received] PH - 2015/01/26 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00094653 SA - ClinicalTrials.gov/NCT00495066 SA - ClinicalTrials.gov/NCT00623766 SA - ClinicalTrials.gov/NCT01274338 SL - https://clinicaltrials.gov/search/term=NCT00094653 SL - https://clinicaltrials.gov/search/term=NCT00495066 SL - https://clinicaltrials.gov/search/term=NCT00623766 SL - https://clinicaltrials.gov/search/term=NCT01274338 GI - No: K12 CA090625 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 TR000445 Organization: (TR) *NCATS NIH HHS* Country: United States No: K12 CA 0906525 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20150203 DP - 2015 May DC - 20150505 EZ - 2015/02/05 06:00 DA - 2016/02/09 06:00 DT - 2015/02/05 06:00 YR - 2015 ED - 20160208 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=25649350 <165. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25786871 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - El Khatib MM AU - Sakuma T AU - Tonne JM AU - Mohamed MS AU - Holditch SJ AU - Lu B AU - Kudva YC AU - Ikeda Y AI - Ikeda, Y; ORCID: https://orcid.org/0000000298747537 FA - El Khatib, M M FA - Sakuma, T FA - Tonne, J M FA - Mohamed, M S FA - Holditch, S J FA - Lu, B FA - Kudva, Y C FA - Ikeda, Y IN - El Khatib, M M. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. IN - Sakuma, T. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. IN - Tonne, J M. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. IN - Mohamed, M S. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. IN - Holditch, S J. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. IN - Lu, B. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. IN - Kudva, Y C. Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA. IN - Ikeda, Y. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. TI - beta-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. SO - Gene Therapy. 22(5):430-8, 2015 May AS - Gene Ther. 22(5):430-8, 2015 May NJ - Gene therapy PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cce, 9421525 IO - Gene Ther. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520544 OI - Source: NLM. NIHMS708388 SB - Index Medicus CP - England MH - Animals MH - *Antigens, CD274/im [Immunology] MH - *Autoimmunity MH - *CTLA-4 Antigen/im [Immunology] MH - *Diabetes Mellitus, Experimental/im [Immunology] MH - Diabetes Mellitus, Experimental/th [Therapy] MH - *Graft Rejection MH - HEK293 Cells MH - Humans MH - Immunosuppression MH - *Insulin-Secreting Cells/im [Immunology] MH - Insulin-Secreting Cells/tr [Transplantation] MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred ICR MH - Mice, Inbred NOD MH - Transplantation, Homologous AB - Protection of beta cells from autoimmune destruction potentially cures type 1 diabetes mellitus (T1D). During antigen presentation, interactions between cytotoxic T-lymphocyte antigen-4 (CTLA4) and B7 molecules, or programmed death 1 (PD1) and its ligand PDL1, negatively regulate immune responses in a non-redundant manner. Here we employed beta-cell-targeted adeno-associated virus serotype 8 (AAV8)-based vectors to overexpress an artificial PDL1-CTLA4Ig polyprotein or interleukin 10 (IL10). beta-Cell-targeted expression of PDL1-CTLA4Ig or IL10 preserved beta-cell mass and protected NOD mice from T1D development. When NOD mice were treated with vectors at early onset of hyperglycemia, PDL1-CTLA4Ig or IL10 alone failed to normalize the early onset of hyperglycemia. When drug-induced diabetic mice received major histocompatibility complex (MHC)-matched allo-islets, with or without pretreatment of the PDL1-CTLA4Ig-expressing vector, PDL1-CTLA4Ig-expressing islets were protected from rejection for at least 120 days. Similarly, transplantation of PDL1-CTLA4Ig-expressing MHC-matched islets into mice with established T1D resulted in protection of allo-islets from acute rejection, although islet grafts were eventually rejected. Thus the present study demonstrates the potent immuno-suppressive effects of beta-cell-targeted PDL1-CTLA4Ig overexpression against T1D development and allo-islet rejection. The gene-based simultaneous inhibition of PD1 and CTLA4 pathways provides a unique strategy for immunosuppression-free tissue/organ transplantation, especially in the setting of no established autoimmunity. RN - 0 (Antigens, CD274) RN - 0 (CTLA-4 Antigen) ES - 1476-5462 IL - 0969-7128 DI - gt201518 DO - https://dx.doi.org/10.1038/gt.2015.18 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 25786871 [pubmed] ID - gt201518 [pii] ID - 10.1038/gt.2015.18 [doi] ID - PMC4520544 [pmc] ID - NIHMS708388 [mid] PP - ppublish PH - 2014/09/03 [received] PH - 2015/01/07 [revised] PH - 2015/02/12 [accepted] GI - No: R01 HL098502 Organization: (HL) *NHLBI NIH HHS* Country: United States No: HL098502 Organization: (HL) *NHLBI NIH HHS* Country: United States LG - English EP - 20150319 DP - 2015 May DC - 20150507 EZ - 2015/03/20 06:00 DA - 2016/02/04 06:00 DT - 2015/03/20 06:00 YR - 2015 ED - 20160203 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25786871 <166. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26304716 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wang Z AU - Lai ST AU - Ma NY AU - Deng Y AU - Liu Y AU - Wei DP AU - Zhao JD AU - Jiang GL FA - Wang, Zheng FA - Lai, Song-Tao FA - Ma, Ning-Yi FA - Deng, Yun FA - Liu, Yong FA - Wei, Dong-Ping FA - Zhao, Jian-Dong FA - Jiang, Guo-Liang IN - Wang, Zheng. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China. IN - Lai, Song-Tao. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China. IN - Ma, Ning-Yi. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China. IN - Deng, Yun. Cancer Research Institute, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China. IN - Liu, Yong. Cancer Research Institute, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China. IN - Wei, Dong-Ping. Cancer Research Institute, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China. IN - Zhao, Jian-Dong. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China. IN - Jiang, Guo-Liang. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China; Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, 4365 Kangxin Road, Shanghai 201321, China. Electronic address: guoliang.jiang@sphic.org.cn. TI - Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair. SO - Cancer Letters. 369(1):192-201, 2015 Dec 01 AS - Cancer Lett. 369(1):192-201, 2015 Dec 01 NJ - Cancer letters PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 7600053, cmx IO - Cancer Lett. SB - Index Medicus CP - Ireland MH - Apoptosis/re [Radiation Effects] MH - Cell Cycle Proteins/ai [Antagonists & Inhibitors] MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Line, Tumor MH - Chemoradiotherapy MH - Cyclin-Dependent Kinases/me [Metabolism] MH - *DNA Damage MH - *DNA Repair MH - *G2 Phase Cell Cycle Checkpoints MH - Humans MH - *Metformin/pd [Pharmacology] MH - Mitosis/de [Drug Effects] MH - Nuclear Proteins/ai [Antagonists & Inhibitors] MH - Nuclear Proteins/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Phosphorylation MH - Protein Biosynthesis/de [Drug Effects] MH - Protein Processing, Post-Translational/de [Drug Effects] MH - Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Tyrosine Kinases/me [Metabolism] MH - Rad51 Recombinase/me [Metabolism] MH - Radiation Tolerance MH - *Radiation-Sensitizing Agents/pd [Pharmacology] KW - Metformin; Pancreatic cancer; Rad51; Radiosensitizer; Wee1; mTOR AB - Recent evidences have demonstrated the potential of metformin as a novel agent for cancer prevention and treatment. Here, we investigated its ability of radiosensitization and the underlying mechanisms in human pancreatic cancer cells. In this study, we found that metformin at 5mM concentration enhanced the radiosensitivity of MIA PaCa-2 and PANC-1 cells, with sensitization enhancement ratios of 1.39 and 1.27, respectively. Mechanistically, metformin caused abrogation of the G2 checkpoint and increase of mitotic catastrophe, associated with suppression of Wee1 kinase and in turn CDK1 Tyr15 phosphorylation. Furthermore, metformin inhibited both expression and irradiation-induced foci formation of Rad51, a key player in homologous recombination repair, ultimately leading to persistent DNA damage, as reflected by gamma-H2AX and 53BP1 signaling. Finally, metformin-mediated AMPK/mTOR/p70S6K was identified as a possible upstream pathway controlling translational regulation of Wee1 and Rad51. Our data suggest that metformin radiosensitizes pancreatic cancer cells in vitro via abrogation of the G2 checkpoint and inhibition of DNA damage repair. However, the in vivo study is needed to further confirm the findings from the in vitro study. AB - Copyright © 2015 Elsevier Ireland Ltd. All rights reserved. RN - 0 (Cell Cycle Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Radiation-Sensitizing Agents) RN - 9100L32L2N (Metformin) RN - EC 2-7-10-1 (Protein-Tyrosine Kinases) RN - EC 2-7-10-2 (WEE1 protein, human) RN - EC 2-7-11-22 (CDK1 protein, human) RN - EC 2-7-11-22 (Cyclin-Dependent Kinases) RN - EC 2-7-7 (RAD51 protein, human) RN - EC 2-7-7 (Rad51 Recombinase) ES - 1872-7980 IL - 0304-3835 DI - S0304-3835(15)00544-3 DO - https://dx.doi.org/10.1016/j.canlet.2015.08.015 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26304716 [pubmed] ID - S0304-3835(15)00544-3 [pii] ID - 10.1016/j.canlet.2015.08.015 [doi] PP - ppublish PH - 2015/04/11 [received] PH - 2015/07/14 [revised] PH - 2015/08/18 [accepted] LG - English EP - 20150821 DP - 2015 Dec 01 DC - 20151010 EZ - 2015/08/26 06:00 DA - 2016/02/02 06:00 DT - 2015/08/26 06:00 YR - 2015 ED - 20160201 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26304716 <167. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25901859 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Grizzi F AU - Mirandola L AU - Qehajaj D AU - Cobos E AU - Figueroa JA AU - Chiriva-Internati M FA - Grizzi, F FA - Mirandola, L FA - Qehajaj, D FA - Cobos, E FA - Figueroa, J A FA - Chiriva-Internati, M IN - Grizzi, F. Humanitas Clinical and Research Center , Rozzano, Milan , Italy. TI - Cancer-testis antigens and immunotherapy in the light of cancer complexity. [Review] SO - International Reviews of Immunology. 34(2):143-53, 2015 Mar AS - Int Rev Immunol. 34(2):143-53, 2015 Mar NJ - International reviews of immunology PI - Journal available in: Print PI - Citation processed from: Internet JC - iri, 8712260 IO - Int. Rev. Immunol. SB - Index Medicus CP - England MH - Animals MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antigens, Neoplasm/im [Immunology] MH - Drug Approval MH - Humans MH - *Immunotherapy, Adoptive MH - Male MH - Testicular Neoplasms/im [Immunology] MH - *Testicular Neoplasms/th [Therapy] MH - Tissue Extracts/tu [Therapeutic Use] KW - biomarkers; cancer; cancer-testis antigens; immunotherapy; inflammation; vaccine AB - The ability of immunotherapy to evoke successful antitumor immune responses has been well documented over the past decade. Despite abundant preclinical data, it is only with the recent approval by the Food and Drug Administration (FDA) of the drugs such as sipuleucel-T and ipilimumab that immunotherapy is finally being recognized as a viable alternative to traditional therapies for treatment of various cancers. Despite the ability of immunotherapy to elicit successful antitumor immune responses, its efficacy is hindered by several factors. Among these are the paucity of tumor-associated antigens (TAA) that can be used as effective targets and the systemic toxicities that often lead to treatment interruption. Indeed, such adverse effects, which can be immunological and/or parenchymal, can be particularly severe and even fatal to some patients. A family of TAA called cancer-testis antigens (CTA) has been identified and their encoding genes have been extensively investigated. CTA expression has been demonstrated in a variety of human cancer tissues, and at least 19 CTA have been found to elicit humoral and/or cellular immune responses in cancer patients. Here we discuss how CTA and immunotherapy will most likely play a major role in the cure of cancer in the light of cancer complexity. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, Neoplasm) RN - 0 (Tissue Extracts) RN - 6T8C155666 (ipilimumab) RN - 8Q622VDR18 (sipuleucel-T) ES - 1563-5244 IL - 0883-0185 DO - https://dx.doi.org/10.3109/08830185.2015.1018418 PT - Journal Article PT - Review ID - 25901859 [pubmed] ID - 10.3109/08830185.2015.1018418 [doi] PP - ppublish LG - English DP - 2015 Mar DC - 20150423 EZ - 2015/04/23 06:00 DA - 2016/01/30 06:00 DT - 2015/04/23 06:00 YR - 2015 ED - 20160129 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25901859 <168. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26410424 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Yamazaki N AU - Kiyohara Y AU - Uhara H AU - Fukushima S AU - Uchi H AU - Shibagaki N AU - Tsutsumida A AU - Yoshikawa S AU - Okuyama R AU - Ito Y AU - Tokudome T FA - Yamazaki, N FA - Kiyohara, Y FA - Uhara, H FA - Fukushima, S FA - Uchi, H FA - Shibagaki, N FA - Tsutsumida, A FA - Yoshikawa, S FA - Okuyama, R FA - Ito, Y FA - Tokudome, T IN - Yamazaki, N. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Kiyohara, Y. Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan. IN - Uhara, H. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. IN - Fukushima, S. Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. IN - Uchi, H. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. IN - Shibagaki, N. Department of Dermatology, University of Yamanashi Hospital, Yamanashi, Japan. IN - Tsutsumida, A. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Yoshikawa, S. Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan. IN - Okuyama, R. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. IN - Ito, Y. Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 1631328, Japan. IN - Tokudome, T. Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 1631328, Japan. takuto0806@gmail.com. TI - Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma. SO - Cancer Chemotherapy & Pharmacology. 76(5):997-1004, 2015 Nov AS - Cancer Chemother Pharmacol. 76(5):997-1004, 2015 Nov NJ - Cancer chemotherapy and pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c9s, 7806519 IO - Cancer Chemother. Pharmacol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612321 SB - Index Medicus CP - Germany MH - Adult MH - Aged MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibody Formation MH - Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/im [Immunology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Chemical and Drug Induced Liver Injury/et [Etiology] MH - Disease-Free Survival MH - Drug Eruptions/et [Etiology] MH - Exanthema/ci [Chemically Induced] MH - Female MH - Fever/ci [Chemically Induced] MH - Follow-Up Studies MH - Humans MH - Immunologic Factors/ae [Adverse Effects] MH - *Immunologic Factors/tu [Therapeutic Use] MH - Japan MH - Kaplan-Meier Estimate MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - Treatment Outcome KW - Immune-checkpoint inhibitor; Ipilimumab; Japanese patients; Melanoma; Phase II study AB - PURPOSE: Ipilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma. AB - METHODS: Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015). AB - RESULTS: Data are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively. AB - CONCLUSION: Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients. CLINICALTRIALS. AB - GOV IDENTIFIER: NCT01990859. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Immunologic Factors) RN - 6T8C155666 (ipilimumab) ES - 1432-0843 IL - 0344-5704 DI - 10.1007/s00280-015-2873-x DO - https://dx.doi.org/10.1007/s00280-015-2873-x PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26410424 [pubmed] ID - 10.1007/s00280-015-2873-x [doi] ID - 10.1007/s00280-015-2873-x [pii] ID - PMC4612321 [pmc] PP - ppublish PH - 2015/06/30 [received] PH - 2015/09/09 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01990859 SA - ClinicalTrials.gov/NCT01990859 SL - https://clinicaltrials.gov/search/term=NCT01990859 SL - https://clinicaltrials.gov/search/term=NCT01990859 LG - English EP - 20150926 DP - 2015 Nov DC - 20151021 EZ - 2015/09/28 06:00 DA - 2016/01/29 06:00 DT - 2015/09/28 06:00 YR - 2015 ED - 20160128 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26410424 <169. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26407818 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Yamazaki N AU - Uhara H AU - Fukushima S AU - Uchi H AU - Shibagaki N AU - Kiyohara Y AU - Tsutsumida A AU - Namikawa K AU - Okuyama R AU - Otsuka Y AU - Tokudome T FA - Yamazaki, N FA - Uhara, H FA - Fukushima, S FA - Uchi, H FA - Shibagaki, N FA - Kiyohara, Y FA - Tsutsumida, A FA - Namikawa, K FA - Okuyama, R FA - Otsuka, Y FA - Tokudome, T IN - Yamazaki, N. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Uhara, H. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. IN - Fukushima, S. Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. IN - Uchi, H. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. IN - Shibagaki, N. Department of Dermatology, Yamanashi University Hospital, Yamanashi, Japan. IN - Kiyohara, Y. Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan. IN - Tsutsumida, A. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Namikawa, K. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Okuyama, R. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. IN - Otsuka, Y. Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan. IN - Tokudome, T. Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan. takuto0806@gmail.com. TI - Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma. SO - Cancer Chemotherapy & Pharmacology. 76(5):969-75, 2015 Nov AS - Cancer Chemother Pharmacol. 76(5):969-75, 2015 Nov NJ - Cancer chemotherapy and pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c9s, 7806519 IO - Cancer Chemother. Pharmacol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612320 SB - Index Medicus CP - Germany MH - Adult MH - Aged MH - Alanine Transaminase/bl [Blood] MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Aspartate Aminotransferases/bl [Blood] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Chemical and Drug Induced Liver Injury/bl [Blood] MH - *Chemical and Drug Induced Liver Injury/et [Etiology] MH - Dacarbazine/ad [Administration & Dosage] MH - Dacarbazine/ae [Adverse Effects] MH - Disease Progression MH - Disease-Free Survival MH - Drug Administration Schedule MH - Drug Eruptions/et [Etiology] MH - Endocrine System Diseases/ci [Chemically Induced] MH - Female MH - Humans MH - Immunosuppressive Agents/tu [Therapeutic Use] MH - Japan MH - Kaplan-Meier Estimate MH - Maintenance Chemotherapy MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - Neoplasm Proteins/ai [Antagonists & Inhibitors] MH - Neoplasm Proteins/im [Immunology] MH - Remission Induction MH - Treatment Outcome KW - Dacarbazine; Immune-checkpoint inhibitor; Ipilimumab; Japanese patients; Melanoma; Phase 2 study AB - PURPOSE: Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients. AB - METHODS: Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w x 4), followed by DTIC q3w x 4 and then IPI every 12 weeks until disease progression or intolerable toxicity. AB - RESULTS: All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities. AB - CONCLUSIONS: IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Immunosuppressive Agents) RN - 0 (Neoplasm Proteins) RN - 6T8C155666 (ipilimumab) RN - 7GR28W0FJI (Dacarbazine) RN - EC 2-6-1-1 (Aspartate Aminotransferases) RN - EC 2-6-1-2 (Alanine Transaminase) ES - 1432-0843 IL - 0344-5704 DI - 10.1007/s00280-015-2870-0 DO - https://dx.doi.org/10.1007/s00280-015-2870-0 PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26407818 [pubmed] ID - 10.1007/s00280-015-2870-0 [doi] ID - 10.1007/s00280-015-2870-0 [pii] ID - PMC4612320 [pmc] PP - ppublish PH - 2015/08/03 [received] PH - 2015/09/06 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01681212 SA - ClinicalTrials.gov/NCT01681212 SL - https://clinicaltrials.gov/search/term=NCT01681212 SL - https://clinicaltrials.gov/search/term=NCT01681212 LG - English EP - 20150925 DP - 2015 Nov DC - 20151021 EZ - 2015/09/27 06:00 DA - 2016/01/29 06:00 DT - 2015/09/27 06:00 YR - 2015 ED - 20160128 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26407818 <170. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26407818 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Yamazaki N AU - Uhara H AU - Fukushima S AU - Uchi H AU - Shibagaki N AU - Kiyohara Y AU - Tsutsumida A AU - Namikawa K AU - Okuyama R AU - Otsuka Y AU - Tokudome T FA - Yamazaki, N FA - Uhara, H FA - Fukushima, S FA - Uchi, H FA - Shibagaki, N FA - Kiyohara, Y FA - Tsutsumida, A FA - Namikawa, K FA - Okuyama, R FA - Otsuka, Y FA - Tokudome, T IN - Yamazaki, N. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Uhara, H. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. IN - Fukushima, S. Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. IN - Uchi, H. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. IN - Shibagaki, N. Department of Dermatology, Yamanashi University Hospital, Yamanashi, Japan. IN - Kiyohara, Y. Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan. IN - Tsutsumida, A. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Namikawa, K. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Okuyama, R. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. IN - Otsuka, Y. Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan. IN - Tokudome, T. Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan. takuto0806@gmail.com. TI - Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma. SO - Cancer Chemotherapy & Pharmacology. 76(5):969-75, 2015 Nov AS - Cancer Chemother Pharmacol. 76(5):969-75, 2015 Nov NJ - Cancer chemotherapy and pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c9s, 7806519 IO - Cancer Chemother. Pharmacol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612320 SB - Index Medicus CP - Germany MH - Adult MH - Aged MH - Alanine Transaminase/bl [Blood] MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Aspartate Aminotransferases/bl [Blood] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Chemical and Drug Induced Liver Injury/bl [Blood] MH - *Chemical and Drug Induced Liver Injury/et [Etiology] MH - Dacarbazine/ad [Administration & Dosage] MH - Dacarbazine/ae [Adverse Effects] MH - Disease Progression MH - Disease-Free Survival MH - Drug Administration Schedule MH - Drug Eruptions/et [Etiology] MH - Endocrine System Diseases/ci [Chemically Induced] MH - Female MH - Humans MH - Immunosuppressive Agents/tu [Therapeutic Use] MH - Japan MH - Kaplan-Meier Estimate MH - Maintenance Chemotherapy MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - Neoplasm Proteins/ai [Antagonists & Inhibitors] MH - Neoplasm Proteins/im [Immunology] MH - Remission Induction MH - Treatment Outcome KW - Dacarbazine; Immune-checkpoint inhibitor; Ipilimumab; Japanese patients; Melanoma; Phase 2 study AB - PURPOSE: Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients. AB - METHODS: Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w x 4), followed by DTIC q3w x 4 and then IPI every 12 weeks until disease progression or intolerable toxicity. AB - RESULTS: All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities. AB - CONCLUSIONS: IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Immunosuppressive Agents) RN - 0 (Neoplasm Proteins) RN - 6T8C155666 (ipilimumab) RN - 7GR28W0FJI (Dacarbazine) RN - EC 2-6-1-1 (Aspartate Aminotransferases) RN - EC 2-6-1-2 (Alanine Transaminase) ES - 1432-0843 IL - 0344-5704 DI - 10.1007/s00280-015-2870-0 DO - https://dx.doi.org/10.1007/s00280-015-2870-0 PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26407818 [pubmed] ID - 10.1007/s00280-015-2870-0 [doi] ID - 10.1007/s00280-015-2870-0 [pii] ID - PMC4612320 [pmc] PP - ppublish PH - 2015/08/03 [received] PH - 2015/09/06 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01681212 SL - https://clinicaltrials.gov/search/term=NCT01681212 LG - English EP - 20150925 DP - 2015 Nov DC - 20151021 EZ - 2015/09/27 06:00 DA - 2016/01/29 06:00 DT - 2015/09/27 06:00 YR - 2015 ED - 20160128 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26407818 <171. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26410424 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Yamazaki N AU - Kiyohara Y AU - Uhara H AU - Fukushima S AU - Uchi H AU - Shibagaki N AU - Tsutsumida A AU - Yoshikawa S AU - Okuyama R AU - Ito Y AU - Tokudome T FA - Yamazaki, N FA - Kiyohara, Y FA - Uhara, H FA - Fukushima, S FA - Uchi, H FA - Shibagaki, N FA - Tsutsumida, A FA - Yoshikawa, S FA - Okuyama, R FA - Ito, Y FA - Tokudome, T IN - Yamazaki, N. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Kiyohara, Y. Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan. IN - Uhara, H. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. IN - Fukushima, S. Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. IN - Uchi, H. Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. IN - Shibagaki, N. Department of Dermatology, University of Yamanashi Hospital, Yamanashi, Japan. IN - Tsutsumida, A. Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. IN - Yoshikawa, S. Dermatology Division, Shizuoka Cancer Center, Shizuoka, Japan. IN - Okuyama, R. Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan. IN - Ito, Y. Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 1631328, Japan. IN - Tokudome, T. Research and Development, Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 1631328, Japan. takuto0806@gmail.com. TI - Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma. SO - Cancer Chemotherapy & Pharmacology. 76(5):997-1004, 2015 Nov AS - Cancer Chemother Pharmacol. 76(5):997-1004, 2015 Nov NJ - Cancer chemotherapy and pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c9s, 7806519 IO - Cancer Chemother. Pharmacol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4612321 SB - Index Medicus CP - Germany MH - Adult MH - Aged MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibody Formation MH - Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/im [Immunology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Chemical and Drug Induced Liver Injury/et [Etiology] MH - Disease-Free Survival MH - Drug Eruptions/et [Etiology] MH - Exanthema/ci [Chemically Induced] MH - Female MH - Fever/ci [Chemically Induced] MH - Follow-Up Studies MH - Humans MH - Immunologic Factors/ae [Adverse Effects] MH - *Immunologic Factors/tu [Therapeutic Use] MH - Japan MH - Kaplan-Meier Estimate MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - Treatment Outcome KW - Immune-checkpoint inhibitor; Ipilimumab; Japanese patients; Melanoma; Phase II study AB - PURPOSE: Ipilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma. AB - METHODS: Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015). AB - RESULTS: Data are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively. AB - CONCLUSION: Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients. CLINICALTRIALS. AB - GOV IDENTIFIER: NCT01990859. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Immunologic Factors) RN - 6T8C155666 (ipilimumab) ES - 1432-0843 IL - 0344-5704 DI - 10.1007/s00280-015-2873-x DO - https://dx.doi.org/10.1007/s00280-015-2873-x PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26410424 [pubmed] ID - 10.1007/s00280-015-2873-x [doi] ID - 10.1007/s00280-015-2873-x [pii] ID - PMC4612321 [pmc] PP - ppublish PH - 2015/06/30 [received] PH - 2015/09/09 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01990859 SL - https://clinicaltrials.gov/search/term=NCT01990859 LG - English EP - 20150926 DP - 2015 Nov DC - 20151021 EZ - 2015/09/28 06:00 DA - 2016/01/29 06:00 DT - 2015/09/28 06:00 YR - 2015 ED - 20160128 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26410424 <172. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25986891 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wuerkenbieke D AU - Wang J AU - Li Y AU - Ma C FA - Wuerkenbieke, Delinaer FA - Wang, Jing FA - Li, Yan FA - Ma, Cailing IN - Wuerkenbieke, Delinaer. Department of Gynecology, The First Teaching Hospital of Xinjiang Medical University, No 137 Liyushan South Road, Urumqi, 830054, Xinjiang, People's Republic of China. IN - Wang, Jing. Department of Gynecology, The First Teaching Hospital of Xinjiang Medical University, No 137 Liyushan South Road, Urumqi, 830054, Xinjiang, People's Republic of China. IN - Li, Yan. Department of Gynecology, The First Teaching Hospital of Xinjiang Medical University, No 137 Liyushan South Road, Urumqi, 830054, Xinjiang, People's Republic of China. IN - Ma, Cailing. Department of Gynecology, The First Teaching Hospital of Xinjiang Medical University, No 137 Liyushan South Road, Urumqi, 830054, Xinjiang, People's Republic of China. cailingma117@126.com. TI - miRNA-150 downregulation promotes pertuzumab resistance in ovarian cancer cells via AKT activation. SO - Archives of Gynecology & Obstetrics. 292(5):1109-16, 2015 Nov AS - Arch Gynecol Obstet. 292(5):1109-16, 2015 Nov NJ - Archives of gynecology and obstetrics PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 6ys, 8710213 IO - Arch. Gynecol. Obstet. SB - Index Medicus CP - Germany MH - *Antibodies, Monoclonal, Humanized/pd [Pharmacology] MH - *Antineoplastic Agents/pd [Pharmacology] MH - Apoptosis/de [Drug Effects] MH - Breast Neoplasms/dt [Drug Therapy] MH - Cell Cycle/de [Drug Effects] MH - Cell Line, Tumor MH - Chromones MH - Down-Regulation MH - *Drug Resistance, Neoplasm/ge [Genetics] MH - Female MH - Gene Expression Regulation, Neoplastic/de [Drug Effects] MH - Gene Expression Regulation, Neoplastic/ge [Genetics] MH - Humans MH - *MicroRNAs/ge [Genetics] MH - Morpholines MH - Neoplasms, Glandular and Epithelial/me [Metabolism] MH - Neoplasms, Glandular and Epithelial/pa [Pathology] MH - *Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - Phosphatidylinositol 3-Kinases/ai [Antagonists & Inhibitors] MH - Phosphatidylinositol 3-Kinases/me [Metabolism] MH - Proto-Oncogene Proteins c-akt/me [Metabolism] MH - Receptor, ErbB-2 MH - *Signal Transduction/de [Drug Effects] KW - Drug resistance; Ovarian cancer; Pertuzumab; miR-150 AB - BACKGROUND: Pertuzumab is a humanized mAb that binds to the extracellular region of HER2/ErbB2 and is approved for treating breast cancer. Although ovarian cancer and breast cancer have comparable levels of HER2/ErbB2 expression, clinical studies of pertuzumab in epithelial ovarian cancer patients have not met the same level of success. AB - OBJECTIVES: To investigate the molecular mechanisms by which pertuzumab exerts its anti-tumor effects in ovarian cancer and the mechanisms by which cancer cells achieve pertuzumab resistance. AB - METHODS: We examined expression of miR-150 in ovarian cancer cells treated with pertuzumab or not. miR-150 knockdown impacts on pertuzumab treatment were analyzed by cell proliferation assay, apoptosis analysis and cell cycle analysis. Cell signal pathway was examined by western blot assay. AB - RESULTS: Pertuzumab induced miRNA-150 expression in SKOV3 and SNU119 cells. Furthermore, suppression of miRNA-150 in both cell lines resulted in decreased drug sensitivity to pertuzumab and cell apoptosis. The blockage of G1/S checkpoint by pertuzumab was rescued as well. miRNA-150 knockdown activated PI3K-Akt pathway and LY294002 reversed the effect of miR-150 knockdown. AB - CONCLUSIONS: miRNA-150 downregulation may contribute to the pertuzumab resistance in ovarian cancer via, at least in part, PI3K-akt pathway. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Chromones) RN - 0 (MicroRNAs) RN - 0 (Morpholines) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - EC 2-7-1 (Phosphatidylinositol 3-Kinases) RN - EC 2-7-10-1 (ERBB2 protein, human) RN - EC 2-7-10-1 (Receptor, ErbB-2) RN - EC 2-7-11-1 (Proto-Oncogene Proteins c-akt) RN - K16AIQ8CTM (pertuzumab) RS - Ovarian epithelial cancer ES - 1432-0711 IL - 0932-0067 DI - 10.1007/s00404-015-3742-x DO - https://dx.doi.org/10.1007/s00404-015-3742-x PT - Journal Article ID - 25986891 [pubmed] ID - 10.1007/s00404-015-3742-x [doi] ID - 10.1007/s00404-015-3742-x [pii] PP - ppublish PH - 2015/03/24 [received] PH - 2015/04/27 [accepted] LG - English EP - 20150519 DP - 2015 Nov DC - 20150930 EZ - 2015/05/20 06:00 DA - 2016/01/26 06:00 DT - 2015/05/20 06:00 YR - 2015 ED - 20160125 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25986891 <173. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25678581 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Winograd R AU - Byrne KT AU - Evans RA AU - Odorizzi PM AU - Meyer AR AU - Bajor DL AU - Clendenin C AU - Stanger BZ AU - Furth EE AU - Wherry EJ AU - Vonderheide RH FA - Winograd, Rafael FA - Byrne, Katelyn T FA - Evans, Rebecca A FA - Odorizzi, Pamela M FA - Meyer, Anders R L FA - Bajor, David L FA - Clendenin, Cynthia FA - Stanger, Ben Z FA - Furth, Emma E FA - Wherry, E John FA - Vonderheide, Robert H IN - Winograd, Rafael. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Byrne, Katelyn T. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Evans, Rebecca A. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Odorizzi, Pamela M. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Meyer, Anders R L. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Bajor, David L. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Clendenin, Cynthia. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Stanger, Ben Z. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Furth, Emma E. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Wherry, E John. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. IN - Vonderheide, Robert H. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. rhv@exchange.upenn.edu. TI - Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. SO - Cancer Immunology Research. 3(4):399-411, 2015 Apr AS - Cancer Immunol Res. 3(4):399-411, 2015 Apr NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390506 OI - Source: NLM. NIHMS664805 SB - Index Medicus CP - United States MH - Animals MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Antigens, CD274/im [Immunology] MH - Antigens, CD40/im [Immunology] MH - Antimetabolites, Antineoplastic/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - *CTLA-4 Antigen/im [Immunology] MH - Carcinoma, Pancreatic Ductal/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/th [Therapy] MH - Cell Line, Tumor MH - Combined Modality Therapy MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/tu [Therapeutic Use] MH - Female MH - Genetic Engineering/mt [Methods] MH - Humans MH - Immune Tolerance/de [Drug Effects] MH - Immune Tolerance/im [Immunology] MH - Immunity, Cellular MH - Interferon-gamma/im [Immunology] MH - Lymphocyte Activation/im [Immunology] MH - Mice, Inbred C57BL MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/th [Therapy] MH - *T-Lymphocyte Subsets/im [Immunology] MH - Tumor Microenvironment/im [Immunology] MH - Xenograft Model Antitumor Assays/mt [Methods] AB - Disabling the function of immune checkpoint molecules can unlock T-cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFNgamma in this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with alphaPD-1 mAbs, with or without alphaCTLA-4 mAbs, failed in well-established tumors, recapitulating clinical results. Agonist alphaCD40 mAbs with chemotherapy induced T-cell immunity and reversed the complete resistance of pancreatic tumors to alphaPD-1 and alphaCTLA-4. The combination of alphaCD40/chemotherapy plus alphaPD-1 and/or alphaCTLA-4 induced regression of subcutaneous tumors, improved overall survival, and conferred curative protection from multiple tumor rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers, although no cures were observed. Our findings suggest that in pancreatic carcinoma, a nonimmunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T-cell response with alphaCD40/chemotherapy. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (Antigens, CD40) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (CD274 protein, human) RN - 0 (CTLA-4 Antigen) RN - 0W860991D6 (Deoxycytidine) RN - 82115-62-6 (Interferon-gamma) RN - B76N6SBZ8R (gemcitabine) RS - Pancreatic Carcinoma ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-14-0215 DO - https://dx.doi.org/10.1158/2326-6066.CIR-14-0215 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 25678581 [pubmed] ID - 2326-6066.CIR-14-0215 [pii] ID - 10.1158/2326-6066.CIR-14-0215 [doi] ID - PMC4390506 [pmc] ID - NIHMS664805 [mid] PP - ppublish PH - 2014/11/16 [received] PH - 2015/02/06 [accepted] GI - No: T32 HL007439 Organization: (HL) *NHLBI NIH HHS* Country: United States No: T32 CA009140 Organization: (CA) *NCI NIH HHS* Country: United States No: U19 AI082630 Organization: (AI) *NIAID NIH HHS* Country: United States No: P01 AI112521 Organization: (AI) *NIAID NIH HHS* Country: United States No: R01 CA169123 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA016520 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 HL007775 Organization: (HL) *NHLBI NIH HHS* Country: United States No: U19 AI 082630 Organization: (AI) *NIAID NIH HHS* Country: United States LG - English EP - 20150212 DP - 2015 Apr DC - 20150407 EZ - 2015/02/14 06:00 DA - 2016/01/26 06:00 DT - 2015/02/14 06:00 YR - 2015 ED - 20160125 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25678581 <174. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26118951 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Quirk SK AU - Shure AK AU - Agrawal DK FA - Quirk, Shannon K FA - Shure, Anna K FA - Agrawal, Devendra K IN - Quirk, Shannon K. Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb. IN - Shure, Anna K. Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb. IN - Agrawal, Devendra K. Center for Clinical and Translational Science, Creighton University School of Medicine, Omaha, Neb. Electronic address: dkagr@creighton.edu. TI - Immune-mediated adverse events of anticytotoxic T lymphocyte-associated antigen 4 antibody therapy in metastatic melanoma. [Review] SO - Translational Research: The Journal Of Laboratory & Clinical Medicine. 166(5):412-24, 2015 Nov AS - Transl Res. 166(5):412-24, 2015 Nov NJ - Translational research : the journal of laboratory and clinical medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101280339 IO - Transl Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609598 OI - Source: NLM. NIHMS699615 [Available on 11/01/16] SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *CTLA-4 Antigen/im [Immunology] MH - Clinical Trials, Phase III as Topic MH - Drug Therapy, Combination MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/pa [Pathology] MH - Neoplasm Metastasis AB - Ipilimumab, an antibody that blocks cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; CD152), was approved by the Food and Drug Administration in 2011 for the treatment of unresectable stage III or IV malignant melanoma. Although the addition of this particular immunotherapy has broadened treatment options, immune-related adverse events (irAEs) are associated with ipilimumab therapy, including dermatologic effects, colitis and diarrhea, endocrine effects, hepatotoxicity, ocular effects, renal effects, neurologic effects, and others. In this article, a critical evaluation of the underlying mechanisms of irAEs associated with anti-CTLA-4 therapy is presented. Additionally, potentially beneficial effects of combinational therapies to alleviate ipilimumab-induced irAEs in malignant melanoma are discussed. Future research is warranted to elucidate the efficacy of such combination therapies and specific biomarkers that would help to predict a clinical response to ipilimumab in patients with malignant melanoma. AB - Copyright © 2015 Elsevier Inc. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) RN - QEN1X95CIX (tremelimumab) ES - 1878-1810 IL - 1878-1810 DI - S1931-5244(15)00210-8 DO - https://dx.doi.org/10.1016/j.trsl.2015.06.005 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review ID - 26118951 [pubmed] ID - S1931-5244(15)00210-8 [pii] ID - 10.1016/j.trsl.2015.06.005 [doi] ID - PMC4609598 [pmc] ID - NIHMS699615 [mid] PP - ppublish PH - 2015/04/01 [received] PH - 2015/06/02 [revised] PH - 2015/06/04 [accepted] GI - No: R01HL120659 Organization: (HL) *NHLBI NIH HHS* Country: United States No: R01HL112597 Organization: (HL) *NHLBI NIH HHS* Country: United States No: R01 HL112597 Organization: (HL) *NHLBI NIH HHS* Country: United States No: R01HL116042 Organization: (HL) *NHLBI NIH HHS* Country: United States No: R01 HL116042 Organization: (HL) *NHLBI NIH HHS* Country: United States No: R01 HL120659 Organization: (HL) *NHLBI NIH HHS* Country: United States LG - English EP - 20150611 DP - 2015 Nov DC - 20151017 EZ - 2015/06/30 06:00 DA - 2016/01/20 06:00 DT - 2015/06/30 06:00 YR - 2015 ED - 20160119 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26118951 <175. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25641691 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Cheng R AU - Cooper A AU - Kench J AU - Watson G AU - Bye W AU - McNeil C AU - Shackel N FA - Cheng, Robert FA - Cooper, Adam FA - Kench, James FA - Watson, Geoff FA - Bye, William FA - McNeil, Catriona FA - Shackel, Nicholas IN - Cheng, Robert. A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. TI - Ipilimumab-induced toxicities and the gastroenterologist. [Review] SO - Journal of Gastroenterology & Hepatology. 30(4):657-66, 2015 Apr AS - J Gastroenterol Hepatol. 30(4):657-66, 2015 Apr NJ - Journal of gastroenterology and hepatology PI - Journal available in: Print PI - Citation processed from: Internet JC - a6j, 8607909 IO - J. Gastroenterol. Hepatol. SB - Index Medicus CP - Australia MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Azathioprine/ad [Administration & Dosage] MH - Calcineurin Inhibitors/ad [Administration & Dosage] MH - *Chemical and Drug Induced Liver Injury/dt [Drug Therapy] MH - *Colitis/ci [Chemically Induced] MH - Colitis/dt [Drug Therapy] MH - Glucocorticoids/ad [Administration & Dosage] MH - Humans MH - *Immunosuppressive Agents/ad [Administration & Dosage] MH - Infliximab/ad [Administration & Dosage] MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/sc [Secondary] MH - Methylprednisolone/ad [Administration & Dosage] MH - Mycophenolic Acid/ad [Administration & Dosage] MH - Mycophenolic Acid/aa [Analogs & Derivatives] MH - Patient Care Team MH - Prednisolone/ad [Administration & Dosage] MH - Pulse Therapy, Drug KW - CTLA-4 antibody; colitis; hepatitis; immunotherapy; ipilimumab; melanoma AB - Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune-modulation, and is recognized to cause potentially severe immune-related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis, and hepatitis. The acceptance of ipilimumab as a treatment for metastatic melanoma means patients will continue to be treated with this agent and gastroenterologists will be increasingly called upon to assist in managing severe autoimmune-related hepatitis and colitis. To date, the recommendations for managing irAEs secondary to ipilimumab have been steroids at a moderate dose of prednisolone (1mg/kg) as well as immunosuppressive agents such as mycophenolate mofetil (MMF) for steroid-refractory hepatitis and infliximab in the management of corticosteroid-refractory colitis. However, the dosing and the duration of immunosuppressive therapy have not been systematically studied in the setting of treating ipilimumab-induced irAEs. Therefore, additional immune-modifying agents and/or a change in dosing may be required to manage severe irAEs unresponsive to existing treatment recommendations. We describe a treatment paradigm illustrated by a series of five patients who experienced irAEs. In three cases of metastatic melanoma, ipilimumab-induced hepatitis was successfully treated with high-dose parenteral pulsed methylprednisolone. In two other melanoma patients with ipilimumab-induced colitis, one patient had satisfactory resolution of his colitis with high-dose corticosteroid therapy alone and the other patient required infliximab infusion. We have reviewed the current literature and management algorithms for ipilimumab-induced irAEs. Treatment options and the rationale for their use are discussed, including the use of pulsed high-dose steroids, MMF, azathioprine and calcineurin inhibitors. AB - Copyright © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd. RN - 0 (Antibodies, Monoclonal) RN - 0 (Calcineurin Inhibitors) RN - 0 (Glucocorticoids) RN - 0 (Immunosuppressive Agents) RN - 6T8C155666 (ipilimumab) RN - 9PHQ9Y1OLM (Prednisolone) RN - B72HH48FLU (Infliximab) RN - HU9DX48N0T (Mycophenolic Acid) RN - MRK240IY2L (Azathioprine) RN - X4W7ZR7023 (Methylprednisolone) ES - 1440-1746 IL - 0815-9319 DO - https://dx.doi.org/10.1111/jgh.12888 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 25641691 [pubmed] ID - 10.1111/jgh.12888 [doi] PP - ppublish PH - 2014/12/29 [accepted] LG - English DP - 2015 Apr DC - 20150317 EZ - 2015/02/03 06:00 DA - 2016/01/15 06:00 DT - 2015/02/03 06:00 YR - 2015 ED - 20160114 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25641691 <176. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25885696 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Venditti O AU - De Lisi D AU - Caricato M AU - Caputo D AU - Capolupo GT AU - Taffon C AU - Pagliara E AU - Battisi S AU - Frezza AM AU - Onetti Muda A AU - Tonini G AU - Santini D FA - Venditti, Olga FA - De Lisi, Delia FA - Caricato, Marco FA - Caputo, Damiano FA - Capolupo, Gabriella Teresa FA - Taffon, Chiara FA - Pagliara, Elisa FA - Battisi, Sofia FA - Frezza, Anna Maria FA - Onetti Muda, Andrea FA - Tonini, Giuseppe FA - Santini, Daniele IN - Venditti, Olga. Department of Medical Oncology, Universita Campus Bio-Medico di Roma, via Alvaro del Portillo 200, 00128, Rome, Italy. o.venditti@unicampus.it. IN - De Lisi, Delia. Department of Medical Oncology, Universita Campus Bio-Medico di Roma, via Alvaro del Portillo 200, 00128, Rome, Italy. d.delisi@unicampus.it. IN - Caricato, Marco. Department of General Surgery, Universita Campus Bio-Medico di Roma, Via Alvaro del Portillo, 200, 00128, Rome, Italy. m.caricato@unicampus.it. IN - Caputo, Damiano. Department of General Surgery, Universita Campus Bio-Medico di Roma, Via Alvaro del Portillo, 200, 00128, Rome, Italy. d.caputo@unicampus.it. IN - Capolupo, Gabriella Teresa. Department of General Surgery, Universita Campus Bio-Medico di Roma, Via Alvaro del Portillo, 200, 00128, Rome, Italy. g.capolupo@unicampus.it. IN - Taffon, Chiara. Department of Pathology Universita, Universita Campus Bio-Medico di Roma, Via Alvaro del Portillo, 200, 00128, Rome, Italy. c.taffon@unicampus.it. IN - Pagliara, Elisa. Department of Radiology Universita, Campus Bio-Medico di Roma, Via Alvaro del Portillo, 200, 00128, Rome, Italy. e.pagliara@unicampus.it. IN - Battisi, Sofia. Department of Radiology Universita, Campus Bio-Medico di Roma, Via Alvaro del Portillo, 200, 00128, Rome, Italy. s.battisti@unicampus.it. IN - Frezza, Anna Maria. Department of Medical Oncology, Universita Campus Bio-Medico di Roma, via Alvaro del Portillo 200, 00128, Rome, Italy. a.frezza@unicampus.it. IN - Onetti Muda, Andrea. Department of Pathology Universita, Universita Campus Bio-Medico di Roma, Via Alvaro del Portillo, 200, 00128, Rome, Italy. a.onetti@unicampus.it. IN - Tonini, Giuseppe. Department of Medical Oncology, Universita Campus Bio-Medico di Roma, via Alvaro del Portillo 200, 00128, Rome, Italy. g.tonini@unicampus.it. IN - Santini, Daniele. Department of Medical Oncology, Universita Campus Bio-Medico di Roma, via Alvaro del Portillo 200, 00128, Rome, Italy. d.santini@unicampus.it. TI - Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4 induced ileitis. SO - BMC Cancer. 15:87, 2015 Mar 01 AS - BMC Cancer. 15:87, 2015 Mar 01 NJ - BMC cancer PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 100967800 IO - BMC Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350587 SB - Index Medicus CP - England MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Female MH - Humans MH - *Ileitis/ci [Chemically Induced] MH - *Ileitis/pa [Pathology] MH - Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Neoplasm Metastasis MH - Precision Medicine MH - Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/pa [Pathology] AB - BACKGROUND: Ipilimumab is a fully human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 , a key negative regulator of T-cell activation approved by the Food and Drug Administration as of March 2011 for the treatment of metastatic melanoma. As a result of the up-regulation of the immune system, several immune-mediated adverse effects have been reported including colitis, dermatitis, hepatitis and rarely hypophysitis. The most frequent immune-mediated adverse effects described in literature include gastrointestinal toxicity such as diarrhea, colitis and case of colitis and ileitis. AB - CASE PRESENTATION: In this paper we report an interesting case of immune-mediate ileitis without colitis in a 54 years old woman with metastatic melanoma treated with ipilimumab. We also discuss about case management and the possible pathological mechanisms considering also previous reports. AB - CONCLUSIONS: The aim of this article is to support further investigations concerning epigenetic and genetic analysis in order to personalize biological therapy and to reduce immune related adverse events observed after ipilimumab administration. RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 1471-2407 IL - 1471-2407 DI - 10.1186/s12885-015-1074-7 DO - https://dx.doi.org/10.1186/s12885-015-1074-7 PT - Case Reports PT - Journal Article ID - 25885696 [pubmed] ID - 10.1186/s12885-015-1074-7 [doi] ID - 10.1186/s12885-015-1074-7 [pii] ID - PMC4350587 [pmc] PP - epublish PH - 2014/04/08 [received] PH - 2015/02/09 [accepted] LG - English EP - 20150301 DP - 2015 Mar 01 DC - 20150418 EZ - 2015/04/18 06:00 DA - 2016/01/09 06:00 DT - 2015/04/18 06:00 YR - 2015 ED - 20160108 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25885696 <177. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24955955 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Beeharry N AU - Banina E AU - Hittle J AU - Skobeleva N AU - Khazak V AU - Deacon S AU - Andrake M AU - Egleston BL AU - Peterson JR AU - Astsaturov I AU - Yen TJ FA - Beeharry, Neil FA - Banina, Eugenia FA - Hittle, James FA - Skobeleva, Natalia FA - Khazak, Vladimir FA - Deacon, Sean FA - Andrake, Mark FA - Egleston, Brian L FA - Peterson, Jeffrey R FA - Astsaturov, Igor FA - Yen, Timothy J IN - Beeharry, Neil. Cancer Biology Program; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Banina, Eugenia. Program in Developmental Therapeutics; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Hittle, James. Cancer Biology Program; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Skobeleva, Natalia. Program in Developmental Therapeutics; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Khazak, Vladimir. Program in Developmental Therapeutics; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Deacon, Sean. Reaction Biology Corporation; Malvern, PA USA. IN - Andrake, Mark. Molecular Modeling Facility; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Egleston, Brian L. Biostatistics and Bioinformatics Facility; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Peterson, Jeffrey R. Cancer Biology Program; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Astsaturov, Igor. Program in Developmental Therapeutics; Fox Chase Cancer Center; Philadelphia, PA USA. IN - Yen, Timothy J. Cancer Biology Program; Fox Chase Cancer Center; Philadelphia, PA USA. TI - Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints. CM - Comment in: Cell Cycle. 2014;13(18):2810-1; PMID: 25486467 SO - Cell Cycle. 13(14):2172-91, 2014 AS - Cell Cycle. 13(14):2172-91, 2014 NJ - Cell cycle (Georgetown, Tex.) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101137841 IO - Cell Cycle PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111673 SB - Index Medicus CP - United States MH - Aniline Compounds/pd [Pharmacology] MH - Animals MH - *Antineoplastic Agents/pd [Pharmacology] MH - *Cell Cycle Checkpoints/de [Drug Effects] MH - Cell Cycle Proteins/ai [Antagonists & Inhibitors] MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Line, Tumor MH - *Cell Proliferation/de [Drug Effects] MH - Checkpoint Kinase 1 MH - Cisplatin/pd [Pharmacology] MH - DNA Damage MH - DNA Replication MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Dose-Response Relationship, Drug MH - Doxorubicin/pd [Pharmacology] MH - *Drug Repositioning MH - *Drug Resistance, Neoplasm/de [Drug Effects] MH - Humans MH - Male MH - Mice, Inbred C57BL MH - Mice, SCID MH - Models, Molecular MH - Nitriles/pd [Pharmacology] MH - Nuclear Proteins/ai [Antagonists & Inhibitors] MH - Nuclear Proteins/me [Metabolism] MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/en [Enzymology] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/pa [Pathology] MH - Protein Kinase Inhibitors/ch [Chemistry] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - Protein Kinases/ch [Chemistry] MH - Protein Kinases/ge [Genetics] MH - *Protein Kinases/me [Metabolism] MH - Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Tyrosine Kinases/me [Metabolism] MH - Quinolines/pd [Pharmacology] MH - *Signal Transduction/de [Drug Effects] MH - Time Factors MH - Xenograft Model Antitumor Assays KW - Checkpoint override; DNA damage; Kinase inhibitors; Mitosis; drug repurposing AB - Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as "authentic" bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents' gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient's tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off-target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers. RN - 0 (Aniline Compounds) RN - 0 (Antineoplastic Agents) RN - 0 (Cell Cycle Proteins) RN - 0 (Nitriles) RN - 0 (Nuclear Proteins) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Quinolines) RN - 0W860991D6 (Deoxycytidine) RN - 5018V4AEZ0 (bosutinib) RN - 80168379AG (Doxorubicin) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-10-1 (Protein-Tyrosine Kinases) RN - EC 2-7-10-2 (WEE1 protein, human) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - EC 2-7-11-1 (Chek1 protein, mouse) RN - Q20Q21Q62J (Cisplatin) ES - 1551-4005 IL - 1551-4005 DI - 29214 DO - https://dx.doi.org/10.4161/cc.29214 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. ID - 24955955 [pubmed] ID - 29214 [pii] ID - 10.4161/cc.29214 [doi] ID - PMC4111673 [pmc] PP - ppublish GI - No: R21 CA164205 Organization: (CA) *NCI NIH HHS* Country: United States No: CA06927 Organization: (CA) *NCI NIH HHS* Country: United States No: CA169706 Organization: (CA) *NCI NIH HHS* Country: United States No: K22 CA160725 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 GM083025 Organization: (GM) *NIGMS NIH HHS* Country: United States No: R21 CA169706 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA006927 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20140623 DP - 2014 DC - 20140812 EZ - 2014/06/24 06:00 DA - 2015/12/17 06:00 DT - 2014/06/24 06:00 YR - 2014 ED - 20151215 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24955955 <178. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26503055 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Peng D AU - Kryczek I AU - Nagarsheth N AU - Zhao L AU - Wei S AU - Wang W AU - Sun Y AU - Zhao E AU - Vatan L AU - Szeliga W AU - Kotarski J AU - Tarkowski R AU - Dou Y AU - Cho K AU - Hensley-Alford S AU - Munkarah A AU - Liu R AU - Zou W FA - Peng, Dongjun FA - Kryczek, Ilona FA - Nagarsheth, Nisha FA - Zhao, Lili FA - Wei, Shuang FA - Wang, Weimin FA - Sun, Yuqing FA - Zhao, Ende FA - Vatan, Linda FA - Szeliga, Wojciech FA - Kotarski, Jan FA - Tarkowski, Rafal FA - Dou, Yali FA - Cho, Kathleen FA - Hensley-Alford, Sharon FA - Munkarah, Adnan FA - Liu, Rebecca FA - Zou, Weiping IN - Peng, Dongjun. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Kryczek, Ilona. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Kryczek, Ilona. Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Nagarsheth, Nisha. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Nagarsheth, Nisha. Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Zhao, Lili. Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Wei, Shuang. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Wang, Weimin. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Sun, Yuqing. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Zhao, Ende. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Vatan, Linda. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Szeliga, Wojciech. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Kotarski, Jan. The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland. IN - Tarkowski, Rafal. The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland. IN - Dou, Yali. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Cho, Kathleen. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Cho, Kathleen. The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Hensley-Alford, Sharon. Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA. IN - Munkarah, Adnan. Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA. IN - Liu, Rebecca. The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Liu, Rebecca. Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Zou, Weiping. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Zou, Weiping. Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Zou, Weiping. The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Zou, Weiping. Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. TI - Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. CM - Comment in: Nat Rev Immunol. 2015 Dec;15(12):730; PMID: 26542634 SO - Nature. 527(7577):249-53, 2015 Nov 12 AS - Nature. 527(7577):249-53, 2015 Nov 12 NJ - Nature PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0410462 IO - Nature PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779053 OI - Source: NLM. NIHMS718418 SB - Index Medicus CP - England MH - Animals MH - Antigens, CD274/me [Metabolism] MH - CD8-Positive T-Lymphocytes/cy [Cytology] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - Chemokine CXCL10/bi [Biosynthesis] MH - Chemokine CXCL10/ge [Genetics] MH - Chemokine CXCL10/im [Immunology] MH - Chemokine CXCL9/bi [Biosynthesis] MH - Chemokine CXCL9/ge [Genetics] MH - Chemokine CXCL9/im [Immunology] MH - Chemokines/bi [Biosynthesis] MH - *Chemokines/ge [Genetics] MH - Chemokines/im [Immunology] MH - DNA (Cytosine-5-)-Methyltransferase/ai [Antagonists & Inhibitors] MH - DNA (Cytosine-5-)-Methyltransferase/me [Metabolism] MH - DNA Methylation/de [Drug Effects] MH - Enhancer of Zeste Homolog 2 Protein MH - Epigenesis, Genetic/de [Drug Effects] MH - *Epigenesis, Genetic MH - Female MH - *Gene Silencing MH - Histones/ch [Chemistry] MH - Histones/me [Metabolism] MH - Humans MH - Immunotherapy/mt [Methods] MH - *Immunotherapy MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lysine/me [Metabolism] MH - Mice MH - Ovarian Neoplasms/en [Enzymology] MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/pa [Pathology] MH - *Ovarian Neoplasms/th [Therapy] MH - Polycomb Repressive Complex 2/ai [Antagonists & Inhibitors] MH - Polycomb Repressive Complex 2/me [Metabolism] MH - Prognosis MH - Th1 Cells/im [Immunology] MH - *Th1 Cells/me [Metabolism] MH - Tumor Cells, Cultured MH - Tumor Escape/im [Immunology] MH - Xenograft Model Antitumor Assays AB - Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy. RN - 0 (Antigens, CD274) RN - 0 (CXCL10 protein, human) RN - 0 (CXCL9 protein, human) RN - 0 (Chemokine CXCL10) RN - 0 (Chemokine CXCL9) RN - 0 (Chemokines) RN - 0 (Histones) RN - EC 2-1-1-37 (DNA (Cytosine-5-)-Methyltransferase) RN - EC 2-1-1-37 (DNA (cytosine-5-)-methyltransferase 1) RN - EC 2-1-1-43 (EZH2 protein, human) RN - EC 2-1-1-43 (Enhancer of Zeste Homolog 2 Protein) RN - EC 2-1-1-43 (Polycomb Repressive Complex 2) RN - K3Z4F929H6 (Lysine) ES - 1476-4687 IL - 0028-0836 DI - nature15520 DO - https://dx.doi.org/10.1038/nature15520 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26503055 [pubmed] ID - nature15520 [pii] ID - 10.1038/nature15520 [doi] ID - PMC4779053 [pmc] ID - NIHMS718418 [mid] PP - ppublish PH - 2014/12/09 [received] PH - 2015/08/24 [accepted] GI - No: 5P30CA46592 Organization: (CA) *NCI NIH HHS* Country: United States No: CA099985 Organization: (CA) *NCI NIH HHS* Country: United States No: CA190176 Organization: (CA) *NCI NIH HHS* Country: United States No: CA156685 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA193136 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA046592 Organization: (CA) *NCI NIH HHS* Country: United States No: F31 CA189440 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA171306 Organization: (CA) *NCI NIH HHS* Country: United States No: CA152470 Organization: (CA) *NCI NIH HHS* Country: United States No: CA171306 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA152470 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA156685 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA190176 Organization: (CA) *NCI NIH HHS* Country: United States No: CA123088 Organization: (CA) *NCI NIH HHS* Country: United States No: CA193136 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA123088 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA099985 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20151026 DP - 2015 Nov 12 DC - 20151112 EZ - 2015/10/28 06:00 DA - 2015/12/15 06:00 DT - 2015/10/28 06:00 YR - 2015 ED - 20151214 RD - 20161126 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26503055 <179. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26503055 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Peng D AU - Kryczek I AU - Nagarsheth N AU - Zhao L AU - Wei S AU - Wang W AU - Sun Y AU - Zhao E AU - Vatan L AU - Szeliga W AU - Kotarski J AU - Tarkowski R AU - Dou Y AU - Cho K AU - Hensley-Alford S AU - Munkarah A AU - Liu R AU - Zou W FA - Peng, Dongjun FA - Kryczek, Ilona FA - Nagarsheth, Nisha FA - Zhao, Lili FA - Wei, Shuang FA - Wang, Weimin FA - Sun, Yuqing FA - Zhao, Ende FA - Vatan, Linda FA - Szeliga, Wojciech FA - Kotarski, Jan FA - Tarkowski, Rafal FA - Dou, Yali FA - Cho, Kathleen FA - Hensley-Alford, Sharon FA - Munkarah, Adnan FA - Liu, Rebecca FA - Zou, Weiping IN - Peng, Dongjun. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Kryczek, Ilona. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Kryczek, Ilona. Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Nagarsheth, Nisha. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Nagarsheth, Nisha. Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Zhao, Lili. Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Wei, Shuang. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Wang, Weimin. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Sun, Yuqing. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Zhao, Ende. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Vatan, Linda. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Szeliga, Wojciech. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Kotarski, Jan. The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland. IN - Tarkowski, Rafal. The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland. IN - Dou, Yali. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Cho, Kathleen. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Cho, Kathleen. The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Hensley-Alford, Sharon. Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA. IN - Munkarah, Adnan. Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA. IN - Liu, Rebecca. The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Liu, Rebecca. Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Zou, Weiping. Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. IN - Zou, Weiping. Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Zou, Weiping. The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. IN - Zou, Weiping. Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. TI - Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. CM - Comment in: Nat Rev Immunol. 2015 Dec;15(12):730; PMID: 26542634 SO - Nature. 527(7577):249-53, 2015 Nov 12 AS - Nature. 527(7577):249-53, 2015 Nov 12 NJ - Nature PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0410462 IO - Nature PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779053 OI - Source: NLM. NIHMS718418 SB - Index Medicus CP - England MH - Animals MH - Antigens, CD274/me [Metabolism] MH - CD8-Positive T-Lymphocytes/cy [Cytology] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - Chemokine CXCL10/bi [Biosynthesis] MH - Chemokine CXCL10/ge [Genetics] MH - Chemokine CXCL10/im [Immunology] MH - Chemokine CXCL9/bi [Biosynthesis] MH - Chemokine CXCL9/ge [Genetics] MH - Chemokine CXCL9/im [Immunology] MH - Chemokines/bi [Biosynthesis] MH - *Chemokines/ge [Genetics] MH - Chemokines/im [Immunology] MH - DNA (Cytosine-5-)-Methyltransferase/ai [Antagonists & Inhibitors] MH - DNA (Cytosine-5-)-Methyltransferase/me [Metabolism] MH - DNA Methylation/de [Drug Effects] MH - Enhancer of Zeste Homolog 2 Protein MH - Epigenesis, Genetic/de [Drug Effects] MH - *Epigenesis, Genetic MH - Female MH - *Gene Silencing MH - Histones/ch [Chemistry] MH - Histones/me [Metabolism] MH - Humans MH - Immunotherapy/mt [Methods] MH - *Immunotherapy MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lysine/me [Metabolism] MH - Mice MH - Ovarian Neoplasms/en [Enzymology] MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/pa [Pathology] MH - *Ovarian Neoplasms/th [Therapy] MH - Polycomb Repressive Complex 2/ai [Antagonists & Inhibitors] MH - Polycomb Repressive Complex 2/me [Metabolism] MH - Prognosis MH - Th1 Cells/im [Immunology] MH - *Th1 Cells/me [Metabolism] MH - Tumor Cells, Cultured MH - Tumor Escape/im [Immunology] MH - Xenograft Model Antitumor Assays AB - Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy. RN - 0 (Antigens, CD274) RN - 0 (CXCL10 protein, human) RN - 0 (CXCL9 protein, human) RN - 0 (Chemokine CXCL10) RN - 0 (Chemokine CXCL9) RN - 0 (Chemokines) RN - 0 (Histones) RN - EC 2-1-1-37 (DNA (Cytosine-5-)-Methyltransferase) RN - EC 2-1-1-37 (DNA (cytosine-5-)-methyltransferase 1) RN - EC 2-1-1-43 (EZH2 protein, human) RN - EC 2-1-1-43 (Enhancer of Zeste Homolog 2 Protein) RN - EC 2-1-1-43 (Polycomb Repressive Complex 2) RN - K3Z4F929H6 (Lysine) ES - 1476-4687 IL - 0028-0836 DI - nature15520 DO - https://dx.doi.org/10.1038/nature15520 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 26503055 [pubmed] ID - nature15520 [pii] ID - 10.1038/nature15520 [doi] ID - PMC4779053 [pmc] ID - NIHMS718418 [mid] PP - ppublish PH - 2014/12/09 [received] PH - 2015/08/24 [accepted] GI - No: 5P30CA46592 Organization: (CA) *NCI NIH HHS* Country: United States No: CA099985 Organization: (CA) *NCI NIH HHS* Country: United States No: CA190176 Organization: (CA) *NCI NIH HHS* Country: United States No: CA156685 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA193136 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA046592 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 GM082856 Organization: (GM) *NIGMS NIH HHS* Country: United States No: F31 CA189440 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA171306 Organization: (CA) *NCI NIH HHS* Country: United States No: CA152470 Organization: (CA) *NCI NIH HHS* Country: United States No: CA171306 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA152470 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA156685 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA190176 Organization: (CA) *NCI NIH HHS* Country: United States No: CA123088 Organization: (CA) *NCI NIH HHS* Country: United States No: CA193136 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA123088 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA099985 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20151026 DP - 2015 Nov 12 DC - 20151112 EZ - 2015/10/28 06:00 DA - 2015/12/15 06:00 DT - 2015/10/28 06:00 YR - 2015 ED - 20151214 RD - 20170104 UP - 20170105 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26503055 <180. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25538262 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Min L AU - Hodi FS AU - Giobbie-Hurder A AU - Ott PA AU - Luke JJ AU - Donahue H AU - Davis M AU - Carroll RS AU - Kaiser UB FA - Min, Le FA - Hodi, Frank Stephen FA - Giobbie-Hurder, Anita FA - Ott, Patrick A FA - Luke, Jason J FA - Donahue, Hilary FA - Davis, Meredith FA - Carroll, Rona S FA - Kaiser, Ursula B IN - Min, Le. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts. lmin1@partners.org. IN - Hodi, Frank Stephen. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Giobbie-Hurder, Anita. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Ott, Patrick A. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Luke, Jason J. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Melanoma and Developmental Therapeutics Clinics, University of Chicago, Chicago, Illinois. IN - Donahue, Hilary. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Davis, Meredith. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. IN - Carroll, Rona S. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts. IN - Kaiser, Ursula B. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts. TI - Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. SO - Clinical Cancer Research. 21(4):749-55, 2015 Feb 15 AS - Clin Cancer Res. 21(4):749-55, 2015 Feb 15 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334697 OI - Source: NLM. NIHMS651379 SB - Index Medicus CP - United States MH - *Adrenal Cortex Hormones/tu [Therapeutic Use] MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Cohort Studies MH - Female MH - Humans MH - Kaplan-Meier Estimate MH - Male MH - Melanoma/dt [Drug Therapy] MH - Melanoma/mo [Mortality] MH - Middle Aged MH - *Pituitary Diseases/ci [Chemically Induced] MH - *Pituitary Diseases/dt [Drug Therapy] MH - Pituitary Diseases/mo [Mortality] MH - Retrospective Studies AB - PURPOSE: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS). AB - EXPERIMENTAL DESIGN: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan-Meier. AB - RESULTS: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5-36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms. AB - CONCLUSION: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given. AB - Copyright ©2014 American Association for Cancer Research. RN - 0 (Adrenal Cortex Hormones) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-14-2353 DO - https://dx.doi.org/10.1158/1078-0432.CCR-14-2353 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 25538262 [pubmed] ID - 1078-0432.CCR-14-2353 [pii] ID - 10.1158/1078-0432.CCR-14-2353 [doi] ID - PMC4334697 [pmc] ID - NIHMS651379 [mid] PP - ppublish GI - No: K08 HD070957 Organization: (HD) *NICHD NIH HHS* Country: United States LG - English EP - 20141223 DP - 2015 Feb 15 DC - 20150218 EZ - 2014/12/25 06:00 DA - 2015/12/15 06:00 DT - 2014/12/30 06:00 YR - 2015 ED - 20151209 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25538262 <181. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25792081 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wozniak S AU - Mackiewicz-Wysocka M AU - Krokowicz L AU - Kwinta L AU - Mackiewicz J FA - Wozniak, Sebastian FA - Mackiewicz-Wysocka, Malgorzata FA - Krokowicz, Lukasz FA - Kwinta, Lukasz FA - Mackiewicz, Jacek IN - Wozniak, Sebastian. Department of Chemotherapy, Greater Poland Cancer Centre, Poznan, Poland. TI - Febrile neutropenia in a metastatic melanoma patient treated with ipilimumab - case report. SO - Oncology Research and Treatment. 38(3):105-8, 2015 AS - Oncol Res Treat. 38(3):105-8, 2015 NJ - Oncology research and treatment PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101627692 IO - Oncol Res Treat SB - Index Medicus CP - Netherlands MH - Adult MH - Agranulocytosis/et [Etiology] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Axilla MH - *Febrile Neutropenia/et [Etiology] MH - Humans MH - *Immunologic Factors/ae [Adverse Effects] MH - Lymphatic Metastasis MH - Lymphocytes/pa [Pathology] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Monocytes/pa [Pathology] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/pa [Pathology] AB - BACKGROUND: Ipilimumab is a fully human monoclonal antibody (mAb) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab is currently approved in the U.S. and Europe for the treatment of metastatic melanoma in the first- and second-line treatment. Treatment with ipilimumab is linked to immune-related adverse events (irAEs) occurring in the majority of patients. These specific AEs include dermatitis, gastrointestinal disorders (diarrhea, colitis), hepatitis, hypophysitis, hypothyroidism, neuropathy, and iritis/inflammation of the ciliary body. AB - CASE REPORT: We report a case of febrile neutropenia with agranulocytosis in the blood smear of a 35-year-old metastatic melanoma patient treated with ipilimumab 3 mg/kg. AB - CONCLUSION: This AE was probably caused by antineutrophil antibodies associated with ipilimumab treatment. To our knowledge this is the first case report of febrile neutropenia in a metastatic melanoma patient treated with ipilimumab 3 mg/kg. AB - Copyright © 2015 S. Karger GmbH, Freiburg. RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunologic Factors) RN - 6T8C155666 (ipilimumab) ES - 2296-5262 IL - 2296-5270 DI - 000377650 DO - https://dx.doi.org/10.1159/000377650 PT - Case Reports PT - Journal Article ID - 25792081 [pubmed] ID - 000377650 [pii] ID - 10.1159/000377650 [doi] PP - ppublish PH - 2014/03/17 [received] PH - 2014/09/17 [accepted] LG - English EP - 20150220 DP - 2015 DC - 20150320 EZ - 2015/03/21 06:00 DA - 2015/12/15 06:00 DT - 2015/03/21 06:00 YR - 2015 ED - 20151208 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25792081 <182. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26629422 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Mamdani H AU - Induru R AU - Jalal SI FA - Mamdani, Hirva FA - Induru, Raghava FA - Jalal, Shadia I IN - Mamdani, Hirva. 1 Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA ; 2 Levine Cancer Institute, Carolinas HealthCare Systems, Albemarle, NC, USA. IN - Induru, Raghava. 1 Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA ; 2 Levine Cancer Institute, Carolinas HealthCare Systems, Albemarle, NC, USA. IN - Jalal, Shadia I. 1 Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA ; 2 Levine Cancer Institute, Carolinas HealthCare Systems, Albemarle, NC, USA. TI - Novel therapies in small cell lung cancer. [Review] SO - Translational Lung Cancer Research. 4(5):533-44, 2015 Oct AS - Transl. lung cancer res.. 4(5):533-44, 2015 Oct NJ - Translational lung cancer research PI - Journal available in: Print PI - Citation processed from: Print JC - 101646875 IO - Transl Lung Cancer Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630526 CP - China KW - Notch inhibition; PARP1 inhibition; Small cell lung cancer (SCLC); immune therapy; molecular targeted therapy AB - Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor of the lung with a tendency to metastasize widely early in the course of the disease. The VA staging system classifies the disease into limited stage (LS) which is confined to one hemithorax and can be included into one radiation field or extensive stage (ES) which extends beyond one hemithorax. Current standard of care is concurrent chemoradiation for LS disease and chemotherapy alone for ES disease. Only a quarter of patients with LS disease will be cured with current standard treatments and majority of the patients ultimately succumb to their disease. A very complex genetic landscape of SCLC accounts for its resistance to conventional therapy and a high recurrence rate, however, at the same time this complexity can form the basis for effective targeted therapy for the disease. In recent years, several different therapeutic strategies and targeted agents have been under investigation for their potential role in SCLC. Several of them including EGFR TKIs, BCR-ABL TKIs, mTOR inhibitors, and VEGF inhibitors have been unsuccessful in showing a survival advantage in this disease. Several others including DNA repair inhibitors, cellular developmental pathway inhibitors, antibody drug conjugates (ADCs), as well as immune therapy with vaccines, immunomodulators, and immune checkpoint inhibitors are being tested. So far, none of these agents are approved for use in SCLC and the majority are in phase I/II clinical trials, with immune checkpoint inhibitors being the most promising therapeutic strategy. In this article, we will discuss these novel therapeutic agents and currently available data in SCLC. IS - 2218-6751 IL - 2218-6751 DI - tlcr-04-05-533 DO - https://dx.doi.org/10.3978/j.issn.2218-6751.2015.07.20 PT - Journal Article PT - Review ID - 26629422 [pubmed] ID - 10.3978/j.issn.2218-6751.2015.07.20 [doi] ID - tlcr-04-05-533 [pii] ID - PMC4630526 [pmc] PP - ppublish LG - English DP - 2015 Oct DC - 20151202 EZ - 2015/12/03 06:00 DA - 2015/12/03 06:01 DT - 2015/12/03 06:00 YR - 2015 ED - 20151202 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26629422 <183. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26629425 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Villadolid J AU - Amin A FA - Villadolid, Jeryl FA - Amin, Asim IN - Villadolid, Jeryl. 1 Department of Pharmacy, 2 Divisions of Immunotherapy and Medical Oncology, Carolinas HealthCare System, Levine Cancer Institute, Charlotte, NC 28204, USA. IN - Amin, Asim. 1 Department of Pharmacy, 2 Divisions of Immunotherapy and Medical Oncology, Carolinas HealthCare System, Levine Cancer Institute, Charlotte, NC 28204, USA. TI - Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. [Review] SO - Translational Lung Cancer Research. 4(5):560-75, 2015 Oct AS - Transl. lung cancer res.. 4(5):560-75, 2015 Oct NJ - Translational lung cancer research PI - Journal available in: Print PI - Citation processed from: Print JC - 101646875 IO - Transl Lung Cancer Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630514 CP - China KW - Immunotherapy; checkpoint inhibition; toxicity AB - Immune checkpoint blockade using inhibitors of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) has shown clinically significant antitumor response and has been approved for the treatment of malignant melanoma and squamous non-small cell lung cancer (NSCLC). These immunotherapies are associated with unique set of toxicities termed immune-related adverse events (irAEs) that are very different from toxicities observed with conventional cytotoxic chemotherapy. Prompt recognition and initiation of appropriate management, usually in the form of immunosuppression, usually results in complete reversibility, but failing to do so can lead to severe toxicity or even death. Clinical algorithms describing the management of common irAEs have been published based on clinical trial information and experience in metastatic melanoma with ipilimumab, a human IgG1 monoclonal antibody that binds to CTLA-4 and blocks T cell inhibition. The most common irAEs reported with ipilimumab are dermatologic toxicity, diarrhea/colitis, hepatotoxicity, and endocrinopathies, although other sites can also be affected. Similar irAEs have been observed with agents targeting PD-1. Nivolumab and pembrolizumab are humanized monoclonal antibodies that bind to PD-1 and prevent T cell inactivation. Ipilimumab, pembrolizumab, and nivolumab are approved by the Food and Drug Administration (FDA) for the treatment of advanced melanoma; nivolumab was also recently approved for metastatic squamous NSCLC. This review describes the optimal management of toxicities related to immune checkpoint inhibition from FDA-approved agents targeting CTLA-4 and PD-1. IS - 2218-6751 IL - 2218-6751 DI - tlcr-04-05-560 DO - https://dx.doi.org/10.3978/j.issn.2218-6751.2015.06.06 PT - Journal Article PT - Review ID - 26629425 [pubmed] ID - 10.3978/j.issn.2218-6751.2015.06.06 [doi] ID - tlcr-04-05-560 [pii] ID - PMC4630514 [pmc] PP - ppublish LG - English DP - 2015 Oct DC - 20151202 EZ - 2015/12/03 06:00 DA - 2015/12/03 06:01 DT - 2015/12/03 06:00 YR - 2015 ED - 20151202 RD - 20151214 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26629425 <184. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26141863 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Koh SB AU - Courtin A AU - Boyce RJ AU - Boyle RG AU - Richards FM AU - Jodrell DI FA - Koh, Siang-Boon FA - Courtin, Aurelie FA - Boyce, Richard J FA - Boyle, Robert G FA - Richards, Frances M FA - Jodrell, Duncan I IN - Koh, Siang-Boon. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. IN - Courtin, Aurelie. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. IN - Boyce, Richard J. Sentinel Oncology Limited, Cambridge, United Kingdom. IN - Boyle, Robert G. Sentinel Oncology Limited, Cambridge, United Kingdom. IN - Richards, Frances M. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. Fran.Richards@cruk.cam.ac.uk. IN - Jodrell, Duncan I. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. TI - CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus. SO - Cancer Research. 75(17):3583-95, 2015 Sep 01 AS - Cancer Res. 75(17):3583-95, 2015 Sep 01 NJ - Cancer research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnf, 2984705r IO - Cancer Res. SB - Index Medicus CP - United States MH - Antineoplastic Agents/ad [Administration & Dosage] MH - Cell Division MH - Cell Line, Tumor MH - Checkpoint Kinase 1 MH - DNA Damage/de [Drug Effects] MH - DNA Replication/de [Drug Effects] MH - Deoxycytidine/ad [Administration & Dosage] MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - *Drug Synergism MH - G2 Phase/de [Drug Effects] MH - Humans MH - Mitosis/de [Drug Effects] MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/pa [Pathology] MH - Phosphorylation/de [Drug Effects] MH - Protein Kinase Inhibitors/ad [Administration & Dosage] MH - *Protein Kinases/de [Drug Effects] MH - Tumor Suppressor Protein p53/ge [Genetics] AB - Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G2-M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G2-M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S-G2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a "foot-in-the-door" mechanism for drug synergy where cells were destroyed not by frank G2-M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis. AB - Copyright ©2015 American Association for Cancer Research. RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) ES - 1538-7445 IL - 0008-5472 DI - 0008-5472.CAN-14-3347 DO - https://dx.doi.org/10.1158/0008-5472.CAN-14-3347 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26141863 [pubmed] ID - 0008-5472.CAN-14-3347 [pii] ID - 10.1158/0008-5472.CAN-14-3347 [doi] PP - ppublish PH - 2014/11/13 [received] PH - 2015/06/01 [accepted] GI - No: C14303/A17197 Organization: *Cancer Research UK* Country: United Kingdom LG - English EP - 20150703 DP - 2015 Sep 01 DC - 20150902 EZ - 2015/07/05 06:00 DA - 2015/12/15 06:00 DT - 2015/07/05 06:00 YR - 2015 ED - 20151125 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26141863 <185. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26317466 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Chiappinelli KB AU - Strissel PL AU - Desrichard A AU - Li H AU - Henke C AU - Akman B AU - Hein A AU - Rote NS AU - Cope LM AU - Snyder A AU - Makarov V AU - Budhu S AU - Slamon DJ AU - Wolchok JD AU - Pardoll DM AU - Beckmann MW AU - Zahnow CA AU - Merghoub T AU - Chan TA AU - Baylin SB AU - Strick R FA - Chiappinelli, Katherine B FA - Strissel, Pamela L FA - Desrichard, Alexis FA - Li, Huili FA - Henke, Christine FA - Akman, Benjamin FA - Hein, Alexander FA - Rote, Neal S FA - Cope, Leslie M FA - Snyder, Alexandra FA - Makarov, Vladimir FA - Budhu, Sadna FA - Slamon, Dennis J FA - Wolchok, Jedd D FA - Pardoll, Drew M FA - Beckmann, Matthias W FA - Zahnow, Cynthia A FA - Merghoub, Taha FA - Chan, Timothy A FA - Baylin, Stephen B FA - Strick, Reiner IN - Chiappinelli, Katherine B. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. IN - Strissel, Pamela L. Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany. IN - Desrichard, Alexis. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. IN - Li, Huili. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. IN - Henke, Christine. Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany. IN - Akman, Benjamin. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. IN - Hein, Alexander. Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany. IN - Rote, Neal S. Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH 44106, USA. IN - Cope, Leslie M. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. IN - Snyder, Alexandra. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. IN - Makarov, Vladimir. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. IN - Buhu, Sadna. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. IN - Slamon, Dennis J. The Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA 90095, USA. IN - Wolchok, Jedd D. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. IN - Pardoll, Drew M. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. IN - Beckmann, Matthias W. Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany. IN - Zahnow, Cynthia A. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. IN - Mergoub, Taha. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. IN - Chan, Timothy A. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. IN - Baylin, Stephen B. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu. IN - Strick, Reiner. Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University-Clinic Erlangen, 91054 Erlangen, Germany. Electronic address: reiner.strick@uk-erlangen.de. TI - Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses.[Erratum appears in Cell. 2016 Feb 25;164(5):1073 Note: Buhu, Sadna [corrected to Budhu, Sadna]; Mergoub, Taha [corrected to Merghoub, Taha]; PMID: 27064190] CM - Comment in: Cell. 2015 Aug 27;162(5):938-9; PMID: 26317460 SO - Cell. 162(5):974-86, 2015 Aug 27 AS - Cell. 162(5):974-86, 2015 Aug 27 NJ - Cell PI - Journal available in: Print PI - Citation processed from: Internet JC - cq4, 0413066 IO - Cell PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556003 OI - Source: NLM. NIHMS707501 SB - Index Medicus CP - United States MH - Animals MH - Azacitidine/pd [Pharmacology] MH - Cell Line, Tumor MH - *DNA Methylation/de [Drug Effects] MH - DNA Modification Methylases/ai [Antagonists & Inhibitors] MH - Endogenous Retroviruses/ge [Genetics] MH - Female MH - Humans MH - Immunotherapy MH - *Interferon Type I/im [Immunology] MH - Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/im [Immunology] MH - *Melanoma/im [Immunology] MH - *Melanoma/th [Therapy] MH - Mice MH - Mice, Inbred C57BL MH - Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/th [Therapy] MH - RNA, Double-Stranded/me [Metabolism] AB - We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model. AB - Copyright © 2015 Elsevier Inc. All rights reserved. RN - 0 (Interferon Type I) RN - 0 (RNA, Double-Stranded) RN - EC 2-1-1 (DNA Modification Methylases) RN - M801H13NRU (Azacitidine) ES - 1097-4172 IL - 0092-8674 DI - S0092-8674(15)00848-X DO - https://dx.doi.org/10.1016/j.cell.2015.07.011 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. ID - 26317466 [pubmed] ID - S0092-8674(15)00848-X [pii] ID - 10.1016/j.cell.2015.07.011 [doi] ID - PMC4556003 [pmc] ID - NIHMS707501 [mid] PP - ppublish PH - 2014/12/19 [received] PH - 2015/05/04 [revised] PH - 2015/06/26 [accepted] GI - No: F32CA183214 Organization: (CA) *NCI NIH HHS* Country: United States No: CA058184 Organization: (CA) *NCI NIH HHS* Country: United States No: F32 CA183214 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA058184 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2015 Aug 27 DC - 20150831 EZ - 2015/08/29 06:00 DA - 2015/12/15 06:00 DT - 2015/09/01 06:00 YR - 2015 ED - 20151124 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26317466 <186. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25822767 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Peper JK AU - Stevanovic S FA - Peper, Janet Kerstin FA - Stevanovic, Stefan IN - Peper, Janet Kerstin. Department of Immunology, Institute of Cell Biology, University of Tubingen, Auf der Morgenstelle 15, 72076, Tubingen, Germany, janet-peper@gmx.de. TI - A combined approach of human leukocyte antigen ligandomics and immunogenicity analysis to improve peptide-based cancer immunotherapy. [Review] SO - Cancer Immunology, Immunotherapy. 64(10):1295-303, 2015 Oct AS - Cancer Immunol Immunother. 64(10):1295-303, 2015 Oct NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. SB - Index Medicus CP - Germany MH - Animals MH - Antigens, Neoplasm/me [Metabolism] MH - Clinical Trials as Topic MH - Female MH - HLA Antigens/me [Metabolism] MH - Humans MH - *Immunotherapy/mt [Methods] MH - Immunotherapy/td [Trends] MH - Ligands MH - Molecular Targeted Therapy MH - Ovarian Neoplasms/im [Immunology] MH - *Ovarian Neoplasms/th [Therapy] MH - Peptide Fragments/me [Metabolism] MH - *Vaccines, Subunit AB - The breakthrough development of immune checkpoint inhibitors as clinically effective novel therapies demonstrates the potential of cancer immunotherapy. The identification of suitable targets for specific immunotherapy, however, remains a challenging task. Most peptides previously used for vaccination in clinical trials were able to elicit strong immunological responses but failed with regard to clinical benefit. This might, at least partly, be caused by an inadequate peptide selection, usually derived from established tumor-associated antigens which are not necessarily presented as human leukocyte antigen (HLA) ligands. Recently, HLA ligandome analysis revealed cancer-associated peptides, which have been used in clinical trials showing encouraging impact on survival. To improve peptide-based cancer immunotherapy, our group established a combined approach of HLA ligandomics and immunogenicity analysis for the identification of vaccine peptides. This approach is based on the identification of naturally presented HLA ligands on tumor samples, the selection of tumor-associated/tumor-specific HLA ligands and their subsequent testing for immunogenicity in vitro. In this review, we want to present our pipeline for the identification of vaccine peptides, focusing on ovarian cancer, and want to discuss differences to other approaches. Furthermore, we want to give a short outlook of a potential multi-peptide vaccination trial using the novel identified peptides. RN - 0 (Antigens, Neoplasm) RN - 0 (HLA Antigens) RN - 0 (Ligands) RN - 0 (Peptide Fragments) RN - 0 (Vaccines, Subunit) ES - 1432-0851 IL - 0340-7004 DO - https://dx.doi.org/10.1007/s00262-015-1682-8 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 25822767 [pubmed] ID - 10.1007/s00262-015-1682-8 [doi] PP - ppublish PH - 2015/01/30 [received] PH - 2015/03/10 [accepted] LG - English EP - 20150331 DP - 2015 Oct DC - 20150901 EZ - 2015/03/31 06:00 DA - 2015/11/18 06:00 DT - 2015/03/31 06:00 YR - 2015 ED - 20151117 RD - 20150901 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25822767 <187. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25998800 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Mony JT AU - Zhang L AU - Ma T AU - Grabosch S AU - Tirodkar TS AU - Brozick J AU - Tseng G AU - Elishaev E AU - Edwards RP AU - Huang X AU - Vlad AM FA - Mony, Jyothi Thyagabhavan FA - Zhang, Lixin FA - Ma, Tianzhou FA - Grabosch, Shannon FA - Tirodkar, Tejas S FA - Brozick, Joan FA - Tseng, George FA - Elishaev, Esther FA - Edwards, Robert P FA - Huang, Xin FA - Vlad, Anda M IN - Mony, Jyothi Thyagabhavan. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, 204 Craft Ave, Pittsburgh, PA, 15213, USA. TI - Anti-PD-L1 prolongs survival and triggers T cell but not humoral anti-tumor immune responses in a human MUC1-expressing preclinical ovarian cancer model. SO - Cancer Immunology, Immunotherapy. 64(9):1095-108, 2015 Sep AS - Cancer Immunol Immunother. 64(9):1095-108, 2015 Sep NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4545381 OI - Source: NLM. NIHMS693558 SB - Index Medicus CP - Germany MH - Animals MH - *Antibodies, Monoclonal/im [Immunology] MH - *Antibodies, Monoclonal/pd [Pharmacology] MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Antigens, CD274/im [Immunology] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - Disease Models, Animal MH - Female MH - Humans MH - Mice MH - Mucin-1/bi [Biosynthesis] MH - Mucin-1/ge [Genetics] MH - Mucin-1/im [Immunology] MH - *Ovarian Neoplasms/im [Immunology] MH - *Ovarian Neoplasms/th [Therapy] AB - Monoclonal antibodies that block inhibitory immune checkpoint molecules and enhance anti-tumor responses show clinical promise in advanced solid tumors. Most of the preliminary evidence on therapeutic efficacy of immune checkpoint blockers comes from studies in melanoma, lung and renal cancer. To test the in vivo potential of programmed death-ligand 1 (PD-L1) blockade in ovarian cancer, we recently generated a new transplantable tumor model using human mucin 1 (MUC1)-expressing 2F8 cells. The MUC1 transgenic (MUC1.Tg) mice develop large number of intraperitoneal (IP) tumors following IP injection of 8 x 10(5) syngeneic 2F8 cells. The tumors are aggressive and display little T cell infiltration. Anti-PD-L1 antibody was administered IP every 2 weeks (200 mug/dose) for a total of three doses. Treatment was started 21 days post-tumor challenge, a time point which corresponds to late tumor stage. The anti-PD-L1 treatment led to substantial T cell infiltration within the tumor and significantly increased survival (p = 0.001) compared to isotype control-treated mice. When the same therapy was administered to wild-type mice challenged with 2F8 tumors, no survival benefit was observed, despite the presence of high titer anti-MUC1 antibodies. However, earlier treatment (day 11) and higher frequency of IP injections restored the T cell responses and led to prolonged survival. Splenocyte profiling via Nanostring using probes for 511 immune genes revealed a treatment-induced immune gene signature consistent with increased T cell-mediated immunity. These findings strongly support further preclinical and clinical strategies exploring PD-L1 blockade in ovarian cancer. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD274) RN - 0 (MUC1 protein, human) RN - 0 (Mucin-1) ES - 1432-0851 IL - 0340-7004 DO - https://dx.doi.org/10.1007/s00262-015-1712-6 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. ID - 25998800 [pubmed] ID - 10.1007/s00262-015-1712-6 [doi] ID - PMC4545381 [pmc] ID - NIHMS693558 [mid] PP - ppublish PH - 2014/10/23 [received] PH - 2015/05/06 [accepted] GI - No: UL1 TR000005 Organization: (TR) *NCATS NIH HHS* Country: United States No: R01CA163462 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA159981 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA047904 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA163462 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20150522 DP - 2015 Sep DC - 20150819 EZ - 2015/05/23 06:00 DA - 2015/11/14 06:00 DT - 2015/05/23 06:00 YR - 2015 ED - 20151113 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25998800 <188. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25631244 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Stahl T AU - Loquai C FA - Stahl, T FA - Loquai, C IN - Stahl, T. Zentralinstitut fur diagnostische und interventionelle Radiologie, Klinikum der Stadt Ludwigshafen gGmbH, Bremserstr. 79, 67063, Ludwigshafen, Deutschland, stahlt@klilu.de. TI - [Treatment side effects and follow-up of malignant melanoma]. [German] OT - Therapienebenwirkungen und Nachsorge bei malignem Melanom. SO - Radiologe. 55(2):136-43, 2015 Feb AS - Radiologe. 55(2):136-43, 2015 Feb NJ - Der Radiologe PI - Journal available in: Print PI - Citation processed from: Internet JC - qrl, 0401257 IO - Radiologe SB - Index Medicus CP - Germany MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Diagnosis, Differential MH - *Diagnostic Imaging/mt [Methods] MH - Drug Monitoring/mt [Methods] MH - Humans MH - *Inflammation/ci [Chemically Induced] MH - *Inflammation/di [Diagnosis] MH - Melanoma/di [Diagnosis] MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/sc [Secondary] MH - Treatment Outcome AB - Side effects in the therapy of malignant melanoma are primarily of importance for radiologists in advanced tumor stages. The available treatment options and their respective side effect profiles have undergone a profound change in recent years after the introduction of modern oncological therapies (e.g. immunotherapy and targeted therapy) with an increasing focus on individual tumor biology and differ significantly from those of classical chemotherapy. The immunotherapeutic agents, in particular ipilimumab, take on a special position because of their specific immune-mediated mechanisms of action and the associated side effects, so-called immune-related adverse events (irAE). The majority of the treatment effects are manifested on the skin (>50%) and are generally not detectable by diagnostic radiology. Only a comparatively small proportion of treatment side effects is detectable with diagnostic imaging (15-20%) but as in the example of therapy-induced colitis with ipilimumab, may be rapidly fatal. In addition to colitis (10-20%) further therapy side effects apparent in diagnostic imaging are hypophysitis (1.8-17%), thyroiditis (0.8%), myositis (1.7%), fasciitis and sarcoid-like lymph node alterations (6.8%). To detect radiologically detectable side effects early on and to delineate them especially from tumor progression and (opportunistic) infections, detailed knowledge of the therapeutic methods for melanoma, the mechanisms of action and in particular the sometimes very specific side effects is imperative for radiologists. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) ES - 1432-2102 IL - 0033-832X DO - https://dx.doi.org/10.1007/s00117-014-2764-x PT - English Abstract PT - Journal Article ID - 25631244 [pubmed] ID - 10.1007/s00117-014-2764-x [doi] PP - ppublish LG - German DP - 2015 Feb DC - 20150219 EZ - 2015/01/30 06:00 DA - 2015/11/11 06:00 DT - 2015/01/30 06:00 YR - 2015 ED - 20151110 RD - 20150219 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25631244 <189. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25589420 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Breckwoldt M AU - Bendszus M FA - Breckwoldt, M FA - Bendszus, M IN - Breckwoldt, M. Abteilung Neuroradiologie, Neurologische Klinik, Universitatsklinikum Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Deutschland, michael.breckwoldt@med.uni-heidelberg.de. TI - [Cerebral MR imaging of malignant melanoma]. [German] OT - Zerebrale MR-Bildgebung beim malignen Melanom. SO - Radiologe. 55(2):113-9, 2015 Feb AS - Radiologe. 55(2):113-9, 2015 Feb NJ - Der Radiologe PI - Journal available in: Print PI - Citation processed from: Internet JC - qrl, 0401257 IO - Radiologe SB - Index Medicus CP - Germany MH - *Brain Neoplasms/di [Diagnosis] MH - *Brain Neoplasms/sc [Secondary] MH - Diagnosis, Differential MH - Humans MH - Image Enhancement/mt [Methods] MH - *Magnetic Resonance Imaging/mt [Methods] MH - *Melanoma/di [Diagnosis] MH - *Melanoma/sc [Secondary] MH - *Tomography, X-Ray Computed/mt [Methods] AB - CLINICAL/METHODICAL ISSUE: Melanoma is the third leading cancer entity to metastasize to the central nervous system (CNS) after lung and breast cancer. This is often an early event in the disease course and limits survival. Metastasis in the CNS is the cause of death in 10-40% of melanoma patients and the incidence of brain metastasis is even higher (50-75%). Cerebral metastases are commonly found in the subcortical white matter. The signal characteristics can vary substantially and may change over time due to hemorrhages or the accumulation of melanin and paramagnetic ions. It is not yet clear whether novel targeted therapies (e.g. immunotherapy and kinase inhibitors) alter imaging characteristics. Also immune-related side effects, such as hypophysitis (in approximately 5% of patients receiving ipilimumab therapy) or granulomatous disease (neurosarcoid) can occur. AB - STANDARD RADIOLOGICAL METHODS: Melanoma metastases are usually hyperdense in computed tomography (CT). In magnetic resonance imaging (MRI) T2-weighted (T2-w) fluid-attentuated inversion recovery (FLAIR) and T1-w sequences (with and without i.v. contrast) should be obtained. Coronal and axial imaging planes should be scanned to cross-correlate findings. AB - METHODICAL INNOVATIONS: Susceptibility-weighted imaging is a new sensitive method to detect melanoma metastases. Approximately 66% of melanoma metastases show intratumoral susceptibility signals (ITSS). This sets them apart from other metastases (e.g. lung and breast cancer show less ITSSs, specificity approximately 81-96%). Diffusion imaging plays no major role in melanoma brain imaging. AB - PERFORMANCE: Susceptibility-weighted imaging increases the sensitivity to detect metastases but lacks specificity. Differentiating metastases, microbleeding or calcification can be impossible. It is controversial how to interpret susceptibility signals without correlative signs on other sequences (differential diagnosis: metastasis, microbleeding and calcification). AB - PRACTICAL RECOMMENDATIONS: CNS metastases are common in melanoma. MRI screening starting in stage IIc should be considered even in asymptomatic patients. Stage IV requires quarterly MRI examinations. Melanotic and amelanotic metastases show different MRI characteristics. The differentiation between metastasis and microbleeding can be impossible and might require a follow-up scan. Susceptibility-weighted imaging increases the sensitivity of metastases detection but lacks specificity. It can help to differentiate between different metastatic entities. ES - 1432-2102 IL - 0033-832X DO - https://dx.doi.org/10.1007/s00117-014-2761-0 PT - English Abstract PT - Journal Article ID - 25589420 [pubmed] ID - 10.1007/s00117-014-2761-0 [doi] PP - ppublish LG - German DP - 2015 Feb DC - 20150219 EZ - 2015/01/16 06:00 DA - 2015/11/11 06:00 DT - 2015/01/16 06:00 YR - 2015 ED - 20151110 RD - 20150219 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25589420 <190. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23714523 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Chow LQ FA - Chow, Laura Q M IN - Chow, Laura Q M. From the Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA. TI - Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung cancer. [Review] SO - American Society of Clinical Oncology Educational Book. , 2013 AS - Am. Soc. Clin. Oncol. educ. book. , 2013 NJ - American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting PI - Journal available in: Print PI - Citation processed from: Internet JC - 101233985 IO - Am Soc Clin Oncol Educ Book SB - Index Medicus CP - United States MH - Animals MH - *Antibodies/ae [Adverse Effects] MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antigens, CD274/im [Immunology] MH - Antigens, CD274/me [Metabolism] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Apoptosis/de [Drug Effects] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - CTLA-4 Antigen/me [Metabolism] MH - *Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/im [Immunology] MH - Carcinoma, Non-Small-Cell Lung/me [Metabolism] MH - Carcinoma, Non-Small-Cell Lung/pa [Pathology] MH - Humans MH - *Immunotherapy/ae [Adverse Effects] MH - *Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/im [Immunology] MH - Lung Neoplasms/me [Metabolism] MH - Lung Neoplasms/pa [Pathology] MH - Lymphocyte Activation/de [Drug Effects] MH - Molecular Targeted Therapy/ae [Adverse Effects] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - Risk Factors MH - Signal Transduction/de [Drug Effects] MH - Treatment Outcome AB - Because of dramatic tumor regressions reported with the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PDL-1) antibodies inhibiting the PD-1 immune checkpoint, non-small cell lung cancer (NSCLC) is now recognized as an immune-modifiable disease. As responses were observed in smaller numbers in phase I trials, the immunologic profiles and unique toxicities of these agents have not been fully established in NSCLC. Moreover, PD-1 checkpoint inhibitors in development by different companies may demonstrate diverse spectrums of activity and toxicity. Although the cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors in earlier phase studies appeared to have less impressive responses in NSCLC, their safety profile has been more broadly defined. The anti-CTLA-4 antibody, ipilimumab, has the best characterized immune-related toxicities (predominantly skin, gastrointestinal, hepatic, and endocrine) and management strategies in melanoma. Despite the lack of studies directly comparing these agents, toxicities from PD-1 inhibition seem milder than those of CTLA-4 inhibition, with distinct toxicities of pneumonitis infrequently observed with the BMS-936558 anti-PD-1 antibody, nivolumamb, and frequent mild infusion reactions reported with the BMS-936559 anti-PDL-1 antibody. As lungs are critical organs often already compromised in NSCLC patients, immune-mediated pneumonitis can cause worrisome morbidity and mortality. Even though immune checkpoint inhibitors are being rapidly developed in a multitude of trials, optimal immune-mediated toxicity management has not been determined, is evolving, and will be further explored. Early diagnosis and symptom management with corticosteroids form the basis of treatment. Assessment of new immune-response criteria and use of primary endpoints of overall survival (OS) will be important in the development of these immunotherapies in NSCLC. RN - 0 (Antibodies) RN - 0 (Antigens, CD274) RN - 0 (Antineoplastic Agents) RN - 0 (CD274 protein, human) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1548-8756 IL - 1548-8748 DI - 0011300280 DO - https://dx.doi.org/10.1200/EdBook_AM.2013.33.e280 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PT - Video-Audio Media ID - 23714523 [pubmed] ID - 0011300280 [pii] ID - 10.1200/EdBook_AM.2013.33.e280 [doi] PP - ppublish LG - English DP - 2013 DC - 20140219 EZ - 2013/05/30 06:00 DA - 2015/11/04 06:00 DT - 2013/05/30 06:00 YR - 2013 ED - 20151103 RD - 20161021 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23714523 <191. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26171934 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Fankhauser CD AU - Curioni-Fontecedro A AU - Allmann V AU - Beyer J AU - Tischler V AU - Sulser T AU - Moch H AU - Bode PK FA - Fankhauser, C D FA - Curioni-Fontecedro, A FA - Allmann, V FA - Beyer, J FA - Tischler, V FA - Sulser, T FA - Moch, H FA - Bode, P K IN - Fankhauser, C D. Department of Urology, University Hospital Zurich, Zurich, Switzerland. IN - Curioni-Fontecedro, A. Department of Oncology, University Hospital Zurich, Zurich, Switzerland. IN - Allmann, V. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. IN - Beyer, J. Department of Oncology, University Hospital Zurich, Zurich, Switzerland. IN - Tischler, V. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. IN - Sulser, T. Department of Urology, University Hospital Zurich, Zurich, Switzerland. IN - Moch, H. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. IN - Bode, P K. Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. TI - Frequent PD-L1 expression in testicular germ cell tumors. SO - British Journal of Cancer. 113(3):411-3, 2015 Jul 28 AS - Br J Cancer. 113(3):411-3, 2015 Jul 28 NJ - British journal of cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - av4, 0370635 IO - Br. J. Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522642 SB - Index Medicus CP - England MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antigens, CD274/me [Metabolism] MH - Humans MH - Immunohistochemistry MH - Male MH - Middle Aged MH - *Neoplasms, Germ Cell and Embryonal/ep [Epidemiology] MH - *Neoplasms, Germ Cell and Embryonal/me [Metabolism] MH - Neoplasms, Germ Cell and Embryonal/pa [Pathology] MH - Seminoma/ep [Epidemiology] MH - Seminoma/me [Metabolism] MH - Seminoma/pa [Pathology] MH - *Testicular Neoplasms/ep [Epidemiology] MH - *Testicular Neoplasms/me [Metabolism] MH - Testicular Neoplasms/pa [Pathology] MH - Testis/me [Metabolism] MH - Testis/pa [Pathology] MH - Tissue Array Analysis MH - Young Adult AB - BACKGROUND: Many testicular germ cell cancers are curable despite metastatic disease, but about 10-15% of patients fail cisplatin-based first-line treatment. Immunotherapy is considered as additional treatment approach for these patients. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. We analysed the expression of PD-L1 in testicular germ cell tumours to evaluate its potential as target for immunotherapeutic strategies. AB - METHODS: Immunohistochemistry was performed in 479 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody (E1L3N). The tissue microarray consisted of 208 pure seminomas, 121 non-seminomas, 20 intratubular germ cell neoplasia unclassified (IGCNU) and 20 specimens of non-neoplastic testicular tissue. AB - RESULTS: Programmed Death Receptor Ligand-1 expression was found in 73% of all seminomas and in 64% of all non-seminomas. None of 20 IGCNU and none of 20 normal tissue specimens exhibited PD-L1 expression. PD-L1 positive stromal cells were only detected in seminomas, but not in non-seminomas. The anti PD-L1 antibody showed a pre-dominantly membranous staining pattern in testicular tumour cells, as well as expression in stromal cells. AB - CONCLUSIONS: This frequent expression of PD-L1 in human testicular germ cell tumours suggests that patients with testicular germ cell tumours could profit from immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies. RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RS - Testicular Germ Cell Tumor ES - 1532-1827 IL - 0007-0920 DI - bjc2015244 DO - https://dx.doi.org/10.1038/bjc.2015.244 PT - Journal Article ID - 26171934 [pubmed] ID - bjc2015244 [pii] ID - 10.1038/bjc.2015.244 [doi] ID - PMC4522642 [pmc] PP - ppublish PH - 2015/05/18 [revised] PH - 2015/06/11 [accepted] LG - English EP - 20150714 DP - 2015 Jul 28 DC - 20150729 EZ - 2015/07/15 06:00 DA - 2015/10/16 06:00 DT - 2015/07/15 06:00 YR - 2015 ED - 20151014 RD - 20160728 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26171934 <192. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25751110 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Orlov S AU - Salari F AU - Kashat L AU - Walfish PG FA - Orlov, Steven FA - Salari, Farnaz FA - Kashat, Lawrence FA - Walfish, Paul G IN - Orlov, Steven. Department of Medicine (S.O., F.S., L.K., P.G.W.), Endocrine Division, and Otolaryngology-Head and Neck Surgery Program (P.G.W.), Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada and University of Toronto School of Medicine, Toronto, ON M5S 1A8, Canada. TI - Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. SO - Journal of Clinical Endocrinology & Metabolism. 100(5):1738-41, 2015 May AS - J Clin Endocrinol Metab. 100(5):1738-41, 2015 May NJ - The Journal of clinical endocrinology and metabolism PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hrb, 0375362 IO - J. Clin. Endocrinol. Metab. SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Female MH - Humans MH - *Immunotherapy/ae [Adverse Effects] MH - Immunotherapy/mt [Methods] MH - Lung Neoplasms/dt [Drug Therapy] MH - Male MH - Melanoma/dt [Drug Therapy] MH - Middle Aged MH - *Neoplasm Metastasis/dt [Drug Therapy] MH - *Programmed Cell Death 1 Receptor/im [Immunology] MH - Skin Neoplasms/dt [Drug Therapy] MH - *Thyroiditis/ci [Chemically Induced] MH - Thyroiditis/im [Immunology] MH - *Thyrotoxicosis/ci [Chemically Induced] MH - Thyrotoxicosis/im [Immunology] AB - CONTEXT: Immunotherapies against immune checkpoints that inhibit T cell activation [cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1)] are emerging and promising treatments for several metastatic malignancies. However, the precise adverse effects of these therapies on thyroid gland function have not been well described. AB - CASE DESCRIPTION: We report on 10 cases of painless thyroiditis syndrome (PTS) from a novel etiology, following immunotherapy with anti-PD-1 monoclonal antibodies (mAb) during treatment for metastatic malignancies. Six patients presented with transient thyrotoxicosis in which thyrotropin binding inhibitory immunoglobulins (TBII) were absent for all, whereas four patients had evidence of positive antithyroid antibodies. All thyrotoxic patients required temporary beta-blocker therapy and had spontaneous resolution of thyrotoxicosis with subsequent hypothyroidism. Four patients presented with hypothyroidism without a detected preceding thyrotoxic phase, occurring 6-8 weeks after initial drug exposure. All of these patients had positive antithyroid antibodies and required thyroid hormone replacement therapy for a minimum of 6 months. AB - CONCLUSIONS: Patients receiving anti-PD-1 mAb therapy should be monitored for signs and symptoms of PTS which may require supportive treatment with beta-blockers or thyroid hormone replacement. The anti-PD-1 mAb is a novel exogenous cause of PTS and provides new insight into the possible perturbations of the immune network that may modulate the development of endogenous PTS, including cases of sporadic and postpartum thyroiditis. RN - 0 (Antibodies, Monoclonal) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1945-7197 IL - 0021-972X DO - https://dx.doi.org/10.1210/jc.2014-4560 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25751110 [pubmed] ID - 10.1210/jc.2014-4560 [doi] PP - ppublish LG - English EP - 20150309 DP - 2015 May DC - 20150509 EZ - 2015/03/10 06:00 DA - 2015/10/01 06:00 DT - 2015/03/10 06:00 YR - 2015 ED - 20150930 RD - 20150509 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25751110 <193. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25828465 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Martin-Liberal J AU - Furness AJ AU - Joshi K AU - Peggs KS AU - Quezada SA AU - Larkin J FA - Martin-Liberal, Juan FA - Furness, Andrew Js FA - Joshi, Kroopa FA - Peggs, Karl S FA - Quezada, Sergio A FA - Larkin, James IN - Martin-Liberal, Juan. Renal and Melanoma Unit, The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK. TI - Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. SO - Cancer Immunology, Immunotherapy. 64(6):765-7, 2015 Jun AS - Cancer Immunol Immunother. 64(6):765-7, 2015 Jun NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. SB - Index Medicus CP - Germany MH - *Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *Diabetes Mellitus, Type 1/ci [Chemically Induced] MH - Diabetes Mellitus, Type 1/im [Immunology] MH - Female MH - Humans MH - Melanoma/dt [Drug Therapy] MH - Middle Aged MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Treatment Outcome AB - The anti programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab have been recently licensed by the Food and Drug Administration for the treatment of advanced melanoma. Immune checkpoint inhibitors such as these can induce endocrine adverse events but autoimmune diabetes has not been described to date. However, there is a strong preclinical rationale that supports this autoimmune toxicity. We describe for the first time the case of an adult patient who developed autoimmune diabetes likely as a consequence of PD-1 inhibition with pembrolizumab. The presence of high serum titres of anti-glutamic acid decarboxylase antibodies together with a suggestive clinical presentation, age of the patient and preclinical data strongly support an autoimmune aetiology of the diabetes. Moreover, the patient was found to have a well-known high-risk human leucocyte antigen type for the development of type 1 diabetes in children, so the PD-1 inhibition is very likely to have triggered the autoimmune phenomenon. Our case suggests that insulin-dependent diabetes might be a rare but important anti-PD-1 immune-related adverse event. RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - DPT0O3T46P (pembrolizumab) ES - 1432-0851 IL - 0340-7004 DO - https://dx.doi.org/10.1007/s00262-015-1689-1 PT - Case Reports PT - Journal Article ID - 25828465 [pubmed] ID - 10.1007/s00262-015-1689-1 [doi] PP - ppublish PH - 2015/02/02 [received] PH - 2015/03/21 [accepted] GI - No: 12100 Organization: *Cancer Research UK* Country: United Kingdom LG - English EP - 20150401 DP - 2015 Jun DC - 20150605 EZ - 2015/04/02 06:00 DA - 2015/09/04 06:00 DT - 2015/04/02 06:00 YR - 2015 ED - 20150902 RD - 20161122 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25828465 <194. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25795132 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Aguilar LK AU - Shirley LA AU - Chung VM AU - Marsh CL AU - Walker J AU - Coyle W AU - Marx H AU - Bekaii-Saab T AU - Lesinski GB AU - Swanson B AU - Sanchez D AU - Manzanera AG AU - Aguilar-Cordova E AU - Bloomston M FA - Aguilar, Laura K FA - Shirley, Lawrence A FA - Chung, Vincent M FA - Marsh, Christopher L FA - Walker, Jon FA - Coyle, Walter FA - Marx, Howard FA - Bekaii-Saab, Tanios FA - Lesinski, Gregory B FA - Swanson, Benjamin FA - Sanchez, Daniel FA - Manzanera, Andrea G FA - Aguilar-Cordova, Estuardo FA - Bloomston, Mark IN - Aguilar, Laura K. Advantagene, Inc., Auburndale, MA, 02466, USA. TI - Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma. SO - Cancer Immunology, Immunotherapy. 64(6):727-36, 2015 Jun AS - Cancer Immunol Immunother. 64(6):727-36, 2015 Jun NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. SB - Index Medicus CP - Germany MH - Acyclovir/ad [Administration & Dosage] MH - *Acyclovir/aa [Analogs & Derivatives] MH - Adenocarcinoma/ge [Genetics] MH - Adenocarcinoma/im [Immunology] MH - Adenocarcinoma/pa [Pathology] MH - Adenocarcinoma/su [Surgery] MH - *Adenocarcinoma/th [Therapy] MH - Adenoviridae/ge [Genetics] MH - Adenoviridae/im [Immunology] MH - Adult MH - Aged MH - Chemoradiotherapy MH - Combined Modality Therapy MH - Dose-Response Relationship, Drug MH - Female MH - *Genetic Therapy/mt [Methods] MH - Genetic Vectors/ge [Genetics] MH - Genetic Vectors/im [Immunology] MH - Humans MH - Immunohistochemistry MH - *Immunotherapy/mt [Methods] MH - Male MH - Middle Aged MH - Neoplasm Recurrence, Local MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/su [Surgery] MH - *Pancreatic Neoplasms/th [Therapy] MH - Thymidine Kinase/ge [Genetics] MH - Valine/ad [Administration & Dosage] MH - *Valine/aa [Analogs & Derivatives] AB - BACKGROUND: While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer. AB - METHODS: Four dose levels (3 x 10(10) to 1 x 10(12) vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug. AB - RESULTS: Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8(+) T cell infiltration increased an average of 22-fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration. AB - CONCLUSIONS: AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer. RN - EC 2-7-1-21 (Thymidine Kinase) RN - HG18B9YRS7 (Valine) RN - MZ1IW7Q79D (valacyclovir) RN - X4HES1O11F (Acyclovir) RS - Pancreatic Carcinoma ES - 1432-0851 IL - 0340-7004 DO - https://dx.doi.org/10.1007/s00262-015-1679-3 PT - Clinical Trial PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 25795132 [pubmed] ID - 10.1007/s00262-015-1679-3 [doi] PP - ppublish PH - 2014/11/19 [received] PH - 2015/03/04 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00638612 SL - https://clinicaltrials.gov/search/term=NCT00638612 GI - No: R43CA119847 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20150321 DP - 2015 Jun DC - 20150605 EZ - 2015/03/22 06:00 DA - 2015/09/04 06:00 DT - 2015/03/22 06:00 YR - 2015 ED - 20150902 RD - 20150605 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25795132 <195. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25742933 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Osada T AU - Patel SP AU - Hammond SA AU - Osada K AU - Morse MA AU - Lyerly HK FA - Osada, Takuya FA - Patel, Sandip P FA - Hammond, Scott A FA - Osada, Koya FA - Morse, Michael A FA - Lyerly, H Kim IN - Osada, Takuya. Section of Applied Therapeutics, Department of Surgery, Duke University Medical Center, 403 MSRB, Research Drive, Durham, NC, 27710, USA, osada001@mc.duke.edu. TI - CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1. SO - Cancer Immunology, Immunotherapy. 64(6):677-88, 2015 Jun AS - Cancer Immunol Immunother. 64(6):677-88, 2015 Jun NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. SB - Index Medicus CP - Germany MH - Animals MH - *Antibodies, Bispecific/im [Immunology] MH - *Antibodies, Bispecific/pd [Pharmacology] MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - Antigens, CD274/im [Immunology] MH - *Antigens, CD3/im [Immunology] MH - *Carcinoembryonic Antigen/im [Immunology] MH - Cell Line, Tumor MH - Colorectal Neoplasms/im [Immunology] MH - Colorectal Neoplasms/th [Therapy] MH - HT29 Cells MH - Humans MH - Immunotherapy/mt [Methods] MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/th [Therapy] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - *T-Lymphocytes, Cytotoxic/im [Immunology] AB - Bispecific T cell-engaging (BiTE) antibodies recruit polyclonal cytotoxic T cells (CTL) to tumors. One such antibody is carcinoembryonic antigen (CEA) BiTE that mediates T cell/tumor interaction by simultaneously binding CD3 expressed by T cells and CEA expressed by tumor cells. A widely operative mechanism for mitigating cytotoxic T cell-mediated killing is the interaction of tumor-expressed PD-L1 with T cell-expressed PD-1, which may be partly reversed by PD-1/PD-L1 blockade. We hypothesized that PD-1/PD-L1 blockade during BiTE-mediated T cell killing would enhance CTL function. Here, we determined the effects of PD-1 and PD-L1 blockade during initial T cell-mediated killing of CEA-expressing human tumor cell lines in vitro, as well as subsequent T cell-mediated killing by T lymphocytes that had participated in tumor cell killing. We observed a rapid upregulation of PD-1 expression and diminished cytolytic function of T cells after they had engaged in CEA BiTE-mediated killing of tumors. T cell cytolytic activity in vitro could be maximized by administration of anti-PD-1 or anti-PD-L1 antibodies alone or in combination if applied prior to a round of T cell killing, but T cell inhibition could not be fully reversed by this blockade once the T cells had killed tumor. In conclusion, our findings demonstrate that dual blockade of PD-1 and PD-L1 maximizes T cell killing of tumor directed by CEA BiTE in vitro, is more effective if applied early, and provides a rationale for clinical use. RN - 0 (Antibodies, Bispecific) RN - 0 (Antigens, CD274) RN - 0 (Antigens, CD3) RN - 0 (CD274 protein, human) RN - 0 (Carcinoembryonic Antigen) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1432-0851 IL - 0340-7004 DO - https://dx.doi.org/10.1007/s00262-015-1671-y PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25742933 [pubmed] ID - 10.1007/s00262-015-1671-y [doi] PP - ppublish PH - 2014/07/13 [received] PH - 2015/02/17 [accepted] LG - English EP - 20150306 DP - 2015 Jun DC - 20150605 EZ - 2015/03/07 06:00 DA - 2015/09/04 06:00 DT - 2015/03/07 06:00 YR - 2015 ED - 20150902 RD - 20150605 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25742933 <196. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25964248 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gibney GT AU - Atkins MB FA - Gibney, Geoffrey T FA - Atkins, Michael B IN - Gibney, Geoffrey T. Moffitt Cancer Center; and University of South Florida, Tampa, FL geoffrey.gibney@moffitt.org. IN - Atkins, Michael B. Georgetown-Lombardi Comprehensive Cancer Center; and Medstar-Georgetown University Hospital, Washington, DC. TI - Swinging for the Fences: Long-Term Survival With Ipilimumab in Metastatic Melanoma. SO - Journal of Clinical Oncology. 33(17):1873-7, 2015 Jun 10 AS - J Clin Oncol. 33(17):1873-7, 2015 Jun 10 NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. SB - Index Medicus CP - United States MH - Adrenal Insufficiency/et [Etiology] MH - Adult MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Brain Neoplasms/sc [Secondary] MH - *Brain Neoplasms/th [Therapy] MH - Cisplatin/ad [Administration & Dosage] MH - Dacarbazine/ad [Administration & Dosage] MH - Hormone Replacement Therapy MH - Humans MH - Hypopituitarism/ci [Chemically Induced] MH - *Hypopituitarism/co [Complications] MH - Hypothyroidism/et [Etiology] MH - Interferon-alpha/ad [Administration & Dosage] MH - Interleukin-2/ad [Administration & Dosage] MH - Lung Neoplasms/sc [Secondary] MH - *Lung Neoplasms/th [Therapy] MH - Lymphatic Metastasis MH - Male MH - *Melanoma/di [Diagnosis] MH - Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Melanoma/su [Surgery] MH - *Melanoma/th [Therapy] MH - Neoplasm Staging MH - Parietal Lobe MH - *Radiosurgery MH - Sentinel Lymph Node Biopsy MH - Shoulder MH - *Skin Neoplasms/pa [Pathology] MH - Skin Neoplasms/su [Surgery] MH - Treatment Outcome MH - Vinblastine/ad [Administration & Dosage] AB - A 40-year-old man with stage III melanoma arising from his left shoulder underwent wide local excision, sentinel lymph node biopsy, and lymph node dissection. Nine months after receiving adjuvant biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2 (IL-2), and interferon alfa as part of a clinical trial, he developed headaches and right-hand weakness and was found to have a 2-cm left parietal CNS metastasis. A comprehensive staging workup identified multiple nonspecific subcentimeter pulmonary nodules. The brain mass was resected and confirmed to be metastatic melanoma; the surgical bed was treated with stereotactic radiosurgery. He was monitored off therapy, but 5 months later, he developed a second left parietal CNS metastasis and enlarging lung nodules. The new brain lesion was treated with stereotactic radiosurgery, and he began systemic therapy with ipilimumab on a clinical trial. After the third dose, he presented with headache, nausea, and vomiting; a brain magnetic resonance imaging scan showed left anterior temporal enhancement, possibly representing new disease. His symptoms improved with a course of corticosteroids. Restaging of the chest showed a mixed response among the pulmonary nodules. After tapering off corticosteroids, he received the fourth dose of ipilimumab, which was complicated by grade 3 transaminitis and hypophysitis with documented hypothyroidism and adrenal insufficiency. They were managed with corticosteroids and thyroid and adrenal hormone replacement. Restaging scans showed further disease regression except for new confluent enhancing nodules and edema in the left temporal lobe. Craniotomy and resection of this area showed only necrotic tissue with no viable melanoma cells. Nine years after treatment with ipilimumab, he is alive and shows no evidence of melanoma on the basis of annual computed tomography scans of the chest, abdomen, and pelvis and magnetic resonance imaging scans of the brain. He has full neurologic function but still requires hormone replacement for persistent hypopituitarism. RN - 0 (Antibodies, Monoclonal) RN - 0 (Interferon-alpha) RN - 0 (Interleukin-2) RN - 5V9KLZ54CY (Vinblastine) RN - 6T8C155666 (ipilimumab) RN - 7GR28W0FJI (Dacarbazine) RN - Q20Q21Q62J (Cisplatin) ES - 1527-7755 IL - 0732-183X DI - JCO.2014.60.1807 DO - https://dx.doi.org/10.1200/JCO.2014.60.1807 PT - Case Reports PT - Journal Article ID - 25964248 [pubmed] ID - JCO.2014.60.1807 [pii] ID - 10.1200/JCO.2014.60.1807 [doi] PP - ppublish LG - English EP - 20150511 DP - 2015 Jun 10 DC - 20150609 EZ - 2015/05/13 06:00 DA - 2015/08/22 06:00 DT - 2015/05/13 06:00 YR - 2015 ED - 20150821 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25964248 <197. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26123020 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - McKinney EF AU - Lee JC AU - Jayne DR AU - Lyons PA AU - Smith KG FA - McKinney, Eoin F FA - Lee, James C FA - Jayne, David R W FA - Lyons, Paul A FA - Smith, Kenneth G C IN - McKinney, Eoin F. 1] Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK [2] Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. IN - Lee, James C. 1] Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK [2] Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. IN - Jayne, David R W. Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. IN - Lyons, Paul A. 1] Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK [2] Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. IN - Smith, Kenneth G C. 1] Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK [2] Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. TI - T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. CM - Comment in: Nat Rev Nephrol. 2015 Sep;11(9):503; PMID: 26168738 CM - Comment in: Nat Rev Immunol. 2015 Aug;15(8):468; PMID: 26160615 CM - Comment in: Nat Rev Rheumatol. 2015 Sep;11(9):501; PMID: 26168912 SO - Nature. 523(7562):612-6, 2015 Jul 30 AS - Nature. 523(7562):612-6, 2015 Jul 30 NJ - Nature PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0410462 IO - Nature PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623162 OI - Source: NLM. EMS62964 SB - Index Medicus CP - England MH - Animals MH - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/ge [Genetics] MH - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/im [Immunology] MH - Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/pa [Pathology] MH - Antigens, CD2/im [Immunology] MH - Autoimmune Diseases/ge [Genetics] MH - *Autoimmune Diseases/im [Immunology] MH - Autoimmune Diseases/pa [Pathology] MH - Autoimmunity/ge [Genetics] MH - Autoimmunity/im [Immunology] MH - *CD4-Positive T-Lymphocytes/im [Immunology] MH - CD4-Positive T-Lymphocytes/me [Metabolism] MH - *CD8-Positive T-Lymphocytes/im [Immunology] MH - CD8-Positive T-Lymphocytes/me [Metabolism] MH - *CD8-Positive T-Lymphocytes/pa [Pathology] MH - Humans MH - Infection/ge [Genetics] MH - *Infection/im [Immunology] MH - Infection/pa [Pathology] MH - Infection/vi [Virology] MH - Inflammation/im [Immunology] MH - Inflammation/pa [Pathology] MH - Inflammation/vi [Virology] MH - Inflammatory Bowel Diseases/ge [Genetics] MH - Inflammatory Bowel Diseases/im [Immunology] MH - Inflammatory Bowel Diseases/pa [Pathology] MH - Lupus Erythematosus, Systemic/ge [Genetics] MH - Lupus Erythematosus, Systemic/im [Immunology] MH - Lupus Erythematosus, Systemic/pa [Pathology] MH - Mice MH - Phenotype MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - Receptors, Antigen, T-Cell/im [Immunology] MH - Receptors, Interleukin-7/im [Immunology] MH - Receptors, Interleukin-7/me [Metabolism] MH - Transcriptome AB - The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non-exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities. RN - 0 (Antigens, CD2) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Receptors, Interleukin-7) ES - 1476-4687 IL - 0028-0836 DI - nature14468 DO - https://dx.doi.org/10.1038/nature14468 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 26123020 [pubmed] ID - nature14468 [pii] ID - 10.1038/nature14468 [doi] ID - PMC4623162 [pmc] ID - EMS62964 [mid] PP - ppublish PH - 2014/02/12 [received] PH - 2015/04/10 [accepted] GI - No: 104064 Organization: *Wellcome Trust* Country: United Kingdom No: 079895 Organization: *Wellcome Trust* Country: United Kingdom No: 083650/Z/07/Z Organization: *Wellcome Trust* Country: United Kingdom No: 083650 Organization: *Wellcome Trust* Country: United Kingdom No: 094227/Z/10/Z Organization: *Wellcome Trust* Country: United Kingdom No: G0400929 Organization: *Medical Research Council* Country: United Kingdom No: 094227 Organization: *Wellcome Trust* Country: United Kingdom No: 104064/Z/14/Z Organization: *Wellcome Trust* Country: United Kingdom No: MR/L019027/1 Organization: *Medical Research Council* Country: United Kingdom No: 100140 Organization: *Wellcome Trust* Country: United Kingdom LG - English EP - 20150629 DP - 2015 Jul 30 DC - 20150730 EZ - 2015/07/01 06:00 DA - 2015/08/21 06:00 DT - 2015/07/01 06:00 YR - 2015 ED - 20150820 RD - 20161122 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=26123020 <198. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25127260 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Chodakiewitz Y AU - Brown S AU - Boxerman JL AU - Brody JM AU - Rogg JM FA - Chodakiewitz, Yosef FA - Brown, Sanford FA - Boxerman, Jerrold L FA - Brody, Jeffrey M FA - Rogg, Jeffrey M IN - Chodakiewitz, Yosef. Alpert Medical School, Brown University, 222 Richmond St, Providence 02903, USA. IN - Brown, Sanford. Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence 02903, USA. IN - Boxerman, Jerrold L. Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence 02903, USA. IN - Brody, Jeffrey M. Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence 02903, USA. IN - Rogg, Jeffrey M. Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence 02903, USA. Electronic address: jrogg@lifespan.org. TI - Ipilimumab treatment associated pituitary hypophysitis: clinical presentation and imaging diagnosis. [Review] SO - Clinical Neurology & Neurosurgery. 125:125-30, 2014 Oct AS - Clin Neurol Neurosurg. 125:125-30, 2014 Oct NJ - Clinical neurology and neurosurgery PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - df4, 7502039 IO - Clin Neurol Neurosurg SB - Index Medicus CP - Netherlands MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Diagnostic Imaging MH - Humans MH - Hypopituitarism/di [Diagnosis] MH - *Hypopituitarism/dt [Drug Therapy] MH - Magnetic Resonance Imaging/mt [Methods] MH - Melanoma/di [Diagnosis] MH - *Melanoma/dt [Drug Therapy] MH - *Pituitary Gland/pa [Pathology] KW - Autoimmune lymphocytic hypophysitis; Ipilimumab; MRI; Melanoma; Pituitary AB - Ipilimumab is an immunomodulating drug for use in treatment of unresectable or metastatic melanoma with autoimmune lymphocytic hypophysitis as a reported complication. We describe three recent cases of ipilimumab associated autoimmune hypophysitis (IAH) at our institution, and provide a selected literature review showing its variable clinical presentation, imaging appearance and treatment in order to expedite early and appropriate IAH management. Patients had variable clinical presentation of hypophysitis, including headache, fatigue, visual changes, endocrinopathy, and/or hyponatremia. Contrast enhanced MRI showed symmetric pituitary gland and stalk enlargement in all of our cases and received a presumptive diagnosis of IAH. Following cessation of therapy and treatment there was normalization of pituitary morphology at follow-up MRI and return to clinical baseline. Varying clinical presentation can complicate the diagnosis of lymphocytic hypophysitis. One must be cognizant of its overall clinical and radiologic picture in patients receiving ipilimumab, now commonly used for the treatment of metastatic melanoma. AB - Copyright © 2014 Elsevier B.V. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 1872-6968 IL - 0303-8467 DI - S0303-8467(14)00215-7 DO - https://dx.doi.org/10.1016/j.clineuro.2014.06.011 PT - Journal Article PT - Review ID - 25127260 [pubmed] ID - S0303-8467(14)00215-7 [pii] ID - 10.1016/j.clineuro.2014.06.011 [doi] PP - ppublish PH - 2014/03/19 [received] PH - 2014/06/05 [revised] PH - 2014/06/08 [accepted] LG - English EP - 20140729 DP - 2014 Oct DC - 20140920 EZ - 2014/08/16 06:00 DA - 2015/08/20 06:00 DT - 2014/08/16 06:00 YR - 2014 ED - 20150819 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25127260 <199. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25415283 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Soares KC AU - Rucki AA AU - Wu AA AU - Olino K AU - Xiao Q AU - Chai Y AU - Wamwea A AU - Bigelow E AU - Lutz E AU - Liu L AU - Yao S AU - Anders RA AU - Laheru D AU - Wolfgang CL AU - Edil BH AU - Schulick RD AU - Jaffee EM AU - Zheng L FA - Soares, Kevin C FA - Rucki, Agnieszka A FA - Wu, Annie A FA - Olino, Kelly FA - Xiao, Qian FA - Chai, Yi FA - Wamwea, Anthony FA - Bigelow, Elaine FA - Lutz, Eric FA - Liu, Linda FA - Yao, Sheng FA - Anders, Robert A FA - Laheru, Daniel FA - Wolfgang, Christopher L FA - Edil, Barish H FA - Schulick, Richard D FA - Jaffee, Elizabeth M FA - Zheng, Lei IN - Soares, Kevin C. Departments of *Oncology #Pathology +Surgery ++The Sidney Kimmel Cancer Center The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD PAmplimmune Inc., Gaithersburg, MD **Department of Surgery, University of Colorado School of Medicine, Aurora, CO. TI - PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. SO - Journal of Immunotherapy. 38(1):1-11, 2015 Jan AS - J Immunother. 38(1):1-11, 2015 Jan NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258151 OI - Source: NLM. NIHMS636576 SB - Index Medicus CP - United States MH - Animals MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Cancer Vaccines/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/im [Immunology] MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Flow Cytometry MH - Humans MH - Immunohistochemistry MH - Immunotherapy/mt [Methods] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Mice MH - Mice, Inbred C57BL MH - *Pancreatic Neoplasms/im [Immunology] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] AB - Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-gamma production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment. RN - 0 (Antigens, CD274) RN - 0 (Cancer Vaccines) RN - 0 (GVAX vaccine) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1537-4513 IL - 1524-9557 DO - https://dx.doi.org/10.1097/CJI.0000000000000062 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 25415283 [pubmed] ID - 10.1097/CJI.0000000000000062 [doi] ID - PMC4258151 [pmc] ID - NIHMS636576 [mid] PP - ppublish GI - No: T32 GM007309 Organization: (GM) *NIGMS NIH HHS* Country: United States No: P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA006973 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964-01 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 DK 7713-18 Organization: (DK) *NIDDK NIH HHS* Country: United States No: T32 DK007713 Organization: (DK) *NIDDK NIH HHS* Country: United States No: T32 GM008752 Organization: (GM) *NIGMS NIH HHS* Country: United States LG - English DP - 2015 Jan DC - 20141206 EZ - 2014/11/22 06:00 DA - 2015/08/01 06:00 DT - 2014/11/22 06:00 YR - 2015 ED - 20150731 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25415283 <200. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25415283 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Soares KC AU - Rucki AA AU - Wu AA AU - Olino K AU - Xiao Q AU - Chai Y AU - Wamwea A AU - Bigelow E AU - Lutz E AU - Liu L AU - Yao S AU - Anders RA AU - Laheru D AU - Wolfgang CL AU - Edil BH AU - Schulick RD AU - Jaffee EM AU - Zheng L FA - Soares, Kevin C FA - Rucki, Agnieszka A FA - Wu, Annie A FA - Olino, Kelly FA - Xiao, Qian FA - Chai, Yi FA - Wamwea, Anthony FA - Bigelow, Elaine FA - Lutz, Eric FA - Liu, Linda FA - Yao, Sheng FA - Anders, Robert A FA - Laheru, Daniel FA - Wolfgang, Christopher L FA - Edil, Barish H FA - Schulick, Richard D FA - Jaffee, Elizabeth M FA - Zheng, Lei IN - Soares, Kevin C. Departments of *Oncology #Pathology +Surgery ++The Sidney Kimmel Cancer Center The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD PAmplimmune Inc., Gaithersburg, MD **Department of Surgery, University of Colorado School of Medicine, Aurora, CO. TI - PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. SO - Journal of Immunotherapy. 38(1):1-11, 2015 Jan AS - J Immunother. 38(1):1-11, 2015 Jan NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258151 OI - Source: NLM. NIHMS636576 SB - Index Medicus CP - United States MH - Animals MH - *Antigens, CD274/ai [Antagonists & Inhibitors] MH - *Cancer Vaccines/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/im [Immunology] MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - Flow Cytometry MH - Humans MH - Immunohistochemistry MH - Immunotherapy/mt [Methods] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Mice MH - Mice, Inbred C57BL MH - *Pancreatic Neoplasms/im [Immunology] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] AB - Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-gamma production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment. RN - 0 (Antigens, CD274) RN - 0 (Cancer Vaccines) RN - 0 (GVAX vaccine) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1537-4513 IL - 1524-9557 DO - https://dx.doi.org/10.1097/CJI.0000000000000062 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 10.1097/CJI.0000000000000062 [doi] ID - PMC4258151 [pmc] ID - NIHMS636576 [mid] PP - ppublish GI - No: T32 GM007309 Organization: (GM) *NIGMS NIH HHS* Country: United States No: P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA006973 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964-01 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 DK 7713-18 Organization: (DK) *NIDDK NIH HHS* Country: United States No: T32 DK007713 Organization: (DK) *NIDDK NIH HHS* Country: United States No: T32 GM008752 Organization: (GM) *NIGMS NIH HHS* Country: United States No: R01 CA169702 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2015 Jan DC - 20141206 EZ - 2014/11/22 06:00 DA - 2015/08/01 06:00 DT - 2014/11/22 06:00 YR - 2015 ED - 20150731 RD - 20170408 UP - 20170410 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=25415283 <201. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24942756 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lutz ER AU - Wu AA AU - Bigelow E AU - Sharma R AU - Mo G AU - Soares K AU - Solt S AU - Dorman A AU - Wamwea A AU - Yager A AU - Laheru D AU - Wolfgang CL AU - Wang J AU - Hruban RH AU - Anders RA AU - Jaffee EM AU - Zheng L FA - Lutz, Eric R FA - Wu, Annie A FA - Bigelow, Elaine FA - Sharma, Rajni FA - Mo, Guanglan FA - Soares, Kevin FA - Solt, Sara FA - Dorman, Alvin FA - Wamwea, Anthony FA - Yager, Allison FA - Laheru, Daniel FA - Wolfgang, Christopher L FA - Wang, Jiang FA - Hruban, Ralph H FA - Anders, Robert A FA - Jaffee, Elizabeth M FA - Zheng, Lei IN - Lutz, Eric R. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Wu, Annie A. Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; IN - Bigelow, Elaine. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; IN - Sharma, Rajni. Pathology, and. IN - Mo, Guanglan. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Soares, Kevin. Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Solt, Sara. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Dorman, Alvin. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Wamwea, Anthony. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Yager, Allison. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; IN - Laheru, Daniel. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Wolfgang, Christopher L. Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Wang, Jiang. Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. IN - Hruban, Ralph H. Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Anders, Robert A. Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Jaffee, Elizabeth M. Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and lzheng6@jhmi.edu ejaffee@jhmi.edu. IN - Zheng, Lei. Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and lzheng6@jhmi.edu ejaffee@jhmi.edu. TI - Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. SO - Cancer Immunology Research. 2(7):616-31, 2014 Jul AS - Cancer Immunol Res. 2(7):616-31, 2014 Jul NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082460 OI - Source: NLM. NIHMS589592 SB - Index Medicus CP - United States MH - Adenocarcinoma/ge [Genetics] MH - Adenocarcinoma/im [Immunology] MH - *Adenocarcinoma/th [Therapy] MH - Antineoplastic Agents, Alkylating/ad [Administration & Dosage] MH - Antineoplastic Agents, Alkylating/tu [Therapeutic Use] MH - *Cancer Vaccines/tu [Therapeutic Use] MH - Cell Aggregation/im [Immunology] MH - Chemotherapy, Adjuvant MH - Cyclophosphamide/ad [Administration & Dosage] MH - Cyclophosphamide/tu [Therapeutic Use] MH - Drug Administration Schedule MH - Gene Expression Profiling/mt [Methods] MH - Gene Expression Regulation, Neoplastic/im [Immunology] MH - Humans MH - Interferon-gamma/bi [Biosynthesis] MH - Lymphocyte Activation/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/de [Drug Effects] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/th [Therapy] MH - T-Lymphocytes, Regulatory/im [Immunology] MH - Up-Regulation/im [Immunology] AB - Pancreatic ductal adenocarcinoma (PDAC) is considered a "nonimmunogenic" neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other "nonimmunogenic" tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a "nonimmunogenic" neoplasm into an "immunogenic" neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1-PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naive patients for immune checkpoint and other immunomodulatory therapies. AB - Copyright ©2014 American Association for Cancer Research. RN - 0 (Antineoplastic Agents, Alkylating) RN - 0 (Cancer Vaccines) RN - 0 (GVAX vaccine) RN - 82115-62-6 (Interferon-gamma) RN - 8N3DW7272P (Cyclophosphamide) RS - Pancreatic Carcinoma ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-14-0027 DO - https://dx.doi.org/10.1158/2326-6066.CIR-14-0027 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 24942756 [pubmed] ID - 2326-6066.CIR-14-0027 [pii] ID - 10.1158/2326-6066.CIR-14-0027 [doi] ID - PMC4082460 [pmc] ID - NIHMS589592 [mid] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00727441 SL - https://clinicaltrials.gov/search/term=NCT00727441 GI - No: K23 CA148964 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA058236 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964-01 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20140618 DP - 2014 Jul DC - 20140703 EZ - 2014/06/20 06:00 DA - 2015/07/24 06:00 DT - 2014/06/20 06:00 YR - 2014 ED - 20150723 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24942756 <202. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24554495 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Marlier J AU - Cocquyt V AU - Brochez L AU - Van Belle S AU - Kruse V FA - Marlier, Joke FA - Cocquyt, Veronique FA - Brochez, Lieve FA - Van Belle, Simon FA - Kruse, Vibeke IN - Marlier, Joke. Department of Medical Oncology, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium, Joke.Marlier@ugent.be. TI - Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports. SO - Endocrine. 47(3):878-83, 2014 Dec AS - Endocrine. 47(3):878-83, 2014 Dec NJ - Endocrine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9434444, CV9 IO - Endocrine SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Female MH - Humans MH - *Hypopituitarism/ci [Chemically Induced] MH - Male MH - Melanoma/dt [Drug Therapy] MH - Middle Aged MH - Retrospective Studies AB - Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen4 (CTLA-4), an inhibitory molecule typically expressed on T cells. Blockade of CTLA-4 induces an overall activation of T cells, including an immune-mediated anti-tumour response. Unfortunately, this broad T cell stimulation also causes immune-related adverse events (irAEs), such as dermatitis, colitis, hepatitis and hypophysitis. Ipilimumab is currently available in Belgium as a second line of treatment for patients with advanced melanoma, and is used at a dose of 3 mg/kg of body weight, although higher doses were previously used (up to 10 mg/kg). We performed a retrospective analysis to identify melanoma patients treated with ipilimumab at the Ghent University Hospital between 2010 and 2013. Data on symptoms, stage and timing of ipilimumab, response and adverse events were collected with a special attention to endocrine disturbances, going from a limited involvement of one endocrine axis to development of a hypophysitis. We identified a total of 39 patients with stage III (No. = 7) or stage IV (No. = 32) melanoma, who received a dose of 3 (No. = 31) or 10 (No. = 8) mg/kg. Six patients developed a severe form of irAEs, including one case of colitis (2 %), one case of sarcoidosis (2 %) and 4 cases (10 %) of hypophysitis. Hypophysitis developed between the second and fourth cycle of ipilimumab administration and was independent of the dose used. We describe four cases of involvement of the pituitary gland during treatment with ipilimumab. When managed with vigilant monitoring and high-dose corticosteroids, the acute symptoms resolve, but lifelong hormone substitution therapy can be necessary. Involvement of the pituitary axes is a severe side effect of treatment with ipilimumab with an urgent need for the correct medical intervention. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 1559-0100 IL - 1355-008X DO - https://dx.doi.org/10.1007/s12020-014-0199-9 PT - Case Reports PT - Journal Article ID - 24554495 [pubmed] ID - 10.1007/s12020-014-0199-9 [doi] PP - ppublish PH - 2013/09/16 [received] PH - 2014/01/31 [accepted] LG - English EP - 20140221 DP - 2014 Dec DC - 20141121 EZ - 2014/02/21 06:00 DA - 2015/07/24 06:00 DT - 2014/02/21 06:00 YR - 2014 ED - 20150723 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24554495 <203. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24942756 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lutz ER AU - Wu AA AU - Bigelow E AU - Sharma R AU - Mo G AU - Soares K AU - Solt S AU - Dorman A AU - Wamwea A AU - Yager A AU - Laheru D AU - Wolfgang CL AU - Wang J AU - Hruban RH AU - Anders RA AU - Jaffee EM AU - Zheng L FA - Lutz, Eric R FA - Wu, Annie A FA - Bigelow, Elaine FA - Sharma, Rajni FA - Mo, Guanglan FA - Soares, Kevin FA - Solt, Sara FA - Dorman, Alvin FA - Wamwea, Anthony FA - Yager, Allison FA - Laheru, Daniel FA - Wolfgang, Christopher L FA - Wang, Jiang FA - Hruban, Ralph H FA - Anders, Robert A FA - Jaffee, Elizabeth M FA - Zheng, Lei IN - Lutz, Eric R. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Wu, Annie A. Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; IN - Bigelow, Elaine. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; IN - Sharma, Rajni. Pathology, and. IN - Mo, Guanglan. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Soares, Kevin. Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Solt, Sara. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Dorman, Alvin. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Wamwea, Anthony. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Yager, Allison. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; IN - Laheru, Daniel. Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; IN - Wolfgang, Christopher L. Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Wang, Jiang. Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. IN - Hruban, Ralph H. Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Anders, Robert A. Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and. IN - Jaffee, Elizabeth M. Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and lzheng6@jhmi.edu ejaffee@jhmi.edu. IN - Zheng, Lei. Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and lzheng6@jhmi.edu ejaffee@jhmi.edu. TI - Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. SO - Cancer Immunology Research. 2(7):616-31, 2014 Jul AS - Cancer Immunol Res. 2(7):616-31, 2014 Jul NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082460 OI - Source: NLM. NIHMS589592 SB - Index Medicus CP - United States MH - Adenocarcinoma/ge [Genetics] MH - Adenocarcinoma/im [Immunology] MH - *Adenocarcinoma/th [Therapy] MH - Antineoplastic Agents, Alkylating/ad [Administration & Dosage] MH - Antineoplastic Agents, Alkylating/tu [Therapeutic Use] MH - *Cancer Vaccines/tu [Therapeutic Use] MH - Cell Aggregation/im [Immunology] MH - Chemotherapy, Adjuvant MH - Cyclophosphamide/ad [Administration & Dosage] MH - Cyclophosphamide/tu [Therapeutic Use] MH - Drug Administration Schedule MH - Gene Expression Profiling/mt [Methods] MH - Gene Expression Regulation, Neoplastic/im [Immunology] MH - Humans MH - Interferon-gamma/bi [Biosynthesis] MH - Lymphocyte Activation/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/de [Drug Effects] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/th [Therapy] MH - T-Lymphocytes, Regulatory/im [Immunology] MH - Up-Regulation/im [Immunology] AB - Pancreatic ductal adenocarcinoma (PDAC) is considered a "nonimmunogenic" neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other "nonimmunogenic" tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a "nonimmunogenic" neoplasm into an "immunogenic" neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1-PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naive patients for immune checkpoint and other immunomodulatory therapies. AB - Copyright ©2014 American Association for Cancer Research. RN - 0 (Antineoplastic Agents, Alkylating) RN - 0 (Cancer Vaccines) RN - 0 (GVAX vaccine) RN - 82115-62-6 (Interferon-gamma) RN - 8N3DW7272P (Cyclophosphamide) RS - Pancreatic Carcinoma ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-14-0027 DO - https://dx.doi.org/10.1158/2326-6066.CIR-14-0027 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 2326-6066.CIR-14-0027 [pii] ID - 10.1158/2326-6066.CIR-14-0027 [doi] ID - PMC4082460 [pmc] ID - NIHMS589592 [mid] PP - ppublish GI - No: P50 CA058236 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964-01 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA169702 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20140618 DP - 2014 Jul DC - 20140703 EZ - 2014/06/20 06:00 DA - 2015/07/24 06:00 DT - 2014/06/20 06:00 YR - 2014 ED - 20150723 RD - 20170408 UP - 20170410 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=24942756 <204. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25712539 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Twa DD AU - Mottok A AU - Chan FC AU - Ben-Neriah S AU - Woolcock BW AU - Tan KL AU - Mungall AJ AU - McDonald H AU - Zhao Y AU - Lim RS AU - Nelson BH AU - Milne K AU - Shah SP AU - Morin RD AU - Marra MA AU - Scott DW AU - Gascoyne RD AU - Steidl C FA - Twa, David D W FA - Mottok, Anja FA - Chan, Fong Chun FA - Ben-Neriah, Susana FA - Woolcock, Bruce W FA - Tan, King L FA - Mungall, Andrew J FA - McDonald, Helen FA - Zhao, Yongjun FA - Lim, Raymond S FA - Nelson, Brad H FA - Milne, Katy FA - Shah, Sohrab P FA - Morin, Ryan D FA - Marra, Marco A FA - Scott, David W FA - Gascoyne, Randy D FA - Steidl, Christian IN - Twa, David D W. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Twa, David D W. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. IN - Mottok, Anja. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Mottok, Anja. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. IN - Chan, Fong Chun. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Chan, Fong Chun. Bioinformatics Training Programme, University of British Columbia, Vancouver, BC, Canada. IN - Ben-Neriah, Susana. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Woolcock, Bruce W. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Tan, King L. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Mungall, Andrew J. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Mungall, Andrew J. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada. IN - McDonald, Helen. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada. IN - Zhao, Yongjun. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada. IN - Lim, Raymond S. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Nelson, Brad H. Deeley Research Centre, BC Cancer Agency, Victoria, BC, Canada. IN - Nelson, Brad H. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. IN - Milne, Katy. Deeley Research Centre, BC Cancer Agency, Victoria, BC, Canada. IN - Shah, Sohrab P. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Shah, Sohrab P. Bioinformatics Training Programme, University of British Columbia, Vancouver, BC, Canada. IN - Morin, Ryan D. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Morin, Ryan D. Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada. IN - Marra, Marco A. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Marra, Marco A. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada. IN - Scott, David W. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Gascoyne, Randy D. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Gascoyne, Randy D. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. IN - Steidl, Christian. Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC, Canada. IN - Steidl, Christian. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. TI - Recurrent genomic rearrangements in primary testicular lymphoma. SO - Journal of Pathology. 236(2):136-41, 2015 Jun AS - J Pathol. 236(2):136-41, 2015 Jun NJ - The Journal of pathology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - jlb, 0204634 IO - J. Pathol. SB - Index Medicus CP - England MH - *Antigens, CD274/ge [Genetics] MH - Chromosome Breakpoints MH - Chromosomes, Artificial, Bacterial MH - *Forkhead Transcription Factors/ge [Genetics] MH - Gene Deletion MH - *Gene Rearrangement, B-Lymphocyte/ge [Genetics] MH - Humans MH - Immunohistochemistry MH - In Situ Hybridization, Fluorescence MH - *Lymphoma, Large B-Cell, Diffuse/ge [Genetics] MH - Male MH - Nuclear Proteins/ge [Genetics] MH - *Programmed Cell Death 1 Ligand 2 Protein/ge [Genetics] MH - Recurrence MH - *Repressor Proteins/ge [Genetics] MH - *Testicular Neoplasms/ge [Genetics] MH - Trans-Activators/ge [Genetics] MH - Translocation, Genetic/ge [Genetics] KW - CD274; CIITA; FOXP1; PDCD1LG2; capture sequencing; fluorescence in situ hybridization (FISH); genomic rearrangements; primary testicular lymphoma (PTL); programmed death ligands AB - Primary testicular diffuse large B cell lymphoma (PTL) is an aggressive malignancy that occurs in the immune-privileged anatomical site of the testis. We have previously shown that structural genomic rearrangements involving the MHC class II transactivator CIITA and programmed death ligands (PDLs) 1 and 2 are frequent across multiple B cell lymphoma entities. Specifically in PTL, we found rearrangements in the PDL locus by fluorescence in situ hybridization (FISH). However, breakpoint anatomy and rearrangement partners were undetermined, while CIITA rearrangements had not been reported previously in PTL. Here, we performed bacterial artificial chromosome capture sequencing on three archival, formalin-fixed, paraffin-embedded tissue biopsies, interrogating 20 known rearrangement hotspots in B cell lymphomas. We report novel CIITA, FOXP1 and PDL rearrangements involving IGHG4, FLJ45248, RFX3, SMARCA2 and SNX29. Moreover, we present immunohistochemistry data supporting the association between PDL rearrangements and increased protein expression. Finally, using FISH, we show that CIITA (8/82; 10%) and FOXP1 (5/74; 7%) rearrangements are recurrent in PTL. In summary, we describe rearrangement frequencies and novel rearrangement partners of the CIITA, FOXP1 and PDL loci at base-pair resolution in a rare, aggressive lymphoma. Our data suggest immune-checkpoint inhibitor therapy as a promising intervention for PTL patients harbouring PDL rearrangements. AB - Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (FOXP1 protein, human) RN - 0 (Forkhead Transcription Factors) RN - 0 (MHC class II transactivator protein) RN - 0 (Nuclear Proteins) RN - 0 (PDCD1LG2 protein, human) RN - 0 (Programmed Cell Death 1 Ligand 2 Protein) RN - 0 (Repressor Proteins) RN - 0 (Trans-Activators) ES - 1096-9896 IL - 0022-3417 DO - https://dx.doi.org/10.1002/path.4522 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25712539 [pubmed] ID - 10.1002/path.4522 [doi] PP - ppublish PH - 2014/12/15 [received] PH - 2015/02/05 [revised] PH - 2015/02/18 [accepted] GI - Organization: *Canadian Institutes of Health Research* Country: Canada LG - English EP - 20150326 DP - 2015 Jun DC - 20150511 EZ - 2015/02/26 06:00 DA - 2015/07/21 06:00 DT - 2015/02/26 06:00 YR - 2015 ED - 20150720 RD - 20150511 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25712539 <205. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25840693 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Eggermont AM AU - Chiarion-Sileni V AU - Grob JJ AU - Dummer R AU - Wolchok JD AU - Schmidt H AU - Hamid O AU - Robert C AU - Ascierto PA AU - Richards JM AU - Lebbe C AU - Ferraresi V AU - Smylie M AU - Weber JS AU - Maio M AU - Konto C AU - Hoos A AU - de Pril V AU - Gurunath RK AU - de Schaetzen G AU - Suciu S AU - Testori A FA - Eggermont, Alexander M M FA - Chiarion-Sileni, Vanna FA - Grob, Jean-Jacques FA - Dummer, Reinhard FA - Wolchok, Jedd D FA - Schmidt, Henrik FA - Hamid, Omid FA - Robert, Caroline FA - Ascierto, Paolo A FA - Richards, Jon M FA - Lebbe, Celeste FA - Ferraresi, Virginia FA - Smylie, Michael FA - Weber, Jeffrey S FA - Maio, Michele FA - Konto, Cyril FA - Hoos, Axel FA - de Pril, Veerle FA - Gurunath, Ravichandra Karra FA - de Schaetzen, Gaetan FA - Suciu, Stefan FA - Testori, Alessandro IN - Eggermont, Alexander M M. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr. IN - Chiarion-Sileni, Vanna. IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. IN - Grob, Jean-Jacques. Aix-Marseille University, Hopital de La Timone APHM, Marseille, France. IN - Dummer, Reinhard. University of Zurich Hospital, Zurich, Switzerland. IN - Wolchok, Jedd D. Memorial Sloan-Kettering Cancer Center, New York, NY, USA. IN - Schmidt, Henrik. Aarhus University Hospital, Aarhus, Denmark. IN - Hamid, Omid. The Angeles Clinic and Research Institute, Los Angeles, CA, USA. IN - Robert, Caroline. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. IN - Ascierto, Paolo A. Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. IN - Richards, Jon M. Oncology Specialists SC, Park Ridge, IL, USA. IN - Lebbe, Celeste. Assistance Publique Hopitaux de Paris, Dermatology and CIC Departments, Hopital Saint Louis, University Paris 7, INSERM U976, France. IN - Ferraresi, Virginia. Istituti Fisioterapici Ospitalieri, Rome, Italy. IN - Smylie, Michael. Cross Cancer Institute, Edmonton, Alberta, Canada. IN - Weber, Jeffrey S. H Lee Moffitt Cancer Center, Tampa, FL, USA. IN - Maio, Michele. University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. IN - Konto, Cyril. Bristol-Myers Squibb, Wallingford, CT, USA. IN - Hoos, Axel. Bristol-Myers Squibb, Wallingford, CT, USA. IN - de Pril, Veerle. Bristol-Myers Squibb, Braine-l'Alleud, Belgium. IN - Gurunath, Ravichandra Karra. EORTC Headquarters, Brussels, Belgium. IN - de Schaetzen, Gaetan. EORTC Headquarters, Brussels, Belgium. IN - Suciu, Stefan. EORTC Headquarters, Brussels, Belgium. IN - Testori, Alessandro. European Institute of Oncology, Milan, Italy. TI - Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial.[Erratum appears in Lancet Oncol. 2015 Jun;16(6):e262; PMID: 26065611] CM - Comment in: Lancet Oncol. 2015 May;16(5):478-80; PMID: 25840692 SO - Lancet Oncology. 16(5):522-30, 2015 May AS - Lancet Oncol. 16(5):522-30, 2015 May NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - *Adjuvants, Immunologic/ad [Administration & Dosage] MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Combined Modality Therapy MH - Disease-Free Survival MH - Double-Blind Method MH - Female MH - Humans MH - Lymphatic Metastasis MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Melanoma/su [Surgery] MH - Middle Aged MH - *Neoplasm Recurrence, Local/dt [Drug Therapy] MH - Neoplasm Recurrence, Local/pa [Pathology] MH - Neoplasm Recurrence, Local/su [Surgery] AB - BACKGROUND: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. AB - METHODS: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis <=1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. AB - FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2.74 years (IQR 2.28-3.22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26.1 months (95% CI 19.3-39.3) in the ipilimumab group versus 17.1 months (95% CI 13.4-21.6) in the placebo group (hazard ratio 0.75; 95% CI 0.64-0.90; p=0.0013); 3-year recurrence-free survival was 46.5% (95% CI 41.5-51.3) in the ipilimumab group versus 34.8% (30.1-39.5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barre syndrome. AB - INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. AB - FUNDING: Bristol-Myers Squibb. AB - Copyright © 2015 Elsevier Ltd. All rights reserved. RN - 0 (Adjuvants, Immunologic) RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(15)70122-1 DO - https://dx.doi.org/10.1016/S1470-2045(15)70122-1 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't ID - 25840693 [pubmed] ID - S1470-2045(15)70122-1 [pii] ID - 10.1016/S1470-2045(15)70122-1 [doi] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00636168 SL - https://clinicaltrials.gov/search/term=NCT00636168 GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20150331 DP - 2015 May DC - 20150506 EZ - 2015/04/05 06:00 DA - 2015/07/15 06:00 DT - 2015/04/05 06:00 YR - 2015 ED - 20150714 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25840693 <206. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25765457 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Matsumoto K AU - Onda T AU - Yaegashi N FA - Matsumoto, Koji FA - Onda, Takashi FA - Yaegashi, Nobuo IN - Matsumoto, Koji. Division of Medical Oncology, Hyogo Cancer Center, Akashi kojmatsu@hp.pref.hyogo.jp. IN - Onda, Takashi. Division of Gynecology and Obstetrics, Kitasato University, Sagamihara. IN - Yaegashi, Nobuo. Division of Gynecology and Obstetrics, Tohoku University, Sendai, Japan. TI - Pharmacotherapy for recurrent ovarian cancer: current status and future perspectives. [Review] SO - Japanese Journal of Clinical Oncology. 45(5):408-10, 2015 May AS - Jpn J Clin Oncol. 45(5):408-10, 2015 May NJ - Japanese journal of clinical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - kin, 0313225 IO - Jpn. J. Clin. Oncol. SB - Index Medicus CP - England MH - Angiogenesis Inhibitors/pd [Pharmacology] MH - Angiogenesis Inhibitors/tu [Therapeutic Use] MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal, Humanized/ad [Administration & Dosage] MH - Antimetabolites, Antineoplastic/pd [Pharmacology] MH - Antimetabolites, Antineoplastic/tu [Therapeutic Use] MH - *Antineoplastic Agents/pd [Pharmacology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Benzimidazoles/ad [Administration & Dosage] MH - Carboplatin/ad [Administration & Dosage] MH - Deoxycytidine/ad [Administration & Dosage] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Doxorubicin/ad [Administration & Dosage] MH - Doxorubicin/aa [Analogs & Derivatives] MH - Everolimus MH - Female MH - Folic Acid/ad [Administration & Dosage] MH - Folic Acid/aa [Analogs & Derivatives] MH - Humans MH - *Neoplasm Recurrence, Local/dt [Drug Therapy] MH - *Neoplasms, Glandular and Epithelial/dt [Drug Therapy] MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Paclitaxel/ad [Administration & Dosage] MH - Phthalazines/ad [Administration & Dosage] MH - Piperazines/ad [Administration & Dosage] MH - Poly(ADP-ribose) Polymerase Inhibitors MH - Polyethylene Glycols/ad [Administration & Dosage] MH - Pyrimidines/ad [Administration & Dosage] MH - Quinazolines/ad [Administration & Dosage] MH - Recombinant Fusion Proteins/ad [Administration & Dosage] MH - Sirolimus/ad [Administration & Dosage] MH - Sirolimus/aa [Analogs & Derivatives] MH - Sulfonamides/ad [Administration & Dosage] MH - TOR Serine-Threonine Kinases/ai [Antagonists & Inhibitors] MH - Topotecan/ad [Administration & Dosage] MH - Vinca Alkaloids/ad [Administration & Dosage] KW - chemo-gynecology; gynecol-med; molecular Dx AB - Several 'lines of therapy' that utilize cytotoxic agents and are driven by platinum-free intervals are the current standard of care for patients with recurrent ovarian cancer. For patients with platinum-resistant disease, single agent chemotherapy (pegylated liposomal doxorubicin, topotecan, gemcitabine or weekly paclitaxel) is the standard of care. For patients with platinum-sensitive disease, combination chemotherapy (carboplatin plus paclitaxel, pegylated liposomal doxorubicin or gemcitabine) is the standard of care. In addition, antiangiogenic therapy using bevacizumab is an established option. Future directions could include 'lines of therapy' with biologic agents driven by specific biologic targets. Data from antiangiogenic agents (trebananib, pazopanib and cediranib), antifolate drugs (farletuzumab and vintafolide), poly(ADP-ribose) polymerase inhibitors (olaparib and veliparib), mTOR inhibitors (everolimus and temsirolimus) and immune editing agents (nivolumab) have been summarized in this review. AB - Copyright © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. RN - 0 (Angiogenesis Inhibitors) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Antineoplastic Agents) RN - 0 (Benzimidazoles) RN - 0 (EC145) RN - 0 (Phthalazines) RN - 0 (Piperazines) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (Quinazolines) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Sulfonamides) RN - 0 (Vinca Alkaloids) RN - 0 (farletuzumab) RN - 0 (liposomal doxorubicin) RN - 01O4K0631N (veliparib) RN - 0W860991D6 (Deoxycytidine) RN - 30IQX730WE (Polyethylene Glycols) RN - 31YO63LBSN (nivolumab) RN - 624KN6GM2T (temsirolimus) RN - 7M7YKX2N15 (Topotecan) RN - 7RN5DR86CK (pazopanib) RN - 80168379AG (Doxorubicin) RN - 935E97BOY8 (Folic Acid) RN - 9HW64Q8G6G (Everolimus) RN - B76N6SBZ8R (gemcitabine) RN - BG3F62OND5 (Carboplatin) RN - EC 2-7-1-1 (MTOR protein, human) RN - EC 2-7-1-1 (TOR Serine-Threonine Kinases) RN - NQU9IPY4K9 (cediranib) RN - P88XT4IS4D (Paclitaxel) RN - W36ZG6FT64 (Sirolimus) RN - WOH1JD9AR8 (olaparib) RN - X8Y5U6NC7E (trebananib) RS - Ovarian epithelial cancer ES - 1465-3621 IL - 0368-2811 DI - hyv014 DO - https://dx.doi.org/10.1093/jjco/hyv014 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 25765457 [pubmed] ID - hyv014 [pii] ID - 10.1093/jjco/hyv014 [doi] PP - ppublish PH - 2014/10/31 [received] PH - 2015/01/05 [accepted] LG - English EP - 20150311 DP - 2015 May DC - 20150429 EZ - 2015/03/14 06:00 DA - 2015/07/15 06:00 DT - 2015/03/15 06:00 YR - 2015 ED - 20150714 RD - 20151119 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25765457 <207. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25867264 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Abiko K AU - Matsumura N AU - Hamanishi J AU - Horikawa N AU - Murakami R AU - Yamaguchi K AU - Yoshioka Y AU - Baba T AU - Konishi I AU - Mandai M FA - Abiko, K FA - Matsumura, N FA - Hamanishi, J FA - Horikawa, N FA - Murakami, R FA - Yamaguchi, K FA - Yoshioka, Y FA - Baba, T FA - Konishi, I FA - Mandai, M IN - Abiko, K. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Matsumura, N. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Hamanishi, J. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Horikawa, N. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Murakami, R. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Yamaguchi, K. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Yoshioka, Y. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Baba, T. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Konishi, I. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. IN - Mandai, M. Department of Obstetrics and Gynecology, Faculty of Medicine, Kinki University, 377-2 Onohigashi, Osakasayama, Osaka 589-0014, Japan. TI - IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. SO - British Journal of Cancer. 112(9):1501-9, 2015 Apr 28 AS - Br J Cancer. 112(9):1501-9, 2015 Apr 28 NJ - British journal of cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - av4, 0370635 IO - Br. J. Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453666 SB - Index Medicus CP - England MH - Animals MH - *Antigens, CD274/me [Metabolism] MH - Apoptosis MH - Blotting, Western MH - CD8-Positive T-Lymphocytes/de [Drug Effects] MH - *CD8-Positive T-Lymphocytes/im [Immunology] MH - CD8-Positive T-Lymphocytes/pa [Pathology] MH - Cell Proliferation MH - Disease Progression MH - Female MH - Flow Cytometry MH - Humans MH - Immunoenzyme Techniques MH - *Interferon-gamma/pd [Pharmacology] MH - Lymphocytes, Tumor-Infiltrating/de [Drug Effects] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Lymphocytes, Tumor-Infiltrating/pa [Pathology] MH - Mice MH - Mice, Inbred C57BL MH - Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/im [Immunology] MH - *Ovarian Neoplasms/me [Metabolism] MH - *Ovarian Neoplasms/pa [Pathology] MH - Peritoneal Neoplasms/dt [Drug Therapy] MH - Peritoneal Neoplasms/im [Immunology] MH - *Peritoneal Neoplasms/me [Metabolism] MH - *Peritoneal Neoplasms/sc [Secondary] MH - Prognosis MH - Tumor Cells, Cultured MH - Tumor Microenvironment/de [Drug Effects] MH - Up-Regulation MH - Xenograft Model Antitumor Assays AB - BACKGROUND: PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear. AB - METHODS: The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-gamma signals was assessed. AB - RESULTS: The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-gamma receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-gamma into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-gamma injection (P=0.01). AB - CONCLUSIONS: Interferon-gamma secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-gamma status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer. RN - 0 (Antigens, CD274) RN - 82115-62-6 (Interferon-gamma) ES - 1532-1827 IL - 0007-0920 DI - bjc2015101 DO - https://dx.doi.org/10.1038/bjc.2015.101 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25867264 [pubmed] ID - bjc2015101 [pii] ID - 10.1038/bjc.2015.101 [doi] ID - PMC4453666 [pmc] PP - ppublish PH - 2014/12/22 [received] PH - 2015/02/19 [revised] PH - 2015/02/19 [accepted] LG - English EP - 20150331 DP - 2015 Apr 28 DC - 20150429 EZ - 2015/04/14 06:00 DA - 2015/07/15 06:00 DT - 2015/04/14 06:00 YR - 2015 ED - 20150709 RD - 20160428 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25867264 <208. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25801435 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Buddhisa S AU - Rinchai D AU - Ato M AU - Bancroft GJ AU - Lertmemongkolchai G FA - Buddhisa, Surachat FA - Rinchai, Darawan FA - Ato, Manabu FA - Bancroft, Gregory J FA - Lertmemongkolchai, Ganjana IN - Buddhisa, Surachat. Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; IN - Rinchai, Darawan. Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; IN - Ato, Manabu. Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; and. IN - Bancroft, Gregory J. Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London WC1E 7HT, United Kingdom. IN - Lertmemongkolchai, Ganjana. Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand; ganja_le@kku.ac.th. TI - Programmed death ligand 1 on Burkholderia pseudomallei-infected human polymorphonuclear neutrophils impairs T cell functions. SO - Journal of Immunology. 194(9):4413-21, 2015 May 01 AS - J Immunol. 194(9):4413-21, 2015 May 01 NJ - Journal of immunology (Baltimore, Md. : 1950) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ifb, 2985117r IO - J. Immunol. SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - Aged MH - *Antigens, CD274/me [Metabolism] MH - *Burkholderia pseudomallei/im [Immunology] MH - CD4-Positive T-Lymphocytes/im [Immunology] MH - CD4-Positive T-Lymphocytes/me [Metabolism] MH - Cell Communication MH - Diabetes Mellitus, Type 2/im [Immunology] MH - Diabetes Mellitus, Type 2/me [Metabolism] MH - Female MH - Humans MH - Immunomodulation MH - Male MH - Melioidosis/im [Immunology] MH - Melioidosis/me [Metabolism] MH - Middle Aged MH - *Neutrophils/im [Immunology] MH - *Neutrophils/me [Metabolism] MH - Neutrophils/mi [Microbiology] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - Signal Transduction MH - *T-Lymphocyte Subsets/im [Immunology] MH - *T-Lymphocyte Subsets/me [Metabolism] AB - Polymorphonuclear neutrophils (PMNs) are terminally differentiated cells that are involved in innate immune responses and form an early line of defense against pathogens. More recently, it has been shown that PMNs have immunosuppressive abilities on other immune cells. However, the effect of PMNs on T cell responses during bacterial infection remains to be determined. In this report, we examined the interaction of PMNs and T cells in response to infection with Burkholderia pseudomallei, the causative agent of human melioidosis. We observed that CD4(+) T cell proliferation and IFN-gamma production in response to polyclonal activators is significantly inhibited by uninfected PMNs, and to a greater extent B. pseudomallei-infected PMNs. Programmed death ligand 1 (PD-L1), a known regulator of T cell activation, is increased in mRNA expression in the blood of patients and upon infection of PMNs in vitro. The increased expression of PD-L1 was correlated with the degree of T cell inhibition in individuals with type 2 diabetes, a major risk factor of melioidosis. In vitro, addition of anti-PD-L1 Abs blocked this inhibitory activity and restored proliferation of CD4(+) T cells and IFN-gamma production, suggesting that PD-L1 on B. pseudomallei-infected PMNs is a regulatory molecule for the functions of T cells and may be involved in pathogenesis versus control of melioidosis. AB - Copyright © 2015 by The American Association of Immunologists, Inc. RN - 0 (Antigens, CD274) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1550-6606 IL - 0022-1767 DI - jimmunol.1402417 DO - https://dx.doi.org/10.4049/jimmunol.1402417 PT - Journal Article ID - 25801435 [pubmed] ID - jimmunol.1402417 [pii] ID - 10.4049/jimmunol.1402417 [doi] PP - ppublish PH - 2014/09/23 [received] PH - 2015/02/18 [accepted] LG - English EP - 20150323 DP - 2015 May 01 DC - 20150418 EZ - 2015/03/25 06:00 DA - 2015/07/01 06:00 DT - 2015/03/25 06:00 YR - 2015 ED - 20150630 RD - 20150418 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25801435 <209. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25207976 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - McElnea E AU - Ni Mhealoid A AU - Moran S AU - Kelly R AU - Fulcher T FA - McElnea, Elizabeth FA - Ni Mhealoid, Aine FA - Moran, Sarah FA - Kelly, Rory FA - Fulcher, Tim IN - McElnea, Elizabeth. Department of Ophthalmology, Mater Misericordiae University Hospital , Dublin , Ireland. TI - Thyroid-like ophthalmopathy in a euthyroid patient receiving Ipilimumab. SO - Orbit. 33(6):424-7, 2014 Dec AS - Orbit. 33(6):424-7, 2014 Dec NJ - Orbit (Amsterdam, Netherlands) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 8301221 IO - Orbit SB - Index Medicus CP - England MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Euthyroid Sick Syndromes/bl [Blood] MH - *Euthyroid Sick Syndromes/co [Complications] MH - Exophthalmos/ci [Chemically Induced] MH - Exophthalmos/di [Diagnosis] MH - Female MH - Glucocorticoids/tu [Therapeutic Use] MH - *Graves Ophthalmopathy/ci [Chemically Induced] MH - Graves Ophthalmopathy/di [Diagnosis] MH - Graves Ophthalmopathy/dt [Drug Therapy] MH - Humans MH - Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Methylprednisolone/tu [Therapeutic Use] MH - Ophthalmoplegia/ci [Chemically Induced] MH - Ophthalmoplegia/di [Diagnosis] MH - Thyroid Function Tests MH - Thyrotropin/bl [Blood] MH - Thyroxine/bl [Blood] KW - Ipilimumab; myositis; thyroid eye disease; thyroid orbitopathy AB - A 68-year-old lady with metastatic malignant melanoma was treated with Ipilimumab. She presented to Eye Casualty unable to move her eyes. Physical examination confirmed ophthalmoplegia and identified proptosis bilaterally. Radiological imaging showed bilateral enlargement of all the extra-ocular muscles suggestive of thyroid eye disease. Laboratory investigations found this patient to be euthyroid. A diagnosis of thyroid-like orbitopathy secondary to Ipilimumab therapy was made. Thyroid function tests should be performed for all patients prior to their commencement of Ipilimumab. Thyroid-like eye disease may develop in patients treated with Ipilimumab even if they remain euthyroid. RN - 0 (Antibodies, Monoclonal) RN - 0 (Glucocorticoids) RN - 6T8C155666 (ipilimumab) RN - 9002-71-5 (Thyrotropin) RN - Q51BO43MG4 (Thyroxine) RN - X4W7ZR7023 (Methylprednisolone) ES - 1744-5108 IL - 0167-6830 DO - https://dx.doi.org/10.3109/01676830.2014.949792 PT - Case Reports PT - Journal Article ID - 25207976 [pubmed] ID - 10.3109/01676830.2014.949792 [doi] PP - ppublish LG - English EP - 20140910 DP - 2014 Dec DC - 20141028 EZ - 2014/09/11 06:00 DA - 2015/05/20 06:00 DT - 2014/09/11 06:00 YR - 2014 ED - 20150519 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25207976 <210. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25409618 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wang DH AU - Guo L AU - Wu XH FA - Wang, Dong-hui FA - Guo, Liang FA - Wu, Xiao-hua IN - Wang, Dong-hui. First Department of Gynecology, Cangzhou Central Hospital, Cangzhou, 061001, Hebei, China, czwangdonghui@hotmail.com. TI - Checkpoint inhibitors in immunotherapy of ovarian cancer. [Review] SO - Tumour Biology. 36(1):33-9, 2015 Jan AS - Tumour Biol. 36(1):33-9, 2015 Jan NJ - Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - tub, 8409922 IO - Tumour Biol. SB - Index Medicus CP - Netherlands MH - Animals MH - *Antineoplastic Agents/pd [Pharmacology] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Apoptosis/de [Drug Effects] MH - Cell Cycle Checkpoints/de [Drug Effects] MH - Female MH - Humans MH - *Immunologic Factors/pd [Pharmacology] MH - Immunologic Factors/tu [Therapeutic Use] MH - Immunotherapy MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/th [Therapy] MH - T-Lymphocytes, Cytotoxic/de [Drug Effects] AB - The treatment of ovarian cancer is a major challenge in oncology as mortality from ovarian cancer remains very high. The immune system plays a critical role in controlling cancer through a dynamic relationship with cancer cells. Immunotherapy can establish a sustained immune system response against recurring cancer cells leading to long-term remissions for ovarian cancer patient. The use of immune checkpoint inhibitors, which work by targeting molecules that serve as checks and balances in the regulation of immune responses, might be a promising avenue of immunotherapeutic research in ovarian cancer. In this review, we have focused on the potential of certain immune checkpoint inhibitors, such as anti-cytotoxic T lymphocyte antigens, anti-programmed death agents, and anti-program death ligands against ovarian cancer, with their mechanism of actions. Also, the problems arising due to checkpoint inhibitor immunotherapy have been discussed in this review. Checkpoint inhibitor immunotherapy is still in early-phase testing for ovarian cancer. Understanding the pivotal role of the tumor microenvironment in suppressing anticancer immunity, the unique adverse effects profiles of these agents, and the exploration of combinatorial treatment regimens will ultimately lead to enhance the efficacy of ovarian cancer immunotherapies and improved patient care. RN - 0 (Antineoplastic Agents) RN - 0 (Immunologic Factors) ES - 1423-0380 IL - 1010-4283 DO - https://dx.doi.org/10.1007/s13277-014-2848-2 PT - Journal Article PT - Review ID - 25409618 [pubmed] ID - 10.1007/s13277-014-2848-2 [doi] PP - ppublish PH - 2014/10/10 [received] PH - 2014/11/12 [accepted] LG - English EP - 20141120 DP - 2015 Jan DC - 20150203 EZ - 2014/11/21 06:00 DA - 2015/05/12 06:00 DT - 2014/11/21 06:00 YR - 2015 ED - 20150511 RD - 20150203 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25409618 <211. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25409618 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wang DH AU - Guo L AU - Wu XH FA - Wang, Dong-hui FA - Guo, Liang FA - Wu, Xiao-hua IN - Wang, Dong-hui. First Department of Gynecology, Cangzhou Central Hospital, Cangzhou, 061001, Hebei, China, czwangdonghui@hotmail.com. TI - Checkpoint inhibitors in immunotherapy of ovarian cancer. [Review] SO - Tumour Biology. 36(1):33-9, 2015 Jan AS - Tumour Biol. 36(1):33-9, 2015 Jan NJ - Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - tub, 8409922 IO - Tumour Biol. SB - Index Medicus CP - United States MH - Animals MH - *Antineoplastic Agents/pd [Pharmacology] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Apoptosis/de [Drug Effects] MH - Cell Cycle Checkpoints/de [Drug Effects] MH - Female MH - Humans MH - *Immunologic Factors/pd [Pharmacology] MH - Immunologic Factors/tu [Therapeutic Use] MH - Immunotherapy MH - *Ovarian Neoplasms/im [Immunology] MH - Ovarian Neoplasms/th [Therapy] MH - T-Lymphocytes, Cytotoxic/de [Drug Effects] AB - The treatment of ovarian cancer is a major challenge in oncology as mortality from ovarian cancer remains very high. The immune system plays a critical role in controlling cancer through a dynamic relationship with cancer cells. Immunotherapy can establish a sustained immune system response against recurring cancer cells leading to long-term remissions for ovarian cancer patient. The use of immune checkpoint inhibitors, which work by targeting molecules that serve as checks and balances in the regulation of immune responses, might be a promising avenue of immunotherapeutic research in ovarian cancer. In this review, we have focused on the potential of certain immune checkpoint inhibitors, such as anti-cytotoxic T lymphocyte antigens, anti-programmed death agents, and anti-program death ligands against ovarian cancer, with their mechanism of actions. Also, the problems arising due to checkpoint inhibitor immunotherapy have been discussed in this review. Checkpoint inhibitor immunotherapy is still in early-phase testing for ovarian cancer. Understanding the pivotal role of the tumor microenvironment in suppressing anticancer immunity, the unique adverse effects profiles of these agents, and the exploration of combinatorial treatment regimens will ultimately lead to enhance the efficacy of ovarian cancer immunotherapies and improved patient care. RN - 0 (Antineoplastic Agents) RN - 0 (Immunologic Factors) ES - 1423-0380 IL - 1010-4283 DO - https://dx.doi.org/10.1007/s13277-014-2848-2 PT - Journal Article PT - Review ID - 25409618 [pubmed] ID - 10.1007/s13277-014-2848-2 [doi] PP - ppublish PH - 2014/10/10 [received] PH - 2014/11/12 [accepted] LG - English EP - 20141120 DP - 2015 Jan DC - 20150203 EZ - 2014/11/21 06:00 DA - 2015/05/12 06:00 DT - 2014/11/21 06:00 YR - 2015 ED - 20150511 RD - 20170124 UP - 20170126 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=25409618 <212. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25918658 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Yun S AU - Vincelette ND AU - Mansour I AU - Hariri D AU - Motamed S AI - Yun, Seongseok; ORCID: https://orcid.org/0000-0001-7343-1635 FA - Yun, Seongseok FA - Vincelette, Nicole D FA - Mansour, Iyad FA - Hariri, Dana FA - Motamed, Sara IN - Yun, Seongseok. Department of Medicine, University of Arizona, Tucson, AZ 85721, USA. IN - Vincelette, Nicole D. Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA. IN - Mansour, Iyad. Department of Medicine, University of Arizona, Tucson, AZ 85721, USA. IN - Hariri, Dana. Department of Pathology, University of Arizona, Tucson, AZ 85721, USA. IN - Motamed, Sara. Midwestern University, Arizona College of Osteopathic Medicine, Glendale, AZ 85308, USA. TI - Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication. SO - Case Reports in Oncological Medicine. 2015:794842, 2015 AS - Case Rep Oncol Med. 2015:794842, 2015 NJ - Case reports in oncological medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101581035 IO - Case Rep Oncol Med PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396732 CP - United States AB - Metastatic cutaneous melanoma has poor prognosis with 2-year survival rate of 10-20%. Melanoma cells express various antigens including gp100, melanoma antigen recognized by T cells 1 (MART-1), and tyrosinase, which can induce immune-mediated anticancer response via T cell activation. Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is an immune check point molecule that negatively regulates T cell activation and proliferation. Accordingly, recent phase III clinical trials demonstrated significant survival benefit with ipilimumab, a human monoclonal antibody (IgG1) that blocks the interaction of CTLA-4 with its ligands. Since the efficacy of ipilimumab depends on T cell activation, it is associated with substantial risk of immune mediated adverse reactions such as colitis, hepatitis, thyroiditis, and hypophysitis. We report the first case of late onset pericarditis and cardiac tamponade associated with ipilimumab treatment in patient with metastatic cutaneous melanoma. IS - 2090-6706 DO - https://dx.doi.org/10.1155/2015/794842 PT - Journal Article ID - 25918658 [pubmed] ID - 10.1155/2015/794842 [doi] ID - PMC4396732 [pmc] PP - ppublish PH - 2015/02/11 [received] PH - 2015/03/23 [accepted] LG - English EP - 20150330 DP - 2015 DC - 20150428 EZ - 2015/04/29 06:00 DA - 2015/04/29 06:01 DT - 2015/04/29 06:00 YR - 2015 ED - 20150428 RD - 20150430 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=25918658 <213. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25582496 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Schultheis AM AU - Scheel AH AU - Ozretic L AU - George J AU - Thomas RK AU - Hagemann T AU - Zander T AU - Wolf J AU - Buettner R FA - Schultheis, Anne M FA - Scheel, Andreas H FA - Ozretic, Luka FA - George, Julie FA - Thomas, Roman K FA - Hagemann, Thorsten FA - Zander, Thomas FA - Wolf, Jurgen FA - Buettner, Reinhard IN - Schultheis, Anne M. Institute of Pathology, University Hospital Cologne, Cologne, Germany. Electronic address: anne.schultheis@uk-koeln.de. IN - Scheel, Andreas H. Institute of Pathology, University Hospital Cologne, Cologne, Germany. IN - Ozretic, Luka. Institute of Pathology, University Hospital Cologne, Cologne, Germany. IN - George, Julie. Department of Translational Genomics, University of Cologne, Cologne, Germany. IN - Thomas, Roman K. Department of Translational Genomics, University of Cologne, Cologne, Germany. IN - Hagemann, Thorsten. Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London, UK. IN - Zander, Thomas. Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Cologne/Bonn, Germany. IN - Wolf, Jurgen. Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Cologne/Bonn, Germany. IN - Buettner, Reinhard. Institute of Pathology, University Hospital Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Cologne/Bonn, Germany. TI - PD-L1 expression in small cell neuroendocrine carcinomas. CM - Comment in: Eur J Cancer. 2015 Sep;51(13):1853-5; PMID: 26148861 SO - European Journal of Cancer. 51(3):421-6, 2015 Feb AS - Eur J Cancer. 51(3):421-6, 2015 Feb NJ - European journal of cancer (Oxford, England : 1990) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - arv, 9005373 IO - Eur. J. Cancer SB - Index Medicus CP - England MH - *Antigens, CD274/ge [Genetics] MH - *Antigens, CD274/me [Metabolism] MH - *Carcinoma, Small Cell/ge [Genetics] MH - *Carcinoma, Small Cell/me [Metabolism] MH - Carcinoma, Small Cell/pa [Pathology] MH - Gene Expression Regulation, Neoplastic MH - High-Throughput Nucleotide Sequencing MH - Humans MH - Immunohistochemistry MH - Lung Neoplasms/ge [Genetics] MH - Lung Neoplasms/me [Metabolism] MH - Lung Neoplasms/pa [Pathology] MH - Lymphocytes, Tumor-Infiltrating/me [Metabolism] MH - Macrophages/me [Metabolism] MH - Neoplasm Metastasis MH - *Neuroendocrine Tumors/ge [Genetics] MH - *Neuroendocrine Tumors/me [Metabolism] MH - Neuroendocrine Tumors/pa [Pathology] MH - Programmed Cell Death 1 Ligand 2 Protein/ge [Genetics] MH - Programmed Cell Death 1 Ligand 2 Protein/me [Metabolism] MH - Programmed Cell Death 1 Receptor/ge [Genetics] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - Tissue Array Analysis KW - Immunohistochemistry; PD-L1; Small cell lung cancer; Small cell neuroendocrine carcinoma AB - Small cell lung cancer and extrapulmonary small cell carcinomas are the most aggressive type of neuroendocrine carcinomas. Clinical treatment relies on conventional chemotherapy and radiotherapy; relapses are frequent. The PD-1/PD-L1/PD-L2 pathway is a major target of anti-tumour immunotherapy. Aberrant PD-L1 or PD-L2 expression may cause local immune-suppression. Here we investigated expression of PD-1 and its ligands by immunohistochemistry and RNA-seq in small cell carcinomas. PD-L1 and PD-1 protein expression were analysed in 94 clinical cases of small cell carcinomas (61 pulmonary, 33 extrapulmonary) by immunohistochemistry using two different monoclonal antibodies (5H1, E1L3N). RNA expression was profiled by RNA-seq in 43 clinical cases. None of the small cell carcinomas showed PD-L1 protein expression in tumour cells. PD-L1 and PD-1 expression was noticed in the stroma: Using immunohistochemistry, 18.5% of cases (17/92) showed PD-L1 expression in tumour-infiltrating macrophages and 48% showed PD-1 positive lymphocytes (45/94). RNA-seq showed moderate PD-L1 gene expression in 37.2% (16/43). PD-L1 was correlated with macrophage and T-cell markers. The second PD-1 ligand PD-L2 was expressed in 27.9% (12/43) and showed similar correlations. Thus, the PD-1/PD-L1 pathway seems activated in a fraction of small cell carcinomas. The carcinoma cells were negative in all cases, PD-L1 was expressed in tumour-infiltrating macrophages and was correlated with tumour-infiltrating lymphocytes. Patients with stromal PD-L1/PD-L2 expression may respond to anti-PD-1 treatment. Thus, evaluation of the composition of the tumour microenvironment should be included in clinical trials. Besides conventional immunohistochemistry, RNA-seq seems suitable for detection of PD-L1/PD-L2 expression and might prove to be more sensitive. AB - Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved. RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (PDCD1LG2 protein, human) RN - 0 (Programmed Cell Death 1 Ligand 2 Protein) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1879-0852 IL - 0959-8049 DI - S0959-8049(14)01166-6 DO - https://dx.doi.org/10.1016/j.ejca.2014.12.006 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25582496 [pubmed] ID - S0959-8049(14)01166-6 [pii] ID - 10.1016/j.ejca.2014.12.006 [doi] PP - ppublish PH - 2014/07/17 [received] PH - 2014/10/22 [revised] PH - 2014/12/11 [accepted] LG - English EP - 20150109 DP - 2015 Feb DC - 20150204 EZ - 2015/01/14 06:00 DA - 2015/04/16 06:00 DT - 2015/01/15 06:00 YR - 2015 ED - 20150415 RD - 20151016 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25582496 <214. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25099440 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Nallapaneni NN AU - Mourya R AU - Bhatt VR AU - Malhotra S AU - Ganti AK AU - Tendulkar KK FA - Nallapaneni, Neelima N FA - Mourya, Rajesh FA - Bhatt, Vijaya Raj FA - Malhotra, Sakshi FA - Ganti, Apar Kishor FA - Tendulkar, Ketki K IN - Nallapaneni, Neelima N. From the University of Nebraska Medical Center, Department of Internal Medicine, Division of Nephrology; Creighton University Medical Center, Department of Internal Medicine; University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology; VA Nebraska-Western Iowa Health Care System, Department of Internal Medicine; and VA Nebraska-Western Iowa Health Care System, and University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology, Omaha, Nebraska. IN - Mourya, Rajesh. From the University of Nebraska Medical Center, Department of Internal Medicine, Division of Nephrology; Creighton University Medical Center, Department of Internal Medicine; University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology; VA Nebraska-Western Iowa Health Care System, Department of Internal Medicine; and VA Nebraska-Western Iowa Health Care System, and University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology, Omaha, Nebraska. IN - Bhatt, Vijaya Raj. From the University of Nebraska Medical Center, Department of Internal Medicine, Division of Nephrology; Creighton University Medical Center, Department of Internal Medicine; University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology; VA Nebraska-Western Iowa Health Care System, Department of Internal Medicine; and VA Nebraska-Western Iowa Health Care System, and University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology, Omaha, Nebraska. IN - Malhotra, Sakshi. From the University of Nebraska Medical Center, Department of Internal Medicine, Division of Nephrology; Creighton University Medical Center, Department of Internal Medicine; University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology; VA Nebraska-Western Iowa Health Care System, Department of Internal Medicine; and VA Nebraska-Western Iowa Health Care System, and University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology, Omaha, Nebraska. IN - Ganti, Apar Kishor. From the University of Nebraska Medical Center, Department of Internal Medicine, Division of Nephrology; Creighton University Medical Center, Department of Internal Medicine; University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology; VA Nebraska-Western Iowa Health Care System, Department of Internal Medicine; and VA Nebraska-Western Iowa Health Care System, and University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology, Omaha, Nebraska. IN - Tendulkar, Ketki K. From the University of Nebraska Medical Center, Department of Internal Medicine, Division of Nephrology; Creighton University Medical Center, Department of Internal Medicine; University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology; VA Nebraska-Western Iowa Health Care System, Department of Internal Medicine; and VA Nebraska-Western Iowa Health Care System, and University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology and Oncology, Omaha, Nebraska. TI - Ipilimumab-induced hypophysitis and uveitis in a patient with metastatic melanoma and a history of ipilimumab-induced skin rash. SO - Journal of the National Comprehensive Cancer Network. 12(8):1077-81, 2014 Aug AS - J. Natl. Compr. Cancer Netw.. 12(8):1077-81, 2014 Aug NJ - Journal of the National Comprehensive Cancer Network : JNCCN PI - Journal available in: Print PI - Citation processed from: Internet JC - 101162515 IO - J Natl Compr Canc Netw SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Drug-Related Side Effects and Adverse Reactions/im [Immunology] MH - *Drug-Related Side Effects and Adverse Reactions/pa [Pathology] MH - Exanthema/ci [Chemically Induced] MH - Exanthema/im [Immunology] MH - *Exanthema/pa [Pathology] MH - Humans MH - Male MH - Melanoma/co [Complications] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Pituitary Diseases/ci [Chemically Induced] MH - Pituitary Diseases/pa [Pathology] MH - Uveitis/ci [Chemically Induced] MH - Uveitis/pa [Pathology] AB - Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4, leading to enhanced T-cell activation and proliferation, is associated with improved overall survival in melanoma. Its use can result in immune-related adverse events, the most common of which are skin rash, diarrhea, and colitis. Ipilimumab-induced hypophysitis is uncommon, mostly involves anterior pituitary, and is associated with abnormalities in pituitary MRI, whereas uveitis has been rarely reported. These immune-related adverse events occur during therapy. This report describes a patient who developed uveitis and hypophysitis involving both anterior and posterior pituitary, without MRI findings more than 3 weeks after the fourth dose of ipilimumab. This case illustrates the unusual presentation of and diagnostic challenges associated with ipilimumab-induced immune-related adverse events. AB - Copyright © 2014 by the National Comprehensive Cancer Network. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) ES - 1540-1413 IL - 1540-1405 DI - 12/8/1077 PT - Case Reports PT - Journal Article ID - 25099440 [pubmed] ID - 12/8/1077 [pii] PP - ppublish LG - English DP - 2014 Aug DC - 20140807 EZ - 2014/08/08 06:00 DA - 2015/04/14 06:00 DT - 2014/08/08 06:00 YR - 2014 ED - 20150413 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25099440 <215. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25861234 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Mahzari M AU - Liu D AU - Arnaout A AU - Lochnan H FA - Mahzari, Moeber FA - Liu, Dora FA - Arnaout, Amel FA - Lochnan, Heather IN - Mahzari, Moeber. Division of Endocrinology and Metabolism, Department of Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, Canada. IN - Liu, Dora. Division of Endocrinology and Metabolism, Department of Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, Canada. IN - Arnaout, Amel. Division of Endocrinology and Metabolism, Department of Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, Canada. IN - Lochnan, Heather. Division of Endocrinology and Metabolism, Department of Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, Canada. TI - Immune checkpoint inhibitor therapy associated hypophysitis. [Review] SO - Clinical Medicine Insights. 8:21-8, 2015 AS - Clin Med Insights Endocrinol Diabetes. 8:21-8, 2015 NJ - Clinical medicine insights. Endocrinology and diabetes PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101578235 IO - Clin Med Insights Endocrinol Diabetes PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376202 CP - United States KW - CTLA4; hypoadrenalism; hypophysitis; ipilimumab AB - Ipilimumab is a monoclonal antibody directed against CTLA4 T-lymphocyte antigen used as cancer therapy. Immune-related adverse events are common side effects and may include hypophysitis-related hypopituitarism. The clinical features of six patients with ipilimumab-induced hypophysitis (IH) are described. The clinical features of IH reported in clinical trials, including the incidence of IH by gender and the likelihood of adrenal axis recovery, are summarized. Following the development of IH, most patients remain on glucocorticoid replacement despite efforts to withdraw therapy. Analysis of gender information in published clinical trials suggests that men are more prone to developing IH than women, and few patients fully recover the pituitary-adrenal axis function. Ipilimumab and other drugs within its class are likely to be used to treat many forms of cancer. Endocrinologists should anticipate a significant increase in the incidence of autoimmune hypophysitis. Strategies for early detection of IH and long-term management should be considered. IL - 1179-5514 DI - cmed-8-2015-021 DO - https://dx.doi.org/10.4137/CMED.S22469 PT - Journal Article PT - Review ID - 25861234 [pubmed] ID - 10.4137/CMED.S22469 [doi] ID - cmed-8-2015-021 [pii] ID - PMC4376202 [pmc] PP - epublish PH - 2014/12/05 [received] PH - 2015/01/26 [revised] PH - 2015/01/28 [accepted] LG - English EP - 20150325 DP - 2015 DC - 20150411 EZ - 2015/04/11 06:00 DA - 2015/04/11 06:01 DT - 2015/04/11 06:00 YR - 2015 ED - 20150411 RD - 20161024 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=25861234 <216. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25104095 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bryant C AU - Rawlinson R AU - Massey AJ FA - Bryant, Christopher FA - Rawlinson, Rebecca FA - Massey, Andrew J IN - Massey, Andrew J. Vernalis R&D Ltd, Granta Park, Cambridge CB21 6GB, UK. a.massey@vernalis.com. TI - Chk1 inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers. SO - BMC Cancer. 14:570, 2014 Aug 07 AS - BMC Cancer. 14:570, 2014 Aug 07 NJ - BMC cancer PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 100967800 IO - BMC Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137066 SB - Index Medicus CP - England MH - Benzodiazepinones/pd [Pharmacology] MH - Benzodiazepinones/tu [Therapeutic Use] MH - *Biomarkers, Tumor/me [Metabolism] MH - Cell Line, Tumor MH - Checkpoint Kinase 1 MH - Cisplatin/pd [Pharmacology] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Drug Synergism MH - Female MH - Gene Expression Regulation, Neoplastic/de [Drug Effects] MH - HT29 Cells MH - Humans MH - *Indoles/pd [Pharmacology] MH - Indoles/tu [Therapeutic Use] MH - MCF-7 Cells MH - *Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - Protein Kinase Inhibitors/tu [Therapeutic Use] MH - *Protein Kinases/me [Metabolism] MH - Pyrazoles/pd [Pharmacology] MH - Pyrazoles/tu [Therapeutic Use] MH - *Pyridones/pd [Pharmacology] MH - Pyridones/tu [Therapeutic Use] MH - Thiophenes/pd [Pharmacology] MH - Thiophenes/tu [Therapeutic Use] MH - *Triple Negative Breast Neoplasms/me [Metabolism] MH - Triple Negative Breast Neoplasms/pa [Pathology] MH - Urea/aa [Analogs & Derivatives] MH - Urea/pd [Pharmacology] MH - Urea/tu [Therapeutic Use] AB - BACKGROUND: Chk1 inhibitors are currently in clinical trials as putative potentiators of cytotoxic chemotherapy drugs. Chk1 inhibitors may exhibit single agent anti-tumor activity in cancers with underlying DNA repair, DNA damage response or DNA replication defects. AB - METHODS: Here we describe the cellular effects of the pharmacological inhibition of the checkpoint kinase Chk1 by the novel inhibitor V158411 in triple-negative breast cancer and ovarian cancer. Cytotoxicity, the effect on DNA damage response and cell cycle along with the ability to potentiate gemcitabine and cisplatin cytotoxicity in cultured cells was investigated. Western blotting of proteins involved in DNA repair, checkpoint activation, cell cycle and apoptosis was used to identify potential predictive biomarkers of Chk1 inhibitor sensitivity. AB - RESULTS: The Chk1 inhibitors V158411, PF-477736 and AZD7762 potently inhibited the proliferation of triple-negative breast cancer cells as well as ovarian cancer cells, and these cell lines were sensitive compared to ER positive breast and other solid cancer cells lines. Inhibition of Chk1 in these sensitive cell lines induced DNA damage and caspase-3/7 dependent apoptosis. Western blot profiling identified pChk1 (S296) as a predictive biomarker of Chk1 inhibitor sensitivity in ovarian and triple-negative breast cancer and pH2AX (S139) in luminal breast cancer. AB - CONCLUSIONS: This finding suggests that Chk1 inhibitors either as single agents or in combination chemotherapy represents a viable therapeutic option for the treatment of triple-negative breast cancer. pChk1 (S296) tumor expression levels could serve as a useful biomarker to stratify patients who might benefit from Chk1 inhibitor therapy. RN - 0 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide) RN - 0 (Benzodiazepinones) RN - 0 (Biomarkers, Tumor) RN - 0 (Indoles) RN - 0 (PF 00477736) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Pyridones) RN - 0 (Thiophenes) RN - 0 (V158411) RN - 0W860991D6 (Deoxycytidine) RN - 8W8T17847W (Urea) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - Q20Q21Q62J (Cisplatin) ES - 1471-2407 IL - 1471-2407 DI - 1471-2407-14-570 DO - https://dx.doi.org/10.1186/1471-2407-14-570 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25104095 [pubmed] ID - 1471-2407-14-570 [pii] ID - 10.1186/1471-2407-14-570 [doi] ID - PMC4137066 [pmc] PP - epublish PH - 2014/05/01 [received] PH - 2014/07/28 [accepted] LG - English EP - 20140807 DP - 2014 Aug 07 DC - 20140816 EZ - 2014/08/09 06:00 DA - 2015/04/08 06:00 DT - 2014/08/12 06:00 YR - 2014 ED - 20150407 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25104095 <217. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24986059 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Simeone E AU - Grimaldi AM AU - Esposito A AU - Curvietto M AU - Palla M AU - Paone M AU - Mozzillo N AU - Ascierto PA FA - Simeone, Ester FA - Grimaldi, Antonio Maria FA - Esposito, Assunta FA - Curvietto, Marcello FA - Palla, Marco FA - Paone, Miriam FA - Mozzillo, Nicola FA - Ascierto, Paolo Antonio IN - Ascierto, Paolo Antonio. Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori Fondazione "G, Pascale", Via Mariano Semmola, 80131 Napoli, Italy. paolo.ascierto@gmail.com. TI - Serious haematological toxicity during and after ipilimumab treatment: a case series. SO - Journal of Medical Case Reports [Electronic Resource]. 8:240, 2014 Jul 01 AS - J Med Case Reports. 8:240, 2014 Jul 01 NJ - Journal of medical case reports PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101293382 IO - J Med Case Rep PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090655 SB - Index Medicus CP - England MH - Aged MH - *Anemia/ci [Chemically Induced] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Female MH - Humans MH - Male MH - Middle Aged MH - Neoplasms/dt [Drug Therapy] MH - *Neutropenia/ci [Chemically Induced] MH - Severity of Illness Index AB - INTRODUCTION: Immunotherapy with the anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody ipilimumab has been shown to improve overall survival in previously treated and treatment-naive patients with unresectable stage III or IV melanoma. Consistent with its proposed immunomodulating mechanism of action, the most common toxicities associated with ipilimumab therapy are immune-related in nature and include those related to the skin and gastrointestinal tract, with endocrine and hepatic events also frequent. Other rare adverse events, including haematological aberrations, may also occur and can have serious consequences if unrecognised. Here we describe three patients who developed serious haematological adverse events during or after treatment with ipilimumab. AB - CASE PRESENTATION: Three Caucasian patients (two women aged 68 and 49 years and one man aged 70 years) with metastatic melanoma experienced anaemia and/or leukopenia (neutropenia) with toxicity of various grades during or after treatment with ipilimumab, without significant changes to other haematological values. Two of the patients stopped treatment after the third ipilimumab dose, one because of severe anaemia that required blood transfusion and the other due to febrile neutropenia that was treated with antibiotics and granulocyte-macrophage colony-stimulating factor stimulation. The third patient developed anaemia and leukopenia after treatment during the follow-up period. The results of autoimmunity tests performed were positive and corticosteroids were used to treat these events as per side-effects treatment algorithms specifically developed for the management of immune-related adverse events associated with ipilimumab, an approach that was safe and effective. AB - CONCLUSIONS: Haematological toxicity is a rare but potentially serious immune-related side effect of ipilimumab therapy. However, if promptly recognised and treated, haematological toxicity is manageable and can be reversed with standard corticosteroid treatment as recommended for other ipilimumab immune-related side effects. RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 1752-1947 IL - 1752-1947 DI - 1752-1947-8-240 DO - https://dx.doi.org/10.1186/1752-1947-8-240 PT - Case Reports PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 24986059 [pubmed] ID - 1752-1947-8-240 [pii] ID - 10.1186/1752-1947-8-240 [doi] ID - PMC4090655 [pmc] PP - epublish PH - 2014/02/10 [received] PH - 2014/04/07 [accepted] LG - English EP - 20140701 DP - 2014 Jul 01 DC - 20140711 EZ - 2014/07/03 06:00 DA - 2015/04/01 06:00 DT - 2014/07/06 06:00 YR - 2014 ED - 20150331 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24986059 <218. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24285017 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Tse BW AU - Collins A AU - Oehler MK AU - Zippelius A AU - Heinzelmann-Schwarz VA FA - Tse, B W C FA - Collins, A FA - Oehler, M K FA - Zippelius, A FA - Heinzelmann-Schwarz, V A IN - Tse, B W C. Ovarian Cancer Group, Lowy Cancer Research Centre, Prince of Wales Clinical School. TI - Antibody-based immunotherapy for ovarian cancer: where are we at?. [Review] SO - Annals of Oncology. 25(2):322-31, 2014 Feb AS - Ann Oncol. 25(2):322-31, 2014 Feb NJ - Annals of oncology : official journal of the European Society for Medical Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ayf, 9007735 IO - Ann. Oncol. SB - Index Medicus CP - England MH - Animals MH - Antibodies, Bispecific/tu [Therapeutic Use] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibodies, Monoclonal, Humanized/tu [Therapeutic Use] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Clinical Trials as Topic MH - Diphtheria Toxin/tu [Therapeutic Use] MH - Female MH - Humans MH - Immunoglobulin G/tu [Therapeutic Use] MH - Immunotherapy MH - Interleukin-2/tu [Therapeutic Use] MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Recombinant Fusion Proteins/tu [Therapeutic Use] KW - antibody; clinical trials; diagnosis; gynaecological cancers; immunology; treatment regimens AB - Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAMxanti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens. RN - 0 (Antibodies, Bispecific) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Diphtheria Toxin) RN - 0 (Immunoglobulin G) RN - 0 (Interleukin-2) RN - 0 (Recombinant Fusion Proteins) RN - 0 (abagovomab) RN - 0 (catumaxomab) RN - 25E79B5CTM (denileukin diftitox) RN - 6T8C155666 (ipilimumab) RN - CUJ2MVI71Y (daclizumab) ES - 1569-8041 IL - 0923-7534 DI - mdt405 DO - https://dx.doi.org/10.1093/annonc/mdt405 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 24285017 [pubmed] ID - mdt405 [pii] ID - 10.1093/annonc/mdt405 [doi] PP - ppublish LG - English EP - 20131126 DP - 2014 Feb DC - 20140130 EZ - 2013/11/29 06:00 DA - 2015/03/31 06:00 DT - 2013/11/29 06:00 YR - 2014 ED - 20150330 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24285017 <219. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25416723 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Albarel F AU - Gaudy C AU - Castinetti F AU - Carre T AU - Morange I AU - Conte-Devolx B AU - Grob JJ AU - Brue T FA - Albarel, Frederique FA - Gaudy, Caroline FA - Castinetti, Frederic FA - Carre, Tiphaine FA - Morange, Isabelle FA - Conte-Devolx, Bernard FA - Grob, Jean-Jacques FA - Brue, Thierry IN - Albarel, Frederique. Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France. IN - Gaudy, Caroline. Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France. IN - Castinetti, Frederic. Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France. IN - Carre, Tiphaine. Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France. IN - Morange, Isabelle. Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France. IN - Conte-Devolx, Bernard. Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France. IN - Grob, Jean-Jacques. Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France. IN - Brue, Thierry. Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France Assistance Publique - Hopitaux de Marseille (AP-HM)Hopital Timone, Service d'Endocrinologie et Centre de Reference des Maladies Rares d'Origine Hypophysaire DEFHY, 13385 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteCNRS, CRN2M-UMR7286, 13344 Marseille Cedex 15, Marseille, FranceAix-Marseille UniversiteAssistance Publique - Hopitaux de Marseille (AP-HM), Hopital Timone, Service de dermatologie, 13385 Marseille Cedex 15, Marseille, France thierry.brue@univ-amu.fr. TI - Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. SO - European Journal of Endocrinology. 172(2):195-204, 2015 Feb AS - EUR. J. ENDOCRINOL.. 172(2):195-204, 2015 Feb NJ - European journal of endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bxu, 9423848 IO - Eur. J. Endocrinol. SB - Index Medicus CP - England MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - CTLA-4 Antigen/bl [Blood] MH - *CTLA-4 Antigen MH - Double-Blind Method MH - Female MH - Follow-Up Studies MH - Humans MH - Male MH - Melanoma/bl [Blood] MH - *Melanoma/dt [Drug Therapy] MH - Middle Aged MH - Pituitary Diseases/bl [Blood] MH - *Pituitary Diseases/ci [Chemically Induced] MH - *Pituitary Diseases/di [Diagnosis] MH - Skin Neoplasms/bl [Blood] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Time Factors AB - OBJECTIVE: Few data are published on the long-term follow-up of ipilimumab-induced hypophysitis, a cytotoxic T-lymphocyte antigen 4 antibody. We characterized hypophysitis in terms of clinical signs, endocrinological profile, and imaging at diagnosis and during a long-term follow-up. AB - DESIGN AND PATIENTS: Fifteen patients, treated for malignant melanoma and who presented ipilimumab-induced hypophysitis, were observed between June 2006 and August 2012 in Timone Hospital, Marseille. AB - METHODS: Symptoms, pituitary function, and pituitary imaging at diagnosis of hypophysitis and during the follow-up were recorded. AB - RESULTS: Of 131 patients treated with ipilimumab or a placebo, 15 patients (10 mg/kg in 11/15) presented with hypophysitis (>=11.5%) at 9.5+/-5.9 weeks (mean+/-s.d.) after treatment start, occurring in 66% after the third infusion. The main initial symptoms were headache (n=13) and asthenia (n=11). All patients but one had at least one hormonal defect: thyrotroph (n=13), gonadotroph (n=12), or corticotroph (n=11) deficiencies. None had diabetes insipidus. Pituitary imaging showed a moderately enlarged gland in 12 patients. Clinical symptoms improved rapidly on high-dose glucocorticoids (n=11) or physiological replacement doses (n=4). At the end of follow-up (median 33.6 months, range 7-53.5), corticotroph deficiency remained in 13 patients, 11 recovered thyrotroph and ten gonadotroph functions. Pituitary imaging remained abnormal in 11 patients. AB - CONCLUSION: Ipilimumab-induced hypophysitis is a common side-effect with frequent hormonal deficiencies at diagnosis. Usually, hormonal deficiencies improved, except for corticotroph function. Patients receiving these immunomodulatory therapies should be closely monitored especially by systematic baseline hormone measurements after the third infusion and remain at a risk of adrenal insufficiency in the long-term. AB - Copyright © 2015 European Society of Endocrinology. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) ES - 1479-683X IL - 0804-4643 DI - EJE-14-0845 DO - https://dx.doi.org/10.1530/EJE-14-0845 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't ID - 25416723 [pubmed] ID - EJE-14-0845 [pii] ID - 10.1530/EJE-14-0845 [doi] PP - ppublish LG - English EP - 20141121 DP - 2015 Feb DC - 20150110 EZ - 2014/11/23 06:00 DA - 2015/03/21 06:00 DT - 2014/11/25 06:00 YR - 2015 ED - 20150320 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25416723 <220. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25759760 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Yu C AU - Chopra IJ AU - Ha E FA - Yu, Christine FA - Chopra, Inder J FA - Ha, Edward IN - Yu, Christine. Department of Medicine, University of California , Los Angeles, Los Angeles, California, 90095 , USA. IN - Chopra, Inder J. Division of Endocrinology, Department of Medicine, University of California , 757 Westwood Plaza Blvd, Suite 7501, Los Angeles, CA, 90095 , USA. IN - Ha, Edward. Department of Medicine, University of California , Los Angeles, Los Angeles, California, 90095 , USA. TI - A novel melanoma therapy stirs up a storm: ipilimumab-induced thyrotoxicosis. SO - Endocrinology, Diabetes & Metabolism Case Reports. 2015:140092, 2015 AS - Endocrinol Diabetes Metab Case Rep. 2015:140092, 2015 NJ - Endocrinology, diabetes & metabolism case reports PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101618943 IO - Endocrinol Diabetes Metab Case Rep PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330494 CP - England AB - UNLABELLED: Ipilimumab, a novel therapy for metastatic melanoma, inhibits cytotoxic T-lymphocyte apoptosis, causing both antitumor activity and significant autoimmunity, including autoimmune thyroiditis. Steroids are frequently used in treatment of immune-related adverse events; however, a concern regarding the property of steroids to reduce therapeutic antitumor response exists. This study describes the first reported case of ipilimumab-associated thyroid storm and implicates iopanoic acid as an alternative therapy for immune-mediated adverse effects. An 88-year-old woman with metastatic melanoma presented with fatigue, anorexia, decreased functional status, and intermittent diarrhea for several months, shortly after initiation of ipilimumab - a recombinant human monoclonal antibody to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). On arrival, she was febrile, tachycardic, and hypertensive with a wide pulse pressure, yet non-toxic appearing. She had diffuse, non-tender thyromegaly. An electrocardiogram (EKG) revealed supraventricular tachycardia. Blood, urine, and stool cultures were collected, and empiric antibiotics were started. A computed tomography (CT) angiogram of the chest was negative for pulmonary embolism or pneumonia, but confirmed a diffusely enlarged thyroid gland, which prompted thyroid function testing. TSH was decreased at 0.16 muIU/ml (normal 0.3-4.7); free tri-iodothyronine (T3) was markedly elevated at 1031 pg/dl (normal 249-405), as was free thyroxine (T4) at 5.6 ng/dl (normal 0.8-1.6). With iopanoic acid and methimazole therapy, she markedly improved within 48 h, which could be attributed to lowering of serum T3 with iopanoic acid rather than to any effect of the methimazole. Ipilimumab is a cause of overt thyrotoxicosis and its immune-mediated adverse effects can be treated with iopanoic acid, a potent inhibitor of T4-to-T3 conversion. AB - LEARNING POINTS: While ipilimumab more commonly causes autoimmune thyroiditis, it can also cause thyroid storm and clinicians should include thyroid storm in their differential diagnosis for patients who present with systemic inflammatory response syndrome.Immune-related adverse reactions usually occur after 1-3 months of ipilimumab and baseline thyroid function testing should be completed before initiation with ipilimumab.Conflicting data exist on the use of prednisone for treatment of CTLA4 adverse effects and its attenuation of ipilimumab's antitumor effect. Iopanoic acid may be considered as an alternative therapy in this setting. IL - 2052-0573 DI - EDM140092 DO - https://dx.doi.org/10.1530/EDM-14-0092 PT - Journal Article ID - 25759760 [pubmed] ID - 10.1530/EDM-14-0092 [doi] ID - EDM140092 [pii] ID - PMC4330494 [pmc] PP - ppublish PH - 2015/01/14 [received] PH - 2015/01/26 [accepted] LG - English EP - 20150201 DP - 2015 DC - 20150311 EZ - 2015/03/12 06:00 DA - 2015/03/12 06:01 DT - 2015/03/12 06:00 YR - 2015 ED - 20150311 RD - 20150313 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=25759760 <221. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25301449 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Xia Y AU - Lei Q AU - Zhu Y AU - Ye T AU - Wang N AU - Li G AU - Shi X AU - Liu Y AU - Shao B AU - Yin T AU - Zhao L AU - Wu W AU - Song X AU - Xiong Y AU - Wei Y AU - Yu L FA - Xia, Yong FA - Lei, Qian FA - Zhu, Yongxia FA - Ye, Tinghong FA - Wang, Ningyu FA - Li, Guobo FA - Shi, Xuanhong FA - Liu, Yantong FA - Shao, Bin FA - Yin, Tao FA - Zhao, Lifeng FA - Wu, Wenshuang FA - Song, Xuejiao FA - Xiong, Ying FA - Wei, Yuquan FA - Yu, Luoting IN - Xia, Yong. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Lei, Qian. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Zhu, Yongxia. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Ye, Tinghong. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Wang, Ningyu. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Li, Guobo. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Shi, Xuanhong. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Liu, Yantong. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Shao, Bin. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Yin, Tao. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Zhao, Lifeng. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Wu, Wenshuang. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Song, Xuejiao. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Xiong, Ying. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China; Department of Pharmacy, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. IN - Wei, Yuquan. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. IN - Yu, Luoting. State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: yuluot@scu.edu.cn. TI - SKLB316, a novel small-molecule inhibitor of cell-cycle progression, induces G2/M phase arrest and apoptosis in vitro and inhibits tumor growth in vivo. SO - Cancer Letters. 355(2):297-309, 2014 Dec 28 AS - Cancer Lett. 355(2):297-309, 2014 Dec 28 NJ - Cancer letters PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 7600053, cmx IO - Cancer Lett. SB - Index Medicus CP - Ireland MH - Animals MH - *Antineoplastic Agents/pd [Pharmacology] MH - *Apoptosis/de [Drug Effects] MH - *Benzothiazoles/pd [Pharmacology] MH - CDC2 Protein Kinase/ge [Genetics] MH - CDC2 Protein Kinase/me [Metabolism] MH - Caspase 9/me [Metabolism] MH - Cell Proliferation/de [Drug Effects] MH - Checkpoint Kinase 2/me [Metabolism] MH - *Colorectal Neoplasms/dt [Drug Therapy] MH - Colorectal Neoplasms/me [Metabolism] MH - Colorectal Neoplasms/pa [Pathology] MH - Cyclins/me [Metabolism] MH - Female MH - *G2 Phase Cell Cycle Checkpoints/de [Drug Effects] MH - HCT116 Cells MH - Humans MH - Membrane Potential, Mitochondrial/de [Drug Effects] MH - Mice MH - Mice, Nude MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - Phosphorylation/de [Drug Effects] MH - Reactive Oxygen Species/me [Metabolism] MH - Xenograft Model Antitumor Assays MH - bcl-2-Associated X Protein/ge [Genetics] MH - bcl-2-Associated X Protein/me [Metabolism] MH - cdc25 Phosphatases/me [Metabolism] KW - Anti-cancer; Apoptosis; Cell cycle arrest; Drug discovery; SKLB316 AB - Benzothiazole derivatives have received considerable attentions for their potencies in cancer therapy. In the present study, we reported that SKLB316, a novel synthesized benzothiazole derivative, exhibits activities to inhibit colorectal and pancreatic cancer in vitro and in vivo by inducing G2/M cell cycle arrest and apoptosis. In vitro, it exhibited significant anti-proliferative activities against human cancer cells derived from different histotypes including the colorectal cancer cell line HCT116 and pancreatic cancer cell line CFPAC-1. We chose these cell lines to study the possible anti-tumor mechanism because they are sensitive to SKLB316 treatment. Flow cytometry assays showed that SKLB316 could induce G2/M cell cycle arrest. Mechanistically, SKLB316 could decrease the activities of cdc2/cyclin B1 complex, including decreasing the synthesis of cyclin B1, cdc2 and cdc25c, while accumulating the levels of phosphorylated cdc2 (Tyr15) and checkpoint kinase 2. SKLB316 could also decrease the level of cyclin E and A2. Moreover, SKLB316 could induce cancer cell apoptosis, which was associated with activation of caspase 9, downregulation of Bcl-2 and upregulation of Bax. SKLB316 could also decrease the mitochondrial membrane potential and induce the generation of reactive oxygen species in cells. The results implied that SKLB316 may induce apoptosis via the mitochondria-mediated apoptotic pathway. Moreover, SKLB316 could suppress the growth of established colorectal and pancreatic cancer tumors in nude mice without causing obvious side effects. TUNEL assays confirmed that SKLB316 could also induce tumor cell apoptosis in vivo. Taken together, these findings demonstrate the potential value of SKLB316 as a novel anti-tumor drug candidate. AB - Copyright © 2014 Elsevier Ireland Ltd. All rights reserved. RN - 0 (Antineoplastic Agents) RN - 0 (Benzothiazoles) RN - 0 (Cyclins) RN - 0 (Reactive Oxygen Species) RN - 0 (bcl-2-Associated X Protein) RN - EC 2-7-1-11 (Checkpoint Kinase 2) RN - EC 2-7-11-22 (CDC2 Protein Kinase) RN - EC 3-1-3-48 (CDC25C protein, human) RN - EC 3-1-3-48 (cdc25 Phosphatases) RN - EC 3-4-22 (Caspase 9) ES - 1872-7980 IL - 0304-3835 DI - S0304-3835(14)00583-7 DO - https://dx.doi.org/10.1016/j.canlet.2014.09.042 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 25301449 [pubmed] ID - S0304-3835(14)00583-7 [pii] ID - 10.1016/j.canlet.2014.09.042 [doi] PP - ppublish PH - 2014/07/22 [received] PH - 2014/09/28 [revised] PH - 2014/09/29 [accepted] LG - English EP - 20141007 DP - 2014 Dec 28 DC - 20141202 EZ - 2014/10/11 06:00 DA - 2015/03/04 06:00 DT - 2014/10/11 06:00 YR - 2014 ED - 20150303 RD - 20141202 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25301449 <222. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24687600 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Izzedine H AU - Gueutin V AU - Gharbi C AU - Mateus C AU - Robert C AU - Routier E AU - Thomas M AU - Baumelou A AU - Rouvier P FA - Izzedine, Hassane FA - Gueutin, Victor FA - Gharbi, Chems FA - Mateus, Christine FA - Robert, Caroline FA - Routier, Emilie FA - Thomas, Marina FA - Baumelou, Alain FA - Rouvier, Philippe IN - Izzedine, Hassane. Department of Nephrology, Pitie-Salpetriere, 47-80 Boulevard de l'Hopital, 75013, Paris, France, hassan.izzedine@psl.aphp.fr. TI - Kidney injuries related to ipilimumab. SO - Investigational New Drugs. 32(4):769-73, 2014 Aug AS - Invest New Drugs. 32(4):769-73, 2014 Aug NJ - Investigational new drugs PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - gwj, 8309330 IO - Invest New Drugs SB - Index Medicus CP - United States MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Female MH - Humans MH - *Kidney Diseases/ci [Chemically Induced] MH - Male MH - Middle Aged AB - Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) have been investigated in metastatic melanoma and other cancers and have shown promising results. Inhibition of CTLA-4 characteristically induces well-known side effects called "immune-related adverse events" (irAEs). IrAEs mainly include colitis, dermatitis, hepatitis, endocrinopathies; uveitis, iridocyclitis, neuropathies, and inflammatory myopathy have occasionally been reported. Kidney involvement is rare. We report 2 cases of acute granulomatous interstitial nephritis and present, based on literature review, renal disorders related to Ipilimumab therapy. Autoimmune symptoms have to be carefully checked for patients treated with CTLA-4 inhibitors. In order to reduce the risk of sequelae, early recognition of irAEs and treatment initiation are crucial. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) ES - 1573-0646 IL - 0167-6997 DO - https://dx.doi.org/10.1007/s10637-014-0092-7 PT - Case Reports PT - Journal Article ID - 24687600 [pubmed] ID - 10.1007/s10637-014-0092-7 [doi] PP - ppublish PH - 2014/01/20 [received] PH - 2014/03/18 [accepted] LG - English EP - 20140401 DP - 2014 Aug DC - 20140717 EZ - 2014/04/02 06:00 DA - 2015/03/03 06:00 DT - 2014/04/02 06:00 YR - 2014 ED - 20150302 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24687600 <223. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24282275 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Slee RB AU - Grimes BR AU - Bansal R AU - Gore J AU - Blackburn C AU - Brown L AU - Gasaway R AU - Jeong J AU - Victorino J AU - March KL AU - Colombo R AU - Herbert BS AU - Korc M FA - Slee, Roger B FA - Grimes, Brenda R FA - Bansal, Ruchi FA - Gore, Jesse FA - Blackburn, Corinne FA - Brown, Lyndsey FA - Gasaway, Rachel FA - Jeong, Jaesik FA - Victorino, Jose FA - March, Keith L FA - Colombo, Riccardo FA - Herbert, Brittney-Shea FA - Korc, Murray IN - Slee, Roger B. Corresponding Authors: B.R. Grimes, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 W. Walnut St, IB30, Indianapolis, IN 46202. brgrimes@iu.edu. TI - Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715. SO - Molecular Cancer Therapeutics. 13(2):307-15, 2014 Feb AS - Mol Cancer Ther. 13(2):307-15, 2014 Feb NJ - Molecular cancer therapeutics PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101132535 IO - Mol. Cancer Ther. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217310 OI - Source: NLM. NIHMS545057 SB - Index Medicus CP - United States MH - Adenocarcinoma/ge [Genetics] MH - Adenocarcinoma/me [Metabolism] MH - Adenocarcinoma/pa [Pathology] MH - Animals MH - Apoptosis/de [Drug Effects] MH - Apoptosis/ge [Genetics] MH - Blotting, Western MH - Carcinoma, Pancreatic Ductal/ge [Genetics] MH - Carcinoma, Pancreatic Ductal/me [Metabolism] MH - Carcinoma, Pancreatic Ductal/pa [Pathology] MH - *Cell Cycle Proteins/ai [Antagonists & Inhibitors] MH - Cell Cycle Proteins/ge [Genetics] MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Line, Tumor MH - *Cell Proliferation/de [Drug Effects] MH - Dose-Response Relationship, Drug MH - Gene Expression Regulation, Neoplastic/de [Drug Effects] MH - Humans MH - In Situ Hybridization, Fluorescence MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - Prognosis MH - Protein Kinase Inhibitors/pd [Pharmacology] MH - *Protein-Serine-Threonine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Serine-Threonine Kinases/ge [Genetics] MH - Protein-Serine-Threonine Kinases/me [Metabolism] MH - *Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Tyrosine Kinases/ge [Genetics] MH - Protein-Tyrosine Kinases/me [Metabolism] MH - *Pyrazoles/pd [Pharmacology] MH - *Quinazolines/pd [Pharmacology] MH - Survival Analysis MH - Time Factors MH - Transcriptome AB - Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy. RN - 0 (Cell Cycle Proteins) RN - 0 (N-(2,6-diethylphenyl)-1-methyl-8-((4-((1-methylpiperidin-4-yl)carbamoyl)-2-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Quinazolines) RN - EC 2-7-10-1 (Protein-Tyrosine Kinases) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - EC 2-7-12-1 (TTK protein, human) ES - 1538-8514 IL - 1535-7163 DI - 1535-7163.MCT-13-0324 DO - https://dx.doi.org/10.1158/1535-7163.MCT-13-0324 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 24282275 [pubmed] ID - 1535-7163.MCT-13-0324 [pii] ID - 10.1158/1535-7163.MCT-13-0324 [doi] ID - PMC4217310 [pmc] ID - NIHMS545057 [mid] PP - ppublish GI - No: R25 GM067592 Organization: (GM) *NIGMS NIH HHS* Country: United States No: R37 CA075059 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA082709 Organization: (CA) *NCI NIH HHS* Country: United States No: R25-GM67592 Organization: (GM) *NIGMS NIH HHS* Country: United States No: R37-CA-075059 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA075059 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20131126 DP - 2014 Feb DC - 20140211 EZ - 2013/11/28 06:00 DA - 2015/02/20 06:00 DT - 2013/11/28 06:00 YR - 2014 ED - 20150219 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24282275 <224. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25694832 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Majchel D AU - Korytkowski MT AI - Majchel, Deborah; ORCID: https://orcid.org/0000-0002-4598-9524 FA - Majchel, Deborah FA - Korytkowski, Mary T IN - Majchel, Deborah. Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh Medical Center, 3601 Fifth Avenue, Suite 3B, Pittsburgh, PA 15213, USA. IN - Korytkowski, Mary T. Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh Medical Center, 3601 Fifth Avenue, Suite 3B, Pittsburgh, PA 15213, USA. TI - Anticytotoxic T-lymphocyte antigen-4 induced autoimmune hypophysitis: a case report and literature review. SO - Case Reports in Endocrinology Print. 2015:570293, 2015 AS - case report. endocrinol.. 2015:570293, 2015 NJ - Case reports in endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101576457 IO - Case Rep Endocrinol PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4324809 CP - United States AB - Objective. We describe a case of autoimmune hypophysitis induced by the anticytotoxic T-lymphocyte antigen-4 (CTLA-4) agent, ipilimumab. Methods. Case presentation and review of the literature. Results. Autoimmune hypophysitis, a previously described rare disorder, is being recognized more frequently as a side effect of novel immunomodulatory agents used in the treatment of malignancies such as melanoma. CTLA-4 agents are associated with immune-related adverse effects (irAE) which occur as a result of activation (or lack of inactivation) of the immune response. This impacts not only malignant cells but also different host organ-systems. Autoimmune hypophysitis is one of several endocrinopathies associated with these agents. Conclusion. It is important that endocrinologists become familiar with the endocrinopathies, such as autoimmune hypophysitis, associated with new immunomodulator agents which are being used with increasing frequency to treat a variety of malignancies. IS - 2090-6501 IL - 2090-651X DO - https://dx.doi.org/10.1155/2015/570293 PT - Journal Article ID - 25694832 [pubmed] ID - 10.1155/2015/570293 [doi] ID - PMC4324809 [pmc] PP - ppublish PH - 2014/09/19 [received] PH - 2015/01/09 [accepted] LG - English EP - 20150128 DP - 2015 DC - 20150219 EZ - 2015/02/20 06:00 DA - 2015/02/20 06:01 DT - 2015/02/20 06:00 YR - 2015 ED - 20150219 RD - 20150221 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=25694832 <225. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24622375 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Min L AU - Ibrahim N FA - Min, Le FA - Ibrahim, Nageatte IN - Min, Le. Brigham and Women's Hospital, Boston MA, USA. Electronic address: lmin1@partners.org. IN - Ibrahim, Nageatte. Dana-Farber Cancer Institute, Boston, MA, USA. TI - Ipilimumab-induced autoimmune adrenalitis. SO - The Lancet Diabetes & Endocrinology. 1(3):e15, 2013 Nov AS - Lancet Diabetes Endocrinol. 1(3):e15, 2013 Nov NJ - The lancet. Diabetes & endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101618821 IO - Lancet Diabetes Endocrinol PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106239 OI - Source: NLM. NIHMS603111 SB - Index Medicus CP - England MH - *Adrenal Gland Diseases/ci [Chemically Induced] MH - Adrenal Gland Diseases/co [Complications] MH - Adrenal Gland Diseases/dg [Diagnostic Imaging] MH - Adrenal Insufficiency/et [Etiology] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Autoimmune Diseases/ci [Chemically Induced] MH - Autoimmune Diseases/co [Complications] MH - Autoimmune Diseases/dg [Diagnostic Imaging] MH - Female MH - Humans MH - Inflammation MH - *Melanoma/dt [Drug Therapy] MH - Middle Aged MH - Tomography, X-Ray Computed RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 2213-8595 IL - 2213-8587 DI - S2213-8587(13)70031-7 DO - https://dx.doi.org/10.1016/S2213-8587(13)70031-7 PT - Case Reports PT - Journal Article ID - 24622375 [pubmed] ID - S2213-8587(13)70031-7 [pii] ID - 10.1016/S2213-8587(13)70031-7 [doi] ID - PMC4106239 [pmc] ID - NIHMS603111 [mid] PP - ppublish GI - No: K08 HD070957 Organization: (HD) *NICHD NIH HHS* Country: United States No: T32 DK007529 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English EP - 20130709 DP - 2013 Nov DC - 20140313 EZ - 2014/03/14 06:00 DA - 2015/02/04 06:00 DT - 2014/03/14 06:00 YR - 2013 ED - 20150203 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24622375 <226. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25430657 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Alonso-Gordoa T AU - Capdevila J AU - Grande E FA - Alonso-Gordoa, T FA - Capdevila, J FA - Grande, E IN - Alonso-Gordoa, T. Medical Oncology DepartmentRamon y Cajal University Hospital, Carretera de Colmenar Km 9,100, 28034 Madrid, SpainMedical Oncology DepartmentVall d'Hebron University Hospital, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain. IN - Capdevila, J. Medical Oncology DepartmentRamon y Cajal University Hospital, Carretera de Colmenar Km 9,100, 28034 Madrid, SpainMedical Oncology DepartmentVall d'Hebron University Hospital, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain. IN - Grande, E. Medical Oncology DepartmentRamon y Cajal University Hospital, Carretera de Colmenar Km 9,100, 28034 Madrid, SpainMedical Oncology DepartmentVall d'Hebron University Hospital, Passeig de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain egrande@oncologiahrc.com. TI - GEP-NETs update: Biotherapy for neuroendocrine tumours. [Review] SO - European Journal of Endocrinology. 172(1):R31-46, 2015 Jan AS - EUR. J. ENDOCRINOL.. 172(1):R31-46, 2015 Jan NJ - European journal of endocrinology PI - Journal available in: Print PI - Citation processed from: Internet JC - bxu, 9423848 IO - Eur. J. Endocrinol. SB - Index Medicus CP - England MH - Amino Acid Sequence MH - Animals MH - *Biological Therapy/mt [Methods] MH - Humans MH - Molecular Sequence Data MH - Neuroendocrine Tumors/di [Diagnosis] MH - Neuroendocrine Tumors/ge [Genetics] MH - *Neuroendocrine Tumors/th [Therapy] MH - Receptors, Somatostatin/ge [Genetics] MH - *Somatostatin/ad [Administration & Dosage] MH - Somatostatin/ge [Genetics] AB - Neuroendocrine tumours (NETs) represent a less frequent and heterogeneous group of tumours, which has experienced, in recent years, a significant increase in effective therapeutic possibilities overcoming the disappointing results from chemotherapy. Initial improvements in treatment strategies came from somatostatin analogues (SSAs) that have widely demonstrated a significant improvement in symptomatic relief and tumour control growth by a complex mechanism of action over cell survival, angiogenesis and immunomodulation. Recent investigations have pointed out novel SSAs with a wider binding profile (pasireotide), chimeric molecules against somatostatin receptors and dopamine receptors and the combination with targeted agents, such as mTOR inhibitors or antiangiogenic agents. Immunotherapy is the second cornerstone in NET treatment and has been represented with interferon alpha for a long time, with a demonstrated activity on tumour and clinical response. Its less manageable adverse events have limited its usage. However, different checkpoints in immune system regulation have been effectively targeted in different solid tumours, and novel approaches are currently arising in NETs. In conclusion, biotherapy remains an active treatment strategy for initial approach in patients with NETs. Further investigation on patients' selection, molecular profiles, treatment sequence or combination and optimisation of current and novel biotherapy agents is required. AB - Copyright © 2015 European Society of Endocrinology. RN - 0 (Receptors, Somatostatin) RN - 51110-01-1 (Somatostatin) ES - 1479-683X IL - 0804-4643 DI - 172/1/R31 DO - https://dx.doi.org/10.1530/EJE-14-0354 PT - Journal Article PT - Review ID - 25430657 [pubmed] ID - 172/1/R31 [pii] ID - 10.1530/EJE-14-0354 [doi] PP - ppublish LG - English DP - 2015 Jan DC - 20141128 EZ - 2014/11/29 06:00 DA - 2015/01/27 06:00 DT - 2014/11/29 06:00 YR - 2015 ED - 20150126 RD - 20161018 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25430657 <227. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25614822 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Rodrigues BT AU - Otty Z AU - Sangla K AU - Shenoy VV FA - Rodrigues, Beverly T FA - Otty, Zulfiquer FA - Sangla, Kunwarjit FA - Shenoy, Vasant V IN - Rodrigues, Beverly T. Department of Diabetes and Endocrinology, The Townsville Hospital , Townsville, Queensland , Australia ; School of Medicine and Dentistry, James Cook University , Douglas, Queensland , Australia. IN - Otty, Zulfiquer. Department of Oncology, The Townsville Hospital , Townsville, Queensland , Australia. IN - Sangla, Kunwarjit. Department of Diabetes and Endocrinology, The Townsville Hospital , Townsville, Queensland , Australia. IN - Shenoy, Vasant V. Department of Diabetes and Endocrinology, The Townsville Hospital , Townsville, Queensland , Australia ; School of Medicine and Dentistry, James Cook University , Douglas, Queensland , Australia. TI - Ipilimumab-induced autoimmune hypophysitis: a differential for sellar mass lesions. SO - Endocrinology, Diabetes & Metabolism Case Reports. 2014:140098, 2014 AS - Endocrinol Diabetes Metab Case Rep. 2014:140098, 2014 NJ - Endocrinology, diabetes & metabolism case reports PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101618943 IO - Endocrinol Diabetes Metab Case Rep PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276072 CP - England AB - UNLABELLED: Autoimmune hypophysitis (AH) has been previously described in a typical demographic population, primarily women in the reproductive age group and perinatal period. The era of immune modulation using anti-cytotoxic T-lymphocyte-associated antigen 4 biological therapy (ipilimumab) against advanced cancers like metastatic melanomas has now resulted in a new form of hypophysitis being increasingly recognised under a spectrum of immune-related adverse events. Drug-related AH often presents with subtle symptoms and a pituitary mass, with the potential for fatality necessitating wide awareness and a high index of clinical suspicion given that it is usually treatable. We describe below two cases of AH within the last three months at our centre, which were treated with different regimens and produced good endocrine outcomes. AB - LEARNING POINTS: AH is a new and defined clinical entity occurring as a side effect of ipilimumab, which enhances immune-mediated destruction of metastatic melanoma.It can present insidiously and have life-threatening complications related to hypocortisolism, hence a high index of clinical suspicion must be exerted by treating physicians, and seems to result in resolution of pituitary masses and variable improvements of pituitary function.Clinical improvement, radiological resolution of pituitary masses and variable normalisation of pituitary function are possible with early treatment with high-dose oral or i.v. steroids and hormone replacement therapy, although duration and dosing protocols are unclear at this stage.Ipilimumab should continue to be prescribed as treatment for metastatic melanoma; however, close clinical observation of patient's progress must be maintained while they are on this drug.Predictive factors for onset of AH remain unclear and it is imperative that AH is distinguished from pituitary metastases.Further studies are required to determine the safety of continuing therapy with ipilimumab in patients who have developed AH while on treatment. IL - 2052-0573 DI - EDM140098 DO - https://dx.doi.org/10.1530/EDM-14-0098 PT - Journal Article ID - 25614822 [pubmed] ID - 10.1530/EDM-14-0098 [doi] ID - EDM140098 [pii] ID - PMC4276072 [pmc] PP - ppublish PH - 2014/11/16 [received] PH - 2014/11/21 [accepted] LG - English EP - 20141201 DP - 2014 DC - 20150123 EZ - 2015/01/24 06:00 DA - 2015/01/24 06:01 DT - 2015/01/24 06:00 YR - 2014 ED - 20150123 RD - 20150125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=25614822 <228. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25082815 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Zhu Y AU - Knolhoff BL AU - Meyer MA AU - Nywening TM AU - West BL AU - Luo J AU - Wang-Gillam A AU - Goedegebuure SP AU - Linehan DC AU - DeNardo DG FA - Zhu, Yu FA - Knolhoff, Brett L FA - Meyer, Melissa A FA - Nywening, Timothy M FA - West, Brian L FA - Luo, Jingqin FA - Wang-Gillam, Andrea FA - Goedegebuure, S Peter FA - Linehan, David C FA - DeNardo, David G IN - Zhu, Yu. Department of Medicine, Washington University School of Medicine, St Louis, Missouri. BRIGHT Institute, Washington University School of Medicine, St Louis, Missouri. IN - Knolhoff, Brett L. Department of Medicine, Washington University School of Medicine, St Louis, Missouri. BRIGHT Institute, Washington University School of Medicine, St Louis, Missouri. IN - Meyer, Melissa A. Department of Medicine, Washington University School of Medicine, St Louis, Missouri. BRIGHT Institute, Washington University School of Medicine, St Louis, Missouri. IN - Nywening, Timothy M. Department of Surgery, Washington University School of Medicine, St Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri. IN - West, Brian L. Plexxikon Inc., Berkeley, California. IN - Luo, Jingqin. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri. Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri. IN - Wang-Gillam, Andrea. Department of Medicine, Washington University School of Medicine, St Louis, Missouri. IN - Goedegebuure, S Peter. Department of Surgery, Washington University School of Medicine, St Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri. IN - Linehan, David C. Department of Surgery, Washington University School of Medicine, St Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri. IN - DeNardo, David G. Department of Medicine, Washington University School of Medicine, St Louis, Missouri. BRIGHT Institute, Washington University School of Medicine, St Louis, Missouri. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri. ddenardo@dom.wustl.edu. TI - CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. SO - Cancer Research. 74(18):5057-69, 2014 Sep 15 AS - Cancer Res. 74(18):5057-69, 2014 Sep 15 NJ - Cancer research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnf, 2984705r IO - Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182950 OI - Source: NLM. NIHMS618198 SB - Index Medicus CP - United States MH - *Adenocarcinoma/im [Immunology] MH - Adenocarcinoma/pa [Pathology] MH - Animals MH - Carcinoma, Pancreatic Ductal/im [Immunology] MH - Carcinoma, Pancreatic Ductal/pa [Pathology] MH - *Carcinoma, Pancreatic Ductal/th [Therapy] MH - Cohort Studies MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Female MH - Humans MH - *Immunotherapy/mt [Methods] MH - Lectins, C-Type/bi [Biosynthesis] MH - Lectins, C-Type/im [Immunology] MH - *Macrophage Colony-Stimulating Factor/ai [Antagonists & Inhibitors] MH - Macrophage Colony-Stimulating Factor/bi [Biosynthesis] MH - Macrophage Colony-Stimulating Factor/im [Immunology] MH - *Macrophages/im [Immunology] MH - Mannose-Binding Lectins/bi [Biosynthesis] MH - Mannose-Binding Lectins/im [Immunology] MH - Mice MH - Mice, Inbred C57BL MH - Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/pa [Pathology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Random Allocation MH - *Receptor, Macrophage Colony-Stimulating Factor/ai [Antagonists & Inhibitors] MH - Receptor, Macrophage Colony-Stimulating Factor/im [Immunology] MH - Receptors, Cell Surface/bi [Biosynthesis] MH - Receptors, Cell Surface/im [Immunology] MH - Signal Transduction MH - *T-Lymphocytes/im [Immunology] MH - Tissue Array Analysis MH - Tumor Microenvironment AB - Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages and myeloid-derived suppressor cells, which not only mediate immune suppression, but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive antitumor T-cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T-cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics. AB - Copyright ©2014 American Association for Cancer Research. RN - 0 (Lectins, C-Type) RN - 0 (Mannose-Binding Lectins) RN - 0 (Receptors, Cell Surface) RN - 0 (mannose receptor) RN - 0W860991D6 (Deoxycytidine) RN - 81627-83-0 (Macrophage Colony-Stimulating Factor) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7-10-1 (Receptor, Macrophage Colony-Stimulating Factor) ES - 1538-7445 IL - 0008-5472 DI - 0008-5472.CAN-13-3723 DO - https://dx.doi.org/10.1158/0008-5472.CAN-13-3723 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 25082815 [pubmed] ID - 0008-5472.CAN-13-3723 [pii] ID - 10.1158/0008-5472.CAN-13-3723 [doi] ID - PMC4182950 [pmc] ID - NIHMS618198 [mid] PP - ppublish GI - No: T32 CA113275 Organization: (CA) *NCI NIH HHS* Country: United States No: KL2TR000450 Organization: (TR) *NCATS NIH HHS* Country: United States No: T32 CA 009621 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 CA009621 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA177670-01 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1RR024992 Organization: (RR) *NCRR NIH HHS* Country: United States No: UL1 RR024992 Organization: (RR) *NCRR NIH HHS* Country: United States No: P30 CA91842 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA168863-01 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA091842 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA177670 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 TR000448 Organization: (TR) *NCATS NIH HHS* Country: United States No: KL2 RR024994 Organization: (RR) *NCRR NIH HHS* Country: United States No: R01 CA168863 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA182701 Organization: (CA) *NCI NIH HHS* Country: United States No: KL2 TR000450 Organization: (TR) *NCATS NIH HHS* Country: United States LG - English EP - 20140731 DP - 2014 Sep 15 DC - 20140916 EZ - 2014/08/02 06:00 DA - 2015/01/21 06:00 DT - 2014/08/02 06:00 YR - 2014 ED - 20150120 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25082815 <229. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25078147 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Faje AT AU - Sullivan R AU - Lawrence D AU - Tritos NA AU - Fadden R AU - Klibanski A AU - Nachtigall L FA - Faje, Alexander T FA - Sullivan, Ryan FA - Lawrence, Donald FA - Tritos, Nicholas A FA - Fadden, Riley FA - Klibanski, Anne FA - Nachtigall, Lisa IN - Faje, Alexander T. Neuroendocrine Unit (A.T.F., N.A.T., A.K., L.N.), Massachusetts General Hospital and Harvard Medical School, and Center for Melanoma (R.S., D.L., R.F.), Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114. TI - Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. SO - Journal of Clinical Endocrinology & Metabolism. 99(11):4078-85, 2014 Nov AS - J Clin Endocrinol Metab. 99(11):4078-85, 2014 Nov NJ - The Journal of clinical endocrinology and metabolism PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hrb, 0375362 IO - J. Clin. Endocrinol. Metab. SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - Age Factors MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Female MH - Humans MH - *Hypopituitarism/ci [Chemically Induced] MH - Hypopituitarism/mo [Mortality] MH - Hypopituitarism/pa [Pathology] MH - Longitudinal Studies MH - Magnetic Resonance Imaging MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/mo [Mortality] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - *Pituitary Gland/pa [Pathology] MH - Prognosis MH - Retrospective Studies MH - Risk Factors MH - Sex Factors AB - CONTEXT: Ipilimumab (Ipi) is approved by the Food and Drug Administration for the treatment of unresectable or metastatic melanoma. Little is known about Ipi-induced hypophysitis (IH), an important treatment complication. AB - OBJECTIVE: The objectives of the study were as follows: 1) to examine the prevalence of IH, 2) to characterize the clinical course and treatment outcomes in IH, 3) to identify the risk factors for the development of IH, and 4) to determine optimal strategies for the management of IH. AB - DESIGN: This was a retrospective review. AB - SETTING: The study was conducted at a tertiary referral center. AB - SUBJECTS: One hundred fifty-four adult patients with metastatic melanoma were evaluated at Massachusetts General Hospital and were treated with Ipi between March 2008 and December 2013. AB - INTERVENTION(S): The intervention included treatment with Ipi. AB - MAIN OUTCOME MEASURE(S): Pituitary magnetic resonance imaging, pituitary hormone assessment, and patient survival were measured. AB - RESULTS: IH was diagnosed in 17 patients (11%). Male gender (P = .02) and older age (P = .005), but not the cumulative dose of Ipi, were risk factors for IH. All patients with IH had anterior hypopituitarism (none had diabetes insipidus). Hypopituitarism was persistent in most individuals (76%). Diffuse pituitary enlargement was observed exclusively in all cases of IH and, upon retrospective review of magnetic resonance imaging scans, this finding preceded the clinical diagnosis of hypophysitis in eight patients. Pituitary enlargement resolved rapidly (within 40 d in seven of seven patients). Median survival in patients with IH was 19.4 vs 8.8 months (P = .05) in the remainder of the cohort. AB - CONCLUSIONS: Male gender and older age are risk factors for IH. Pituitary enlargement is sensitive and specific for IH in the appropriate setting, can precede the clinical diagnosis, and resolves rapidly. Anterior pituitary function recovery is uncommon. The incidence of hypophysitis may positively predict survival in melanoma patients treated with Ipi. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 1945-7197 IL - 0021-972X DO - https://dx.doi.org/10.1210/jc.2014-2306 PT - Journal Article ID - 25078147 [pubmed] ID - 10.1210/jc.2014-2306 [doi] PP - ppublish LG - English EP - 20140731 DP - 2014 Nov DC - 20141106 EZ - 2014/08/01 06:00 DA - 2015/01/17 06:00 DT - 2014/08/01 06:00 YR - 2014 ED - 20150116 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25078147 <230. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24804869 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Shigetomi H AU - Sudo T AU - Shimada K AU - Uekuri C AU - Tsuji Y AU - Kanayama S AU - Naruse K AU - Yamada Y AU - Konishi N AU - Kobayashi H FA - Shigetomi, Hiroshi FA - Sudo, Tamotsu FA - Shimada, Keiji FA - Uekuri, Chiharu FA - Tsuji, Yoriko FA - Kanayama, Seiji FA - Naruse, Katsuhiko FA - Yamada, Yoshihiko FA - Konishi, Noboru FA - Kobayashi, Hiroshi IN - Shigetomi, Hiroshi. *Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara; +Section of Translational Research, Hyogo Cancer Center, Akashi, Hyogo; ++Department of Pathology, Nara Medical University, Kashihara, Nara; and Department of Obstetrics and Gynecology, Yao Municipal Hospital, Yao-city, Osaka, Japan. TI - Inhibition of cell death and induction of G2 arrest accumulation in human ovarian clear cells by HNF-1beta transcription factor: chemosensitivity is regulated by checkpoint kinase CHK1. SO - International Journal of Gynecological Cancer. 24(5):838-43, 2014 Jun AS - Int J Gynecol Cancer. 24(5):838-43, 2014 Jun NJ - International journal of gynecological cancer : official journal of the International Gynecological Cancer Society PI - Journal available in: Print PI - Citation processed from: Internet JC - dzp, 9111626 IO - Int. J. Gynecol. Cancer SB - Index Medicus CP - United States MH - Adenocarcinoma, Clear Cell/me [Metabolism] MH - Adenocarcinoma, Clear Cell/pa [Pathology] MH - *Apoptosis MH - Blotting, Western MH - *Cell Cycle Checkpoints MH - Cell Proliferation MH - Checkpoint Kinase 1 MH - *DNA Damage MH - *Drug Resistance, Neoplasm MH - Female MH - Flow Cytometry MH - *G2 Phase MH - Hepatocyte Nuclear Factor 1-beta/ai [Antagonists & Inhibitors] MH - Hepatocyte Nuclear Factor 1-beta/ge [Genetics] MH - *Hepatocyte Nuclear Factor 1-beta/me [Metabolism] MH - Humans MH - *Ovarian Neoplasms/me [Metabolism] MH - *Ovarian Neoplasms/pa [Pathology] MH - *Protein Kinases/me [Metabolism] MH - RNA, Small Interfering/ge [Genetics] MH - Tumor Cells, Cultured AB - OBJECTIVE: Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1beta (HNF-1beta) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1beta in regulation of the cell cycle in CCA. AB - METHODS: To clarify the effects of HNF-1beta on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1beta had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1beta (+) cells were arrested in G2 phase because of DNA damage. AB - RESULTS: HNF-1beta (-) cells died because of a checkpoint mechanism. G2 arrest of HNF-1beta (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1beta (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage-induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor. AB - CONCLUSIONS: The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1beta. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA. RN - 0 (HNF1B protein, human) RN - 0 (RNA, Small Interfering) RN - 138674-15-4 (Hepatocyte Nuclear Factor 1-beta) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) ES - 1525-1438 IL - 1048-891X DO - https://dx.doi.org/10.1097/IGC.0000000000000136 PT - Journal Article ID - 24804869 [pubmed] ID - 10.1097/IGC.0000000000000136 [doi] PP - ppublish LG - English DP - 2014 Jun DC - 20140521 EZ - 2014/05/09 06:00 DA - 2015/01/13 06:00 DT - 2014/05/09 06:00 YR - 2014 ED - 20150109 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24804869 <231. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24832153 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - De Remigis A AU - de Gruijl TD AU - Uram JN AU - Tzou SC AU - Iwama S AU - Talor MV AU - Armstrong TD AU - Santegoets SJ AU - Slovin SF AU - Zheng L AU - Laheru DA AU - Jaffee EM AU - Gerritsen WR AU - van den Eertwegh AJ AU - Le DT AU - Caturegli P FA - De Remigis, Alessandra FA - de Gruijl, Tanja D FA - Uram, Jennifer N FA - Tzou, Schey-Cherng FA - Iwama, Shintaro FA - Talor, Monica V FA - Armstrong, Todd D FA - Santegoets, Saskia J A M FA - Slovin, Susan F FA - Zheng, Lei FA - Laheru, Daniel A FA - Jaffee, Elizabeth M FA - Gerritsen, Winald R FA - van den Eertwegh, Alfons J M FA - Le, Dung T FA - Caturegli, Patrizio IN - De Remigis, Alessandra. Department of Pathology, Johns Hopkins University, Baltimore, MD. TI - Development of thyroglobulin antibodies after GVAX immunotherapy is associated with prolonged survival. SO - International Journal of Cancer. 136(1):127-37, 2015 Jan 01 AS - Int J Cancer. 136(1):127-37, 2015 Jan 01 NJ - International journal of cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - gqu, 0042124 IO - Int. J. Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199892 OI - Source: NLM. NIHMS596021 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Neoplasm/bl [Blood] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - Autoantibodies/bl [Blood] MH - CD4-Positive T-Lymphocytes/im [Immunology] MH - CD4-Positive T-Lymphocytes/me [Metabolism] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - CD8-Positive T-Lymphocytes/me [Metabolism] MH - *Cancer Vaccines/ad [Administration & Dosage] MH - Cancer Vaccines/im [Immunology] MH - Cell Line, Tumor MH - Cohort Studies MH - Colonic Neoplasms/bl [Blood] MH - Colonic Neoplasms/im [Immunology] MH - Colonic Neoplasms/mo [Mortality] MH - *Colonic Neoplasms/th [Therapy] MH - Combined Modality Therapy MH - Humans MH - Male MH - Pancreatic Neoplasms/bl [Blood] MH - Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/mo [Mortality] MH - *Pancreatic Neoplasms/th [Therapy] MH - Prostatic Neoplasms/bl [Blood] MH - Prostatic Neoplasms/im [Immunology] MH - Prostatic Neoplasms/mo [Mortality] MH - *Prostatic Neoplasms/th [Therapy] MH - RNA, Messenger/ge [Genetics] MH - RNA, Messenger/me [Metabolism] MH - Survival Analysis MH - Thyroglobulin/ge [Genetics] MH - *Thyroglobulin/im [Immunology] MH - Thyroglobulin/me [Metabolism] MH - Thyrotropin/bl [Blood] MH - Vaccination KW - CTLA-4; GVAX; immunotherapy; thyroglobulin antibodies AB - Cancer immunotherapy induces a variety of autoinflammatory responses, including those against the thyroid gland, which can be exploited to predict clinical outcomes. Considering the paucity of information about thyroid autoimmunity in patients receiving cancer vaccines, we designed our study to assess the development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and correlated seroconversion with survival. Using both in house and commercial ELISA assays, we measured TgAbs in patients with pancreatic (No.=53), prostate (No.=35) or colon (No.=8) cancer, before and after treatment with GVAX only (No.=34), GVAX plus ipilimumab (No.=42) or ipilimumab (No.=20), and correlated their levels with patient's survival, disease status and T-cell surface markers. Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin were also measured. TgAbs specifically developed after GVAX, independent of the underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer) and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus ipilimumab). This TgAbs seroconversion could be detected mainly by the in house assay, suggesting that the thyroglobulin epitopes recognized by the antibodies induced by GVAX are different from the epitopes seen in the classic form of Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with significantly prolonged survival (p=0.01 for pancreas and p=0.005 for prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival. AB - Copyright © 2014 UICC. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Neoplasm) RN - 0 (Antineoplastic Agents) RN - 0 (Autoantibodies) RN - 0 (Cancer Vaccines) RN - 0 (GVAX vaccine) RN - 0 (RNA, Messenger) RN - 6T8C155666 (ipilimumab) RN - 9002-71-5 (Thyrotropin) RN - 9010-34-8 (Thyroglobulin) ES - 1097-0215 IL - 0020-7136 DO - https://dx.doi.org/10.1002/ijc.28973 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 24832153 [pubmed] ID - 10.1002/ijc.28973 [doi] ID - PMC4199892 [pmc] ID - NIHMS596021 [mid] PP - ppublish PH - 2013/10/09 [received] PH - 2014/04/30 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00389610 SA - ClinicalTrials.gov/NCT00656123 SA - ClinicalTrials.gov/NCT00323882 SA - ClinicalTrials.gov/NCT00836407 SA - ClinicalTrials.gov/NCT01510288 SL - https://clinicaltrials.gov/search/term=NCT00389610 SL - https://clinicaltrials.gov/search/term=NCT00656123 SL - https://clinicaltrials.gov/search/term=NCT00323882 SL - https://clinicaltrials.gov/search/term=NCT00836407 SL - https://clinicaltrials.gov/search/term=NCT01510288 GI - No: DK080351 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 DK080351 Organization: (DK) *NIDDK NIH HHS* Country: United States No: K23 CA148964-01 Organization: (CA) *NCI NIH HHS* Country: United States No: 2P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA1266058 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA126058 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA163672 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20140528 DP - 2015 Jan 01 DC - 20141016 EZ - 2014/05/17 06:00 DA - 2014/12/23 06:00 DT - 2014/05/17 06:00 YR - 2015 ED - 20141222 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24832153 <232. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24832153 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - De Remigis A AU - de Gruijl TD AU - Uram JN AU - Tzou SC AU - Iwama S AU - Talor MV AU - Armstrong TD AU - Santegoets SJ AU - Slovin SF AU - Zheng L AU - Laheru DA AU - Jaffee EM AU - Gerritsen WR AU - van den Eertwegh AJ AU - Le DT AU - Caturegli P FA - De Remigis, Alessandra FA - de Gruijl, Tanja D FA - Uram, Jennifer N FA - Tzou, Schey-Cherng FA - Iwama, Shintaro FA - Talor, Monica V FA - Armstrong, Todd D FA - Santegoets, Saskia J A M FA - Slovin, Susan F FA - Zheng, Lei FA - Laheru, Daniel A FA - Jaffee, Elizabeth M FA - Gerritsen, Winald R FA - van den Eertwegh, Alfons J M FA - Le, Dung T FA - Caturegli, Patrizio IN - De Remigis, Alessandra. Department of Pathology, Johns Hopkins University, Baltimore, MD. TI - Development of thyroglobulin antibodies after GVAX immunotherapy is associated with prolonged survival. SO - International Journal of Cancer. 136(1):127-37, 2015 Jan 01 AS - Int J Cancer. 136(1):127-37, 2015 Jan 01 NJ - International journal of cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - gqu, 0042124 IO - Int. J. Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199892 OI - Source: NLM. NIHMS596021 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Neoplasm/bl [Blood] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - Autoantibodies/bl [Blood] MH - CD4-Positive T-Lymphocytes/im [Immunology] MH - CD4-Positive T-Lymphocytes/me [Metabolism] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - CD8-Positive T-Lymphocytes/me [Metabolism] MH - *Cancer Vaccines/ad [Administration & Dosage] MH - Cancer Vaccines/im [Immunology] MH - Cell Line, Tumor MH - Cohort Studies MH - Colonic Neoplasms/bl [Blood] MH - Colonic Neoplasms/im [Immunology] MH - Colonic Neoplasms/mo [Mortality] MH - *Colonic Neoplasms/th [Therapy] MH - Combined Modality Therapy MH - Humans MH - Male MH - Pancreatic Neoplasms/bl [Blood] MH - Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/mo [Mortality] MH - *Pancreatic Neoplasms/th [Therapy] MH - Prostatic Neoplasms/bl [Blood] MH - Prostatic Neoplasms/im [Immunology] MH - Prostatic Neoplasms/mo [Mortality] MH - *Prostatic Neoplasms/th [Therapy] MH - RNA, Messenger/ge [Genetics] MH - RNA, Messenger/me [Metabolism] MH - Survival Analysis MH - Thyroglobulin/ge [Genetics] MH - *Thyroglobulin/im [Immunology] MH - Thyroglobulin/me [Metabolism] MH - Thyrotropin/bl [Blood] MH - Vaccination KW - CTLA-4; GVAX; immunotherapy; thyroglobulin antibodies AB - Cancer immunotherapy induces a variety of autoinflammatory responses, including those against the thyroid gland, which can be exploited to predict clinical outcomes. Considering the paucity of information about thyroid autoimmunity in patients receiving cancer vaccines, we designed our study to assess the development of thyroglobulin antibodies (TgAbs) in patients treated with GVAX (vaccine made of a tumor cell type transfected with GM-CSF) and/or ipilimumab and correlated seroconversion with survival. Using both in house and commercial ELISA assays, we measured TgAbs in patients with pancreatic (No.=53), prostate (No.=35) or colon (No.=8) cancer, before and after treatment with GVAX only (No.=34), GVAX plus ipilimumab (No.=42) or ipilimumab (No.=20), and correlated their levels with patient's survival, disease status and T-cell surface markers. Antibodies to thyroperoxidase, myeloperoxidase, proteinase 3, insulin and actin were also measured. TgAbs specifically developed after GVAX, independent of the underlying cancer (81% in prostate, 75% colon cancer and 76% pancreatic cancer) and co-administration of ipilimumab (75% in GVAX only and 78% in GVAX plus ipilimumab). This TgAbs seroconversion could be detected mainly by the in house assay, suggesting that the thyroglobulin epitopes recognized by the antibodies induced by GVAX are different from the epitopes seen in the classic form of Hashimoto thyroiditis. Notably, TgAbs seroconversion was associated with significantly prolonged survival (p=0.01 for pancreas and p=0.005 for prostate cancer). In conclusion, GVAX immunotherapy induces the appearance of TgAbs that recognize a unique antigenic repertoire and associate with prolonged survival. AB - Copyright © 2014 UICC. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Neoplasm) RN - 0 (Antineoplastic Agents) RN - 0 (Autoantibodies) RN - 0 (Cancer Vaccines) RN - 0 (GVAX vaccine) RN - 0 (RNA, Messenger) RN - 6T8C155666 (ipilimumab) RN - 9002-71-5 (Thyrotropin) RN - 9010-34-8 (Thyroglobulin) ES - 1097-0215 IL - 0020-7136 DO - https://dx.doi.org/10.1002/ijc.28973 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 24832153 [pubmed] ID - 10.1002/ijc.28973 [doi] ID - PMC4199892 [pmc] ID - NIHMS596021 [mid] PP - ppublish PH - 2013/10/09 [received] PH - 2014/04/30 [accepted] GI - No: DK080351 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 DK080351 Organization: (DK) *NIDDK NIH HHS* Country: United States No: K23 CA148964-01 Organization: (CA) *NCI NIH HHS* Country: United States No: 2P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA1266058 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA126058 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA163672 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20140528 DP - 2015 Jan 01 DC - 20141016 EZ - 2014/05/17 06:00 DA - 2014/12/23 06:00 DT - 2014/05/17 06:00 YR - 2015 ED - 20141222 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=24832153 <233. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24778161 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Min L AU - Hodi FS FA - Min, Le FA - Hodi, F Stephen IN - Min, Le. Authors' Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. TI - Anti-PD1 following ipilimumab for mucosal melanoma: durable tumor response associated with severe hypothyroidism and rhabdomyolysis. SO - Cancer Immunology Research. 2(1):15-8, 2014 Jan AS - Cancer Immunol Res. 2(1):15-8, 2014 Jan NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006358 OI - Source: NLM. NIHMS542984 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/pd [Pharmacology] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Agents/pd [Pharmacology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Humans MH - Hypothyroidism/di [Diagnosis] MH - Hypothyroidism/et [Etiology] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/pa [Pathology] MH - Middle Aged MH - *Mucous Membrane/pa [Pathology] MH - Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Rhabdomyolysis/di [Diagnosis] MH - Rhabdomyolysis/et [Etiology] MH - Treatment Outcome AB - Treatment with fully human monoclonal antibodies against programmed death 1 (PD1) receptor has shown great promise for a number of advanced malignancies. Although inflammatory adverse events have been well described with anti-CTL antigen 4 (CTLA4) therapy, experience with the range of adverse effects of anti-PD1 remains comparatively limited. Here, we report on a patient with advanced mucosal melanoma who received four doses of MK-3475, a fully human monoclonal antibody against PD1, and experienced a durable near-complete response but developed severe hypothyroidism, rhabdomyolysis, and acute kidney injury. To our knowledge, this is the first case reported of a patient with advanced mucosal melanoma who responded to anti-PD1 therapy. With the promising antitumor effects of anti-PD1 in a wide array of tumors, we expect an increasing number of patients to be exposed to anti-PD1 therapies. Recognition of infrequent presentations of adverse events such as elevated creatine kinase levels and thyroid disorders in patients who receive anti-PD1 therapy is important. AB - Copyright ©2014 AACR. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (Programmed Cell Death 1 Receptor) RN - 6T8C155666 (ipilimumab) RN - DPT0O3T46P (pembrolizumab) ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-13-0146 DO - https://dx.doi.org/10.1158/2326-6066.CIR-13-0146 PT - Case Reports PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 24778161 [pubmed] ID - 2326-6066.CIR-13-0146 [pii] ID - 10.1158/2326-6066.CIR-13-0146 [doi] ID - PMC4006358 [pmc] ID - NIHMS542984 [mid] PP - ppublish GI - No: K08 HD070957 Organization: (HD) *NICHD NIH HHS* Country: United States No: T32 DK007529 Organization: (DK) *NIDDK NIH HHS* Country: United States No: 5K08HD070957 Organization: (HD) *NICHD NIH HHS* Country: United States LG - English EP - 20131007 DP - 2014 Jan DC - 20140429 EZ - 2014/04/30 06:00 DA - 2014/12/19 06:00 DT - 2014/04/30 06:00 YR - 2014 ED - 20141218 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24778161 <234. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24778314 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Fearon DT FA - Fearon, Douglas T IN - Fearon, Douglas T. Author's Affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. TI - The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. SO - Cancer Immunology Research. 2(3):187-93, 2014 Mar AS - Cancer Immunol Res. 2(3):187-93, 2014 Mar NJ - Cancer immunology research PI - Journal available in: Print PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res SB - Index Medicus CP - United States MH - Animals MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/pa [Pathology] MH - Chemokine CXCL12/im [Immunology] MH - Drug Resistance, Neoplasm MH - *Fibroblasts/me [Metabolism] MH - Gelatinases/me [Metabolism] MH - Humans MH - Membrane Proteins/me [Metabolism] MH - Mice MH - Neoplasms, Experimental MH - *Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/pa [Pathology] MH - Receptors, CXCR4/im [Immunology] MH - Serine Endopeptidases/me [Metabolism] MH - Stromal Cells/ph [Physiology] MH - *Tumor Escape MH - Tumor Microenvironment AB - The fibroblastic element of the tumor microenvironment has been of great interest to cancer biologists but less so to cancer immunologists. Yet, the sharing of a common mesenchymal cell type in the stroma of tumors and at sites of chronic inflammatory lesions, some of which have an autoimmune basis, has been a strong hint that this cellular component of the tumor microenvironment may have an immunologic function. Recent studies have confirmed this possibility. These fibroblast-like cells, which are termed carcinoma-associated fibroblasts (CAF), can be identified by their expression of the membrane protein, fibroblast activation protein-alpha (FAP). The conditional depletion of the FAP(+) CAF permits immune control not only of an artificial, transplanted tumor, but also of an autochthonous model of pancreatic ductal adenocarcinoma (PDA) that replicates the molecular, histologic, clinical, and immunologic characteristics of the human disease. Immune suppression by the FAP(+) CAF is mediated by CXCL12, the chemokine that binds to cancer cells and excludes T cells by a mechanism that depends on signaling by the CXCL12 receptor CXCR4. Inhibition of CXCR4 leads to the elimination of cancer cells by enabling the rapid, intratumoral accumulation of preexisting, PDA-specific CD8(+) T cells, and reveals the antitumor efficacy of the T-cell checkpoint antagonist anti-PD-L1. Recent studies have also shown that the FAP(+) CAF is related to FAP-expressing stromal cells of normal tissues, demonstrating that cancers recruit a member of an essential stromal cell lineage that is involved not only in wound repair but also in normal tissue homeostasis. These findings extend the concept introduced by cancer biologists that the fibroblastic component of tumors has a critical role in the adaptation of the cancer to the host. AB - Copyright ©2014 AACR. RN - 0 (Chemokine CXCL12) RN - 0 (Membrane Proteins) RN - 0 (Receptors, CXCR4) RN - EC 3-4-21 (Serine Endopeptidases) RN - EC 3-4-21 (fibroblast activation protein alpha) RN - EC 3-4-24 (Gelatinases) ES - 2326-6074 IL - 2326-6066 DI - 2/3/187 DO - https://dx.doi.org/10.1158/2326-6066.CIR-14-0002 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 24778314 [pubmed] ID - 2/3/187 [pii] ID - 10.1158/2326-6066.CIR-14-0002 [doi] PP - ppublish LG - English DP - 2014 Mar DC - 20140429 EZ - 2014/04/30 06:00 DA - 2014/12/15 06:00 DT - 2014/04/30 06:00 YR - 2014 ED - 20141208 RD - 20160122 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24778314 <235. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24695685 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Iwama S AU - De Remigis A AU - Callahan MK AU - Slovin SF AU - Wolchok JD AU - Caturegli P FA - Iwama, Shintaro FA - De Remigis, Alessandra FA - Callahan, Margaret K FA - Slovin, Susan F FA - Wolchok, Jedd D FA - Caturegli, Patrizio IN - Iwama, Shintaro. Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA. TI - Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. SO - Science Translational Medicine. 6(230):230ra45, 2014 Apr 02 AS - Sci Transl Med. 6(230):230ra45, 2014 Apr 02 NJ - Science translational medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - 101505086 IO - Sci Transl Med SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Animals MH - *Antibodies, Blocking/ad [Administration & Dosage] MH - *Antibodies, Blocking/ae [Adverse Effects] MH - Antibodies, Blocking/bl [Blood] MH - Antibodies, Blocking/tu [Therapeutic Use] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Autoantibodies/bl [Blood] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - *CTLA-4 Antigen/me [Metabolism] MH - Complement System Proteins/me [Metabolism] MH - Disease Models, Animal MH - Female MH - Flow Cytometry MH - Fluorescent Antibody Technique MH - Hematopoiesis/de [Drug Effects] MH - Humans MH - Magnetic Resonance Imaging MH - Male MH - Mice MH - Middle Aged MH - Pituitary Diseases/bl [Blood] MH - Pituitary Diseases/dt [Drug Therapy] MH - *Pituitary Diseases/et [Etiology] MH - *Pituitary Diseases/im [Immunology] MH - Pituitary Gland/im [Immunology] MH - *Pituitary Gland/me [Metabolism] MH - Pituitary Gland/pa [Pathology] MH - Pituitary Neoplasms/bl [Blood] MH - Pituitary Neoplasms/dt [Drug Therapy] MH - Pituitary Neoplasms/im [Immunology] MH - Prolactin/se [Secretion] MH - Thyrotropin/se [Secretion] AB - Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of patients through unknown mechanisms. We first established a model of secondary hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or C57BL/6J mice, and showed that they developed lymphocytic infiltration of the pituitary gland and circulating pituitary antibodies. We next assessed the prevalence of pituitary antibodies in a cohort of 20 patients with advanced melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before and after ipilimumab administration. Pituitary antibodies, negative at baseline, developed in the 7 patients with hypophysitis but not in the 13 without it; these antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone-, and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4 antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed "ectopically" on pituitary endocrine cells. Pituitary glands indeed expressed CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin- and thyrotropin-secreting cells. Notably, these cells became the site of complement activation, featuring deposition of C3d and C4d components and an inflammatory cascade akin to that seen in type II hypersensitivity. In summary, the study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis. RN - 0 (Antibodies, Blocking) RN - 0 (Antibodies, Monoclonal) RN - 0 (Autoantibodies) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) RN - 9002-62-4 (Prolactin) RN - 9002-71-5 (Thyrotropin) RN - 9007-36-7 (Complement System Proteins) ES - 1946-6242 IL - 1946-6234 DI - 6/230/230ra45 DO - https://dx.doi.org/10.1126/scitranslmed.3008002 PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 24695685 [pubmed] ID - 6/230/230ra45 [pii] ID - 10.1126/scitranslmed.3008002 [doi] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00323882 SA - ClinicalTrials.gov/NCT00495066 SA - ClinicalTrials.gov/NCT00623766 SA - ClinicalTrials.gov/NCT00920907 SL - https://clinicaltrials.gov/search/term=NCT00323882 SL - https://clinicaltrials.gov/search/term=NCT00495066 SL - https://clinicaltrials.gov/search/term=NCT00623766 SL - https://clinicaltrials.gov/search/term=NCT00920907 GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States No: DK080351 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English DP - 2014 Apr 02 DC - 20140403 EZ - 2014/04/04 06:00 DA - 2014/11/19 06:00 DT - 2014/04/04 06:00 YR - 2014 ED - 20141118 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24695685 <236. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24610577 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ryder M AU - Callahan M AU - Postow MA AU - Wolchok J AU - Fagin JA FA - Ryder, Mabel FA - Callahan, Margaret FA - Postow, Michael A FA - Wolchok, Jedd FA - Fagin, James A IN - Ryder, Mabel. Human Oncology and Pathogenesis Program, Department of Medicine Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA. TI - Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. [Review] SO - Endocrine-Related Cancer. 21(2):371-81, 2014 Apr AS - Endocr Relat Cancer. 21(2):371-81, 2014 Apr NJ - Endocrine-related cancer PI - Journal available in: Electronic-Print PI - Citation processed from: Internet JC - 9436481, dgr IO - Endocr. Relat. Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573438 OI - Source: NLM. NIHMS616115 SB - Index Medicus CP - England MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *Endocrine System Diseases/ci [Chemically Induced] MH - Endocrine System Diseases/ep [Epidemiology] MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/ep [Epidemiology] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/ep [Epidemiology] MH - Testosterone/bl [Blood] KW - hypophysitis; immune-related adverse effects; ipilimumab; nivolumab; thyroiditis AB - Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 3XMK78S47O (Testosterone) RN - 6T8C155666 (ipilimumab) ES - 1479-6821 IL - 1351-0088 DI - 21/2/371 DO - https://dx.doi.org/10.1530/ERC-13-0499 PT - Journal Article PT - Review ID - 24610577 [pubmed] ID - 21/2/371 [pii] ID - 10.1530/ERC-13-0499 [doi] ID - PMC4573438 [pmc] ID - NIHMS616115 [mid] PP - epublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01245556 SA - ClinicalTrials.gov/NCT00920907 SA - ClinicalTrials.gov/NCT00289640 SA - ClinicalTrials.gov/NCT01024231 SA - ClinicalTrials.gov/NCT00324155 SA - ClinicalTrials.gov/NCT00495066 SA - ClinicalTrials.gov/NCT00289627 SA - ClinicalTrials.gov/NCT00162123 SA - ClinicalTrials.gov/NCT01323517 SA - ClinicalTrials.gov/NCT00796991 SL - https://clinicaltrials.gov/search/term=NCT01245556 SL - https://clinicaltrials.gov/search/term=NCT00920907 SL - https://clinicaltrials.gov/search/term=NCT00289640 SL - https://clinicaltrials.gov/search/term=NCT01024231 SL - https://clinicaltrials.gov/search/term=NCT00324155 SL - https://clinicaltrials.gov/search/term=NCT00495066 SL - https://clinicaltrials.gov/search/term=NCT00289627 SL - https://clinicaltrials.gov/search/term=NCT00162123 SL - https://clinicaltrials.gov/search/term=NCT01323517 SL - https://clinicaltrials.gov/search/term=NCT00796991 GI - No: K08 CA133183 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA172012 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20140307 DP - 2014 Apr DC - 20140310 EZ - 2014/03/11 06:00 DA - 2014/11/15 06:00 DT - 2014/03/13 06:00 YR - 2014 ED - 20141114 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24610577 <237. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24610577 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ryder M AU - Callahan M AU - Postow MA AU - Wolchok J AU - Fagin JA FA - Ryder, Mabel FA - Callahan, Margaret FA - Postow, Michael A FA - Wolchok, Jedd FA - Fagin, James A IN - Ryder, Mabel. Human Oncology and Pathogenesis Program, Department of Medicine Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA. TI - Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. [Review] SO - Endocrine-Related Cancer. 21(2):371-81, 2014 Apr AS - Endocr Relat Cancer. 21(2):371-81, 2014 Apr NJ - Endocrine-related cancer PI - Journal available in: Electronic-Print PI - Citation processed from: Internet JC - 9436481, dgr IO - Endocr. Relat. Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573438 OI - Source: NLM. NIHMS616115 SB - Index Medicus CP - England MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *Endocrine System Diseases/ci [Chemically Induced] MH - Endocrine System Diseases/ep [Epidemiology] MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/ep [Epidemiology] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/ep [Epidemiology] MH - Testosterone/bl [Blood] KW - hypophysitis; immune-related adverse effects; ipilimumab; nivolumab; thyroiditis AB - Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 3XMK78S47O (Testosterone) RN - 6T8C155666 (ipilimumab) ES - 1479-6821 IL - 1351-0088 DI - 21/2/371 DO - https://dx.doi.org/10.1530/ERC-13-0499 PT - Journal Article PT - Review ID - 24610577 [pubmed] ID - 21/2/371 [pii] ID - 10.1530/ERC-13-0499 [doi] ID - PMC4573438 [pmc] ID - NIHMS616115 [mid] PP - epublish GI - No: K08 CA133183 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA172012 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20140307 DP - 2014 Apr DC - 20140310 EZ - 2014/03/11 06:00 DA - 2014/11/15 06:00 DT - 2014/03/13 06:00 YR - 2014 ED - 20141114 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=24610577 <238. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25092294 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Eytan E AU - Wang K AU - Miniowitz-Shemtov S AU - Sitry-Shevah D AU - Kaisari S AU - Yen TJ AU - Liu ST AU - Hershko A FA - Eytan, Esther FA - Wang, Kexi FA - Miniowitz-Shemtov, Shirly FA - Sitry-Shevah, Danielle FA - Kaisari, Sharon FA - Yen, Tim J FA - Liu, Song-Tao FA - Hershko, Avram IN - Eytan, Esther. Unit of Biochemistry, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel; IN - Wang, Kexi. Department of Biological Sciences, University of Toledo, Toledo, OH 43606; and. IN - Miniowitz-Shemtov, Shirly. Unit of Biochemistry, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel; IN - Sitry-Shevah, Danielle. Unit of Biochemistry, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel; IN - Kaisari, Sharon. Unit of Biochemistry, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel; IN - Yen, Tim J. Fox Chase Cancer Center, Philadelphia, PA 19111. IN - Liu, Song-Tao. Department of Biological Sciences, University of Toledo, Toledo, OH 43606; and. IN - Hershko, Avram. Unit of Biochemistry, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel; hershko@tx.technion.ac.il. TI - Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31(comet). SO - Proceedings of the National Academy of Sciences of the United States of America. 111(33):12019-24, 2014 Aug 19 AS - Proc Natl Acad Sci U S A. 111(33):12019-24, 2014 Aug 19 NJ - Proceedings of the National Academy of Sciences of the United States of America PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - pv3, 7505876 IO - Proc. Natl. Acad. Sci. U.S.A. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142996 SB - Index Medicus CP - United States MH - Adaptor Proteins, Signal Transducing/me [Metabolism] MH - *Adaptor Proteins, Signal Transducing/ph [Physiology] MH - Carrier Proteins/me [Metabolism] MH - *Carrier Proteins/ph [Physiology] MH - Cdc20 Proteins/me [Metabolism] MH - Cell Cycle Proteins/me [Metabolism] MH - *Cell Cycle Proteins/ph [Physiology] MH - HeLa Cells MH - Humans MH - Mad2 Proteins/me [Metabolism] MH - *Mitosis MH - Nuclear Proteins/me [Metabolism] MH - *Nuclear Proteins/ph [Physiology] MH - Protein Binding KW - mitosis; spindle checkpoint AB - The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. When the checkpoint signal is turned off, MCC is disassembled and the checkpoint is inactivated. The mechanisms of the disassembly of MCC are not sufficiently understood. We have previously observed that ATP hydrolysis is required for the action of the Mad2-binding protein p31(comet) to disassemble MCC. We now show that HeLa cell extracts contain a factor that promotes ATP- and p31(comet)-dependent disassembly of a Cdc20-Mad2 subcomplex and identify it as Thyroid Receptor Interacting Protein 13 (TRIP13), an AAA-ATPase known to interact with p31(comet). The joint action of TRIP13 and p31(comet) also promotes the release of Mad2 from MCC, participates in the complete disassembly of MCC and abrogates checkpoint inhibition of APC/C. We propose that TRIP13 plays centrally important roles in the sequence of events leading to MCC disassembly and checkpoint inactivation. RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Carrier Proteins) RN - 0 (Cdc20 Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (MAD2L1 protein, human) RN - 0 (MAD2L1BP protein, human) RN - 0 (Mad2 Proteins) RN - 0 (Nuclear Proteins) RN - 0 (TRIP13 protein, human) RN - 156288-95-8 (CDC20 protein, human) ES - 1091-6490 IL - 0027-8424 DI - 1412901111 DO - https://dx.doi.org/10.1073/pnas.1412901111 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. ID - 25092294 [pubmed] ID - 1412901111 [pii] ID - 10.1073/pnas.1412901111 [doi] ID - PMC4142996 [pmc] PP - ppublish GI - No: CA06927 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA169500 Organization: (CA) *NCI NIH HHS* Country: United States No: CA169706 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA169500 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA169706 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA006927 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20140804 DP - 2014 Aug 19 DC - 20140820 EZ - 2014/08/06 06:00 DA - 2014/11/05 06:00 DT - 2014/08/06 06:00 YR - 2014 ED - 20141103 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=25092294 <239. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24594636 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gelao L AU - Criscitiello C AU - Esposito A AU - Goldhirsch A AU - Curigliano G FA - Gelao, Lucia FA - Criscitiello, Carmen FA - Esposito, Angela FA - Goldhirsch, Aron FA - Curigliano, Giuseppe IN - Gelao, Lucia. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. lucia.gelao@ieo.it. IN - Criscitiello, Carmen. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. carmen.criscitiello@ieo.it. IN - Esposito, Angela. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. angela.esposito@ieo.it. IN - Goldhirsch, Aron. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. aaron.goldhirsch@ieo.it. IN - Curigliano, Giuseppe. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. giuseppe.curigliano@ieo.it. TI - Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an "innocent bystander". [Review] SO - Toxins. 6(3):914-33, 2014 Mar 03 AS - Toxins (Basel). 6(3):914-33, 2014 Mar 03 NJ - Toxins PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101530765 IO - Toxins (Basel) PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968368 SB - Index Medicus CP - Switzerland MH - Animals MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Humans MH - Immune Tolerance MH - Immunologic Factors/ae [Adverse Effects] MH - Immunologic Factors/tu [Therapeutic Use] MH - *Immunotherapy/ae [Adverse Effects] MH - *Neoplasms/th [Therapy] AB - Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific "immune-related adverse events" (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique "innocent bystander" effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment. RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunologic Factors) ES - 2072-6651 IL - 2072-6651 DI - toxins6030914 DO - https://dx.doi.org/10.3390/toxins6030914 PT - Journal Article PT - Review ID - 24594636 [pubmed] ID - toxins6030914 [pii] ID - 10.3390/toxins6030914 [doi] ID - PMC3968368 [pmc] PP - epublish PH - 2013/11/27 [received] PH - 2014/01/21 [revised] PH - 2014/02/18 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01454102 SA - ClinicalTrials.gov/NCT01927419 SA - ClinicalTrials.gov/NCT01608594 SA - ClinicalTrials.gov/NCT01750983 SA - ClinicalTrials.gov/NCT01844505 SA - ClinicalTrials.gov/NCT01840579 SA - ClinicalTrials.gov/NCT01822509 SA - ClinicalTrials.gov/NCT01896869 SA - ClinicalTrials.gov/NCT01633970 SA - ClinicalTrials.gov/NCT01846416 SA - ClinicalTrials.gov/NCT00636168 SA - ClinicalTrials.gov/NCT01668784 SA - ClinicalTrials.gov/NCT00836407 SA - ClinicalTrials.gov/NCT01103635 SA - ClinicalTrials.gov/NCT00612664 SA - ClinicalTrials.gov/NCT01832870 SA - ClinicalTrials.gov/NCT01866319 SA - ClinicalTrials.gov/NCT01498978 SA - ClinicalTrials.gov/NCT01750580 SA - ClinicalTrials.gov/NCT01810016 SA - ClinicalTrials.gov/NCT01565837 SA - ClinicalTrials.gov/NCT01590082 SA - ClinicalTrials.gov/NCT01729806 SA - ClinicalTrials.gov/NCT01738139 SA - ClinicalTrials.gov/NCT01024231 SA - ClinicalTrials.gov/NCT01604889 SA - ClinicalTrials.gov/NCT01471210 SA - ClinicalTrials.gov/NCT01473940 SA - ClinicalTrials.gov/NCT01988077 SA - ClinicalTrials.gov/NCT01643278 SA - ClinicalTrials.gov/NCT01468311 SA - ClinicalTrials.gov/NCT01905657 SA - ClinicalTrials.gov/NCT01524991 SA - ClinicalTrials.gov/NCT01689974 SA - ClinicalTrials.gov/NCT01673854 SA - ClinicalTrials.gov/NCT01307618 SA - ClinicalTrials.gov/NCT01629758 SA - ClinicalTrials.gov/NCT01775631 SA - ClinicalTrials.gov/NCT01827111 SA - ClinicalTrials.gov/NCT01295827 SA - ClinicalTrials.gov/NCT01363206 SA - ClinicalTrials.gov/NCT01331525 SA - ClinicalTrials.gov/NCT01274338 SA - ClinicalTrials.gov/NCT01489059 SA - ClinicalTrials.gov/NCT01642004 SA - ClinicalTrials.gov/NCT01853618 SA - ClinicalTrials.gov/NCT00729664 SA - ClinicalTrials.gov/NCT01767454 SA - ClinicalTrials.gov/NCT01928394 SA - ClinicalTrials.gov/NCT01721772 SA - ClinicalTrials.gov/NCT01592370 SA - ClinicalTrials.gov/NCT01656642 SA - ClinicalTrials.gov/NCT01611558 SA - ClinicalTrials.gov/NCT01968109 SA - ClinicalTrials.gov/NCT01711515 SA - ClinicalTrials.gov/NCT01740297 SA - ClinicalTrials.gov/NCT01450761 SA - ClinicalTrials.gov/NCT01285609 SA - ClinicalTrials.gov/NCT01783938 SA - ClinicalTrials.gov/NCT01676649 SA - ClinicalTrials.gov/NCT01903993 SA - ClinicalTrials.gov/NCT01843374 SA - ClinicalTrials.gov/NCT01848834 SA - ClinicalTrials.gov/NCT01860430 SA - ClinicalTrials.gov/NCT01975831 SA - ClinicalTrials.gov/NCT01856023 SA - ClinicalTrials.gov/NCT01896999 SL - https://clinicaltrials.gov/search/term=NCT01454102 SL - https://clinicaltrials.gov/search/term=NCT01927419 SL - https://clinicaltrials.gov/search/term=NCT01608594 SL - https://clinicaltrials.gov/search/term=NCT01750983 SL - https://clinicaltrials.gov/search/term=NCT01844505 SL - https://clinicaltrials.gov/search/term=NCT01840579 SL - https://clinicaltrials.gov/search/term=NCT01822509 SL - https://clinicaltrials.gov/search/term=NCT01896869 SL - https://clinicaltrials.gov/search/term=NCT01633970 SL - https://clinicaltrials.gov/search/term=NCT01846416 SL - https://clinicaltrials.gov/search/term=NCT00636168 SL - https://clinicaltrials.gov/search/term=NCT01668784 SL - https://clinicaltrials.gov/search/term=NCT00836407 SL - https://clinicaltrials.gov/search/term=NCT01103635 SL - https://clinicaltrials.gov/search/term=NCT00612664 SL - https://clinicaltrials.gov/search/term=NCT01832870 SL - https://clinicaltrials.gov/search/term=NCT01866319 SL - https://clinicaltrials.gov/search/term=NCT01498978 SL - https://clinicaltrials.gov/search/term=NCT01750580 SL - https://clinicaltrials.gov/search/term=NCT01810016 SL - https://clinicaltrials.gov/search/term=NCT01565837 SL - https://clinicaltrials.gov/search/term=NCT01590082 SL - https://clinicaltrials.gov/search/term=NCT01729806 SL - https://clinicaltrials.gov/search/term=NCT01738139 SL - https://clinicaltrials.gov/search/term=NCT01024231 SL - https://clinicaltrials.gov/search/term=NCT01604889 SL - https://clinicaltrials.gov/search/term=NCT01471210 SL - https://clinicaltrials.gov/search/term=NCT01473940 SL - https://clinicaltrials.gov/search/term=NCT01988077 SL - https://clinicaltrials.gov/search/term=NCT01643278 SL - https://clinicaltrials.gov/search/term=NCT01468311 SL - https://clinicaltrials.gov/search/term=NCT01905657 SL - https://clinicaltrials.gov/search/term=NCT01524991 SL - https://clinicaltrials.gov/search/term=NCT01689974 SL - https://clinicaltrials.gov/search/term=NCT01673854 SL - https://clinicaltrials.gov/search/term=NCT01307618 SL - https://clinicaltrials.gov/search/term=NCT01629758 SL - https://clinicaltrials.gov/search/term=NCT01775631 SL - https://clinicaltrials.gov/search/term=NCT01827111 SL - https://clinicaltrials.gov/search/term=NCT01295827 SL - https://clinicaltrials.gov/search/term=NCT01363206 SL - https://clinicaltrials.gov/search/term=NCT01331525 SL - https://clinicaltrials.gov/search/term=NCT01274338 SL - https://clinicaltrials.gov/search/term=NCT01489059 SL - https://clinicaltrials.gov/search/term=NCT01642004 SL - https://clinicaltrials.gov/search/term=NCT01853618 SL - https://clinicaltrials.gov/search/term=NCT00729664 SL - https://clinicaltrials.gov/search/term=NCT01767454 SL - https://clinicaltrials.gov/search/term=NCT01928394 SL - https://clinicaltrials.gov/search/term=NCT01721772 SL - https://clinicaltrials.gov/search/term=NCT01592370 SL - https://clinicaltrials.gov/search/term=NCT01656642 SL - https://clinicaltrials.gov/search/term=NCT01611558 SL - https://clinicaltrials.gov/search/term=NCT01968109 SL - https://clinicaltrials.gov/search/term=NCT01711515 SL - https://clinicaltrials.gov/search/term=NCT01740297 SL - https://clinicaltrials.gov/search/term=NCT01450761 SL - https://clinicaltrials.gov/search/term=NCT01285609 SL - https://clinicaltrials.gov/search/term=NCT01783938 SL - https://clinicaltrials.gov/search/term=NCT01676649 SL - https://clinicaltrials.gov/search/term=NCT01903993 SL - https://clinicaltrials.gov/search/term=NCT01843374 SL - https://clinicaltrials.gov/search/term=NCT01848834 SL - https://clinicaltrials.gov/search/term=NCT01860430 SL - https://clinicaltrials.gov/search/term=NCT01975831 SL - https://clinicaltrials.gov/search/term=NCT01856023 SL - https://clinicaltrials.gov/search/term=NCT01896999 LG - English EP - 20140303 DP - 2014 Mar 03 DC - 20140305 EZ - 2014/03/06 06:00 DA - 2014/11/02 06:00 DT - 2014/03/07 06:00 YR - 2014 ED - 20141031 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24594636 <240. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24594636 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gelao L AU - Criscitiello C AU - Esposito A AU - Goldhirsch A AU - Curigliano G FA - Gelao, Lucia FA - Criscitiello, Carmen FA - Esposito, Angela FA - Goldhirsch, Aron FA - Curigliano, Giuseppe IN - Gelao, Lucia. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. lucia.gelao@ieo.it. IN - Criscitiello, Carmen. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. carmen.criscitiello@ieo.it. IN - Esposito, Angela. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. angela.esposito@ieo.it. IN - Goldhirsch, Aron. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. aaron.goldhirsch@ieo.it. IN - Curigliano, Giuseppe. Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. giuseppe.curigliano@ieo.it. TI - Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an "innocent bystander". [Review] SO - Toxins. 6(3):914-33, 2014 Mar 03 AS - Toxins (Basel). 6(3):914-33, 2014 Mar 03 NJ - Toxins PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101530765 IO - Toxins (Basel) PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968368 SB - Index Medicus CP - Switzerland MH - Animals MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Humans MH - Immune Tolerance MH - Immunologic Factors/ae [Adverse Effects] MH - Immunologic Factors/tu [Therapeutic Use] MH - *Immunotherapy/ae [Adverse Effects] MH - *Neoplasms/th [Therapy] AB - Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific "immune-related adverse events" (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique "innocent bystander" effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment. RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunologic Factors) ES - 2072-6651 IL - 2072-6651 DI - toxins6030914 DO - https://dx.doi.org/10.3390/toxins6030914 PT - Journal Article PT - Review ID - 24594636 [pubmed] ID - toxins6030914 [pii] ID - 10.3390/toxins6030914 [doi] ID - PMC3968368 [pmc] PP - epublish PH - 2013/11/27 [received] PH - 2014/01/21 [revised] PH - 2014/02/18 [accepted] LG - English EP - 20140303 DP - 2014 Mar 03 DC - 20140305 EZ - 2014/03/06 06:00 DA - 2014/11/02 06:00 DT - 2014/03/07 06:00 YR - 2014 ED - 20141031 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=24594636 <241. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24556918 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kopper F AU - Binkowski AM AU - Bierwirth C AU - Dobbelstein M FA - Kopper, Frederik FA - Binkowski, Anna Maria FA - Bierwirth, Cathrin FA - Dobbelstein, Matthias IN - Kopper, Frederik. Institute of Molecular Oncology; Gottingen Centre of Molecular Biosciences (GZMB); Faculty of Medicine; University of Gottingen; Gottingen, Germany. IN - Binkowski, Anna Maria. Institute of Molecular Oncology; Gottingen Centre of Molecular Biosciences (GZMB); Faculty of Medicine; University of Gottingen; Gottingen, Germany. IN - Bierwirth, Cathrin. Institute of Molecular Oncology; Gottingen Centre of Molecular Biosciences (GZMB); Faculty of Medicine; University of Gottingen; Gottingen, Germany. IN - Dobbelstein, Matthias. Institute of Molecular Oncology; Gottingen Centre of Molecular Biosciences (GZMB); Faculty of Medicine; University of Gottingen; Gottingen, Germany. TI - The MAPK-activated protein kinase 2 mediates gemcitabine sensitivity in pancreatic cancer cells. SO - Cell Cycle. 13(6):884-9, 2014 AS - Cell Cycle. 13(6):884-9, 2014 NJ - Cell cycle (Georgetown, Tex.) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101137841 IO - Cell Cycle PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984311 SB - Index Medicus CP - United States MH - *Adenocarcinoma/me [Metabolism] MH - Adenocarcinoma/pa [Pathology] MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - Cell Line, Tumor/de [Drug Effects] MH - Cell Survival/de [Drug Effects] MH - Checkpoint Kinase 1 MH - DNA Damage MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - *Drug Resistance, Neoplasm MH - Histones/me [Metabolism] MH - Humans MH - Intracellular Signaling Peptides and Proteins/ai [Antagonists & Inhibitors] MH - *Intracellular Signaling Peptides and Proteins/me [Metabolism] MH - *Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - Phosphorylation MH - Protein Kinases/me [Metabolism] MH - Protein-Serine-Threonine Kinases/ai [Antagonists & Inhibitors] MH - *Protein-Serine-Threonine Kinases/me [Metabolism] KW - Chk1; DNA damage; MAPKAPK2; MK2; chemotherapy; gemcitabine; pancreatic carcinoma AB - Pancreatic carcinoma is the major clinical entity where the nucleoside analog gemcitabine is used for first-line therapy. Overcoming cellular resistance toward gemcitabine remains a major challenge in this context. This raises the need to identify factors that determine gemcitabine sensitivity in pancreatic carcinoma cells. We previously found the MAPK-activated protein kinase 2 (MK2), part of the p38/MK2 stress response pathway, to be required for DNA replication fork stalling when osteosarcoma-derived cells were treated with gemcitabine. As a consequence, inhibition or depletion of MK2 protects these cells from gemcitabine-induced death (Kopper, et al. Proc Natl Acad Sci USA 2013; 110:16856-61). Here, we addressed whether MK2 also determines the sensitivity of pancreatic cancer cells toward gemcitabine. We found that MK2 inhibition reduced the intensity of the DNA damage response and enhanced survival of the pancreatic cancer cell lines BxPC-3, MIA PaCa-2, and Panc-1, which display a moderate to strong sensitivity to gemcitabine. In contrast, MK2 inhibition only weakly attenuated the DNA damage response intensity and did not enhance long-term survival in the gemcitabine-resistant cell line PaTu 8902. Importantly, in BxPC-3 and MIA PaCa-2 cells, inhibition of MK2 also rescued increased H2AX phosphorylation caused by inhibition of the checkpoint kinase Chk1 in the presence of gemcitabine. These results indicate that MK2 mediates gemcitabine efficacy in pancreatic cancer cells that respond to the drug, suggesting that the p38/MK2 pathway represents a determinant of the efficacy by that gemcitabine counteracts pancreatic cancer. RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Histones) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-1 (MAP-kinase-activated kinase 2) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RS - Pancreatic Carcinoma ES - 1551-4005 IL - 1551-4005 DI - 28292 DO - https://dx.doi.org/10.4161/cc.28292 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 24556918 [pubmed] ID - 28292 [pii] ID - 10.4161/cc.28292 [doi] ID - PMC3984311 [pmc] PP - ppublish LG - English EP - 20140221 DP - 2014 DC - 20140320 EZ - 2014/02/22 06:00 DA - 2014/10/23 06:00 DT - 2014/02/22 06:00 YR - 2014 ED - 20141022 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24556918 <242. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24686174 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Mackay C AU - Carroll E AU - Ibrahim AF AU - Garg A AU - Inman GJ AU - Hay RT AU - Alpi AF FA - Mackay, Craig FA - Carroll, Eilis FA - Ibrahim, Adel F M FA - Garg, Amit FA - Inman, Gareth J FA - Hay, Ronald T FA - Alpi, Arno F IN - Mackay, Craig. Authors' Affiliations: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Science; Division of Cancer Research, Medical Research Institute, Ninewells Hospital and Medical School; and Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom. TI - E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin. SO - Cancer Research. 74(8):2246-57, 2014 Apr 15 AS - Cancer Res. 74(8):2246-57, 2014 Apr 15 NJ - Cancer research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnf, 2984705r IO - Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990471 OI - Source: NLM. EMS57229 SB - Index Medicus CP - United States MH - *Antineoplastic Agents/pd [Pharmacology] MH - *Apoptosis/de [Drug Effects] MH - Apoptosis/ph [Physiology] MH - Cell Cycle Checkpoints/ph [Physiology] MH - Cell Death/de [Drug Effects] MH - Cell Death/ph [Physiology] MH - *Cisplatin/pd [Pharmacology] MH - DNA Damage MH - Female MH - HCT116 Cells MH - HEK293 Cells MH - HeLa Cells MH - Humans MH - MAP Kinase Kinase 4/me [Metabolism] MH - Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/en [Enzymology] MH - Ovarian Neoplasms/pa [Pathology] MH - RNA, Small Interfering/ad [Administration & Dosage] MH - RNA, Small Interfering/ge [Genetics] MH - Signal Transduction MH - Ubiquitin-Protein Ligases/ge [Genetics] MH - *Ubiquitin-Protein Ligases/me [Metabolism] AB - The genotoxin cisplatin is commonly used in chemotherapy to treat solid tumors, yet our understanding of the mechanism underlying the drug response is limited. In a focused siRNA screen, using an siRNA library targeting genes involved in ubiquitin and ubiquitin-like signaling, we identified the E3 ubiquitin ligase HOIP as a key regulator of cisplatin-induced genotoxicity. HOIP forms, with SHARPIN and HOIL-1L, the linear ubiquitin assembly complex (LUBAC). We show that cells deficient in the HOIP ligase complex exhibit hypersensitivity to cisplatin. This is due to a dramatic increase in caspase-8/caspase-3-mediated apoptosis that is strictly dependent on ATM-, but not ATR-mediated DNA damage checkpoint activation. Moreover, basal and cisplatin-induced activity of the stress response kinase JNK is enhanced in HOIP-depleted cells and, conversely, JNK inhibition can increase cellular resistance to cisplatin and reverse the apoptotic hyperactivation in HOIP-depleted cells. Furthermore, we show that HOIP depletion sensitizes cancer cells, derived from carcinomas of various origins, through an enhanced apoptotic cell death response. We also provide evidence that ovarian cancer cells classified as cisplatin-resistant can regain sensitivity following HOIP downregulation. Cumulatively, our study identifies a HOIP-regulated antiapoptotic signaling pathway, and we envisage HOIP as a potential target for the development of combinatorial chemotherapies to potentiate the efficacy of platinum-based anticancer drugs. AB - Copyright ©2014 AACR. RN - 0 (Antineoplastic Agents) RN - 0 (RNA, Small Interfering) RN - EC 2-3-2-27 (RNF31 protein, human) RN - EC 2-3-2-27 (Ubiquitin-Protein Ligases) RN - EC 2-7-12-2 (MAP Kinase Kinase 4) RN - Q20Q21Q62J (Cisplatin) ES - 1538-7445 IL - 0008-5472 DI - 0008-5472.CAN-13-2131 DO - https://dx.doi.org/10.1158/0008-5472.CAN-13-2131 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 24686174 [pubmed] ID - 0008-5472.CAN-13-2131 [pii] ID - 10.1158/0008-5472.CAN-13-2131 [doi] ID - PMC3990471 [pmc] ID - EMS57229 [mid] PP - ppublish GI - No: 097945 Organization: *Wellcome Trust* Country: United Kingdom LG - English EP - 20140331 DP - 2014 Apr 15 DC - 20140416 EZ - 2014/04/02 06:00 DA - 2014/07/25 06:00 DT - 2014/04/02 06:00 YR - 2014 ED - 20140724 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24686174 <243. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24122241 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lammert A AU - Schneider HJ AU - Bergmann T AU - Benck U AU - Kramer BK AU - Gartner R AU - Metzner C AU - Schofl C AU - Berking C FA - Lammert, A FA - Schneider, H J FA - Bergmann, T FA - Benck, U FA - Kramer, B K FA - Gartner, R FA - Metzner, C FA - Schofl, C FA - Berking, C IN - Lammert, A. Fifth Medical Clinic, University Medical Center Mannheim, Mannheim, Germany. TI - Hypophysitis caused by ipilimumab in cancer patients: hormone replacement or immunosuppressive therapy. SO - Experimental & Clinical Endocrinology & Diabetes. 121(10):581-7, 2013 Nov AS - Exp Clin Endocrinol Diabetes. 121(10):581-7, 2013 Nov NJ - Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ccv, 9505926 IO - Exp. Clin. Endocrinol. Diabetes SB - Index Medicus CP - Germany MH - Adrenal Cortex Hormones/ae [Adverse Effects] MH - Adrenal Cortex Hormones/tu [Therapeutic Use] MH - *Adrenal Cortex Hormones MH - Adult MH - Aged MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Female MH - *Hormone Replacement Therapy/ae [Adverse Effects] MH - Humans MH - *Immunosuppression/ae [Adverse Effects] MH - Melanoma/dg [Diagnostic Imaging] MH - Melanoma/dt [Drug Therapy] MH - *Melanoma MH - Middle Aged MH - Neoplasm Metastasis MH - *Pituitary Diseases/ci [Chemically Induced] MH - *Pituitary Diseases/dg [Diagnostic Imaging] MH - Radiography AB - Ipilimumab is besides the BRAF inhibitor vemurafenib the first officially approved medical treatment for metastatic melanoma, which results in improved survival. Ipilimumab leads to a release of a CTLA4-mediated inhibition of T-cell immunoreactions. Therefore, patients may also suffer from immune-related adverse events affecting different organs, which are typically treated by high-dose corticosteroids. Ipilimumab-induced hypophysitis (iH) has been reported in up to 17% of melanoma patients in clinical trials.Here we present 5 patients with metastatic melanoma and 2 patients with prostate cancer who developed hypophysitis after ipilimumab therapy. Patients were treated by high-dose corticosteroid therapy resulting in the resolution of local inflammation but not of pituitary deficiencies. Partial or complete hypopituitarism remained in all patients. Pharmacotherapy with high-dose corticosteroids caused complications in 5 patients, necessitating hospitalization in 4. 2 of the 3 patients with progressive disease died, while 3 patients had stable disease and 1 patient showed tumor regression after discontinuation of ipilimumab.In summary, with regard to safety and simplicity of hormonal substitution therapy we have to scrutinize high-dose corticosteroid therapy, though it only improves inflammation but not neuro-endocrine function and may cause further morbidity. Regression of the tumor depends on the ipilimumab-mediated immune events, in which high-dose and long-term corticosteroid therapy for iH appears to be counter-intuitive. Herein, we discuss screening and the diagnostic as well as therapeutic management of iH in metastatic cancer patients from an endocrinologic perspective. AB - Copyright © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart . New York. RN - 0 (Adrenal Cortex Hormones) RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 1439-3646 IL - 0947-7349 DO - https://dx.doi.org/10.1055/s-0033-1355337 PT - Case Reports PT - Journal Article ID - 24122241 [pubmed] ID - 10.1055/s-0033-1355337 [doi] PP - ppublish LG - English EP - 20131011 DP - 2013 Nov DC - 20131126 EZ - 2013/10/15 06:00 DA - 2014/07/08 06:00 DT - 2013/10/15 06:00 YR - 2013 ED - 20140707 RD - 20161128 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24122241 <244. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23750887 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Torino F AU - Barnabei A AU - Paragliola R AU - Baldelli R AU - Appetecchia M AU - Corsello SM FA - Torino, Francesco FA - Barnabei, Agnese FA - Paragliola, Rosamaria FA - Baldelli, Roberto FA - Appetecchia, Marialuisa FA - Corsello, Salvatore Maria IN - Torino, Francesco. 1 Department of Systems Medicine, Tor Vergata University of Rome , Rome, Italy . TI - Thyroid dysfunction as an unintended side effect of anticancer drugs. [Review] SO - Thyroid. 23(11):1345-66, 2013 Nov AS - Thyroid. 23(11):1345-66, 2013 Nov NJ - Thyroid : official journal of the American Thyroid Association PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bjw, 9104317 IO - Thyroid SB - Index Medicus CP - United States MH - Animals MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Diphtheria Toxin/ae [Adverse Effects] MH - Humans MH - Hypothyroidism/ci [Chemically Induced] MH - Interferon-alpha/me [Metabolism] MH - Interleukin-2/ae [Adverse Effects] MH - Interleukin-2/me [Metabolism] MH - Neoplasms/co [Complications] MH - *Neoplasms/dt [Drug Therapy] MH - Recombinant Fusion Proteins/ae [Adverse Effects] MH - Tetrahydronaphthalenes/ae [Adverse Effects] MH - Thalidomide/ae [Adverse Effects] MH - Thalidomide/aa [Analogs & Derivatives] MH - *Thyroid Diseases/ci [Chemically Induced] MH - *Thyroid Gland/de [Drug Effects] MH - Thyroid Hormones/me [Metabolism] MH - Thyroxine/me [Metabolism] AB - BACKGROUND: Several of the currently used anticancer drugs may variably affect thyroid function, with impairment ranging from modified total but not free concentration of thyroid hormones to overt thyroid disease. AB - SUMMARY: Cytotoxic agents seem to alter thyroid function in a relatively small proportion of adult patients. Anticancer hormone drugs may mainly alter serum levels of thyroid hormone-binding proteins without clinically relevant thyroid dysfunction. Old immunomodulating drugs, such as interferon-alpha and interleukin-2, are known to induce variably high incidence of autoimmune thyroid dysfunction. Newer immune checkpoint inhibitors, such as anti-CTLA4 monoclonal antibodies, are responsible for a relatively low incidence of thyroiditis and may induce secondary hypothyroidism resulting from hypophysitis. Central hypothyroidism is a well-recognized side effect of bexarotene. Despite their inherent selectivity, tyrosine kinase inhibitors may cause high rates of thyroid dysfunction. Notably, thyroid toxicity seems to be restricted to tyrosine kinase inhibitors targeting key kinase-receptors in angiogenic pathways, but not other kinase-receptors (e.g., epidermal growth factor receptors family or c-KIT). In addition, a number of these agents may also increase the levothyroxine requirement in thyroidectomized patients. AB - CONCLUSIONS: The pathophysiology of thyroid toxicity induced by many anticancer agents is not fully clarified and for others it remains speculative. Thyroid dysfunction induced by anticancer agents is generally manageable and dose reduction or discontinuation of these agents is not required. The prognostic relevance of thyroid autoimmunity, overt and subclinical hypothyroidism induced by anticancer drugs, the value of thyroid hormone replacement in individuals with abnormal thyrotropin following anticancer systemic therapy, and the correct timing of replacement therapy in cancer patients need to be defined more accurately in well-powered prospective clinical trials. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Diphtheria Toxin) RN - 0 (Interferon-alpha) RN - 0 (Interleukin-2) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Tetrahydronaphthalenes) RN - 0 (Thyroid Hormones) RN - 25E79B5CTM (denileukin diftitox) RN - 3A189DH42V (alemtuzumab) RN - 4Z8R6ORS6L (Thalidomide) RN - A61RXM4375 (bexarotene) RN - F0P408N6V4 (lenalidomide) RN - Q51BO43MG4 (Thyroxine) ES - 1557-9077 IL - 1050-7256 DO - https://dx.doi.org/10.1089/thy.2013.0241 PT - Journal Article PT - Review ID - 23750887 [pubmed] ID - 10.1089/thy.2013.0241 [doi] PP - ppublish LG - English EP - 20130921 DP - 2013 Nov DC - 20131107 EZ - 2013/06/12 06:00 DA - 2014/07/01 06:00 DT - 2013/06/12 06:00 YR - 2013 ED - 20140630 RD - 20141120 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23750887 <245. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24570590 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Della Vittoria Scarpati G AU - Fusciello C AU - Perri F AU - Sabbatino F AU - Ferrone S AU - Carlomagno C AU - Pepe S FA - Della Vittoria Scarpati, Giuseppina FA - Fusciello, Celeste FA - Perri, Francesco FA - Sabbatino, Francesco FA - Ferrone, Soldano FA - Carlomagno, Chiara FA - Pepe, Stefano IN - Della Vittoria Scarpati, Giuseppina. Department of Medicine, University of Salerno, Salerno, Italy ; Division of Oncology, "San Giovanni di Dio e Ruggi d'Aragona" Hospital, Salerno, Italy. IN - Fusciello, Celeste. Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy. IN - Perri, Francesco. Head and Neck Medical Oncology Unit, National Tumor Institute, Naples, Italy. IN - Sabbatino, Francesco. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. IN - Ferrone, Soldano. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. IN - Carlomagno, Chiara. Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy. IN - Pepe, Stefano. Department of Medicine, University of Salerno, Salerno, Italy ; Division of Oncology, "San Giovanni di Dio e Ruggi d'Aragona" Hospital, Salerno, Italy. TI - Ipilimumab in the treatment of metastatic melanoma: management of adverse events. [Review] SO - OncoTargets and therapy. 7:203-9, 2014 AS - Onco Targets Ther. 7:203-9, 2014 NJ - OncoTargets and therapy PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101514322 IO - Onco Targets Ther PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933725 CP - New Zealand KW - CTLA-4; T-cells; adverse events; autoimmunity; melanoma AB - Recently, "ipilimumab," an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody, has been demonstrated to improve overall survival in metastatic melanoma. "CTLA-4" is an immune-checkpoint molecule that downregulates pathways of T-cell activation. Ipilimumab, by targeting CTLA-4, is able to remove the CTLA-4 inhibitory signal, allowing the immune system to react to cancer cells. Due to its immune-based mechanism of action, ipilimumab causes the inhibition of CTLA-4-mediated immunomodulatory effects, the enhancement of antitumor specific immune response mediated by the weakening of self-tolerance mechanisms while exacerbating the development of autoimmune diseases and immune-related adverse events, including dermatitis, hepatitis, enterocolitis, hypophysitis, and uveitis. IL - 1178-6930 DI - ott-7-203 DO - https://dx.doi.org/10.2147/OTT.S57335 PT - Journal Article PT - Review ID - 24570590 [pubmed] ID - 10.2147/OTT.S57335 [doi] ID - ott-7-203 [pii] ID - PMC3933725 [pmc] PP - epublish LG - English EP - 20140219 DP - 2014 DC - 20140226 EZ - 2014/02/27 06:00 DA - 2014/02/27 06:01 DT - 2014/02/27 06:00 YR - 2014 ED - 20140624 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=24570590 <246. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24904570 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Kong YC AU - Flynn JC FA - Kong, Yi-Chi M FA - Flynn, Jeffrey C IN - Kong, Yi-Chi M. Department of Immunology and Microbiology, Wayne State University School of Medicine , Detroit, MI , USA. IN - Flynn, Jeffrey C. Department of Orthopaedic Surgery, Providence Hospital and Medical Centers , Southfield, MI , USA. TI - Opportunistic Autoimmune Disorders Potentiated by Immune-Checkpoint Inhibitors Anti-CTLA-4 and Anti-PD-1. [Review] SO - Frontiers in Immunology. 5:206, 2014 AS - Front. immunol.. 5:206, 2014 NJ - Frontiers in immunology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101560960 IO - Front Immunol PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032988 CP - Switzerland KW - anti-CTLA-4; anti-PD-1; autoimmune disease; immune-checkpoint inhibitor; tumor immunity AB - To improve the efficacy of immunotherapy for cancer and autoimmune diseases, recent ongoing and completed clinical trials have focused on specific targets to redirect the immune network toward eradicating a variety of tumors and ameliorating the self-destructive process. In a previous review, both systemic immunomodulators and monoclonal antibodies (mAbs), anti-CTLA-4, and anti-CD52, were discussed regarding therapeutics and autoimmune sequelae, as well as predisposing factors known to exacerbate immune-related adverse events (irAEs). This review will focus on immune-checkpoint inhibitors, and the data from most clinical trials involve blockade with anti-CTLA-4 such as ipilimumab. However, despite the mild to severe irAEs observed with ipilimumab in ~60% of patients, overall survival (OS) averaged ~22-25% at 3-5years. To boost OS, other mAbs targeting programed death-1 and its ligand are undergoing clinical trials as monotherapy or dual therapy with anti-CTLA-4. Therapeutic combinations may generate different spectrum of opportunistic autoimmune disorders. To simulate clinical scenarios, we have applied regulatory T cell perturbation to murine models combined to examine the balance between thyroid autoimmunity and tumor-specific immunity. IL - 1664-3224 DO - https://dx.doi.org/10.3389/fimmu.2014.00206 PT - Journal Article PT - Review ID - 24904570 [pubmed] ID - 10.3389/fimmu.2014.00206 [doi] ID - PMC4032988 [pmc] PP - epublish PH - 2014/02/11 [received] PH - 2014/04/25 [accepted] LG - English EP - 20140516 DP - 2014 DC - 20140606 EZ - 2014/06/07 06:00 DA - 2014/06/07 06:01 DT - 2014/06/07 06:00 YR - 2014 ED - 20140624 RD - 20140624 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=24904570 <247. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24782152 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Fischli S AU - Allelein S AU - Zander T AU - Henzen C FA - Fischli, S FA - Allelein, S FA - Zander, T FA - Henzen, C IN - Fischli, S. Departement Medizin, Klinik fur Endokrinologie, Diabetologie und Klinische Ernahrung, Luzerner Kantonsspital, Luzern. IN - Allelein, S. Departement Medizin, Klinik fur Endokrinologie, Diabetologie und Klinische Ernahrung, Luzerner Kantonsspital, Luzern. IN - Zander, T. Departement Medizin, Klinik fur Medizinische Onkologie, Luzerner Kantonsspital, Luzern. IN - Henzen, C. Departement Medizin, Klinik fur Endokrinologie, Diabetologie und Klinische Ernahrung, Luzerner Kantonsspital, Luzern. TI - [Endocrinologic side effects of oncologic treatment with anti-CTLA-4-antibodies]. [German] OT - Endokrinologische Nebenwirkungen einer onkologischen Therapie mit Anti-CTLA-4-Antikorpern. SO - Deutsche Medizinische Wochenschrift. 139(19):996-1000, 2014 May AS - Dtsch Med Wochenschr. 139(19):996-1000, 2014 May NJ - Deutsche medizinische Wochenschrift (1946) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ecl, 0006723 IO - Dtsch. Med. Wochenschr. SB - Index Medicus CP - Germany MH - Adrenal Gland Diseases/ci [Chemically Induced] MH - Adrenal Gland Diseases/di [Diagnosis] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Brain Neoplasms/dt [Drug Therapy] MH - *Brain Neoplasms/sc [Secondary] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Colitis/ci [Chemically Induced] MH - Colitis/di [Diagnosis] MH - Follow-Up Studies MH - Humans MH - Hyperthyroidism/ci [Chemically Induced] MH - Hyperthyroidism/di [Diagnosis] MH - *Hypopituitarism/ci [Chemically Induced] MH - Hypopituitarism/di [Diagnosis] MH - *Liver Neoplasms/dt [Drug Therapy] MH - *Liver Neoplasms/sc [Secondary] MH - *Lung Neoplasms/dt [Drug Therapy] MH - *Lung Neoplasms/sc [Secondary] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/sc [Secondary] MH - Middle Aged MH - *Skin Neoplasms/dt [Drug Therapy] MH - Thyroiditis/ci [Chemically Induced] MH - Thyroiditis/di [Diagnosis] AB - New immune-modulating treatments like the anti-CTLA-4-antibodies-based therapies are increasingly used in medical oncology. The action of Ipilimumab, a monoclonal anti-CTLA-4-antibody used for the treatment of metastasized melanoma and other solid tumors, is well documented. Blocking the CTLA-4-receptors on lymphocytes leads to T-cell activation and hence reduction of the tumor-mediated immunotolerance. This mechanism constitutes the basis of the antiproliferative effects but is also responsible for a spectrum of specific adverse events (immune-related adverse events, IRAE). IRAE of the endocrine system comprise hypophysitis, thyroiditis and adrenalitis. Especially adrenal insufficiency can be fatal when not diagnosed and treated. Symptoms often are unspecific and early diagnosis and targeted treatment are crucial. We present a case report and summarize - based upon the current literature - the diagnosis and treatment of endocrinologic IRAEs. AB - Copyright © Georg Thieme Verlag KG Stuttgart . New York. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) RS - Combined Pituitary Hormone Deficiency ES - 1439-4413 IL - 0012-0472 DO - https://dx.doi.org/10.1055/s-0034-1369961 PT - Case Reports PT - Journal Article ID - 24782152 [pubmed] ID - 10.1055/s-0034-1369961 [doi] PP - ppublish LG - German EP - 20140429 DP - 2014 May DC - 20140430 EZ - 2014/05/01 06:00 DA - 2014/06/17 06:00 DT - 2014/05/02 06:00 YR - 2014 ED - 20140616 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24782152 <248. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24106007 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gupta S AU - Jaworska-Bieniek K AU - Lubinski J AU - Jakubowska A FA - Gupta, Satish FA - Jaworska-Bieniek, Katarzyna FA - Lubinski, Jan FA - Jakubowska, Anna IN - Gupta, Satish. International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, 70-115, Szczecin, Poland and. TI - Can selenium be a modifier of cancer risk in CHEK2 mutation carriers?. SO - Mutagenesis. 28(6):625-9, 2013 Nov AS - Mutagenesis. 28(6):625-9, 2013 Nov NJ - Mutagenesis PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - mug, 8707812 IO - Mutagenesis SB - Index Medicus CP - England MH - *Checkpoint Kinase 2/ge [Genetics] MH - Checkpoint Kinase 2/me [Metabolism] MH - Dietary Supplements MH - Humans MH - Mutation MH - *Neoplasms/en [Enzymology] MH - Neoplasms/ge [Genetics] MH - Neoplasms/pc [Prevention & Control] MH - Selenium/ad [Administration & Dosage] MH - *Selenium/ph [Physiology] MH - Selenoproteins/me [Metabolism] MH - Signal Transduction AB - Selenium is an essential trace element for humans, playing an important role in various major metabolic pathways. Selenium helps to protect the body from the poisonous effects of heavy metals and other harmful substances. Medical studies have provided evidence of selenium supplementation in preventing certain cancers. Low and too high selenium (Se) status correlates with increased risk of e.g. lung, larynx, colorectal and prostate cancers. A higher level of selenium and supplementation with selenium has been shown to be associated with substantially reduced cancer mortality. Selenium exerts its biological roles through selenoproteins, which are involved in oxidoreductions, redox signalling, antioxidant defence, thyroid hormone metabolism and immune responses. Checkpoint kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage and acts as a tumour suppressor gene. Mutations in the CHEK2 gene have been shown to be associated with increased risks of several cancers. Four common mutations in CHEK2 gene (1100delC, IVS2+1G>A, del5395 and I157T) have been identified in the Polish population. Studies have provided evidence that CHEK2-truncating and/or missense mutations are associated with increased risk of breast, prostate, thyroid, colon and kidney cancers. The variability in penetrance and cancer expression in CHEK2 mutation carriers can probably be explained by the influence of other genetic or environmental factors. One of the possible candidates is Se, which together with genetic variations in selenoprotein genes may influence susceptibility to cancer risk. RN - 0 (Selenoproteins) RN - EC 2-7-1-11 (Checkpoint Kinase 2) RN - EC 2-7-11-1 (CHEK2 protein, human) RN - H6241UJ22B (Selenium) ES - 1464-3804 IL - 0267-8357 DI - get050 DO - https://dx.doi.org/10.1093/mutage/get050 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 24106007 [pubmed] ID - get050 [pii] ID - 10.1093/mutage/get050 [doi] PP - ppublish LG - English EP - 20131008 DP - 2013 Nov DC - 20131023 EZ - 2013/10/10 06:00 DA - 2014/05/31 06:00 DT - 2013/10/10 06:00 YR - 2013 ED - 20140530 RD - 20131023 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24106007 <249. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23855452 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Duong HQ AU - Hong YB AU - Kim JS AU - Lee HS AU - Yi YW AU - Kim YJ AU - Wang A AU - Zhao W AU - Cho CH AU - Seong YS AU - Bae I FA - Duong, Hong-Quan FA - Hong, Young Bin FA - Kim, Jung Soon FA - Lee, Hee-Seok FA - Yi, Yong Weon FA - Kim, Yeon Jeong FA - Wang, Antai FA - Zhao, Wenjing FA - Cho, Chi Heum FA - Seong, Yeon-Sun FA - Bae, Insoo IN - Duong, Hong-Quan. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA; WCU (World Class University) Research Center of Nanobiomedical Science, Dankook University, Cheonan, Korea. TI - Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine. SO - Journal of Cellular & Molecular Medicine. 17(10):1261-70, 2013 Oct AS - J Cell Mol Med. 17(10):1261-70, 2013 Oct NJ - Journal of cellular and molecular medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101083777 IO - J. Cell. Mol. Med. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159025 SB - Index Medicus CP - England MH - *Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/me [Metabolism] MH - Adenocarcinoma/pa [Pathology] MH - *Antimetabolites, Antineoplastic/tu [Therapeutic Use] MH - Apoptosis MH - Blotting, Western MH - Cell Line, Tumor MH - *Checkpoint Kinase 2/ai [Antagonists & Inhibitors] MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/tu [Therapeutic Use] MH - Humans MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - Phosphorylation MH - Reactive Oxygen Species/me [Metabolism] KW - Checkpoint kinase 2 (CHK2) inhibitor; NSC109555; combination; gemcitabine; pancreatic adenocarcinoma; synergism AB - Checkpoint kinase 2 (CHK2) plays pivotal function as an effector of cell cycle checkpoint arrest following DNA damage. Recently, we found that co-treatment of NSC109555 (a potent and selective CHK2 inhibitor) potentiated the cytotoxic effect of gemcitabine (GEM) in pancreatic cancer MIA PaCa-2 cells. Here, we further examined whether NSC109555 could enhance the antitumour effect of GEM in pancreatic adenocarcinoma cell lines. In this study, the combination treatment of NSC109555 plus GEM demonstrated strong synergistic antitumour effect in four pancreatic cancer cells (MIA PaCa-2, CFPAC-1, Panc-1 and BxPC-3). In addition, the GEM/NSC109555 combination significantly increased the level of intracellular reactive oxygen species (ROS), accompanied by induction of apoptotic cell death. Inhibition of ROS generation by N-acetyl cysteine (NAC) significantly reversed the effect of GEM/NSC109555 in apoptosis and cytotoxicity. Furthermore, genetic knockdown of CHK2 by siRNA enhanced GEM-induced apoptotic cell death. These findings suggest that inhibition of CHK2 would be a beneficial therapeutic approach for pancreatic cancer therapy in clinical treatment. AB - Copyright © 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Reactive Oxygen Species) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7-1-11 (Checkpoint Kinase 2) ES - 1582-4934 IL - 1582-1838 DO - https://dx.doi.org/10.1111/jcmm.12101 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 23855452 [pubmed] ID - 10.1111/jcmm.12101 [doi] ID - PMC4159025 [pmc] PP - ppublish PH - 2013/01/15 [received] PH - 2013/05/26 [revised] PH - 2013/06/03 [accepted] GI - No: P30 CA051008 Organization: (CA) *NCI NIH HHS* Country: United States No: R03 CA152530 Organization: (CA) *NCI NIH HHS* Country: United States No: 1R03CA152530 Organization: (CA) *NCI NIH HHS* Country: United States No: P30-CA051008 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20130716 DP - 2013 Oct DC - 20131127 EZ - 2013/07/17 06:00 DA - 2014/05/28 06:00 DT - 2013/07/17 06:00 YR - 2013 ED - 20140527 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23855452 <250. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23687379 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Fredebohm J AU - Wolf J AU - Hoheisel JD AU - Boettcher M FA - Fredebohm, Johannes FA - Wolf, Jonas FA - Hoheisel, Jorg D FA - Boettcher, Michael IN - Fredebohm, Johannes. Functional Genome Analysis, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. TI - Depletion of RAD17 sensitizes pancreatic cancer cells to gemcitabine. SO - Journal of Cell Science. 126(Pt 15):3380-9, 2013 Aug 01 AS - J Cell Sci. 126(Pt 15):3380-9, 2013 Aug 01 NJ - Journal of cell science PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hnk, 0052457 IO - J. Cell. Sci. SB - Index Medicus CP - England MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - *Cell Cycle Proteins/df [Deficiency] MH - *Cell Cycle Proteins/ge [Genetics] MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Line, Tumor MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Humans MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/ge [Genetics] MH - *Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - Phosphorylation MH - RNA, Small Interfering/ge [Genetics] MH - RNA, Small Interfering/me [Metabolism] MH - Signal Transduction KW - ATR/CHK1 signalling pathway; Gemcitabine; Gemcitabine-combination therapy; Pancreatic cancer; RAD17; shRNA screening AB - Chemotherapy of advanced pancreatic cancer has mainly been gemcitabine-based for the past 15 years, with only limited effect. Recently, combination therapy that also targets checkpoint kinase 1 (CHK1) has become an attractive option. The central role of CHK1 in many DNA-damage response pathways, however, may result in undesired cytotoxicity in normal cells, causing side effects. We were searching for other target molecules of similar function that may be more specific and thus better suited for combination therapy. To this end a negative selection RNAi screen was performed in cell lines with small hairpin RNA molecules targeting over 10,000 genes. Genes that were found to be synthetically lethal with gemcitabine and whose proteins act upstream of CHK1 were characterised in more detail. In particular, the inhibition of RAD17 potentiated gemcitabine cytotoxicity in the pancreatic cancer cell lines BxPC-3 and MiaPaca-2 and in the primary cell line JoPaca-1 that closely resembles primary tumour tissue. Further analysis showed that the synergistic effect of RAD17 knockdown and gemcitabine leads to forced mitotic entry of cells arrested in S phase by gemcitabine treatment, resulting in asymmetric DNA distribution during anaphase followed by DNA fragmentation and finally cell death by mitotic catastrophe. Our data suggest RAD17 as a novel target protein for gemcitabine combination therapy supplementing or complementing inhibition of CHK1. In contrast to CHK1, RAD17 knockdown by itself does not lead to abnormal DNA segregation, suggesting a more specific action. RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Cell Cycle Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (Rad17 protein, human) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) ES - 1477-9137 IL - 0021-9533 DI - jcs.124768 DO - https://dx.doi.org/10.1242/jcs.124768 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 23687379 [pubmed] ID - jcs.124768 [pii] ID - 10.1242/jcs.124768 [doi] PP - ppublish LG - English EP - 20130517 DP - 2013 Aug 01 DC - 20130802 EZ - 2013/05/21 06:00 DA - 2014/05/23 06:00 DT - 2013/05/21 06:00 YR - 2013 ED - 20140522 RD - 20130802 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23687379 <251. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24516200 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kim PS AU - Jochems C AU - Grenga I AU - Donahue RN AU - Tsang KY AU - Gulley JL AU - Schlom J AU - Farsaci B FA - Kim, Peter S FA - Jochems, Caroline FA - Grenga, Italia FA - Donahue, Renee N FA - Tsang, Kwong Y FA - Gulley, James L FA - Schlom, Jeffrey FA - Farsaci, Benedetto IN - Kim, Peter S. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. TI - Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory lymphocytes while preserving effector T lymphocytes: a rationale for its use in combination immunotherapy. SO - Journal of Immunology. 192(6):2622-33, 2014 Mar 15 AS - J Immunol. 192(6):2622-33, 2014 Mar 15 NJ - Journal of immunology (Baltimore, Md. : 1950) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ifb, 2985117r IO - J. Immunol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122292 OI - Source: NLM. NIHMS555469 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Apoptosis/de [Drug Effects] MH - Apoptosis/im [Immunology] MH - CTLA-4 Antigen/im [Immunology] MH - CTLA-4 Antigen/me [Metabolism] MH - Cells, Cultured MH - Combined Modality Therapy MH - Dose-Response Relationship, Drug MH - Down-Regulation/de [Drug Effects] MH - Down-Regulation/im [Immunology] MH - Female MH - Flow Cytometry MH - Forkhead Transcription Factors/im [Immunology] MH - Forkhead Transcription Factors/me [Metabolism] MH - Humans MH - Immunotherapy/mt [Methods] MH - Leukocytes, Mononuclear/de [Drug Effects] MH - Leukocytes, Mononuclear/im [Immunology] MH - Leukocytes, Mononuclear/me [Metabolism] MH - Lymphocyte Activation/de [Drug Effects] MH - Lymphocyte Activation/im [Immunology] MH - Ovarian Neoplasms/bl [Blood] MH - Ovarian Neoplasms/pa [Pathology] MH - *Proto-Oncogene Proteins c-bcl-2/ai [Antagonists & Inhibitors] MH - Proto-Oncogene Proteins c-bcl-2/im [Immunology] MH - Proto-Oncogene Proteins c-bcl-2/me [Metabolism] MH - *Pyrroles/pd [Pharmacology] MH - *T-Lymphocyte Subsets/de [Drug Effects] MH - T-Lymphocyte Subsets/im [Immunology] MH - T-Lymphocyte Subsets/me [Metabolism] MH - *T-Lymphocytes, Regulatory/de [Drug Effects] MH - T-Lymphocytes, Regulatory/im [Immunology] MH - T-Lymphocytes, Regulatory/me [Metabolism] MH - Time Factors AB - Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment of patients with solid tumors and hematopoietic malignancies. In this study we explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15; obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects of GX15 on human T cell subsets obtained from PBMCs in terms of activation, memory, and suppressive function. Our results indicated that in healthy-donor PBMCs, mature-activated T cells were more resistant to GX15 than early-activated T cells, and that GX15 preserved memory but not non-memory T cell populations. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly downregulated FOXP3 and CTLA-4 in a dose-dependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8(+):Treg and CD4(+):Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8(+) T cells and decreased Treg function brought about by GX15. Taken together, these findings suggest that when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitor. RN - 0 (CTLA-4 Antigen) RN - 0 (FOXP3 protein, human) RN - 0 (Forkhead Transcription Factors) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (Pyrroles) RN - 0 (obatoclax) ES - 1550-6606 IL - 0022-1767 DI - jimmunol.1301369 DO - https://dx.doi.org/10.4049/jimmunol.1301369 PT - Journal Article PT - Research Support, N.I.H., Intramural ID - 24516200 [pubmed] ID - jimmunol.1301369 [pii] ID - 10.4049/jimmunol.1301369 [doi] ID - PMC4122292 [pmc] ID - NIHMS555469 [mid] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00088413 SL - https://clinicaltrials.gov/search/term=NCT00088413 GI - No: ZIA BC010944-06 Organization: *Intramural NIH HHS* Country: United States LG - English EP - 20140210 DP - 2014 Mar 15 DC - 20140310 EZ - 2014/02/12 06:00 DA - 2014/05/16 06:00 DT - 2014/02/12 06:00 YR - 2014 ED - 20140515 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24516200 <252. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24516200 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kim PS AU - Jochems C AU - Grenga I AU - Donahue RN AU - Tsang KY AU - Gulley JL AU - Schlom J AU - Farsaci B FA - Kim, Peter S FA - Jochems, Caroline FA - Grenga, Italia FA - Donahue, Renee N FA - Tsang, Kwong Y FA - Gulley, James L FA - Schlom, Jeffrey FA - Farsaci, Benedetto IN - Kim, Peter S. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. TI - Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory lymphocytes while preserving effector T lymphocytes: a rationale for its use in combination immunotherapy. SO - Journal of Immunology. 192(6):2622-33, 2014 Mar 15 AS - J Immunol. 192(6):2622-33, 2014 Mar 15 NJ - Journal of immunology (Baltimore, Md. : 1950) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ifb, 2985117r IO - J. Immunol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122292 OI - Source: NLM. NIHMS555469 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Apoptosis/de [Drug Effects] MH - Apoptosis/im [Immunology] MH - CTLA-4 Antigen/im [Immunology] MH - CTLA-4 Antigen/me [Metabolism] MH - Cells, Cultured MH - Combined Modality Therapy MH - Dose-Response Relationship, Drug MH - Down-Regulation/de [Drug Effects] MH - Down-Regulation/im [Immunology] MH - Female MH - Flow Cytometry MH - Forkhead Transcription Factors/im [Immunology] MH - Forkhead Transcription Factors/me [Metabolism] MH - Humans MH - Immunotherapy/mt [Methods] MH - Leukocytes, Mononuclear/de [Drug Effects] MH - Leukocytes, Mononuclear/im [Immunology] MH - Leukocytes, Mononuclear/me [Metabolism] MH - Lymphocyte Activation/de [Drug Effects] MH - Lymphocyte Activation/im [Immunology] MH - Ovarian Neoplasms/bl [Blood] MH - Ovarian Neoplasms/pa [Pathology] MH - *Proto-Oncogene Proteins c-bcl-2/ai [Antagonists & Inhibitors] MH - Proto-Oncogene Proteins c-bcl-2/im [Immunology] MH - Proto-Oncogene Proteins c-bcl-2/me [Metabolism] MH - *Pyrroles/pd [Pharmacology] MH - *T-Lymphocyte Subsets/de [Drug Effects] MH - T-Lymphocyte Subsets/im [Immunology] MH - T-Lymphocyte Subsets/me [Metabolism] MH - *T-Lymphocytes, Regulatory/de [Drug Effects] MH - T-Lymphocytes, Regulatory/im [Immunology] MH - T-Lymphocytes, Regulatory/me [Metabolism] MH - Time Factors AB - Bcl-2 inhibitors are currently being evaluated in clinical studies for treatment of patients with solid tumors and hematopoietic malignancies. In this study we explored the potential for combining the pan-Bcl-2 inhibitor GX15-070 (GX15; obatoclax) with immunotherapeutic modalities. We evaluated the in vitro effects of GX15 on human T cell subsets obtained from PBMCs in terms of activation, memory, and suppressive function. Our results indicated that in healthy-donor PBMCs, mature-activated T cells were more resistant to GX15 than early-activated T cells, and that GX15 preserved memory but not non-memory T cell populations. Furthermore, GX15 increased the apoptosis of regulatory T cells (Tregs), profoundly downregulated FOXP3 and CTLA-4 in a dose-dependent manner, and decreased their suppressive function. Treating PBMCs obtained from ovarian cancer patients with GX15 also resulted in increased CD8(+):Treg and CD4(+):Treg ratios. These results support preclinical studies in which mice vaccinated before treatment with GX15 showed the greatest reduction in metastatic lung tumors as a result of increased apoptotic resistance of mature CD8(+) T cells and decreased Treg function brought about by GX15. Taken together, these findings suggest that when a Bcl-2 inhibitor is combined with active immunotherapy in humans, such as the use of a vaccine or immune checkpoint inhibitor, immunotherapy should precede administration of the Bcl-2 inhibitor to allow T cells to become mature, and thus resistant to the cytotoxic effects of the Bcl-2 inhibitor. RN - 0 (CTLA-4 Antigen) RN - 0 (FOXP3 protein, human) RN - 0 (Forkhead Transcription Factors) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (Pyrroles) RN - 0 (obatoclax) ES - 1550-6606 IL - 0022-1767 DI - jimmunol.1301369 DO - https://dx.doi.org/10.4049/jimmunol.1301369 PT - Journal Article PT - Research Support, N.I.H., Intramural ID - 24516200 [pubmed] ID - jimmunol.1301369 [pii] ID - 10.4049/jimmunol.1301369 [doi] ID - PMC4122292 [pmc] ID - NIHMS555469 [mid] PP - ppublish GI - No: ZIA BC010944-06 Organization: *Intramural NIH HHS* Country: United States LG - English EP - 20140210 DP - 2014 Mar 15 DC - 20140310 EZ - 2014/02/12 06:00 DA - 2014/05/16 06:00 DT - 2014/02/12 06:00 YR - 2014 ED - 20140515 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=24516200 <253. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23717490 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gardiner D AU - Lalezari J AU - Lawitz E AU - DiMicco M AU - Ghalib R AU - Reddy KR AU - Chang KM AU - Sulkowski M AU - Marro SO AU - Anderson J AU - He B AU - Kansra V AU - McPhee F AU - Wind-Rotolo M AU - Grasela D AU - Selby M AU - Korman AJ AU - Lowy I FA - Gardiner, David FA - Lalezari, Jay FA - Lawitz, Eric FA - DiMicco, Michael FA - Ghalib, Rheem FA - Reddy, K Rajender FA - Chang, Kyong-Mi FA - Sulkowski, Mark FA - Marro, Steven O' FA - Anderson, Jeffrey FA - He, Bing FA - Kansra, Vikram FA - McPhee, Fiona FA - Wind-Rotolo, Megan FA - Grasela, Dennis FA - Selby, Mark FA - Korman, Alan J FA - Lowy, Israel IN - Gardiner, David. Bristol-Myers Squibb, Pennington, New Jersey, USA. david.gardiner@bms.com TI - A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. SO - PLoS ONE [Electronic Resource]. 8(5):e63818, 2013 AS - PLoS ONE. 8(5):e63818, 2013 NJ - PloS one PI - Journal available in: Electronic-Print PI - Citation processed from: Internet JC - 101285081 IO - PLoS ONE PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661719 SB - Index Medicus CP - United States MH - Adult MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/pk [Pharmacokinetics] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antiviral Agents/ae [Adverse Effects] MH - *Antiviral Agents/tu [Therapeutic Use] MH - Double-Blind Method MH - Female MH - Half-Life MH - *Hepacivirus/de [Drug Effects] MH - Hepacivirus/ge [Genetics] MH - *Hepatitis C, Chronic/dt [Drug Therapy] MH - Humans MH - Interferon-alpha/tu [Therapeutic Use] MH - Male MH - Middle Aged MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - RNA, Viral/ge [Genetics] MH - Viral Load/de [Drug Effects] MH - Viral Load/ge [Genetics] AB - UNLABELLED: Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5:1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naive patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA >=0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4(+), CD8(+) and CD19(+) cells, including both naive and memory CD4(+) and CD8(+) subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20-24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted. AB - TRIAL REGISTRATION: ClinicalTrials.gov NCT00703469. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antiviral Agents) RN - 0 (Interferon-alpha) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (RNA, Viral) RN - 31YO63LBSN (nivolumab) ES - 1932-6203 IL - 1932-6203 DI - PONE-D-12-35786 DO - https://dx.doi.org/10.1371/journal.pone.0063818 PT - Clinical Trial PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't ID - 23717490 [pubmed] ID - 10.1371/journal.pone.0063818 [doi] ID - PONE-D-12-35786 [pii] ID - PMC3661719 [pmc] PP - epublish PH - 2012/11/08 [received] PH - 2013/04/04 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00703469 SA - ClinicalTrials.gov/NCT00703469 SA - ClinicalTrials.gov/NCT01642004 SA - ClinicalTrials.gov/NCT01668784 SA - ClinicalTrials.gov/NCT01673867 SL - https://clinicaltrials.gov/search/term=NCT00703469 SL - https://clinicaltrials.gov/search/term=NCT00703469 SL - https://clinicaltrials.gov/search/term=NCT01642004 SL - https://clinicaltrials.gov/search/term=NCT01668784 SL - https://clinicaltrials.gov/search/term=NCT01673867 GI - No: K24 DA034621 Organization: (DA) *NIDA NIH HHS* Country: United States No: R01 DA016065 Organization: (DA) *NIDA NIH HHS* Country: United States LG - English EP - 20130522 DP - 2013 DC - 20130529 EZ - 2013/05/30 06:00 DA - 2014/04/18 06:00 DT - 2013/05/30 06:00 YR - 2013 ED - 20140417 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23717490 <254. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23717490 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gardiner D AU - Lalezari J AU - Lawitz E AU - DiMicco M AU - Ghalib R AU - Reddy KR AU - Chang KM AU - Sulkowski M AU - Marro SO AU - Anderson J AU - He B AU - Kansra V AU - McPhee F AU - Wind-Rotolo M AU - Grasela D AU - Selby M AU - Korman AJ AU - Lowy I FA - Gardiner, David FA - Lalezari, Jay FA - Lawitz, Eric FA - DiMicco, Michael FA - Ghalib, Rheem FA - Reddy, K Rajender FA - Chang, Kyong-Mi FA - Sulkowski, Mark FA - Marro, Steven O' FA - Anderson, Jeffrey FA - He, Bing FA - Kansra, Vikram FA - McPhee, Fiona FA - Wind-Rotolo, Megan FA - Grasela, Dennis FA - Selby, Mark FA - Korman, Alan J FA - Lowy, Israel IN - Gardiner, David. Bristol-Myers Squibb, Pennington, New Jersey, USA. david.gardiner@bms.com TI - A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. SO - PLoS ONE [Electronic Resource]. 8(5):e63818, 2013 AS - PLoS ONE. 8(5):e63818, 2013 NJ - PloS one PI - Journal available in: Electronic-Print PI - Citation processed from: Internet JC - 101285081 IO - PLoS ONE PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661719 SB - Index Medicus CP - United States MH - Adult MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/pk [Pharmacokinetics] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antiviral Agents/ae [Adverse Effects] MH - *Antiviral Agents/tu [Therapeutic Use] MH - Double-Blind Method MH - Female MH - Half-Life MH - *Hepacivirus/de [Drug Effects] MH - Hepacivirus/ge [Genetics] MH - *Hepatitis C, Chronic/dt [Drug Therapy] MH - Humans MH - Interferon-alpha/tu [Therapeutic Use] MH - Male MH - Middle Aged MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - RNA, Viral/ge [Genetics] MH - Viral Load/de [Drug Effects] MH - Viral Load/ge [Genetics] AB - UNLABELLED: Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5:1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naive patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA >=0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4(+), CD8(+) and CD19(+) cells, including both naive and memory CD4(+) and CD8(+) subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20-24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted. AB - TRIAL REGISTRATION: ClinicalTrials.gov NCT00703469. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antiviral Agents) RN - 0 (Interferon-alpha) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (RNA, Viral) RN - 31YO63LBSN (nivolumab) ES - 1932-6203 IL - 1932-6203 DI - PONE-D-12-35786 DO - https://dx.doi.org/10.1371/journal.pone.0063818 PT - Clinical Trial PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't ID - 23717490 [pubmed] ID - 10.1371/journal.pone.0063818 [doi] ID - PONE-D-12-35786 [pii] ID - PMC3661719 [pmc] PP - epublish PH - 2012/11/08 [received] PH - 2013/04/04 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00703469 SL - https://clinicaltrials.gov/search/term=NCT00703469 GI - No: K24 DA034621 Organization: (DA) *NIDA NIH HHS* Country: United States No: R01 DA016065 Organization: (DA) *NIDA NIH HHS* Country: United States LG - English EP - 20130522 DP - 2013 DC - 20130529 EZ - 2013/05/30 06:00 DA - 2014/04/18 06:00 DT - 2013/05/30 06:00 YR - 2013 ED - 20140417 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=23717490 <255. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23804422 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Engelke CG AU - Parsels LA AU - Qian Y AU - Zhang Q AU - Karnak D AU - Robertson JR AU - Tanska DM AU - Wei D AU - Davis MA AU - Parsels JD AU - Zhao L AU - Greenson JK AU - Lawrence TS AU - Maybaum J AU - Morgan MA FA - Engelke, Carl G FA - Parsels, Leslie A FA - Qian, Yushen FA - Zhang, Qiang FA - Karnak, David FA - Robertson, Jordan R FA - Tanska, Daria M FA - Wei, Dongping FA - Davis, Mary A FA - Parsels, Joshua D FA - Zhao, Lili FA - Greenson, Joel K FA - Lawrence, Theodore S FA - Maybaum, Jonathan FA - Morgan, Meredith A IN - Engelke, Carl G. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5637, USA. TI - Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776. SO - Clinical Cancer Research. 19(16):4412-21, 2013 Aug 15 AS - Clin Cancer Res. 19(16):4412-21, 2013 Aug 15 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745540 OI - Source: NLM. NIHMS498288 SB - Index Medicus CP - United States MH - Animals MH - Cell Line, Tumor MH - Checkpoint Kinase 1 MH - Chemoradiotherapy MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Disease Models, Animal MH - Drug Resistance, Neoplasm/ge [Genetics] MH - Female MH - Humans MH - Inhibitory Concentration 50 MH - Mice MH - Pancreatic Neoplasms/ge [Genetics] MH - *Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/th [Therapy] MH - Protein Kinase Inhibitors/ad [Administration & Dosage] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - *Protein Kinases/me [Metabolism] MH - *Pyrazoles/pd [Pharmacology] MH - *Pyrimidines/pd [Pharmacology] MH - Radiation-Sensitizing Agents/pd [Pharmacology] MH - Recombinational DNA Repair/de [Drug Effects] MH - Xenograft Model Antitumor Assays AB - PURPOSE: The combination of radiation with chemotherapy is the most effective therapy for unresectable pancreatic cancer. To improve upon this regimen, we combined the selective Checkpoint kinase 1 (Chk1) inhibitor MK8776 with gemcitabine-based chemoradiation in preclinical pancreatic cancer models. AB - EXPERIMENTAL DESIGN: We tested the ability of MK8776 to sensitize to gemcitabine-radiation in homologous recombination repair (HRR)-proficient and -deficient pancreatic cancer cells and assessed Rad51 focus formation. In vivo, we investigated the efficacy, tumor cell selectivity, and pharmacodynamic biomarkers of sensitization by MK8776. AB - RESULTS: We found that MK8776 significantly sensitized HRR-proficient (AsPC-1, MiaPaCa-2, BxPC-3) but not -deficient (Capan-1) pancreatic cancer cells to gemcitabine-radiation and inhibited Rad51 focus formation in HRR-proficient cells. In vivo, MiaPaCa-2 xenografts were significantly sensitized to gemcitabine-radiation by MK8776 without significant weight loss or observable toxicity in the small intestine, the dose-limiting organ for chemoradiation therapy in pancreatic cancer. We also assessed pChk1 (S345), a pharmacodynamic biomarker of DNA damage in response to Chk1 inhibition in both tumor and small intestine and found that MK8776 combined with gemcitabine or gemcitabine-radiation produced a significantly greater increase in pChk1 (S345) in tumor relative to small intestine, suggesting greater DNA damage in tumor than in normal tissue. Furthermore, we demonstrated the utility of an ex vivo platform for assessment of pharmacodynamic biomarkers of Chk1 inhibition in pancreatic cancer. AB - CONCLUSIONS: Together, our results suggest that MK8776 selectively sensitizes HRR-proficient pancreatic cancer cells and xenografts to gemcitabine-radiation and support the clinical investigation of MK8776 in combination with gemcitabine-radiation in locally advanced pancreatic cancer. AB - Copyright ©2013 AACR. RN - 0 (MK-8776) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Pyrimidines) RN - 0 (Radiation-Sensitizing Agents) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - EC 2-7-11-1 (Chek1 protein, mouse) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-12-3748 DO - https://dx.doi.org/10.1158/1078-0432.CCR-12-3748 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 23804422 [pubmed] ID - 1078-0432.CCR-12-3748 [pii] ID - 10.1158/1078-0432.CCR-12-3748 [doi] ID - PMC3745540 [pmc] ID - NIHMS498288 [mid] PP - ppublish GI - No: R01CA163895 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA046592 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA130810 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA163895 Organization: (CA) *NCI NIH HHS* Country: United States No: P50CA130810 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20130626 DP - 2013 Aug 15 DC - 20130815 EZ - 2013/06/28 06:00 DA - 2014/04/02 06:00 DT - 2013/06/28 06:00 YR - 2013 ED - 20140401 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23804422 <256. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23716015 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Postow MA AU - Luke JJ AU - Bluth MJ AU - Ramaiya N AU - Panageas KS AU - Lawrence DP AU - Ibrahim N AU - Flaherty KT AU - Sullivan RJ AU - Ott PA AU - Callahan MK AU - Harding JJ AU - D'Angelo SP AU - Dickson MA AU - Schwartz GK AU - Chapman PB AU - Gnjatic S AU - Wolchok JD AU - Hodi FS AU - Carvajal RD FA - Postow, Michael A FA - Luke, Jason J FA - Bluth, Mark J FA - Ramaiya, Nikhil FA - Panageas, Katherine S FA - Lawrence, Donald P FA - Ibrahim, Nageatte FA - Flaherty, Keith T FA - Sullivan, Ryan J FA - Ott, Patrick A FA - Callahan, Margaret K FA - Harding, James J FA - D'Angelo, Sandra P FA - Dickson, Mark A FA - Schwartz, Gary K FA - Chapman, Paul B FA - Gnjatic, Sacha FA - Wolchok, Jedd D FA - Hodi, F Stephen FA - Carvajal, Richard D IN - Postow, Michael A. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. carvajar@mskcc.org TI - Ipilimumab for patients with advanced mucosal melanoma. CM - Comment in: Oncologist. 2013 Jun;18(6):658-60; PMID: 23814163 SO - Oncologist. 18(6):726-32, 2013 Jun AS - Oncologist. 18(6):726-32, 2013 Jun NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063400 SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antigens, Neoplasm/bi [Biosynthesis] MH - CTLA-4 Antigen/bi [Biosynthesis] MH - Clinical Trials as Topic MH - Female MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Mucous Membrane/de [Drug Effects] MH - Mucous Membrane/pa [Pathology] MH - *Neoplasm Metastasis/dt [Drug Therapy] MH - Neoplasm Metastasis/pa [Pathology] MH - Retrospective Studies MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/pa [Pathology] MH - Survival Analysis KW - CTLA-4; Cancer-testis antigens; Immunotherapy; Ipilimumab; Mucosal melanoma AB - The outcome of patients with mucosal melanoma treated with ipilimumab is not defined. To assess the efficacy and safety of ipilimumab in this melanoma subset, we performed a multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab. The clinical characteristics, treatments, toxicities, radiographic assessment of disease burden by central radiology review at each site, and mutational profiles of the patients' tumors were recorded. Available peripheral blood samples were used to assess humoral immunity against a panel of cancer-testis antigens and other antigens. By the immune-related response criteria of the 30 patients who underwent radiographic assessment after ipilimumab at approximately week 12, there were 1 immune-related complete response, 1 immune-related partial response, 6 immune-related stable disease, and 22 immune-related progressive disease. By the modified World Health Organization criteria, there were 1 immune-related complete response, 1 immune-related partial response, 5 immune-related stable disease, and 23 immune-related progressive disease. Immune-related adverse events (as graded by Common Terminology Criteria for Adverse Events version 4.0) consisted of six patients with rash (four grade 1, two grade 2), three patients with diarrhea (one grade 1, two grade 3), one patient with grade 1 thyroiditis, one patient with grade 3 hepatitis, and 1 patient with grade 2 hypophysitis. The median overall survival from the time of the first dose of ipilimumab was 6.4 months (range: 1.8-26.7 months). Several patients demonstrated serologic responses to cancer-testis antigens and other antigens. Durable responses to ipilimumab were observed, but the overall response rate was low. Additional investigation is necessary to clarify the role of ipilimumab in patients with mucosal melanoma. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, Neoplasm) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) ES - 1549-490X IL - 1083-7159 DI - theoncologist.2012-0464 DO - https://dx.doi.org/10.1634/theoncologist.2012-0464 PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 23716015 [pubmed] ID - theoncologist.2012-0464 [pii] ID - 10.1634/theoncologist.2012-0464 [doi] ID - PMC4063400 [pmc] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT 01355120 SL - https://clinicaltrials.gov/search/term=NCT 01355120 GI - No: RC2CA148468 Organization: (CA) *NCI NIH HHS* Country: United States No: RC2 CA148468 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1-TR000457 Organization: (TR) *NCATS NIH HHS* Country: United States No: UL1 TR000457 Organization: (TR) *NCATS NIH HHS* Country: United States LG - English EP - 20130528 DP - 2013 Jun DC - 20130701 EZ - 2013/05/30 06:00 DA - 2014/02/14 06:00 DT - 2013/05/30 06:00 YR - 2013 ED - 20140213 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23716015 <257. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23716015 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Postow MA AU - Luke JJ AU - Bluth MJ AU - Ramaiya N AU - Panageas KS AU - Lawrence DP AU - Ibrahim N AU - Flaherty KT AU - Sullivan RJ AU - Ott PA AU - Callahan MK AU - Harding JJ AU - D'Angelo SP AU - Dickson MA AU - Schwartz GK AU - Chapman PB AU - Gnjatic S AU - Wolchok JD AU - Hodi FS AU - Carvajal RD FA - Postow, Michael A FA - Luke, Jason J FA - Bluth, Mark J FA - Ramaiya, Nikhil FA - Panageas, Katherine S FA - Lawrence, Donald P FA - Ibrahim, Nageatte FA - Flaherty, Keith T FA - Sullivan, Ryan J FA - Ott, Patrick A FA - Callahan, Margaret K FA - Harding, James J FA - D'Angelo, Sandra P FA - Dickson, Mark A FA - Schwartz, Gary K FA - Chapman, Paul B FA - Gnjatic, Sacha FA - Wolchok, Jedd D FA - Hodi, F Stephen FA - Carvajal, Richard D IN - Postow, Michael A. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. carvajar@mskcc.org TI - Ipilimumab for patients with advanced mucosal melanoma. CM - Comment in: Oncologist. 2013 Jun;18(6):658-60; PMID: 23814163 SO - Oncologist. 18(6):726-32, 2013 Jun AS - Oncologist. 18(6):726-32, 2013 Jun NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063400 SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antigens, Neoplasm/bi [Biosynthesis] MH - CTLA-4 Antigen/bi [Biosynthesis] MH - Clinical Trials as Topic MH - Female MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Mucous Membrane/de [Drug Effects] MH - Mucous Membrane/pa [Pathology] MH - *Neoplasm Metastasis/dt [Drug Therapy] MH - Neoplasm Metastasis/pa [Pathology] MH - Retrospective Studies MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/pa [Pathology] MH - Survival Analysis KW - CTLA-4; Cancer-testis antigens; Immunotherapy; Ipilimumab; Mucosal melanoma AB - The outcome of patients with mucosal melanoma treated with ipilimumab is not defined. To assess the efficacy and safety of ipilimumab in this melanoma subset, we performed a multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab. The clinical characteristics, treatments, toxicities, radiographic assessment of disease burden by central radiology review at each site, and mutational profiles of the patients' tumors were recorded. Available peripheral blood samples were used to assess humoral immunity against a panel of cancer-testis antigens and other antigens. By the immune-related response criteria of the 30 patients who underwent radiographic assessment after ipilimumab at approximately week 12, there were 1 immune-related complete response, 1 immune-related partial response, 6 immune-related stable disease, and 22 immune-related progressive disease. By the modified World Health Organization criteria, there were 1 immune-related complete response, 1 immune-related partial response, 5 immune-related stable disease, and 23 immune-related progressive disease. Immune-related adverse events (as graded by Common Terminology Criteria for Adverse Events version 4.0) consisted of six patients with rash (four grade 1, two grade 2), three patients with diarrhea (one grade 1, two grade 3), one patient with grade 1 thyroiditis, one patient with grade 3 hepatitis, and 1 patient with grade 2 hypophysitis. The median overall survival from the time of the first dose of ipilimumab was 6.4 months (range: 1.8-26.7 months). Several patients demonstrated serologic responses to cancer-testis antigens and other antigens. Durable responses to ipilimumab were observed, but the overall response rate was low. Additional investigation is necessary to clarify the role of ipilimumab in patients with mucosal melanoma. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, Neoplasm) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) ES - 1549-490X IL - 1083-7159 DI - theoncologist.2012-0464 DO - https://dx.doi.org/10.1634/theoncologist.2012-0464 PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 23716015 [pubmed] ID - theoncologist.2012-0464 [pii] ID - 10.1634/theoncologist.2012-0464 [doi] ID - PMC4063400 [pmc] PP - ppublish GI - No: RC2CA148468 Organization: (CA) *NCI NIH HHS* Country: United States No: RC2 CA148468 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1-TR000457 Organization: (TR) *NCATS NIH HHS* Country: United States No: UL1 TR000457 Organization: (TR) *NCATS NIH HHS* Country: United States LG - English EP - 20130528 DP - 2013 Jun DC - 20130701 EZ - 2013/05/30 06:00 DA - 2014/02/14 06:00 DT - 2013/05/30 06:00 YR - 2013 ED - 20140213 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=23716015 <258. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23487828 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bot I AU - Blank CU AU - Boogerd W AU - Brandsma D FA - Bot, Ilja FA - Blank, Christian U FA - Boogerd, Willem FA - Brandsma, Dieta IN - Bot, Ilja. Department of Neurology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands. i.bot@neuro.umcn.nl TI - Neurological immune-related adverse events of ipilimumab. SO - Practical Neurology. 13(4):278-80, 2013 Aug AS - Pract. neurol.. 13(4):278-80, 2013 Aug NJ - Practical neurology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101130961 IO - Pract Neurol SB - Index Medicus CP - England MH - Aged MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - CTLA-4 Antigen/im [Immunology] MH - Humans MH - *Immunologic Factors/tu [Therapeutic Use] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Middle Aged KW - NEUROONCOLOGY; NEUROPHARMACOLOGY AB - Ipilimumab enhances the T lymphocyte mediated immune response to both tumour cells and healthy tissue, improving survival in patients with metastatic melanoma but also leads to more immune-related adverse events (irAEs) than previously used treatments, such as dacarbazine. We present three patients with neurological irAEs from ipilimumab treatment: hypophysitis, meningitis and Guillain-Barre syndrome. Once an irAE occurs, ipilimumab should be stopped and corticosteroids started. Usually, ipilimumab-induced irAE symptoms improve within days to weeks, but can be life-threatening if unrecognised. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 0 (Immunologic Factors) RN - 6T8C155666 (ipilimumab) ES - 1474-7766 IL - 1474-7758 DI - practneurol-2012-000447 DO - https://dx.doi.org/10.1136/practneurol-2012-000447 PT - Case Reports PT - Journal Article ID - 23487828 [pubmed] ID - practneurol-2012-000447 [pii] ID - 10.1136/practneurol-2012-000447 [doi] PP - ppublish LG - English EP - 20130313 DP - 2013 Aug DC - 20130705 EZ - 2013/03/15 06:00 DA - 2014/02/11 06:00 DT - 2013/03/15 06:00 YR - 2013 ED - 20140210 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23487828 <259. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23588667 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Xu J AU - Zhu W AU - Xu W AU - Cui X AU - Chen L AU - Ji S AU - Qin Y AU - Yao W AU - Liu L AU - Liu C AU - Long J AU - Li M AU - Yu X FA - Xu, Jin FA - Zhu, Wenwei FA - Xu, Wenyan FA - Cui, Xiaobo FA - Chen, Leon FA - Ji, Shunrong FA - Qin, Yi FA - Yao, Wantong FA - Liu, Liang FA - Liu, Chen FA - Long, Jiang FA - Li, Min FA - Yu, Xianjun IN - Xu, Jin. Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China. TI - Silencing of MBD1 reverses pancreatic cancer therapy resistance through inhibition of DNA damage repair. SO - International Journal of Oncology. 42(6):2046-52, 2013 Jun AS - Int J Oncol. 42(6):2046-52, 2013 Jun NJ - International journal of oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cx5, 9306042 IO - Int. J. Oncol. SB - Index Medicus CP - Greece MH - Cell Cycle Proteins/ge [Genetics] MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Line, Tumor/de [Drug Effects] MH - Cell Line, Tumor/re [Radiation Effects] MH - Chemoradiotherapy MH - Chromatin/me [Metabolism] MH - Cisplatin/pd [Pharmacology] MH - DNA Damage MH - *DNA Repair/ge [Genetics] MH - *DNA-Binding Proteins/ge [Genetics] MH - DNA-Binding Proteins/me [Metabolism] MH - *Drug Resistance, Neoplasm/ge [Genetics] MH - Gene Knockdown Techniques MH - Gene Silencing MH - Humans MH - Nuclear Proteins/ge [Genetics] MH - Nuclear Proteins/me [Metabolism] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - *Pancreatic Neoplasms/ge [Genetics] MH - *Pancreatic Neoplasms/rt [Radiotherapy] MH - Radiation Tolerance/ge [Genetics] MH - Trans-Activators/ge [Genetics] MH - Trans-Activators/me [Metabolism] MH - *Transcription Factors/ge [Genetics] MH - Transcription Factors/me [Metabolism] AB - High resistance to traditional chemo- and radiotherapies contributes to the poor prognosis of pancreatic cancer (PC). Methyl-CpG binding domain protein 1 (MBD1), which plays an important role in disease progression, contributes to the drug resistance of PC cells; however, the mechanism underlying the drug resistance endowed by MBD1 remains unknown. In this study, we found that MBD1 was recruited to DNA damage sites under DNA damage conditions. Silencing of MBD1 significantly impaired activation of the DNA damage checkpoint response and inhibited DNA repair capacity. MBD1 binds mediator of DNA damage checkpoint protein 1 (MDC1), which is induced by radiation and regulates NBS1 activation in the presence of DNA damage repair. Knockdown of MBD1 significantly increased the sensitivity of cells to radiation and cisplatin (diamindichloridoplatin, DDP) in vitro. Importantly, the function of MBD1 in regulating chemoradioresistance is also partially dependent on DNA damage repair. Thus, we hypothesize that MBD1 may promote PC chemoradioresistance by regulating PC cell fate in the presence of DNA damage. Collectively, these findings reveal an important function of MBD1 in DNA repair and mediation of chemoradioresistance of cancer cells. Moreover, this study suggests that MBD1 is a promising molecular target for sensitizing resistant PC tumor cells to chemoradiotherapy. RN - 0 (Cell Cycle Proteins) RN - 0 (Chromatin) RN - 0 (DNA-Binding Proteins) RN - 0 (MBD1 protein, human) RN - 0 (MDC1 protein, human) RN - 0 (NBN protein, human) RN - 0 (Nuclear Proteins) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - Q20Q21Q62J (Cisplatin) ES - 1791-2423 IL - 1019-6439 DO - https://dx.doi.org/10.3892/ijo.2013.1901 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 23588667 [pubmed] ID - 10.3892/ijo.2013.1901 [doi] PP - ppublish PH - 2013/01/18 [received] PH - 2013/02/22 [accepted] LG - English EP - 20130416 DP - 2013 Jun DC - 20130419 EZ - 2013/04/17 06:00 DA - 2013/12/24 06:00 DT - 2013/04/17 06:00 YR - 2013 ED - 20131223 RD - 20130419 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23588667 <260. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24001893 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Torino F AU - Barnabei A AU - Paragliola RM AU - Marchetti P AU - Salvatori R AU - Corsello SM FA - Torino, Francesco FA - Barnabei, Agnese FA - Paragliola, Rosa Maria FA - Marchetti, Paolo FA - Salvatori, Roberto FA - Corsello, Salvatore Maria IN - Torino, Francesco. Department of Systems Medicine, Chair of Medical Oncology, Tor Vergata University of Rome, Rome, Italy. TI - Endocrine side-effects of anti-cancer drugs: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses. [Review] SO - European Journal of Endocrinology. 169(6):R153-64, 2013 Dec AS - EUR. J. ENDOCRINOL.. 169(6):R153-64, 2013 Dec NJ - European journal of endocrinology PI - Journal available in: Electronic-Print PI - Citation processed from: Internet JC - bxu, 9423848 IO - Eur. J. Endocrinol. SB - Index Medicus CP - England MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/im [Immunology] MH - *CTLA-4 Antigen/de [Drug Effects] MH - CTLA-4 Antigen/me [Metabolism] MH - Endocrine System/de [Drug Effects] MH - Endocrine System/pp [Physiopathology] MH - Humans MH - *Hypopituitarism/ci [Chemically Induced] MH - *Hypopituitarism/me [Metabolism] MH - Hypopituitarism/pa [Pathology] MH - Hypopituitarism/pp [Physiopathology] MH - Inflammation/ci [Chemically Induced] MH - Inflammation/me [Metabolism] MH - Pituitary Diseases/ci [Chemically Induced] MH - Pituitary Diseases/me [Metabolism] MH - *Pituitary Gland/de [Drug Effects] MH - *Pituitary Gland/me [Metabolism] MH - Pituitary Gland/pa [Pathology] MH - Pituitary Gland/pp [Physiopathology] MH - *Programmed Cell Death 1 Receptor/de [Drug Effects] MH - Programmed Cell Death 1 Receptor/me [Metabolism] AB - mAbs are established targeted therapies for several diseases, including hematological and solid malignancies. These agents have shown a favorable toxicity profile, but, despite their high selectivity, new typical side-effects have emerged. In cancer patients, pituitary dysfunction may be mainly due to brain metastases or primary tumors and to related surgery and radiotherapy. Anticancer agents may induce hypopituitarism in patients cured for childhood cancers. These agents infrequently affect pituitary function in adult cancer patients. Notably, hypophysitis, a previously very rare disease, has emerged as a distinctive side-effect of ipilimumab and tremelimumab, two mAbs inhibiting the cytotoxic T-lymphocyte antigen-4 receptor, being occasionally seen with nivolumab, another immune checkpoint inhibitor. Enhanced antitumor immunity is the suggested mechanism of action of these drugs and autoimmunity the presumptive mechanism of their toxicity. Recently, ipilimumab has been licensed for the treatment of patients affected by metastatic melanoma. With the expanding use of these drugs, hypophysitis will be progressively encountered by oncologists and endocrinologists in clinical practice. The optimal management of this potentially life-threatening adverse event needs a rapid and timely diagnostic and therapeutic intervention. Hypopituitarism caused by these agents is rarely reversible, requiring prolonged or lifelong substitutive hormonal treatment. Further studies are needed to clarify several clinical and pathogenic aspects of this new form of secondary pituitary dysfunction. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) RN - 6T8C155666 (ipilimumab) RN - QEN1X95CIX (tremelimumab) ES - 1479-683X IL - 0804-4643 DI - EJE-13-0434 DO - https://dx.doi.org/10.1530/EJE-13-0434 PT - Journal Article PT - Review ID - 24001893 [pubmed] ID - EJE-13-0434 [pii] ID - 10.1530/EJE-13-0434 [doi] PP - epublish LG - English EP - 20131023 DP - 2013 Dec DC - 20131024 EZ - 2013/09/05 06:00 DA - 2013/12/18 06:00 DT - 2013/09/05 06:00 YR - 2013 ED - 20131216 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24001893 <261. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23773743 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lecouflet M AU - Verschoore M AU - Giard C AU - Gohier P AU - Le Corre Y AU - Milea D AU - Martin L FA - Lecouflet, M FA - Verschoore, M FA - Giard, C FA - Gohier, P FA - Le Corre, Y FA - Milea, D FA - Martin, L IN - Lecouflet, M. Service de dermatologie, universite L'UNAM, CHU d'Angers, 4, rue Larrey, 49933 Angers cedex 9, France. marie.lecouflet@gmail.com TI - [Orbital myositis associated with ipilimumab]. [French] OT - Myosite orbitaire associee a un traitement par ipilimumab. SO - Annales de Dermatologie et de Venereologie. 140(6-7):448-51, 2013 Jun-Jul AS - Ann Dermatol Venereol. 140(6-7):448-51, 2013 Jun-Jul NJ - Annales de dermatologie et de venereologie PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 5rc, 7702013 IO - Ann Dermatol Venereol SB - Index Medicus CP - France MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/im [Immunology] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - CD4-Positive T-Lymphocytes/de [Drug Effects] MH - CTLA-4 Antigen/im [Immunology] MH - Cavernous Sinus Thrombosis/di [Diagnosis] MH - Cellulitis/di [Diagnosis] MH - Combined Modality Therapy MH - Diagnosis, Differential MH - Diplopia/et [Etiology] MH - Exophthalmos/et [Etiology] MH - Female MH - Foot Diseases/su [Surgery] MH - Foot Diseases/th [Therapy] MH - Humans MH - *Immunotherapy MH - Lymphatic Metastasis MH - Melanoma/sc [Secondary] MH - Melanoma/su [Surgery] MH - Melanoma/th [Therapy] MH - *Orbital Myositis/ci [Chemically Induced] MH - Orbital Myositis/co [Complications] MH - Orbital Myositis/di [Diagnosis] MH - Orbital Myositis/dt [Drug Therapy] MH - Skin Neoplasms/su [Surgery] MH - Skin Neoplasms/th [Therapy] AB - BACKGROUND: Ipilimumab is a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) that allows increased survival and, occasionally, complete remission, in the treatment of metastatic melanoma. The most frequent adverse effects are attributed to dysimmunity. We report the case of a female patient who developed orbital myositis during treatment with ipilimumab. AB - PATIENTS AND METHODS: A woman on ipilimumab for a heel melanoma with mediastinal metastases was referred for evaluation of painful diplopia and proptosis that began three days after the fourth infusion of ipilimumab. The clinical examination disclosed a left abductiondeficit associated with conjunctival hyperaemia and palpebral oedema. Orbital MRI disclosed enlargement of the left lateral rectus, enhancing after contrast. An extensive work-up did not find any evidence for thyroid-related eye disease, as well as other orbital inflammatory processes, orbital cellulitis or orbital metastases. Treatment with high-dose oral steroids resulted in complete clinical recovery within a few days. AB - DISCUSSION: To our knowledge, this is the first clinical report of orbital myositis as an adverse event related to anti-CTLA-4 antibody treatment. Both timing and usual profile of adverse events support the hypothesis that orbital myositis has to be attributed there to ipilimumab. Several dysimmune toxicities were observed with ipilimumab. Ophtalmic toxicity has unusually been described. Most cases were uveitis. Whether immune-related adverse events correlate with clinical response to ipilimumab treatment remains to be determined. AB - Copyright © 2013 Elsevier Masson SAS. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) IS - 0151-9638 IL - 0151-9638 DI - S0151-9638(13)00720-5 DO - https://dx.doi.org/10.1016/j.annder.2013.02.029 PT - Case Reports PT - Journal Article ID - 23773743 [pubmed] ID - S0151-9638(13)00720-5 [pii] ID - 10.1016/j.annder.2013.02.029 [doi] PP - ppublish PH - 2012/10/22 [received] PH - 2013/01/05 [revised] PH - 2013/02/14 [accepted] LG - French EP - 20130509 DP - 2013 Jun-Jul DC - 20130618 EZ - 2013/06/19 06:00 DA - 2013/12/16 06:00 DT - 2013/06/19 06:00 YR - 2013 ED - 20131209 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23773743 <262. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24278787 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Tarhini A FA - Tarhini, Ahmad IN - Tarhini, Ahmad. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue, Room 555, Pittsburgh, PA 15232, USA. TI - Immune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy: the underlying mechanisms and clinical management. [Review] SO - Scientifica. 2013:857519, 2013 AS - Scientifica (Cairo). 2013:857519, 2013 NJ - Scientifica PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101589932 IO - Scientifica (Cairo) PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820355 CP - Egypt AB - Immunomodulation with the anti-CTLA-4 monoclonal antibody ipilimumab has been shown to extend overall survival (OS) in previously treated and treatment-naive patients with unresectable stage III or IV melanoma. Blockade of CTLA-4 signaling with ipilimumab prolongs T-cell activation and restores T-cell proliferation, thus amplifying T-cell-mediated immunity and the patient's capacity to mount an effective antitumor immune response. While this immunostimulation has unprecedented OS benefits in the melanoma setting, it can also result in immune-mediated effects on various organ systems, leading to immune-related adverse events (irAEs). Ipilimumab-associated irAEs are common and typically low grade and manageable, but can also be serious and life threatening. The skin and gastrointestinal tract are most frequently affected, while hepatic, endocrine, and neurologic events are less common. With proper management, most irAEs resolve within a relatively short time, with a predictable resolution pattern. Prompt and appropriate management of these irAEs is essential and treatment guidelines have been developed to assist oncologists and their teams. Implementation of these irAE management algorithms will help ensure that patients are able to benefit from ipilimumab therapy with adequate control of toxicities. IL - 2090-908X DO - https://dx.doi.org/10.1155/2013/857519 PT - Journal Article PT - Review ID - 24278787 [pubmed] ID - 10.1155/2013/857519 [doi] ID - PMC3820355 [pmc] PP - ppublish PH - 2012/12/06 [received] PH - 2013/01/10 [accepted] LG - English EP - 20130417 DP - 2013 DC - 20131126 EZ - 2013/11/27 06:00 DA - 2013/11/28 06:01 DT - 2013/11/28 06:00 YR - 2013 ED - 20131126 RD - 20131216 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=24278787 <263. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 24175496 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Anderson L AU - Bhatia V FA - Anderson, Laura FA - Bhatia, Vishal IN - Anderson, Laura. Sanford School of Medicine, University of South Dakota, USA. TI - Ipilimumab immune-related adverse reactions: a case report. SO - South Dakota Medicine: The Journal of the South Dakota State Medical Association. 66(8):315-7, 2013 Aug AS - S D Med. 66(8):315-7, 2013 Aug NJ - South Dakota medicine : the journal of the South Dakota State Medical Association PI - Journal available in: Print PI - Citation processed from: Print JC - 101265265 IO - S D Med SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/im [Immunology] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Autoimmune Diseases/ci [Chemically Induced] MH - Autoimmune Diseases/im [Immunology] MH - Female MH - Follow-Up Studies MH - Humans MH - Hydrocortisone/tu [Therapeutic Use] MH - *Hypopituitarism/ci [Chemically Induced] MH - Hypopituitarism/dt [Drug Therapy] MH - *Hypopituitarism/im [Immunology] MH - Hypothyroidism/co [Complications] MH - Hypothyroidism/dt [Drug Therapy] MH - Hypothyroidism/im [Immunology] MH - Immunomodulation/de [Drug Effects] MH - Immunomodulation/im [Immunology] MH - Liver Neoplasms/co [Complications] MH - Liver Neoplasms/dt [Drug Therapy] MH - Liver Neoplasms/sc [Secondary] MH - Lung Neoplasms/co [Complications] MH - Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/sc [Secondary] MH - *Melanoma/pa [Pathology] MH - Middle Aged MH - Prednisone/tu [Therapeutic Use] MH - Thyroxine/tu [Therapeutic Use] MH - Up-Regulation/de [Drug Effects] MH - Up-Regulation/im [Immunology] AB - Ipilimumab is an immunomodulating agent approved by the Food and Drug Administration (FDA) as of March 2011 for the treatment of metastatic melanoma. The medication works by inhibiting cytotoxic T-lymphocyte antigen 4, which typically works to down-regulate the T-cell response and protects self-antigens from recognition by the immune system. Since the T-cells are no longer down-regulated by this antigen, they are allowed to proliferate, thereby helping to prevent melanoma tumor evasion. As a result of the up-regulation of the immune system, numerous immune-mediated adverse effects have been reported including colitis, dermatitis, hepatitis and rarely hypophysitis. Typically, these effects are treated with high-dose steroids and most eventually resolve. We present a case of autoimmune (lymphocytic) hypophysitis following treatment with four doses of ipilimumab 3mg/kg and discuss the work-up, treatment and prognosis of the event. RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) RN - Q51BO43MG4 (Thyroxine) RN - VB0R961HZT (Prednisone) RN - WI4X0X7BPJ (Hydrocortisone) IS - 0038-3317 IL - 0038-3317 PT - Case Reports PT - Journal Article ID - 24175496 [pubmed] PP - ppublish LG - English DP - 2013 Aug DC - 20131101 EZ - 2013/11/02 06:00 DA - 2013/11/20 06:00 DT - 2013/11/02 06:00 YR - 2013 ED - 20131119 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=24175496 <264. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23835677 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hamed SS AU - Straubinger RM AU - Jusko WJ FA - Hamed, Salaheldin S FA - Straubinger, Robert M FA - Jusko, William J IN - Hamed, Salaheldin S. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA. TI - Pharmacodynamic modeling of cell cycle and apoptotic effects of gemcitabine on pancreatic adenocarcinoma cells. SO - Cancer Chemotherapy & Pharmacology. 72(3):553-63, 2013 Sep AS - Cancer Chemother Pharmacol. 72(3):553-63, 2013 Sep NJ - Cancer chemotherapy and pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c9s, 7806519 IO - Cancer Chemother. Pharmacol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777243 OI - Source: NLM. NIHMS503569 SB - Index Medicus CP - Germany MH - *Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/pa [Pathology] MH - Antimetabolites, Antineoplastic/ad [Administration & Dosage] MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - *Apoptosis/de [Drug Effects] MH - Cell Cycle Checkpoints/de [Drug Effects] MH - Cell Line, Tumor MH - Cell Proliferation MH - Deoxycytidine/ad [Administration & Dosage] MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Dose-Response Relationship, Drug MH - Humans MH - Models, Biological MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/pa [Pathology] MH - Time Factors AB - PURPOSE: The standard of care for treating patients with pancreatic adenocarcinomas includes gemcitabine (2',2'-difluorodeoxycytidine). Gemcitabine primarily elicits its response by stalling the DNA replication forks of cells in the S phase of the cell cycle. To provide a quantitative framework for characterizing the cell cycle and apoptotic effects of gemcitabine, we developed a pharmacodynamic model in which the activation of cell cycle checkpoints or cell death is dependent on gemcitabine exposure. AB - METHODS: Three pancreatic adenocarcinoma cell lines (AsPC-1, BxPC-3, and MiaPaca-2) were exposed to varying concentrations (0-100,000 ng/mL) of gemcitabine over a period of 96 h in order to quantify proliferation kinetics and cell distributions among the cell cycle phases. The model assumes that the drug can inhibit cycle-phase transitioning in each of the 3 phases (G1, S, and G2/M) and can cause apoptosis of cells in G1 and G2/M phases. Fitting was performed using the ADAPT5 program. AB - RESULTS: The time course of gemcitabine effects was well described by the model, and parameters were estimated with good precision. Model predictions and experimental data show that gemcitabine induces cell cycle arrest in the S phase at low concentrations, whereas higher concentrations induce arrest in all cell cycle phases. Furthermore, apoptotic effects of gemcitabine appear to be minimal and take place at later time points. AB - CONCLUSION: The pharmacodynamic model developed provides a quantitative, mechanistic interpretation of gemcitabine efficacy in 3 pancreatic cancer cell lines, and provides useful insights for rational selection of chemotherapeutic agents for combination therapy. RN - 0 (Antimetabolites, Antineoplastic) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) ES - 1432-0843 IL - 0344-5704 DO - https://dx.doi.org/10.1007/s00280-013-2226-6 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 23835677 [pubmed] ID - 10.1007/s00280-013-2226-6 [doi] ID - PMC3777243 [pmc] ID - NIHMS503569 [mid] PP - ppublish PH - 2012/12/05 [received] PH - 2013/06/08 [accepted] GI - No: R01 GM057980 Organization: (GM) *NIGMS NIH HHS* Country: United States No: GM57980 Organization: (GM) *NIGMS NIH HHS* Country: United States LG - English EP - 20130709 DP - 2013 Sep DC - 20130827 EZ - 2013/07/10 06:00 DA - 2013/10/24 06:00 DT - 2013/07/10 06:00 YR - 2013 ED - 20131023 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23835677 <265. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23924790 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Le DT AU - Lutz E AU - Uram JN AU - Sugar EA AU - Onners B AU - Solt S AU - Zheng L AU - Diaz LA Jr AU - Donehower RC AU - Jaffee EM AU - Laheru DA FA - Le, Dung T FA - Lutz, Eric FA - Uram, Jennifer N FA - Sugar, Elizabeth A FA - Onners, Beth FA - Solt, Sara FA - Zheng, Lei FA - Diaz, Luis A Jr FA - Donehower, Ross C FA - Jaffee, Elizabeth M FA - Laheru, Daniel A IN - Le, Dung T. The Sidney Kimmel Cancer Center, the Skip Viragh Center for Pancreatic Cancer, Research and Clinical Care, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, MD, USA. dle2@jhmi.edu TI - Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. CM - Comment in: J Immunother. 2013 Sep;36(7):362-4; PMID: 23924787 SO - Journal of Immunotherapy. 36(7):382-9, 2013 Sep AS - J Immunother. 36(7):382-9, 2013 Sep NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779664 OI - Source: NLM. NIHMS505598 SB - Index Medicus CP - United States MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antineoplastic Agents/ad [Administration & Dosage] MH - CTLA-4 Antigen/im [Immunology] MH - *Cancer Vaccines/ad [Administration & Dosage] MH - Carcinoma, Pancreatic Ductal/dg [Diagnostic Imaging] MH - Carcinoma, Pancreatic Ductal/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/th [Therapy] MH - Combined Modality Therapy MH - Female MH - GPI-Linked Proteins/im [Immunology] MH - Granulocyte-Macrophage Colony-Stimulating Factor/ge [Genetics] MH - Humans MH - Male MH - Middle Aged MH - Pancreatic Neoplasms/dg [Diagnostic Imaging] MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Radiography MH - T-Lymphocytes/im [Immunology] MH - Transfection AB - Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Cancer Vaccines) RN - 0 (GPI-Linked Proteins) RN - 0 (mesothelin) RN - 6T8C155666 (ipilimumab) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) ES - 1537-4513 IL - 1524-9557 DI - 00002371-201309000-00005 DO - https://dx.doi.org/10.1097/CJI.0b013e31829fb7a2 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 23924790 [pubmed] ID - 10.1097/CJI.0b013e31829fb7a2 [doi] ID - 00002371-201309000-00005 [pii] ID - PMC3779664 [pmc] ID - NIHMS505598 [mid] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00836407 SL - https://clinicaltrials.gov/search/term=NCT00836407 GI - No: P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964 Organization: (CA) *NCI NIH HHS* Country: United States No: 2P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA1266058 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA126058 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA163672 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2013 Sep DC - 20130808 EZ - 2013/08/09 06:00 DA - 2013/10/23 06:00 DT - 2013/08/09 06:00 YR - 2013 ED - 20131022 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23924790 <266. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23924790 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Le DT AU - Lutz E AU - Uram JN AU - Sugar EA AU - Onners B AU - Solt S AU - Zheng L AU - Diaz LA Jr AU - Donehower RC AU - Jaffee EM AU - Laheru DA FA - Le, Dung T FA - Lutz, Eric FA - Uram, Jennifer N FA - Sugar, Elizabeth A FA - Onners, Beth FA - Solt, Sara FA - Zheng, Lei FA - Diaz, Luis A Jr FA - Donehower, Ross C FA - Jaffee, Elizabeth M FA - Laheru, Daniel A IN - Le, Dung T. The Sidney Kimmel Cancer Center, the Skip Viragh Center for Pancreatic Cancer, Research and Clinical Care, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, MD, USA. dle2@jhmi.edu TI - Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. CM - Comment in: J Immunother. 2013 Sep;36(7):362-4; PMID: 23924787 SO - Journal of Immunotherapy. 36(7):382-9, 2013 Sep AS - J Immunother. 36(7):382-9, 2013 Sep NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779664 OI - Source: NLM. NIHMS505598 SB - Index Medicus CP - United States MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antineoplastic Agents/ad [Administration & Dosage] MH - CTLA-4 Antigen/im [Immunology] MH - *Cancer Vaccines/ad [Administration & Dosage] MH - Carcinoma, Pancreatic Ductal/dg [Diagnostic Imaging] MH - Carcinoma, Pancreatic Ductal/im [Immunology] MH - *Carcinoma, Pancreatic Ductal/th [Therapy] MH - Combined Modality Therapy MH - Female MH - GPI-Linked Proteins/im [Immunology] MH - Granulocyte-Macrophage Colony-Stimulating Factor/ge [Genetics] MH - Humans MH - Male MH - Middle Aged MH - Pancreatic Neoplasms/dg [Diagnostic Imaging] MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Radiography MH - T-Lymphocytes/im [Immunology] MH - Transfection AB - Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Cancer Vaccines) RN - 0 (GPI-Linked Proteins) RN - 0 (mesothelin) RN - 6T8C155666 (ipilimumab) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) ES - 1537-4513 IL - 1524-9557 DI - 00002371-201309000-00005 DO - https://dx.doi.org/10.1097/CJI.0b013e31829fb7a2 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 10.1097/CJI.0b013e31829fb7a2 [doi] ID - 00002371-201309000-00005 [pii] ID - PMC3779664 [pmc] ID - NIHMS505598 [mid] PP - ppublish GI - No: P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA148964 Organization: (CA) *NCI NIH HHS* Country: United States No: 2P50 CA062924 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA1266058 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA169702 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA126058 Organization: (CA) *NCI NIH HHS* Country: United States No: K23 CA163672 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2013 Sep DC - 20130808 EZ - 2013/08/09 06:00 DA - 2013/10/23 06:00 DT - 2013/08/09 06:00 YR - 2013 ED - 20131022 RD - 20170408 UP - 20170410 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=23924790 <267. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23340297 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Abiko K AU - Mandai M AU - Hamanishi J AU - Yoshioka Y AU - Matsumura N AU - Baba T AU - Yamaguchi K AU - Murakami R AU - Yamamoto A AU - Kharma B AU - Kosaka K AU - Konishi I FA - Abiko, Kaoru FA - Mandai, Masaki FA - Hamanishi, Junzo FA - Yoshioka, Yumiko FA - Matsumura, Noriomi FA - Baba, Tsukasa FA - Yamaguchi, Ken FA - Murakami, Ryusuke FA - Yamamoto, Ayaka FA - Kharma, Budiman FA - Kosaka, Kenzo FA - Konishi, Ikuo IN - Abiko, Kaoru. Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan. TI - PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. SO - Clinical Cancer Research. 19(6):1363-74, 2013 Mar 15 AS - Clin Cancer Res. 19(6):1363-74, 2013 Mar 15 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. SB - Index Medicus CP - United States MH - Animals MH - *Antigens, CD274/ge [Genetics] MH - Antigens, CD274/me [Metabolism] MH - Ascites/ge [Genetics] MH - Ascites/pa [Pathology] MH - Cell Line, Tumor MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Mice MH - Neoplasm Invasiveness/ge [Genetics] MH - Neoplasm Invasiveness/pa [Pathology] MH - *Ovarian Neoplasms/ge [Genetics] MH - Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - *Peritoneal Cavity/pa [Pathology] MH - *T-Lymphocytes, Cytotoxic/me [Metabolism] MH - T-Lymphocytes, Cytotoxic/pa [Pathology] AB - PURPOSE: Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be expressed in cancer cells. The purpose of this study is to elucidate the function of PD-L1 in peritoneal dissemination. AB - EXPERIMENTAL DESIGN: Ovarian cancer cases were studied by microarray and immunohistochemistry. PD-L1 expression in mouse ovarian cancer cell line in various conditions was assessed by flow cytometry. PD-L1-overexpression cell line and PD-L1-depleted cell line were generated, and cytolysis by CTLs was analyzed, and alterations in CTLs were studied by means of timelapse and microarray. These cell lines were injected intraperitoneally to syngeneic immunocompetent mice. AB - RESULTS: Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and peritoneal positive cytology. PD-L1 expression in mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and coculture with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression inhibited gathering and degranulation of CTLs. Gene expression profile of CTLs caused by PD-L1-overexpressing ovarian cancer was associated with CTLs exhaustion. In mouse models, PD-L1 depletion resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. AB - CONCLUSION: PD-L1 expression in tumor cell promotes peritoneal dissemination by repressing CTL function. PD-L1-targeted therapy is a promising strategy for preventing and treating peritoneal dissemination. RN - 0 (Antigens, CD274) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-12-2199 DO - https://dx.doi.org/10.1158/1078-0432.CCR-12-2199 PT - Journal Article ID - 23340297 [pubmed] ID - 1078-0432.CCR-12-2199 [pii] ID - 10.1158/1078-0432.CCR-12-2199 [doi] PP - ppublish LG - English EP - 20130122 DP - 2013 Mar 15 DC - 20130318 EZ - 2013/01/24 06:00 DA - 2013/09/24 06:00 DT - 2013/01/24 06:00 YR - 2013 ED - 20130923 RD - 20130318 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23340297 <268. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23455528 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - van der Hiel B AU - Blank CU AU - Haanen JB AU - Stokkel MP FA - van der Hiel, Bernies FA - Blank, Christian U FA - Haanen, John B A G FA - Stokkel, Marcel P M IN - van der Hiel, Bernies. Division of Nuclear Medicine, Leiden University Medical Center, Leiden, The Netherlands. TI - Detection of early onset of hypophysitis by (18)F-FDG PET-CT in a patient with advanced stage melanoma treated with ipilimumab. SO - Clinical Nuclear Medicine. 38(4):e182-4, 2013 Apr AS - Clin Nucl Med. 38(4):e182-4, 2013 Apr NJ - Clinical nuclear medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - df6, 7611109 IO - Clin Nucl Med SB - Index Medicus CP - United States MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Disease Progression MH - *Fluorodeoxyglucose F18 MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/pa [Pathology] MH - *Multimodal Imaging MH - Neoplasm Staging MH - *Pituitary Diseases/ci [Chemically Induced] MH - *Pituitary Diseases/dg [Diagnostic Imaging] MH - *Positron-Emission Tomography MH - *Tomography, X-Ray Computed AB - Ipilimumab is a human monoclonal antibody directed against a receptor expressed on activated T-lymphocytes (CTLA-4). Binding to this receptor induces T-cell activation against tumor cells. A 77-year-old man with a stage IV metastatic melanoma was treated with ipilimumab. F-FDG PET-CT performed for response evaluation revealed intense uptake in the pituitary gland. Two weeks later, biochemical parameters altered confirming hypophysitis. Treatment of the hypophysitis was started, and shortly thereafter, biochemical parameters normalized. Follow-up PET-CT revealed normalization of F-FDG uptake in the pituitary gland. In this case, we present a patient with ipilimumab-induced hypophysitis initially diagnosed on F-FDG PET-CT. RN - 0 (Antibodies, Monoclonal) RN - 0Z5B2CJX4D (Fluorodeoxyglucose F18) RN - 6T8C155666 (ipilimumab) ES - 1536-0229 IL - 0363-9762 DO - https://dx.doi.org/10.1097/RLU.0b013e3182639765 PT - Case Reports PT - Journal Article ID - 23455528 [pubmed] ID - 10.1097/RLU.0b013e3182639765 [doi] PP - ppublish LG - English DP - 2013 Apr DC - 20130308 EZ - 2013/03/05 06:00 DA - 2013/09/07 06:00 DT - 2013/03/05 06:00 YR - 2013 ED - 20130906 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23455528 <269. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23262440 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bernardo SG AU - Moskalenko M AU - Pan M AU - Shah S AU - Sidhu HK AU - Sicular S AU - Harcharik S AU - Chang R AU - Friedlander P AU - Saenger YM FA - Bernardo, Sebastian G FA - Moskalenko, Marina FA - Pan, Michael FA - Shah, Shaily FA - Sidhu, Harleen K FA - Sicular, Serge FA - Harcharik, Sara FA - Chang, Rui FA - Friedlander, Philip FA - Saenger, Yvonne M IN - Bernardo, Sebastian G. Departments of Dermatology, Mount Sinai School of Medicine, New York, New York 10029, USA. TI - Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma. SO - Melanoma Research. 23(1):47-54, 2013 Feb AS - Melanoma Res. 23(1):47-54, 2013 Feb NJ - Melanoma research PI - Journal available in: Print PI - Citation processed from: Internet JC - bjr, 9109623 IO - Melanoma Res. SB - Index Medicus CP - England MH - *Alanine Transaminase/bl [Blood] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Aspartate Aminotransferases/bl [Blood] MH - *Chemical and Drug Induced Liver Injury/bl [Blood] MH - Chemical and Drug Induced Liver Injury/im [Immunology] MH - Chi-Square Distribution MH - Female MH - Humans MH - *Immunologic Factors/ae [Adverse Effects] MH - Immunologic Factors/tu [Therapeutic Use] MH - Kaplan-Meier Estimate MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - Retrospective Studies MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/pa [Pathology] AB - Melanoma is the deadliest form of skin cancer. Ipilimumab, a novel immunotherapy, is the first treatment shown to improve survival in patients with metastatic melanoma in large randomized controlled studies. The most concerning side effects reported in clinical studies of ipilimumab fall into the category of immune-related adverse events, which include enterocolitis, dermatitis, thyroiditis, hepatitis, hypophysitis, uveitis, and others. During the course of routine clinical care at Mount Sinai Medical Center, frequent hepatotoxicity was noted when ipilimumab was administered at a dose of 3 mg/kg according to Food and Drug Administration (FDA) guidelines. To better characterize these adverse events, we conducted a retrospective review of the first 11 patients with metastatic melanoma treated with ipilimumab at the Mount Sinai Medical Center after FDA approval. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation, as defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events, each occurred in six of 11 cases (>=grade 1), a notably higher frequency than could be expected on the basis of the FDA licensing study where elevations were reported in 0.8 and 1.5% of patients for AST and ALT, respectively. Grade 3 elevations in AST occurred in three of 11 patients as compared with 0% in the licensing trial. All cases of transaminitis resolved when ipilimumab was temporarily withheld without administration of immunosuppressive medication. During routine clinical care of late-stage melanoma patients with ipilimumab, physicians should monitor patients closely for hepatotoxicity and be aware that toxicity rates may differ across populations during ipilimumab therapy. RN - 0 (Antibodies, Monoclonal) RN - 0 (Immunologic Factors) RN - 6T8C155666 (ipilimumab) RN - EC 2-6-1-1 (Aspartate Aminotransferases) RN - EC 2-6-1-2 (Alanine Transaminase) ES - 1473-5636 IL - 0960-8931 DI - 00008390-201302000-00008 DO - https://dx.doi.org/10.1097/CMR.0b013e32835c7e68 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 23262440 [pubmed] ID - 10.1097/CMR.0b013e32835c7e68 [doi] ID - 00008390-201302000-00008 [pii] PP - ppublish LG - English DP - 2013 Feb DC - 20121224 EZ - 2012/12/25 06:00 DA - 2013/06/19 06:00 DT - 2012/12/25 06:00 YR - 2013 ED - 20130617 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23262440 <270. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23471977 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Corsello SM AU - Barnabei A AU - Marchetti P AU - De Vecchis L AU - Salvatori R AU - Torino F FA - Corsello, Salvatore Maria FA - Barnabei, Agnese FA - Marchetti, Paolo FA - De Vecchis, Liana FA - Salvatori, Roberto FA - Torino, Francesco IN - Corsello, Salvatore Maria. Endocrinology Unit, Universita Cattolica, Via Federico Cesi 72, I-00193 Rome, Italy. corsello.sm@mclink.it TI - Endocrine side effects induced by immune checkpoint inhibitors. [Review] SO - Journal of Clinical Endocrinology & Metabolism. 98(4):1361-75, 2013 Apr AS - J Clin Endocrinol Metab. 98(4):1361-75, 2013 Apr NJ - The Journal of clinical endocrinology and metabolism PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hrb, 0375362 IO - J. Clin. Endocrinol. Metab. SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - *Cell Cycle Checkpoints/im [Immunology] MH - Drug-Related Side Effects and Adverse Reactions/ci [Chemically Induced] MH - Drug-Related Side Effects and Adverse Reactions/ep [Epidemiology] MH - *Endocrine System/de [Drug Effects] MH - *Endocrine System Diseases/ci [Chemically Induced] MH - Endocrine System Diseases/ep [Epidemiology] MH - Humans MH - Immunotherapy/ae [Adverse Effects] MH - Neoplasms/th [Therapy] AB - CONTEXT: In recent years, progress has been made in cancer immunotherapy by the development of drugs acting as modulators of immune checkpoint proteins, such as the cytotoxic T-lymphocyte antigen-4 (CTLA4) and programmed death-1 (PD-1), two co-inhibitory receptors that are expressed on T cells upon activation. These molecules play crucial roles in maintaining immune homeostasis by down-regulating T-cell signaling, thereby preventing unbridled T-cell proliferation while maintaining tolerance to self-antigens, such as tumor-associated antigens. CTLA4 blockade through systemic administration of the CTLA4-blocking antibody ipilimumab was shown to confer significant survival benefit and prolonged stable disease in patients affected by advanced cutaneous melanoma. Other immune checkpoint inhibitors are under clinical evaluation. However, immune checkpoint blockade can lead to the breaking of immune self-tolerance, thereby inducing a novel syndrome of autoimmune/autoinflammatory side effects, designated as "immune-related adverse events," mainly including rash, colitis, hepatitis, and endocrinopathies. AB - DATA ACQUISITION: We searched the medical literature using the words "hypophysitis," "hypopituitarism," "thyroid," "adrenal insufficiency," and "endocrine adverse events" in association with "immune checkpoint inhibitors," "ipilimumab," "tremelimumab," "PD-1," and "PD-1-L." AB - EVIDENCE SYNTHESIS: The spectrum of endocrine disease experienced by patients treated with ipilimumab includes most commonly hypophysitis, more rarely thyroid disease or abnormalities in thyroid function tests, and occasionally primary adrenal insufficiency. Hypophysitis has emerged as a distinctive side effect of CTLA4-blocking antibodies, establishing a new form of autoimmune pituitary disease. This condition, if not promptly recognized, may be life-threatening (due to secondary hypoadrenalism). Hypopituitarism caused by these agents is rarely reversible, and prolonged or lifelong substitutive hormonal treatment is often required. The precise mechanism of injury to the endocrine system triggered by these drugs is yet to be fully elucidated. AB - CONCLUSIONS: Although reports of endocrine side effects caused by cancer immune therapy are abundant, their exact prevalence and mechanism are unclear. Well-designed correlative studies oriented to finding and validating predictive factors of autoimmune toxicity are urgently needed. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) ES - 1945-7197 IL - 0021-972X DI - jc.2012-4075 DO - https://dx.doi.org/10.1210/jc.2012-4075 PT - Evaluation Studies PT - Journal Article PT - Review ID - 23471977 [pubmed] ID - jc.2012-4075 [pii] ID - 10.1210/jc.2012-4075 [doi] PP - ppublish LG - English EP - 20130307 DP - 2013 Apr DC - 20130408 EZ - 2013/03/09 06:00 DA - 2013/06/12 06:00 DT - 2013/03/09 06:00 YR - 2013 ED - 20130611 RD - 20131121 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23471977 <271. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23154861 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Schleder S AU - Schreml S AU - Heiss P FA - Schleder, S FA - Schreml, S FA - Heiss, P TI - [Ipilimumab-induced hypophysitis]. [German] OT - Ipilimumab-induzierte Hypophysitis. SO - Rofo: Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin. 185(3):268-9, 2013 Mar AS - ROFO Fortschr Geb Rontgenstr Nuklearmed. 185(3):268-9, 2013 Mar NJ - RoFo : Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - rof, 7507497 IO - Rofo SB - Index Medicus CP - Germany MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *Brain Neoplasms/dt [Drug Therapy] MH - Brain Neoplasms/pa [Pathology] MH - *Brain Neoplasms/sc [Secondary] MH - Diagnosis, Differential MH - Dose-Response Relationship, Drug MH - Female MH - Frontal Lobe/de [Drug Effects] MH - Frontal Lobe/pa [Pathology] MH - Humans MH - *Image Interpretation, Computer-Assisted MH - Infusions, Intravenous MH - *Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/pa [Pathology] MH - *Lung Neoplasms/sc [Secondary] MH - *Magnetic Resonance Imaging MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - *Melanoma/sc [Secondary] MH - Middle Aged MH - Neoplasm Staging MH - *Pituitary Diseases/ci [Chemically Induced] MH - Pituitary Diseases/di [Diagnosis] MH - *Pituitary Gland/de [Drug Effects] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/pa [Pathology] RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 1438-9010 IL - 1438-9010 DO - https://dx.doi.org/10.1055/s-0032-1325515 PT - Case Reports PT - Journal Article ID - 23154861 [pubmed] ID - 10.1055/s-0032-1325515 [doi] PP - ppublish LG - German EP - 20121115 DP - 2013 Mar DC - 20130226 EZ - 2012/11/17 06:00 DA - 2013/04/24 06:00 DT - 2012/11/17 06:00 YR - 2013 ED - 20130423 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23154861 <272. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23116250 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Sharma A AU - Shah SR AU - Illum H AU - Dowell J FA - Sharma, Anant FA - Shah, Sachin R FA - Illum, Henrik FA - Dowell, Jonathan IN - Sharma, Anant. VA North Texas Health Care System, Dallas, TX 75216, USA. Anant.Sharma@va.gov TI - Vemurafenib: targeted inhibition of mutated BRAF for treatment of advanced melanoma and its potential in other malignancies. [Review] SO - Drugs. 72(17):2207-22, 2012 Dec 03 AS - Drugs. 72(17):2207-22, 2012 Dec 03 NJ - Drugs PI - Journal available in: Print PI - Citation processed from: Internet JC - ec2, 7600076 IO - Drugs SB - Index Medicus CP - New Zealand MH - *Antineoplastic Agents/pd [Pharmacology] MH - Humans MH - *Indoles/pd [Pharmacology] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/me [Metabolism] MH - Mitogen-Activated Protein Kinases/me [Metabolism] MH - *Mutation MH - *Proto-Oncogene Proteins B-raf/ai [Antagonists & Inhibitors] MH - Proto-Oncogene Proteins B-raf/ge [Genetics] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/me [Metabolism] MH - *Sulfonamides/pd [Pharmacology] MH - Treatment Outcome AB - Vemurafenib is the first molecularly targeted therapy to be licensed in the US and Europe for treatment of advanced melanoma. Its mechanism of action involves selective inhibition of the mutated BRAF V600E kinase that leads to reduced signalling through the aberrant mitogen-activated protein kinase (MAPK) pathway. Its efficacy is restricted to melanomas carrying the BRAF V600E mutation, which is seen in approximately 50% of all melanomas. In a randomized phase III trial, it was superior to dacarbazine in first-line treatment of advanced melanoma, with an overall response rate (ORR) of 48% (95% CI 42, 45), an estimated 6-month progression-free survival (PFS) of 5.3 versus 1.6 months (hazard ratio [HR] 0.26; 95% CI 0.20, 0.33; p<0.001) and a statistically superior 12-month overall survival (OS) rate of 55% versus 43% (HR 0.62 [95% CI 0.49, 0.77]). Vemurafenib is generally well tolerated, but its use can be associated with development of cutaneous neoplasms such as squamous cell carcinoma (SCC) and keratoacanthoma (KA). These lesions can be excised safely without the need for withholding the drug or reducing its dose. Mechanisms of resistance to vemurafenib do not involve development of secondary mutations in the BRAF kinase domain, but may be related to BRAF V600E over-amplification, bypassing mechanisms via upregulation and overexpression of other components in the MAPK signalling cascade or activation of alternative pathways with potential to enhance cell growth, proliferation and survival. Clinical trials to test the efficacy of vemurafenib in combination with immunomodulatory agents, such as ipilimumab, and MAPK kinase (MEK) inhibitors, such as GDC-0973, in the treatment of advanced melanoma are currently underway. Also under investigation is the use of vemurafenib in other solid tumours with BRAF mutations, such as papillary thyroid cancer. RN - 0 (Antineoplastic Agents) RN - 0 (Indoles) RN - 0 (Sulfonamides) RN - 207SMY3FQT (vemurafenib) RN - EC 2-7-11-1 (BRAF protein, human) RN - EC 2-7-11-1 (Proto-Oncogene Proteins B-raf) RN - EC 2-7-11-24 (Mitogen-Activated Protein Kinases) ES - 1179-1950 IL - 0012-6667 DO - https://dx.doi.org/10.2165/11640870-000000000-00000 PT - Journal Article PT - Review ID - 23116250 [pubmed] ID - 10.2165/11640870-000000000-00000 [doi] PP - ppublish LG - English DP - 2012 Dec 03 DC - 20121122 EZ - 2012/11/03 06:00 DA - 2013/04/10 06:00 DT - 2012/11/03 06:00 YR - 2012 ED - 20130409 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=23116250 <273. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23559884 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Assi H AU - Wilson KS FA - Assi, H FA - Wilson, K S TI - Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases. SO - Current Oncology. 20(2):e165-9, 2013 Apr AS - Curr. oncol.. 20(2):e165-9, 2013 Apr NJ - Current oncology (Toronto, Ont.) PI - Journal available in: Print PI - Citation processed from: Print JC - 9502503 IO - Curr Oncol PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615868 CP - Canada KW - Ipilimumab; immune response; melanoma; safety AB - New antitumour immunotherapy strategies for stage iv metastatic melanoma include ipilimumab, a monoclonal antibody against ctla-4. Patterns of response with cancer immunotherapy differ from those with cytotoxic chemotherapy. We present two cases of long-duration immune-related responses with ipilimumab in a phase ii trial. A 66-year-old woman with multiple lung metastases from a scalp primary melanoma received 4 doses of ipilimumab with mixed clinical response. However, after the first maintenance dose, she developed severe ileitis and colitis that responded to steroid therapy. Four months later, she had surgery and radiotherapy for a single brain metastasis. Radiologically, stable disease continued for 36 months after the last ipilimumab dose, and partial response for 5 years after ipilimumab start. A 54-year-old man with cervical lymph node and pulmonary metastases from a scalp primary melanoma received three induction doses of ipilimumab. He developed alopecia universalis and widespread vitiligo, and he discontinued treatment because of hypophysitis. Maintenance ipilimumab was started after a 6-month drug-free interval, with no further adverse events over 15 cycles. At week 12, computed tomography imaging showed no lung metastases and partial response in a supraclavicular lymph node, which was positive on positron-emission tomography. Five years after starting ipilimumab, the supraclavicular lymph node was calcified, and the patient was off steroid therapy and asymptomatic. The foregoing patients demonstrate long responses with ipilimumab (in association with delayed severe colitis in one case, and a constellation of immune events, including alopecia universalis in another). Re-treatment with ipilimumab may be possible even after significant immune adverse events. IS - 1198-0052 IL - 1198-0052 DI - conc-20-e165 DO - https://dx.doi.org/10.3747/co.20.1265 PT - Journal Article ID - 23559884 [pubmed] ID - 10.3747/co.20.1265 [doi] ID - conc-20-e165 [pii] ID - PMC3615868 [pmc] PP - ppublish LG - English DP - 2013 Apr DC - 20130405 EZ - 2013/04/06 06:00 DA - 2013/04/06 06:01 DT - 2013/04/06 06:00 YR - 2013 ED - 20130408 RD - 20130408 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=23559884 <274. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23306915 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Takahashi S FA - Takahashi, Shunji IN - Takahashi, Shunji. Dept. of Medical Oncology, Japanese Foundation for Cancer Research, Japan. TI - [Molecular-target therapy for advanced malignant melanoma]. [Japanese] SO - Gan to Kagaku Ryoho [Japanese Journal of Cancer & Chemotherapy]. 40(1):19-25, 2013 Jan AS - Gan To Kagaku Ryoho. 40(1):19-25, 2013 Jan NJ - Gan to kagaku ryoho. Cancer & chemotherapy PI - Journal available in: Print PI - Citation processed from: Print JC - 7810034, 6t8 IO - Gan To Kagaku Ryoho SB - Index Medicus CP - Japan MH - Clinical Trials as Topic MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/ge [Genetics] MH - Melanoma/pa [Pathology] MH - *Molecular Targeted Therapy MH - Mutation MH - Neoplasm Staging AB - Malignant melanoma is insensitive to chemotherapy, and standard therapy for metastatic melanoma has been dacarbazine for years. Molecular abnormalities of malignant melanoma, mainly of MAP kinase signals such as BRAF mutation, have been clarified, and molecular target therapy for melanoma has been developed recently. Vemurafenib, an inhibitor for mutated BRAF, has shown its efficacy for the first time, with response rate of more than 50%, and an overall improvement in survival compared with dacarbazine in a phase III study. Skin toxicities including squamous cell carcinoma, are the most severe adverse events. Another BRAF inhibitor, dabrafenib, and a MEK inhibitor, trametinib, have shown excellent efficacy in clinical studies. Melanoma also has high immunogenicity, and cytokines or cell immunotherapy have shown some efficacy. Recently, the importance of immune checkpoints which adjust T-cell activation, such as the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), -B7 or the programmed cell death protein-1(PD1)-PD1 ligand(PDL1), have been clarified. Targeting those immune checkpoints is expected to be effective for enhancing tumor immunity. CTLA-4 antibody ipilimumab has been reported to improve overall survival in two phase III studies. Major adverse events were autoimmune response such as colitis, eruption, liver dysfunction and endocrineopathies. Antibodies to PD1 or PDL1 have shown a higher response rate than those of ipilimumab, and seem to accompany fewer autoimmune responses in phase I studies. These two types of targeting therapy are expected to be standard therapies for melanoma. IS - 0385-0684 IL - 0385-0684 PT - English Abstract PT - Journal Article ID - 23306915 [pubmed] PP - ppublish LG - Japanese DP - 2013 Jan DC - 20130111 EZ - 2013/01/12 06:00 DA - 2013/03/09 06:00 DT - 2013/01/12 06:00 YR - 2013 ED - 20130308 RD - 20130111 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medl&AN=23306915 <275. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23316667 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lotem M AU - Merims S AU - Frank S AU - Ospovat I AU - Peretz T FA - Lotem, Michal FA - Merims, Sharon FA - Frank, Steven FA - Ospovat, Inna FA - Peretz, Tamar IN - Lotem, Michal. Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Jerusalem. mlotem@hadassah.org.il TI - [Ctla-4 blockade: a new hope for the immunotherapy of malignant melanoma]. [Review] [Hebrew] SO - Harefuah. 151(10):585-8, 604, 2012 Oct AS - Harefuah. 151(10):585-8, 604, 2012 Oct NJ - Harefuah PI - Journal available in: Print PI - Citation processed from: Print JC - 0034351, fzf IO - Harefuah SB - Index Medicus CP - Israel MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal MH - Antineoplastic Agents, Alkylating/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols MH - Autoimmunity/de [Drug Effects] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Clinical Trials, Phase II as Topic MH - Clinical Trials, Phase III as Topic MH - Dacarbazine/tu [Therapeutic Use] MH - Drug Approval MH - Drug Monitoring MH - Humans MH - Immunotherapy/mt [Methods] MH - Immunotherapy/td [Trends] MH - *Immunotherapy MH - Melanoma/pa [Pathology] MH - Melanoma/th [Therapy] MH - *Melanoma MH - Pharmacovigilance MH - Proportional Hazards Models MH - Skin Neoplasms/pa [Pathology] MH - Skin Neoplasms/th [Therapy] MH - *Skin Neoplasms MH - T-Lymphocytes, Cytotoxic/im [Immunology] MH - Treatment Outcome AB - Ipilimumab (Yervoy) is a monocLonal antibody designed to block cytotoxic T cell antigen 4 (CTLA-4), an inhibitory receptor of T lymphocytes. This drug is the first to receive US FDAs approval for advanced stage malignant melanoma in the last 13 years. So far, no survival benefit was achieved for this patient group with single drug or combination chemo- and chemo-immunotherapy. In phase II and III trials, up to 15% of patients had melanoma regressions, with a decreased hazard ratio of death of 0.72 compared to the standard chemotherapy with Dacarbazine. The development of Ipilimumab marks a success in deciphering the check-point control on the immune response. Activated T cells over-express CTLA-4 molecule on their surface and become susceptible to its inhibitory effect. CTLA-4 decreases the signaling network derived by antigen recognition of T cells. Alongside of its therapeutic effect, the CTLA-4 blockade enhances autoimmune responses. Severe diarrhea results from toxicity to the colonic mucosa which may eventuate in perforation and, in rare cases, death. Other adverse events of varying severity occur in many patients and include skin eruption, uveitis, endocrinopathies such as thyroiditis and hypophysitis and autoimmune hepatitis. Ipilimumab toxicity is reversible with systemic use of corticosteroids, but the use of TNF inhibitors is sometimes indicated in the absence of resolution. The clinical success of the CTLA-4 blockade motivated intense searches for additional check-point modifiers, such as PD-1 molecule, with encouraging preliminary results. Ipilimumab's entry into the clinic is the opening of a new chapter in the immunotherapy of melanoma in particular, and of cancer, in general. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents, Alkylating) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) RN - 7GR28W0FJI (Dacarbazine) IS - 0017-7768 IL - 0017-7768 PT - Journal Article PT - Review ID - 23316667 [pubmed] PP - ppublish LG - Hebrew DP - 2012 Oct DC - 20130115 EZ - 2013/01/16 06:00 DA - 2013/02/16 06:00 DT - 2013/01/16 06:00 YR - 2012 ED - 20130215 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=23316667 <276. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22889227 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Nikolajczyk BS AU - Jagannathan-Bogdan M AU - Denis GV FA - Nikolajczyk, Barbara S FA - Jagannathan-Bogdan, Madhumita FA - Denis, Gerald V IN - Nikolajczyk, Barbara S. Department of Microbiology, Boston University, Boston, MA 02118, USA. bnikol@bu.edu TI - The outliers become a stampede as immunometabolism reaches a tipping point. [Review] SO - Immunological Reviews. 249(1):253-75, 2012 Sep AS - Immunol Rev. 249(1):253-75, 2012 Sep NJ - Immunological reviews PI - Journal available in: Print PI - Citation processed from: Internet JC - gg4, 7702118 IO - Immunol. Rev. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419483 OI - Source: NLM. NIHMS379470 SB - Index Medicus CP - England MH - Adipocytes/im [Immunology] MH - Adipose Tissue/im [Immunology] MH - Adipose Tissue/me [Metabolism] MH - Animals MH - B-Lymphocytes/im [Immunology] MH - Cell Differentiation MH - *Diabetes Mellitus, Type 2/im [Immunology] MH - *Diabetes Mellitus, Type 2/me [Metabolism] MH - *Energy Metabolism MH - Humans MH - Inflammation/im [Immunology] MH - Insulin Resistance MH - Leukocytes/im [Immunology] MH - Mice MH - Obesity/im [Immunology] MH - *Obesity/me [Metabolism] MH - T-Lymphocytes/im [Immunology] AB - Obesity and Type 2 diabetes mellitus (T2D) are characterized by pro-inflammatory alterations in the immune system including shifts in leukocyte subset differentiation and in cytokine/chemokine balance. The chronic, low-grade inflammation resulting largely from changes in T-cell, B-cell, and myeloid compartments promotes and/or exacerbates insulin resistance (IR) that, together with pancreatic islet failure, defines T2D. Animal model studies show that interruption of immune cell-mediated inflammation by any one of several methods almost invariably results in the prevention or delay of obesity and/or IR. However, anti-inflammatory therapies have had a modest impact on established T2D in clinical trials. These seemingly contradictory results indicate that a more comprehensive understanding of human IR/T2D-associated immune cell function is needed to leverage animal studies into clinical treatments. Important outstanding analyses include identifying potential immunological checkpoints in disease etiology, detailing immune cell/adipose tissue cross-talk, and defining strengths/weaknesses of model organism studies to determine whether we can harness the promising new field of immunometabolism to curb the global obesity and T2D epidemics. AB - Copyright © 2012 John Wiley & Sons A/S. ES - 1600-065X IL - 0105-2896 DO - https://dx.doi.org/10.1111/j.1600-065X.2012.01142.x PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review ID - 22889227 [pubmed] ID - PMC3419483 [pmc] ID - NIHMS379470 [mid] ID - 10.1111/j.1600-065X.2012.01142.x [doi] PP - ppublish GI - No: DK046200 Organization: (DK) *NIDDK NIH HHS* Country: United States No: R21 DE021154 Organization: (DE) *NIDCR NIH HHS* Country: United States No: U01 CA182898 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 DK089270 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P30 DK046200 Organization: (DK) *NIDDK NIH HHS* Country: United States No: R56 DK090455 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P30 DK057521 Organization: (DK) *NIDDK NIH HHS* Country: United States No: R21DK089270 Organization: (DK) *NIDDK NIH HHS* Country: United States No: 5R21DE021154 Organization: (DE) *NIDCR NIH HHS* Country: United States No: T32 AI007309 Organization: (AI) *NIAID NIH HHS* Country: United States No: AI007309 Organization: (AI) *NIAID NIH HHS* Country: United States LG - English DP - 2012 Sep DC - 20120814 EZ - 2012/08/15 06:00 DA - 2013/02/05 06:00 DT - 2012/08/15 06:00 YR - 2012 ED - 20130204 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22889227 <277. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23060594 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Forde PM AU - Rock K AU - Wilson G AU - O'Byrne KJ FA - Forde, Patrick M FA - Rock, Kathy FA - Wilson, Graham FA - O'Byrne, Kenneth J IN - Forde, Patrick M. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD 21231, USA. pforde1@jhmi.edu TI - Ipilimumab-induced immune-related renal failure--a case report. SO - Anticancer Research. 32(10):4607-8, 2012 Oct AS - Anticancer Res. 32(10):4607-8, 2012 Oct NJ - Anticancer research PI - Journal available in: Print PI - Citation processed from: Internet JC - 59l, 8102988 IO - Anticancer Res. SB - Index Medicus CP - Greece MH - *Acute Kidney Injury/ci [Chemically Induced] MH - Acute Kidney Injury/dg [Diagnostic Imaging] MH - Acute Kidney Injury/dt [Drug Therapy] MH - Acute Kidney Injury/im [Immunology] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Creatinine/bl [Blood] MH - Glucocorticoids/tu [Therapeutic Use] MH - Humans MH - Lymphatic Metastasis MH - Male MH - Melanoma/dt [Drug Therapy] MH - Methylprednisolone/tu [Therapeutic Use] MH - Middle Aged MH - Radiography MH - Skin Neoplasms/dt [Drug Therapy] MH - Treatment Outcome AB - Ipilimumab is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4 and has become the first immune checkpoint inhibitor to enter clinical practice, being recently approved for the treatment of metastatic melanoma. Immune toxicity due to ipilimumab causing colitis, hepatitis, dermatitis and hypophysitis is well-described. We report on a case of acute renal failure resolving rapidly with high-dose corticosteroid treatment highlighting the importance of vigilance for rarer immune-related toxicities as clinical experience with ipilimumab grows. RN - 0 (Antibodies, Monoclonal) RN - 0 (Glucocorticoids) RN - 6T8C155666 (ipilimumab) RN - AYI8EX34EU (Creatinine) RN - X4W7ZR7023 (Methylprednisolone) ES - 1791-7530 IL - 0250-7005 DI - 32/10/4607 PT - Case Reports PT - Journal Article ID - 23060594 [pubmed] ID - 32/10/4607 [pii] PP - ppublish LG - English DP - 2012 Oct DC - 20121012 EZ - 2012/10/13 06:00 DA - 2013/01/15 06:00 DT - 2012/10/13 06:00 YR - 2012 ED - 20130114 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=23060594 <278. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22787433 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Venkatesha VA AU - Parsels LA AU - Parsels JD AU - Zhao L AU - Zabludoff SD AU - Simeone DM AU - Maybaum J AU - Lawrence TS AU - Morgan MA FA - Venkatesha, Venkatasubbaiah A FA - Parsels, Leslie A FA - Parsels, Joshua D FA - Zhao, Lili FA - Zabludoff, Sonya D FA - Simeone, Diane M FA - Maybaum, Jonathan FA - Lawrence, Theodore S FA - Morgan, Meredith A IN - Venkatesha, Venkatasubbaiah A. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109-5637, USA. TI - Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition. SO - Neoplasia (New York). 14(6):519-25, 2012 Jun AS - Neoplasia. 14(6):519-25, 2012 Jun NJ - Neoplasia (New York, N.Y.) PI - Journal available in: Print PI - Citation processed from: Internet JC - dru, 100886622 IO - Neoplasia PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394194 SB - Index Medicus CP - United States MH - Animals MH - Antimetabolites, Antineoplastic/ad [Administration & Dosage] MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - Checkpoint Kinase 1 MH - Deoxycytidine/ad [Administration & Dosage] MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Humans MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - *Neoplastic Stem Cells/de [Drug Effects] MH - *Neoplastic Stem Cells/me [Metabolism] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - *Pancreatic Neoplasms/me [Metabolism] MH - Protein Kinase Inhibitors/ad [Administration & Dosage] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - *Protein Kinases/me [Metabolism] MH - Tumor Burden/de [Drug Effects] MH - Xenograft Model Antitumor Assays AB - Checkpoint kinase 1 (Chk1) inhibition sensitizes pancreatic cancer cells and tumors to gemcitabine. We hypothesized that Chk1 inhibition would sensitize pancreatic cancer stem cells to gemcitabine. We tested this hypothesis by using two patient-derived xenograft models (designated J and F) and the pancreatic cancer stem cell markers CD24, CD44, and ESA. We determined the percentage of marker-positive cells and their tumor-initiating capacity (by limiting dilution assays) after treatment with gemcitabine and the Chk1 inhibitor, AZD7762. We found that marker-positive cells were significantly reduced by the combination of gemcitabine and AZD7762. In addition, secondary tumor initiation was significantly delayed in response to primary tumor treatment with gemcitabine + AZD7762 compared with control, gemcitabine, or AZD7762 alone. Furthermore, for the same number of stem cells implanted from gemcitabine- versus gemcitabine + AZD7762-treated primary tumors, secondary tumor initiation at 10 weeks was 83% versus 43%, respectively. We also found that pS345 Chk1, which is a measure of DNA damage, was induced in marker-positive cells but not in the marker-negative cells. These data demonstrate that Chk1 inhibition in combination with gemcitabine reduces both the percentage and the tumor-initiating capacity of pancreatic cancer stem cells. Furthermore, the finding that the Chk1-mediated DNA damage response was greater in stem cells than in non-stem cells suggests that Chk1 inhibition may selectively sensitize pancreatic cancer stem cells to gemcitabine, thus making Chk1 a potential therapeutic target for improving pancreatic cancer therapy. RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Protein Kinase Inhibitors) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - EC 2-7-11-1 (Chek1 protein, mouse) ES - 1476-5586 IL - 1476-5586 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 22787433 [pubmed] ID - PMC3394194 [pmc] PP - ppublish PH - 2012/03/19 [received] PH - 2012/04/30 [revised] PH - 2012/05/04 [accepted] GI - No: P30 CA046592 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA78554 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA130810 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA078554 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2012 Jun DC - 20120712 EZ - 2012/07/13 06:00 DA - 2012/11/14 06:00 DT - 2012/07/13 06:00 YR - 2012 ED - 20121113 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22787433 <279. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22477725 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Torino F AU - Barnabei A AU - De Vecchis L AU - Salvatori R AU - Corsello SM FA - Torino, Francesco FA - Barnabei, Agnese FA - De Vecchis, Liana FA - Salvatori, Roberto FA - Corsello, Salvatore M IN - Torino, Francesco. Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. TI - Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. [Review] SO - Oncologist. 17(4):525-35, 2012 AS - Oncologist. 17(4):525-35, 2012 NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336822 SB - Index Medicus CP - United States MH - Adrenal Cortex Hormones/tu [Therapeutic Use] MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Autoimmune Diseases/ci [Chemically Induced] MH - Autoimmune Diseases/di [Diagnosis] MH - Autoimmune Diseases/dt [Drug Therapy] MH - Autoimmune Diseases/im [Immunology] MH - *CTLA-4 Antigen/im [Immunology] MH - Clinical Trials, Phase III as Topic MH - Humans MH - *Inflammation/ci [Chemically Induced] MH - *Inflammation/di [Diagnosis] MH - Inflammation/dt [Drug Therapy] MH - Inflammation/im [Immunology] MH - Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - *Pituitary Diseases/ci [Chemically Induced] MH - *Pituitary Diseases/di [Diagnosis] MH - Pituitary Diseases/im [Immunology] MH - Randomized Controlled Trials as Topic MH - *Rare Diseases/ci [Chemically Induced] MH - *Rare Diseases/di [Diagnosis] MH - Rare Diseases/dt [Drug Therapy] MH - Rare Diseases/im [Immunology] MH - Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] AB - Specific human monoclonal antibodies antagonize cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4 mAbs), a negative regulator of the immune system, inducing unrestrained T-cell activation. In patients with advanced or metastatic melanoma, one of these agents, ipilimumab, produced considerable disease control rates and, for the first time, a clear improvement in overall survival outcomes. However, accumulating clinical experience with anti-CTLA-4 mAbs identified a novel syndrome of autoimmune and autoinflammatory side effects, designated as "immune-related adverse events," including mainly rash, colitis, and hepatitis. Autoimmune hypophysitis has emerged as a distinctive side effect induced by anti-CTLA-4 mAbs. This condition may be life threatening because of adrenal insufficiency if not promptly recognized, but it may easily be diagnosed and treated if clinically suspected. Hypopituitarism caused by these agents is rarely reversible and prolonged or life-long substitutive hormonal treatment is often required. The precise mechanism of injury to the pituitary triggered by anti-CTLA-4 mAbs is yet to be fully elucidated. RN - 0 (Adrenal Cortex Hormones) RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) ES - 1549-490X IL - 1083-7159 DI - theoncologist.2011-0404 DO - https://dx.doi.org/10.1634/theoncologist.2011-0404 PT - Journal Article PT - Review ID - 22477725 [pubmed] ID - theoncologist.2011-0404 [pii] ID - 10.1634/theoncologist.2011-0404 [doi] ID - PMC3336822 [pmc] PP - ppublish LG - English EP - 20120403 DP - 2012 DC - 20120425 EZ - 2012/04/06 06:00 DA - 2012/10/24 06:00 DT - 2012/04/06 06:00 YR - 2012 ED - 20121023 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22477725 <280. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 23049279 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Andrews S AU - Holden R FA - Andrews, Stephanie FA - Holden, Rita IN - Andrews, Stephanie. H Lee Moffitt Cancer Center and Research Institute, Tampa, FL. TI - Characteristics and management of immunerelated adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma. SO - Cancer management and research. 4:299-307, 2012 AS - Cancer Manag Res. 4:299-307, 2012 NJ - Cancer management and research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101512700 IO - Cancer Manag Res PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459593 CP - New Zealand KW - case studies; immunotherapy; ipilimumab; melanoma AB - When diagnosed in its early stages, melanoma is highly treatable and associated with good long-term outcomes; however, the prognosis is much poorer for patients diagnosed with advanced or metastatic melanoma. For decades, available treatments were effective in only a few patients and associated with significant safety concerns. Ipilimumab is a novel immunotherapy which has proved to be an exciting breakthrough in the treatment of melanoma. It is the first drug approved for the treatment of melanoma by the Food and Drug Administration (FDA) which has shown a survival benefit in a randomized Phase III clinical trial. The objective of this review is to provide information on the administration, treatment responses, and expected outcomes of treatment of metastatic melanoma with the new immunotherapeutic agent, ipilimumab, a drug with a unique mechanism of action that differentiates it from current treatments. Guidelines for the management of immune-related adverse events associated with ipilimumab therapy are also presented. These stress vigilance, prompt intervention, and the use of corticosteroids as appropriate. Various ipilimumab-associated immune-related adverse events, both common (enterocolitis, dermatitis) and less frequent (hepatitis, hypophysitis), are illustrated in case studies. Nurses are uniquely positioned to provide patient and caregiver education on how this new therapy differs from traditional cytotoxic agents, to recognize the signs and symptoms of immune-related adverse events, and to report them immediately, and finally, to be aware of the patterns of response that are commonly observed in patients receiving ipilimumab therapy. ES - 1179-1322 IL - 1179-1322 DI - cmar-4-299 DO - https://dx.doi.org/10.2147/CMAR.S31873 PT - Journal Article ID - 23049279 [pubmed] ID - 10.2147/CMAR.S31873 [doi] ID - cmar-4-299 [pii] ID - PMC3459593 [pmc] PP - ppublish LG - English EP - 20120912 DP - 2012 DC - 20121010 EZ - 2012/10/11 06:00 DA - 2012/10/11 06:01 DT - 2012/10/11 06:00 YR - 2012 ED - 20121011 RD - 20130530 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=23049279 <281. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22698916 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Henry RA AU - Kendall PL AU - Thomas JW FA - Henry, Rachel A FA - Kendall, Peggy L FA - Thomas, James W IN - Henry, Rachel A. Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University, Nashville, Tennessee, USA. TI - Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes. SO - Diabetes. 61(8):2037-44, 2012 Aug AS - Diabetes. 61(8):2037-44, 2012 Aug NJ - Diabetes PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - e8x, 0372763 IO - Diabetes PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402296 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Animals MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigens, CD86/bi [Biosynthesis] MH - *Autoantigens/im [Immunology] MH - *B-Lymphocytes/im [Immunology] MH - *Diabetes Mellitus, Type 1/im [Immunology] MH - Humans MH - *Immune Tolerance/im [Immunology] MH - Insulin/im [Immunology] MH - Mice MH - Mice, Inbred NOD MH - Mice, Transgenic MH - *Receptors, Antigen, B-Cell/im [Immunology] AB - Eliminating autoantigen-specific B cells is an attractive alternative to global B-cell depletion for autoimmune disease treatment. To identify the potential for targeting a key autoimmune B-cell specificity in type 1 diabetes, insulin-binding B cells were tracked within a polyclonal repertoire using heavy chain B-cell receptor (BCR) transgenic (VH125Tg) mice. Insulin-specific B cells are rare in the periphery of nonautoimmune VH125Tg/C57BL/6 mice and WT/NOD autoimmune mice, whereas they clearly populate 1% of mature B-cell subsets in VH125Tg/NOD mice. Autoantigen upregulates CD86 in anti-insulin B cells, suggesting they are competent to interact with T cells. Endogenous insulin occupies anti-insulin BCR beginning with antigen commitment in bone marrow parenchyma, as identified by a second anti-insulin monoclonal antibody. Administration of this monoclonal antibody selectively eliminates insulin-reactive B cells in vivo and prevents disease in WT/NOD mice. Unexpectedly, developing B cells are less amenable to depletion, despite increased BCR sensitivity. These findings exemplify how a critical type 1 diabetes B-cell specificity escapes immune tolerance checkpoints. Disease liability is corrected by eliminating this B-cell specificity, providing proof of concept for a novel therapeutic approach for autoimmune disease. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD86) RN - 0 (Autoantigens) RN - 0 (Cd86 protein, mouse) RN - 0 (Insulin) RN - 0 (Receptors, Antigen, B-Cell) ES - 1939-327X IL - 0012-1797 DI - db11-1746 DO - https://dx.doi.org/10.2337/db11-1746 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 22698916 [pubmed] ID - db11-1746 [pii] ID - 10.2337/db11-1746 [doi] ID - PMC3402296 [pmc] PP - ppublish GI - No: R01 DK084246 Organization: (DK) *NIDDK NIH HHS* Country: United States No: 5T32-AR-059039 Organization: (AR) *NIAMS NIH HHS* Country: United States No: R01-DK-08246 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P30 CA68485 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 DK058404 Organization: (DK) *NIDDK NIH HHS* Country: United States No: R01 AI051448 Organization: (AI) *NIAID NIH HHS* Country: United States No: T32 AR059039 Organization: (AR) *NIAMS NIH HHS* Country: United States No: T32 HL069765 Organization: (HL) *NHLBI NIH HHS* Country: United States No: P30 CA068485 Organization: (CA) *NCI NIH HHS* Country: United States No: R01-AI-051448 Organization: (AI) *NIAID NIH HHS* Country: United States No: DK058404 Organization: (DK) *NIDDK NIH HHS* Country: United States No: 5T32-HL-069765 Organization: (HL) *NHLBI NIH HHS* Country: United States LG - English EP - 20120614 DP - 2012 Aug DC - 20120724 EZ - 2012/06/16 06:00 DA - 2012/10/09 06:00 DT - 2012/06/16 06:00 YR - 2012 ED - 20121008 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22698916 <282. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22614989 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Weber JS AU - Kahler KC AU - Hauschild A FA - Weber, Jeffrey S FA - Kahler, Katharina C FA - Hauschild, Axel IN - Weber, Jeffrey S. H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. jeffrey.weber@moffitt.org TI - Management of immune-related adverse events and kinetics of response with ipilimumab. [Review] SO - Journal of Clinical Oncology. 30(21):2691-7, 2012 Jul 20 AS - J Clin Oncol. 30(21):2691-7, 2012 Jul 20 NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/im [Immunology] MH - Antibodies, Monoclonal/pk [Pharmacokinetics] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/im [Immunology] MH - *CTLA-4 Antigen/de [Drug Effects] MH - *CTLA-4 Antigen/im [Immunology] MH - Chemical and Drug Induced Liver Injury/im [Immunology] MH - Colitis/im [Immunology] MH - Diarrhea/im [Immunology] MH - Drug Eruptions/im [Immunology] MH - Humans MH - Liver/de [Drug Effects] MH - Liver/im [Immunology] MH - Lymphatic Diseases/ci [Chemically Induced] MH - Lymphatic Diseases/im [Immunology] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/me [Metabolism] MH - Melanoma/sc [Secondary] MH - Mucous Membrane/de [Drug Effects] MH - Mucous Membrane/im [Immunology] MH - Pancreatitis/ci [Chemically Induced] MH - Pancreatitis/im [Immunology] MH - Peripheral Nervous System Diseases/ci [Chemically Induced] MH - Peripheral Nervous System Diseases/im [Immunology] MH - Pituitary Gland/de [Drug Effects] MH - Pituitary Gland/im [Immunology] MH - Scleritis/ci [Chemically Induced] MH - Scleritis/im [Immunology] MH - Skin/de [Drug Effects] MH - Skin/im [Immunology] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] MH - Skin Neoplasms/me [Metabolism] MH - Skin Neoplasms/pa [Pathology] MH - Stevens-Johnson Syndrome/im [Immunology] MH - Uveitis/ci [Chemically Induced] MH - Uveitis/im [Immunology] AB - Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)-ipilimumab and tremelimumab-have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) RN - QEN1X95CIX (tremelimumab) ES - 1527-7755 IL - 0732-183X DI - JCO.2012.41.6750 DO - https://dx.doi.org/10.1200/JCO.2012.41.6750 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 22614989 [pubmed] ID - JCO.2012.41.6750 [pii] ID - 10.1200/JCO.2012.41.6750 [doi] PP - ppublish LG - English EP - 20120521 DP - 2012 Jul 20 DC - 20120720 EZ - 2012/05/23 06:00 DA - 2012/09/25 06:00 DT - 2012/05/23 06:00 YR - 2012 ED - 20120924 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22614989 <283. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22495490 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Juszczak A AU - Gupta A AU - Karavitaki N AU - Middleton MR AU - Grossman AB FA - Juszczak, Agata FA - Gupta, Avinash FA - Karavitaki, Niki FA - Middleton, Mark R FA - Grossman, Ashley B IN - Juszczak, Agata. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK. TI - Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review. [Review] SO - European Journal of Endocrinology. 167(1):1-5, 2012 Jul AS - EUR. J. ENDOCRINOL.. 167(1):1-5, 2012 Jul NJ - European journal of endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bxu, 9423848 IO - Eur. J. Endocrinol. SB - Index Medicus CP - England MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Autoimmune Diseases/ci [Chemically Induced] MH - Autoimmune Diseases/im [Immunology] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Humans MH - *Hypopituitarism/ci [Chemically Induced] MH - Hypopituitarism/im [Immunology] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Middle Aged MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] MH - T-Lymphocytes, Cytotoxic/im [Immunology] AB - Ipilimumab (Yervoy; Medarex and Bristol-Myers Squibb) is a human MAB against cytotoxic T-lymphocyte antigen 4, which enhances co-stimulation of cytotoxic T-lymphocytes, resulting in their proliferation and an anti-tumour response. It is licensed for the treatment of unresectable or metastatic malignant melanoma, while multiple clinical trials using this medication in the treatment of other malignancies are ongoing. As a clinical response to ipilimumab results from immunostimulation, predictably it generates autoimmunity as well, causing immune-related adverse events in the majority of patients. Of those, endocrinopathies are frequently seen, and in particular, autoimmune lymphocytic hypophysitis with anterior panhypopituitarism has been reported a number of times in North America. We present a case of a male referred to our department with manifestations of anterior panhypopituitarism after his third dose of ipilimumab for metastatic malignant melanoma, and we discuss the management of his case in the light of previous reports. We also review the published literature on the presenting symptoms, time to presentation, investigations, imaging, treatment and follow-up of ipilimumab-induced autoimmune lymphocytic hypophysitis. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) ES - 1479-683X IL - 0804-4643 DI - EJE-12-0167 DO - https://dx.doi.org/10.1530/EJE-12-0167 PT - Case Reports PT - Journal Article PT - Review ID - 22495490 [pubmed] ID - EJE-12-0167 [pii] ID - 10.1530/EJE-12-0167 [doi] PP - ppublish LG - English EP - 20120410 DP - 2012 Jul DC - 20120625 EZ - 2012/04/13 06:00 DA - 2012/09/15 06:00 DT - 2012/04/13 06:00 YR - 2012 ED - 20120914 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22495490 <284. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22138079 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Min L AU - Vaidya A AU - Becker C FA - Min, Le FA - Vaidya, Anand FA - Becker, Carolyn IN - Min, Le. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. TI - Association of ipilimumab therapy for advanced melanoma with secondary adrenal insufficiency: a case series. SO - Endocrine Practice. 18(3):351-5, 2012 May-Jun AS - Endocr Pract. 18(3):351-5, 2012 May-Jun NJ - Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists PI - Journal available in: Print PI - Citation processed from: Internet JC - 9607439, dy1 IO - Endocr Pract PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997164 OI - Source: NLM. NIHMS498257 SB - Index Medicus CP - United States MH - *Adrenal Insufficiency/ci [Chemically Induced] MH - Adrenal Insufficiency/pp [Physiopathology] MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - Drug Monitoring MH - Female MH - Humans MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - Severity of Illness Index AB - OBJECTIVE: To present a case series of ipilimumab-related secondary adrenal insufficiency. AB - METHODS: In this cases series, we review the presentation, evaluation, diagnosis, and management of patients with advanced melanoma who received ipilimumab and were referred to our endocrinology clinic for evaluation of hormonal abnormalities. AB - RESULTS: Seven patients presented with symptoms, signs, or biochemical evidence of adrenal insufficiency 6 to 12 weeks after starting ipilimumab therapy. Ipilimumab is a cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibody that is approved for the treatment of metastatic melanoma and has widespread use for this disease. All 7 patients had biochemical evidence of profound secondary adrenal insufficiency. Thyroid function abnormalities, central hypogonadism, and low insulinlike growth factor 1 levels were seen in a subset of patients. Only 2 patients had abnormal findings on pituitary magnetic resonance imaging. Posterior pituitary function remained normal. AB - CONCLUSIONS: Our findings suggest that the enhanced immune response associated with ipilimumab therapy may have a predilection for corticotroph and possibly thyrotroph cells. We recommend periodic hypothalamic-pituitary-adrenal axis monitoring for patients on this therapy. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) ES - 1934-2403 IL - 1530-891X DI - 48L3427473P81522 DO - https://dx.doi.org/10.4158/EP11273.OR PT - Case Reports PT - Journal Article ID - 22138079 [pubmed] ID - 48L3427473P81522 [pii] ID - 10.4158/EP11273.OR [doi] ID - PMC3997164 [pmc] ID - NIHMS498257 [mid] PP - ppublish GI - No: F32 HL104776 Organization: (HL) *NHLBI NIH HHS* Country: United States No: F32 HL104776-02 Organization: (HL) *NHLBI NIH HHS* Country: United States No: K08 HD070957 Organization: (HD) *NICHD NIH HHS* Country: United States No: T32 DK007529 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English DP - 2012 May-Jun DC - 20120517 EZ - 2011/12/06 06:00 DA - 2012/09/15 06:00 DT - 2011/12/06 06:00 YR - 2012 ED - 20120914 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22138079 <285. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22735122 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Thomsen HH FA - Thomsen, Henrik Holm IN - Thomsen, Henrik Holm. Medicinsk Endokrinologisk Afdeling, Aarhus Universitetshospital, Norrebrogade 44, 8000 Aarhus C, Denmark. hehoth@gmail.com TI - [Lymphocytic hypophysitis due to ipilimumap therapy]. [Danish] OT - Lymfocytaer hypofysitis pa baggrund af behandling med ipilimumab. SO - Ugeskrift for Laeger. 174(26):1829-30, 2012 Jun 25 AS - Ugeskr Laeger. 174(26):1829-30, 2012 Jun 25 NJ - Ugeskrift for laeger PI - Journal available in: Print PI - Citation processed from: Internet JC - 0141730, wm8 IO - Ugeskr. Laeg. SB - Index Medicus CP - Denmark MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/pk [Pharmacokinetics] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/pk [Pharmacokinetics] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Fatal Outcome MH - Humans MH - Immune System Diseases/ci [Chemically Induced] MH - Immunologic Factors/ae [Adverse Effects] MH - Immunologic Factors/pk [Pharmacokinetics] MH - Immunologic Factors/tu [Therapeutic Use] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - *Neoplasm Metastasis/dt [Drug Therapy] MH - Neoplasm Recurrence, Local/dt [Drug Therapy] MH - *Pituitary Diseases/ci [Chemically Induced] AB - Ipilimumab is a newer drug that has shown considerable improvement of survival rates in malignant melanoma. It works by stimulating the immune system. Frequently harmless side effects can be seen, but serious reactions also occur. We report a case of hypophysitis and a case with severe diarrhoea on tapering off from glucocorticoid therapy for hypophysitis. Attentiveness of these adverse reactions is important, since they can be rapidly fatal if they are left untreated. The relevant specialties are required to ensure diagnosis, treatment and follow-up at an early stage. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Immunologic Factors) RN - 6T8C155666 (ipilimumab) ES - 1603-6824 IL - 0041-5782 DI - VP10110481 PT - Case Reports PT - Journal Article ID - 22735122 [pubmed] ID - VP10110481 [pii] PP - ppublish LG - Danish DP - 2012 Jun 25 DC - 20120627 EZ - 2012/06/28 06:00 DA - 2012/09/08 06:00 DT - 2012/06/28 06:00 YR - 2012 ED - 20120907 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22735122 <286. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22134241 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Vance S AU - Liu E AU - Zhao L AU - Parsels JD AU - Parsels LA AU - Brown JL AU - Maybaum J AU - Lawrence TS AU - Morgan MA FA - Vance, Sean FA - Liu, Erqi FA - Zhao, Lili FA - Parsels, Joshua D FA - Parsels, Leslie A FA - Brown, Jeffery L FA - Maybaum, Jonathan FA - Lawrence, Theodore S FA - Morgan, Meredith A IN - Vance, Sean. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA. TI - Selective radiosensitization of p53 mutant pancreatic cancer cells by combined inhibition of Chk1 and PARP1. SO - Cell Cycle. 10(24):4321-9, 2011 Dec 15 AS - Cell Cycle. 10(24):4321-9, 2011 Dec 15 NJ - Cell cycle (Georgetown, Tex.) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101137841 IO - Cell Cycle PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272262 SB - Index Medicus CP - United States MH - Analysis of Variance MH - Cell Cycle Checkpoints/de [Drug Effects] MH - Checkpoint Kinase 1 MH - DNA Repair/de [Drug Effects] MH - *DNA Repair/ph [Physiology] MH - Drug Combinations MH - Flow Cytometry MH - Histones/me [Metabolism] MH - Humans MH - Immunoblotting MH - Intestinal Mucosa/cy [Cytology] MH - Intestinal Mucosa/me [Metabolism] MH - Mutation/ge [Genetics] MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/rt [Radiotherapy] MH - Phthalazines/pd [Pharmacology] MH - Piperazines/pd [Pharmacology] MH - Poly (ADP-Ribose) Polymerase-1 MH - *Poly(ADP-ribose) Polymerase Inhibitors MH - *Protein Kinases/me [Metabolism] MH - *Radiation Tolerance/de [Drug Effects] MH - *Radiation-Sensitizing Agents/pd [Pharmacology] MH - Thiophenes/pd [Pharmacology] MH - *Tumor Suppressor Protein p53/ge [Genetics] MH - Urea/aa [Analogs & Derivatives] MH - Urea/pd [Pharmacology] AB - We have recently shown that inhibition of HRR (homologous recombination repair) by Chk1 (checkpoint kinase 1) inhibition radiosensitizes pancreatic cancer cells and others have demonstrated that Chk1 inhibition selectively sensitizes p53 mutant tumor cells. Furthermore, PARP1 [poly (ADP-ribose) polymerase-1] inhibitors dramatically radiosensitize cells with DNA double strand break repair defects. Thus, we hypothesized that inhibition of HRR (mediated by Chk1 via AZD7762) and PARP1 [via olaparib (AZD2281)] would selectively sensitize p53 mutant pancreatic cancer cells to radiation. We also used 2 isogenic p53 cell models to assess the role of p53 status in cancer cells and intestinal epithelial cells to assess overall cancer specificity. DNA damage response and repair were assessed by flow cytometry, gammaH2AX, and an HRR reporter assay. We found that the combination of AZD7762 and olaparib produced significant radiosensitization in p53 mutant pancreatic cancer cells and in all of the isogenic cancer cell lines. The magnitude of radiosensitization by AZD7762 and olaparib was greater in p53 mutant cells compared with p53 wild type cells. Importantly, normal intestinal epithelial cells were not radiosensitized. The combination of AZD7762 and olaparib caused G 2 checkpoint abrogation, inhibition of HRR, and persistent DNA damage responses. These findings demonstrate that the combination of Chk1 and PARP1 inhibition selectively radiosensitizes p53 mutant pancreatic cancer cells. Furthermore, these studies suggest that inhibition of HRR by Chk1 inhibitors may be a useful strategy for selectively inducing a BRCA1/2 'deficient-like' phenotype in p53 mutant tumor cells, while sparing normal tissue. RN - 0 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide) RN - 0 (Drug Combinations) RN - 0 (H2AFX protein, human) RN - 0 (Histones) RN - 0 (Phthalazines) RN - 0 (Piperazines) RN - 0 (Poly(ADP-ribose) Polymerase Inhibitors) RN - 0 (Radiation-Sensitizing Agents) RN - 0 (Thiophenes) RN - 0 (Tumor Suppressor Protein p53) RN - 8W8T17847W (Urea) RN - EC 2-4-2-30 (PARP1 protein, human) RN - EC 2-4-2-30 (Poly (ADP-Ribose) Polymerase-1) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - WOH1JD9AR8 (olaparib) ES - 1551-4005 IL - 1551-4005 DI - 18661 DO - https://dx.doi.org/10.4161/cc.10.24.18661 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 22134241 [pubmed] ID - 18661 [pii] ID - 10.4161/cc.10.24.18661 [doi] ID - PMC3272262 [pmc] PP - ppublish GI - No: R01CA78554 10S1 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA046592 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA78554 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA130810 Organization: (CA) *NCI NIH HHS* Country: United States No: P50CA130810 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA078554 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20111215 DP - 2011 Dec 15 DC - 20120117 EZ - 2011/12/03 06:00 DA - 2012/08/30 06:00 DT - 2011/12/03 06:00 YR - 2011 ED - 20120829 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22134241 <287. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22271879 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Prieto PA AU - Yang JC AU - Sherry RM AU - Hughes MS AU - Kammula US AU - White DE AU - Levy CL AU - Rosenberg SA AU - Phan GQ FA - Prieto, Peter A FA - Yang, James C FA - Sherry, Richard M FA - Hughes, Marybeth S FA - Kammula, Udai S FA - White, Donald E FA - Levy, Catherine L FA - Rosenberg, Steven A FA - Phan, Giao Q IN - Prieto, Peter A. Surgery Branch, National Cancer Institute, NIH, Bldg 10-CRC, Room 3-5760, 10 Center Drive, Bethesda, MD 20892, USA. TI - CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. CM - Comment in: Clin Cancer Res. 2012 Apr 1;18(7):1821-3; PMID: 22338019 SO - Clinical Cancer Research. 18(7):2039-47, 2012 Apr 01 AS - Clin Cancer Res. 18(7):2039-47, 2012 Apr 01 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319861 OI - Source: NLM. NIHMS352309 SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - *CTLA-4 Antigen/ai [Antagonists & Inhibitors] MH - CTLA-4 Antigen/im [Immunology] MH - Cancer Vaccines/ad [Administration & Dosage] MH - Cancer Vaccines/ae [Adverse Effects] MH - Clinical Trials as Topic MH - Dermatitis/et [Etiology] MH - Female MH - Follow-Up Studies MH - Humans MH - Interleukin-2/ad [Administration & Dosage] MH - Interleukin-2/ae [Adverse Effects] MH - Male MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Neoplasm Metastasis MH - Pituitary Diseases/ci [Chemically Induced] MH - Survival Analysis MH - Treatment Outcome MH - Young Adult AB - PURPOSE: Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses. AB - EXPERIMENTAL DESIGN: Patients with metastatic melanoma were treated in three trials from 2002 to 2005. In protocol 1, 56 patients received ipilimumab with gp100 peptides. In protocol 2, 36 patients received ipilimumab with interleukin-2. In protocol 3, 85 patients received ipilimumab with intrapatient dose-escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data. AB - RESULTS: With median follow-up for protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with 5-year survival rates being 13%, 25%, and 23%, respectively. Patients in protocol 2 had a 17% complete response (CR) rate, compared with 7% in protocol 1 and 6% in protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became complete responders had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months. AB - CONCLUSIONS: This report provides the longest follow-up of patients with melanoma treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma. The combination of ipilimumab and interleukin-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial. AB - Copyright ©2012 AACR. RN - 0 (Antibodies, Monoclonal) RN - 0 (CTLA-4 Antigen) RN - 0 (Cancer Vaccines) RN - 0 (Interleukin-2) RN - 0 (gp100(209-2M) vaccine) RN - 6T8C155666 (ipilimumab) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-11-1823 DO - https://dx.doi.org/10.1158/1078-0432.CCR-11-1823 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 22271879 [pubmed] ID - 1078-0432.CCR-11-1823 [pii] ID - 10.1158/1078-0432.CCR-11-1823 [doi] ID - PMC3319861 [pmc] ID - NIHMS352309 [mid] PP - ppublish GI - No: Z99 CA999999 Organization: *Intramural NIH HHS* Country: United States LG - English EP - 20120123 DP - 2012 Apr 01 DC - 20120404 EZ - 2012/01/25 06:00 DA - 2012/08/24 06:00 DT - 2012/01/25 06:00 YR - 2012 ED - 20120823 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22271879 <288. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21264545 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Barnard ZR AU - Walcott BP AU - Kahle KT AU - Nahed BV AU - Coumans JV FA - Barnard, Zachary R FA - Walcott, Brian P FA - Kahle, Kristopher T FA - Nahed, Brian V FA - Coumans, Jean Valery IN - Barnard, Zachary R. Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, White Building Room 502, Boston, MA 02114, USA. TI - Hyponatremia associated with Ipilimumab-induced hypophysitis. SO - Medical Oncology. 29(1):374-7, 2012 Mar AS - Med Oncol. 29(1):374-7, 2012 Mar NJ - Medical oncology (Northwood, London, England) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - b3a, 9435512 IO - Med. Oncol. SB - Index Medicus CP - United States MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Female MH - Humans MH - *Hyponatremia/et [Etiology] MH - Hyponatremia/pp [Physiopathology] MH - Inappropriate ADH Syndrome/et [Etiology] MH - Inappropriate ADH Syndrome/pp [Physiopathology] MH - Melanoma/dt [Drug Therapy] MH - *Pituitary Diseases/ci [Chemically Induced] MH - *Pituitary Diseases/co [Complications] MH - Pituitary Diseases/pp [Physiopathology] AB - A 75-year-old woman with a history of stage IV metastatic melanoma underwent treatment with the CTLA-4 blocking agent Ipilimumab. She presented 2 months after initiating treatment with a severe headache. Laboratories were consistent with severe hyponatremia. MRI of the brain revealed enlargement of the pituitary gland, enhancement of the infundibulum, and an enhancing, centrally necrotic foci in the anterior pituitary. Based on the clinical and radiographic findings, she was diagnosed with treatment-related syndrome of inappropriate antidiuretic hormone secretion (SIADH). Effective treatment consisted of fluid restriction, hyperosmolar therapy, and steroids. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 1559-131X IL - 1357-0560 DO - https://dx.doi.org/10.1007/s12032-010-9794-7 PT - Case Reports PT - Journal Article ID - 21264545 [pubmed] ID - 10.1007/s12032-010-9794-7 [doi] PP - ppublish PH - 2010/10/02 [received] PH - 2010/12/20 [accepted] LG - English EP - 20110125 DP - 2012 Mar DC - 20120209 EZ - 2011/01/26 06:00 DA - 2012/08/24 06:00 DT - 2011/01/26 06:00 YR - 2012 ED - 20120823 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21264545 <289. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22423263 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Tomasini P AU - Khobta N AU - Greillier L AU - Barlesi F FA - Tomasini, Pascale FA - Khobta, Nataliya FA - Greillier, Laurent FA - Barlesi, Fabrice IN - Tomasini, Pascale. Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University - Assistance Publique Hopitaux de Marseille; Aix Marseille University - Inserm U911, Marseille, France. TI - Ipilimumab: its potential in non-small cell lung cancer. SO - Therapeutic Advances in Medical Oncology. 4(2):43-50, 2012 Mar AS - Ther Adv Med Oncol. 4(2):43-50, 2012 Mar NJ - Therapeutic advances in medical oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - 101510808 IO - Ther Adv Med Oncol PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296082 CP - England KW - biomarkers; immunotherapy; ipilimumab; lung cancer; targeted therapy AB - Ipilimumab is a fully human monoclonal antibody that enhances antitumor immunity by way of cytotoxic T-lymphocyte antigen 4 blockade. It has already been approved by the US Food and Drug Administration for the treatment of metastatic melanoma and is being investigated for treating other solid tumors such as renal cell, prostate and lung cancers. This review details the potential of ipilimumab in the management of non-small cell lung cancer (NSCLC). In particular, ipilimumab showed promising results in a first-line NSCLC phase II study combining carboplatin/paclitaxel chemotherapy with concurrent or phased ipilimumab. The median immune-related progression-free survival was 5.68 months for the phased ipilimumab arm versus 4.63 months for chemotherapy alone (hazard ratio [HR] = 0.68, p = 0.026) and 5.52 months for the concurrent ipilimumab arm versus 4.63 months for chemotherapy alone (HR = 0.77, p = 0.094). The main adverse events were immune related, such as hypophysitis, enterocolitis, and hyperthyroidism. These adverse events may be improved with high-dose glucocorticoids and may be correlated with tumor response. Phase III studies are ongoing. Future studies may investigate ipilimumab in the management of early stage lung cancer. Strategies for potential translational research studies are also discussed to identify prognostic and predictive biomarkers for the use of ipilimumab in the treatment of patients with NSCLC. ES - 1758-8359 IL - 1758-8340 DI - 10.1177_1758834011431718 DO - https://dx.doi.org/10.1177/1758834011431718 PT - Journal Article ID - 22423263 [pubmed] ID - 10.1177/1758834011431718 [doi] ID - 10.1177_1758834011431718 [pii] ID - PMC3296082 [pmc] PP - ppublish LG - English DP - 2012 Mar DC - 20120316 EZ - 2012/03/17 06:00 DA - 2012/03/17 06:01 DT - 2012/03/17 06:00 YR - 2012 ED - 20120823 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=22423263 <290. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22822590 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Anonymous TI - Ipilimumab. Immunostimulant; more assessment needed. CM - Comment in: Prescrire Int. 2012 Jun;21(128):144; PMID: 22822589 SO - Prescrire International. 21(128):145-7, 2012 Jun AS - Prescrire Int. 21(128):145-7, 2012 Jun NJ - Prescrire international PI - Journal available in: Print PI - Citation processed from: Print JC - c9k, 9439295 IO - Prescrire Int SB - Health Technology Assessment Journals CP - France MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - CTLA-4 Antigen/ph [Physiology] MH - Clinical Trials as Topic MH - Humans MH - *Lymphocyte Activation/de [Drug Effects] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/mo [Mortality] MH - gp100 Melanoma Antigen/an [Analysis] AB - In patients with inoperable or metastatic melanoma, first-line cytotoxic drugs have no proven impact on survival, which is generally limited to only a few months. There is no standard second-line treatment. Ipilimumab, a monoclonal antibody, stimulates T lymphocyte proliferation and activation. It has been authorised in the European Union for melanoma patients in whom one or more lines of chemotherapy have failed. Clinical evaluation is based on a double-blind randomised trial in 676 patients comparing ipilimumab + gp 100, ipilimumab + placebo, and 100 gp + placebo. Gp 100 is an experimental mixture of proteins being tested in melanoma. The median overall survival time was significantly longer among patients treated with ipilimumab, with or without gp 100 (about 10 months), than among those receiving gp 100 + placebo (about 6 months). In another trial, involving previously untreated melanoma patients, adding ipilimumab (at a dose 3 times higher than in the previous trial) to dacarbazine prolonged median overall survival by 2 months. The main adverse effects of ipilimumab are immune-related adverse reactions, and include gastrointestinal, cutaneous and endocrine disorders (enterocolitis with or without perforation, dermatitis, hypopituitarism and hepatitis). In practice, in patients with metastatic melanoma in whom one or more treatments have failed, the use of ipilimumab should be restricted to well-designed clinical trials designed to better assess the survival benefit, serious adverse effects, and the optimal dosage. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (gp100 Melanoma Antigen) RN - 6T8C155666 (ipilimumab) IS - 1167-7422 IL - 1167-7422 PT - Journal Article ID - 22822590 [pubmed] PP - ppublish LG - English DP - 2012 Jun DC - 20120724 EZ - 2012/07/25 06:00 DA - 2012/08/08 06:00 DT - 2012/07/25 06:00 YR - 2012 ED - 20120807 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22822590 <291. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22406592 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Strimpakos AS AU - Syrigos KN AU - Saif MW FA - Strimpakos, Alexios S FA - Syrigos, Kostas N FA - Saif, Muhammad Wasif IN - Strimpakos, Alexios S. Oncology Unit, Third Department of Medicine, University of Athens, Sotiria General Hospital, Athens, Greece. TI - Novel agents in early phase clinical studies on refractory pancreatic cancer. [Review] SO - Jop: Journal of the Pancreas [Electronic Resource]. 13(2):166-8, 2012 Mar 10 AS - JOP. 13(2):166-8, 2012 Mar 10 NJ - JOP : Journal of the pancreas PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101091810 IO - JOP SB - Index Medicus CP - Italy MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antimetabolites, Antineoplastic/tu [Therapeutic Use] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/tu [Therapeutic Use] MH - Erlotinib Hydrochloride MH - Humans MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/mo [Mortality] MH - Protein Kinase Inhibitors/tu [Therapeutic Use] MH - *Quinazolines/tu [Therapeutic Use] MH - Radiation-Sensitizing Agents/tu [Therapeutic Use] AB - The standard current treatment options in advanced pancreatic cancer have demonstrated minimal or modest only efficacy for the majority of patients. Unfortunately, the mortality and morbidity remain high crying out for better treatments and results. With the exception of erlotinib, which received approval by the Food and Drug Administration of the United States in 2005, no other novel agents have since been added in our treatment quiver. Therefore, the search for novel approaches continuous at the laboratory and clinical level. At the 2012 American Society of Clinical Oncology Gastrointestinal Symposium, results of some interesting early phases clinical studies were presented. First, in Abstract #198, toxicity and efficacy results from the phase I/II study of cixutumumab, an insulin growth factor-1 receptor (IGF-1R) antibody combined with the standard gemcitabine and erlotinib treatment were presented, but the outcomes suggest no real clinical benefit. Second, the early safety and clinical data from the novel monoclonal antibody (ensituximab) against the mucin epitope NPC-1C in pancreatic and colon cancer patients were presented (Abstract #233) and again no particular efficacy was observed. Finally, interesting results which definitely deserve further exploration were presented in Abstract #211, which tested the combination of ipilimumab, an antibody against the cytotoxic T-lymphocyte antigen 4 (CTLA-4), with a cell-based vaccine transfected with the granulocyte macrophage colony-stimulating factor (GM-CSF) gene in advanced refractory pancreatic cancer. Though, it seems we have not yet found the culprit and the solution of this devastating disease, a small step forward might have been achieved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Quinazolines) RN - 0 (Radiation-Sensitizing Agents) RN - 0 (anti-IGF-1R antibody A12) RN - 0W860991D6 (Deoxycytidine) RN - 6T8C155666 (ipilimumab) RN - B76N6SBZ8R (gemcitabine) RN - DA87705X9K (Erlotinib Hydrochloride) ES - 1590-8577 IL - 1590-8577 PT - Journal Article PT - Review ID - 22406592 [pubmed] PP - epublish LG - English EP - 20120310 DP - 2012 Mar 10 DC - 20120312 EZ - 2012/03/13 06:00 DA - 2012/07/14 06:00 DT - 2012/03/13 06:00 YR - 2012 ED - 20120713 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22406592 <292. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22658128 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Brahmer JR AU - Tykodi SS AU - Chow LQ AU - Hwu WJ AU - Topalian SL AU - Hwu P AU - Drake CG AU - Camacho LH AU - Kauh J AU - Odunsi K AU - Pitot HC AU - Hamid O AU - Bhatia S AU - Martins R AU - Eaton K AU - Chen S AU - Salay TM AU - Alaparthy S AU - Grosso JF AU - Korman AJ AU - Parker SM AU - Agrawal S AU - Goldberg SM AU - Pardoll DM AU - Gupta A AU - Wigginton JM FA - Brahmer, Julie R FA - Tykodi, Scott S FA - Chow, Laura Q M FA - Hwu, Wen-Jen FA - Topalian, Suzanne L FA - Hwu, Patrick FA - Drake, Charles G FA - Camacho, Luis H FA - Kauh, John FA - Odunsi, Kunle FA - Pitot, Henry C FA - Hamid, Omid FA - Bhatia, Shailender FA - Martins, Renato FA - Eaton, Keith FA - Chen, Shuming FA - Salay, Theresa M FA - Alaparthy, Suresh FA - Grosso, Joseph F FA - Korman, Alan J FA - Parker, Susan M FA - Agrawal, Shruti FA - Goldberg, Stacie M FA - Pardoll, Drew M FA - Gupta, Ashok FA - Wigginton, Jon M IN - Brahmer, Julie R. Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA. TI - Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. CM - Comment in: Nat Rev Clin Oncol. 2012 Aug;9(8):427; PMID: 22710340 CM - Comment in: N Engl J Med. 2012 Jun 28;366(26):2517-9; PMID: 22658126 CM - Comment in: Cancer Cell. 2012 Jul 10;22(1):7-8; PMID: 22789534 CM - Comment in: J Urol. 2012 Dec;188(6):2148-9; PMID: 23141220 SO - New England Journal of Medicine. 366(26):2455-65, 2012 Jun 28 AS - N Engl J Med. 366(26):2455-65, 2012 Jun 28 NJ - The New England journal of medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0255562, now IO - N. Engl. J. Med. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563263 OI - Source: NLM. NIHMS396200 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ad [Administration & Dosage] MH - Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Breast Neoplasms/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Renal Cell/dt [Drug Therapy] MH - Colorectal Neoplasms/dt [Drug Therapy] MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Male MH - Melanoma/dt [Drug Therapy] MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - Stomach Neoplasms/dt [Drug Therapy] AB - BACKGROUND: Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. AB - METHODS: In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. AB - RESULTS: As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. AB - CONCLUSIONS: Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.). RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) ES - 1533-4406 IL - 0028-4793 DO - https://dx.doi.org/10.1056/NEJMoa1200694 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 22658128 [pubmed] ID - 10.1056/NEJMoa1200694 [doi] ID - PMC3563263 [pmc] ID - NIHMS396200 [mid] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00729664 SL - https://clinicaltrials.gov/search/term=NCT00729664 GI - No: P30 CA015704 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA006973 Organization: (CA) *NCI NIH HHS* Country: United States No: 5R01 CA142779 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 TR000454 Organization: (TR) *NCATS NIH HHS* Country: United States No: UL1 RR024148 Organization: (RR) *NCRR NIH HHS* Country: United States No: R01 CA142779 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20120602 DP - 2012 Jun 28 DC - 20120628 EZ - 2012/06/05 06:00 DA - 2012/07/12 06:00 DT - 2012/06/05 06:00 YR - 2012 ED - 20120711 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=22658128 <293. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22658128 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Brahmer JR AU - Tykodi SS AU - Chow LQ AU - Hwu WJ AU - Topalian SL AU - Hwu P AU - Drake CG AU - Camacho LH AU - Kauh J AU - Odunsi K AU - Pitot HC AU - Hamid O AU - Bhatia S AU - Martins R AU - Eaton K AU - Chen S AU - Salay TM AU - Alaparthy S AU - Grosso JF AU - Korman AJ AU - Parker SM AU - Agrawal S AU - Goldberg SM AU - Pardoll DM AU - Gupta A AU - Wigginton JM FA - Brahmer, Julie R FA - Tykodi, Scott S FA - Chow, Laura Q M FA - Hwu, Wen-Jen FA - Topalian, Suzanne L FA - Hwu, Patrick FA - Drake, Charles G FA - Camacho, Luis H FA - Kauh, John FA - Odunsi, Kunle FA - Pitot, Henry C FA - Hamid, Omid FA - Bhatia, Shailender FA - Martins, Renato FA - Eaton, Keith FA - Chen, Shuming FA - Salay, Theresa M FA - Alaparthy, Suresh FA - Grosso, Joseph F FA - Korman, Alan J FA - Parker, Susan M FA - Agrawal, Shruti FA - Goldberg, Stacie M FA - Pardoll, Drew M FA - Gupta, Ashok FA - Wigginton, Jon M IN - Brahmer, Julie R. Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA. TI - Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. CM - Comment in: Nat Rev Clin Oncol. 2012 Aug;9(8):427; PMID: 22710340 CM - Comment in: N Engl J Med. 2012 Jun 28;366(26):2517-9; PMID: 22658126 CM - Comment in: Cancer Cell. 2012 Jul 10;22(1):7-8; PMID: 22789534 CM - Comment in: J Urol. 2012 Dec;188(6):2148-9; PMID: 23141220 SO - New England Journal of Medicine. 366(26):2455-65, 2012 Jun 28 AS - N Engl J Med. 366(26):2455-65, 2012 Jun 28 NJ - The New England journal of medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0255562, now IO - N. Engl. J. Med. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563263 OI - Source: NLM. NIHMS396200 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/ad [Administration & Dosage] MH - Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Breast Neoplasms/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Renal Cell/dt [Drug Therapy] MH - Colorectal Neoplasms/dt [Drug Therapy] MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Male MH - Melanoma/dt [Drug Therapy] MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - *Programmed Cell Death 1 Receptor/ai [Antagonists & Inhibitors] MH - Programmed Cell Death 1 Receptor/im [Immunology] MH - Programmed Cell Death 1 Receptor/me [Metabolism] MH - Stomach Neoplasms/dt [Drug Therapy] AB - BACKGROUND: Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. AB - METHODS: In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. AB - RESULTS: As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. AB - CONCLUSIONS: Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.). RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 31YO63LBSN (nivolumab) ES - 1533-4406 IL - 0028-4793 DO - https://dx.doi.org/10.1056/NEJMoa1200694 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 22658128 [pubmed] ID - 10.1056/NEJMoa1200694 [doi] ID - PMC3563263 [pmc] ID - NIHMS396200 [mid] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00729664 SA - ClinicalTrials.gov/NCT00729664 SL - https://clinicaltrials.gov/search/term=NCT00729664 SL - https://clinicaltrials.gov/search/term=NCT00729664 GI - No: P30 CA015704 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA006973 Organization: (CA) *NCI NIH HHS* Country: United States No: 5R01 CA142779 Organization: (CA) *NCI NIH HHS* Country: United States No: UL1 TR000454 Organization: (TR) *NCATS NIH HHS* Country: United States No: UL1 RR024148 Organization: (RR) *NCRR NIH HHS* Country: United States No: R01 CA142779 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20120602 DP - 2012 Jun 28 DC - 20120628 EZ - 2012/06/05 06:00 DA - 2012/07/12 06:00 DT - 2012/06/05 06:00 YR - 2012 ED - 20120711 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22658128 <294. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22326924 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Madan RA AU - Mohebtash M AU - Arlen PM AU - Vergati M AU - Rauckhorst M AU - Steinberg SM AU - Tsang KY AU - Poole DJ AU - Parnes HL AU - Wright JJ AU - Dahut WL AU - Schlom J AU - Gulley JL FA - Madan, Ravi A FA - Mohebtash, Mahsa FA - Arlen, Philip M FA - Vergati, Matteo FA - Rauckhorst, Myrna FA - Steinberg, Seth M FA - Tsang, Kwong Y FA - Poole, Diane J FA - Parnes, Howard L FA - Wright, John J FA - Dahut, William L FA - Schlom, Jeffrey FA - Gulley, James L IN - Madan, Ravi A. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. TI - Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. CM - Comment in: Lancet Oncol. 2012 May;13(5):440-2; PMID: 22326921 SO - Lancet Oncology. 13(5):501-8, 2012 May AS - Lancet Oncol. 13(5):501-8, 2012 May NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigens, CD/im [Immunology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Cancer Vaccines/im [Immunology] MH - *Cancer Vaccines/tu [Therapeutic Use] MH - Dose-Response Relationship, Drug MH - Humans MH - Immunotherapy, Active MH - Male MH - Middle Aged MH - Orchiectomy MH - Poxviridae/im [Immunology] MH - *Poxviridae MH - *Prostate-Specific Antigen/im [Immunology] MH - Prostatic Neoplasms/im [Immunology] MH - Prostatic Neoplasms/sc [Secondary] MH - *Prostatic Neoplasms/th [Therapy] MH - Viral Vaccines/im [Immunology] MH - *Viral Vaccines/tu [Therapeutic Use] AB - BACKGROUND: Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. AB - METHODS: We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2x10(8) plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1x10(9) plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984. AB - FINDINGS: We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%. AB - INTERPRETATION: The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC. AB - FUNDING: US National Institutes of Health. AB - Copyright © 2012 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antineoplastic Agents) RN - 0 (Cancer Vaccines) RN - 0 (Viral Vaccines) RN - 6T8C155666 (ipilimumab) RN - EC 3-4-21-77 (Prostate-Specific Antigen) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(12)70006-2 DO - https://dx.doi.org/10.1016/S1470-2045(12)70006-2 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Intramural ID - 22326924 [pubmed] ID - S1470-2045(12)70006-2 [pii] ID - 10.1016/S1470-2045(12)70006-2 [doi] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00113984 SL - https://clinicaltrials.gov/search/term=NCT00113984 GI - Organization: *Intramural NIH HHS* Country: United States LG - English EP - 20120210 DP - 2012 May DC - 20120504 EZ - 2012/02/14 06:00 DA - 2012/06/27 06:00 DT - 2012/02/14 06:00 YR - 2012 ED - 20120626 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22326924 <295. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22326922 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - van den Eertwegh AJ AU - Versluis J AU - van den Berg HP AU - Santegoets SJ AU - van Moorselaar RJ AU - van der Sluis TM AU - Gall HE AU - Harding TC AU - Jooss K AU - Lowy I AU - Pinedo HM AU - Scheper RJ AU - Stam AG AU - von Blomberg BM AU - de Gruijl TD AU - Hege K AU - Sacks N AU - Gerritsen WR FA - van den Eertwegh, Alfons J M FA - Versluis, Jurjen FA - van den Berg, H Pieter FA - Santegoets, Saskia J A M FA - van Moorselaar, R Jeroen A FA - van der Sluis, Tim M FA - Gall, Helen E FA - Harding, Thomas C FA - Jooss, Karin FA - Lowy, Israel FA - Pinedo, Herbert M FA - Scheper, Rik J FA - Stam, Anita G M FA - von Blomberg, B Mary E FA - de Gruijl, Tanja D FA - Hege, Kristen FA - Sacks, Natalie FA - Gerritsen, Winald R IN - van den Eertwegh, Alfons J M. Department of Medical Oncology, VU University Medical Centre, Amsterdam, Netherlands. TI - Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. CM - Comment in: Immunotherapy. 2012 Jun;4(6):577-80; PMID: 22788125 CM - Comment in: Lancet Oncol. 2012 May;13(5):440-2; PMID: 22326921 SO - Lancet Oncology. 13(5):509-17, 2012 May AS - Lancet Oncol. 13(5):509-17, 2012 May NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. SB - Index Medicus CP - England MH - Adult MH - Aged MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Cancer Vaccines/tu [Therapeutic Use] MH - Combined Modality Therapy MH - Granulocyte-Macrophage Colony-Stimulating Factor/im [Immunology] MH - *Granulocyte-Macrophage Colony-Stimulating Factor/tu [Therapeutic Use] MH - Humans MH - Immunotherapy MH - Male MH - Middle Aged MH - Orchiectomy MH - Prostatic Neoplasms/im [Immunology] MH - Prostatic Neoplasms/sc [Secondary] MH - *Prostatic Neoplasms/th [Therapy] MH - Transplantation, Homologous MH - Tumor Cells, Cultured AB - BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). AB - METHODS: We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5x10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3x10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0.3, 1.0, 3.0, or 5.0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. AB - FINDINGS: We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3.0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5.0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3.0 mg/kg dose level, rather than enrol a further three patients at the 5.0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3.0 mg/kg or 5.0 mg/kg ipilimumab. AB - INTERPRETATION: GVAX combined with 3.0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. AB - FUNDING: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam. AB - Copyright © 2012 Elsevier Ltd. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (Cancer Vaccines) RN - 6T8C155666 (ipilimumab) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(12)70007-4 DO - https://dx.doi.org/10.1016/S1470-2045(12)70007-4 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 22326922 [pubmed] ID - S1470-2045(12)70007-4 [pii] ID - 10.1016/S1470-2045(12)70007-4 [doi] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT01510288 SL - https://clinicaltrials.gov/search/term=NCT01510288 LG - English EP - 20120210 DP - 2012 May DC - 20120504 EZ - 2012/02/14 06:00 DA - 2012/06/27 06:00 DT - 2012/02/14 06:00 YR - 2012 ED - 20120626 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22326922 <296. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22272332 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wei N AU - Liu SS AU - Chan KK AU - Ngan HY FA - Wei, Na FA - Liu, Stephanie S FA - Chan, Karen K L FA - Ngan, Hextan Y S IN - Wei, Na. Department of Obstetrics & Gynaecology, Queen Mary Hospital, the University of Hong Kong, Hong Kong, Hong Kong. TI - Tumour suppressive function and modulation of programmed cell death 4 (PDCD4) in ovarian cancer. SO - PLoS ONE [Electronic Resource]. 7(1):e30311, 2012 AS - PLoS ONE. 7(1):e30311, 2012 NJ - PloS one PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101285081 IO - PLoS ONE PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260274 SB - Index Medicus CP - United States MH - Apoptosis Regulatory Proteins/ge [Genetics] MH - Apoptosis Regulatory Proteins/me [Metabolism] MH - *Apoptosis Regulatory Proteins/ph [Physiology] MH - Blotting, Western MH - *Cell Cycle/ph [Physiology] MH - Cell Line, Tumor MH - Cell Movement/ph [Physiology] MH - *Cell Proliferation MH - Culture Media, Serum-Free/pd [Pharmacology] MH - Cyclin-Dependent Kinase Inhibitor p21/me [Metabolism] MH - Cyclin-Dependent Kinase Inhibitor p27/me [Metabolism] MH - Down-Regulation/de [Drug Effects] MH - Extracellular Signal-Regulated MAP Kinases/me [Metabolism] MH - Female MH - Humans MH - Neoplasm Invasiveness MH - Ovarian Neoplasms/ge [Genetics] MH - Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - PTEN Phosphohydrolase/me [Metabolism] MH - Phosphatidylinositol 3-Kinases/me [Metabolism] MH - Protein Transport/de [Drug Effects] MH - Proto-Oncogene Proteins c-akt/me [Metabolism] MH - RNA-Binding Proteins/ge [Genetics] MH - RNA-Binding Proteins/me [Metabolism] MH - *RNA-Binding Proteins/ph [Physiology] MH - Transfection MH - Tumor Suppressor Proteins/ge [Genetics] MH - Tumor Suppressor Proteins/me [Metabolism] MH - *Tumor Suppressor Proteins/ph [Physiology] AB - BACKGROUND: Programmed cell death 4 (PDCD4), originally identified as the neoplastic transformation inhibitor, was attenuated in various cancer types. Our previous study demonstrated a continuous down-regulation of PDCD4 expression in the sequence of normal-borderline-malignant ovarian tissue samples and a significant correlation of PDCD4 expression with disease-free survival. The objective of the current study was to further investigate the function and modulation of PDCD4 in ovarian cancer cells. AB - PRINCIPAL FINDINGS: We demonstrated that ectopic PDCD4 expression significantly inhibited cell proliferation by inducing cell cycle arrest at G(1) stage and up-regulation of cell cycle inhibitors of p27 and p21. Cell migration and invasion were also inhibited by PDCD4. PDCD4 over-expressing cells exhibited elevated phosphatase and tensin homolog (PTEN) and inhibited protein kinase B (p-Akt). In addition, the expression of PDCD4 was up-regulated and it was exported to the cytoplasm upon serum withdrawal treatment, but it was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of PDCD4, indicating the involvement of PI3K-Akt pathway in the modulation of PDCD4. AB - CONCLUSION: PDCD4 may play a critical function in arresting cell cycle progression at key checkpoint, thus inhibiting cell proliferation, as well as suppressing tumour metastasis. The PI3K-Akt pathway was implied to be involved in the regulation of PDCD4 degradation in ovarian cancer cells. In response to the stress condition, endogenous PDCD4 was able to shuttle between cell compartments to perform its diverted functions. RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Culture Media, Serum-Free) RN - 0 (Cyclin-Dependent Kinase Inhibitor p21) RN - 0 (PDCD4 protein, human) RN - 0 (RNA-Binding Proteins) RN - 0 (Tumor Suppressor Proteins) RN - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27) RN - EC 2-7-1 (Phosphatidylinositol 3-Kinases) RN - EC 2-7-11-1 (Proto-Oncogene Proteins c-akt) RN - EC 2-7-11-24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3-1-3-67 (PTEN Phosphohydrolase) ES - 1932-6203 IL - 1932-6203 DI - PONE-D-11-08426 DO - https://dx.doi.org/10.1371/journal.pone.0030311 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 22272332 [pubmed] ID - 10.1371/journal.pone.0030311 [doi] ID - PONE-D-11-08426 [pii] ID - PMC3260274 [pmc] PP - ppublish PH - 2011/05/12 [received] PH - 2011/12/13 [accepted] LG - English EP - 20120117 DP - 2012 DC - 20120124 EZ - 2012/01/25 06:00 DA - 2012/06/12 06:00 DT - 2012/01/25 06:00 YR - 2012 ED - 20120611 RD - 20150128 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22272332 <297. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22340593 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Katayama H AU - Wang J AU - Treekitkarnmongkol W AU - Kawai H AU - Sasai K AU - Zhang H AU - Wang H AU - Adams HP AU - Jiang S AU - Chakraborty SN AU - Suzuki F AU - Arlinghaus RB AU - Liu J AU - Mobley JA AU - Grizzle WE AU - Wang H AU - Sen S FA - Katayama, Hiroshi FA - Wang, Jin FA - Treekitkarnmongkol, Warapen FA - Kawai, Hidehiko FA - Sasai, Kaori FA - Zhang, Hui FA - Wang, Hua FA - Adams, Henry P FA - Jiang, Shoulei FA - Chakraborty, Sandip N FA - Suzuki, Fumio FA - Arlinghaus, Ralph B FA - Liu, Jinsong FA - Mobley, James A FA - Grizzle, William E FA - Wang, Huamin FA - Sen, Subrata IN - Katayama, Hiroshi. Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA. TI - Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73. SO - Cancer Cell. 21(2):196-211, 2012 Feb 14 AS - Cancer Cell. 21(2):196-211, 2012 Feb 14 NJ - Cancer cell PI - Journal available in: Print PI - Citation processed from: Internet JC - 101130617 IO - Cancer Cell PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760020 OI - Source: NLM. NIHMS354870 SB - Index Medicus CP - United States MH - *Apoptosis MH - Aurora Kinase A MH - Aurora Kinases MH - *DNA Damage MH - DNA-Binding Proteins/me [Metabolism] MH - *DNA-Binding Proteins/ph [Physiology] MH - HSP70 Heat-Shock Proteins/me [Metabolism] MH - Humans MH - *M Phase Cell Cycle Checkpoints MH - Nuclear Proteins/me [Metabolism] MH - *Nuclear Proteins/ph [Physiology] MH - Pancreatic Neoplasms/me [Metabolism] MH - Phosphorylation MH - Protein-Serine-Threonine Kinases/ge [Genetics] MH - Protein-Serine-Threonine Kinases/me [Metabolism] MH - *Protein-Serine-Threonine Kinases/ph [Physiology] MH - Tumor Cells, Cultured MH - Tumor Protein p73 MH - Tumor Suppressor Proteins/me [Metabolism] MH - *Tumor Suppressor Proteins/ph [Physiology] AB - Elevated Aurora kinase-A expression is correlated with abrogation of DNA damage-induced apoptotic response and mitotic spindle assembly checkpoint (SAC) override in human tumor cells. We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin. Aurora-A phosphorylated p73 also facilitates inactivation of SAC through dissociation of the MAD2-CDC20 complex in cells undergoing mitosis. Cells expressing phosphor-mimetic mutant (S235D) of p73 manifest altered growth properties, resistance to cisplatin- induced apoptosis, as well as premature dissociation of the MAD2-CDC20 complex, and accelerated mitotic exit with SAC override in the presence of spindle damage. Elevated cytoplasmic p73 in Aurora-A overexpressing primary human tumors corroborates the experimental findings. AB - Copyright A© 2012 Elsevier Inc. All rights reserved. RN - 0 (DNA-Binding Proteins) RN - 0 (HSP70 Heat-Shock Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Tumor Protein p73) RN - 0 (Tumor Suppressor Proteins) RN - 0 (mortalin) RN - 0 (p73 protein, human) RN - EC 2-7-11-1 (AURKA protein, human) RN - EC 2-7-11-1 (Aurora Kinase A) RN - EC 2-7-11-1 (Aurora Kinases) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) ES - 1878-3686 IL - 1535-6108 DI - S1535-6108(12)00004-9 DO - https://dx.doi.org/10.1016/j.ccr.2011.12.025 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 22340593 [pubmed] ID - S1535-6108(12)00004-9 [pii] ID - 10.1016/j.ccr.2011.12.025 [doi] ID - PMC3760020 [pmc] ID - NIHMS354870 [mid] PP - ppublish PH - 2010/03/11 [received] PH - 2011/09/21 [revised] PH - 2011/12/23 [accepted] GI - No: 5P30CA0101955 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA016672 Organization: (CA) *NCI NIH HHS* Country: United States No: P20 CA101955 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA089716-06 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA101955 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA089716 Organization: (CA) *NCI NIH HHS* Country: United States No: U01 CA111302 Organization: (CA) *NCI NIH HHS* Country: United States No: U01CA111302 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA089716 Organization: (CA) *NCI NIH HHS* Country: United States No: CA16872 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA089716-08 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA089716-07 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2012 Feb 14 DC - 20120220 EZ - 2012/02/21 06:00 DA - 2012/05/05 06:00 DT - 2012/02/22 06:00 YR - 2012 ED - 20120504 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22340593 <298. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21878655 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ewton DZ AU - Hu J AU - Vilenchik M AU - Deng X AU - Luk KC AU - Polonskaia A AU - Hoffman AF AU - Zipf K AU - Boylan JF AU - Friedman EA FA - Ewton, Daina Z FA - Hu, Jing FA - Vilenchik, Maria FA - Deng, Xiaobing FA - Luk, Kin-Chun FA - Polonskaia, Ann FA - Hoffman, Ann F FA - Zipf, Karen FA - Boylan, John F FA - Friedman, Eileen A IN - Ewton, Daina Z. SUNY Upstate Medical University, Department of Pathology, Syracuse, New York 13210, USA. TI - Inactivation of mirk/dyrk1b kinase targets quiescent pancreatic cancer cells. SO - Molecular Cancer Therapeutics. 10(11):2104-14, 2011 Nov AS - Mol Cancer Ther. 10(11):2104-14, 2011 Nov NJ - Molecular cancer therapeutics PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101132535 IO - Mol. Cancer Ther. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3213302 OI - Source: NLM. NIHMS321716 SB - Index Medicus CP - United States MH - *Antineoplastic Agents/pd [Pharmacology] MH - Apoptosis MH - Cell Aging MH - Cell Cycle/de [Drug Effects] MH - Cell Line, Tumor MH - Cisplatin/pd [Pharmacology] MH - DNA Damage/de [Drug Effects] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Drug Synergism MH - Exons MH - Humans MH - *Pancreatic Neoplasms/en [Enzymology] MH - Pancreatic Neoplasms/ge [Genetics] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - *Protein-Serine-Threonine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Serine-Threonine Kinases/ge [Genetics] MH - Protein-Serine-Threonine Kinases/me [Metabolism] MH - *Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Tyrosine Kinases/ge [Genetics] MH - Protein-Tyrosine Kinases/me [Metabolism] MH - *Resting Phase, Cell Cycle/de [Drug Effects] AB - A major problem in the treatment of cancer arises from quiescent cancer cells that are relatively insensitive to most chemotherapeutic drugs and radiation. Such residual cancer cells can cause tumor regrowth or recurrence when they reenter the cell cycle. Earlier studies showed that levels of the serine/theronine kinase Mirk/dyrk1B are elevated up to 10-fold in quiescent G(0) tumor cells. Mirk uses several mechanisms to block cell cycling, and Mirk increases expression of antioxidant genes that decrease reactive oxygen species (ROS) levels and increase quiescent cell viability. We now show that a novel small molecule Mirk kinase inhibitor blocked tumor cells from undergoing reversible arrest in a quiescent G(0) state and enabled some cells to exit quiescence. The inhibitor increased cycling in Panc1, AsPc1, and SW620 cells that expressed Mirk, but not in HCT116 cells that did not. Mirk kinase inhibition elevated ROS levels and DNA damage detected by increased phosphorylation of the histone protein H2AX and by S-phase checkpoints. The Mirk kinase inhibitor increased cleavage of the apoptotic proteins PARP and caspase 3, and increased tumor cell kill several-fold by gemcitabine and cisplatin. A phenocopy of these effects occurred following Mirk depletion, showing drug specificity. In previous studies Mirk knockout or depletion had no detectable effect on normal tissue, suggesting that the Mirk kinase inhibitor could have a selective effect on cancer cells expressing elevated levels of Mirk kinase. RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7-1 (Dyrk kinase) RN - EC 2-7-10-1 (Protein-Tyrosine Kinases) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - Q20Q21Q62J (Cisplatin) ES - 1538-8514 IL - 1535-7163 DI - 1535-7163.MCT-11-0498 DO - https://dx.doi.org/10.1158/1535-7163.MCT-11-0498 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 21878655 [pubmed] ID - 1535-7163.MCT-11-0498 [pii] ID - 10.1158/1535-7163.MCT-11-0498 [doi] ID - PMC3213302 [pmc] ID - NIHMS321716 [mid] PP - ppublish GI - No: R01 CA067405 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA135164 Organization: (CA) *NCI NIH HHS* Country: United States No: R21 CA135164-02 Organization: (CA) *NCI NIH HHS* Country: United States No: 5R21CA135164 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20110830 DP - 2011 Nov DC - 20111110 EZ - 2011/09/01 06:00 DA - 2012/03/16 06:00 DT - 2011/09/01 06:00 YR - 2011 ED - 20120315 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21878655 <299. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22335028 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Huo X AU - Ren L AU - Shang L AU - Wang X AU - Wang J FA - Huo, X FA - Ren, L FA - Shang, L FA - Wang, X FA - Wang, J IN - Huo, X. Department of Obstetrics and Gynecology, Beijing General Hospital of Beijing Military Command, Beijing China. TI - Effect of WT1 antisense mRNA on the induction of apoptosis in ovarian carcinoma SKOV3 cells. SO - European Journal of Gynaecological Oncology. 32(6):651-6, 2011 AS - Eur J Gynaecol Oncol. 32(6):651-6, 2011 NJ - European journal of gynaecological oncology PI - Journal available in: Print PI - Citation processed from: Print JC - ena, 8100357 IO - Eur. J. Gynaecol. Oncol. SB - Index Medicus CP - Italy MH - *Apoptosis MH - Cell Cycle MH - Cell Line, Tumor MH - Cell Proliferation MH - Female MH - Humans MH - Ovarian Neoplasms/pa [Pathology] MH - *Ovarian Neoplasms/th [Therapy] MH - *RNA, Antisense/tu [Therapeutic Use] MH - *RNA, Messenger/an [Analysis] MH - Transfection MH - *WT1 Proteins/ai [Antagonists & Inhibitors] MH - WT1 Proteins/ge [Genetics] AB - PURPOSE: To study the effect of WT1 antisense oligodeoxynucleotide (ASODN) transfection on the proliferation and apoptosis of SKOV3 cells. AB - METHODS: There were four groups in our study: normal control group, WT1 ASODN group, WT1 SODN group and lipofectamine group. Cell apoptosis was observed by flow cytometry. The effect of WT1 ASODN on cell proliferation was assayed by the MTT method. RT-PCR and Western blot were used to detect the expression level of WT1 mRNA and protein. AB - RESULTS: The growth of the ovarian cancer cell line SKOV3 became significantly slower and its activity was reduced after being transfected by WT1 ASODN, with the inhibition rate of 49.48%. WT1 antisense phosphorothioate oligonucleotides did not only inhibit cell proliferation, arrest cell cycle at G0-G1 checkpoint and induce apoptosis in SKOV3 ovarian carcinoma cells, but also downregulated WT1 mRNA and protein expression, which contributed to the apoptosis (p < 0.05). AB - CONCLUSION: WT1 antisense phosphorothioate oligonucleotides could both inhibit the proliferation and induce the apoptosis in SKOV3 ovarin carcinoma cell lines. Antisense oligonucleotides of WT1 may potentially help with the gene therapy of ovarian carcinoma. RN - 0 (RNA, Antisense) RN - 0 (RNA, Messenger) RN - 0 (WT1 Proteins) IS - 0392-2936 IL - 0392-2936 PT - Journal Article ID - 22335028 [pubmed] PP - ppublish LG - English DP - 2011 DC - 20120216 EZ - 2012/02/17 06:00 DA - 2012/03/14 06:00 DT - 2012/02/18 06:00 YR - 2011 ED - 20120313 RD - 20120216 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22335028 <300. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22109345 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bronstein Y AU - Ng CS AU - Hwu P AU - Hwu WJ FA - Bronstein, Yulia FA - Ng, Chaan S FA - Hwu, Patrick FA - Hwu, Wen-Jen IN - Bronstein, Yulia. Department of Diagnostic Radiology, M. D. Anderson Cancer Center, T. Boone Pickens Academic Tower, Houston, TX 77030, USA. yulia.bronstein@mdanderson.org TI - Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. SO - AJR. American Journal of Roentgenology. 197(6):W992-W1000, 2011 Dec AS - AJR Am J Roentgenol. 197(6):W992-W1000, 2011 Dec NJ - AJR. American journal of roentgenology PI - Journal available in: Print PI - Citation processed from: Internet JC - 3ae, 7708173 IO - AJR Am J Roentgenol SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Aged, 80 and over MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - Antigens, Neoplasm/im [Immunology] MH - *CTLA-4 Antigen/im [Immunology] MH - Female MH - Humans MH - *Immunotherapy/ae [Adverse Effects] MH - Magnetic Resonance Imaging MH - Male MH - *Melanoma/dt [Drug Therapy] MH - *Melanoma/im [Immunology] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Positron-Emission Tomography MH - Retrospective Studies MH - Statistics, Nonparametric MH - Tomography, X-Ray Computed MH - Treatment Outcome AB - OBJECTIVE: Monoclonal antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) used for treatment of metastatic melanoma produce inflammatory immune-related adverse events. The purpose of the current study was to retrospectively identify and characterize the radiologic manifestations of immune-related adverse events and to evaluate the possible association between these events and clinical responses to anti-CTLA-4 therapy. AB - MATERIALS AND METHODS: We retrospectively reviewed the images and medical records of 119 patients with metastatic melanoma treated with anti-CTLA-4 at our institution and assessed the presence of radiologic manifestations of immune-related adverse events and the clinical responses to therapy. The responses were categorized as progressive or controlled disease. The controlled disease category included stable disease, partial response, and complete response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. AB - RESULTS: Radiologic manifestations of immune-related adverse events were found in 20 patients (16.8%). Clinically evident manifestations included colitis, hypophysitis, thyroiditis, and arthritis. Clinically silent manifestations were benign lymphadenopathy and inflammatory changes in the soft tissues, such as myositis, fasciitis, and retroperitoneal fat haziness. There was a significant association between the incidence of radiologic manifestations of immune-related adverse events and clinical responses to anti-CTLA-4 therapy. The disease control rates were 18% for the entire group, 55% for the group with, and 10% for the group without radiologic manifestations of immune-related adverse events. In three patients (2.5%), lymphadenopathy related to radiologic manifestations of immune-related adverse events was interpreted as suspected metastasis but was proved benign at biopsy. AB - CONCLUSION: Radiologic manifestations of immune-related adverse events are associated with significant clinical benefit of anti-CTLA-4 therapy. In the era of developing immune checkpoint-targeted therapy for metastatic melanoma, radiologists should be alert to the possibility of these manifestations, which can mimic radiologic disease progression. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, Neoplasm) RN - 0 (CTLA-4 Antigen) RN - 6T8C155666 (ipilimumab) RN - QEN1X95CIX (tremelimumab) ES - 1546-3141 IL - 0361-803X DI - 197/6/W992 DO - https://dx.doi.org/10.2214/AJR.10.6198 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 22109345 [pubmed] ID - 197/6/W992 [pii] ID - 10.2214/AJR.10.6198 [doi] PP - ppublish GI - No: CA016672 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2011 Dec DC - 20111123 EZ - 2011/11/24 06:00 DA - 2012/01/27 06:00 DT - 2011/11/24 06:00 YR - 2011 ED - 20120126 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22109345 <301. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21976060 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Man J AU - Zhang X FA - Man, Jianghong FA - Zhang, Xuemin IN - Man, Jianghong. Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing 100850, China. TI - CUEDC2: an emerging key player in inflammation and tumorigenesis. [Review] SO - Protein & Cell. 2(9):699-703, 2011 Sep AS - Protein Cell. 2(9):699-703, 2011 Sep NJ - Protein & cell PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101532368 IO - Protein Cell PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875262 SB - Index Medicus CP - Germany MH - Anaphase-Promoting Complex-Cyclosome MH - Breast Neoplasms/pa [Pathology] MH - *Carrier Proteins/me [Metabolism] MH - Cell Cycle Proteins/me [Metabolism] MH - *Cell Transformation, Neoplastic/pa [Pathology] MH - Estrogen Receptor alpha/me [Metabolism] MH - Female MH - Humans MH - I-kappa B Kinase/me [Metabolism] MH - Inflammation/pa [Pathology] MH - *M Phase Cell Cycle Checkpoints MH - *Membrane Proteins/me [Metabolism] MH - Mitosis MH - NF-kappa B p50 Subunit/me [Metabolism] MH - Receptor-Interacting Protein Serine-Threonine Kinases/me [Metabolism] MH - Signal Transduction MH - Ubiquitin-Protein Ligase Complexes/me [Metabolism] MH - Ubiquitination AB - CUE domain-containing 2 (CUEDC2) is a protein involved in the regulation of the cell cycle, inflammation, and tumorigenesis and is highly expressed in many types of tumors. CUEDC2 is phosphorylated by Cdk1 during mitosis and promotes the release of anaphase-promoting complex or cyclosome (APC/C) from checkpoint inhibition. CUEDC2 is also known to interact with IkB kinase alpha (IKKalpha) and IKKbeta and has an inhibitory role in the activation of transcription factor nuclear factor-kappaB. Moreover, CUEDC2 plays an important role in downregulating the expression of hormone receptors estrogen receptor-alpha and progesterone receptor, thereby impairing the responsiveness of breast cancer to endocrine therapies. In this review, current knowledge on the multi-functions of CUEDC2 in normal processes and tumorigenesis are discussed and summarized. RN - 0 (CUEDC2 protein, human) RN - 0 (Carrier Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (Estrogen Receptor alpha) RN - 0 (Membrane Proteins) RN - 0 (NF-kappa B p50 Subunit) RN - 0 (NFKB1 protein, human) RN - 0 (estrogen receptor alpha, human) RN - EC 2-3-2-23 (Ubiquitin-Protein Ligase Complexes) RN - EC 2-3-2-27 (Anaphase-Promoting Complex-Cyclosome) RN - EC 2-7-11-1 (Receptor-Interacting Protein Serine-Threonine Kinases) RN - EC 2-7-11-10 (I-kappa B Kinase) ES - 1674-8018 IL - 1674-800X DO - https://dx.doi.org/10.1007/s13238-011-1089-z PT - Journal Article PT - Review ID - 21976060 [pubmed] ID - 10.1007/s13238-011-1089-z [doi] ID - PMC4875262 [pmc] PP - ppublish PH - 2011/08/02 [received] PH - 2011/08/14 [accepted] LG - English EP - 20111006 DP - 2011 Sep DC - 20111006 EZ - 2011/10/07 06:00 DA - 2012/01/27 06:00 DT - 2011/10/07 06:00 YR - 2011 ED - 20120126 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21976060 <302. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22003106 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Tu Z AU - Li Y AU - Smith DS AU - Sheibani N AU - Huang S AU - Kern T AU - Lin F FA - Tu, Zhidan FA - Li, Yan FA - Smith, Dawn S FA - Sheibani, Nader FA - Huang, Suber FA - Kern, Timothy FA - Lin, Feng IN - Tu, Zhidan. Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. TI - Retinal pericytes inhibit activated T cell proliferation. SO - Investigative Ophthalmology & Visual Science. 52(12):9005-10, 2011 Nov 21 AS - Invest Ophthalmol Vis Sci. 52(12):9005-10, 2011 Nov 21 NJ - Investigative ophthalmology & visual science PI - Journal available in: Electronic PI - Citation processed from: Internet JC - gwi, 7703701 IO - Invest. Ophthalmol. Vis. Sci. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3231798 SB - Index Medicus CP - United States MH - Animals MH - Apoptosis/im [Immunology] MH - *Cell Communication/im [Immunology] MH - Cell Division/im [Immunology] MH - Cell Line, Transformed MH - Diabetic Retinopathy/im [Immunology] MH - Diabetic Retinopathy/pa [Pathology] MH - *Endothelial Cells/cy [Cytology] MH - Endothelial Cells/im [Immunology] MH - Humans MH - Hyperglycemia/im [Immunology] MH - Hyperglycemia/pa [Pathology] MH - Membrane Proteins/im [Immunology] MH - Mice MH - Mice, Transgenic MH - *Pericytes/cy [Cytology] MH - Pericytes/im [Immunology] MH - *Retina/cy [Cytology] MH - Retina/im [Immunology] MH - *Retinitis/im [Immunology] MH - Retinitis/pa [Pathology] MH - *T-Lymphocytes/cy [Cytology] AB - PURPOSE: To test the hypothesis that retinal pericytes (RPCs) are immunosuppressive; therefore, their loss of function under hyperglycemic conditions favors retinal inflammation and contributes to the pathogenesis of diabetic retinopathy (DR). AB - METHODS: Isolated mouse and human RPCs were tested in T cell function assays to evaluate their capability of inhibiting T cell responses. To elucidate the underlying mechanisms, transwell systems, blocking mAbs against PD-L1 and IL-10 were used. The efficacy of RPCs in protecting retinal endothelial cells (RECs) from inflammation-induced apoptosis was assessed by apoptosis detection staining. Finally, to test whether hyperglycemic conditions impair the immunomodulatory activity of RPCs, RPCs pre-incubated in high glucose or methylglyoxal (MGO) were evaluated using the T cell proliferation assays. AB - RESULTS: RPCs profoundly inhibited activated T cell proliferation and inflammatory cytokine production. The T cell inhibitory activity of RPCs was decreased, but was not abolished, in transwell experiments. RPCs express PD-L1, and blocking PD-L1 reduced RPCs' efficacy of T cell inhibition. RPCs also produce IL-10, and neutralization of IL-10 reduced their immunosuppressive activity. There were significantly reduced numbers of inflammation-induced apoptosis-detected RECs in the presence of RPCs. Incubation of RPCs with either high glucose or MGO reduced the activity of RPCs to inhibit activated T cell proliferation. AB - CONCLUSIONS: RPCs are highly immunosuppressive and they protected RECs from inflammation-mediated apoptosis. Hyperglycemic conditions impaired the T cell inhibitory activity of RPCs. These results reveal a new function of RPCs, and its regulation under hyperglycemic conditions. This may represent a novel mechanism by which RPCs contribute to preservation of retinal integrity in diseases, including DR. RN - 0 (Membrane Proteins) ES - 1552-5783 IL - 0146-0404 DI - iovs.11-8008 DO - https://dx.doi.org/10.1167/iovs.11-8008 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 22003106 [pubmed] ID - iovs.11-8008 [pii] ID - 10.1167/iovs.11-8008 [doi] ID - PMC3231798 [pmc] PP - epublish GI - No: RC4 EY021357 Organization: (EY) *NEI NIH HHS* Country: United States No: R01 EY000300 Organization: (EY) *NEI NIH HHS* Country: United States No: NS052471 Organization: (NS) *NINDS NIH HHS* Country: United States No: R01 NS052471 Organization: (NS) *NINDS NIH HHS* Country: United States No: EY020956 Organization: (EY) *NEI NIH HHS* Country: United States No: EY21357 Organization: (EY) *NEI NIH HHS* Country: United States No: R21 EY020956 Organization: (EY) *NEI NIH HHS* Country: United States LG - English EP - 20111121 DP - 2011 Nov 21 DC - 20111122 EZ - 2011/10/18 06:00 DA - 2012/01/17 06:00 DT - 2011/10/18 06:00 YR - 2011 ED - 20120116 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22003106 <303. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 22010182 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Hamnvik OP AU - Larsen PR AU - Marqusee E FA - Hamnvik, Ole-Petter Riksfjord FA - Larsen, P Reed FA - Marqusee, Ellen IN - Hamnvik, Ole-Petter Riksfjord. Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. ohamnvik@partners.org TI - Thyroid dysfunction from antineoplastic agents. [Review] CM - Comment in: J Natl Cancer Inst. 2012 Mar 7;104(5):422-3; author reply 423; PMID: 22291212 SO - Journal of the National Cancer Institute. 103(21):1572-87, 2011 Nov 02 AS - J Natl Cancer Inst. 103(21):1572-87, 2011 Nov 02 NJ - Journal of the National Cancer Institute PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - j9j, 7503089 IO - J. Natl. Cancer Inst. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206040 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal, Humanized/ae [Adverse Effects] MH - Antibodies, Neoplasm/ae [Adverse Effects] MH - Anticarcinogenic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Diphtheria Toxin/ae [Adverse Effects] MH - Humans MH - Hyperthyroidism/bl [Blood] MH - *Hyperthyroidism/ci [Chemically Induced] MH - Hyperthyroidism/di [Diagnosis] MH - Hypopituitarism/co [Complications] MH - Hypopituitarism/et [Etiology] MH - Hypothyroidism/bl [Blood] MH - *Hypothyroidism/ci [Chemically Induced] MH - Hypothyroidism/di [Diagnosis] MH - Hypothyroidism/dt [Drug Therapy] MH - Hypothyroidism/et [Etiology] MH - Interferon-alpha/ae [Adverse Effects] MH - Interleukin-2/ae [Adverse Effects] MH - Interleukin-2/aa [Analogs & Derivatives] MH - Iodine Radioisotopes/ad [Administration & Dosage] MH - Molecular Targeted Therapy/mt [Methods] MH - *Neoplasms/dt [Drug Therapy] MH - Neoplasms/im [Immunology] MH - Protein-Tyrosine Kinases/ai [Antagonists & Inhibitors] MH - Quality of Life MH - Radioimmunotherapy MH - Recombinant Fusion Proteins/ae [Adverse Effects] MH - Recombinant Proteins/ae [Adverse Effects] MH - Tetrahydronaphthalenes/ae [Adverse Effects] MH - Thalidomide/ae [Adverse Effects] MH - Thalidomide/aa [Analogs & Derivatives] MH - Thyroid Function Tests MH - *Thyroid Gland/de [Drug Effects] MH - Thyroid Gland/me [Metabolism] MH - *Thyroid Hormones/bl [Blood] MH - Thyroiditis, Autoimmune/ci [Chemically Induced] AB - Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-alpha, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antibodies, Neoplasm) RN - 0 (Anticarcinogenic Agents) RN - 0 (Antineoplastic Agents) RN - 0 (Diphtheria Toxin) RN - 0 (Interferon-alpha) RN - 0 (Interleukin-2) RN - 0 (Iodine Radioisotopes) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Recombinant Proteins) RN - 0 (Tetrahydronaphthalenes) RN - 0 (Thyroid Hormones) RN - 25E79B5CTM (denileukin diftitox) RN - 3A189DH42V (alemtuzumab) RN - 4Z8R6ORS6L (Thalidomide) RN - 6T8C155666 (ipilimumab) RN - A61RXM4375 (bexarotene) RN - EC 2-7-10-1 (Protein-Tyrosine Kinases) RN - F0P408N6V4 (lenalidomide) RN - M89N0Q7EQR (aldesleukin) RN - QEN1X95CIX (tremelimumab) ES - 1460-2105 IL - 0027-8874 DI - djr373 DO - https://dx.doi.org/10.1093/jnci/djr373 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review ID - 22010182 [pubmed] ID - djr373 [pii] ID - 10.1093/jnci/djr373 [doi] ID - PMC3206040 [pmc] PP - ppublish GI - No: R01 DK044128 Organization: (DK) *NIDDK NIH HHS* Country: United States No: DK36256 Organization: (DK) *NIDDK NIH HHS* Country: United States No: DK44128 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English EP - 20111018 DP - 2011 Nov 02 DC - 20111102 EZ - 2011/10/20 06:00 DA - 2011/12/21 06:00 DT - 2011/10/20 06:00 YR - 2011 ED - 20111220 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=22010182 <304. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21737890 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Cheng H AU - Merika E AU - Syrigos KN AU - Saif MW FA - Cheng, Haiying FA - Merika, Eirini FA - Syrigos, Kostas N FA - Saif, Muhammad Wasif IN - Cheng, Haiying. Columbia University College of Physicians and Surgeons, New York, NY, USA. TI - Novel agents for the treatment of pancreatic adenocarcinoma. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011. [Review] SO - Jop: Journal of the Pancreas [Electronic Resource]. 12(4):334-8, 2011 Jul 08 AS - JOP. 12(4):334-8, 2011 Jul 08 NJ - JOP : Journal of the pancreas PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101091810 IO - JOP SB - Index Medicus CP - Italy MH - *Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/me [Metabolism] MH - Animals MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Chicago MH - Congresses as Topic MH - Drugs, Investigational/ad [Administration & Dosage] MH - *Drugs, Investigational/tu [Therapeutic Use] MH - Humans MH - Medical Oncology MH - Models, Biological MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/me [Metabolism] MH - Signal Transduction/ge [Genetics] MH - Signal Transduction/ph [Physiology] MH - Societies, Medical MH - United States AB - There are urgent needs to develop novel and more effective regimens to improve outcomes of pancreatic cancer given its dismal prognosis and limited treatment options. Several phase I clinical trials involving novel agents were recently presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting. It appears that hedgehog inhibition with IPI-926 was well-tolerated and might be effective in treating pancreatic cancer when combined with gemcitabine. The survival benefits will be tested in the following randomized phase II trial. The new combination of gemcitabine and blockade of checkpoint kinases with AZD7762 showed an acceptable safety profile. Furthermore, inhibition of PI3K by BAY80-6946 was well tolerated with PET-CT suggesting reduction in FDG uptake in some pancreatic cancer. The benefits of above novel agents/regimens need to be further tested in phase II trials. RN - 0 (Drugs, Investigational) ES - 1590-8577 IL - 1590-8577 DI - v12i04a05 PT - Journal Article PT - Review ID - 21737890 [pubmed] ID - v12i04a05 [pii] PP - epublish LG - English EP - 20110708 DP - 2011 Jul 08 DC - 20110708 EZ - 2011/07/09 06:00 DA - 2011/12/16 06:00 DT - 2011/07/09 06:00 YR - 2011 ED - 20111215 RD - 20110708 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21737890 <305. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21815696 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lowery MA AU - O'Reilly EM FA - Lowery, Maeve A FA - O'Reilly, Eileen M IN - Lowery, Maeve A. Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, USA. TI - New approaches to the treatment of pancreatic cancer: from tumor-directed therapy to immunotherapy. SO - Biodrugs. 25(4):207-16, 2011 Aug 01 AS - BioDrugs. 25(4):207-16, 2011 Aug 01 NJ - BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy PI - Journal available in: Print PI - Citation processed from: Internet JC - d3a, 9705305 IO - BioDrugs SB - Index Medicus CP - New Zealand MH - Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/ge [Genetics] MH - Adenocarcinoma/im [Immunology] MH - *Adenocarcinoma/th [Therapy] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Camptothecin/aa [Analogs & Derivatives] MH - Camptothecin/tu [Therapeutic Use] MH - Cancer Vaccines/tu [Therapeutic Use] MH - Combined Modality Therapy/mt [Methods] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/tu [Therapeutic Use] MH - Fluorouracil/tu [Therapeutic Use] MH - Humans MH - Immunotherapy/mt [Methods] MH - Leucovorin/tu [Therapeutic Use] MH - Organoplatinum Compounds/tu [Therapeutic Use] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/th [Therapy] AB - The development of novel therapeutic strategies for pancreatic adenocarcinoma (PAC) has traditionally been considered particularly challenging for clinical and laboratory investigators due to its aggressive underlying biology and inherent resistance to currently available therapies. More recently, however, advances have been made in the identification of promising therapeutic targets for intervention, along with several key insights into the complex sequence of genetic alterations involved in the evolution of PAC from premalignant precursor lesion to malignant cells with metastatic potential. FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) has recently been identified as a combination cytotoxic therapy associated with a significant survival benefit over single-agent gemcitabine in good performance status patients with advanced disease; it is hoped that a similar benefit will be seen in planned trials of FOLFIRINOX as perioperative therapy. The success of immune therapy with the anti-cytotoxic T-lymphocyte antigen-4 antibody ipilimumab in advanced melanoma has spurred interest in the development of vaccines and immune therapies for other solid tumors. Certainly, the concept of harnessing the power of the immune system for cancer treatment is an attractive concept to patients and clinicians alike. Herein we discuss recent advances in the development of novel therapeutic approaches to PAC, focusing in particular on recent developments in immune and vaccine therapy. RN - 0 (Antibodies, Monoclonal) RN - 0 (Cancer Vaccines) RN - 0 (Organoplatinum Compounds) RN - 04ZR38536J (oxaliplatin) RN - 0W860991D6 (Deoxycytidine) RN - 6T8C155666 (ipilimumab) RN - B76N6SBZ8R (gemcitabine) RN - Q573I9DVLP (Leucovorin) RN - U3P01618RT (Fluorouracil) RN - XT3Z54Z28A (Camptothecin) PS - IFL protocol ES - 1179-190X IL - 1173-8804 DI - 1 DO - https://dx.doi.org/10.2165/11592470-000000000-00000 PT - Journal Article ID - 21815696 [pubmed] ID - 1 [pii] ID - 10.2165/11592470-000000000-00000 [doi] PP - ppublish LG - English DP - 2011 Aug 01 DC - 20110805 EZ - 2011/08/06 06:00 DA - 2011/12/13 00:00 DT - 2011/08/06 06:00 YR - 2011 ED - 20111207 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21815696 <306. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21242854 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Borodic G AU - Hinkle DM AU - Cia Y FA - Borodic, Gary FA - Hinkle, David M FA - Cia, Yihong IN - Borodic, Gary. Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02142, USA. borodic@aol.com TI - Drug-induced graves disease from CTLA-4 receptor suppression. CM - Comment in: Ophthal Plast Reconstr Surg. 2013 May-Jun;29(3):239-40; PMID: 23652294 CM - Comment in: Ophthal Plast Reconstr Surg. 2013 May-Jun;29(3):241; PMID: 23652295 SO - Ophthalmic Plastic & Reconstructive Surgery. 27(4):e87-8, 2011 Jul-Aug AS - Ophthal Plast Reconstr Surg. 27(4):e87-8, 2011 Jul-Aug NJ - Ophthalmic plastic and reconstructive surgery PI - Journal available in: Print PI - Citation processed from: Internet JC - ay2, 8508431 IO - Ophthal Plast Reconstr Surg SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antigens, CD/de [Drug Effects] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - CTLA-4 Antigen MH - Diplopia/ci [Chemically Induced] MH - Exophthalmos/ci [Chemically Induced] MH - Female MH - *Graves Ophthalmopathy/ci [Chemically Induced] MH - Humans MH - Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/sc [Secondary] MH - Magnetic Resonance Imaging MH - Melanoma/dt [Drug Therapy] MH - Melanoma/sc [Secondary] MH - Middle Aged MH - Neoplasms, Unknown Primary/dt [Drug Therapy] MH - Neoplasms, Unknown Primary/pa [Pathology] MH - Oculomotor Muscles/de [Drug Effects] AB - Monoclonal antibody, ipilimumab, useful for treatment of metastatic melanoma, blocks CTLA-4 mediated T-cell suppression and can also cause a Graves ophthalmopathy like syndrome. Epidemiologic study has linked variant polymorphisms of CTLA-4 receptor gene to the presence of thyroid eye disease. The combination of these observations suggests CTLA-4 mediated T-cell functions are important to the pathogenesis of thyroid-associated eye disease. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) ES - 1537-2677 IL - 0740-9303 DO - https://dx.doi.org/10.1097/IOP.0b013e3181ef72a1 PT - Case Reports PT - Journal Article ID - 21242854 [pubmed] ID - 10.1097/IOP.0b013e3181ef72a1 [doi] PP - ppublish LG - English DP - 2011 Jul-Aug DC - 20110712 EZ - 2011/01/19 06:00 DA - 2011/09/22 06:00 DT - 2011/01/19 06:00 YR - 2011 ED - 20110921 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21242854 <307. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21083648 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kahler KC AU - Hauschild A FA - Kahler, Katharina C FA - Hauschild, Axel IN - Kahler, Katharina C. Department of Dermatology, Venerology and Allergology, University of Schleswig-Holstein Hospital, Campus Kiel, Germany. TI - Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. [Review] SO - Journal der Deutschen Dermatologischen Gesellschaft. 9(4):277-86, 2011 Apr AS - J.Deutschen Dermatologischen Gesellschaft. 9(4):277-86, 2011 Apr NJ - Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101164708 IO - J Dtsch Dermatol Ges SB - Index Medicus CP - Germany MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antigens, CD/de [Drug Effects] MH - Antigens, CD/im [Immunology] MH - CTLA-4 Antigen MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - *Melanoma/sc [Secondary] MH - Models, Immunological MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] MH - Treatment Outcome AB - Immune-modifying monoclonal antibodies may induce or enhance the natural immune response against tumor cells. The complex interaction between antigen-presenting cells and T lymphocytes as an immune response is strongly affected by anti-CD152 (CTLA-4)-antibodies. The cytotoxic T-lymphocyte (CTLA-4) receptor binds molecules of the B7-family which leads to a suppression of T cells. Specific CTLA-4 antibodies induce an unrestrained T-cell activation. Treatment with the CTLA-4 antibodies ipilimumab and tremelimumab has been investigated in metastatic melanoma only within clinical trials. Currently, the critical phase III trial on ipilimumab is in the final analysis process and expected to lead to approval. CTLA-4 antibodies belong to the most promising new molecules for the treatment of advanced melanoma. During treatment with CTLA-4 antibodies, distinct adverse events may occur. Treating physicians must be familiar with their appropriate treatment and prophylaxis. The most frequently observed side effects are diseases such as an autoimmune colitis which is typically characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Other autoimmune-mediated side effects like hypophysitis, hepatitis, iridocyclitis or an exacerbation of lupus nephritis have been reported in the literature. Their early recognition and treatment are mandatory to reduce the risk of sequelae for CTLA-4-antibod-treated patients. Autoimmune-mediated side effects are reported to correlate positively with treatment response. We review the mechanisms of action, provide an update on clinical trials with the two CTLA-4-antibodies for metastatic melanoma, and present detailed recommendations for managing the side effects of these new agents. AB - Copyright © The Authors * Journal compilation © Blackwell Verlag GmbH, Berlin. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) ES - 1610-0387 IL - 1610-0379 DO - https://dx.doi.org/10.1111/j.1610-0387.2010.07568.x PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 21083648 [pubmed] ID - 10.1111/j.1610-0387.2010.07568.x [doi] PP - ppublish LG - English LG - German EP - 20101117 DP - 2011 Apr DC - 20110328 EZ - 2010/11/19 06:00 DA - 2011/08/24 06:00 DT - 2010/11/19 06:00 YR - 2011 ED - 20110823 RD - 20111117 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21083648 <308. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21249150 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Lee SJ AU - Lee MH AU - Kim DW AU - Lee S AU - Huang S AU - Ryu MJ AU - Kim YK AU - Kim SJ AU - Kim SJ AU - Hwang JH AU - Oh S AU - Cho H AU - Kim JM AU - Lim DS AU - Jo YS AU - Shong M FA - Lee, Seong Jin FA - Lee, Min Hee FA - Kim, Dong Wook FA - Lee, Seongeun FA - Huang, Songmei FA - Ryu, Min Jeong FA - Kim, Yong Kyung FA - Kim, Sung Jin FA - Kim, Soung Jung FA - Hwang, Jung Hwan FA - Oh, Sangphil FA - Cho, Heeyeong FA - Kim, Jin Man FA - Lim, Dae-Sik FA - Jo, Young Suk FA - Shong, Minho IN - Lee, Seong Jin. Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea. TI - Cross-regulation between oncogenic BRAF(V600E) kinase and the MST1 pathway in papillary thyroid carcinoma. SO - PLoS ONE [Electronic Resource]. 6(1):e16180, 2011 Jan 13 AS - PLoS ONE. 6(1):e16180, 2011 Jan 13 NJ - PloS one PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101285081 IO - PLoS ONE PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020965 SB - Index Medicus CP - United States MH - Animals MH - Apoptosis MH - Carcinoma MH - Cell Cycle Proteins MH - Forkhead Box Protein O3 MH - Forkhead Transcription Factors/me [Metabolism] MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Mice MH - Mutation, Missense MH - Neoplasms, Experimental MH - Phenotype MH - Protein-Serine-Threonine Kinases/ai [Antagonists & Inhibitors] MH - *Protein-Serine-Threonine Kinases/me [Metabolism] MH - Proto-Oncogene Proteins B-raf/ge [Genetics] MH - *Proto-Oncogene Proteins B-raf/me [Metabolism] MH - *Receptor Cross-Talk/ph [Physiology] MH - Thyroid Neoplasms/me [Metabolism] MH - Thyroid Neoplasms/pa [Pathology] MH - Tumor Suppressor Proteins/ai [Antagonists & Inhibitors] MH - Tumor Suppressor Proteins/me [Metabolism] AB - BACKGROUND: The BRAF(V600E) mutation leading to constitutive signaling of MEK-ERK pathways causes papillary thyroid cancer (PTC). Ras association domain family 1A (RASSF1A), which is an important regulator of MST1 tumor suppressor pathways, is inactivated by hypermethylation of its promoter region in 20 to 32% of PTC. However, in PTC without RASSF1A methylation, the regulatory mechanisms of RASSF1A-MST1 pathways remain to be elucidated, and the functional cooperation or cross regulation between BRAF(V600E) and MST1,which activates Foxo3,has not been investigated. AB - METHODOLOGY/PRINCIPAL FINDINGS: The negative regulators of the cell cycle, p21 and p27, are strongly induced by transcriptional activation of FoxO3 in BRAF(V600E) positive thyroid cancer cells. The FoxO3 transactivation is augmented by RASSF1A and the MST1 signaling pathway. Interestingly, introduction of BRAF(V600E)markedly abolished FoxO3 transactivation and resulted in the suppression of p21 and p27 expression. The suppression of FoxO3 transactivation by BRAF(V600E)is strongly increased by coexpression of MST1 but it is not observed in the cells in which MST1, but not MST2,is silenced. Mechanistically, BRAF(V600E)was able to bind to the C-terminal region of MST1 and resulted in the suppression of MST1 kinase activities. The induction of the G1-checkpoint CDK inhibitors, p21 and p27,by the RASSF1A-MST1-FoxO3 pathway facilitates cellular apoptosis, whereas addition of BRAF(V600E) inhibits the apoptotic processes through the inactivation of MST1. Transgenic induction of BRAF(V600E)in the thyroid gland results in cancers resembling human papillary thyroid cancers. The development of BRAF(V600E)transgenic mice with the MST1 knockout background showed that these mice had abundant foci of poorly differentiated carcinomas and large areas without follicular architecture or colloid formation. AB - CONCLUSIONS/SIGNIFICANCE: The results of this study revealed that the oncogenic effect of BRAF(V600E) is associated with the inhibition of MST1 tumor suppressor pathways, and that the activity of RASSF1A-MST1-FoxO3 pathways determines the phenotypes of BRAF(V600E) tumors. RN - 0 (Cell Cycle Proteins) RN - 0 (FOXO3 protein, human) RN - 0 (Forkhead Box Protein O3) RN - 0 (Forkhead Transcription Factors) RN - 0 (RASSF1 protein, human) RN - 0 (Tumor Suppressor Proteins) RN - EC 2-7-1 (STK4 protein, human) RN - EC 2-7-11-1 (BRAF protein, human) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - EC 2-7-11-1 (Proto-Oncogene Proteins B-raf) RS - Thyroid cancer, papillary ES - 1932-6203 IL - 1932-6203 DO - https://dx.doi.org/10.1371/journal.pone.0016180 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 21249150 [pubmed] ID - 10.1371/journal.pone.0016180 [doi] ID - PMC3020965 [pmc] PP - epublish PH - 2010/09/08 [received] PH - 2010/12/07 [accepted] LG - English EP - 20110113 DP - 2011 Jan 13 DC - 20110120 EZ - 2011/01/21 06:00 DA - 2011/08/04 06:00 DT - 2011/01/21 06:00 YR - 2011 ED - 20110802 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21249150 <309. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20842054 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Royal RE AU - Levy C AU - Turner K AU - Mathur A AU - Hughes M AU - Kammula US AU - Sherry RM AU - Topalian SL AU - Yang JC AU - Lowy I AU - Rosenberg SA FA - Royal, Richard E FA - Levy, Catherine FA - Turner, Keli FA - Mathur, Aarti FA - Hughes, Marybeth FA - Kammula, Udai S FA - Sherry, Richard M FA - Topalian, Suzanne L FA - Yang, James C FA - Lowy, Israel FA - Rosenberg, Steven A IN - Royal, Richard E. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. rroyal@mdanderson.org TI - Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. SO - Journal of Immunotherapy. 33(8):828-33, 2010 Oct AS - J Immunother. 33(8):828-33, 2010 Oct NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. SB - Index Medicus CP - United States MH - Adenocarcinoma/im [Immunology] MH - Adenocarcinoma/pa [Pathology] MH - Adenocarcinoma/pp [Physiopathology] MH - *Adenocarcinoma/th [Therapy] MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antigens, CD/im [Immunology] MH - CTLA-4 Antigen MH - Colitis/et [Etiology] MH - Colitis/im [Immunology] MH - Disease Progression MH - Female MH - Humans MH - *Immunotherapy MH - Injections, Intravenous MH - Male MH - Middle Aged MH - Neoplasm Metastasis MH - Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/pa [Pathology] MH - Pancreatic Neoplasms/pp [Physiopathology] MH - *Pancreatic Neoplasms/th [Therapy] MH - Treatment Failure AB - New, effective therapies are needed for pancreatic ductal adenocarcinoma. Ipilimumab can mediate an immunologic tumor regression in other histologies. This phase II trial evaluated the efficacy of Ipilimumab for advanced pancreatic cancer. Subjects were adults with locally advanced or metastatic pancreas adenocarcinoma with measurable disease, good performance status, and minimal comorbidities. Ipilimumab was administered intravenously (3.0 mg/kg every 3 wk; 4 doses/course) for a maximum of 2 courses. Response rate by response evaluation criteria in solid tumors criteria and toxicity were measured. Twenty-seven subjects were enrolled (metastatic disease: 20 and locally advanced: 7) with median age of 55 years (27 to 68 y) and good performance status (26 with Eastern Cooperative Oncology Group performance status =0 to 1). Three subjects experienced >= grade 3 immune-mediated adverse events (colitis:1, encephalitis:1, hypohysitis:1). There were no responders by response evaluation criteria in solid tumors criteria but a subject experienced a delayed response after initial progressive disease. In this subject, new metastases after 2 doses of Ipilimumab established progressive disease. But continued administration of the agent per protocol resulted in significant delayed regression of the primary lesion and 20 hepatic metastases. This was reflected in tumor markers normalization, and clinically significant improvement of performance status. Single agent Ipilimumab at 3.0 mg/kg/dose is ineffective for the treatment of advanced pancreas cancer. However, a significant delayed response in one subject of this trial suggests that immunotherapeutic approaches to pancreas cancer deserve further exploration. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) ES - 1537-4513 IL - 1524-9557 DO - https://dx.doi.org/10.1097/CJI.0b013e3181eec14c PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, N.I.H., Intramural ID - 20842054 [pubmed] ID - 10.1097/CJI.0b013e3181eec14c [doi] PP - ppublish GI - Organization: *Intramural NIH HHS* Country: United States LG - English DP - 2010 Oct DC - 20100924 EZ - 2010/09/16 06:00 DA - 2011/05/18 06:00 DT - 2010/09/16 06:00 YR - 2010 ED - 20110517 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=20842054 <310. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20871480 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Xia QS AU - Ishigaki Y AU - Zhao X AU - Shimasaki T AU - Nakajima H AU - Nakagawa H AU - Takegami T AU - Chen ZH AU - Motoo Y FA - Xia, Qi-sheng FA - Ishigaki, Yasuhito FA - Zhao, Xia FA - Shimasaki, Takeo FA - Nakajima, Hideo FA - Nakagawa, Hideaki FA - Takegami, Tsutomu FA - Chen, Zhi-hua FA - Motoo, Yoshiharu IN - Xia, Qi-sheng. Department of Medical Oncology, Kanazawa Medical University, Uchinada, Ishikawa, Japan. TI - Human SMG-1 is involved in gemcitabine-induced primary microRNA-155/BIC up-regulation in human pancreatic cancer PANC-1 cells. SO - Pancreas. 40(1):55-60, 2011 Jan AS - Pancreas. 40(1):55-60, 2011 Jan NJ - Pancreas PI - Journal available in: Print PI - Citation processed from: Internet JC - prs, 8608542 IO - Pancreas SB - Index Medicus CP - United States MH - Androstadienes/pd [Pharmacology] MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - Ataxia Telangiectasia Mutated Proteins MH - Cell Cycle Proteins/ph [Physiology] MH - Cell Line, Tumor MH - DNA-Binding Proteins/ph [Physiology] MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Extracellular Signal-Regulated MAP Kinases/ph [Physiology] MH - Gene Expression Regulation, Neoplastic MH - Humans MH - JNK Mitogen-Activated Protein Kinases/ph [Physiology] MH - *MicroRNAs/ge [Genetics] MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/pa [Pathology] MH - *Phosphatidylinositol 3-Kinases/ph [Physiology] MH - Protein-Serine-Threonine Kinases/ph [Physiology] MH - Tumor Suppressor Proteins/ph [Physiology] MH - Up-Regulation AB - OBJECTIVES: Human primary microRNA-155/B-cell integration cluster (BIC) transcript is the precursor of microRNA-155. The overexpression of them has been widely observed in the progression of various types of tumors. Our objective was to investigate the effect of anticancer agents on the expression of BIC and possible signal pathways that involved in. AB - METHODS: Quantitative real-time reverse transcriptase polymerase chain reaction was used to measure the expression of BIC. Chemical inhibitors against c-Jun N-terminal kinase 1, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2, protein kinase C, checkpoint kinase 1, and phosphatidylinositol 3 kinase (PI3K) were used for the evaluation of involved signal pathways. RNA interference was used to knock down the expression of ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3 related, and suppressor of morphogenesis in genitalia-1 (SMG-1), and Western blot was carried out to evaluate the knockdown effect. AB - RESULTS: B-cell integration cluster expression was induced by a representative anti-pancreatic cancer drug, gemcitabine, in human pancreatic cancer PANC-1 cells. The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 and c-Jun N-terminal kinase inhibitors, but not the checkpoint kinase 1 and protein kinase C inhibitors, suppressed the up-regulation of BIC. B-cell integration cluster up-regulation was also significantly inhibited by the PI3K inhibitor wortmannin. RNA interference studies showed that wortmannin-sensitive SMG-1 but not ataxia-telangiectasia mutated or ataxia-telangiectasia and Rad3 related was involved in the up-regulation. AB - CONCLUSIONS: Our results show that multiple pathways can be involved in the up-regulation of BIC. Furthermore, we demonstrate for the first time that PI3K SMG-1 is required for gemcitabine-induced up-regulation of BIC transcript. RN - 0 (Androstadienes) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Cell Cycle Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (MIRN155 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Tumor Suppressor Proteins) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7-1 (Phosphatidylinositol 3-Kinases) RN - EC 2-7-1-137 (SMG1 protein, human) RN - EC 2-7-11-1 (ATM protein, human) RN - EC 2-7-11-1 (ATR protein, human) RN - EC 2-7-11-1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - EC 2-7-11-24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2-7-11-24 (JNK Mitogen-Activated Protein Kinases) RN - XVA4O219QW (wortmannin) ES - 1536-4828 IL - 0885-3177 DO - https://dx.doi.org/10.1097/MPA.0b013e3181e89f74 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 20871480 [pubmed] ID - 10.1097/MPA.0b013e3181e89f74 [doi] PP - ppublish LG - English DP - 2011 Jan DC - 20101216 EZ - 2010/09/28 06:00 DA - 2011/04/19 06:00 DT - 2010/09/28 06:00 YR - 2011 ED - 20110418 RD - 20151119 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=20871480 <311. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21150603 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bouwhuis MG AU - Ten Hagen TL AU - Suciu S AU - Eggermont AM FA - Bouwhuis, Marna G FA - Ten Hagen, Timo L M FA - Suciu, Stefan FA - Eggermont, Alexander Mm IN - Bouwhuis, Marna G. Department of Surgery, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. TI - Autoimmunity and treatment outcome in melanoma. [Review] SO - Current Opinion in Oncology. 23(2):170-6, 2011 Mar AS - Curr Opin Oncol. 23(2):170-6, 2011 Mar NJ - Current opinion in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - a1v, 9007265 IO - Curr Opin Oncol SB - Index Medicus CP - United States MH - Autoimmunity/im [Immunology] MH - Humans MH - *Immunotherapy/mt [Methods] MH - *Melanoma/im [Immunology] MH - *Melanoma/th [Therapy] MH - Treatment Outcome AB - PURPOSE OF REVIEW: Only a subset of melanoma patients with advanced disease seems to benefit from immunotherapy. Predictive markers identifying these patients are unfortunately not available. Whether immune-related side effects could serve as predictors for treatment response or just resemble unwanted side effects from immunotherapy will be outlined in this review. AB - RECENT FINDINGS: Early studies suggested an association of immune-related side effects such as vitiligo and autoimmune thyroiditis with response in patients receiving IL-2 or IFNalpha. However, conflicting data have been reported as well, mentioning the effect of a higher rate of immune-related toxicities during prolonged administration of the drug in responders/survivors. This type of bias is also known as guarantee-time bias. Recently, a clearly significant and clinically relevant prolongation of survival was demonstrated in patients with metastatic melanoma treated with ipilimumab. Immune-related adverse events were associated with response to ipilimumab, however, at the cost of considerable toxicity. AB - SUMMARY: Evidence for an association of immune-related toxicities and response in patients receiving IL-2 or IFNalpha is weak, considering guarantee-time bias. On the contrary, this association for patients receiving anti-cytotoxic T-lymphocyte antigen-4 therapy (ipilimumab) appears much stronger. Importantly, can we uncouple tumor immunity from autoimmunity in order to optimize immunotherapy in melanoma? ES - 1531-703X IL - 1040-8746 DO - https://dx.doi.org/10.1097/CCO.0b013e328341edff PT - Journal Article PT - Review ID - 21150603 [pubmed] ID - 10.1097/CCO.0b013e328341edff [doi] PP - ppublish LG - English DP - 2011 Mar DC - 20110210 EZ - 2010/12/15 06:00 DA - 2011/04/09 06:00 DT - 2010/12/15 06:00 YR - 2011 ED - 20110408 RD - 20110210 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21150603 <312. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21088057 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Min L AU - Vaidya A AU - Becker C FA - Min, Le FA - Vaidya, Anand FA - Becker, Carolyn IN - Min, Le. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. TI - Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. SO - European Journal of Endocrinology. 164(2):303-7, 2011 Feb AS - EUR. J. ENDOCRINOL.. 164(2):303-7, 2011 Feb NJ - European journal of endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bxu, 9423848 IO - Eur. J. Endocrinol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080629 OI - Source: NLM. NIHMS367388 SB - Index Medicus CP - England MH - Adult MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Female MH - *Graves Ophthalmopathy/ci [Chemically Induced] MH - Graves Ophthalmopathy/di [Diagnosis] MH - Graves Ophthalmopathy/im [Immunology] MH - Humans MH - Male MH - Melanoma/im [Immunology] MH - *Melanoma/th [Therapy] MH - Middle Aged MH - Skin Neoplasms/im [Immunology] MH - *Skin Neoplasms/th [Therapy] MH - *Thyroiditis, Autoimmune/ci [Chemically Induced] MH - Thyroiditis, Autoimmune/di [Diagnosis] MH - Thyroiditis, Autoimmune/im [Immunology] AB - OBJECTIVE: Ipilimumab is a fully human MAB against cytotoxic T-lymphocyte antigen 4 (CTLA4). CTLA4 negatively regulates immune cell activation. In patients with metastatic melanoma, ipilimumab increases survival time and induces complete remission in some patients. However, immune-related adverse events including endocrinopathies have been reported. Bevacizumab, an angiogenesis inhibitor, has been used in combination with ipilimumab in patients with advanced melanoma. AB - PATIENTS AND METHODS: In this study, we report three patients who received ipilimumab alone or combined with bevacizumab therapy and developed thyroiditis, and the first report of euthyroid Graves' ophthalmopathy. AB - RESULTS: Case 1 is a 51-year-old female who presented with severe eye pain, proptosis, and periorbital edema. Laboratory results revealed normal TSH, elevated thyroid antibodies but low titer of anti-TSH receptor antibody. Imaging was consistent with Graves' ophthalmopathy. Cases 2 and 3 were referred for hyperthyroidism, and workup revealed thyroiditis. These three cases suggest that patients with advanced melanoma treated with ipilimumab +/- bevacizumab may be susceptible to a variety of thyroid disorders. AB - CONCLUSIONS: Anti-CTLA4 therapy has shown promising results in treating advanced malignancy such as melanoma and renal carcinoma. A number of endocrinopathies, including thyroid disorders, may develop during ipilimumab therapy. The association of bevacizumab with endocrinopathies is not clear, although a few reports suggest a link to hypothyroidism. All patients on ipilimumab and/or bevacizumab therapy should be monitored for signs or symptoms of thyroiditis. RN - 0 (Antibodies, Monoclonal) RN - 6T8C155666 (ipilimumab) ES - 1479-683X IL - 0804-4643 DI - EJE-10-0833 DO - https://dx.doi.org/10.1530/EJE-10-0833 PT - Case Reports PT - Journal Article ID - 21088057 [pubmed] ID - EJE-10-0833 [pii] ID - 10.1530/EJE-10-0833 [doi] ID - PMC4080629 [pmc] ID - NIHMS367388 [mid] PP - ppublish GI - No: F32 HL104776 Organization: (HL) *NHLBI NIH HHS* Country: United States No: F32 HL104776-01 Organization: (HL) *NHLBI NIH HHS* Country: United States No: K08 HD070957 Organization: (HD) *NICHD NIH HHS* Country: United States No: T32 DK007529 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English EP - 20101118 DP - 2011 Feb DC - 20110119 EZ - 2010/11/20 06:00 DA - 2011/02/22 06:00 DT - 2010/11/20 06:00 YR - 2011 ED - 20110218 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med7&AN=21088057 <313. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21220230 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Andre T AU - Wislez M AU - Goncalves A AU - de La Motte Rouge T AU - Blay JY AU - Massard C AU - Bay JO AU - comite de redaction du Bulletin du Cancer FA - Andre, T FA - Wislez, M FA - Goncalves, A FA - de La Motte Rouge, T FA - Blay, J-Y FA - Massard, C FA - Bay, J-O FA - comite de redaction du Bulletin du Cancer IN - Andre, T. Service d'hepatogastroenterologie, hopital Pitie-Salpetriere, 47-83, boulevard de l'Hopital, 75651 Paris cedex 13, France. thierry.andre@psl.aphp.fr TI - [Following communications made at American Society of Clinical Oncology 2010, what will change our practice? The point of view of the editorial board of Bulletin du Cancer]. [French] OT - Suite aux communications faites au congres de l'American Society of Clinical Oncology 2010, qu'est ce qui va changer nos pratiques ? Le point de vue du comite de redaction du Bulletin du cancer. SO - Bulletin du Cancer. 97(12):1551-62, 2010 Dec AS - Bull Cancer. 97(12):1551-62, 2010 Dec NJ - Bulletin du cancer PI - Journal available in: Print PI - Citation processed from: Internet JC - 0072416 IO - Bull Cancer SB - Index Medicus CP - France MH - Breast Neoplasms/th [Therapy] MH - Digestive System Neoplasms/th [Therapy] MH - Female MH - Gastrointestinal Stromal Tumors/dt [Drug Therapy] MH - Genital Neoplasms, Female/dt [Drug Therapy] MH - Hematologic Neoplasms/th [Therapy] MH - Humans MH - Lung Neoplasms/dt [Drug Therapy] MH - Male MH - *Medical Oncology/st [Standards] MH - Melanoma/dt [Drug Therapy] MH - *Neoplasms/th [Therapy] MH - *Practice Patterns, Physicians'/st [Standards] MH - Prostatic Neoplasms/dt [Drug Therapy] MH - Sarcoma/dt [Drug Therapy] MH - *Societies, Medical/st [Standards] MH - Testicular Neoplasms/dt [Drug Therapy] MH - Thyroid Neoplasms/dt [Drug Therapy] MH - United States AB - The congress of Asco made the object of numerous summaries of congress made in the heat of the moment and the Bulletin du Cancer decided to ask to his editorial board, a digested summary, at distance of the congress, to try to sum up the data of the congress which are going to change practice. Of the considerable number of communications, editorial board chose 40 communications which appeared to answer these rules. Best understanding of biological mechanisms and new molecules to inhibit targets allow in certain case, to use therapeutic targeting in the true sense. The identification of the gene of fusion EML4-ALK in lung adenocarcinoma, and its inhibition by the crizotinib, constitute a considerable progress for 5% of patients with this disease. Molecular biology with the mutations of the exon 11 in GIST, allow to better define the population which is going to benefit from adjuvant imatinib. In Advanced non-small cell lung cancer, myeloma and advanced lymphoma, maintenance therapy by monoclonal anti-body or inhibitors of tyrosines kinases showed the proof of their effectiveness. In advanced melanoma, ipilimumab is a light of hope in a pathology in always prognostic is so dark. In metastatic adenocarcinoma of the pancreas, there is finally an alternative to gemcitabine with the Folfirinox regimen, with an improvement of overall survival. Biological personalization of cancer treatments is on the road run but the road is still long. ES - 1769-6917 IL - 0007-4551 DI - S0007-4551(15)30739-6 DO - https://dx.doi.org/10.1684/bdc.2010.1221 PT - English Abstract PT - Journal Article ID - 21220230 [pubmed] ID - S0007-4551(15)30739-6 [pii] ID - 10.1684/bdc.2010.1221 [doi] PP - ppublish LG - French DP - 2010 Dec DC - 20110111 EZ - 2011/01/12 06:00 DA - 2011/02/04 06:00 DT - 2011/01/12 06:00 YR - 2010 ED - 20110203 RD - 20151119 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=21220230 <314. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21074064 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kaehler KC AU - Piel S AU - Livingstone E AU - Schilling B AU - Hauschild A AU - Schadendorf D FA - Kaehler, Katharina C FA - Piel, Sarah FA - Livingstone, Elisabeth FA - Schilling, Bastian FA - Hauschild, Axel FA - Schadendorf, Dirk IN - Kaehler, Katharina C. Department of Dermatology and Skin Cancer Center, University Hospital Schleswig-Holtstein, Campus Kiel, Germany. TI - Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. [Review][Erratum appears in Semin Oncol. 2012 Oct;39(5):625] SO - Seminars in Oncology. 37(5):485-98, 2010 Oct AS - Semin Oncol. 37(5):485-98, 2010 Oct NJ - Seminars in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - un5, 0420432 IO - Semin. Oncol. SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - *Antigens, CD/im [Immunology] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/im [Immunology] MH - Biomarkers/bl [Blood] MH - C-Reactive Protein/me [Metabolism] MH - CTLA-4 Antigen MH - Chemical and Drug Induced Liver Injury/im [Immunology] MH - Chemical and Drug Induced Liver Injury/th [Therapy] MH - Digestive System Diseases/ci [Chemically Induced] MH - Digestive System Diseases/im [Immunology] MH - Digestive System Diseases/th [Therapy] MH - Endocrine System Diseases/ci [Chemically Induced] MH - Endocrine System Diseases/im [Immunology] MH - Endocrine System Diseases/th [Therapy] MH - Humans MH - *Immune System Diseases/ci [Chemically Induced] MH - Immune System Diseases/th [Therapy] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Skin Diseases/ci [Chemically Induced] MH - Skin Diseases/im [Immunology] MH - Skin Diseases/th [Therapy] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] AB - Immune-modifying monoclonal antibodies may induce or enhance the natural immune response against tumor cells. The complex interaction between antigen-presenting cells and T lymphocytes as an immune response is strongly affected by anti-CD152 (cytotoxic T-lymphocyte antigen-4, CTLA-4)-antibodies. However, specific CTLA-4 antibodies can block the CTLA-4 receptor and thus induce an unrestrained T-cell activation. To this stage, treatment of patients with metastatic melanoma with the CTLA-4 antibodies ipilimumab and tremelimumab has only been investigated within clinical trials. The results of a phase III trial in patients with advanced disease treated with ipilimumab alone or in combination with a peptide vaccination (gp100) recently presented at the 2010 annual meeting of the Ameircan Society of Clinical Oncology (ASCO) made groundbreaking news as ipilimumab was demonstrated to be the first drug in melanoma treatment to show a significant prolongation of survival time. Patients undergoing treatment with CTLA-4 antibodies may experience immune-related phenomena and adverse events (irAEs) that differ greatly from the well-known adverse events of cytotoxic drugs and which are due to the CTLA-4 antibodies' specific mode of action. This review gives a condensed overview on the mechanisms of action, an update on clinical data of the two CTLA-4 antibodies, ipilimumab and tremelimumab, and detailed recommendations for adverse event management strategies. AB - Copyright © 2010 Elsevier Inc. All rights reserved. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) RN - 9007-41-4 (C-Reactive Protein) RN - QEN1X95CIX (tremelimumab) ES - 1532-8708 IL - 0093-7754 DI - S0093-7754(10)00157-0 DO - https://dx.doi.org/10.1053/j.seminoncol.2010.09.003 PT - Journal Article PT - Review ID - 21074064 [pubmed] ID - S0093-7754(10)00157-0 [pii] ID - 10.1053/j.seminoncol.2010.09.003 [doi] PP - ppublish LG - English DP - 2010 Oct DC - 20101115 EZ - 2010/11/16 06:00 DA - 2010/12/16 06:00 DT - 2010/11/16 06:00 YR - 2010 ED - 20101214 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=21074064 <315. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 21074058 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Boasberg P AU - Hamid O AU - O'Day S FA - Boasberg, Peter FA - Hamid, Omid FA - O'Day, Steven IN - Boasberg, Peter. The Angeles Clinic & Research Institute, 2001 Santa Monica Blvd, Suite 560W, Santa Monica, CA 90404, USA. pboasberg@theangelesclinic.org TI - Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. [Review] SO - Seminars in Oncology. 37(5):440-9, 2010 Oct AS - Semin Oncol. 37(5):440-9, 2010 Oct NJ - Seminars in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - un5, 0420432 IO - Semin. Oncol. SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antigens, CD/im [Immunology] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - CTLA-4 Antigen MH - Dacarbazine/ad [Administration & Dosage] MH - Drug-Related Side Effects and Adverse Reactions MH - Humans MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] AB - Malignant melanoma is rising faster in incidence than any other malignancy. Long-term remission or "cure" is rare and is almost exclusively limited to therapies that stimulate an immune antitumor response. Ipilimumab is a novel targeted human immunostimulatory monoclonal antibody that blocks cytotoxic T-lymphocyte antigen4 (CTLA-4), an immune-inhibitory site expressed on activated T cells. Ipilimumab is well tolerated as an outpatient infusion therapy. Multiple studies have confirmed significant antimelanoma activity. A randomized trial has documented a survival benefit when ipilimumab was compared to a gp-100 vaccine only arm. The unique mechanism of action of ipilimumab makes assessment of response by conventional criteria difficult. Benefit from ipilimumab can occur after what would be considered progression with World Health Oganization (WHO) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria. New immune response criteria have been proposed. Therapeutic responses peak between 12 and 24 weeks, with slow responses continuing up to and beyond 12 months. The major drug- related adverse side effects (10%-15% grade 3 or above) are immune-related and consist most commonly of rash, colitis, hypophysitis, thyroiditis, and hepatitis. Colonic perforation can occur and patients with diarrhea have to be monitored carefully with strict adherence to treatment algorithms. Algorithms for the treatment of other adverse side effects have been developed. The treatment of immune-related side effects with immunosuppressive agents, such as corticosteroids, does not appear to impair antitumor response. With proper monitoring and management of side effects, ipilimumab is an extremely safe drug to administer. The benefits of ipilimumab will most certainly extend to other malignancies in the near future. AB - Copyright © 2010. Published by Elsevier Inc. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) RN - 7GR28W0FJI (Dacarbazine) ES - 1532-8708 IL - 0093-7754 DI - S0093-7754(10)00158-2 DO - https://dx.doi.org/10.1053/j.seminoncol.2010.09.004 PT - Journal Article PT - Review ID - 21074058 [pubmed] ID - S0093-7754(10)00158-2 [pii] ID - 10.1053/j.seminoncol.2010.09.004 [doi] PP - ppublish LG - English DP - 2010 Oct DC - 20101115 EZ - 2010/11/16 06:00 DA - 2010/12/16 06:00 DT - 2010/11/16 06:00 YR - 2010 ED - 20101214 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=21074058 <316. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20455200 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Pinto-Garcia L AU - Efferth T AU - Torres A AU - Hoheisel JD AU - Youns M FA - Pinto-Garcia, Lina FA - Efferth, Thomas FA - Torres, Amada FA - Hoheisel, Jorg D FA - Youns, Mahmoud IN - Pinto-Garcia, Lina. Department of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. TI - Berberine inhibits cell growth and mediates caspase-independent cell death in human pancreatic cancer cells. SO - Planta Medica. 76(11):1155-61, 2010 Aug AS - Planta Med. 76(11):1155-61, 2010 Aug NJ - Planta medica PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0066751, p9f IO - Planta Med. SB - Index Medicus CP - Germany MH - Antineoplastic Agents, Phytogenic/an [Analysis] MH - *Antineoplastic Agents, Phytogenic/pd [Pharmacology] MH - Antineoplastic Agents, Phytogenic/tu [Therapeutic Use] MH - *Apoptosis/de [Drug Effects] MH - Berberine/an [Analysis] MH - *Berberine/pd [Pharmacology] MH - Berberine/tu [Therapeutic Use] MH - Caspase Inhibitors MH - Caspases/me [Metabolism] MH - *Caspases/ph [Physiology] MH - Cell Line, Tumor MH - Cell Proliferation/de [Drug Effects] MH - Enzyme Activation MH - Gene Expression Profiling MH - Humans MH - Immunohistochemistry MH - Oligonucleotide Array Sequence Analysis MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/ge [Genetics] MH - *Pancreatic Neoplasms/pa [Pathology] MH - RNA, Messenger/me [Metabolism] MH - Signal Transduction/de [Drug Effects] AB - Pancreatic cancer is one of the most aggressive human malignancies with an increasing incidence worldwide. In addition to the poor survival rates, combinations using gemcitabine as a backbone have failed to show any benefit beyond monotherapy. These facts underscore an urgent need for novel therapeutic options and motivated us to study the effect of berberine on pancreatic cancer cells. Here, we undertook an mRNA-based gene expression profiling study in order to get deeper insight into the molecular targets mediating the growth inhibitory effects of berberine on pancreatic cancer cells compared to normal ones. Twenty-four hours after treatment, berberine showed preferential selectivity toward pancreatic cancer cells compared to normal ones. Moreover, expression profiling and Ingenuity pathway analysis results showed that the cytotoxicity of berberine was accompanied with an activation of BRCA1-mediated DNA damage response, G1/S and G2/M cell cycle checkpoint regulation, and P53 signalling pathways. The activation of these signalling pathways might be explained by the fact that berberine intercalates DNA and induces DNA strand break through inhibition of topoisomerases and induction of DNA lesions. AB - Copyright Georg Thieme Verlag KG Stuttgart-New York. RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (Caspase Inhibitors) RN - 0 (RNA, Messenger) RN - 0I8Y3P32UF (Berberine) RN - EC 3-4-22 (Caspases) ES - 1439-0221 IL - 0032-0943 DO - https://dx.doi.org/10.1055/s-0030-1249931 PT - Journal Article ID - 20455200 [pubmed] ID - 10.1055/s-0030-1249931 [doi] PP - ppublish LG - English EP - 20100507 DP - 2010 Aug DC - 20100728 EZ - 2010/05/11 06:00 DA - 2010/12/14 06:00 DT - 2010/05/11 06:00 YR - 2010 ED - 20101202 RD - 20131121 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=20455200 <317. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20734041 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Frankel TL AU - Burns W AU - Riley J AU - Morgan RA AU - Davis JL AU - Hanada K AU - Quezado M AU - Rosenberg SA AU - Royal RE FA - Frankel, Timothy L FA - Burns, William FA - Riley, John FA - Morgan, Richard A FA - Davis, Jeremy L FA - Hanada, Kenichi FA - Quezado, Martha FA - Rosenberg, Steven A FA - Royal, Richard E IN - Frankel, Timothy L. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. TI - Identification and characterization of a tumor infiltrating CD56(+)/CD16 (-) NK cell subset with specificity for pancreatic and prostate cancer cell lines. SO - Cancer Immunology, Immunotherapy. 59(12):1757-69, 2010 Dec AS - Cancer Immunol Immunother. 59(12):1757-69, 2010 Dec NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. SB - Index Medicus CP - Germany MH - *Antigens, CD56/an [Analysis] MH - Cell Line, Tumor MH - Female MH - GPI-Linked Proteins MH - HLA-A2 Antigen/im [Immunology] MH - Humans MH - Immunophenotyping MH - Immunotherapy MH - Interferon-gamma/bi [Biosynthesis] MH - *Killer Cells, Natural/im [Immunology] MH - *Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Male MH - *Pancreatic Neoplasms/im [Immunology] MH - Pancreatic Neoplasms/pa [Pathology] MH - Pancreatic Neoplasms/th [Therapy] MH - *Prostatic Neoplasms/im [Immunology] MH - Prostatic Neoplasms/pa [Pathology] MH - Prostatic Neoplasms/th [Therapy] MH - *Receptors, IgG/an [Analysis] MH - TNF-Related Apoptosis-Inducing Ligand/ph [Physiology] AB - In a recent clinical trial, a patient exhibited regression of several pancreatic cancer metastases following the administration of the immune modulator Ipilimumab (anti-CTLA-4 antibody). We sought to characterize the immune cells responsible for this regression. Tumor infiltrating lymphocytes (TIL-2742) and an autologous tumor line (TC-2742) were expanded from a regressing metastatic lesion excised from this patient. Natural killer (NK) cells predominated in the TIL (92% CD56(+)) with few T cells (12% CD3(+)). A majority (88%) of the NK cells were CD56(bright)CD16(-). TIL-2742 secreted IFN-gamma and GM-CSF following co-culture with TC-2742 and major histocompatibility complex mismatched pancreatic tumor lines. After sorting TIL-2742, the purified CD56(+)CD16(-)CD3(-) subset showed reactivity similar to TIL-2742 while the CD56(-)CD16(-)CD3(+) cells exhibited no tumor recognition. In co-culture assays, TIL-2742 and the NK subset expressed high reactivity to several pancreatic and prostate cancer cell lines and could lyse the autologous tumor as well as pancreas and prostate cancer lines. Reactivity was partially abrogated by blockade of TRAIL. We thus identified a unique subset of NK cells (CD56(bright)CD16(dim)) isolated from a regressing metastatic pancreatic cancer in a patient responding to Ipilimumab. This represents the first report of CD56(+)CD16(-) NK cells with apparent specificity for pancreatic and prostate cancer cell lines and associated with tumor regression following the treatment with an immune modulating agent. RN - 0 (Antigens, CD56) RN - 0 (FCGR3B protein, human) RN - 0 (GPI-Linked Proteins) RN - 0 (HLA-A2 Antigen) RN - 0 (Receptors, IgG) RN - 0 (TNF-Related Apoptosis-Inducing Ligand) RN - 0 (TNFSF10 protein, human) RN - 82115-62-6 (Interferon-gamma) ES - 1432-0851 IL - 0340-7004 DO - https://dx.doi.org/10.1007/s00262-010-0897-y PT - Journal Article ID - 20734041 [pubmed] ID - 10.1007/s00262-010-0897-y [doi] PP - ppublish PH - 2010/04/13 [received] PH - 2010/07/22 [accepted] LG - English EP - 20100824 DP - 2010 Dec DC - 20100927 EZ - 2010/08/25 06:00 DA - 2010/10/22 06:00 DT - 2010/08/25 06:00 YR - 2010 ED - 20101021 RD - 20101118 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=20734041 <318. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20004555 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Van Belle TL AU - Juntti T AU - Liao J AU - von Herrath MG FA - Van Belle, Tom L FA - Juntti, Therese FA - Liao, Jeanette FA - von Herrath, Matthias G IN - Van Belle, Tom L. Diabetes Center at San Diego, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. TI - Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment. SO - Journal of Autoimmunity. 34(4):445-52, 2010 Jun AS - J Autoimmun. 34(4):445-52, 2010 Jun NJ - Journal of autoimmunity PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - adl, 8812164 IO - J. Autoimmun. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860005 OI - Source: NLM. NIHMS160979 SB - Index Medicus CP - England MH - Animals MH - *Autoimmunity MH - CD8-Positive T-Lymphocytes/cy [Cytology] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - Cell Proliferation MH - Dendritic Cells/cy [Cytology] MH - *Diabetes Mellitus, Type 1/dt [Drug Therapy] MH - Humans MH - Islets of Langerhans/im [Immunology] MH - *Membrane Proteins/tu [Therapeutic Use] MH - Mice MH - Mice, Inbred NOD MH - T-Lymphocytes, Regulatory/cy [Cytology] MH - Treatment Outcome AB - Redirection of immune responses by manipulation of antigen-presenting cells is an emerging strategy for immunosuppressive treatment of autoimmune diseases. In vivo expansion of dendritic cells (DC) by Fms-like tyrosine kinase-3 (Flt3)-Ligand (FL) treatment was shown to delay diabetes onset in the NOD model of autoimmune diabetes. However, we show here that Flt3 stimulation actually accelerates autoimmunity when autoreactive CD8 T cells are detectable in blood prior to treatment. With autoreactive CD8 cells present, the capacity of FL to expand DCs and induce Treg remained intact, but both numbers and the functional response of islet-specific CD8s were boosted. Also, the inhibitory receptor PD-1 on (autoreactive) CD8 T cells and its ligand PD-L1 on Treg were no longer upregulated. These data highlight the need to pre-screen for T cell autoreactivity prior to generalized DC expansion and illustrate how accelerated disease can occur when the intended initiation of regulatory mechanisms is impaired later in diabetogenesis. RN - 0 (Membrane Proteins) RN - 0 (flt3 ligand protein) ES - 1095-9157 IL - 0896-8411 DI - S0896-8411(09)00150-4 DO - https://dx.doi.org/10.1016/j.jaut.2009.11.010 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 20004555 [pubmed] ID - S0896-8411(09)00150-4 [pii] ID - 10.1016/j.jaut.2009.11.010 [doi] ID - PMC2860005 [pmc] ID - NIHMS160979 [mid] PP - ppublish PH - 2009/10/26 [received] PH - 2009/11/13 [revised] PH - 2009/11/16 [accepted] GI - No: R01 AI044451-08 Organization: (AI) *NIAID NIH HHS* Country: United States No: R01 AI044451 Organization: (AI) *NIAID NIH HHS* Country: United States No: R01 DK066346-05S1 Organization: (DK) *NIDDK NIH HHS* Country: United States No: R01 DK066346 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P01 AI058105 Organization: (AI) *NIAID NIH HHS* Country: United States No: P01 AI058105-05 Organization: (AI) *NIAID NIH HHS* Country: United States LG - English EP - 20091209 DP - 2010 Jun DC - 20100426 EZ - 2009/12/17 06:00 DA - 2010/08/14 06:00 DT - 2009/12/17 06:00 YR - 2010 ED - 20100813 RD - 20161215 UP - 20161221 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=20004555 <319. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20004555 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Van Belle TL AU - Juntti T AU - Liao J AU - von Herrath MG FA - Van Belle, Tom L FA - Juntti, Therese FA - Liao, Jeanette FA - von Herrath, Matthias G IN - Van Belle, Tom L. Diabetes Center at San Diego, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA. TI - Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment. SO - Journal of Autoimmunity. 34(4):445-52, 2010 Jun AS - J Autoimmun. 34(4):445-52, 2010 Jun NJ - Journal of autoimmunity PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - adl, 8812164 IO - J. Autoimmun. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860005 OI - Source: NLM. NIHMS160979 SB - Index Medicus CP - England MH - Animals MH - *Autoimmunity MH - CD8-Positive T-Lymphocytes/cy [Cytology] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - Cell Proliferation MH - Dendritic Cells/cy [Cytology] MH - *Diabetes Mellitus, Type 1/dt [Drug Therapy] MH - Humans MH - Islets of Langerhans/im [Immunology] MH - *Membrane Proteins/tu [Therapeutic Use] MH - Mice MH - Mice, Inbred NOD MH - T-Lymphocytes, Regulatory/cy [Cytology] MH - Treatment Outcome AB - Redirection of immune responses by manipulation of antigen-presenting cells is an emerging strategy for immunosuppressive treatment of autoimmune diseases. In vivo expansion of dendritic cells (DC) by Fms-like tyrosine kinase-3 (Flt3)-Ligand (FL) treatment was shown to delay diabetes onset in the NOD model of autoimmune diabetes. However, we show here that Flt3 stimulation actually accelerates autoimmunity when autoreactive CD8 T cells are detectable in blood prior to treatment. With autoreactive CD8 cells present, the capacity of FL to expand DCs and induce Treg remained intact, but both numbers and the functional response of islet-specific CD8s were boosted. Also, the inhibitory receptor PD-1 on (autoreactive) CD8 T cells and its ligand PD-L1 on Treg were no longer upregulated. These data highlight the need to pre-screen for T cell autoreactivity prior to generalized DC expansion and illustrate how accelerated disease can occur when the intended initiation of regulatory mechanisms is impaired later in diabetogenesis. RN - 0 (Membrane Proteins) RN - 0 (flt3 ligand protein) ES - 1095-9157 IL - 0896-8411 DI - S0896-8411(09)00150-4 DO - https://dx.doi.org/10.1016/j.jaut.2009.11.010 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 20004555 [pubmed] ID - S0896-8411(09)00150-4 [pii] ID - 10.1016/j.jaut.2009.11.010 [doi] ID - PMC2860005 [pmc] ID - NIHMS160979 [mid] PP - ppublish PH - 2009/10/26 [received] PH - 2009/11/13 [revised] PH - 2009/11/16 [accepted] SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00445913 SL - https://clinicaltrials.gov/search/term=NCT00445913 GI - No: R01 AI044451-08 Organization: (AI) *NIAID NIH HHS* Country: United States No: R01 AI044451 Organization: (AI) *NIAID NIH HHS* Country: United States No: R01 DK066346-05S1 Organization: (DK) *NIDDK NIH HHS* Country: United States No: R01 DK066346 Organization: (DK) *NIDDK NIH HHS* Country: United States No: P01 AI058105 Organization: (AI) *NIAID NIH HHS* Country: United States No: P01 AI058105-05 Organization: (AI) *NIAID NIH HHS* Country: United States LG - English EP - 20091209 DP - 2010 Jun DC - 20100426 EZ - 2009/12/17 06:00 DA - 2010/08/14 06:00 DT - 2009/12/17 06:00 YR - 2010 ED - 20100813 RD - 20161206 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=20004555 <320. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20501833 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Morgan MA AU - Parsels LA AU - Zhao L AU - Parsels JD AU - Davis MA AU - Hassan MC AU - Arumugarajah S AU - Hylander-Gans L AU - Morosini D AU - Simeone DM AU - Canman CE AU - Normolle DP AU - Zabludoff SD AU - Maybaum J AU - Lawrence TS FA - Morgan, Meredith A FA - Parsels, Leslie A FA - Zhao, Lili FA - Parsels, Joshua D FA - Davis, Mary A FA - Hassan, Maria C FA - Arumugarajah, Sankari FA - Hylander-Gans, Linda FA - Morosini, Deborah FA - Simeone, Diane M FA - Canman, Christine E FA - Normolle, Daniel P FA - Zabludoff, Sonya D FA - Maybaum, Jonathan FA - Lawrence, Theodore S IN - Morgan, Meredith A. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5637, USA. mmccrack@med.umich.edu TI - Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. SO - Cancer Research. 70(12):4972-81, 2010 Jun 15 AS - Cancer Res. 70(12):4972-81, 2010 Jun 15 NJ - Cancer research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnf, 2984705r IO - Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889008 OI - Source: NLM. NIHMS201260 SB - Index Medicus CP - United States MH - Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/me [Metabolism] MH - Adenocarcinoma/pa [Pathology] MH - Animals MH - Blotting, Western MH - Cell Line, Tumor MH - Checkpoint Kinase 1 MH - Checkpoint Kinase 2 MH - DNA Damage/de [Drug Effects] MH - DNA Damage/re [Radiation Effects] MH - *DNA Repair/de [Drug Effects] MH - DNA Repair/re [Radiation Effects] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Drug Therapy, Combination MH - Flow Cytometry MH - Fluorescent Antibody Technique MH - *G2 Phase/de [Drug Effects] MH - G2 Phase/re [Radiation Effects] MH - Gamma Rays MH - Humans MH - Immunoblotting MH - Immunoenzyme Techniques MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - *Pancreatic Neoplasms/rt [Radiotherapy] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - Protein Kinases/ch [Chemistry] MH - Protein Kinases/me [Metabolism] MH - *Protein-Serine-Threonine Kinases/ai [Antagonists & Inhibitors] MH - RNA, Messenger/ge [Genetics] MH - RNA, Messenger/me [Metabolism] MH - Rad51 Recombinase/me [Metabolism] MH - *Radiation-Sensitizing Agents/pd [Pharmacology] MH - Recombination, Genetic/de [Drug Effects] MH - Recombination, Genetic/re [Radiation Effects] MH - Reverse Transcriptase Polymerase Chain Reaction MH - *Thiophenes/pd [Pharmacology] MH - *Urea/aa [Analogs & Derivatives] MH - Urea/pd [Pharmacology] MH - Xenograft Model Antitumor Assays AB - The median survival for patients with locally advanced pancreatic cancer treated with gemcitabine and radiation is approximately 1 year. To develop improved treatment, we have combined a Chk1/2-targeted agent, AZD7762, currently in phase I clinical trials, with gemcitabine and ionizing radiation in preclinical pancreatic tumor models. We found that in vitro AZD7762 alone or in combination with gemcitabine significantly sensitized MiaPaCa-2 cells to radiation. AZD7762 inhibited Chk1 autophosphorylation (S296 Chk1), stabilized Cdc25A, and increased ATR/ATM-mediated Chk1 phosphorylation (S345 Chk1). Radiosensitization by AZD7762 was associated with abrogation of the G(2) checkpoint as well as with inhibition of Rad51 focus formation, inhibition of homologous recombination repair, and persistent gamma-H2AX expression. AZD7762 was also a radiation sensitizer in multiple tumor xenograft models. In both MiaPaCa-2- and patient-derived xenografts, AZD7762 significantly prolonged the median time required for tumor volume doubling in response to gemcitabine and radiation. Together, our findings suggest that G(2) checkpoint abrogation and homologous recombination repair inhibition both contribute to sensitization by Chk1 inhibition. Furthermore, they support the clinical use of AZD7762 in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. RN - 0 (3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide) RN - 0 (Protein Kinase Inhibitors) RN - 0 (RNA, Messenger) RN - 0 (Radiation-Sensitizing Agents) RN - 0 (Thiophenes) RN - 0W860991D6 (Deoxycytidine) RN - 8W8T17847W (Urea) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-1-11 (Checkpoint Kinase 2) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (CHEK2 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - EC 2-7-11-1 (Chek1 protein, mouse) RN - EC 2-7-11-1 (Chek2 protein, mouse) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - EC 2-7-7 (Rad51 Recombinase) ES - 1538-7445 IL - 0008-5472 DI - 0008-5472.CAN-09-3573 DO - https://dx.doi.org/10.1158/0008-5472.CAN-09-3573 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 20501833 [pubmed] ID - 0008-5472.CAN-09-3573 [pii] ID - 10.1158/0008-5472.CAN-09-3573 [doi] ID - PMC2889008 [pmc] ID - NIHMS201260 [mid] PP - ppublish GI - No: P30 CA046592 Organization: (CA) *NCI NIH HHS* Country: United States No: R01CA78554 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA138723 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA078554-11 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA078554 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA046592-22S39027 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20100525 DP - 2010 Jun 15 DC - 20100616 EZ - 2010/05/27 06:00 DA - 2010/07/23 06:00 DT - 2010/05/27 06:00 YR - 2010 ED - 20100722 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=20501833 <321. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 18577252 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Selvakumar E AU - Hsieh TC FA - Selvakumar, Elangovan FA - Hsieh, Tze-Chen IN - Selvakumar, Elangovan. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595, USA. eselva@gmail.com TI - Regulation of cell cycle transition and induction of apoptosis in HL-60 leukemia cells by lipoic acid: role in cancer prevention and therapy. SO - Journal of hematology & oncology. 1:4, 2008 May 30 AS - J Hematol Oncol. 1:4, 2008 May 30 NJ - Journal of hematology & oncology PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101468937 IO - J Hematol Oncol PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2438439 SB - Index Medicus CP - England MH - *Anticarcinogenic Agents/pd [Pharmacology] MH - Anticarcinogenic Agents/tu [Therapeutic Use] MH - *Apoptosis/de [Drug Effects] MH - Apoptosis Inducing Factor/me [Metabolism] MH - *Cell Cycle/de [Drug Effects] MH - Cytochromes c/me [Metabolism] MH - HL-60 Cells MH - Humans MH - *Leukemia/pc [Prevention & Control] MH - Poly(ADP-ribose) Polymerases/me [Metabolism] MH - Protein Transport/de [Drug Effects] MH - Proto-Oncogene Proteins c-bcl-2/me [Metabolism] MH - *Thioctic Acid/pd [Pharmacology] MH - Thioctic Acid/tu [Therapeutic Use] MH - bcl-2-Associated X Protein/me [Metabolism] AB - BACKGROUND: Lipoic acid (LA), a potent antioxidant, has been used as a dietary supplement to prevent and treat many diseases, including stroke, diabetes, neurodegenerative and hepatic disorders. Recently, potent anti-tumorigenic effects induced by LA were also reported and evident as assayed by suppression of cell proliferation and induction of apoptosis in malignant cells. However, the mechanism by which LA elicits its chemopreventive effects remains unclear. AB - METHODS AND RESULTS: Herein, we investigated whether LA elicits its anti-tumor effects by inducing cell cycle arrest and cell death in human promyelocytic HL-60 cells. The results showed that LA inhibits both cell growth and viability in a time- and dose-dependent manner. Disruption of the G1/S and G2/M phases of cell cycle progression accompanied by the induction of apoptosis was also observed following LA treatment. Cell cycle arrest by LA was correlated with dose-dependent down regulation of Rb phosphorylation, likely via suppression of E2F-dependent cell cycle progression with an accompanying inhibition of cyclin E/cdk2 and cyclin B1/cdk1 levels. Evidence supporting the induction of apoptosis by LA was based on the appearance of sub-G1 peak in flow cytometry analysis and the cleavage of poly(ADP-ribose) polymerase (PARP) from its native 112-kDa form to the 89-kDa truncated product in immunoblot assays. Apoptosis elicited by LA was preceded by diminution in the expression of anti-apoptotic protein bcl-2 and increased expression of apoptogenic protein bax, and also the release and translocation of apoptosis inducing factor AIF and cytochrome c from the mitochondria to the nucleus, without altering the subcellular distribution of the caspases. AB - CONCLUSION: This study provides evidence that LA induces multiple cell cycle checkpoint arrest and caspase-independent cell death in HL-60 cells, in support of its efficacious potential as a chemopreventive agent. RN - 0 (Anticarcinogenic Agents) RN - 0 (Apoptosis Inducing Factor) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (bcl-2-Associated X Protein) RN - 73Y7P0K73Y (Thioctic Acid) RN - 9007-43-6 (Cytochromes c) RN - EC 2-4-2-30 (Poly(ADP-ribose) Polymerases) ES - 1756-8722 IL - 1756-8722 DI - 1756-8722-1-4 DO - https://dx.doi.org/10.1186/1756-8722-1-4 PT - Journal Article ID - 18577252 [pubmed] ID - 1756-8722-1-4 [pii] ID - 10.1186/1756-8722-1-4 [doi] ID - PMC2438439 [pmc] PP - epublish PH - 2008/04/30 [received] PH - 2008/05/30 [accepted] LG - English EP - 20080530 DP - 2008 May 30 DC - 20080625 EZ - 2008/06/26 09:00 DA - 2010/06/04 06:00 DT - 2008/06/26 09:00 YR - 2008 ED - 20100603 RD - 20140903 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=18577252 <322. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20385810 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Matsuzaki J AU - Gnjatic S AU - Mhawech-Fauceglia P AU - Beck A AU - Miller A AU - Tsuji T AU - Eppolito C AU - Qian F AU - Lele S AU - Shrikant P AU - Old LJ AU - Odunsi K FA - Matsuzaki, Junko FA - Gnjatic, Sacha FA - Mhawech-Fauceglia, Paulette FA - Beck, Amy FA - Miller, Austin FA - Tsuji, Takemasa FA - Eppolito, Cheryl FA - Qian, Feng FA - Lele, Shashikant FA - Shrikant, Protul FA - Old, Lloyd J FA - Odunsi, Kunle IN - Matsuzaki, Junko. Departments of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. TI - Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. SO - Proceedings of the National Academy of Sciences of the United States of America. 107(17):7875-80, 2010 Apr 27 AS - Proc Natl Acad Sci U S A. 107(17):7875-80, 2010 Apr 27 NJ - Proceedings of the National Academy of Sciences of the United States of America PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - pv3, 7505876 IO - Proc. Natl. Acad. Sci. U.S.A. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867907 SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/pd [Pharmacology] MH - *Antigens, CD/me [Metabolism] MH - Antigens, Neoplasm/im [Immunology] MH - *Antigens, Neoplasm/me [Metabolism] MH - *Apoptosis Regulatory Proteins/me [Metabolism] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - *CD8-Positive T-Lymphocytes/me [Metabolism] MH - Cytokines/me [Metabolism] MH - Enzyme-Linked Immunosorbent Assay MH - Female MH - *Gene Expression Regulation, Neoplastic/im [Immunology] MH - Humans MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - *Lymphocytes, Tumor-Infiltrating/me [Metabolism] MH - Membrane Proteins/im [Immunology] MH - *Membrane Proteins/me [Metabolism] MH - *Ovarian Neoplasms/im [Immunology] MH - Programmed Cell Death 1 Receptor MH - Signal Transduction/de [Drug Effects] MH - Signal Transduction/im [Immunology] AB - NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8(+) T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8(+) T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8(+) T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8(+)LAG-3(+)PD-1(+) T cells were more impaired in IFN-gamma/TNF-alpha production compared with LAG-3(+)PD-1(-) or LAG-3(-)PD-1(-) subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8(+) T cells, indicating that antitumor function of NY-ESO-1-specific CD8(+) T cells could potentially be improved by therapeutic targeting of these inhibitory receptors. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antigens, Neoplasm) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (CD223 antigen) RN - 0 (CTAG1B protein, human) RN - 0 (Cytokines) RN - 0 (Membrane Proteins) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) ES - 1091-6490 IL - 0027-8424 DI - 1003345107 DO - https://dx.doi.org/10.1073/pnas.1003345107 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 20385810 [pubmed] ID - 1003345107 [pii] ID - 10.1073/pnas.1003345107 [doi] ID - PMC2867907 [pmc] PP - ppublish LG - English EP - 20100412 DP - 2010 Apr 27 DC - 20100428 EZ - 2010/04/14 06:00 DA - 2010/06/03 06:00 DT - 2010/04/14 06:00 YR - 2010 ED - 20100602 RD - 20141203 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=20385810 <323. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19162512 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Schmelz HU AU - Port M AU - Stockinger M AU - Ruf C AU - Martinscheck A AU - Sparwasser C AU - Weidner W AU - Abend M FA - Schmelz, Hans U FA - Port, Matthias FA - Stockinger, Markus FA - Ruf, Christian FA - Martinscheck, Andreas FA - Sparwasser, Christoph FA - Weidner, Wolfgang FA - Abend, Michael IN - Schmelz, Hans U. Department of Urology, Federal Armed Forces Hospital, Koblenz, Germany. Hans.U.Schmelz@web.de TI - Testis cancer cells have a genetic determination for a high sensitivity to apoptosis inducing stimuli. SO - Urologic Oncology. 28(1):49-58, 2010 Jan-Feb AS - UROL. ONCOL.. 28(1):49-58, 2010 Jan-Feb NJ - Urologic oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9805460 IO - Urol. Oncol. SB - Index Medicus CP - United States MH - Adult MH - *Apoptosis/ge [Genetics] MH - Biopsy MH - Gene Expression Regulation MH - Humans MH - Male MH - *Testicular Neoplasms/ge [Genetics] MH - *Testicular Neoplasms/pa [Pathology] MH - Young Adult AB - OBJECTIVE: The effect of cytotoxic therapy in testicular tumors (TGCT) has been shown to be mediated mainly by the induction of apoptosis. So far, it is not known which genes play a role for this inherent sensitivity to apoptosis inducing drugs. The aim of this study was to investigate the differential gene expression of apoptosis regulating genes in testicular tumors and in normal testis tissue using a quantitative method. As a premature S-phase entry was shown to induce apoptosis, genes controlling the G1/S-phase checkpoint were also investigated. AB - MATERIAL AND METHODS: Gene expression levels of a representative subset of 19 genes involved in apoptosis and cell cycle control were investigated in vivo in 19 TGCTs using real-time quantitative PCR. Measurements were performed in tumor tissues of both tumor entities, seminomatous and non-seminomatous tumors (SGCT and NSGCT), and in corresponding biopsies from the unaffected site of the resected testis. AB - RESULTS: There was an up-regulation of genes that play a role in facilitating apoptosis, such as FasL, TRAIL, and Bax in both tumor entities. Genes inhibiting apoptosis, such as Bcl-2 were predominantly down-regulated. Regarding cell cycle regulators, a gene expression profile was found that corresponds to a premature S phase entry and subsequent apoptosis induction. AB - CONCLUSION: This study for the first time identified in vivo a panel of genes that give TGCT an inherent sensitivity to apoptotic stimuli after exposure to DNA damaging agents. Studies on these genes in therapy-refractory cancers should provide further insight into the mechanisms of chemotherapy resistance. Furthermore, these genes are promising targets for a future targeted therapy of testis cancer. AB - Copyright 2010 Elsevier Inc. All rights reserved. ES - 1873-2496 IL - 1078-1439 DI - S1078-1439(08)00328-1 DO - https://dx.doi.org/10.1016/j.urolonc.2008.11.003 PT - Journal Article ID - 19162512 [pubmed] ID - S1078-1439(08)00328-1 [pii] ID - 10.1016/j.urolonc.2008.11.003 [doi] PP - ppublish PH - 2008/05/06 [received] PH - 2008/11/05 [revised] PH - 2008/11/08 [accepted] LG - English EP - 20090122 DP - 2010 Jan-Feb DC - 20100203 EZ - 2009/01/24 09:00 DA - 2010/05/26 06:00 DT - 2009/01/24 09:00 YR - 2010 ED - 20100525 RD - 20100203 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19162512 <324. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19639414 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Dillard T AU - Yedinak CG AU - Alumkal J AU - Fleseriu M FA - Dillard, Troy FA - Yedinak, Chris G FA - Alumkal, Joshi FA - Fleseriu, Maria IN - Dillard, Troy. Department of Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, OR, USA. TI - Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. [Review] [41 refs] SO - Pituitary. 13(1):29-38, 2010 AS - Pituitary. 13(1):29-38, 2010 NJ - Pituitary PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dsi, 9814578 IO - Pituitary SB - Index Medicus CP - United States MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antigens, CD/im [Immunology] MH - Autoimmune Diseases/di [Diagnosis] MH - Autoimmune Diseases/et [Etiology] MH - Autoimmune Diseases/th [Therapy] MH - CTLA-4 Antigen MH - Carcinoma, Renal Cell/co [Complications] MH - Carcinoma, Renal Cell/dt [Drug Therapy] MH - Humans MH - Male MH - Melanoma/co [Complications] MH - Melanoma/dt [Drug Therapy] MH - Middle Aged MH - Pituitary Diseases/ci [Chemically Induced] MH - Pituitary Diseases/di [Diagnosis] MH - *Pituitary Diseases/im [Immunology] MH - Pituitary Diseases/th [Therapy] MH - Prostatic Neoplasms/co [Complications] MH - Prostatic Neoplasms/dt [Drug Therapy] AB - Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapies represent a novel approach to cancer treatment via disruption of immune tolerance to antigens located on tumor cells. Disruption of immune tolerance, however, may occur at a cost. A host of immune related adverse events (IRAEs) are associated with anti-CTLA-4 therapy. Autoimmune hypophysitis has been reported in up to 17% of patients with melanoma and renal cell carcinoma treated with this therapy. Familiarity with the spectrum of IRAEs connected to these therapies is paramount for endocrinologists, oncologists and those involved in the care of these subjects. We review here key aspects of diagnosis and treatment of anti-CTLA-4 antibody therapy resultant IRAEs. We describe the first two cases of hypopituitarism in prostate cancer subjects undergoing experimental therapy with ipilimumab. The clinical evidence strongly suggests that the prostate cancer subjects developed autoimmune hypophysitis as a consequence of anti-CTLA-4 treatment. High dose glucocorticoid treatment resulted in markedly improved symptoms, and resolution of focal symptoms and diabetes insipidus. One subject recovered pituitary-thyroid axis function after 9 months; however, both continue to require GC replacement. These cases highlight the importance of early screening and treatment for hypopituitarism in all subjects undergoing treatment with anti-CTLA-4 therapy to prevent a potentially fatal outcome from secondary adrenal insufficiency, a readily treatable disease. We recommend mandatory long term follow-up to monitor the development of other hormonal deficits. [References: 41] RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) ES - 1573-7403 IL - 1386-341X DO - https://dx.doi.org/10.1007/s11102-009-0193-z PT - Case Reports PT - Journal Article PT - Review ID - 19639414 [pubmed] ID - 10.1007/s11102-009-0193-z [doi] PP - ppublish PH - 2009/06/12 [received] PH - 2009/07/19 [accepted] LG - English EP - 20090729 DP - 2010 DC - 20100118 EZ - 2009/07/30 09:00 DA - 2010/05/14 06:00 DT - 2009/07/30 09:00 YR - 2010 ED - 20100513 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19639414 <325. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20412757 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ziegler AG AU - Nepom GT FA - Ziegler, Anette-G FA - Nepom, Gerald T IN - Ziegler, Anette-G. Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universitat Munchen, Kolner Platz 1, 80804 Munchen, Germany. anziegler@lrz.uni-muenchen.de TI - Prediction and pathogenesis in type 1 diabetes. [Review] [98 refs] SO - Immunity. 32(4):468-78, 2010 Apr 23 AS - Immunity. 32(4):468-78, 2010 Apr 23 NJ - Immunity PI - Journal available in: Print PI - Citation processed from: Internet JC - ccf, 9432918 IO - Immunity PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861716 OI - Source: NLM. NIHMS195204 SB - Index Medicus CP - United States MH - Animals MH - Biomarkers MH - *Diabetes Mellitus, Type 1/et [Etiology] MH - *Diabetes Mellitus, Type 1/ge [Genetics] MH - Diabetes Mellitus, Type 1/im [Immunology] MH - *Genetic Predisposition to Disease MH - Genetic Variation MH - Humans MH - Risk Factors AB - A combination of genetic and immunological features is useful for prediction of autoimmune diabetes. Patterns of immune response correspond to the progression from a preclinical phase of disease to end-stage islet damage, with biomarkers indicating transition from susceptibility to active autoimmunity, and to a final loss of immune regulation. Here, we review the markers that provide evidence for immunological checkpoint failure and that also provide tools for assessment of individualized disease risk. When viewed in the context of genetic variation that influences immune response thresholds, progression from susceptibility to overt disease displays predictable modalities of clinical presentation resulting from a sequential series of failed homeostatic checkpoints for selection and activation of immunity. AB - Copyright 2010 Elsevier Inc. All rights reserved. [References: 98] RN - 0 (Biomarkers) ES - 1097-4180 IL - 1074-7613 DI - S1074-7613(10)00125-1 DO - https://dx.doi.org/10.1016/j.immuni.2010.03.018 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review ID - 20412757 [pubmed] ID - S1074-7613(10)00125-1 [pii] ID - 10.1016/j.immuni.2010.03.018 [doi] ID - PMC2861716 [pmc] ID - NIHMS195204 [mid] PP - ppublish PH - 2010/03/15 [received] PH - 2010/03/15 [revised] PH - 2010/03/30 [accepted] GI - No: U19 AI050864 Organization: (AI) *NIAID NIH HHS* Country: United States No: U19 AI050864-090001 Organization: (AI) *NIAID NIH HHS* Country: United States LG - English DP - 2010 Apr 23 DC - 20100423 EZ - 2010/04/24 06:00 DA - 2010/05/07 06:00 DT - 2010/04/24 06:00 YR - 2010 ED - 20100506 RD - 20161122 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=20412757 <326. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 20042274 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Zuco V AU - Benedetti V AU - Zunino F FA - Zuco, Valentina FA - Benedetti, Valentina FA - Zunino, Franco IN - Zuco, Valentina. Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, 20133 Milan, Italy. TI - ATM- and ATR-mediated response to DNA damage induced by a novel camptothecin, ST1968. SO - Cancer Letters. 292(2):186-96, 2010 Jun 28 AS - Cancer Lett. 292(2):186-96, 2010 Jun 28 NJ - Cancer letters PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 7600053, cmx IO - Cancer Lett. SB - Index Medicus CP - Ireland MH - Ataxia Telangiectasia Mutated Proteins MH - *Camptothecin/aa [Analogs & Derivatives] MH - Camptothecin/pd [Pharmacology] MH - Carcinoma, Squamous Cell/pa [Pathology] MH - Cell Cycle MH - *Cell Cycle Proteins/ph [Physiology] MH - Cell Line, Tumor MH - *DNA Damage MH - *DNA-Binding Proteins/ph [Physiology] MH - Female MH - Humans MH - Infrared Rays MH - Ovarian Neoplasms/pa [Pathology] MH - *Protein-Serine-Threonine Kinases/ph [Physiology] MH - *Tumor Suppressor Proteins/ph [Physiology] MH - Ultraviolet Rays AB - DNA damage response and checkpoint activation are expected to influence the sensitivity to DNA-damaging agents. This study was designed to investigate the DNA damage response to the novel camptothecin, ST1968, in two tumor cell lines with a different biological background (A2780 and KB), which underwent distinct cell cycle perturbations and cell death modalities. Following treatment with the camptothecin or ionizing radiation, both inducing double-strand DNA breaks, the ovarian carcinoma A2780 cells exhibited activation of the ATM-Chk2 pathway and early induction of apoptosis. In contrast, the squamous carcinoma KB cells exhibited activation of ATR-Chk1 pathway, a persistent G(2)/M-phase arrest, cellular senescence, mitotic catastrophe and delayed apoptosis, suggesting a defective ATM pathway. The cellular response to UV-induced DNA damage, which activates ATR-Chk1 pathway, was similar in the two cell lines exhibiting early apoptosis induction. Inhibition of ATM in A2780 cells, resulting in reduced phosphorylation of Chk2, enhanced ST1968-induced apoptosis, but had no effect in KB cells. The susceptibility to camptothecin-induced apoptosis of A2780 cells was likely p53-dependent but not related to the activation of the ATM pathway. In contrast, the inhibition of Chk1 enhanced apoptosis response in KB cell but not in A2780. Thus, depending on the biological context, the camptothecin activated ATM-Chk2 or ATR-Chk1 pathways, both having a protective role. In conclusion, our results are consistent with the interpretation that the modality of cell death response is not the critical determinant of sensitivity to camptothecins, and support the interest of inhibition of checkpoint kinases to improve the efficacy of camptothecins. AB - Copyright 2009 Elsevier Ireland Ltd. All rights reserved. RN - 0 (Cell Cycle Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (Tumor Suppressor Proteins) RN - 0 (namitecan) RN - EC 2-7-11-1 (ATM protein, human) RN - EC 2-7-11-1 (ATR protein, human) RN - EC 2-7-11-1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - XT3Z54Z28A (Camptothecin) ES - 1872-7980 IL - 0304-3835 DI - S0304-3835(09)00694-6 DO - https://dx.doi.org/10.1016/j.canlet.2009.12.001 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 20042274 [pubmed] ID - S0304-3835(09)00694-6 [pii] ID - 10.1016/j.canlet.2009.12.001 [doi] PP - ppublish PH - 2009/10/15 [received] PH - 2009/11/30 [revised] PH - 2009/12/01 [accepted] LG - English EP - 20091229 DP - 2010 Jun 28 DC - 20100420 EZ - 2010/01/01 06:00 DA - 2010/05/05 06:00 DT - 2010/01/01 06:00 YR - 2010 ED - 20100504 RD - 20131121 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=20042274 <327. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19676051 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Zuco V AU - Benedetti V AU - De Cesare M AU - Zunino F FA - Zuco, Valentina FA - Benedetti, Valentina FA - De Cesare, Michelandrea FA - Zunino, Franco IN - Zuco, Valentina. Preclinical Chemotherapy and Pharmacology Unit, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy. TI - Sensitization of ovarian carcinoma cells to the atypical retinoid ST1926 by the histone deacetylase inhibitor, RC307: enhanced DNA damage response. SO - International Journal of Cancer. 126(5):1246-55, 2010 Mar 01 AS - Int J Cancer. 126(5):1246-55, 2010 Mar 01 NJ - International journal of cancer PI - Journal available in: Print PI - Citation processed from: Internet JC - gqu, 0042124 IO - Int. J. Cancer SB - Index Medicus CP - United States MH - Adamantane/ad [Administration & Dosage] MH - Adamantane/aa [Analogs & Derivatives] MH - Animals MH - *Antineoplastic Combined Chemotherapy Protocols/pd [Pharmacology] MH - *Apoptosis/de [Drug Effects] MH - Blotting, Western MH - Cell Line, Tumor MH - Cell Proliferation/de [Drug Effects] MH - Cinnamates/ad [Administration & Dosage] MH - *DNA Damage/de [Drug Effects] MH - Enzyme Inhibitors/ad [Administration & Dosage] MH - Female MH - Histone Deacetylases/de [Drug Effects] MH - Humans MH - In Situ Nick-End Labeling MH - Mice MH - Mice, Nude MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Retinoids/ad [Administration & Dosage] MH - Xenograft Model Antitumor Assays AB - The synthetic atypical retinoids containing an adamantyl group exhibit antiproliferative or proapoptotic activities. Apoptosis induction is a dose-dependent effect independent of retinoid receptors. We have reported that induction of apoptosis by the atypical retinoid, ST1926, is associated with early manifestations of genotoxic stress. Indeed, in this study performed in ovarian carcinoma cells, we show that exposure to ST1926 resulted in an increase of early markers of DNA damage, including ATM and H2AX phosphorylation. In addition, we found that a novel histone deacetylase (HDAC) inhibitor (RC307) was able to enhance sensitivity of ovarian carcinoma cells to ST1926. Under conditions where single-agent treatment caused only antiproliferative effects, the combination of the atypical retinoid and HDAC inhibitor resulted in marked apoptotic cell death with a more rapid onset in wild-type p53 ovarian carcinoma cells. The sensitization to ST1926-induced apoptosis was associated with an enhanced DNA damage response, because a prolonged expression of DNA damage markers (e.g., H2AX, p53 and RPA-2 phosphorylation) and a marked activation of DNA damage checkpoint kinases (in particular, phosphorylation of Chk1) were observed indicating an accumulation of DNA damage by the ST1926/HDAC inhibitor combination. The study provides additional support to the role of DNA damage as a primary event leading to the activation of apoptosis in ovarian carcinoma cells by adamantyl retinoids and documents the potential therapeutic efficacy of the combination of ST1926 and HDAC inhibitors of the novel series. RN - 0 (3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic acid) RN - 0 (Cinnamates) RN - 0 (Enzyme Inhibitors) RN - 0 (Retinoids) RN - EC 3-5-1-98 (Histone Deacetylases) RN - PJY633525U (Adamantane) ES - 1097-0215 IL - 0020-7136 DO - https://dx.doi.org/10.1002/ijc.24819 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 19676051 [pubmed] ID - 10.1002/ijc.24819 [doi] PP - ppublish LG - English DP - 2010 Mar 01 DC - 20100104 EZ - 2009/08/14 09:00 DA - 2010/01/23 06:00 DT - 2009/08/14 09:00 YR - 2010 ED - 20100122 RD - 20160303 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19676051 <328. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19732843 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ouyang G AU - Yao L AU - Ruan K AU - Song G AU - Mao Y AU - Bao S FA - Ouyang, Gaoliang FA - Yao, Luming FA - Ruan, Kai FA - Song, Gang FA - Mao, Yubin FA - Bao, Shideng IN - Ouyang, Gaoliang. Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, China. oygldz@yahoo.com.cn TI - Genistein induces G2/M cell cycle arrest and apoptosis of human ovarian cancer cells via activation of DNA damage checkpoint pathways. SO - Cell Biology International. 33(12):1237-44, 2009 Dec AS - Cell Biol Int. 33(12):1237-44, 2009 Dec NJ - Cell biology international PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bpn, 9307129 IO - Cell Biol. Int. SB - Index Medicus CP - England MH - *Anticarcinogenic Agents/pd [Pharmacology] MH - *Apoptosis/de [Drug Effects] MH - Apoptosis/ge [Genetics] MH - Ataxia Telangiectasia Mutated Proteins MH - BRCA1 Protein/me [Metabolism] MH - *Cell Cycle/de [Drug Effects] MH - Cell Cycle/ge [Genetics] MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Line, Tumor MH - Cell Proliferation/de [Drug Effects] MH - Checkpoint Kinase 1 MH - Checkpoint Kinase 2 MH - Cyclin B/me [Metabolism] MH - Cyclin-Dependent Kinases MH - *DNA Damage/de [Drug Effects] MH - DNA-Binding Proteins/me [Metabolism] MH - Female MH - *Genistein/pd [Pharmacology] MH - Humans MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - *Ovarian Neoplasms/ge [Genetics] MH - Ovarian Neoplasms/me [Metabolism] MH - *Ovarian Neoplasms/pa [Pathology] MH - Phosphorylation MH - Protein Kinases/me [Metabolism] MH - Protein-Serine-Threonine Kinases/me [Metabolism] MH - *Signal Transduction/de [Drug Effects] MH - Signal Transduction/ge [Genetics] MH - Tumor Suppressor Proteins/me [Metabolism] MH - bcl-2-Associated X Protein/me [Metabolism] MH - bcl-X Protein/me [Metabolism] MH - cdc25 Phosphatases/me [Metabolism] AB - Genistein is a major isoflavonoid in dietary soybean, commonly consumed in Asia. Genistein exerts inhibitory effects on the proliferation of various cancer cells and plays an important role in cancer prevention. However, the molecular and cellular mechanisms of genistein on human ovarian cancer cells are still little known. We show that exposure of human ovarian cancer HO-8910 cells to genistein induces DNA damage, and triggers G2/M phase arrest and apoptosis. Furthermore, we also found that checkpoint proteins ATM and ATR are phosphorylated and activated in the cells treated with genistein. It is also shown that genistein increases the phosphorylation and activation of Chk1 and Chk2, which results in the phosphorylation and inactivation of phosphatases Cdc25C and Cdc25A, and thereby the phosphorylation and inactivation of Cdc2 which arrests cells in G2/M phase. Moreover, genistein enhances the phosphorylation and activation of p53, while decreases the ratio of Bcl-2/Bax and Bcl-xL/Bax and the level of phosphorylated Akt, which result in cells undergoing apoptosis. These results demonstrate that genistein-activated ATM-Chk2-Cdc25 and ATR-Chk1-Cdc25 DNA damage checkpoint pathways can arrest ovarian cancer cells in G2/M phase, and induce apoptosis while the cellular DNA damage is too serious to be repaired. Thus, the antiproliferative, DNA damage-inducing and pro-apoptotic activities of genistein are probably responsible for its genotoxic effects on human ovarian cancer HO-8910 cells. RN - 0 (Anticarcinogenic Agents) RN - 0 (BRCA1 Protein) RN - 0 (Cell Cycle Proteins) RN - 0 (Cyclin B) RN - 0 (DNA-Binding Proteins) RN - 0 (Rad17 protein, human) RN - 0 (Tumor Suppressor Proteins) RN - 0 (bcl-2-Associated X Protein) RN - 0 (bcl-X Protein) RN - DH2M523P0H (Genistein) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-1-11 (Checkpoint Kinase 2) RN - EC 2-7-11-1 (ATM protein, human) RN - EC 2-7-11-1 (ATR protein, human) RN - EC 2-7-11-1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (CHEK2 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - EC 2-7-11-22 (CDK1 protein, human) RN - EC 2-7-11-22 (Cyclin-Dependent Kinases) RN - EC 3-1-3-48 (CDC25A protein, human) RN - EC 3-1-3-48 (CDC25C protein, human) RN - EC 3-1-3-48 (cdc25 Phosphatases) ES - 1095-8355 IL - 1065-6995 DI - S1065-6995(09)00223-6 DO - https://dx.doi.org/10.1016/j.cellbi.2009.08.011 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 19732843 [pubmed] ID - S1065-6995(09)00223-6 [pii] ID - 10.1016/j.cellbi.2009.08.011 [doi] PP - ppublish PH - 2009/01/19 [received] PH - 2009/06/09 [revised] PH - 2009/08/25 [accepted] LG - English EP - 20090902 DP - 2009 Dec DC - 20091120 EZ - 2009/09/08 06:00 DA - 2010/01/20 06:00 DT - 2009/09/08 06:00 YR - 2009 ED - 20100119 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19732843 <329. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19850680 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Mitchell AL AU - Cordell HJ AU - Soemedi R AU - Owen K AU - Skinningsrud B AU - Wolff AB AU - Ericksen M AU - Undlien D AU - Husebye E AU - Pearce SH FA - Mitchell, Anna L FA - Cordell, Heather J FA - Soemedi, Rachel FA - Owen, Kate FA - Skinningsrud, Beate FA - Wolff, Anette Boe FA - Ericksen, Martina FA - Undlien, Dag FA - Husebye, Eystein FA - Pearce, Simon H S IN - Mitchell, Anna L. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom. TI - Programmed death ligand 1 (PD-L1) gene variants contribute to autoimmune Addison's disease and Graves' disease susceptibility. SO - Journal of Clinical Endocrinology & Metabolism. 94(12):5139-45, 2009 Dec AS - J Clin Endocrinol Metab. 94(12):5139-45, 2009 Dec NJ - The Journal of clinical endocrinology and metabolism PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hrb, 0375362 IO - J. Clin. Endocrinol. Metab. SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Addison Disease/ep [Epidemiology] MH - *Addison Disease/ge [Genetics] MH - Addison Disease/pa [Pathology] MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Alleles MH - *Antigens, CD/ge [Genetics] MH - Antigens, CD274 MH - Autoimmune Diseases/ep [Epidemiology] MH - *Autoimmune Diseases/ge [Genetics] MH - Autoimmune Diseases/pa [Pathology] MH - Cohort Studies MH - Female MH - Genetic Markers MH - Genetic Predisposition to Disease MH - Genetic Variation MH - Genotype MH - *Graves Disease/ge [Genetics] MH - Graves Disease/pa [Pathology] MH - Haplotypes MH - Humans MH - Male MH - Middle Aged MH - Norway/ep [Epidemiology] MH - Polymorphism, Single Nucleotide MH - United Kingdom/ep [Epidemiology] MH - Young Adult AB - CONTEXT: Despite much investigation, a substantial amount of the genetic susceptibility to autoimmune diseases remains unaccounted for. Recently, a single-nucleotide polymorphism (SNP) in the programmed death ligand 1 (PD-L1) gene has been associated with Graves' disease (GD) in a Japanese patient cohort. Our aim was to determine whether variants in PD-L1 are also associated with autoimmune Addison's disease (AAD) and to replicate the previous association in patients with GD from the United Kingdom. AB - DESIGN AND PATIENTS: We analyzed eight SNPs within PD-L1 in a United Kingdom cohort of 315 AAD subjects and 316 healthy controls. We then replicated our experiment in a cohort of 342 Norwegian AAD cases and 379 controls and in 496 United Kingdom GD subjects. AB - RESULTS: Three of the eight SNPs studied, part of a haplotype block in the PD-L1 gene, showed modest association with both AAD and GD in the United Kingdom cohort, with maximum evidence at the marker RS1411262 [United Kingdom AAD odds ratio 1.33 (5-95% confidence interval 1.02-1.73), P(genotype) = 0.028; GD odds ratio 1.36 (5-95% confidence interval 1.07-1.72), P(genotype) = 0.033]. Association with genotypes at the same three markers was confirmed in the Norwegian AAD cohort [P(genotype) = 0.011-0.020]. A recessive effect at the most associated alleles was observed in both the AAD and GD cohorts. AB - CONCLUSIONS: We confirm the role of PD-L1 variants in GD susceptibility and extend these findings to demonstrate association in two Northern European patient cohorts with AAD. PD-L1 joins the growing number of known susceptibility loci exerting modest effects in these autoimmune disorders. RN - 0 (Antigens, CD) RN - 0 (Antigens, CD274) RN - 0 (CD274 protein, human) RN - 0 (Genetic Markers) ES - 1945-7197 IL - 0021-972X DI - jc.2009-1404 DO - https://dx.doi.org/10.1210/jc.2009-1404 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 19850680 [pubmed] ID - jc.2009-1404 [pii] ID - 10.1210/jc.2009-1404 [doi] PP - ppublish GI - No: G84/5959 Organization: *Medical Research Council* Country: United Kingdom LG - English EP - 20091022 DP - 2009 Dec DC - 20091204 EZ - 2009/10/24 06:00 DA - 2010/01/06 06:00 DT - 2009/10/24 06:00 YR - 2009 ED - 20100105 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19850680 <330. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19474123 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Carpenter KJ AU - Murtagh RD AU - Lilienfeld H AU - Weber J AU - Murtagh FR FA - Carpenter, K J FA - Murtagh, R D FA - Lilienfeld, H FA - Weber, J FA - Murtagh, F R IN - Carpenter, K J. Department of Radiology, University of South Florida, Tampa, FL 33629, USA. TI - Ipilimumab-induced hypophysitis: MR imaging findings. SO - Ajnr: American Journal of Neuroradiology. 30(9):1751-3, 2009 Oct AS - AJNR Am J Neuroradiol. 30(9):1751-3, 2009 Oct NJ - AJNR. American journal of neuroradiology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 3ag, 8003708 IO - AJNR Am J Neuroradiol SB - Index Medicus CP - United States MH - Aged MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antineoplastic Agents/ae [Adverse Effects] MH - *Brain/de [Drug Effects] MH - *Brain/pa [Pathology] MH - Female MH - Humans MH - *Magnetic Resonance Imaging/mt [Methods] MH - Male MH - Middle Aged MH - *Pituitary Diseases/ci [Chemically Induced] MH - *Pituitary Diseases/pa [Pathology] AB - Ipilimumab is a promising new immunotherapeutic antineoplastic agent with clinical activity in the treatment of metastatic melanoma and renal cell carcinoma. With advances in immunotherapy, however, a host of new side effects related to the mechanism of action of these drugs has appeared. At our institution, 3 patients presented with hypophysitis, which was attributed to an autoimmune process based on the documented relationship of the drug to other autoimmune phenomena and significant and rapid improvement with discontinuation of the drug and addition of steroids. We present the imaging findings in 3 patients with presumed ipilimumab-induced hypophysitis. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) ES - 1936-959X IL - 0195-6108 DI - ajnr.A1623 DO - https://dx.doi.org/10.3174/ajnr.A1623 PT - Case Reports PT - Journal Article ID - 19474123 [pubmed] ID - ajnr.A1623 [pii] ID - 10.3174/ajnr.A1623 [doi] PP - ppublish LG - English EP - 20090527 DP - 2009 Oct DC - 20091009 EZ - 2009/05/29 09:00 DA - 2010/01/05 06:00 DT - 2009/05/29 09:00 YR - 2009 ED - 20100104 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19474123 <331. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19318477 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Klein O AU - Ebert LM AU - Nicholaou T AU - Browning J AU - Russell SE AU - Zuber M AU - Jackson HM AU - Dimopoulos N AU - Tan BS AU - Hoos A AU - Luescher IF AU - Davis ID AU - Chen W AU - Cebon J FA - Klein, Oliver FA - Ebert, Lisa M FA - Nicholaou, Theo FA - Browning, Judy FA - Russell, Sarah E FA - Zuber, Marina FA - Jackson, Heather M FA - Dimopoulos, Nektaria FA - Tan, Bee Shin FA - Hoos, Axel FA - Luescher, Immanuel F FA - Davis, Ian D FA - Chen, Weisan FA - Cebon, Jonathan IN - Klein, Oliver. Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Heidelberg, Victoria, Australia. TI - Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4. SO - Clinical Cancer Research. 15(7):2507-13, 2009 Apr 01 AS - Clin Cancer Res. 15(7):2507-13, 2009 Apr 01 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - c2h, 9502500 IO - Clin. Cancer Res. SB - Index Medicus CP - United States MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antigens, Neoplasm/im [Immunology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Autoimmunity MH - Cytotoxicity, Immunologic MH - Double-Blind Method MH - Exanthema/ci [Chemically Induced] MH - Exanthema/im [Immunology] MH - Humans MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - MART-1 Antigen MH - Melanoma/dg [Diagnostic Imaging] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - *Neoplasm Proteins/im [Immunology] MH - Skin Neoplasms/dg [Diagnostic Imaging] MH - *Skin Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/im [Immunology] MH - *T-Lymphocytes, Cytotoxic/im [Immunology] MH - Tomography, X-Ray Computed AB - PURPOSE: Ipilimumab is a monoclonal antibody that blocks the immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands on T cells. Clinical trials in cancer patients with ipilimumab have shown promising antitumor activity, particularly in patients with advanced melanoma. Often, tumor regressions in these patients are correlated with immune-related side effects such as dermatitis, enterocolitis, and hypophysitis. Although these reactions are believed to be immune-mediated, the antigenic targets for the cellular or humoral immune response are not known. AB - EXPERIMENTAL DESIGN: We enrolled patients with advanced melanoma in a phase II study with ipilimumab. One of these patients experienced a complete remission of his tumor. The specificity and functional properties of CD8-positive T cells in his peripheral blood, in regressing tumor tissue, and at the site of an immune-mediated skin rash were investigated. AB - RESULTS: Regressing tumor tissue was infiltrated with CD8-positive T cells, a high proportion of which were specific for Melan-A. The skin rash was similarly infiltrated with Melan-A-specific CD8-positive T cells, and a dramatic (>30-fold) increase in Melan-A-specific CD8-positive T cells was apparent in peripheral blood. These cells had an effector phenotype and lysed Melan-A-expressing tumor cells. AB - CONCLUSIONS: Our results show that Melan-A may be a major target for both the autoimmune and antitumor reactions in patients treated with anti-CTLA-4, and describe for the first time the antigen specificity of CD8-positive T cells that mediate tumor rejection in a patient undergoing treatment with an anti-CTLA-4 antibody. These findings may allow a better integration of ipilimumab into other forms of immunotherapy. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, Neoplasm) RN - 0 (Antineoplastic Agents) RN - 0 (MART-1 Antigen) RN - 0 (MLANA protein, human) RN - 0 (Neoplasm Proteins) RN - 6T8C155666 (ipilimumab) IS - 1078-0432 IL - 1078-0432 DI - 1078-0432.CCR-08-2424 DO - https://dx.doi.org/10.1158/1078-0432.CCR-08-2424 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't ID - 19318477 [pubmed] ID - 1078-0432.CCR-08-2424 [pii] ID - 10.1158/1078-0432.CCR-08-2424 [doi] PP - ppublish LG - English EP - 20090324 DP - 2009 Apr 01 DC - 20090402 EZ - 2009/03/26 09:00 DA - 2009/10/23 06:00 DT - 2009/03/26 09:00 YR - 2009 ED - 20091022 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19318477 <332. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19136343 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Ledezma B FA - Ledezma, Blanca IN - Ledezma, Blanca. Angeles Clinic and Research Institute, Santa Monica, CA, USA. bledezma@theangelesclinic.org TI - Ipilimumab for advanced melanoma: a nursing perspective. [Review] [28 refs] SO - Oncology Nursing Forum. 36(1):97-104, 2009 Jan AS - Oncol Nurs Forum. 36(1):97-104, 2009 Jan NJ - Oncology nursing forum PI - Journal available in: Print PI - Citation processed from: Internet JC - 7809033, 7809033 IO - Oncol Nurs Forum SB - Index Medicus SB - Nursing Journal CP - United States MH - Aged MH - Anti-Inflammatory Agents/tu [Therapeutic Use] MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigens, CD/im [Immunology] MH - CTLA-4 Antigen MH - Chemical and Drug Induced Liver Injury/dt [Drug Therapy] MH - Chemical and Drug Induced Liver Injury/et [Etiology] MH - Clinical Trials as Topic MH - Diarrhea/ci [Chemically Induced] MH - Diarrhea/dh [Diet Therapy] MH - Diarrhea/dt [Drug Therapy] MH - Drug Eruptions/et [Etiology] MH - Female MH - Humans MH - Immunity, Cellular MH - Immunologic Factors/ad [Administration & Dosage] MH - Immunologic Factors/ae [Adverse Effects] MH - *Immunologic Factors/tu [Therapeutic Use] MH - Immunosuppressive Agents/tu [Therapeutic Use] MH - Interleukin-2/ad [Administration & Dosage] MH - Interleukin-2/tu [Therapeutic Use] MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/im [Immunology] MH - Melanoma/nu [Nursing] MH - Melanoma/pa [Pathology] MH - Middle Aged MH - Nurse's Role MH - Patient Education as Topic MH - Pituitary Diseases/ci [Chemically Induced] MH - Pruritus/ci [Chemically Induced] MH - *Salvage Therapy MH - T-Lymphocytes, Cytotoxic/de [Drug Effects] MH - T-Lymphocytes, Cytotoxic/im [Immunology] AB - PURPOSE/OBJECTIVES: To discuss the response patterns and side effects related to ipilimumab, a new immunotherapeutic agent under investigation in the treatment of advanced melanoma and other malignancies. AB - DATA SOURCES: Published articles, abstracts, research data, and clinical experience. AB - DATA SYNTHESIS: Ipilimumab is a fully human monoclonal antibody that inhibits the activity of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a naturally immunosuppressive molecule. The most common side effects are immune mediated (e.g., inflammatory diarrhea, pruritus) and appear to occur as a direct result of CTLA-4 inhibition and enhanced immune system activation. Side effects generally are grade I or II and resolve with standard treatments. Most grade III or IV events are managed successfully after swift diagnosis and treatment with corticosteroids; steroid-refractory events resolve after treatment with infliximab or mycophenolate. AB - CONCLUSIONS: The response patterns and side effects associated with ipilimumab therapy greatly differ from those common to other advanced melanoma therapies (e.g., chemotherapy, cytokines, vaccines). AB - IMPLICATIONS FOR NURSING: Nurses have an important role in educating patients about the differences between anti-CTLA-4 therapy and chemotherapy. In addition, teaching patients to recognize ipilimumab's side effects and report them early can result in fast treatment to prevent symptom progression from grade I or II to III or IV. Communication between nurses and patients throughout the treatment process will help patients benefit maximally from the new therapeutic strategy. [References: 28] RN - 0 (Anti-Inflammatory Agents) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Immunologic Factors) RN - 0 (Immunosuppressive Agents) RN - 0 (Interleukin-2) RN - 6T8C155666 (ipilimumab) ES - 1538-0688 IL - 0190-535X DI - 42U6741253M0P145 DO - https://dx.doi.org/10.1188/09.ONF.97-104 PT - Case Reports PT - Journal Article PT - Review ID - 19136343 [pubmed] ID - 42U6741253M0P145 [pii] ID - 10.1188/09.ONF.97-104 [doi] PP - ppublish LG - English DP - 2009 Jan DC - 20090112 EZ - 2009/01/13 09:00 DA - 2009/05/09 09:00 DT - 2009/01/13 09:00 YR - 2009 ED - 20090508 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19136343 <333. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19236381 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Montopoli M AU - Ragazzi E AU - Froldi G AU - Caparrotta L FA - Montopoli, M FA - Ragazzi, E FA - Froldi, G FA - Caparrotta, L IN - Montopoli, M. Department of Pharmacology and Anaesthesiology, University of Padova, Padova, Italy. TI - Cell-cycle inhibition and apoptosis induced by curcumin and cisplatin or oxaliplatin in human ovarian carcinoma cells. SO - Cell Proliferation. 42(2):195-206, 2009 Apr AS - Cell Prolif. 42(2):195-206, 2009 Apr NJ - Cell proliferation PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - a3a, 9105195 IO - Cell Prolif. SB - Index Medicus CP - England MH - Antineoplastic Agents/pd [Pharmacology] MH - *Apoptosis/de [Drug Effects] MH - *Cell Cycle/de [Drug Effects] MH - Cell Line, Tumor MH - Cell Survival/de [Drug Effects] MH - *Cisplatin/pd [Pharmacology] MH - *Curcumin/pd [Pharmacology] MH - Dose-Response Relationship, Drug MH - Drug Resistance, Neoplasm MH - Female MH - Glutathione/me [Metabolism] MH - Humans MH - *Organoplatinum Compounds/pd [Pharmacology] MH - Ovarian Neoplasms/me [Metabolism] MH - *Ovarian Neoplasms/pa [Pathology] MH - Reactive Oxygen Species/me [Metabolism] AB - UNLABELLED: Alteration of appropriate cell-cycle progression and of closely related apoptotic process is a basic feature of tumour cells, and development of new tumour-targeted agents focus on apoptosis, either during cell-cycle arrest or following premature cell-cycle checkpoint exit. Increasingly, epidemiological and experimental studies suggest that curcumin protects against cancer, not only because of its well-known antioxidant properties, but also because it modulates intracellular signalling, which is related to cell proliferation and apoptosis. Cisplatin and oxaliplatin are first-line drugs in treatment of many types of epithelial cancer and their combination with other cytostatics are under investigation to limit their side effects and resistance to them. AB - OBJECTIVES: The aim of this study was to evaluate effects of a combined treatment using curcumin with cisplatin or with oxaliplatin, in a human ovarian cancer cell line (2008) and in its cisplatin-resistant variant (C13). AB - RESULTS: Curcumin per se caused concentration-dependent (0.1-100 microm) and time-persistent (24-72 h) reduction in cell proliferation, as well as altered cell cycle parameters and induced apoptosis, in both cell lines. When carcinoma cells were simultaneously exposed to curcumin and to cisplatin or oxaliplatin (at concentrations lower than IC(50)) cell viability was reduced more than with single-drug treatment. Moreover, dose and time related effects of curcumin, when combined with platinum drugs, were linked to consistent reduction in cell cycling and increased apoptosis, in comparison with single-drug treatment. These effects were significant both in wild type and in cisplatin-resistant cells, indicating that curcumin was also able to increase sensitivity of resistant ovarian cancer cells to cisplatin. AB - CONCLUSIONS: The data suggests that curcumin is an interesting natural compound capable of limiting cell proliferation and possibly increasing clinical impact of platinum drugs, in ovarian cancer patients. RN - 0 (Antineoplastic Agents) RN - 0 (Organoplatinum Compounds) RN - 0 (Reactive Oxygen Species) RN - 04ZR38536J (oxaliplatin) RN - GAN16C9B8O (Glutathione) RN - IT942ZTH98 (Curcumin) RN - Q20Q21Q62J (Cisplatin) ES - 1365-2184 IL - 0960-7722 DI - CPR585 DO - https://dx.doi.org/10.1111/j.1365-2184.2009.00585.x PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 19236381 [pubmed] ID - CPR585 [pii] ID - 10.1111/j.1365-2184.2009.00585.x [doi] PP - ppublish LG - English EP - 20090218 DP - 2009 Apr DC - 20090325 EZ - 2009/02/25 09:00 DA - 2009/04/17 09:00 DT - 2009/02/25 09:00 YR - 2009 ED - 20090416 RD - 20141120 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19236381 <334. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19198837 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Weber J FA - Weber, Jeffrey IN - Weber, Jeffrey. H. Lee Moffitt Cancer Center and Research Institute, Donald A. Adam Comprehensive Melanoma Research Center, Department of Oncologic Sciences, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA. Jeffrey.Weber@moffitt.org TI - Ipilimumab: controversies in its development, utility and autoimmune adverse events. [Review] [35 refs] SO - Cancer Immunology, Immunotherapy. 58(5):823-30, 2009 May AS - Cancer Immunol Immunother. 58(5):823-30, 2009 May NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. SB - Index Medicus CP - Germany MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/im [Immunology] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigen Presentation MH - *Antigens, CD/im [Immunology] MH - Antigens, CD28/im [Immunology] MH - Antigens, Neoplasm/im [Immunology] MH - Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/im [Immunology] MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - Autoimmune Diseases/et [Etiology] MH - CTLA-4 Antigen MH - Clinical Trials as Topic/sn [Statistics & Numerical Data] MH - Clonal Anergy MH - Digestive System Diseases/di [Diagnosis] MH - Digestive System Diseases/dt [Drug Therapy] MH - Digestive System Diseases/et [Etiology] MH - Digestive System Diseases/im [Immunology] MH - Humans MH - Hypopituitarism/et [Etiology] MH - Hypopituitarism/im [Immunology] MH - Lymphocyte Activation MH - Melanoma/im [Immunology] MH - Melanoma/sc [Secondary] MH - *Melanoma/th [Therapy] MH - Models, Immunological MH - *T-Lymphocytes, Cytotoxic/im [Immunology] MH - Tumor Escape/im [Immunology] AB - A promising new class of anti-cancer drugs includes antibodies that mediate immune regulatory effects. It has become very clear over the last decade that different types of immune cells and different pathways serve to suppress anti-cancer immunity, particularly in the microenvironment of the tumor. The first examples of immune modulating antibodies are those directed against cytotoxic T lymphocyte antigen-4 (CTLA-4), a molecule present on activated T cells. Human antibodies that abrogate the function of CTLA-4 have been tested in the clinic and found to have clinical activity against melanoma. In this review, we discuss some of the controversies surrounding the potential clinical utility of one of those antibodies, ipilimumab, formerly MDX-010, from Medarex and Bristol Myers Squibb. The optimal dose and schedule of ipilimumab was derived in multiple clinical trials whose latest results are described below. Favorable survival in patients with stage IV melanoma were observed that appear to be associated with unique side effects of the drug called "immune-related adverse events". The management of these side effects is described, and the unusual kinetics of anti-tumor response with ipilimumab as well as a newly proposed schema for assessing anti-tumor responses in patients receiving biologic compounds like ipilimumab, which may supercede RECIST or WHO criteria, are addressed. [References: 35] RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antigens, CD28) RN - 0 (Antigens, Neoplasm) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) ES - 1432-0851 IL - 0340-7004 DO - https://dx.doi.org/10.1007/s00262-008-0653-8 PT - Journal Article PT - Review ID - 19198837 [pubmed] ID - 10.1007/s00262-008-0653-8 [doi] PP - ppublish PH - 2008/12/02 [received] PH - 2008/12/30 [accepted] PH - 2008/12/23 [revised] LG - English EP - 20090206 DP - 2009 May DC - 20090224 EZ - 2009/02/10 09:00 DA - 2009/04/02 09:00 DT - 2009/02/10 09:00 YR - 2009 ED - 20090401 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19198837 <335. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 18974373 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bashey A AU - Medina B AU - Corringham S AU - Pasek M AU - Carrier E AU - Vrooman L AU - Lowy I AU - Solomon SR AU - Morris LE AU - Holland HK AU - Mason JR AU - Alyea EP AU - Soiffer RJ AU - Ball ED FA - Bashey, Asad FA - Medina, Bridget FA - Corringham, Sue FA - Pasek, Mildred FA - Carrier, Ewa FA - Vrooman, Linda FA - Lowy, Israel FA - Solomon, Scott R FA - Morris, Lawrence E FA - Holland, H Kent FA - Mason, James R FA - Alyea, Edwin P FA - Soiffer, Robert J FA - Ball, Edward D IN - Bashey, Asad. Division of Blood and Marrow Transplantation, University of California, San Diego Moores Cancer Center, La Jolla, CA, USA. abashey@bmtga.com TI - CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. SO - Blood. 113(7):1581-8, 2009 Feb 12 AS - Blood. 113(7):1581-8, 2009 Feb 12 NJ - Blood PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - a8g, 7603509 IO - Blood PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2644086 SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - *Adoptive Transfer MH - Adult MH - Aged MH - *Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/pk [Pharmacokinetics] MH - Antigens, CD/im [Immunology] MH - *Antigens, CD/me [Metabolism] MH - Arthritis, Rheumatoid/ci [Chemically Induced] MH - CTLA-4 Antigen MH - Female MH - Graft vs Host Disease/et [Etiology] MH - *Graft vs Leukemia Effect/de [Drug Effects] MH - Humans MH - Kaplan-Meier Estimate MH - Leukemia/mo [Mortality] MH - *Leukemia/th [Therapy] MH - Lymphoma/mo [Mortality] MH - Lymphoma/th [Therapy] MH - Male MH - Middle Aged MH - Neoplasm Recurrence, Local/mo [Mortality] MH - *Neoplasm Recurrence, Local/pc [Prevention & Control] MH - Pneumonia/ci [Chemically Induced] MH - Transplantation, Homologous AB - Relapse of malignancy after allogeneic hematopoietic cell transplantation (allo-HCT) remains a therapeutic challenge. Blockade of the CTLA4 molecule can effectively augment antitumor immunity mediated by autologous effector T cells. We have assessed the safety and preliminary efficacy of a neutralizing, human anti-CTLA4 monoclonal antibody, ipilimumab, in stimulating the graft-versus-malignancy (GVM) effect after allo-HCT. Twenty-nine patients with malignancies that were recurrent or progressive after allo-HCT, received ipilimumab as a single infusion at dose cohorts between 0.1 and 3.0 mg/kg. Dose-limiting toxicity was not encountered, and ipilimumab did not induce graft-versus-host disease (GVHD) or graft rejection. Organ-specific immune adverse events (IAE) were seen in 4 patients (grade 3 arthritis, grade 2 hyperthyroidism, recurrent grade 4 pneumonitis). Three patients with lymphoid malignancy developed objective disease responses following ipilimumab: complete remission (CR) in 2 patients with Hodgkin disease and partial remission (PR) in a patient with refractory mantle cell lymphoma. At the 3.0 mg/kg dose, active serum concentrations of ipilimumab were maintained for more than 30 days after a single infusion. Ipilimumab, as administered in this clinical trial, does not induce or exacerbate clinical GVHD, but may cause organ-specific IAE and regression of malignancy. This study is registered at (http://clinicaltrials.gov) under NCI protocol ID P6082. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) ES - 1528-0020 IL - 0006-4971 DI - blood-2008-07-168468 DO - https://dx.doi.org/10.1182/blood-2008-07-168468 PT - Clinical Trial PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural ID - 18974373 [pubmed] ID - blood-2008-07-168468 [pii] ID - 10.1182/blood-2008-07-168468 [doi] ID - PMC2644086 [pmc] PP - ppublish SI - ClinicalTrials.gov SA - ClinicalTrials.gov/NCT00060372 SL - https://clinicaltrials.gov/search/term=NCT00060372 GI - No: R01 CA 9389-01A1 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20081030 DP - 2009 Feb 12 DC - 20090217 EZ - 2008/11/01 09:00 DA - 2009/03/25 09:00 DT - 2008/11/01 09:00 YR - 2009 ED - 20090324 RD - 20161125 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=18974373 <336. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 19139112 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Parsels LA AU - Morgan MA AU - Tanska DM AU - Parsels JD AU - Palmer BD AU - Booth RJ AU - Denny WA AU - Canman CE AU - Kraker AJ AU - Lawrence TS AU - Maybaum J FA - Parsels, Leslie A FA - Morgan, Meredith A FA - Tanska, Daria M FA - Parsels, Joshua D FA - Palmer, Brian D FA - Booth, R John FA - Denny, William A FA - Canman, Christine E FA - Kraker, Alan J FA - Lawrence, Theodore S FA - Maybaum, Jonathan IN - Parsels, Leslie A. Department of Pharmacology, University of Michigan Medical School, Upjohn Center for Clinical Pharmacology, 4742E Medical Science II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5633, USA. TI - Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells. SO - Molecular Cancer Therapeutics. 8(1):45-54, 2009 Jan AS - Mol Cancer Ther. 8(1):45-54, 2009 Jan NJ - Molecular cancer therapeutics PI - Journal available in: Print PI - Citation processed from: Print JC - 101132535 IO - Mol. Cancer Ther. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730564 OI - Source: NLM. NIHMS117821 SB - Index Medicus CP - United States MH - Biocatalysis MH - Carbazoles/pd [Pharmacology] MH - Cell Line, Tumor MH - Cell Survival/de [Drug Effects] MH - Checkpoint Kinase 1 MH - DNA Damage MH - *Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Humans MH - *Pancreatic Neoplasms/en [Enzymology] MH - Pancreatic Neoplasms/ge [Genetics] MH - *Pancreatic Neoplasms/pa [Pathology] MH - Phosphorylation/de [Drug Effects] MH - *Protein Kinase Inhibitors/pd [Pharmacology] MH - *Protein Kinases/me [Metabolism] MH - *Rad51 Recombinase/ge [Genetics] MH - *Rad51 Recombinase/me [Metabolism] AB - The protein kinase checkpoint kinase 1 (Chk1) has been implicated as a key regulator of cell cycle progression and DNA repair, and inhibitors of Chk1 (e.g., UCN-01 and EXEL-9844) potentiate the cytotoxic actions of chemotherapeutic drugs in tumor cells. We have examined the ability of PD-321852, a small-molecule Chk1 inhibitor, to potentiate gemcitabine-induced clonogenic death in a panel of pancreatic cancer cell lines and evaluated the relationship between endpoints associated with Chk1 inhibition and chemosensitization. Gemcitabine chemosensitization by minimally toxic concentrations of PD-321852 ranged from minimal (<3-fold change in survival) in Panc1 cells to >30-fold in MiaPaCa2 cells. PD-321852 inhibited Chk1 in all cell lines as evidenced by stabilization of Cdc25A; in combination with gemcitabine, a synergistic loss of Chk1 protein was observed in the more sensitized cell lines. Gemcitabine chemosensitization, however, did not correlate with abrogation of the S-M or G2-M checkpoint; PD-321852 did not induce premature mitotic entry in gemcitabine-treated BxPC3 or M-Panc96 cells, which were sensitized to gemcitabine 6.2- and 4.6-fold, respectively. In the more sensitized cells lines, PD-321852 not only inhibited gemcitabine-induced Rad51 focus formation and the recovery from gemcitabine-induced replication stress, as evidenced by persistence of gamma-H2AX, but also depleted these cells of Rad51 protein. Our data suggest the inhibition of this Chk1-mediated Rad51 response to gemcitabine-induced replication stress is an important factor in determining gemcitabine chemosensitization by Chk1 inhibition in pancreatic cancer cells. RN - 0 (4-(2,6-dichlorophenyl)-9-hydroxy-6-(3-methylaminopropyl)-6H-pyrrolo(3,4-c)carbazole-1,3-dione) RN - 0 (Carbazoles) RN - 0 (Protein Kinase Inhibitors) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - EC 2-7-7 (Rad51 Recombinase) IS - 1535-7163 IL - 1535-7163 DI - 8/1/45 DO - https://dx.doi.org/10.1158/1535-7163.MCT-08-0662 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 19139112 [pubmed] ID - 8/1/45 [pii] ID - 10.1158/1535-7163.MCT-08-0662 [doi] ID - PMC2730564 [pmc] ID - NIHMS117821 [mid] PP - ppublish GI - No: R01 CA078554 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA078554-09 Organization: (CA) *NCI NIH HHS* Country: United States No: R01-CA078554 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2009 Jan DC - 20090113 EZ - 2009/01/14 09:00 DA - 2009/02/20 09:00 DT - 2009/01/14 09:00 YR - 2009 ED - 20090219 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=19139112 <337. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 18716842 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Phan GQ AU - Weber JS AU - Sondak VK FA - Phan, Giao Q FA - Weber, Jeffrey S FA - Sondak, Vernon K IN - Phan, Giao Q. Division of Cutaneous Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA. TI - CTLA-4 blockade with monoclonal antibodies in patients with metastatic cancer: surgical issues. [Review] [37 refs] SO - Annals of Surgical Oncology. 15(11):3014-21, 2008 Nov AS - Ann Surg Oncol. 15(11):3014-21, 2008 Nov NJ - Annals of surgical oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - b9r, 9420840 IO - Ann. Surg. Oncol. SB - Index Medicus CP - United States MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - *Antigens, CD/im [Immunology] MH - CTLA-4 Antigen MH - Clinical Trials as Topic MH - Enterocolitis/ci [Chemically Induced] MH - Enterocolitis/dt [Drug Therapy] MH - Guidelines as Topic MH - Humans MH - Immunotherapy MH - *Melanoma/dt [Drug Therapy] MH - Melanoma/pa [Pathology] MH - Neoplasm Metastasis AB - BACKGROUND: CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) is a modulatory receptor on T cells involved in downregulating T cell activation. In animal models, CTLA-4 blockade abrogates tolerance to "self" antigens, resulting in the augmentation of antitumor immunity and induction of autoimmunity. CTLA-4 blockade by means of monoclonal antibodies (ipilimumab and tremelimumab) has been evaluated in multiple clinical trials in patients with metastatic cancer, mainly those with melanoma and renal cell cancer. AB - METHODS: We examine available literature and ongoing clinical trials with ipilimumab and tremelimumab and review our own experience with patients treated with CTLA-4 blockade, with an emphasis on issues of direct relevance to surgical oncologists. AB - RESULTS: CTLA-4 blockade can cause durable tumor regression in patients with metastatic melanoma and other solid tumors. Grade III/IV autoimmune toxicity has been frequently encountered in clinical trials and includes enterocolitis, dermatitis, hypophysitis, uveitis, and hepatitis. Enterocolitis is the most common immune-related adverse event and may cause severe diarrhea requiring intravenous hydration, high-dose corticosteroids, and blockade of tumor necrosis factor alpha with infliximab. Most patients respond to medical treatment, but up to 12% with grade III/IV enterocolitis develop perforation or bleeding that requires colectomy. AB - CONCLUSIONS: As more patients are enrolled onto clinical trials involving ipilimumab and tremelimumab, an increasing number of surgeons may be involved in the care of these patients who develop treatment-related complications. In this report, we review the rationale for CTLA-4 blockade and review selected clinical studies published so far with ipilimumab and tremelimumab. We offer guidelines on the management of patients who develop enterocolitis. [References: 37] RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 6T8C155666 (ipilimumab) RN - QEN1X95CIX (tremelimumab) ES - 1534-4681 IL - 1068-9265 DO - https://dx.doi.org/10.1245/s10434-008-0104-y PT - Journal Article PT - Review ID - 18716842 [pubmed] ID - 10.1245/s10434-008-0104-y [doi] PP - ppublish PH - 2008/03/27 [received] PH - 2008/07/15 [accepted] PH - 2008/07/14 [revised] LG - English EP - 20080821 DP - 2008 Nov DC - 20081029 EZ - 2008/08/22 09:00 DA - 2009/01/30 09:00 DT - 2008/08/22 09:00 YR - 2008 ED - 20090129 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=18716842 <338. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 18433847 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Durrant D AU - Richards JE AU - Walker WT AU - Baker KA AU - Simoni D AU - Lee RM FA - Durrant, David FA - Richards, Joanna E FA - Walker, Winston T FA - Baker, Kristen A FA - Simoni, Daniele FA - Lee, Ray M IN - Durrant, David. Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA. TI - Mechanism of cell death induced by cis-3, 4', 5-trimethoxy-3'-aminostilbene in ovarian cancer. SO - Gynecologic Oncology. 110(1):110-7, 2008 Jul AS - Gynecol Oncol. 110(1):110-7, 2008 Jul NJ - Gynecologic oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - fxc, 0365304 IO - Gynecol. Oncol. SB - Index Medicus CP - United States MH - *Apoptosis/de [Drug Effects] MH - *Cell Cycle/de [Drug Effects] MH - *Cell Death/de [Drug Effects] MH - Cell Line, Tumor MH - Female MH - Humans MH - Membrane Potentials/de [Drug Effects] MH - Membrane Potentials/ph [Physiology] MH - Mitochondria/de [Drug Effects] MH - Mitochondria/ph [Physiology] MH - *Ovarian Neoplasms/pa [Pathology] MH - Reactive Oxygen Species/me [Metabolism] MH - *Stilbenes/pd [Pharmacology] AB - OBJECTIVE: Stilbene derivative, cis-3, 4', 5-trimethoxy-3'-aminostilbene (stilbene 5c), is highly potent to induce cell death in ovarian cancer cells. This study is to investigate its mechanism to induce cell death. AB - METHODS: UCI101 ovarian cancer cells were used for this study. Cell death was analyzed by Alamar blue staining. Cell cycle was analyzed by flow cytometry after PI staining. Mitochondrial potential and reactive oxygen species were determined by MitoTracker green and DCF-DA, respectively. Immunofluorescent staining was done with tubulin antibody following by confocal microscope examination. Cell lysates were collected after treatment with stilbene 5c for Western blotting analysis of various cell cycle regulators and signal transduction mediators. AB - RESULTS: Stilbene-treated cells die in both cell cycle-dependent and -independent pathways. Low concentration (30 nM) induces cell death without cell cycle arrest. This process involves disruption of mitochondrial potential and production of ROS by a Bcl-2-independent pathway. Higher concentration of stilbene 5c arrests cell cycle in G(2)/M phase, which is supported by dephosphorylation of Cdc2 and Cdc25C, and transiently elevation of spindle checkpoint BubR1. Although phosphorylation of Chk1 and Chk2 both increases after treatment, loss of Chk1 suppresses, whereas loss of Chk2 enhances, stilbene 5c-induced cell death. Phosphorylation of Akt and Stat3, but not MAPK, is suppressed after stilbene 5c treatment. AB - CONCLUSION: These studies provide a mechanistic insight in using stilbenes in ovarian cancer. Stilbenes could be potentially useful agents for ovarian cancer therapy and induce cell death through mitochondrial damage and cell cycle arrest. RN - 0 (3,4',5-trimethoxy-3'-aminostilbene) RN - 0 (Reactive Oxygen Species) RN - 0 (Stilbenes) ES - 1095-6859 IL - 0090-8258 DI - S0090-8258(08)00182-0 DO - https://dx.doi.org/10.1016/j.ygyno.2008.02.031 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 18433847 [pubmed] ID - S0090-8258(08)00182-0 [pii] ID - 10.1016/j.ygyno.2008.02.031 [doi] PP - ppublish PH - 2007/12/17 [received] PH - 2008/02/22 [revised] PH - 2008/02/28 [accepted] GI - No: P30 CA16059 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20080422 DP - 2008 Jul DC - 20080630 EZ - 2008/04/25 09:00 DA - 2008/08/02 09:00 DT - 2008/04/25 09:00 YR - 2008 ED - 20080801 RD - 20080630 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=18433847 <339. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 18539263 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Liu M AU - Yu H AU - Huo L AU - Liu J AU - Li M AU - Zhou J FA - Liu, Min FA - Yu, Haiyang FA - Huo, Lihong FA - Liu, Jianchao FA - Li, Minggang FA - Zhou, Jun IN - Liu, Min. Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China. TI - Validating the mitotic kinesin Eg5 as a therapeutic target in pancreatic cancer cells and tumor xenografts using a specific inhibitor. SO - Biochemical Pharmacology. 76(2):169-78, 2008 Jul 15 AS - Biochem Pharmacol. 76(2):169-78, 2008 Jul 15 NJ - Biochemical pharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9z4, 0101032 IO - Biochem. Pharmacol. SB - Index Medicus CP - England MH - Animals MH - *Antineoplastic Agents/pd [Pharmacology] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Apoptosis MH - Caspase 3/me [Metabolism] MH - Cell Line, Tumor MH - Cell Proliferation/de [Drug Effects] MH - Female MH - Humans MH - *Kinesin/ai [Antagonists & Inhibitors] MH - Mice MH - Mice, Nude MH - *Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/me [Metabolism] MH - *Quinazolines/pd [Pharmacology] MH - Quinazolines/tu [Therapeutic Use] MH - *Thiones/pd [Pharmacology] MH - Thiones/tu [Therapeutic Use] MH - Xenograft Model Antitumor Assays AB - Pancreatic cancer is a devastating disease with a high mortality rate. Treatment of this malignancy remains a big challenge in oncology, and none of the currently available chemotherapeutic agents has a remarkable impact on improving patient survival. Consequently, it is important to explore new targets and find effective drugs for the management of this disease. Here we report that inhibition of the mitotic kinesin Eg5 by a pharmacological compound effectively prevents the proliferation of pancreatic cancer cells by halting mitotic progression, resulting in robust apoptosis. The mitotic arrest induced by this agent is attributed to its interference with spindle formation and activation of the spindle checkpoint. Impairment of the spindle checkpoint significantly compromises both mitotic arrest and apoptosis induced by the Eg5 inhibitor, suggesting the importance of the spindle checkpoint in monitoring Eg5 inhibitor sensitivity. Furthermore, treatment of nude mice bearing tumor xenografts of human pancreatic cancer results in pronounced tumor regression by triggering apoptosis. These data thus indicate Eg5 as a potential target for pancreatic cancer treatment. RN - 0 (Antineoplastic Agents) RN - 0 (KIF11 protein, human) RN - 0 (Quinazolines) RN - 0 (Thiones) RN - 0 (dimethylenastron) RN - EC 3-4-22 (Caspase 3) RN - EC 3-6-4-4 (Kinesin) ES - 1873-2968 IL - 0006-2952 DI - S0006-2952(08)00258-X DO - https://dx.doi.org/10.1016/j.bcp.2008.04.018 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 18539263 [pubmed] ID - S0006-2952(08)00258-X [pii] ID - 10.1016/j.bcp.2008.04.018 [doi] PP - ppublish PH - 2008/03/10 [received] PH - 2008/04/13 [revised] PH - 2008/04/15 [accepted] LG - English EP - 20080504 DP - 2008 Jul 15 DC - 20080630 EZ - 2008/06/10 09:00 DA - 2008/08/01 09:00 DT - 2008/06/10 09:00 YR - 2008 ED - 20080731 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=18539263 <340. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 18261847 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Righetti SC AU - Perego P AU - Carenini N AU - Zunino F FA - Righetti, Sabina Carla FA - Perego, Paola FA - Carenini, Nives FA - Zunino, Franco IN - Righetti, Sabina Carla. Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy. TI - Cooperation between p53 and p73 in cisplatin-induced apoptosis in ovarian carcinoma cells. SO - Cancer Letters. 263(1):140-4, 2008 May 08 AS - Cancer Lett. 263(1):140-4, 2008 May 08 NJ - Cancer letters PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 7600053, cmx IO - Cancer Lett. SB - Index Medicus CP - Ireland MH - *Antineoplastic Agents/pd [Pharmacology] MH - *Apoptosis/de [Drug Effects] MH - *Cisplatin/pd [Pharmacology] MH - *DNA-Binding Proteins/me [Metabolism] MH - Female MH - Humans MH - *Nuclear Proteins/me [Metabolism] MH - *Ovarian Neoplasms/pa [Pathology] MH - Protein Binding MH - Tumor Protein p73 MH - *Tumor Suppressor Protein p53/me [Metabolism] MH - *Tumor Suppressor Proteins/me [Metabolism] AB - The present study was designed to explore the role of p73 in response to cisplatin. In contrast to cisplatin-resistant ovarian carcinoma cells, pharmacological drug concentrations, which caused induction of p53, induced a marginal increase of p73 in sensitive cells. The effect was more marked at high concentrations, with no evidence of p21(WAF1) induction. This behaviour, associated with substantial apoptosis, suggests cell inability to activate DNA damage checkpoint following extensive stress. Although p73 appears to be implicated mainly in response to high stress conditions, the available results support a cooperation between p53 and p73 in cisplatin-induced apoptosis in sensitive cells. RN - 0 (Antineoplastic Agents) RN - 0 (DNA-Binding Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Tumor Protein p73) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (Tumor Suppressor Proteins) RN - 0 (p73 protein, human) RN - Q20Q21Q62J (Cisplatin) IS - 0304-3835 IL - 0304-3835 DI - S0304-3835(07)00638-6 DO - https://dx.doi.org/10.1016/j.canlet.2007.12.024 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 18261847 [pubmed] ID - S0304-3835(07)00638-6 [pii] ID - 10.1016/j.canlet.2007.12.024 [doi] PP - ppublish PH - 2007/10/17 [received] PH - 2007/12/19 [revised] PH - 2007/12/19 [accepted] LG - English EP - 20080207 DP - 2008 May 08 DC - 20080331 EZ - 2008/02/12 09:00 DA - 2008/06/06 09:00 DT - 2008/02/12 09:00 YR - 2008 ED - 20080605 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med6&AN=18261847 <341. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 18094405 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Danial NN FA - Danial, Nika N IN - Danial, Nika N. Department of Pathology, Harvard Medical School and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. nika_danial@dfci.harvard.edu TI - BCL-2 family proteins: critical checkpoints of apoptotic cell death. [Review] [128 refs] SO - Clinical Cancer Research. 13(24):7254-63, 2007 Dec 15 AS - Clin Cancer Res. 13(24):7254-63, 2007 Dec 15 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print PI - Citation processed from: Print JC - c2h, 9502500 IO - Clin. Cancer Res. SB - Index Medicus CP - United States MH - Animals MH - *Apoptosis/ph [Physiology] MH - Humans MH - Multiprotein Complexes/ph [Physiology] MH - *Proto-Oncogene Proteins c-bcl-2/ph [Physiology] AB - Apoptosis is a morphologically distinct form of programmed cell death essential for normal development and tissue homeostasis. Aberrant regulation of this pathway is linked to multiple human diseases, including cancer, autoimmunity, neurodegenerative disorders, and diabetes. The BCL-2 family of proteins constitutes a critical control point in apoptosis residing immediately upstream of irreversible cellular damage, where family members control the release of apoptogenic factors from mitochondria. The cardinal member of this family, BCL-2, was originally discovered as the defining oncogene in follicular lymphomas, located at one reciprocal breakpoint of the t(14;18) (q32;q21) chromosomal translocation. Since this original discovery, remarkable efforts marshaled by many investigators around the world have advanced our knowledge of the basic biology, molecular mechanisms, and therapeutic targets in the apoptotic pathway. This review highlights findings from many laboratories that have helped uncover some of the critical control points in apoptosis. The emerging picture is that of an intricate cellular machinery orchestrated by tightly regulated molecular interactions and conformational changes within BCL-2 family proteins that ultimately govern the cellular commitment to apoptotic death. [References: 128] RN - 0 (Multiprotein Complexes) RN - 0 (Proto-Oncogene Proteins c-bcl-2) IS - 1078-0432 IL - 1078-0432 DI - 13/24/7254 DO - https://dx.doi.org/10.1158/1078-0432.CCR-07-1598 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review ID - 18094405 [pubmed] ID - 13/24/7254 [pii] ID - 10.1158/1078-0432.CCR-07-1598 [doi] PP - ppublish GI - No: K01CA10659 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2007 Dec 15 DC - 20071220 EZ - 2007/12/21 09:00 DA - 2008/03/05 09:00 DT - 2007/12/21 09:00 YR - 2007 ED - 20080304 RD - 20071220 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=18094405 <342. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 18049334 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Yang JC AU - Hughes M AU - Kammula U AU - Royal R AU - Sherry RM AU - Topalian SL AU - Suri KB AU - Levy C AU - Allen T AU - Mavroukakis S AU - Lowy I AU - White DE AU - Rosenberg SA FA - Yang, James C FA - Hughes, Marybeth FA - Kammula, Udai FA - Royal, Richard FA - Sherry, Richard M FA - Topalian, Suzanne L FA - Suri, Kimberly B FA - Levy, Catherine FA - Allen, Tamika FA - Mavroukakis, Sharon FA - Lowy, Israel FA - White, Donald E FA - Rosenberg, Steven A IN - Yang, James C. Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. JamesYang@mail.nih.gov TI - Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. SO - Journal of Immunotherapy. 30(8):825-30, 2007 Nov-Dec AS - J Immunother. 30(8):825-30, 2007 Nov-Dec NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print PI - Citation processed from: Print JC - cuq, 9706083 IO - J. Immunother. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2134980 OI - Source: NLM. NIHMS35214 SB - Index Medicus CP - United States MH - Adrenal Insufficiency/ci [Chemically Induced] MH - Adult MH - Aged MH - Antibodies, Monoclonal/ad [Administration & Dosage] MH - Antibodies, Monoclonal/ae [Adverse Effects] MH - *Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antineoplastic Agents/ad [Administration & Dosage] MH - Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - Bone Neoplasms/dt [Drug Therapy] MH - Bone Neoplasms/im [Immunology] MH - Bone Neoplasms/sc [Secondary] MH - *Carcinoma, Renal Cell/dt [Drug Therapy] MH - Carcinoma, Renal Cell/im [Immunology] MH - Carcinoma, Renal Cell/pa [Pathology] MH - Colitis/ci [Chemically Induced] MH - Duodenitis/ci [Chemically Induced] MH - *Enteritis/ci [Chemically Induced] MH - Female MH - Humans MH - Hypopituitarism/ci [Chemically Induced] MH - *Kidney Neoplasms/dt [Drug Therapy] MH - Kidney Neoplasms/im [Immunology] MH - Kidney Neoplasms/pa [Pathology] MH - Liver Neoplasms/dt [Drug Therapy] MH - Liver Neoplasms/im [Immunology] MH - Liver Neoplasms/sc [Secondary] MH - Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/im [Immunology] MH - Lung Neoplasms/sc [Secondary] MH - Male MH - Meningitis, Aseptic/ci [Chemically Induced] MH - Middle Aged MH - *Pituitary Diseases/ci [Chemically Induced] MH - Treatment Outcome AB - The inhibitory receptor CTLA4 has a key role in peripheral tolerance of T cells for both normal and tumor-associated antigens. Murine experiments suggested that blockade of CTLA4 might have antitumor activity and a clinical experience with the blocking antibody ipilimumab in patients with metastatic melanoma did show durable tumor regressions in some patients. Therefore, a phase II study of ipilimumab was conducted in patients with metastatic renal cell cancer with a primary end point of response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Two sequential cohorts received either 3 mg/kg followed by 1 mg/kg or all doses at 3 mg/kg every 3 weeks (with no intention of comparing cohort response rates). Major toxicities were enteritis and endocrine deficiencies of presumed autoimmune origin. One of 21 patients receiving the lower dose had a partial response. Five of 40 patients at the higher dose had partial responses (95% confidence interval for cohort response rate 4% to 27%) and responses were seen in patients who had previously not responded to IL-2. Thirty-three percent of patients experienced a grade III or IV immune-mediated toxicity. There was a highly significant association between autoimmune events (AEs) and tumor regression (response rate=30% with AE, 0% without AE). CTLA4 blockade with ipilimumab induces cancer regression in some patients with metastatic clear cell renal cancer, even if they have not responded to other immunotherapies. These regressions are highly associated with other immune-mediated events of presumed autoimmune origin by mechanisms as yet undefined. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 6T8C155666 (ipilimumab) IS - 1524-9557 IL - 1524-9557 DI - 00002371-200711000-00005 DO - https://dx.doi.org/10.1097/CJI.0b013e318156e47e PT - Clinical Trial, Phase II PT - Journal Article ID - 18049334 [pubmed] ID - 10.1097/CJI.0b013e318156e47e [doi] ID - 00002371-200711000-00005 [pii] ID - PMC2134980 [pmc] ID - NIHMS35214 [mid] PP - ppublish GI - No: Z01 SC003811-32 Organization: *Intramural NIH HHS* Country: United States LG - English DP - 2007 Nov-Dec DC - 20071130 EZ - 2007/12/01 09:00 DA - 2008/01/25 09:00 DT - 2007/12/01 09:00 YR - 2007 ED - 20080124 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=18049334 <343. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 17729038 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Gatzka M AU - Walsh CM FA - Gatzka, Martina FA - Walsh, Craig M IN - Gatzka, Martina. Department of Molecular Biology and Biochemistry, Center for Immunology, University of California, Irvine, CA, USA. mgatzka@uci.edu TI - Apoptotic signal transduction and T cell tolerance. [Review] [125 refs] SO - Autoimmunity. 40(6):442-52, 2007 Sep AS - Autoimmunity. 40(6):442-52, 2007 Sep NJ - Autoimmunity PI - Journal available in: Print PI - Citation processed from: Print JC - a5h, 8900070 IO - Autoimmunity SB - Index Medicus CP - England MH - Animals MH - *Apoptosis MH - Autoimmunity MH - Clonal Deletion MH - Humans MH - Lymphocyte Activation MH - Receptors, Antigen, T-Cell/ge [Genetics] MH - *Receptors, Antigen, T-Cell/im [Immunology] MH - Receptors, Antigen, T-Cell/me [Metabolism] MH - Self Tolerance/ge [Genetics] MH - *Self Tolerance MH - *Signal Transduction MH - T-Lymphocyte Subsets/im [Immunology] MH - T-Lymphocyte Subsets/me [Metabolism] MH - T-Lymphocytes/cy [Cytology] MH - *T-Lymphocytes/im [Immunology] MH - T-Lymphocytes/me [Metabolism] MH - Thymus Gland/im [Immunology] AB - The healthy immune system makes use of a variety of surveillance mechanisms at different stages of lymphoid development to prevent the occurrence and expansion of potentially harmful autoreactive T cell clones. Disruption of these mechanisms may lead to inappropriate activation of T cells and the development of autoimmune and lymphoproliferative diseases [such as multiple sclerosis, rheumatoid arthritis, lupus erythematosus, diabetes and autoimmune lymphoproliferative syndrome (ALPS)]. Clonal deletion of T cells with high affinities for self-peptide-MHC via programmed cell death (apoptosis) is an essential mechanism leading to self-tolerance. Referred to as negative selection, central tolerance in the thymus serves as the first checkpoint for the developing T cell repertoire and involves the apoptotic elimination of potentially autoreactive T cells clones bearing high affinity T cell receptors (TCR) that recognize autoantigens presented by thymic epithelial cells. Autoreactive T cells that escape negative selection are held in check in the periphery by either functional inactivation ("anergy") or extrathymic clonal deletion, both of which are dependent on the strength and frequency of the TCR signal and the costimulatory context, or by regulatory T cells. This review provides an overview of the different molecular executioners of cell death programs that are vital to intrathymic or extrathymic clonal deletion of T cells. Further, the potential involvement of various apoptotic signaling paradigms are discussed with respect to the genesis and pathophysiology of autoimmune disease. [References: 125] RN - 0 (Receptors, Antigen, T-Cell) IS - 0891-6934 IL - 0891-6934 DI - 781631027 DO - https://dx.doi.org/10.1080/08916930701464962 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review ID - 17729038 [pubmed] ID - 781631027 [pii] ID - 10.1080/08916930701464962 [doi] PP - ppublish GI - No: R01AI0506 Organization: (AI) *NIAID NIH HHS* Country: United States No: R01AI63419 Organization: (AI) *NIAID NIH HHS* Country: United States LG - English DP - 2007 Sep DC - 20070830 EZ - 2007/08/31 09:00 DA - 2007/12/14 09:00 DT - 2007/08/31 09:00 YR - 2007 ED - 20071213 RD - 20070830 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=17729038 <344. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 17684018 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Selvendiran K AU - Tong L AU - Vishwanath S AU - Bratasz A AU - Trigg NJ AU - Kutala VK AU - Hideg K AU - Kuppusamy P FA - Selvendiran, Karuppaiyah FA - Tong, Liyue FA - Vishwanath, Shilpa FA - Bratasz, Anna FA - Trigg, Nancy J FA - Kutala, Vijay K FA - Hideg, Kalman FA - Kuppusamy, Periannan IN - Selvendiran, Karuppaiyah. Department of Internal Medicine, Davis Heart and Lung Research Institute and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA. TI - EF24 induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by increasing PTEN expression. SO - Journal of Biological Chemistry. 282(39):28609-18, 2007 Sep 28 AS - J Biol Chem. 282(39):28609-18, 2007 Sep 28 NJ - The Journal of biological chemistry PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - hiv, 2985121r IO - J. Biol. Chem. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610350 OI - Source: NLM. NIHMS46456 SB - Index Medicus CP - United States MH - Animals MH - *Antineoplastic Agents/pd [Pharmacology] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *Apoptosis/de [Drug Effects] MH - *Benzylidene Compounds/pd [Pharmacology] MH - Benzylidene Compounds/tu [Therapeutic Use] MH - Caspase Inhibitors MH - Caspases/me [Metabolism] MH - *Cell Division/de [Drug Effects] MH - Cell Survival MH - Cisplatin MH - Cysteine Proteinase Inhibitors/pd [Pharmacology] MH - Drug Resistance, Neoplasm/de [Drug Effects] MH - Fas Ligand Protein/bi [Biosynthesis] MH - Female MH - *G2 Phase/de [Drug Effects] MH - *Gene Expression Regulation, Neoplastic/de [Drug Effects] MH - Humans MH - Mice MH - Mice, Nude MH - Ovarian Neoplasms/dt [Drug Therapy] MH - *Ovarian Neoplasms/me [Metabolism] MH - PTEN Phosphohydrolase/ai [Antagonists & Inhibitors] MH - *PTEN Phosphohydrolase/bi [Biosynthesis] MH - Phosphorylation/de [Drug Effects] MH - *Piperidones/pd [Pharmacology] MH - Piperidones/tu [Therapeutic Use] MH - Proto-Oncogene Proteins c-akt/me [Metabolism] MH - Proto-Oncogene Proteins c-mdm2/me [Metabolism] MH - RNA, Small Interfering/pd [Pharmacology] MH - Time Factors MH - Tumor Suppressor Protein p53/me [Metabolism] MH - Ubiquitin/me [Metabolism] MH - Up-Regulation/de [Drug Effects] MH - Xenograft Model Antitumor Assays AB - We report that EF24, a synthetic compound 3,5-bis(2-flurobenzylidene)piperidin-4-one, greatly inhibits cisplatin-resistant (CR) human ovarian cancer cell proliferation. The inhibitory effect of EF24 on cell proliferation is associated with G(2)/M phase cell cycle arrest and increased G(2)/M checkpoint protein (pp53, p53, and p21) levels. Within 24 h following treatment, EF24 induced apoptosis in CR cells. The apoptosis was partially blocked by the general caspase inhibitor z-VAD. Within 12 h, EF24 induced a membranous FasL expression, consistent with a substantial decrease in the Ser(473) and Thr(308) phosphorylation of Akt, a known negative regulator of FasL transcription. Also, EF24 activated the phosphorylated PTEN and marginally up-regulated total PTEN expression through the inhibition of ubiquitin-mediated PTEN degradation. Suppression of PTEN expression with siRNA significantly reduced the p53 and p21 levels and activated Akt phosphorylation at Ser(473) and Thr(308), resulting in decreased apoptosis and increased cell survival. On the other hand, overexpression of PTEN markedly induced apoptosis. Our results clearly suggested that EF24 induced significant increase in PTEN expression. The up-regulation of PTEN inhibited Akt and MDM2, which enhanced the level of p53, thereby inducing G(2)/M arrest and apoptosis. Therefore, EF24 appears to have a potential therapeutic role in human ovarian cancer through the activation of PTEN. RN - 0 (3,5-bis(2-fluorobenzylidene)piperidin-4-one) RN - 0 (Antineoplastic Agents) RN - 0 (Benzylidene Compounds) RN - 0 (Caspase Inhibitors) RN - 0 (Cysteine Proteinase Inhibitors) RN - 0 (FASLG protein, human) RN - 0 (Fas Ligand Protein) RN - 0 (Piperidones) RN - 0 (RNA, Small Interfering) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (Ubiquitin) RN - EC 2-3-2-27 (MDM2 protein, human) RN - EC 2-3-2-27 (Proto-Oncogene Proteins c-mdm2) RN - EC 2-7-11-1 (Proto-Oncogene Proteins c-akt) RN - EC 3-1-3-67 (PTEN Phosphohydrolase) RN - EC 3-1-3-67 (PTEN protein, human) RN - EC 3-4-22 (Caspases) RN - Q20Q21Q62J (Cisplatin) IS - 0021-9258 IL - 0021-9258 DI - M703796200 DO - https://dx.doi.org/10.1074/jbc.M703796200 PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't ID - 17684018 [pubmed] ID - M703796200 [pii] ID - 10.1074/jbc.M703796200 [doi] ID - PMC4610350 [pmc] ID - NIHMS46456 [mid] PP - ppublish GI - No: R01 CA102264 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA102264-04 Organization: (CA) *NCI NIH HHS* Country: United States No: CA102264 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20070807 DP - 2007 Sep 28 DC - 20070924 EZ - 2007/08/09 09:00 DA - 2007/11/09 09:00 DT - 2007/08/09 09:00 YR - 2007 ED - 20071108 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=17684018 <345. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 17671210 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Jacquemont C AU - Taniguchi T FA - Jacquemont, Celine FA - Taniguchi, Toshiyasu IN - Jacquemont, Celine. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. TI - Proteasome function is required for DNA damage response and fanconi anemia pathway activation. SO - Cancer Research. 67(15):7395-405, 2007 Aug 01 AS - Cancer Res. 67(15):7395-405, 2007 Aug 01 NJ - Cancer research PI - Journal available in: Print PI - Citation processed from: Print JC - cnf, 2984705r IO - Cancer Res. SB - Index Medicus CP - United States MH - Ataxia Telangiectasia Mutated Proteins MH - BRCA1 Protein/ai [Antagonists & Inhibitors] MH - BRCA1 Protein/ge [Genetics] MH - BRCA1 Protein/me [Metabolism] MH - Blotting, Western MH - Boronic Acids/pd [Pharmacology] MH - Bortezomib MH - Cell Cycle Proteins/ai [Antagonists & Inhibitors] MH - Cell Cycle Proteins/ge [Genetics] MH - Cell Cycle Proteins/me [Metabolism] MH - Cells, Cultured MH - *DNA Damage/re [Radiation Effects] MH - DNA Repair MH - DNA-Binding Proteins/ai [Antagonists & Inhibitors] MH - DNA-Binding Proteins/ge [Genetics] MH - DNA-Binding Proteins/me [Metabolism] MH - *Fanconi Anemia MH - Fanconi Anemia Complementation Group D2 Protein/ai [Antagonists & Inhibitors] MH - Fanconi Anemia Complementation Group D2 Protein/ge [Genetics] MH - *Fanconi Anemia Complementation Group D2 Protein/me [Metabolism] MH - Female MH - Flow Cytometry MH - Gamma Rays MH - HeLa Cells MH - Humans MH - Leupeptins/pd [Pharmacology] MH - Microscopy, Fluorescence MH - Nuclear Proteins/ai [Antagonists & Inhibitors] MH - Nuclear Proteins/ge [Genetics] MH - Nuclear Proteins/me [Metabolism] MH - Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - Phosphorylation/de [Drug Effects] MH - Phosphorylation/re [Radiation Effects] MH - Proteasome Endopeptidase Complex/ge [Genetics] MH - *Proteasome Endopeptidase Complex/me [Metabolism] MH - Proteasome Endopeptidase Complex/re [Radiation Effects] MH - Proteasome Inhibitors MH - Protein-Serine-Threonine Kinases/ai [Antagonists & Inhibitors] MH - Protein-Serine-Threonine Kinases/ge [Genetics] MH - Protein-Serine-Threonine Kinases/me [Metabolism] MH - Pyrazines/pd [Pharmacology] MH - RNA, Small Interfering/pd [Pharmacology] MH - Rad51 Recombinase/ai [Antagonists & Inhibitors] MH - Rad51 Recombinase/ge [Genetics] MH - Rad51 Recombinase/me [Metabolism] MH - *Signal Transduction MH - Tumor Suppressor Proteins/ai [Antagonists & Inhibitors] MH - Tumor Suppressor Proteins/ge [Genetics] MH - Tumor Suppressor Proteins/me [Metabolism] MH - *Ubiquitin/me [Metabolism] AB - Proteasome inhibitors sensitize tumor cells to DNA-damaging agents, including ionizing radiation (IR), and DNA cross-linking agents (melphalan and cisplatin) through unknown mechanisms. The Fanconi anemia pathway is a DNA damage-activated signaling pathway, which regulates cellular resistance to DNA cross-linking agents. Monoubiquitination and nuclear foci formation of FANCD2 are critical steps of the Fanconi anemia pathway. Here, we show that proteasome function is required for the activation of the Fanconi anemia pathway and for DNA damage signaling. Proteasome inhibitors (bortezomib and MG132) and depletion of 19S and 20S proteasome subunits (PSMD4, PSMD14, and PSMB3) inhibited monoubiquitination and/or nuclear foci formation of FANCD2, whereas depletion of DSS1/SHFM1, a subunit of the 19S proteasome that also directly binds to BRCA2, did not inhibit FANCD2 monoubiquitination or foci formation. On the other hand, DNA damage-signaling processes, such as IR-induced foci formation of phosphorylated ATM (phospho-ATM), 53BP1, NBS1, BRCA1, FANCD2, and RAD51, were delayed in the presence of proteasome inhibitors, whereas ATM autophosphorylation and nuclear foci formation of gammaH2AX, MDC1, and RPA were not inhibited. Furthermore, persistence of DNA damage and abrogation of the IR-induced G(1)-S checkpoint resulted from proteasome inhibition. In summary, we showed that the proteasome function is required for monoubiquitination of FANCD2, foci formation of 53BP1, phospho-ATM, NBS1, BRCA1, FANCD2, and RAD51. The dependence of specific DNA damage-signaling steps on the proteasome may explain the sensitization of tumor cells to DNA-damaging chemotherapeutic agents by proteasome inhibitors. RN - 0 (BRCA1 Protein) RN - 0 (Boronic Acids) RN - 0 (Cell Cycle Proteins) RN - 0 (DNA-Binding Proteins) RN - 0 (FANCD2 protein, human) RN - 0 (Fanconi Anemia Complementation Group D2 Protein) RN - 0 (Leupeptins) RN - 0 (NBN protein, human) RN - 0 (Nuclear Proteins) RN - 0 (PSMD4 protein, human) RN - 0 (Proteasome Inhibitors) RN - 0 (Pyrazines) RN - 0 (RNA, Small Interfering) RN - 0 (Tumor Suppressor Proteins) RN - 0 (Ubiquitin) RN - 69G8BD63PP (Bortezomib) RN - EC 2-7-11-1 (ATM protein, human) RN - EC 2-7-11-1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - EC 2-7-7 (Rad51 Recombinase) RN - EC 3-4-25-1 (Proteasome Endopeptidase Complex) RN - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde) IS - 0008-5472 IL - 0008-5472 DI - 67/15/7395 DO - https://dx.doi.org/10.1158/0008-5472.CAN-07-1015 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 17671210 [pubmed] ID - 67/15/7395 [pii] ID - 10.1158/0008-5472.CAN-07-1015 [doi] PP - ppublish LG - English DP - 2007 Aug 01 DC - 20070802 EZ - 2007/08/03 09:00 DA - 2007/09/12 09:00 DT - 2007/08/03 09:00 YR - 2007 ED - 20070911 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=17671210 <346. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 17537491 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Welch S AU - Hirte HW AU - Carey MS AU - Hotte SJ AU - Tsao MS AU - Brown S AU - Pond GR AU - Dancey JE AU - Oza AM FA - Welch, Stephen FA - Hirte, Hal W FA - Carey, Mark S FA - Hotte, Sebastian J FA - Tsao, Ming-Sound FA - Brown, Shirley FA - Pond, Gregory R FA - Dancey, Janet E FA - Oza, Amit M IN - Welch, Stephen. Princess Margaret Hospital, Toronto, Ontario, Canada M56 2M9. TI - UCN-01 in combination with topotecan in patients with advanced recurrent ovarian cancer: a study of the Princess Margaret Hospital Phase II consortium. SO - Gynecologic Oncology. 106(2):305-10, 2007 Aug AS - Gynecol Oncol. 106(2):305-10, 2007 Aug NJ - Gynecologic oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - fxc, 0365304 IO - Gynecol. Oncol. SB - Index Medicus CP - United States MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/ae [Adverse Effects] MH - *Antineoplastic Combined Chemotherapy Protocols/tu [Therapeutic Use] MH - Female MH - Humans MH - Middle Aged MH - *Neoplasm Recurrence, Local/dt [Drug Therapy] MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Staurosporine/ad [Administration & Dosage] MH - Staurosporine/ae [Adverse Effects] MH - Staurosporine/aa [Analogs & Derivatives] MH - Topotecan/ad [Administration & Dosage] MH - Topotecan/ae [Adverse Effects] AB - BACKGROUND AND OBJECTIVE: UCN-01 is a staurosporine analogue shown to abrogate the G2 checkpoint through inhibition of cyclin-dependent kinases. Preclinical evidence suggests synergy between UCN-01 and cytotoxic chemotherapy. Topotecan is an active agent in ovarian cancer. This phase II study was conducted to investigate the safety and efficacy of topotecan and UCN-01 in patients with advanced ovarian cancer. AB - METHODS: A two-stage phase II trial was designed for patients with advanced ovarian cancer with progressive disease despite prior treatment with platinum and paclitaxel. Patients with advanced ovarian cancer were treated with topotecan, 1 mg/m(2) IV, days 1 to 5, and UCN-01 70 mg/m(2) on day 1 of the first cycle, and 35 mg/m(2) on day 1 of all subsequent cycles. Treatment was repeated on a 3-week cycle. The primary objective of this study was objective response rate while secondary objectives included rates of stable disease, duration of response, progression-free and overall survival, as well as toxicity. Tumor biopsy specimens were also collected where possible for molecular correlative studies. AB - RESULTS: Twenty-nine patients are evaluable for toxicity and efficacy. Three patients (10%) achieved a partial response. The median time to progression was 3.3 months (95% CI 1.5-NA), and the median overall survival was 9.7 months (95% CI: 7.5-15.3). The most common grade 3-4 toxicities were neutropenia (79%), anemia (41%), thrombocytopenia (14%), hyperglycemia (10%), and pain (10%). AB - CONCLUSION: The combination of UCN-01 and topotecan is generally well tolerated, however, this combination is not considered to have significant antitumor activity against advanced ovarian cancer. RN - 7BU5H4V94A (7-hydroxystaurosporine) RN - 7M7YKX2N15 (Topotecan) RN - H88EPA0A3N (Staurosporine) IS - 0090-8258 IL - 0090-8258 DI - S0090-8258(07)00146-1 DO - https://dx.doi.org/10.1016/j.ygyno.2007.02.018 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 17537491 [pubmed] ID - S0090-8258(07)00146-1 [pii] ID - 10.1016/j.ygyno.2007.02.018 [doi] PP - ppublish PH - 2006/10/31 [received] PH - 2007/01/13 [revised] PH - 2007/02/20 [accepted] GI - No: #N01-CM-1701 Organization: (CM) *NCI NIH HHS* Country: United States LG - English EP - 20070529 DP - 2007 Aug DC - 20070730 EZ - 2007/06/01 09:00 DA - 2007/09/07 09:00 DT - 2007/06/01 09:00 YR - 2007 ED - 20070906 RD - 20131121 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=17537491 <347. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 17404099 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Nomi T AU - Sho M AU - Akahori T AU - Hamada K AU - Kubo A AU - Kanehiro H AU - Nakamura S AU - Enomoto K AU - Yagita H AU - Azuma M AU - Nakajima Y FA - Nomi, Takeo FA - Sho, Masayuki FA - Akahori, Takahiro FA - Hamada, Kaoru FA - Kubo, Atsushi FA - Kanehiro, Hiromichi FA - Nakamura, Shinji FA - Enomoto, Koji FA - Yagita, Hideo FA - Azuma, Miyuki FA - Nakajima, Yoshiyuki IN - Nomi, Takeo. Department of Surgery, Second Department of Internal Medicine, First Department of Internal Medicine, Nara Medical University, Nara, Japan. TI - Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. SO - Clinical Cancer Research. 13(7):2151-7, 2007 Apr 01 AS - Clin Cancer Res. 13(7):2151-7, 2007 Apr 01 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print PI - Citation processed from: Print JC - c2h, 9502500 IO - Clin. Cancer Res. SB - Index Medicus CP - United States MH - Adenocarcinoma/im [Immunology] MH - *Adenocarcinoma/me [Metabolism] MH - Adenocarcinoma/pa [Pathology] MH - Aged MH - Animals MH - Antibodies, Monoclonal/pd [Pharmacology] MH - Antigens, CD/de [Drug Effects] MH - *Antigens, CD/me [Metabolism] MH - Antigens, CD274 MH - Antineoplastic Combined Chemotherapy Protocols/pd [Pharmacology] MH - *Biomarkers, Tumor/an [Analysis] MH - CD8-Positive T-Lymphocytes/de [Drug Effects] MH - CD8-Positive T-Lymphocytes/im [Immunology] MH - Deoxycytidine/aa [Analogs & Derivatives] MH - Deoxycytidine/pd [Pharmacology] MH - Female MH - Humans MH - Immunohistochemistry MH - Lymphocytes, Tumor-Infiltrating/de [Drug Effects] MH - Lymphocytes, Tumor-Infiltrating/im [Immunology] MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Middle Aged MH - Pancreatic Neoplasms/im [Immunology] MH - *Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - Peptides/me [Metabolism] MH - Prognosis MH - Programmed Cell Death 1 Ligand 2 Protein MH - Reverse Transcriptase Polymerase Chain Reaction AB - PURPOSE: The programmed death-1 ligand/programmed death-1 (PD-L/PD-1) pathway has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In this study, we tried to reveal the clinical importance and therapeutic potential of the PD-L/PD-1 pathway in pancreatic cancer, which is one of the most aggressive and intractable malignant tumors. AB - EXPERIMENTAL DESIGN: We used immunohistochemistry to investigate PD-L expression in 51 patients with pancreatic cancer who underwent surgery and explored the therapeutic efficacy of blocking the PD-L1/PD-1 pathway in murine pancreatic cancer in vivo. AB - RESULTS: PD-L1-positive patients had a significantly poorer prognosis than the PD-L1-negative patients, whereas there was no significant correlation of tumor PD-L2 expression with patient survival. PD-L1 expression was inversely correlated with tumor-infiltrating T lymphocytes, particularly CD8(+) T cells. These clinical data have suggested that the PD-L1/PD-1 pathway may be a critical regulator in human pancreatic cancer. Monoclonal antibodies against PD-L1 or PD-1 induced a substantial antitumor effect on murine pancreatic cancer in vivo. PD-L1 blockade promoted CD8(+) T-cell infiltration into the tumor and induced local immune activation. Furthermore, the combination of anti-PD-L1 monoclonal antibody and gemcitabine exhibited a significant synergistic effect on murine pancreatic cancer and resulted in complete response without overt toxicity. AB - CONCLUSION: Our data suggest for the first time that PD-L1 status may be a new predictor of prognosis for patients with pancreatic cancer and provide the rationale for developing a novel therapy of targeting the PD-L/PD-1 pathway against this fatal disease. RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antigens, CD274) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - 0 (PDCD1LG2 protein, human) RN - 0 (Pdcd1lg2 protein, mouse) RN - 0 (Peptides) RN - 0 (Programmed Cell Death 1 Ligand 2 Protein) RN - 0W860991D6 (Deoxycytidine) RN - B76N6SBZ8R (gemcitabine) IS - 1078-0432 IL - 1078-0432 DI - 13/7/2151 DO - https://dx.doi.org/10.1158/1078-0432.CCR-06-2746 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 17404099 [pubmed] ID - 13/7/2151 [pii] ID - 10.1158/1078-0432.CCR-06-2746 [doi] PP - ppublish LG - English DP - 2007 Apr 01 DC - 20070403 EZ - 2007/04/04 09:00 DA - 2007/06/22 09:00 DT - 2007/04/04 09:00 YR - 2007 ED - 20070621 RD - 20151119 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=17404099 <348. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 16968694 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Fikaris AJ AU - Lewis AE AU - Abulaiti A AU - Tsygankova OM AU - Meinkoth JL FA - Fikaris, Aphrothiti J FA - Lewis, Aurelia E FA - Abulaiti, Adili FA - Tsygankova, Oxana M FA - Meinkoth, Judy L IN - Fikaris, Aphrothiti J. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. TI - Ras triggers ataxia-telangiectasia-mutated and Rad-3-related activation and apoptosis through sustained mitogenic signaling. SO - Journal of Biological Chemistry. 281(46):34759-67, 2006 Nov 17 AS - J Biol Chem. 281(46):34759-67, 2006 Nov 17 NJ - The Journal of biological chemistry PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - hiv, 2985121r IO - J. Biol. Chem. SB - Index Medicus CP - United States MH - Animals MH - *Apoptosis/ph [Physiology] MH - Ataxia Telangiectasia Mutated Proteins MH - Cell Cycle MH - Cell Cycle Proteins/ge [Genetics] MH - *Cell Cycle Proteins/me [Metabolism] MH - Cells, Cultured MH - Checkpoint Kinase 1 MH - Cyclin-Dependent Kinase 2/me [Metabolism] MH - Gene Expression Regulation MH - Humans MH - *Mitogens/me [Metabolism] MH - Protein Kinases/me [Metabolism] MH - Protein-Serine-Threonine Kinases/ge [Genetics] MH - *Protein-Serine-Threonine Kinases/me [Metabolism] MH - Rats MH - Rats, Wistar MH - *Signal Transduction MH - Thyroid Gland/cy [Cytology] MH - *Thyroid Gland/me [Metabolism] MH - Up-Regulation MH - ras Proteins/ge [Genetics] MH - *ras Proteins/me [Metabolism] AB - Genetic evidence indicates that Ras plays a critical role in the initiation and progression of human thyroid tumors. Paradoxically, acute expression of activated Ras in normal rat thyroid cells induced deregulated cell cycle progression and apoptosis. We investigated whether cell cycle progression was required for Ras-stimulated apoptosis. Ras increased CDK-2 activity following its introduction into quiescent cells. Apoptotic cells exhibited a sustained increase in CDK-2 activity, accompanied by the loss of CDK-2-associated p27. Blockade of Ras-induced CDK-2 activity and S phase entry via overexpression of p27 inhibited apoptosis. Inactivation of the retinoblastoma protein in quiescent cells through expression of HPV-E7 stimulated cell cycle progression and apoptosis, indicating that deregulated cell cycle progression is sufficient to induce apoptosis. Ras failed to induce G1 phase growth arrest in normal rat thyroid cells. Rather, Ras-expressing thyroid cells progressed into S and G2 phases and evoked a checkpoint response characterized by the activation of ATR. Ras-stimulated ATR activity, as evidenced by Chk1 and p53 phosphorylation, was blocked by p27, suggesting that cell cycle progression triggers checkpoint activation, likely as a consequence of replication stress. These data reveal that Ras is capable of inducing a DNA damage response with characteristics similar to those reported in precancerous lesions. Our findings also suggest that the frequent mutational activation of Ras in thyroid tumors reflects the ability of Ras-expressing cells to bypass checkpoints and evade apoptosis rather than to simply increase proliferative potential. RN - 0 (Cell Cycle Proteins) RN - 0 (Mitogens) RN - EC 2-7 (Protein Kinases) RN - EC 2-7-11-1 (ATR protein, human) RN - EC 2-7-11-1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2-7-11-1 (CHEK1 protein, human) RN - EC 2-7-11-1 (Checkpoint Kinase 1) RN - EC 2-7-11-1 (Chek1 protein, rat) RN - EC 2-7-11-1 (Protein-Serine-Threonine Kinases) RN - EC 2-7-11-22 (Cyclin-Dependent Kinase 2) RN - EC 3-6-5-2 (ras Proteins) IS - 0021-9258 IL - 0021-9258 DI - M606737200 DO - https://dx.doi.org/10.1074/jbc.M606737200 PT - Journal Article PT - Research Support, N.I.H., Extramural ID - 16968694 [pubmed] ID - M606737200 [pii] ID - 10.1074/jbc.M606737200 [doi] PP - ppublish GI - No: DK55757 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English EP - 20060912 DP - 2006 Nov 17 DC - 20061113 EZ - 2006/09/14 09:00 DA - 2007/01/19 09:00 DT - 2006/09/14 09:00 YR - 2006 ED - 20070118 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=16968694 <349. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 16801985 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bayes M AU - Rabasseda X AU - Prous JR FA - Bayes, M FA - Rabasseda, X FA - Prous, J R IN - Bayes, M. Prous Science, Barcelona, Spain. mbayes@prous.com TI - Gateways to clinical trials. SO - Methods & Findings in Experimental & Clinical Pharmacology. 28(4):233-77, 2006 May AS - Methods Find Exp Clin Pharmacol. 28(4):233-77, 2006 May NJ - Methods and findings in experimental and clinical pharmacology PI - Journal available in: Print PI - Citation processed from: Print JC - lzn, 7909595 IO - Methods Find Exp Clin Pharmacol SB - Index Medicus CP - Spain MH - *Clinical Trials as Topic MH - Humans AB - Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com/. This issue focuses on the following selection of drugs: Adalimumab, adenosine triphosphate, alemtuzumab, alendronate sodium/cholecalciferol, aliskiren fumarate, AMGN-0007, aminolevulinic acid methyl ester, anakinra, anidulafungin, aripiprazole, atomoxetine hydrochloride; Bevacizumab, bosentan; Calcipotriol/beta methasone dipropionate, caldaret hydrate, caspofungin acetate, cetuximab, cinacalcet hydrochloride, clopidogrel, cocaine-BSA conjugate, conivaptan hydrochloride, Cypher; Darbepoetin alfa, delmitide, desloratadine, desmoteplase, desoxyepothilone B, disufenton sodium, DU-176b, duloxetine hydrochloride, dutasteride; EBV-specific CTLs, ecogramostim, edodekin alfa, efalizumab, eletriptan, emtricitabine, entecavir, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, etoricoxib, everolimus, ezetimibe; Fanapanel, fondaparinux sodium; Gefitinib, GTI-2040, GW-501516; Her2 E75-peptide vaccine, human insulin; Ibogaine, icatibant acetate, Id-KLH vaccine, imatinib mesylate, immune globulin subcutaneous [human], indacaterol, inolimomab, ipilimumab, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lacosamide, lanthanum carbonate, lenalidomide, levocetirizine, levodopa methyl ester hydrochloride/carbidopa, levodopa/carbidopa/entacapone, lidocaine/prilocaine; Maraviroc, mecasermin, melevodopa hydrochloride, mepolizumab, mitumomab; Nesiritide; Omalizumab, oral insulin; Parathyroid hormone (human recombinant), patupilone, pegaptanib sodium, PEG-filgrastim, pemetrexed disodium, photochlor, pimecrolimus, posaconazole, prasterone, prasugrel, pregabalin, prilocaine, PRX-00023; QS-21; Ranibizumab, ranirestat, rhodamine 123, rotigaptide; Sarcosine, sirolimus-eluting stent, sitaxsentan sodium, solifenacin succinate, Staphylococcus aureus vaccine; Tadalafil, talactoferrin alfa, talaporfin sodium, Taxus, tecadenoson, tegaserod maleate, telithromycin, temsirolimus, tenofovir disoproxil fumarate, teriparatide, terutroban sodium, tesaglitazar, tesmilifene hydrochloride, TG-100115, tigecycline, torcetrapib; Ularitide; Valproic acid, sodium, voriconazole; Zotarolimus, zotarolimus-eluting stent. IS - 0379-0355 IL - 0379-0355 DI - 3155 PT - Bibliography ID - 16801985 [pubmed] ID - 3155 [pii] PP - ppublish LG - English DP - 2006 May DC - 20060627 EZ - 2006/06/28 09:00 DA - 2006/12/09 09:00 DT - 2006/06/28 09:00 YR - 2006 ED - 20061204 RD - 20071115 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=16801985 <350. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 16710025 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Beck KE AU - Blansfield JA AU - Tran KQ AU - Feldman AL AU - Hughes MS AU - Royal RE AU - Kammula US AU - Topalian SL AU - Sherry RM AU - Kleiner D AU - Quezado M AU - Lowy I AU - Yellin M AU - Rosenberg SA AU - Yang JC FA - Beck, Kimberly E FA - Blansfield, Joseph A FA - Tran, Khoi Q FA - Feldman, Andrew L FA - Hughes, Marybeth S FA - Royal, Richard E FA - Kammula, Udai S FA - Topalian, Suzanne L FA - Sherry, Richard M FA - Kleiner, David FA - Quezado, Martha FA - Lowy, Israel FA - Yellin, Michael FA - Rosenberg, Steven A FA - Yang, James C IN - Beck, Kimberly E. Surgery Branch and Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA. TI - Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. CM - Comment in: J Clin Oncol. 2006 Dec 1;24(34):5469-70; author reply 5470-1; PMID: 17135653 CM - Comment in: J Clin Oncol. 2006 May 20;24(15):2230-2; PMID: 16710020 SO - Journal of Clinical Oncology. 24(15):2283-9, 2006 May 20 AS - J Clin Oncol. 24(15):2283-9, 2006 May 20 NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2140223 OI - Source: NLM. NIHMS35289 SB - Index Medicus CP - United States MH - Adrenal Cortex Hormones/tu [Therapeutic Use] MH - *Antibodies, Monoclonal/ae [Adverse Effects] MH - Antibodies, Monoclonal/tu [Therapeutic Use] MH - Antigens, CD MH - *Antigens, Differentiation/im [Immunology] MH - *Antineoplastic Agents/ae [Adverse Effects] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - CTLA-4 Antigen MH - Cancer Vaccines MH - Carcinoma, Renal Cell/dt [Drug Therapy] MH - *Enterocolitis/ci [Chemically Induced] MH - Enterocolitis/dt [Drug Therapy] MH - Female MH - Gastrointestinal Agents/tu [Therapeutic Use] MH - Humans MH - Infliximab MH - Kidney Neoplasms/dt [Drug Therapy] MH - Male MH - Melanoma/dt [Drug Therapy] MH - Middle Aged MH - *Neoplasms/dt [Drug Therapy] MH - Skin Neoplasms/dt [Drug Therapy] AB - PURPOSE: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is an inhibitory receptor on T cells. Knocking out CTLA4 in mice causes lethal lymphoproliferation, and polymorphisms in human CTLA4 are associated with autoimmune disease. Trials of the anti-CTLA4 antibody ipilimumab (MDX-010) have resulted in durable cancer regression and immune-mediated toxicities. A report on the diagnosis, pathology, treatment, clinical outcome, and significance of the immune-mediated enterocolitis seen with ipilimumab is presented. AB - PATIENTS AND METHODS: We treated 198 patients with metastatic melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab. AB - RESULTS: The overall objective tumor response rate was 14%. We observed several immune mediated toxicities including dermatitis, enterocolitis, hypophysitis, uveitis, hepatitis, and nephritis. Enterocolitis, defined by grade 3/4 clinical presentation and/or biopsy documentation, was the most common major toxicity (21% of patients). It presented with diarrhea, and biopsies showed both neutrophilic and lymphocytic inflammation. Most patients who developed enterocolitis responded to high-dose systemic corticosteroids. There was no evidence that steroid administration affected tumor responses. Five patients developed perforation or required colectomy. Four other patients with steroid-refractory enterocolitis appeared to respond promptly to tumor necrosis factor alpha blockade with infliximab. Objective tumor response rates in patients with enterocolitis were 36% for MM and 35% for RCC, compared with 11% and 2% in patients without enterocolitis, respectively (P = .0065 for MM and P = .0016 for RCC). AB - CONCLUSION: CTLA4 seems to be a significant component of tolerance to tumor and in protection against immune mediated enterocolitis and these phenomena are significantly associated in cancer patients. RN - 0 (Adrenal Cortex Hormones) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antigens, CD) RN - 0 (Antigens, Differentiation) RN - 0 (Antineoplastic Agents) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) RN - 0 (Cancer Vaccines) RN - 0 (Ctla4 protein, mouse) RN - 0 (Gastrointestinal Agents) RN - 6T8C155666 (ipilimumab) RN - B72HH48FLU (Infliximab) ES - 1527-7755 IL - 0732-183X DI - 24/15/2283 DO - https://dx.doi.org/10.1200/JCO.2005.04.5716 PT - Journal Article PT - Research Support, N.I.H., Intramural ID - 16710025 [pubmed] ID - 24/15/2283 [pii] ID - 10.1200/JCO.2005.04.5716 [doi] ID - PMC2140223 [pmc] ID - NIHMS35289 [mid] PP - ppublish GI - No: Z01 SC003811-32 Organization: *Intramural NIH HHS* Country: United States LG - English DP - 2006 May 20 DC - 20060519 EZ - 2006/05/20 09:00 DA - 2006/06/08 09:00 DT - 2006/05/20 09:00 YR - 2006 ED - 20060607 RD - 20161128 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=16710025 <351. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 16419058 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Sbrana I AU - Veroni F AU - Nieri M AU - Puliti A AU - Barale R FA - Sbrana, Isabella FA - Veroni, Franca FA - Nieri, Maria FA - Puliti, Aldamaria FA - Barale, Roberto IN - Sbrana, Isabella. Department of Human and Environmental Sciences, University of Pisa, Pisa, Italy. i.sbrana@geog.unipi.it TI - Chromosomal fragile sites FRA3B and FRA16D show correlated expression and association with failure of apoptosis in lymphocytes from patients with thyroid cancer. SO - Genes, Chromosomes & Cancer. 45(5):429-36, 2006 May AS - Genes Chromosomes Cancer. 45(5):429-36, 2006 May NJ - Genes, chromosomes & cancer PI - Journal available in: Print PI - Citation processed from: Print JC - ayv, 9007329 IO - Genes Chromosomes Cancer SB - Index Medicus CP - United States MH - Adolescent MH - Adult MH - *Apoptosis/ge [Genetics] MH - *Chromosome Fragile Sites MH - Chromosome Mapping MH - Female MH - Humans MH - Loss of Heterozygosity MH - *Lymphocytes/ul [Ultrastructure] MH - Male MH - Radioactive Pollutants MH - *Thyroid Neoplasms/ge [Genetics] AB - It has been suggested that common fragile sites (cFSs) are related to cancer development. This appears to be the case for FRA3B and FRA16D, localized in two tumor-suppressor genes (FHIT and WWOX, respectively) that are altered by deletions or loss of heterozygosity (LOH) in many cancers. The features responsible for fragility have not yet been identified. Furthermore, it is still unclear whether instability at these regions causes chance deletions and loss of function of the associated genes, or whether the gene function itself is related to the appearance of fragility. In this study, we analyzed cFS expression in lymphocytes from 20 healthy or thyroid cancer-affected subjects exposed to radiation after the Chernobyl accident. The same cells were examined for apoptosis, a principal function of both the FHIT and WWOX genes. Exceptionally elevated chromosome fragility was observed, particularly in cancer patients, affecting FRA3B, FRA16D, and a cluster of less highly expressed cFSs; levels of chromosome fragility were found to be correlated among these cFSs. Interestingly, most expressed cFSs were sites of LOH reported for thyroid tumors; moreover, cells with the highest fragility also had a reduced ability to undergo apoptosis. These findings reveal previously unknown genetic interactions affecting fragile loci, suggestive of a shared function inside mitotic cells. Attenuation of checkpoint control and apoptosis resistance seem to be the cell phenotypes associated with unusual chromosome fragility. We propose that breakage at specific cFS could derive from early epigenetic events at loci involved in radiation carcinogenesis. This article contains supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. AB - Copyright 2006 Wiley-Liss, Inc RN - 0 (Radioactive Pollutants) IS - 1045-2257 IL - 1045-2257 DO - https://dx.doi.org/10.1002/gcc.20305 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 16419058 [pubmed] ID - 10.1002/gcc.20305 [doi] PP - ppublish LG - English DP - 2006 May DC - 20060306 EZ - 2006/01/19 09:00 DA - 2006/05/31 09:00 DT - 2006/01/19 09:00 YR - 2006 ED - 20060530 RD - 20061115 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=16419058 <352. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 16585202 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Bazzaro M AU - Lee MK AU - Zoso A AU - Stirling WL AU - Santillan A AU - Shih IeM AU - Roden RB FA - Bazzaro, Martina FA - Lee, Michael K FA - Zoso, Alessia FA - Stirling, Wanda L H FA - Santillan, Antonio FA - Shih, Ie-Ming FA - Roden, Richard B S IN - Bazzaro, Martina. Department of Pathology, The Johns Hopkins School of Medicine, Cancer Research Building 2, 1550 Orleans Street, Baltimore, MD 21231, USA. TI - Ubiquitin-proteasome system stress sensitizes ovarian cancer to proteasome inhibitor-induced apoptosis. SO - Cancer Research. 66(7):3754-63, 2006 Apr 01 AS - Cancer Res. 66(7):3754-63, 2006 Apr 01 NJ - Cancer research PI - Journal available in: Print PI - Citation processed from: Print JC - cnf, 2984705r IO - Cancer Res. SB - Index Medicus CP - United States MH - Animals MH - *Apoptosis/de [Drug Effects] MH - Apoptosis/ph [Physiology] MH - Boronic Acids/pd [Pharmacology] MH - Bortezomib MH - Caspases/me [Metabolism] MH - Cell Division/de [Drug Effects] MH - Cell Line, Tumor MH - Female MH - G2 Phase/de [Drug Effects] MH - Humans MH - Leupeptins/pd [Pharmacology] MH - Mice MH - Mice, Nude MH - Oligopeptides/pd [Pharmacology] MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - Ovarian Neoplasms/en [Enzymology] MH - *Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - *Protease Inhibitors/pd [Pharmacology] MH - Proteasome Endopeptidase Complex/bi [Biosynthesis] MH - *Proteasome Endopeptidase Complex/me [Metabolism] MH - *Proteasome Inhibitors MH - Pyrazines/pd [Pharmacology] MH - *Ubiquitin/me [Metabolism] MH - Xenograft Model Antitumor Assays AB - The ubiquitin-proteasome system (UPS) mediates targeted protein degradation. Notably, the UPS determines levels of key checkpoint proteins controlling apoptosis and proliferation by controlling protein half-life. Herein, we show that ovarian carcinoma manifests an overstressed UPS by comparison with normal tissues by accumulation of ubiquitinated proteins despite elevated proteasome levels. Elevated levels of total ubiquitinated proteins and 19S and 20S proteasome subunits are evident in both low-grade and high-grade ovarian carcinoma tissues relative to benign ovarian tumors and in ovarian carcinoma cell lines relative to immortalized surface epithelium. We find that ovarian carcinoma cell lines exhibit greater sensitivity to apoptosis in response to proteasome inhibitors than immortalized ovarian surface epithelial cells. This sensitivity correlates with increased cellular proliferation rate and UPS stress rather than absolute proteasome levels. Proteasomal inhibition in vitro induces cell cycle arrest and the accumulation of p21 and p27 and triggers apoptosis via activation of caspase-3. Furthermore, treatment with the licensed proteasome inhibitor PS-341 slows the growth of ES-2 ovarian carcinoma xenograft in immunodeficient mice. In sum, elevated proliferation and metabolic rate resulting from malignant transformation of the epithelium stresses the UPS and renders ovarian carcinoma more sensitive to apoptosis in response to proteasomal inhibition. RN - 0 (Boronic Acids) RN - 0 (Leupeptins) RN - 0 (Oligopeptides) RN - 0 (Protease Inhibitors) RN - 0 (Proteasome Inhibitors) RN - 0 (Pyrazines) RN - 0 (Ubiquitin) RN - 69G8BD63PP (Bortezomib) RN - EC 3-4-22 (Caspases) RN - EC 3-4-25-1 (Proteasome Endopeptidase Complex) RN - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde) RN - Y0900I3U8U (epoxomicin) IS - 0008-5472 IL - 0008-5472 DI - 66/7/3754 DO - https://dx.doi.org/10.1158/0008-5472.CAN-05-2321 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. ID - 16585202 [pubmed] ID - 66/7/3754 [pii] ID - 10.1158/0008-5472.CAN-05-2321 [doi] PP - ppublish LG - English DP - 2006 Apr 01 DC - 20060404 EZ - 2006/04/06 09:00 DA - 2006/05/23 09:00 DT - 2006/04/06 09:00 YR - 2006 ED - 20060522 RD - 20161128 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=16585202 <353. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 16099193 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - di Pietro A AU - Vries EG AU - Gietema JA AU - Spierings DC AU - de Jong S FA - di Pietro, Alessandra FA - Vries, Elisabeth G E de FA - Gietema, Jourik A FA - Spierings, Diana C J FA - de Jong, Steven IN - di Pietro, Alessandra. Department of Medical Oncology, Internal Medicine, University of Groningen and University Medical Center Groningen, 9713 GZ Hanzeplein 1, Groningen, The Netherlands. TI - Testicular germ cell tumours: the paradigm of chemo-sensitive solid tumours. [Review] [202 refs] SO - International Journal of Biochemistry & Cell Biology. 37(12):2437-56, 2005 Dec AS - Int J Biochem Cell Biol. 37(12):2437-56, 2005 Dec NJ - The international journal of biochemistry & cell biology PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - cdk, 9508482 IO - Int. J. Biochem. Cell Biol. SB - Index Medicus CP - Netherlands MH - Adult MH - Animals MH - Apoptosis MH - Carcinoma in Situ/pp [Physiopathology] MH - Cell Cycle/ph [Physiology] MH - Cell Line, Tumor MH - *Cisplatin/tu [Therapeutic Use] MH - DNA-Binding Proteins/ph [Physiology] MH - Genes, Neoplasm MH - Genes, Tumor Suppressor/ph [Physiology] MH - *Germinoma/dt [Drug Therapy] MH - Germinoma/ge [Genetics] MH - Germinoma/sc [Secondary] MH - Humans MH - Male MH - Membrane Proteins/ph [Physiology] MH - Mice MH - Nuclear Proteins/ph [Physiology] MH - *Testicular Neoplasms/dt [Drug Therapy] MH - Testicular Neoplasms/ge [Genetics] MH - Testicular Neoplasms/pa [Pathology] MH - Testis/cy [Cytology] MH - Tumor Protein p73 MH - Tumor Suppressor Protein p53/ge [Genetics] MH - Tumor Suppressor Protein p53/me [Metabolism] MH - Tumor Suppressor Proteins AB - Testicular germ cell tumours (TGCTs) are the most frequent solid malignant tumour in men 20-40 years of age and the most frequent cause of death from solid tumours in this age group. Up to 50% of the patients suffer from metastatic disease at diagnosis. The majority of metastatic testicular cancer patients, in contrast to most other metastatic solid tumours, can be cured with highly effective cisplatin-based chemotherapy. From a genetic point of view, almost all TGCTs in contrast to solid tumours are characterised by the presence of wild type p53. High p53 expression levels are associated with elevated Mdm2 levels and a loss of p21(Waf1/Cip1) expression suggesting a changed functionality of p53. Expression levels of other proteins involved in the regulation of cell cycle progression indicate a deregulated G1-S phase checkpoint in TGCTs. After cisplatin-induced DNA damage, the increasing levels of p53 lead to the trans-activation of a number of genes but not of p21(Waf1/Cip1), preferentially directing TGCT cells into apoptosis or programmed cell death, both via the mitochondrial and the death receptor apoptosis pathways. The sensitivity of TGCTs to chemotherapeutic drugs may lay in the susceptibility of germ cells to apoptosis. Taken together, this provides TGCT as a tumour type model to investigate and understand the molecular determinants of chemotherapy sensitivity of solid tumours. This review aims to summarise the current knowledge on the biological basis of cisplatin-induced apoptosis and response to chemotherapy in TGCTs. [References: 202] RN - 0 (CKAP4 protein, human) RN - 0 (DNA-Binding Proteins) RN - 0 (Membrane Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Trp73 protein, mouse) RN - 0 (Tumor Protein p73) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (Tumor Suppressor Proteins) RN - Q20Q21Q62J (Cisplatin) IS - 1357-2725 IL - 1357-2725 DI - S1357-2725(05)00198-6 DO - https://dx.doi.org/10.1016/j.biocel.2005.06.014 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 16099193 [pubmed] ID - S1357-2725(05)00198-6 [pii] ID - 10.1016/j.biocel.2005.06.014 [doi] PP - ppublish PH - 2005/03/25 [received] PH - 2005/06/02 [revised] PH - 2005/01/27 [accepted] LG - English EP - 20050811 DP - 2005 Dec DC - 20051007 EZ - 2005/08/16 09:00 DA - 2005/12/24 09:00 DT - 2005/08/16 09:00 YR - 2005 ED - 20051223 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=16099193 <354. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 15827334 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Strait KA AU - Warnick CT AU - Ford CD AU - Dabbas B AU - Hammond EH AU - Ilstrup SJ FA - Strait, Kevin A FA - Warnick, C Terry FA - Ford, Clyde D FA - Dabbas, Bashar FA - Hammond, Elizabeth H FA - Ilstrup, Sarah J IN - Strait, Kevin A. Department of Medicine, Laboratory for Molecular Oncology, LDS Hospital, Salt Lake City, Utah 84143, USA. ldkstrai@ihc.com TI - Histone deacetylase inhibitors induce G2-checkpoint arrest and apoptosis in cisplatinum-resistant ovarian cancer cells associated with overexpression of the Bcl-2-related protein Bad. SO - Molecular Cancer Therapeutics. 4(4):603-11, 2005 Apr AS - Mol Cancer Ther. 4(4):603-11, 2005 Apr NJ - Molecular cancer therapeutics PI - Journal available in: Print PI - Citation processed from: Print JC - 101132535 IO - Mol. Cancer Ther. SB - Index Medicus CP - United States MH - Annexin A5/ch [Chemistry] MH - Annexin A5/me [Metabolism] MH - *Antineoplastic Agents/pd [Pharmacology] MH - *Apoptosis MH - Blotting, Western MH - *Carrier Proteins/bi [Biosynthesis] MH - Cell Differentiation MH - Cell Line, Tumor MH - Cell Proliferation MH - Cell Survival MH - *Cisplatin/pd [Pharmacology] MH - Female MH - Fibroblasts/me [Metabolism] MH - Flow Cytometry MH - G1 Phase MH - G2 Phase MH - *Histone Deacetylase Inhibitors MH - Humans MH - Hydroxamic Acids/pd [Pharmacology] MH - Immunohistochemistry MH - Microscopy, Electron MH - *Mitochondria/me [Metabolism] MH - Mitosis MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - *Ovarian Neoplasms/me [Metabolism] MH - Phenotype MH - *Proto-Oncogene Proteins c-bcl-2/bi [Biosynthesis] MH - Time Factors MH - bcl-Associated Death Protein AB - Trichostatin A produces predominantly G(1) cell-cycle blockade and differentiation of the cisplatinum-sensitive A2780 ovarian cancer cell line. Given the propensity of ovarian tumors to become resistant to cisplatinum, often leading to cross-resistance to other agents, we have extended these observations by examining how the emergence of resistant phenotypes in A2780 cells affects the actions of histone deacetylase (HDAC) inhibitors. Trichostatin A exposure (100 ng/mL, 24 hours) induced ultrastructural differentiation of the "intrinsically" cisplatinum-resistant A2780-9M subline, with the reappearance of intercellular junctions and lumina containing primitive microvilli. Similar trichostatin A exposure in the acquired resistance A2780CP cells produced minimal differentiation consisting of occasional weak intercellular junctions. Independent of the differences in trichostatin A-induced differentiation, in both resistant sublines trichostatin A produced a similar reduction in cell viability, by >90%, within 5 days of treatment. Diminished viability in both A2780-9M and CP cells was associated with the absence of cell cycle arrest in G1, resulting in predominant G2-checkpoint arrest accompanied by a 10- to 20-fold increase in Annexin V binding and the reemergence of apoptosis. Similar cell cycle arrests and apoptosis were also observed using other HDAC inhibitors and in other resistant ovarian cancer cell lines (OVCAR-3 and SK-OV-3). Trichostatin A-induced apoptosis in resistant cells is in sharp contrast to its effects on the parental cisplatinum-sensitive A2780 and normal MRC-5 fibroblast cell lines (predominant cycle arrest in G1 with no detectable apoptosis). Western immunoblot analysis indicated trichostatin A triggers apoptosis in resistant ovarian cancer cells via p53-independent activation of the intrinsic "mitochondrial" pathway, commensurate with induction of the Bcl-2-related protein Bad. These results suggest cisplatinum resistance alters the effects of HDAC inhibition through a shift in cell cycle arrest from the G1 to the G2 checkpoint and reactivation of the intrinsic mitochondrial apoptotic cascade. RN - 0 (Annexin A5) RN - 0 (Antineoplastic Agents) RN - 0 (BAD protein, human) RN - 0 (Carrier Proteins) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Hydroxamic Acids) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (bcl-Associated Death Protein) RN - 3X2S926L3Z (trichostatin A) RN - Q20Q21Q62J (Cisplatin) IS - 1535-7163 IL - 1535-7163 DI - 4/4/603 DO - https://dx.doi.org/10.1158/1535-7163.MCT-04-0107 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 15827334 [pubmed] ID - 4/4/603 [pii] ID - 10.1158/1535-7163.MCT-04-0107 [doi] PP - ppublish LG - English DP - 2005 Apr DC - 20050413 EZ - 2005/04/14 09:00 DA - 2005/10/07 09:00 DT - 2005/04/14 09:00 YR - 2005 ED - 20051006 RD - 20131121 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=15827334 <355. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 15990723 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wasko R AU - Jankowska A AU - Waligorska-Stachura J AU - Andrusiewicz M AU - Jaskula M AU - Sowinski J FA - Wasko, Ryszard FA - Jankowska, Anna FA - Waligorska-Stachura, Joanna FA - Andrusiewicz, Miroslaw FA - Jaskula, Magdalena FA - Sowinski, Jerzy IN - Wasko, Ryszard. University of Medical Sciences in Ponzan, Department of Endocrinology, Metabolism and Internal Diseases, Poland. rwasko@amp.edu.pl TI - Survivin expression in pituitary adenomas. SO - Neuroendocrinology Letters. 26(3):209-12, 2005 Jun AS - Neuroendocrinol Lett. 26(3):209-12, 2005 Jun NJ - Neuro endocrinology letters PI - Journal available in: Print PI - Citation processed from: Print JC - d1z, 8008373 IO - Neuro Endocrinol. Lett. SB - Index Medicus CP - Sweden MH - Acromegaly/ge [Genetics] MH - Acromegaly/pp [Physiopathology] MH - Adenoma/ge [Genetics] MH - *Adenoma/pp [Physiopathology] MH - Adult MH - Aged MH - *Biomarkers, Tumor/ge [Genetics] MH - Female MH - *Gene Expression Regulation, Neoplastic MH - HeLa Cells MH - Humans MH - Inhibitor of Apoptosis Proteins MH - Male MH - *Microtubule-Associated Proteins/ge [Genetics] MH - Middle Aged MH - *Neoplasm Proteins/ge [Genetics] MH - Pituitary Neoplasms/ge [Genetics] MH - *Pituitary Neoplasms/pp [Physiopathology] MH - Predictive Value of Tests MH - Prognosis MH - Prolactinoma/ge [Genetics] MH - Prolactinoma/pp [Physiopathology] MH - RNA, Messenger/an [Analysis] AB - UNLABELLED: Survivin has received great attention due to its expression in many human tumours and its potential as a therapeutic target in cancer. Its expression is developmentally regulated: present during fetal development, it is undetectable in terminally differentiated normal adult tissue. Survivin expression has been described to be cell cycle-dependent and restricted to the G2-M checkpoint, where it inhibits apoptosis in proliferating cells. AB - OBJECTIVES: The aim of our study was to determine the survivin expression in different types of pituitary adenomas. AB - METHODS: Tissue samples were obtained during surgical removal of the tumour from 12 patients with diagnosed: acromegaly in seven cases, non-functioning pituitary tumours in four cases and prolactinoma in one case. Six patients with acromegaly received long-acting somatostatin analogues before tumour resection. After RNA extraction and cDNA synthesis, the amplification of specific survivin's gene fragment was performed. AB - RESULTS: In agreement with the current view that survivin is a tumor-associated antigen, highly expressed in various tumours, we found the presence of survivin expression as a characteristic feature of human pituitary adenomas. The findings of our study demonstrated the presence of an active survivin gene in all twelve analysed pituitary tumours. AB - CONCLUSIONS: Based on these findings, we conclude that the estimation of survivin expression in human pituitary tumours may help predict tumour growth and prognosis. RN - 0 (BIRC5 protein, human) RN - 0 (Biomarkers, Tumor) RN - 0 (Inhibitor of Apoptosis Proteins) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (RNA, Messenger) IS - 0172-780X IL - 0172-780X DI - NEL260305A03 PT - Journal Article ID - 15990723 [pubmed] ID - NEL260305A03 [pii] PP - ppublish PH - 2005/03/20 [received] PH - 2005/04/15 [accepted] LG - English DP - 2005 Jun DC - 20050701 EZ - 2005/07/02 09:00 DA - 2005/10/06 09:00 DT - 2005/07/02 09:00 YR - 2005 ED - 20051005 RD - 20151119 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=15990723 <356. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 15786490 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Whitfield JF FA - Whitfield, James F IN - Whitfield, James F. Institute for Biological Sciences, Montreal Road Campus, National Research Council of Canada, Ottawa, Ontario, K1A 0R6 Canada. pthosteo@rogers.com TI - Osteogenic PTHs and vascular ossification-Is there a danger for osteoporotics?. [Review] [60 refs] SO - Journal of Cellular Biochemistry. 95(3):437-44, 2005 Jun 01 AS - J Cell Biochem. 95(3):437-44, 2005 Jun 01 NJ - Journal of cellular biochemistry PI - Journal available in: Print PI - Citation processed from: Print JC - hnf, 8205768 IO - J. Cell. Biochem. SB - Index Medicus CP - United States MH - Animals MH - Arteries/me [Metabolism] MH - Arteries/pa [Pathology] MH - Calcinosis/ci [Chemically Induced] MH - *Calcinosis/me [Metabolism] MH - Calcinosis/pa [Pathology] MH - Female MH - Heart Ventricles/me [Metabolism] MH - Heart Ventricles/pa [Pathology] MH - Humans MH - Osteoporosis, Postmenopausal/co [Complications] MH - Osteoporosis, Postmenopausal/dt [Drug Therapy] MH - *Osteoporosis, Postmenopausal/me [Metabolism] MH - Parathyroid Hormone-Related Protein/ad [Administration & Dosage] MH - Parathyroid Hormone-Related Protein/ae [Adverse Effects] MH - *Parathyroid Hormone-Related Protein/me [Metabolism] MH - Vascular Diseases/ci [Chemically Induced] MH - *Vascular Diseases/me [Metabolism] MH - Vascular Diseases/pa [Pathology] AB - Inflammation in vascular (mostly arterial) walls and heart valves triggered by the trans-endothelial influx of LDL particles and the action of subsequently modified (e.g., by oxidation) LDL particles can trigger true bone formation by valvar fibroblasts, by a subpopulation of re-differentiation-competent VSMCs (vascular smooth muscle cells) or by vascular pericytes. Vascular ossification can lead to heart failure and death. Elderly osteoporotic women who need osteogenic drugs to restore their lost skeletal bone are paradoxically prone to vascular ossification-the "calcification paradox." The recent introduction into the clinic of a potently osteogenic parathyroid hormone peptide, Lilly's rhPTH-(1-34)OH (Forteotrade mark), to reverse skeletal bone loss raises the question of whether this and other potently osteogenic PTHs still in clinical trial might also stimulate vascular ossification in such osteoporotic women. Indeed the VSMCs in human and rat atherosclerotic lesions hyperexpress PTHrP and the PTHR1 (or PTH1R) receptor as do maturing osteoblasts. And the evidence indicates that endogenous PTHrP with its NLS (nuclear/nucleolar localization sequence) does stimulate VSMC proliferation (a prime prerequisite for atheroma formation and ossification) via intranuclear targets that inactivate pRb, the inhibitory G1/S checkpoint regulator, by stimulating its hyperphosphorylation. But neither externally added full-length PTHrP nor the NLS-lacking PTHrP-(1-34)OH gets into the VSMC nucleus and instead they inhibit proliferation and calcification by only activating the cell's PTHR1 receptors. No PTH has an NLS and, as expected from the observations on the externally added PTHrPs, hPTH-(1-34)OH inhibits calcification by VSMCs and cannot stimulate vascular ossification in a diabetic mouse model. Encouraging though this may be for osteoporotics with their "calcification paradox," more work is needed to be sure that the skeletally osteogenic PTHs do not promote vascular ossification with its cardiovascular consequences. AB - Copyright (c) 2005 Wiley-Liss, Inc. [References: 60] RN - 0 (Parathyroid Hormone-Related Protein) IS - 0730-2312 IL - 0730-2312 DO - https://dx.doi.org/10.1002/jcb.20424 PT - Journal Article PT - Review ID - 15786490 [pubmed] ID - 10.1002/jcb.20424 [doi] PP - ppublish LG - English DP - 2005 Jun 01 DC - 20050516 EZ - 2005/03/24 09:00 DA - 2005/09/01 09:00 DT - 2005/03/24 09:00 YR - 2005 ED - 20050831 RD - 20051116 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=15786490 <357. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 15913739 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Belanger S AU - Cote M AU - Lane D AU - L'Esperance S AU - Rancourt C AU - Piche A FA - Belanger, Sylvie FA - Cote, Marceline FA - Lane, Denis FA - L'Esperance, Sylvain FA - Rancourt, Claudine FA - Piche, Alain IN - Belanger, Sylvie. Departement de Microbiologie et Infectiologie, Faculte de Medecine, Universite de Sherbrooke, 3001, 12ieme Avenue Nord, Sherbooke, Canada J1H 5N1. TI - Bcl-2 decreases cell proliferation and promotes accumulation of cells in S phase without affecting the rate of apoptosis in human ovarian carcinoma cells. SO - Gynecologic Oncology. 97(3):796-806, 2005 Jun AS - Gynecol Oncol. 97(3):796-806, 2005 Jun NJ - Gynecologic oncology PI - Journal available in: Print PI - Citation processed from: Print JC - fxc, 0365304 IO - Gynecol. Oncol. SB - Index Medicus CP - United States MH - *Apoptosis/ph [Physiology] MH - Cell Division/ph [Physiology] MH - Cell Growth Processes/ph [Physiology] MH - Cell Line, Tumor MH - Female MH - G2 Phase/ph [Physiology] MH - Humans MH - Immunoglobulin Fragments/pd [Pharmacology] MH - Immunoglobulin Variable Region/pd [Pharmacology] MH - Ovarian Neoplasms/me [Metabolism] MH - *Ovarian Neoplasms/pa [Pathology] MH - Proto-Oncogene Proteins c-bcl-2/ai [Antagonists & Inhibitors] MH - Proto-Oncogene Proteins c-bcl-2/bi [Biosynthesis] MH - Proto-Oncogene Proteins c-bcl-2/im [Immunology] MH - *Proto-Oncogene Proteins c-bcl-2/ph [Physiology] MH - *S Phase/ph [Physiology] AB - OBJECTIVES: The Bcl-2 protein is an important regulator of the apoptotic cascade and promotes cell survival. Bcl-2 can also delay entry into the cell cycle from quiescence. In the present study, we used two isogenic human ovarian carcinoma cell lines, which expressed differential levels of Bcl-2 proteins, to demonstrate that Bcl-2 may regulate the growth rates of adenocarcinoma cells. AB - METHODS: The growth rates of two isogenic ovarian cancer cell lines were determined by XTT assays and flow cytometry combined with PI staining. Bcl-2-overexpressing SKOV3 cells were modified to express a doxycycline-inducible anti-Bcl-2 single-chain antibody and the effects of Bcl-2 protein inhibition on cell proliferation and apoptosis were assessed. AB - RESULTS: We demonstrate that Bcl-2 promotes the accumulation of proliferating carcinoma cells in S phase. The Bcl-2-overexpressing SKOV3 cell line proliferates markedly faster and shows delayed progression to G2M phase compared to its low Bcl-2-expressing counterpart SKOV3.ip1 cell line. Single-chain antibody-mediated inhibition of Bcl-2 in SKOV3 cells was associated with increased growth rates and more rapid cell cycle progression. Treatment with cisplatin resulted in more cells accumulating in S phase in Bcl-2-overexpressing SKOV3 cells, while the inhibition of Bcl-2 abolished delayed entry into G2M phase without affecting cisplatin-induced apoptosis. AB - CONCLUSIONS: Our results suggest that, in ovarian cancer cells, Bcl-2 delays cell cycle progression by promoting accumulation of cells in S phase without affecting the rate of apoptosis. Thus, in addition to its known role at the G0/G1 checkpoint, we demonstrate for the first time that Bcl-2 also regulates the S phase. RN - 0 (Immunoglobulin Fragments) RN - 0 (Immunoglobulin Variable Region) RN - 0 (Proto-Oncogene Proteins c-bcl-2) IS - 0090-8258 IL - 0090-8258 DI - S0090-8258(05)00130-7 DO - https://dx.doi.org/10.1016/j.ygyno.2005.02.018 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 15913739 [pubmed] ID - S0090-8258(05)00130-7 [pii] ID - 10.1016/j.ygyno.2005.02.018 [doi] PP - ppublish PH - 2004/10/26 [received] PH - 2005/02/02 [revised] PH - 2005/02/10 [accepted] LG - English DP - 2005 Jun DC - 20050609 EZ - 2005/05/26 09:00 DA - 2005/08/12 09:00 DT - 2005/05/26 09:00 YR - 2005 ED - 20050811 RD - 20061115 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=15913739 <358. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 15897900 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Kim D AU - Pemberton H AU - Stratford AL AU - Buelaert K AU - Watkinson JC AU - Lopes V AU - Franklyn JA AU - McCabe CJ FA - Kim, Dae FA - Pemberton, Helen FA - Stratford, Anna L FA - Buelaert, Kristien FA - Watkinson, John C FA - Lopes, Victor FA - Franklyn, Jayne A FA - McCabe, Chris J IN - Kim, Dae. Division of Medical Sciences, 2nd Floor IBR, University of Birmingham, Edgbaston, Birmingham B12 5TT, UK. daekim72@yahoo.co.uk TI - Pituitary tumour transforming gene (PTTG) induces genetic instability in thyroid cells. SO - Oncogene. 24(30):4861-6, 2005 Jul 14 AS - Oncogene. 24(30):4861-6, 2005 Jul 14 NJ - Oncogene PI - Journal available in: Print PI - Citation processed from: Print JC - onc, 8711562 IO - Oncogene SB - Index Medicus CP - England MH - Caspase 3 MH - Caspase 7 MH - Caspases/me [Metabolism] MH - Cell Line MH - *Genomic Instability MH - Humans MH - *Neoplasm Proteins/ge [Genetics] MH - *Neoplasm Proteins/me [Metabolism] MH - RNA, Messenger/ge [Genetics] MH - RNA, Messenger/me [Metabolism] MH - Securin MH - *Thyroid Gland/me [Metabolism] MH - *Thyroid Gland/pa [Pathology] MH - *Thyroid Neoplasms/ge [Genetics] MH - Thyroid Neoplasms/pa [Pathology] AB - Cancer reflects the progressive accumulation of genetic alterations and subsequent genetic instability of cells. Cytogenetic studies have demonstrated the importance of aneuploidy in differentiated thyroid cancer development. The pituitary tumour transforming gene (PTTG), also known as securin, is a mitotic checkpoint protein which inhibits sister chromatid separation during mitosis. PTTG is highly expressed in many cancers and overexpression of PTTG induces aneuploidy in vitro. Using fluorescent intersimple sequence repeat PCR (FISSR-PCR), we investigated the relationship between PTTG expression and the degree of genetic instability in normal and tumorous thyroid samples. The genomic instability index (GI index) was 6.7-72.7% higher in cancers than normal thyroid tissues. Follicular thyroid tumours exhibited greater genetic instability than papillary tumours (27.6% (n=9) versus 14.5% (n=10), P=0.03). We also demonstrated a strong relationship between PTTG expression and the degree of genetic instability in thyroid cancers (R2=0.80, P=0.007). To further investigate PTTG's role in genetic instability, we transfected FTC133 thyroid follicular cells and observed increased genetic instability in cells overexpressing PTTG compared with vector-only-transfected controls (n=3, GI Index VO=29.7+/-5.2 versus PTTG=63.7+/-6.4, P=0.013). Further, we observed a dose response in genetic instability and PTTG expression (GI Index low dose (0.5 microg DNA/ six-well plate) PTTG=15.3%+/-1.7 versus high dose (3 microg DNA) PTTG=50.8%+/-3.3, P=0.006). Overall, we describe the first use of FISSR-PCR in human cancers, and demonstrate that PTTG expression correlates with genetic instability in vivo, and induces genetic instability in vitro. We conclude that PTTG may be an important gene in the mutator phenotype development in thyroid cancer. RN - 0 (Neoplasm Proteins) RN - 0 (RNA, Messenger) RN - 0 (Securin) RN - 0 (pituitary tumor-transforming protein 1, human) RN - EC 3-4-22 (CASP3 protein, human) RN - EC 3-4-22 (CASP7 protein, human) RN - EC 3-4-22 (Caspase 3) RN - EC 3-4-22 (Caspase 7) RN - EC 3-4-22 (Caspases) IS - 0950-9232 IL - 0950-9232 DI - 1208659 DO - https://dx.doi.org/10.1038/sj.onc.1208659 PT - Journal Article ID - 15897900 [pubmed] ID - 1208659 [pii] ID - 10.1038/sj.onc.1208659 [doi] PP - ppublish LG - English DP - 2005 Jul 14 DC - 20050714 EZ - 2005/05/18 09:00 DA - 2005/08/09 09:00 DT - 2005/05/18 09:00 YR - 2005 ED - 20050808 RD - 20131121 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=15897900 <359. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 15254743 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Zhong X AU - Li X AU - Wang G AU - Zhu Y AU - Hu G AU - Zhao J AU - Neace C AU - Ding H AU - Reed E AU - Li QQ FA - Zhong, Xiaosong FA - Li, Xiping FA - Wang, Gangduo FA - Zhu, Yunfeng FA - Hu, Guodong FA - Zhao, Jinshun FA - Neace, Cheryl FA - Ding, Hong FA - Reed, Eddie FA - Li, Qingdi Q IN - Zhong, Xiaosong. Mary Babb Randolph Cancer Center, and Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine and Robert C. Byrd Health Sciences Center, Morgantown, WV 26506, USA. TI - Mechanisms underlying the synergistic effect of SU5416 and cisplatin on cytotoxicity in human ovarian tumor cells. SO - International Journal of Oncology. 25(2):445-51, 2004 Aug AS - Int J Oncol. 25(2):445-51, 2004 Aug NJ - International journal of oncology PI - Journal available in: Print PI - Citation processed from: Print JC - cx5, 9306042 IO - Int. J. Oncol. SB - Index Medicus CP - Greece MH - Angiogenesis Inhibitors/pd [Pharmacology] MH - Angiogenesis Inhibitors/tu [Therapeutic Use] MH - *Angiogenesis Inhibitors/to [Toxicity] MH - Antineoplastic Agents/pd [Pharmacology] MH - Antineoplastic Agents/tu [Therapeutic Use] MH - *Antineoplastic Agents/to [Toxicity] MH - Apoptosis MH - Cell Cycle Proteins/me [Metabolism] MH - Cell Line MH - Cisplatin/pd [Pharmacology] MH - Cisplatin/tu [Therapeutic Use] MH - *Cisplatin/to [Toxicity] MH - Cyclin-Dependent Kinase Inhibitor p21 MH - Cyclin-Dependent Kinase Inhibitor p27 MH - Drug Synergism MH - Female MH - Humans MH - I-kappa B Proteins/me [Metabolism] MH - Indoles/pd [Pharmacology] MH - Indoles/tu [Therapeutic Use] MH - *Indoles/to [Toxicity] MH - JNK Mitogen-Activated Protein Kinases/me [Metabolism] MH - MAP Kinase Kinase 4 MH - Mitogen-Activated Protein Kinase Kinases/me [Metabolism] MH - NF-KappaB Inhibitor alpha MH - Ovarian Neoplasms/dt [Drug Therapy] MH - *Ovarian Neoplasms/me [Metabolism] MH - Proto-Oncogene Proteins/me [Metabolism] MH - Pyrroles/pd [Pharmacology] MH - Pyrroles/tu [Therapeutic Use] MH - *Pyrroles/to [Toxicity] MH - Transcription Factor AP-1/me [Metabolism] MH - Tumor Suppressor Protein p53/me [Metabolism] MH - Tumor Suppressor Proteins/me [Metabolism] MH - Up-Regulation AB - SU5416 is a selective inhibitor of vascular endothelial growth factor (VEGF) receptors with anti-angiogenesis activity for human cancers. We have previously reported that SU5416 sensitizes ovarian cancer cells to cisplatin via suppression of nucleotide excision repair activity. This study sought to gain further insights into the mechanisms underlying the synergistic effect of SU5416 and cisplatin on cytotoxicity in human ovarian tumor cells. Here, we show that SU5416 inhibited the expression of G1 cell cycle checkpoint regulators, p53, p21, p27 and MDM2 in ovarian carcinoma cells. We also demonstrate that SU5416 triggered the apoptosis of these cells, in addition to augmenting the apoptosis induced by cisplatin, as determined by a Sub-G1 profile analysis using a flow cytometer. Furthermore, we show that SU5416-induced apoptosis is associated with a decrease in the expression of the apoptosis inhibitors, MDM2 and Bcl-2, and an increase in the level of NF-kappaB inhibitor, IkappaBalpha. NF-kappaB is an anti-apoptotic transcription factor, which induces the apoptosis inhibitors, Bcl-XL and IAPs (inhibitor of apoptosis proteins), and IkappaBalpha is an inhibitor of NF-kappaB, which binds to the NF-kappaB and retains it in the cytoplasm. Finally, the compound was found to block cisplatin-induced increases in AP-1 expression and JNK activity, as well as Raf-1 protein level in these cells. Together, these results suggest that the chemosensitizing effect of SU5416 on ovarian tumor cells may be mediated, at least in part, through inhibiting G1 checkpoint control and up-regulating the apoptotic response to cisplatin. RN - 0 (Angiogenesis Inhibitors) RN - 0 (Antineoplastic Agents) RN - 0 (CDKN1A protein, human) RN - 0 (Cell Cycle Proteins) RN - 0 (Cyclin-Dependent Kinase Inhibitor p21) RN - 0 (I-kappa B Proteins) RN - 0 (Indoles) RN - 0 (NFKBIA protein, human) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Pyrroles) RN - 0 (Transcription Factor AP-1) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (Tumor Suppressor Proteins) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27) RN - 71IA9S35AJ (Semaxinib) RN - EC 2-7-11-24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2-7-12-2 (MAP Kinase Kinase 4) RN - EC 2-7-12-2 (Mitogen-Activated Protein Kinase Kinases) RN - Q20Q21Q62J (Cisplatin) IS - 1019-6439 IL - 1019-6439 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. ID - 15254743 [pubmed] PP - ppublish GI - No: P20 RR016440 Organization: (RR) *NCRR NIH HHS* Country: United States No: P20RR16440-010003 Organization: (RR) *NCRR NIH HHS* Country: United States LG - English DP - 2004 Aug DC - 20040715 EZ - 2004/07/16 05:00 DA - 2005/01/26 09:00 DT - 2004/07/16 05:00 YR - 2004 ED - 20050125 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=15254743 <360. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 15452549 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Clarke PA AU - Pestell KE AU - Di Stefano F AU - Workman P AU - Walton MI FA - Clarke, P A FA - Pestell, K E FA - Di Stefano, F FA - Workman, P FA - Walton, M I IN - Clarke, P A. Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, UK. TI - Characterisation of molecular events following cisplatin treatment of two curable ovarian cancer models: contrasting role for p53 induction and apoptosis in vivo. SO - British Journal of Cancer. 91(8):1614-23, 2004 Oct 18 AS - Br J Cancer. 91(8):1614-23, 2004 Oct 18 NJ - British journal of cancer PI - Journal available in: Print PI - Citation processed from: Print JC - av4, 0370635 IO - Br. J. Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409921 SB - Index Medicus CP - England MH - Adenocarcinoma/dt [Drug Therapy] MH - Adenocarcinoma/me [Metabolism] MH - Adenocarcinoma/pa [Pathology] MH - Animals MH - *Antineoplastic Agents/tu [Therapeutic Use] MH - *Apoptosis/de [Drug Effects] MH - Cell Cycle MH - *Cisplatin/tu [Therapeutic Use] MH - DNA Adducts MH - DNA Damage MH - Disease Models, Animal MH - Endodermal Sinus Tumor/dt [Drug Therapy] MH - Endodermal Sinus Tumor/me [Metabolism] MH - Endodermal Sinus Tumor/pa [Pathology] MH - Female MH - Gene Expression Profiling MH - Humans MH - In Situ Nick-End Labeling MH - Mice MH - Mice, Nude MH - Mutation MH - Oligonucleotide Array Sequence Analysis MH - *Ovarian Neoplasms/dt [Drug Therapy] MH - *Ovarian Neoplasms/me [Metabolism] MH - Ovarian Neoplasms/pa [Pathology] MH - Transplantation, Heterologous MH - Tumor Suppressor Protein p53/ge [Genetics] MH - *Tumor Suppressor Protein p53/me [Metabolism] AB - The detailed molecular basis and determinants of in vivo tumour sensitivity to conventional anticancer agents remain unclear. We examined the cellular and molecular consequences of cisplatin treatment using two ovarian tumour xenograft models that had not been previously adapted to culture in vitro. Both xenografts were curable with clinically relevant multiple doses of cisplatin. Following a single dose of cisplatin (6 mg kg(-1) i.p.) growth delays of 25 and 75 days were obtained for pxn100 and pxn65, respectively. This difference in response was not due to differences in DNA damage. Pxn100 tumours had a functional p53 response and a wild-type p53 sequence, whereas pxn65 harboured a mutant p53 and lacked a functional p53 response. Microarray analysis revealed the induction of p53-regulated genes and regulators of checkpoint control and apoptosis in pxn100 tumours following cisplatin-treatment. By contrast, there was no p53-dependent response and only limited changes in gene expression were detected in the pxn65 tumours. TUNEL analysis demonstrated high levels of apoptosis in the pxn100 tumours following cisplatin treatment, but there was no detectable apoptosis in the pxn65 tumours. Our observations show that a marked in vivo response to cisplatin can occur via p53-dependent apoptosis or independently of p53 status in human ovarian xenografts. RN - 0 (Antineoplastic Agents) RN - 0 (DNA Adducts) RN - 0 (Tumor Suppressor Protein p53) RN - Q20Q21Q62J (Cisplatin) IS - 0007-0920 IL - 0007-0920 DI - 6602167 DO - https://dx.doi.org/10.1038/sj.bjc.6602167 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 15452549 [pubmed] ID - 10.1038/sj.bjc.6602167 [doi] ID - 6602167 [pii] ID - PMC2409921 [pmc] PP - ppublish LG - English DP - 2004 Oct 18 DC - 20041013 EZ - 2004/09/29 05:00 DA - 2004/11/17 09:00 DT - 2004/09/29 05:00 YR - 2004 ED - 20041116 RD - 20140608 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=15452549 <361. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 15073049 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Guweidhi A AU - Kleeff J AU - Giese N AU - El Fitori J AU - Ketterer K AU - Giese T AU - Buchler MW AU - Korc M AU - Friess H FA - Guweidhi, Ahmed FA - Kleeff, Jorg FA - Giese, Nathalia FA - El Fitori, Jamael FA - Ketterer, Knut FA - Giese, Thomas FA - Buchler, Markus W FA - Korc, Murray FA - Friess, Helmut IN - Guweidhi, Ahmed. Department of General Surgery, University of Heidelberg, Germany. TI - Enhanced expression of 14-3-3sigma in pancreatic cancer and its role in cell cycle regulation and apoptosis. SO - Carcinogenesis. 25(9):1575-85, 2004 Sep AS - Carcinogenesis. 25(9):1575-85, 2004 Sep NJ - Carcinogenesis PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - c9t, 8008055 IO - Carcinogenesis SB - Index Medicus CP - England MH - 14-3-3 Proteins MH - Adult MH - Aged MH - Aged, 80 and over MH - *Apoptosis MH - *Biomarkers, Tumor/me [Metabolism] MH - Blotting, Southern MH - Blotting, Western MH - CDC2 Protein Kinase/me [Metabolism] MH - *Carcinoma, Pancreatic Ductal/me [Metabolism] MH - Carcinoma, Pancreatic Ductal/pa [Pathology] MH - Carrier Proteins/me [Metabolism] MH - Case-Control Studies MH - *Cell Cycle MH - *Exonucleases/me [Metabolism] MH - Exoribonucleases MH - Female MH - Humans MH - Lasers MH - Male MH - Middle Aged MH - *Neoplasm Proteins/me [Metabolism] MH - Oligonucleotide Array Sequence Analysis MH - Pancreas/me [Metabolism] MH - Pancreas/pa [Pathology] MH - *Pancreatic Neoplasms/me [Metabolism] MH - Pancreatic Neoplasms/pa [Pathology] MH - Precipitin Tests MH - Proto-Oncogene Proteins/me [Metabolism] MH - *Proto-Oncogene Proteins c-bcl-2 MH - Reverse Transcriptase Polymerase Chain Reaction MH - bcl-2-Associated X Protein MH - bcl-Associated Death Protein AB - 14-3-3sigma belongs to the 14-3-3 family of proteins, which are involved in the modulation of diverse signal transduction pathways. Loss of 14-3-3sigma expression has been observed in a number of human cancers, suggesting that it may have a role as a tumor suppressor gene. The aim of the study was to investigate the expression and the functional role of 14-3-3sigma in pancreatic ductal adenocarcinoma (PDAC). Expression of 14-3-3sigma was analyzed using laser capture microdissection (LCM), quantitative real-time-PCR (QRT-PCR), DNA arrays, immunohistochemistry and western blot analysis. The role of 14-3-3sigma in apoptosis and cell cycle regulation was evaluated by western blotting, immunoprecipitation and FACS analysis. By QRT-PCR, 14-3-3sigma mRNA levels were 54-fold increased in pancreatic adenocarcinoma in comparison with normal pancreatic samples and localized in pancreatic cancer cells as determined by LCM. In pancreatic cancer cells, the degree of 14-3-3sigma expression was not decisive for the maintenance of G(2)/M cell cycle checkpoint or induction of apoptosis. Responses to radiation or apoptosis-inducing agents were neither accompanied by a significant 14-3-3sigma accumulation nor by a change in association of 14-3-3sigma with cdc2, bad and bax. In conclusion, the marked over-expression of 14-3-3sigma in PADC together with multiple known genetic and epigenetic alterations of potential 14-3-3sigma interacting partners suggests an important role of aberrant 14-3-3sigma downstream signaling in pancreatic cancer. RN - 0 (14-3-3 Proteins) RN - 0 (BAD protein, human) RN - 0 (BAX protein, human) RN - 0 (Biomarkers, Tumor) RN - 0 (Carrier Proteins) RN - 0 (Neoplasm Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (bcl-2-Associated X Protein) RN - 0 (bcl-Associated Death Protein) RN - EC 2-7-11-22 (CDC2 Protein Kinase) RN - EC 3-1 (Exonucleases) RN - EC 3-1 (Exoribonucleases) RN - EC 3-1 (SFN protein, human) IS - 0143-3334 IL - 0143-3334 DI - bgh159 DO - https://dx.doi.org/10.1093/carcin/bgh159 PT - Comparative Study PT - Journal Article ID - 15073049 [pubmed] ID - 10.1093/carcin/bgh159 [doi] ID - bgh159 [pii] PP - ppublish LG - English EP - 20040408 DP - 2004 Sep DC - 20040817 EZ - 2004/04/10 05:00 DA - 2004/10/06 09:00 DT - 2004/04/10 05:00 YR - 2004 ED - 20041005 RD - 20151119 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med5&AN=15073049 <362. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 12915687 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Chung HK AU - Yi YW AU - Jung NC AU - Kim D AU - Suh JM AU - Kim H AU - Park KC AU - Kim DW AU - Hwang ES AU - Song JH AU - Ku BJ AU - Han HJ AU - Ro HK AU - Kim JM AU - Shong M FA - Chung, Hyo Kyun FA - Yi, Yong-Weon FA - Jung, Neon-Cheol FA - Kim, Daegun FA - Suh, Jae Mi FA - Kim, Ho FA - Park, Ki Cheol FA - Kim, Dong Wook FA - Hwang, Eun Suk FA - Song, Jeong Hun FA - Ku, Bon-Jeong FA - Han, Hee Jung FA - Ro, Heung Kyu FA - Kim, Jin Man FA - Shong, Minho IN - Chung, Hyo Kyun. Laboratory of Endocrine Cell Biology, National Research Laboratory Program, Chungnam National University College of Medicine, Daejeon 301-721, Korea. TI - Gadd45gamma expression is reduced in anaplastic thyroid cancer and its reexpression results in apoptosis. SO - Journal of Clinical Endocrinology & Metabolism. 88(8):3913-20, 2003 Aug AS - J Clin Endocrinol Metab. 88(8):3913-20, 2003 Aug NJ - The Journal of clinical endocrinology and metabolism PI - Journal available in: Print PI - Citation processed from: Print JC - hrb, 0375362 IO - J. Clin. Endocrinol. Metab. SB - Core Clinical Journals (AIM) SB - Index Medicus CP - United States MH - Adenoviridae/ge [Genetics] MH - Animals MH - *Apoptosis/ge [Genetics] MH - Blotting, Northern MH - Blotting, Western MH - Carcinoma/ge [Genetics] MH - *Carcinoma/me [Metabolism] MH - *Gene Expression Regulation, Neoplastic/ge [Genetics] MH - Genes, p53/ge [Genetics] MH - Genetic Therapy MH - Humans MH - Immunohistochemistry MH - Indicators and Reagents MH - Intracellular Signaling Peptides and Proteins MH - Mice MH - Mice, Nude MH - Neoplasm Transplantation MH - *Protein Biosynthesis MH - Proteins/ge [Genetics] MH - RNA, Neoplasm/bi [Biosynthesis] MH - Tetrazolium Salts MH - Thiazoles MH - Thyroid Neoplasms/ge [Genetics] MH - *Thyroid Neoplasms/me [Metabolism] MH - Transduction, Genetic MH - Transplantation, Heterologous MH - Tumor Cells, Cultured AB - Anaplastic thyroid carcinomas are a highly aggressive and extremely lethal form of human cancer, but the biological characteristics related to their aggressive nature are not understood. Moreover, Gadd45 family proteins have been implicated in a variety of growth-regulatory mechanisms, including DNA replication and repair, G(2)/M checkpoint control, and apoptosis. In this study we found that Gadd45gamma RNA was present at significantly lower levels in anaplastic cancer cells, compared with normal primary cultured thyrocytes. In addition, the adenovirus-mediated reexpression of Gadd45gamma significantly inhibited the proliferation of anaplastic thyroid carcinoma cells, ARO, FRO, and NPA cells, which was attributed to apoptosis. Furthermore, the adenovirus-mediated delivery of Gadd45gamma gene in anaplastic thyroid cancer resulted in the inhibition of tumor growth in vivo. This in vitro and in vivo activity of the adenovirus-mediated transduction of CR6/Gadd45gamma, on anaplastic thyroid cancer cell growth suppression, was reminiscent of the effects of p53. This study demonstrates that the Gadd45gamma gene has potential use as a candidate gene for gene therapy in anaplastic thyroid cancer. RN - 0 (GADD45 protein) RN - 0 (Indicators and Reagents) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Proteins) RN - 0 (RNA, Neoplasm) RN - 0 (Tetrazolium Salts) RN - 0 (Thiazoles) RN - EUY85H477I (thiazolyl blue) IS - 0021-972X IL - 0021-972X DO - https://dx.doi.org/10.1210/jc.2002-022031 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 12915687 [pubmed] ID - 10.1210/jc.2002-022031 [doi] PP - ppublish LG - English DP - 2003 Aug DC - 20030813 EZ - 2003/08/14 05:00 DA - 2003/09/13 05:00 DT - 2003/08/14 05:00 YR - 2003 ED - 20030911 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=12915687 <363. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 12754734 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Spierings DC AU - de Vries EG AU - Vellenga E AU - de Jong S FA - Spierings, Diana C J FA - de Vries, Elisabeth G E FA - Vellenga, Edo FA - de Jong, Steven IN - Spierings, Diana C J. Departments of Medical Oncology and Haematology, University of Groningen, The Netherlands. TI - The attractive Achilles heel of germ cell tumours: an inherent sensitivity to apoptosis-inducing stimuli. [Review] [159 refs] SO - Journal of Pathology. 200(2):137-48, 2003 Jun AS - J Pathol. 200(2):137-48, 2003 Jun NJ - The Journal of pathology PI - Journal available in: Print PI - Citation processed from: Print JC - jlb, 0204634 IO - J. Pathol. SB - Index Medicus CP - England MH - Antigens, CD95/ph [Physiology] MH - *Apoptosis MH - Cell Cycle MH - Cyclin-Dependent Kinase Inhibitor p21 MH - Cyclins/ph [Physiology] MH - *Germinoma/pa [Pathology] MH - Humans MH - Male MH - Neoplasm Proteins/ph [Physiology] MH - Proto-Oncogene Proteins c-bcl-2/ph [Physiology] MH - *Testicular Neoplasms/pa [Pathology] AB - Testicular germ cell tumours (TGCTs) are extremely sensitive to cisplatin-containing chemotherapy. The rapid time course of apoptosis induction after exposure to cisplatin suggests that TGCT cells are primed to undergo programmed cell death as an inherent property of the cell of origin. In fact, apoptosis induction of germ cells in the testis is an important physiological mechanism to control the quality and quantity of the gametes produced. Although p53 protein is highly expressed in the majority of TGCTs, almost no p53 mutations have been detected. Interestingly, p53 overexpression is associated with loss of p21 and gain of mdm2 expression, which might indicate a partial loss in functionality of the p53 regulatory pathway in TGCTs. Besides p21, TGCTs often show low expression of other proteins involved in the regulation of cell cycle progression, such as the retinoblastoma protein and members of the INK4 family. It can be postulated that the deregulated G(1)-S phase checkpoint results in premature entry into the S phase upon DNA damage. In addition to Bcl-2 family members that are involved in the regulation of germ cell apoptosis in the normal testis via the mitochondrial death pathway, the Fas death pathway is also known to regulate apoptosis of germ cells in the testis. Since chemotherapy has been shown to activate the Fas death pathway and TGCTs co-express both Fas and its ligand FasL, TGCT cells might undergo apoptosis upon cisplatin treatment via autocrine or paracrine activation of the Fas system by FasL. The hypothesis suggested here is that the lack of cell cycle arrest following a cisplatin-containing treatment, together with the activation of the Fas death pathway and the mitochondrial death pathway, explains the rapid and efficient apoptosis of TGCT cells. Defining the mechanisms involved in the cisplatin sensitivity of TGCTs will provide tools to increase cisplatin sensitivity in other human tumours with acquired or intrinsic resistance. AB - Copyright 2003 John Wiley & Sons, Ltd. [References: 159] RN - 0 (Antigens, CD95) RN - 0 (CDKN1A protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p21) RN - 0 (Cyclins) RN - 0 (Neoplasm Proteins) RN - 0 (Proto-Oncogene Proteins c-bcl-2) IS - 0022-3417 IL - 0022-3417 DO - https://dx.doi.org/10.1002/path.1373 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 12754734 [pubmed] ID - 10.1002/path.1373 [doi] PP - ppublish LG - English DP - 2003 Jun DC - 20030519 EZ - 2003/05/20 05:00 DA - 2003/07/19 05:00 DT - 2003/05/20 05:00 YR - 2003 ED - 20030718 RD - 20061115 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=12754734 <364. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 12372342 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Sun D AU - Urrabaz R AU - Buzello C AU - Nguyen M FA - Sun, Daekyu FA - Urrabaz, Rheanna FA - Buzello, Christoph FA - Nguyen, Myhanh IN - Sun, Daekyu. Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245, USA. sun@pharmacy.arizona.edu TI - Induction of DNA ligase I by 1-beta-D-arabinosylcytosine and aphidicolin in MiaPaCa human pancreatic cancer cells. SO - Experimental Cell Research. 280(1):90-6, 2002 Oct 15 AS - Exp Cell Res. 280(1):90-6, 2002 Oct 15 NJ - Experimental cell research PI - Journal available in: Print PI - Citation processed from: Print JC - epb, 0373226 IO - Exp. Cell Res. SB - Index Medicus CP - United States MH - Antimetabolites, Antineoplastic/pk [Pharmacokinetics] MH - *Antimetabolites, Antineoplastic/pd [Pharmacology] MH - Aphidicolin/pk [Pharmacokinetics] MH - *Aphidicolin/pd [Pharmacology] MH - Caffeine/pd [Pharmacology] MH - Cell Count MH - Cell Division/de [Drug Effects] MH - Cell Line MH - Cell Survival/de [Drug Effects] MH - Cytarabine/pk [Pharmacokinetics] MH - *Cytarabine/pd [Pharmacology] MH - DNA Ligase ATP MH - *DNA Ligases/bi [Biosynthesis] MH - DNA Ligases/ge [Genetics] MH - DNA Repair/de [Drug Effects] MH - DNA, Neoplasm/bi [Biosynthesis] MH - DNA-Directed DNA Polymerase/an [Analysis] MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/pk [Pharmacokinetics] MH - *Enzyme Inhibitors/pd [Pharmacology] MH - Humans MH - Nucleic Acid Synthesis Inhibitors/pd [Pharmacology] MH - *Pancreatic Neoplasms/en [Enzymology] MH - Pancreatic Neoplasms/ge [Genetics] MH - Pancreatic Neoplasms/pa [Pathology] MH - Phosphodiesterase Inhibitors/pd [Pharmacology] MH - RNA, Messenger/me [Metabolism] MH - Tumor Cells, Cultured AB - Exposure of MiaPaCa cells to 1-beta-D-arabinosylcytosine (ara-C) resulted in an increase in DNA ligase levels up to threefold compared to that in the untreated control cells, despite significant growth inhibition. Increased levels of DNA ligase I protein appear to correlate with the appearance of increased mRNA levels. The [(3)H]thymidine incorporation experiment and the biochemical assay of total polymerase activity revealed that an increase in DNA ligase I levels after treatment with ara-C was not accompanied by an increase of DNA synthesis or an increased presence of DNA polymerase activity inside cells. When cells resumed DNA synthesis after drug treatment, DNA ligase I levels began to drop, indicating that increased DNA ligase I is not required for DNA synthesis. An increase in DNA ligase I was also observed in cells treated with aphidicolin, another inhibitor of DNA synthesis that inhibits DNA polymerases without incorporating itself into DNA, indicating that an increase in DNA ligase I levels could be caused by the arrest of DNA replication by these agents. Interestingly, caffeine, which is a well-known inhibitor of DNA damage checkpoint kinases, abrogated the increase in DNA ligase I in MiaPaCa cells treated with ara-C and aphidicolin, suggesting that caffeine-sensitive kinases might be important mediators in the pathway leading to the increase in DNA ligase I levels in response to anticancer drugs, including ara-C and aphidicolin. We propose that ara-C and aphidicolin induce damage to the DNA strand by arresting DNA replication forks and subsequently increase DNA ligase I levels to facilitate repair of DNA damage. RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (DNA, Neoplasm) RN - 0 (Enzyme Inhibitors) RN - 0 (LIG1 protein, human) RN - 0 (Nucleic Acid Synthesis Inhibitors) RN - 0 (Phosphodiesterase Inhibitors) RN - 0 (RNA, Messenger) RN - 04079A1RDZ (Cytarabine) RN - 38966-21-1 (Aphidicolin) RN - 3G6A5W338E (Caffeine) RN - EC 2-7-7-7 (DNA-Directed DNA Polymerase) RN - EC 6-5-1 (DNA Ligases) RN - EC 6-5-1-1 (DNA Ligase ATP) IS - 0014-4827 IL - 0014-4827 DI - S0014482702956259 PT - Comparative Study PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. ID - 12372342 [pubmed] ID - S0014482702956259 [pii] PP - ppublish GI - No: CA78715 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2002 Oct 15 DC - 20021009 EZ - 2002/10/10 04:00 DA - 2002/11/26 04:00 DT - 2002/10/10 04:00 YR - 2002 ED - 20021107 RD - 20161124 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=12372342 <365. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 11745415 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Deplanque G AU - Ceraline J AU - Mah-Becherel MC AU - Cazenave JP AU - Bergerat JP AU - Klein-Soyer C FA - Deplanque, G FA - Ceraline, J FA - Mah-Becherel, M C FA - Cazenave, J P FA - Bergerat, J P FA - Klein-Soyer, C IN - Deplanque, G. Laboratoire de Cancerologie Experimentale et de Radiobiologie, Institut de Recherche contre les Cancers de l'Appareil Digestif, Hopitaux Universitaires de Strasbourg, Strasbourg, France. TI - Caffeine and the G2/M block override: a concept resulting from a misleading cell kinetic delay, independent of functional p53. SO - International Journal of Cancer. 94(3):363-9, 2001 Nov 01 AS - Int J Cancer. 94(3):363-9, 2001 Nov 01 NJ - International journal of cancer PI - Journal available in: Print PI - Citation processed from: Print JC - gqu, 0042124 IO - Int. J. Cancer SB - Index Medicus CP - United States MH - Antineoplastic Agents, Phytogenic/pd [Pharmacology] MH - *Caffeine/pd [Pharmacology] MH - Cell Cycle MH - Cell Division MH - Cell Line, Transformed MH - *Central Nervous System Stimulants/pd [Pharmacology] MH - DNA/me [Metabolism] MH - Demecolcine/pd [Pharmacology] MH - Dose-Response Relationship, Drug MH - Fibroblasts/me [Metabolism] MH - *G2 Phase/de [Drug Effects] MH - G2 Phase/re [Radiation Effects] MH - Gamma Rays MH - Genes, Dominant MH - Humans MH - Kinetics MH - *Mitosis/de [Drug Effects] MH - Mitosis/re [Radiation Effects] MH - Mutation MH - Phenotype MH - Purines/me [Metabolism] MH - Pyrimidines/me [Metabolism] MH - Time Factors MH - Tumor Cells, Cultured MH - *Tumor Suppressor Protein p53/ph [Physiology] AB - In the literature the sensitization of DNA to radiation-induced damage by caffeine has been attributed to an override of the G2/M block. This process was supposed to involve the tumor suppressor gene p53 as it was described that p53 negative cells were more sensitive to checkpoint inhibition by caffeine than the wildtype phenotype. We have recently shown that caffeine does not cause an override of the G2/M block induced by radiation in normal human fibroblasts. We demonstrate here that this also applies to a human transformed cell line, the thyroid carcinoma K1, when submitted to gamma- rays irradiation. Within 9 hr after irradiation over 70% of the cells accumulated in the G2/M phase. This block persisted at 16 hr. In caffeine containing cultures the percentage of cells attaining the G2/M phase was reduced by over 30% at 16 hr. This was reflected in an accumulation of the cells in G1 phase and an inhibition of the S phase traverse. Cell cycle analyses from further time points combined with cell proliferation measurements confirmed these data. These results were independent of p53 status as experiments performed with variant K1 cell lines having defective p53 functions, led to similar conclusions. In addition, caffeine restored a G1 delay after irradiation in the cell lines with abrogated p53 functions. The effects of caffeine undeniably cumulate with damages induced by irradiation but probably by inhibiting DNA repair mechanisms or by intervening with purine and pyrimidine metabolisms and not by causing a G2/M block override. AB - Copyright 2001 Wiley-Liss, Inc. RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (Central Nervous System Stimulants) RN - 0 (Purines) RN - 0 (Pyrimidines) RN - 0 (Tumor Suppressor Protein p53) RN - 3G6A5W338E (Caffeine) RN - 9007-49-2 (DNA) RN - K8CXK5Q32L (pyrimidine) RN - W60KTZ3IZY (purine) RN - Z01IVE25KI (Demecolcine) IS - 0020-7136 IL - 0020-7136 DI - 10.1002/ijc.1478 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 11745415 [pubmed] ID - 10.1002/ijc.1478 [pii] PP - ppublish LG - English DP - 2001 Nov 01 DC - 20011217 EZ - 2001/12/18 10:00 DA - 2002/01/10 10:01 DT - 2001/12/18 10:00 YR - 2001 ED - 20020107 RD - 20160303 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=11745415 <366. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 11409710 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Rothe H AU - Ito Y AU - Kolb H FA - Rothe, H FA - Ito, Y FA - Kolb, H IN - Rothe, H. Institute of Diabetes Research, Munich, Germany. helga.rothe@lrz.uni-muenchen.de TI - Disease resistant, NOD-related strains reveal checkpoints of immunoregulation in the pancreas. SO - Journal of Molecular Medicine. 79(4):190-7, 2001 May AS - J Mol Med. 79(4):190-7, 2001 May NJ - Journal of molecular medicine (Berlin, Germany) PI - Journal available in: Print PI - Citation processed from: Print JC - 9504370, b8c IO - J. Mol. Med. SB - Index Medicus CP - Germany MH - Animals MH - Cyclophosphamide/pd [Pharmacology] MH - *Diabetes Mellitus, Type 1/im [Immunology] MH - Female MH - Humans MH - Immunity, Innate MH - Immunosuppressive Agents/pd [Pharmacology] MH - Interferon-gamma/ge [Genetics] MH - Interferon-gamma/me [Metabolism] MH - Interleukins/ge [Genetics] MH - Interleukins/me [Metabolism] MH - Islets of Langerhans/im [Immunology] MH - Mice MH - Mice, Inbred NOD MH - Mice, Inbred Strains MH - Pancreas/de [Drug Effects] MH - *Pancreas/im [Immunology] MH - Polymerase Chain Reaction MH - Th1 Cells/im [Immunology] MH - Th2 Cells/im [Immunology] AB - The autoimmune diabetic NOD mouse serves as a model for human type 1 diabetes. Disease development is due to islet beta cell destruction in the context of immune cell infiltration of islets and inflammatory changes throughout the pancreas. In the present study we tried to identify immune reactivity patterns in the pancreas associated with diabetes resistance in NOD-related mouse strains. The pancreata of diabetes-prone female NOD/LtJ, NOD/Bom and of genetically related but diabetes-resistant strains; NOR, NON, NON.NOD-H2g7, NOD.NON-H-2nbl were obtained at the age of 70 days for semiquantitative analysis of insulitis and of mRNA expression by reverse transcriptase PCR. In addition, the response to a single dose of cyclophosphamide for synchronizing and accelerating the progression of insulitis was determined. The progression of insulitis and immune gene expression in response to cyclophosphamide revealed characteristic differences between the six strains. NOD/LtJ and NOD/Bom mice were found significantly to upregulate pancreatic IL-12p40 and IL-18 expression after cyclophosphamide treatment, followed by an increase in IFN-gamma mRNA levels. In contrast, the two MHC-haplotype H-2nbl expressing strains either up-regulated neither IL-12/IL-18 nor IFN-gamma gene expression. The two strains sharing MHC haplotype H-2g7 expression with NOD did respond to cyclophosphamide with IL-12p40/IL-18 gene expression. However, NON.NOD-H-2g7 mice failed to progress to IFN-gamma gene expression. NOR mice progressed to IFN-gamma expression but exhibited sustained IL-4 gene expression. Only severe intra-insulitis was associated with the expression of inducible NO synthase. The comparison of diabetes-prone and diabetes-resistant strains revealed three checkpoints of immune regulation in the pancreas. The earliest checkpoint is the induction of an IL-12p40/IL-18 response in innate immune or antigen-presenting cells. The next level of control is at the induction of IFN-gamma gene expression, and a third checkpoint is the maintenance or loss of antagonistic Th2 type reactions. RN - 0 (Immunosuppressive Agents) RN - 0 (Interleukins) RN - 82115-62-6 (Interferon-gamma) RN - 8N3DW7272P (Cyclophosphamide) IS - 0946-2716 IL - 0946-2716 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 11409710 [pubmed] PP - ppublish LG - English DP - 2001 May DC - 20010618 EZ - 2001/06/21 10:00 DA - 2002/01/05 10:01 DT - 2001/06/21 10:00 YR - 2001 ED - 20011212 RD - 20131121 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=11409710 <367. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 10935512 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Song SY AU - Meszoely IM AU - Coffey RJ AU - Pietenpol JA AU - Leach SD FA - Song, S Y FA - Meszoely, I M FA - Coffey, R J FA - Pietenpol, J A FA - Leach, S D IN - Song, S Y. Department of Surgery, Vanderbilt University Medical Center and Nashville VAMC, TN 37232-2736, USA. TI - K-Ras-independent effects of the farnesyl transferase inhibitor L-744,832 on cyclin B1/Cdc2 kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells. SO - Neoplasia (New York). 2(3):261-72, 2000 May-Jun AS - Neoplasia. 2(3):261-72, 2000 May-Jun NJ - Neoplasia (New York, N.Y.) PI - Journal available in: Print PI - Citation processed from: Print JC - dru, 100886622 IO - Neoplasia PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1507570 SB - Index Medicus CP - United States MH - *Antineoplastic Agents/pd [Pharmacology] MH - *Apoptosis/de [Drug Effects] MH - *Carcinoma, Ductal, Breast/pa [Pathology] MH - *Cyclin B/me [Metabolism] MH - Cyclin B1 MH - *Enzyme Inhibitors/pd [Pharmacology] MH - G2 Phase/de [Drug Effects] MH - *Genes, ras/ph [Physiology] MH - Humans MH - *Methionine/aa [Analogs & Derivatives] MH - Methionine/pd [Pharmacology] MH - Mitosis/de [Drug Effects] MH - *Pancreatic Neoplasms/pa [Pathology] AB - Pancreatic ductal adenocarcinoma is a highly lethal malignancy that is resistant to traditional cytotoxic therapy. High rates of activating codon 12 K-Ras mutations in this disease have generated considerable interest in the therapeutic application of novel farnesyl transferase inhibitors (FTIs). However, a comprehensive analysis of the effects of FTI treatment on pancreatic cancer cells has not been performed. Treatment of five different human pancreatic cancer cell lines with FTI L-744,832 resulted in inhibition of anchorage-dependent growth, with wide variation in sensitivity among different lines. Effective growth inhibition by L-744,832 correlated with accumulation of cells with a tetraploid (4N) DNA content and high levels of cyclin B1/cdc2 kinase activity, implying cell cycle arrest downstream from the DNA damage-inducible G2/M cell cycle checkpoint. In addition, sensitive cell lines underwent apoptosis as evidenced by changes in nuclear morphology and internucleosomal DNA fragmentation. L-744,832 at a concentration of 1 microM additively enhanced the cytotoxic effect of ionizing radiation, apparently by overriding G2/M checkpoint activation. The effects of FTI treatment on cell growth and cell cycle regulation were associated with changes in posttranslational processing of H-Ras and N-Ras, but not K-Ras. The results confirm the potential therapeutic efficacy of FTI treatment in pancreatic cancer, and suggest that farnesylated proteins other than K-Ras may act as important regulators of G2/M cell cycle kinetics. RN - 0 (Antineoplastic Agents) RN - 0 (CCNB1 protein, human) RN - 0 (Cyclin B) RN - 0 (Cyclin B1) RN - 0 (Enzyme Inhibitors) RN - 0 (L 744832) RN - AE28F7PNPL (Methionine) IS - 1522-8002 IL - 1476-5586 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Research Support, U.S. Gov't, P.H.S. ID - 10935512 [pubmed] ID - PMC1507570 [pmc] PP - ppublish GI - No: F32 CA076698 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA046413 Organization: (CA) *NCI NIH HHS* Country: United States No: CA46413 Organization: (CA) *NCI NIH HHS* Country: United States No: CA76698 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2000 May-Jun DC - 20000817 EZ - 2000/08/10 11:00 DA - 2000/08/19 11:00 DT - 2000/08/10 11:00 YR - 2000 ED - 20000817 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=10935512 <368. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 10210535 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - King TC AU - Estalilla OC AU - Safran H FA - King, T C FA - Estalilla, O C FA - Safran, H IN - King, T C. Departments of Pathology and Laboratory Medicine, Lifespan, Providence, RI, USA. TI - Role of p53 and p16 gene alterations in determining response to concurrent paclitaxel and radiation in solid tumor. [Review] [58 refs] SO - Seminars in Radiation Oncology. 9(2 Suppl 1):4-11, 1999 Apr AS - Semin Radiat Oncol. 9(2 Suppl 1):4-11, 1999 Apr NJ - Seminars in radiation oncology PI - Journal available in: Print PI - Citation processed from: Print JC - c1y, 9202882 IO - Semin Radiat Oncol SB - Index Medicus CP - United States MH - Animals MH - *Antineoplastic Agents, Phytogenic/tu [Therapeutic Use] MH - Apoptosis MH - Carcinoma, Non-Small-Cell Lung/dt [Drug Therapy] MH - Carcinoma, Non-Small-Cell Lung/ge [Genetics] MH - *Carcinoma, Non-Small-Cell Lung/rt [Radiotherapy] MH - Cell Cycle/ph [Physiology] MH - Combined Modality Therapy MH - Genes, cdc/ge [Genetics] MH - *Genes, p16/ge [Genetics] MH - *Genes, p53/ge [Genetics] MH - Humans MH - Lung Neoplasms/dt [Drug Therapy] MH - Lung Neoplasms/ge [Genetics] MH - *Lung Neoplasms/rt [Radiotherapy] MH - Mutation MH - *Paclitaxel/tu [Therapeutic Use] MH - Pancreatic Neoplasms/dt [Drug Therapy] MH - Pancreatic Neoplasms/ge [Genetics] MH - *Pancreatic Neoplasms/rt [Radiotherapy] MH - *Radiation-Sensitizing Agents/tu [Therapeutic Use] MH - Stomach Neoplasms/dt [Drug Therapy] MH - Stomach Neoplasms/ge [Genetics] MH - *Stomach Neoplasms/rt [Radiotherapy] AB - Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation. Many genes that regulate the critical cell cycle checkpoint at G1S are altered in human tumors. These genetic changes can result in uncontrolled cellular proliferation, genetic instability, and altered response to radiation and chemotherapy. The p53 tumor suppressor gene serves a critical role at the G1S transition, where it can either block entry into S phase or activate programmed cell death (apoptosis) in response to DNA damage. p53 Gene mutations are common in human tumors and interfere with the activation of apoptosis in response to most chemotherapeutic agents. Paclitaxel is a potent chemotherapeutic agent that interferes with mitotic spindle function to block cells at G2M, the most radiosensitive phase of the cell cycle. Utilization of paclitaxel as a radiation sensitizer in vivo to treat aggressive, locally advanced neoplasms has resulted in high response rates and acceptable toxicity in protocols for non-small cell lung carcinoma, upper gastrointestinal tract carcinoma, and other malignancies. Recent evidence suggests that paclitaxel is unique in its ability to activate apoptosis in tumor cells with p53 mutations in vitro and in vivo. The p16(INK4a) (MTS-1, CDKN2) gene product acts in the same pathway as p53 to inhibit cell cycle progression at G1/S. p16(INK4a) is deleted and/or mutated in a significant fraction of human tumors, including pancreatic carcinoma. The effects of p16(INK4a) alterations in response to paclitaxel/radiation and the risk of systemic relapse are currently being evaluated. Information about molecular genetic alterations in individual tumors ultimately may be a critical factor in choosing between therapeutic options. [References: 58] RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (Radiation-Sensitizing Agents) RN - P88XT4IS4D (Paclitaxel) IS - 1053-4296 IL - 1053-4296 PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review ID - 10210535 [pubmed] PP - ppublish LG - English DP - 1999 Apr DC - 19990713 EZ - 1999/04/21 00:00 DA - 1999/04/21 00:01 DT - 1999/04/21 YR - 1999 ED - 19990713 RD - 20151119 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=10210535 <369. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 10094876 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Wolf JK AU - Kim TE AU - Fightmaster D AU - Bodurka D AU - Gershenson DM AU - Mills G AU - Wharton JT FA - Wolf, J K FA - Kim, T E FA - Fightmaster, D FA - Bodurka, D FA - Gershenson, D M FA - Mills, G FA - Wharton, J T IN - Wolf, J K. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA. TI - Growth suppression of human ovarian cancer cell lines by the introduction of a p16 gene via a recombinant adenovirus. SO - Gynecologic Oncology. 73(1):27-34, 1999 Apr AS - Gynecol Oncol. 73(1):27-34, 1999 Apr NJ - Gynecologic oncology PI - Journal available in: Print PI - Citation processed from: Print JC - fxc, 0365304 IO - Gynecol. Oncol. SB - Index Medicus CP - United States MH - *Adenoviruses, Human/ge [Genetics] MH - Cell Division MH - DNA, Recombinant MH - Female MH - *Genes, p16 MH - *Genetic Therapy MH - Humans MH - *Ovarian Neoplasms/pa [Pathology] MH - *Ovarian Neoplasms/th [Therapy] MH - Tumor Cells, Cultured AB - OBJECTIVE: The cell cycle regulatory protein p16 (CDKN2/cyclin dependent kinase 4 inhibitor/multiple tumor suppressor-1) causes cell cycle arrest at the G1 checkpoint by inhibiting activity of cyclin D-CDK4 complexes. The purpose of this study is to assess the effect of introduction of the p16 gene into two ovarian cancer cell lines via a recombinant adenoviral vector (Ad5CMV-p16). AB - METHODS: Cells lines used were SKOV3, which has a p16 deletion, and OVCA420, which has normal p16. Transduction efficiency was established by infecting cells with an adenovirus containing the Escherichia coli beta-galactosidase gene (Ad5CMV-beta-gal) at multiplicity of infection from 0 to 1000 and staining for X-gal. Cells were infected with Ad5CMV-p16 and cell growth was assessed by counting cells every other day for up to 7 days. Western blotting was done to assess for p16 expression after infection. Fluorescence-activated cell sorting after staining with propidium iodide was done to assess the effect of p16 on the cell cycle. AB - RESULTS: The SKOV3 cell line was transduced with the adenovirus at a slightly lower MOI than the OVCA420 cell line. Growth of the Ad5CMV-p16-infected cells was suppressed 75-80% by cell count in both cell lines and caused morphologic changes of the cells consistent with apoptosis. The p16 protein expression was seen to increase within 24 h after introduction of the p16 gene. G1 arrest of cells occurred beginning 24 h after introduction of the p16 gene. AB - CONCLUSIONS: These results suggest that Ad5CMV-p16 may be further studied as a potential therapeutic agent for ovarian cancer as introduction of the p16 gene into ovarian cancer cell lines causes a G1 arrest and attenuation of growth, regardless of the endogenous p16 status of the cells. AB - Copyright 1999 Academic Press. RN - 0 (DNA, Recombinant) IS - 0090-8258 IL - 0090-8258 DI - S0090-8258(98)95259-3 DO - https://dx.doi.org/10.1006/gyno.1998.5259 PT - Journal Article ID - 10094876 [pubmed] ID - S0090-8258(98)95259-3 [pii] ID - 10.1006/gyno.1998.5259 [doi] PP - ppublish LG - English DP - 1999 Apr DC - 19990513 EZ - 1999/03/30 00:00 DA - 1999/03/30 00:01 DT - 1999/03/30 YR - 1999 ED - 19990513 RD - 20121115 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=10094876 <370. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 8855976 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - MEDLINE AU - Schuyer M AU - van Staveren IL AU - Klijn JG AU - vd Burg ME AU - Stoter G AU - Henzen-Logmans SC AU - Foekens JA AU - Berns EM FA - Schuyer, M FA - van Staveren, I L FA - Klijn, J G FA - vd Burg, M E FA - Stoter, G FA - Henzen-Logmans, S C FA - Foekens, J A FA - Berns, E M IN - Schuyer, M. Division of Endocrine Oncology (Department of Medical Oncology), Dr Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. TI - Sporadic CDKN2 (MTS1/p16ink4) gene alterations in human ovarian tumours. SO - British Journal of Cancer. 74(7):1069-73, 1996 Oct AS - Br J Cancer. 74(7):1069-73, 1996 Oct NJ - British journal of cancer PI - Journal available in: Print PI - Citation processed from: Print JC - av4, 0370635 IO - Br. J. Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2077110 SB - Index Medicus CP - England MH - *Adenocarcinoma/ge [Genetics] MH - Adult MH - Aged MH - Aged, 80 and over MH - *Carrier Proteins/ge [Genetics] MH - Cyclin-Dependent Kinase Inhibitor p16 MH - Exons/ge [Genetics] MH - Female MH - *Genes, Tumor Suppressor/ge [Genetics] MH - Humans MH - Middle Aged MH - *Ovarian Neoplasms/ge [Genetics] MH - Point Mutation MH - Polymerase Chain Reaction MH - Polymorphism, Single-Stranded Conformational MH - Sequence Deletion MH - Tumor Cells, Cultured AB - The cell cycle regulatory proteins p16 and p21 cause cell cycle arrest at the G1 checkpoint by inhibiting activity of cyclin D-CDK4 complexes. The TP53 gene, regulating the p21 protein, is mutated at high frequency in ovarian cancer. The CDKN2 gene, encoding the p16 protein, has been mapped to chromosome 9p21 and encompasses three exons. To establish the frequency of CDKN2 gene abnormalities in ovarian tumour specimens, we have studied this gene in five ovarian cancer cell lines and in 32 primary and five metastatic ovarian adenocarcinomas. Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and sequencing techniques both exon 1 and 2 of the CDKN2 gene, encompassing 97% of the coding sequence, were analysed. In addition, the TP53 gene was studied for the presence of mutations. The cell line HOC-7 showed a 16 bp deletion in exon 2 of the CDKN2 gene, resulting in a stop codon, whereas in cell line SK-OV-3 this gene was found to be homozygously deleted. Nine primary tumour specimens showed a migration shift on SSCP. Sequencing revealed a common polymorphism (Ala148Thr) in seven of these ovarian tumour specimens. The two other tumour samples were found to contain silent mutations, one at codon 23 (GGT-->GGA) and the other at codon 67 (GGC-->GGT). Mutations in the TP53 gene were observed in 46% of the ovarian tumour specimens. We conclude that CDKN2 gene alterations are rare events in human ovarian cancer. The low prevalence of these alterations do not allow for analysis of an association of this gene with prognosis. RN - 0 (Carrier Proteins) RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) IS - 0007-0920 IL - 0007-0920 PT - Journal Article PT - Research Support, Non-U.S. Gov't ID - 8855976 [pubmed] ID - PMC2077110 [pmc] PP - ppublish LG - English DP - 1996 Oct DC - 19961101 EZ - 1996/10/01 00:00 DA - 1996/10/01 00:01 DT - 1996/10/01 YR - 1996 ED - 19961101 RD - 20130918 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=med4&AN=8855976 <371. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28702249 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Faje A AI - Faje, Alexander; ORCID: https://orcid.org/0000-0002-4092-5409 AI - Faje, Alexander; GRID: grid.32224.35 AI - Faje, Alexander; ISNI: grid.32224.35 FA - Faje, Alexander IN - Faje, Alexander. Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114 USA. TI - Hypophysitis: Evaluation and Management. [Review] SO - Clinical Diabetes & Endocrinology. 2:15, 2016 AS - Clin. diabetes endocrinol.. 2:15, 2016 NJ - Clinical diabetes and endocrinology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101669619 IO - Clin Diabetes Endocrinol CP - England KW - Diabetes insipidus; Hypophysitis; Hypopituitarism AB - Hypophysitis is the acute or chronic inflammation of the pituitary gland. The spectrum of hypophysitis has expanded in recent years with the addition of two histologic subtypes and recognition as a complication of treatment with immune checkpoint inhibitors. Despite the increased number of published cases, the pathogenesis of hypophysitis is poorly understood, and treatment strategies are diverse and controversial. The diagnosis of hypophysitis generally requires histopathologic confirmation. The presentation and clinical course of hypophysitis varies. Hypophysitis can resolve spontaneously, relapse may occur, and some cases can be refractory to treatment. IS - 2055-8260 IL - 2055-8260 DI - 34 DO - https://dx.doi.org/10.1186/s40842-016-0034-8 PT - Journal Article PT - Review ID - 10.1186/s40842-016-0034-8 [doi] ID - 34 [pii] ID - PMC5471685 [pmc] PP - epublish PH - 2016/07/01 [received] PH - 2016/08/26 [accepted] LG - English EP - 20160906 DP - 2016 DC - 20170713 EZ - 2017/07/14 06:00 DA - 2017/07/14 06:01 DT - 2017/07/14 06:00 YR - 2016 RD - 20170716 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28702249 <372. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28533473 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Larkins E AU - Blumenthal GM AU - Yuan W AU - He K AU - Sridhara R AU - Subramaniam S AU - Zhao H AU - Liu C AU - Yu J AU - Goldberg KB AU - McKee AE AU - Keegan P AU - Pazdur R FA - Larkins, Erin FA - Blumenthal, Gideon M FA - Yuan, Weishi FA - He, Kun FA - Sridhara, Rajeshwari FA - Subramaniam, Sriram FA - Zhao, Hong FA - Liu, Chao FA - Yu, Jingyu FA - Goldberg, Kirsten B FA - McKee, Amy E FA - Keegan, Patricia FA - Pazdur, Richard IN - Larkins, Erin. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA erin.larkins@fda.hhs.gov. IN - Blumenthal, Gideon M. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Yuan, Weishi. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - He, Kun. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Sridhara, Rajeshwari. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Subramaniam, Sriram. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Zhao, Hong. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Liu, Chao. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Yu, Jingyu. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Goldberg, Kirsten B. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - McKee, Amy E. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Keegan, Patricia. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Pazdur, Richard. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. TI - FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. SO - Oncologist. 22(7):873-878, 2017 Jul AS - Oncologist. 22(7):873-878, 2017 Jul NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist CP - United States KW - Immunotherapy; Pembrolizumab; Programmed cell death 1 receptor; Squamous cell carcinoma of the head and neck; U.S. Food and Drug Administration AB - On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme Corp., Kenilworth, NJ) for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Approval was based on the objective response rate (ORR) and duration of response (DoR) in a cohort of patients in a nonrandomized multi-cohort trial (KEYNOTE-012) that included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy. Patients received either intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. ORR was determined by independent review according to Response Evaluation Criteria in Solid Tumors 1.1. ORR was 16% (95% confidence interval 11, 22) with a complete response rate of 5%. DoR ranged from 2.4+ months to 27.7+ months. Twenty-three of 28 responding patients (82%) had response durations of >=6 months. Safety was evaluated in 192 patients with HNSCC receiving at least one dose of pembrolizumab. Frequent (>=2%) serious adverse reactions were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders. The benefit-risk profile of pembrolizumab was considered acceptable in this patient population. As a condition of accelerated approval, Merck is required to conduct a confirmatory trial; this trial, KEYNOTE-040, is ongoing. AB - IMPLICATIONS FOR PRACTICE: This accelerated approval expands the U.S. Food and Drug Administration-approved indications for pembrolizumab, providing health care providers with new information regarding pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. Pembrolizumab is the first drug to receive approval for treatment of patients with HNSCC since cetuximab was approved for this indication in 2006. Copyright Published 2017. This article is a U.S. Government work and is in the public domain in the USA. CI - Disclosures of potential conflicts of interest may be found at the end of this article. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2016-0496 DO - https://dx.doi.org/10.1634/theoncologist.2016-0496 PT - Journal Article ID - theoncologist.2016-0496 [pii] ID - 10.1634/theoncologist.2016-0496 [doi] ID - PMC5507654 [pmc] PP - ppublish PH - 2016/12/13 [received] PH - 2017/02/21 [accepted] LG - English EP - 20170522 DP - 2017 Jul DC - 20170523 EZ - 2017/05/24 06:00 DA - 2017/05/24 06:00 DT - 2017/05/24 06:00 YR - 2017 RD - 20170716 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28533473 <373. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28211040 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Wallberg M AU - Recino A AU - Phillips J AU - Howie D AU - Vienne M AU - Paluch C AU - Azuma M AU - Wong FS AU - Waldmann H AU - Cooke A AI - Wallberg, Maja; ORCID: http://orcid.org/0000-0001-8297-7859 FA - Wallberg, Maja FA - Recino, Asha FA - Phillips, Jenny FA - Howie, Duncan FA - Vienne, Margaux FA - Paluch, Christopher FA - Azuma, Miyuki FA - Wong, F Susan FA - Waldmann, Herman FA - Cooke, Anne IN - Wallberg, Maja. Department of Pathology, University of Cambridge, Cambridge, UK. IN - Recino, Asha. Department of Pathology, University of Cambridge, Cambridge, UK. IN - Phillips, Jenny. Department of Pathology, University of Cambridge, Cambridge, UK. IN - Howie, Duncan. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. IN - Vienne, Margaux. Department of Pathology, University of Cambridge, Cambridge, UK. IN - Paluch, Christopher. Department of Pathology, University of Cambridge, Cambridge, UK. IN - Azuma, Miyuki. Department of Molecular Immunology Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. IN - Wong, F Susan. Diabetes Research Group, Institute of Molecular and Experimental Medicine, Cardiff School of Medicine, Cardiff University, Cardiff, UK. IN - Waldmann, Herman. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. IN - Cooke, Anne. Department of Pathology, University of Cambridge, Cambridge, UK. TI - Anti-CD3 treatment up-regulates programmed cell death protein-1 expression on activated effector T cells and severely impairs their inflammatory capacity.[Erratum appears in Immunology. 2017 Aug;151(4):481; PMID: 28699309] SO - Immunology. 151(2):248-260, 2017 Jun AS - Immunology. 151(2):248-260, 2017 Jun NJ - Immunology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - gh7, 0374672 IO - Immunology CP - England KW - antibodies; diabetes; tolerance/suppression/anergy; transgenic/knockout mouse AB - T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)⁺ islet-specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time-points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti-CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon-gamma. Programmed cell death protein 1 (PD-1) expression was up-regulated on the effector cells from anti-CD3-treated mice, and diabetes induced through anti-PD-L1 antibody could only be reversed with anti-CD3 antibody if the anti-CD3 treatment lasted beyond the point when the anti-PD-L1 antibody was washed out of the system. This suggests that PD-1/PD-L1 interaction plays an important role in the anti-CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti-CD3 therapy can reverse diabetogenesis. Copyright © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd. ES - 1365-2567 IL - 0019-2805 DO - https://dx.doi.org/10.1111/imm.12729 PT - Journal Article ID - 10.1111/imm.12729 [doi] ID - PMC5418468 [pmc] PP - ppublish PH - 2016/11/24 [received] PH - 2017/02/03 [revised] PH - 2017/02/13 [accepted] LG - English EP - 20170316 DP - 2017 Jun DC - 20170217 EZ - 2017/02/18 06:00 DA - 2017/02/18 06:00 DT - 2017/02/18 06:00 YR - 2017 RD - 20170716 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28211040 <374. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28680756 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Layer JP AU - Kronmuller MT AU - Quast T AU - van den Boorn-Konijnenberg D AU - Effern M AU - Hinze D AU - Althoff K AU - Schramm A AU - Westermann F AU - Peifer M AU - Hartmann G AU - Tuting T AU - Kolanus W AU - Fischer M AU - Schulte J AU - Holzel M FA - Layer, Julian P FA - Kronmuller, Marie T FA - Quast, Thomas FA - van den Boorn-Konijnenberg, Debby FA - Effern, Maike FA - Hinze, Daniel FA - Althoff, Kristina FA - Schramm, Alexander FA - Westermann, Frank FA - Peifer, Martin FA - Hartmann, Gunther FA - Tuting, Thomas FA - Kolanus, Waldemar FA - Fischer, Matthias FA - Schulte, Johannes FA - Holzel, Michael IN - Layer, Julian P. Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. IN - Kronmuller, Marie T. Division of Molecular Immunology and Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. IN - Quast, Thomas. Division of Molecular Immunology and Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. IN - van den Boorn-Konijnenberg, Debby. Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. IN - Effern, Maike. Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. IN - Effern, Maike. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunology, The University of Melbourne, Melbourne, Victoria, Australia. IN - Hinze, Daniel. Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. IN - Althoff, Kristina. Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany. IN - Schramm, Alexander. Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany. IN - Schramm, Alexander. Molecular Oncology, Internal Medicine/Cancer Research Unit, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. IN - Westermann, Frank. Neuroblastoma Genomics B087, German Cancer Research Center (DKFZ), Heidelberg, Germany. IN - Peifer, Martin. Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany. IN - Peifer, Martin. Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany. IN - Hartmann, Gunther. Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. IN - Tuting, Thomas. Laboratory of Experimental Dermatology, Department of Dermatology, University of Magdeburg, Magdeburg, Germany. IN - Tuting, Thomas. Laboratory of Experimental Dermatology, Department of Dermatology, University of Bonn, Bonn, Germany. IN - Kolanus, Waldemar. Division of Molecular Immunology and Cell Biology, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. IN - Fischer, Matthias. Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany. IN - Fischer, Matthias. Department of Experimental Pediatric Hematology and Oncology, University of Cologne, Cologne, Germany. IN - Fischer, Matthias. Max Planck Institute for Metabolism Research, Cologne, Germany. IN - Schulte, Johannes. Department of Pediatric Hematology, Oncology and SCT, Charite - University Hospital Berlin, Campus Virchow-Klinikum, Berlin, Germany. IN - Holzel, Michael. Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany. TI - Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression. SO - Oncoimmunology. 6(6):e1320626, 2017 AS - Oncoimmunology. 6(6):e1320626, 2017 NJ - Oncoimmunology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101570526 IO - Oncoimmunology CP - United States KW - Chemokine; Cxcl10; N-Myc; STING; immunotherapy; infiltration; interferoninfiltration; neuroblastoma AB - Immune checkpoint inhibitors have significantly improved the treatment of several cancers. T-cell infiltration and the number of neoantigens caused by tumor-specific mutations are correlated to favorable responses in cancers with a high mutation load. Accordingly, checkpoint immunotherapy is thought to be less effective in tumors with low mutation frequencies such as neuroblastoma, a neuroendocrine tumor of early childhood with poor outcome of the high-risk disease group. However, spontaneous regressions and paraneoplastic syndromes seen in neuroblastoma patients suggest substantial immunogenicity. Using an integrative transcriptomic approach, we investigated the molecular characteristics of T-cell infiltration in primary neuroblastomas as an indicator of pre-existing immune responses and potential responsiveness to checkpoint inhibition. Here, we report that a T-cell-poor microenvironment in primary metastatic neuroblastomas is associated with genomic amplification of the MYCN (N-Myc) proto-oncogene. These tumors exhibited lower interferon pathway activity and chemokine expression in line with reduced immune cell infiltration. Importantly, we identified a global role for N-Myc in the suppression of interferon and pro-inflammatory pathways in human and murine neuroblastoma cell lines. N-Myc depletion potently enhanced targeted interferon pathway activation by a small molecule agonist of the cGAS-STING innate immune pathway. This promoted chemokine expression including Cxcl10 and T-cell recruitment in microfluidics migration assays. Hence, our data suggest N-Myc inhibition plus targeted IFN activation as adjuvant strategy to enforce cytotoxic T-cell recruitment in MYCN-amplified neuroblastomas. IS - 2162-4011 IL - 2162-4011 DI - 1320626 DO - https://dx.doi.org/10.1080/2162402X.2017.1320626 PT - Journal Article ID - 10.1080/2162402X.2017.1320626 [doi] ID - 1320626 [pii] ID - PMC5486176 [pmc] PP - epublish PH - 2016/12/13 [received] PH - 2017/03/26 [revised] PH - 2017/04/13 [accepted] PH - 2018/04/28 [pmc-release] LG - English EP - 20170428 DP - 2017 DC - 20170706 EZ - 2017/07/07 06:00 DA - 2017/07/07 06:00 DT - 2017/07/07 06:00 YR - 2017 RD - 20170717 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28680756 <375. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28638725 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Petersen CT AU - Li JM AU - Waller EK FA - Petersen, Christopher T FA - Li, Jian-Ming FA - Waller, Edmund K IN - Petersen, Christopher T. Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA, USA. IN - Li, Jian-Ming. Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA, USA. IN - Waller, Edmund K. Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA, USA. TI - Administration of a vasoactive intestinal peptide antagonist enhances the autologous anti-leukemia T cell response in murine models of acute leukemia. SO - Oncoimmunology. 6(5):e1304336, 2017 AS - Oncoimmunology. 6(5):e1304336, 2017 NJ - Oncoimmunology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101570526 IO - Oncoimmunology CP - United States KW - Antagonist; T cells; checkpoint blockade; co-stimulation; leukemia AB - Vasoactive intestinal peptide (VIP) is a neuroendocrine peptide hormone that has potent anti-inflammatory activities. VIP signaling through its receptor VPAC1 on T cells leads to reduced proliferation and a reduction in pro-inflammatory cytokine secretion. We report here that inhibition of the VIP pathway with a peptide antagonist significantly enhances a T-cell-dependent, autologous anti-leukemia response in murine models of acute myeloid leukemia and T lymphoblastic leukemia. Subcutaneous administration of the VIP antagonist, VIPhyb, resulted in reduced tumor burden and significantly enhanced survival (30-50% survival) over vehicle-treated controls (0-20% survival). The T cells in mice treated with VIPhyb expressed lower levels of the co-inhibitory PD-1 and secreted higher levels of IFNgamma. Furthermore, T cells from VIPhyb-treated survivors were protective against C1498 following adoptive transfer. These data highlight the potential for the VIP pathway as a novel target for immunomodulation in settings of hematological malignancies. IS - 2162-4011 IL - 2162-4011 DI - 1304336 DO - https://dx.doi.org/10.1080/2162402X.2017.1304336 PT - Journal Article ID - 10.1080/2162402X.2017.1304336 [doi] ID - 1304336 [pii] ID - PMC5467986 [pmc] PP - epublish PH - 2016/10/18 [received] PH - 2017/03/02 [revised] PH - 2017/03/03 [accepted] PH - 2018/03/16 [pmc-release] LG - English EP - 20170316 DP - 2017 DC - 20170622 EZ - 2017/06/23 06:00 DA - 2017/06/24 06:00 DT - 2017/06/24 06:00 YR - 2017 RD - 20170717 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28638725 <376. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28611636 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Li L AU - Masood A AU - Bari S AU - Yavuz S AU - Grosbach AB FA - Li, Li FA - Masood, Awais FA - Bari, Shahla FA - Yavuz, Sahzene FA - Grosbach, Alan B IN - Li, Li. aDivision of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida, USA. IN - Li, Li. dDivision of Hematology and Oncology, Malcom Randall VA Medical Center, Gainesville, Florida, USA. IN - Masood, Awais. bDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida, Gainesville, Florida, USA. IN - Masood, Awais. eDivision of Endocrinology, Malcom Randall VA Medical Center, Gainesville, Florida, USA. IN - Bari, Shahla. cDepartment of Medicine, University of Florida, Gainesville, Florida, USA. IN - Yavuz, Sahzene. bDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Florida, Gainesville, Florida, USA. IN - Yavuz, Sahzene. eDivision of Endocrinology, Malcom Randall VA Medical Center, Gainesville, Florida, USA. IN - Grosbach, Alan B. aDivision of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida, USA. IN - Grosbach, Alan B. dDivision of Hematology and Oncology, Malcom Randall VA Medical Center, Gainesville, Florida, USA. TI - Autoimmune Diabetes and Thyroiditis Complicating Treatment with Nivolumab. SO - Case Reports Oncology. 10(1):230-234, 2017 Jan-Apr AS - Case rep., oncol.. 10(1):230-234, 2017 Jan-Apr NJ - Case reports in oncology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101517601 IO - Case Rep Oncol CP - Switzerland KW - Autoimmune diabetes; Nivolumab; PD-1 inhibitor AB - Programmed cell death-1 (PD-1) ligand inhibitors have gained popularity in the treatment of advanced non-small-cell lung cancer. The immune system is regulated by stimulatory and inhibitory signaling and aims to achieve the balance between activation and inhibition. Treatment with immune checkpoint inhibitors enhances immune response, but is also known to diminish immune tolerance and increase autoimmune toxicity. Here we present a case of a patient with advanced squamous cell lung cancer who developed type I diabetes and thyroiditis after treatment with PD-1 checkpoint inhibitor nivolumab. The presence of autoimmune diabetes mellitus and thyroiditis were confirmed by markedly elevated titers of the glutamic acid decarboxylase autoantibody and thyroid peroxidase antibody, respectively. This report serves to heighten awareness of potential autoimmune toxicities related to anti-PD-1 therapy, especially as these toxicities are manageable if identified in a timely manner. IS - 1662-6575 IL - 1662-6575 DI - cro-0010-0230 DO - https://dx.doi.org/10.1159/000456540 PT - Journal Article ID - 10.1159/000456540 [doi] ID - cro-0010-0230 [pii] ID - PMC5465653 [pmc] PP - epublish PH - 2017/01/16 [received] PH - 2017/01/16 [accepted] LG - English EP - 20170302 DP - 2017 Jan-Apr DC - 20170614 EZ - 2017/06/15 06:00 DA - 2017/06/15 06:01 DT - 2017/06/15 06:00 YR - 2017 RD - 20170717 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28611636 <377. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27775076 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Chen F AU - Zhang Y AU - Parra E AU - Rodriguez J AU - Behrens C AU - Akbani R AU - Lu Y AU - Kurie JM AU - Gibbons DL AU - Mills GB AU - Wistuba II AU - Creighton CJ FA - Chen, F FA - Zhang, Y FA - Parra, E FA - Rodriguez, J FA - Behrens, C FA - Akbani, R FA - Lu, Y FA - Kurie, J M FA - Gibbons, D L FA - Mills, G B FA - Wistuba, I I FA - Creighton, C J IN - Chen, F. Dan L. Duncan Comprehensive Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA. IN - Zhang, Y. Dan L. Duncan Comprehensive Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA. IN - Parra, E. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, TX, USA. IN - Rodriguez, J. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, TX, USA. IN - Behrens, C. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, TX, USA. IN - Akbani, R. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. IN - Lu, Y. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. IN - Kurie, J M. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. IN - Gibbons, D L. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. IN - Gibbons, D L. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. IN - Mills, G B. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. IN - Wistuba, I I. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer, Houston, TX, USA. IN - Wistuba, I I. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. IN - Creighton, C J. Dan L. Duncan Comprehensive Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA. IN - Creighton, C J. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. IN - Creighton, C J. Department of Medicine, Baylor College of Medicine, Houston, TX, USA. TI - Multiplatform-based molecular subtypes of non-small-cell lung cancer. SO - Oncogene. 36(10):1384-1393, 2017 Mar AS - Oncogene. 36(10):1384-1393, 2017 Mar NJ - Oncogene PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - onc, 8711562 IO - Oncogene CP - England AB - Non-small-cell lung cancer (NSCLC) demonstrates remarkable molecular diversity. With the completion of The Cancer Genome Atlas (TCGA), there is opportunity for systematic analyses of the entire TCGA NSCLC cohort, including comparisons and contrasts between different disease subsets. On the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy, and RNA and protein expression), 1023 NSCLC cases-519 from TCGA adenocarcinoma (AD) project and 504 from TCGA squamous cell carcinoma (SQCC) project-were classified using a 'cluster-of-clusters' analytic approach. Patterns from TCGA NSCLC subsets were examined in independent external databases, including the PROSPECT (Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax) NSCLC data set. Nine genomic subtypes of NSCLC were identified, three within SQCC and six within AD. SQCC subtypes were associated with transcriptional targets of SOX2 or p63. One predominately AD subtype (with a large proportion of SQCC) shared molecular features with neuroendocrine tumors. Two AD subtypes manifested a CpG island methylator phenotype. Three AD subtypes showed high p38 and mTOR pathway activation. AD subtypes associated with low differentiation showed relatively worse prognosis. SQCC subtypes and two of the AD subtypes expressed cancer testis antigen genes, whereas three AD subtypes expressed several immune checkpoint genes including PDL1 and PDL2, corresponding with patterns of greater immune cell infiltration. Subtype associations for several immune-related markers-including PD1, PDL1, CD3 and CD8-were confirmed in the PROSPECT cohort using immunohistochemistry. NSCLC molecular subtypes have therapeutic implications and lend support to a personalized approach to NSCLC management based on molecular characterization. ES - 1476-5594 IL - 0950-9232 DI - onc2016303 DO - https://dx.doi.org/10.1038/onc.2016.303 PT - Journal Article ID - onc2016303 [pii] ID - 10.1038/onc.2016.303 [doi] ID - PMC5344748 [pmc] ID - NIHMS804251 [mid] PP - ppublish PH - 2016/05/23 [received] PH - 2016/07/12 [revised] PH - 2016/07/15 [accepted] GI - No: P30 CA016672 Organization: (CA) *NCI NIH HHS* Country: United States No: U24 CA210950 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA125123 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA070907 Organization: (CA) *NCI NIH HHS* Country: United States No: U24 CA210949 Organization: (CA) *NCI NIH HHS* Country: United States No: U24 CA143883 Organization: (CA) *NCI NIH HHS* Country: United States No: U24 CA199461 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20161024 DP - 2017 Mar DC - 20161024 EZ - 2016/10/25 06:00 DA - 2016/10/25 06:00 DT - 2016/10/25 06:00 YR - 2017 RD - 20170717 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27775076 <378. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27398650 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Kwok G AU - Yau TC AU - Chiu JW AU - Tse E AU - Kwong YL FA - Kwok, Gerry FA - Yau, Thomas C C FA - Chiu, Joanne W FA - Tse, Eric FA - Kwong, Yok-Lam IN - Kwok, Gerry. a Department of Medicine , Queen Mary Hospital , Hong Kong. IN - Yau, Thomas C C. a Department of Medicine , Queen Mary Hospital , Hong Kong. IN - Chiu, Joanne W. a Department of Medicine , Queen Mary Hospital , Hong Kong. IN - Tse, Eric. a Department of Medicine , Queen Mary Hospital , Hong Kong. IN - Kwong, Yok-Lam. a Department of Medicine , Queen Mary Hospital , Hong Kong. TI - Pembrolizumab (Keytruda). SO - Human vaccines & Immunotherapeutics. 12(11):2777-2789, 2016 Nov AS - Hum Vaccin Immunother. 12(11):2777-2789, 2016 Nov NJ - Human vaccines & immunotherapeutics PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101572652 IO - Hum Vaccin Immunother CP - United States KW - PD1; PDL1; PDL2; lymphoma; melanoma; non-small cell lung cancer; pembrolizumab; solid tumors AB - The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50 % could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment. ES - 2164-554X IL - 2164-5515 DO - https://dx.doi.org/10.1080/21645515.2016.1199310 PT - Journal Article ID - 10.1080/21645515.2016.1199310 [doi] ID - PMC5137544 [pmc] PP - ppublish LG - English EP - 20160711 DP - 2016 Nov DC - 20160711 EZ - 2016/07/12 06:00 DA - 2016/07/12 06:00 DT - 2016/07/12 06:00 YR - 2016 RD - 20170717 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27398650 <379. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27306911 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Gonzalez-Rodriguez E AU - Rodriguez-Abreu D AU - Spanish Group for Cancer Immuno-Biotherapy (GETICA) FA - Gonzalez-Rodriguez, Elisa FA - Rodriguez-Abreu, Delvys FA - Spanish Group for Cancer Immuno-Biotherapy (GETICA) IN - Gonzalez-Rodriguez, Elisa. Section of Endocrinology and Nutrition, Hospital Universitario de Gran Canaria Doctor Negrin, Las Palmas de Gran Canaria, Spain elisaglezrguez@gmail.com. IN - Rodriguez-Abreu, Delvys. Section of Medical Oncology, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain. TI - Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events. [Review] SO - Oncologist. 21(7):804-16, 2016 Jul AS - Oncologist. 21(7):804-16, 2016 Jul NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943391 SB - Index Medicus CP - United States KW - Autoimmune hypophysitis; Cytotoxic T-lymphocyte antigen 4; Monoclonal antibodies; Programmed cell death 1 receptor; Thyroiditis AB - UNLABELLED: : In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and additional tumor locations tested, their use is expected to increase within a short time. Immune-related adverse events (irAEs) affecting the endocrine system are among the most frequent and complex toxicities. Some may be life-threatening if not recognized; hence, appropriate guidance for oncologists is needed. Despite their high incidence, endocrine irAEs have not been fully described for all immunotherapy agents available. This article is a narrative review of endocrinopathies associated with cytotoxic T lymphocyte-associated antigen-4, blockade of programmed death receptor 1 and its ligand inhibitors, and their combination. Thyroid dysfunction is the most frequent irAE reported, and hypophysitis is characteristic of ipilimumab. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for clinical management are suggested. Heterogeneous terminology and lack of appropriate resolution criteria in clinical trials make adequate evaluation of endocrine AEs difficult. It is necessary to standardize definitions to contrast incidences and characterize toxicity patterns. To provide optimal care, a multidisciplinary team that includes endocrinology specialists is recommended. AB - IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitors are already part of oncologists' therapeutic arsenal as effective therapies for otherwise untreatable neoplasias, such as metastatic melanoma or lung cancer. Their use is expected to increase exponentially in the near future as additional agents become available and their approval is extended to different tumor types. Adverse events affecting the endocrine system are among the most frequent and complex toxicities oncologists may face, and some may be life-threatening if not recognized. This study reviews endocrinopathies associated to immune checkpoint inhibitors available to date. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for management are proposed. Copyright ©AlphaMed Press. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2015-0509 DO - https://dx.doi.org/10.1634/theoncologist.2015-0509 PT - Journal Article PT - Review ID - theoncologist.2015-0509 [pii] ID - 10.1634/theoncologist.2015-0509 [doi] ID - PMC4943391 [pmc] PP - ppublish PH - 2015/12/12 [received] PH - 2016/02/19 [accepted] LG - English EP - 20160615 DP - 2016 Jul DC - 20160714 EZ - 2016/06/17 06:00 DA - 2016/06/17 06:00 DT - 2016/06/17 06:00 YR - 2016 RD - 20170717 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27306911 <380. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28682883 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Chen YH AU - Liu FC AU - Hsu CH AU - Chian CF FA - Chen, Yu-Hsiu FA - Liu, Feng-Cheng FA - Hsu, Chang-Hung FA - Chian, Chih-Feng IN - Chen, Yu-Hsiu. aDivision of Rheumatology/Immunology/Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center bDepartment of Neurology, Tri-Service General Hospital, National Defense Medical Center cDivision of Pulmonary Medicine, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. TI - Nivolumab-induced myasthenia gravis in a patient with squamous cell lung carcinoma: Case report. SO - Medicine. 96(27):e7350, 2017 Jul AS - Medicine (Baltimore). 96(27):e7350, 2017 Jul NJ - Medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - mny, 2985248r IO - Medicine (Baltimore) CP - United States AB - RATIONALE: Nivolumab (Nivo) is an immune checkpoint inhibitor that has been used to treat advanced melanoma, nonsmall cell lung carcinoma, and renal cell carcinoma since 2015. Nivo is associated with several side effects, including hepatitis, pneumonitis, acute renal failure, endocrine disorder, and other immune-related adverse events. Here, we describe the case of a 65-year-old man with squamous cell lung carcinoma who developed myasthenia gravis (MG) after a third Nivo infusion. AB - PATIENT CONCERNS: A 65-year-old man with advanced squamous cell lung carcinoma developed ptosis, diplopia, drop head, and general weakness 5 days after a third Nivo infusion. AB - DIAGNOSES, INTERVENTIONS, AND OUTCOMES: We diagnosed him with Nivo-related MG and myositis based on clinical symptoms, elevation of muscle enzymes, negativity for autoantibodies and exclusion of other diagnoses. Steroid treatment with methylprednisolone 1 mg/kg/d and pyridostigmine 60 mg twice a day was administered beginning at admission; however, the patient's condition progressively worsened, despite treatment. Respiratory failure developed 2 weeks after admission, and his family declined the use of a mechanical ventilator. The patient died on day 27 after the third Nivo infusion. AB - LESSONS: Nivo-related MG should be highly suspected in patients who develop ptosis, diplopia, and general weakness. The corresponding treatments include discontinuation of Nivo and steroid treatment with plasmapheresis. The disease course may be rapid and fatal. This report stresses the importance of awareness of this rare and lethal adverse effect while using nivolomab immunotherapy. ES - 1536-5964 IL - 0025-7974 DI - 00005792-201707070-00025 DO - https://dx.doi.org/10.1097/MD.0000000000007350 PT - Journal Article ID - 10.1097/MD.0000000000007350 [doi] ID - 00005792-201707070-00025 [pii] PP - ppublish LG - English DP - 2017 Jul DC - 20170706 EZ - 2017/07/07 06:00 DA - 2017/07/07 06:00 DT - 2017/07/07 06:00 YR - 2017 RD - 20170706 UP - 20170707 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28682883 <381. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28537531 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Yamauchi I AU - Sakane Y AU - Fukuda Y AU - Fujii T AU - Taura D AU - Hirata M AU - Hirota K AU - Ueda Y AU - Kanai Y AU - Yamashita Y AU - Kondo E AU - Sone M AU - Yasoda A AU - Inagaki N FA - Yamauchi, Ichiro FA - Sakane, Yoriko FA - Fukuda, Yorihide FA - Fujii, Toshihito FA - Taura, Daisuke FA - Hirata, Masakazu FA - Hirota, Keisho FA - Ueda, Yohei FA - Kanai, Yugo FA - Yamashita, Yui FA - Kondo, Eri FA - Sone, Masakatsu FA - Yasoda, Akihiro FA - Inagaki, Nobuya IN - Yamauchi, Ichiro. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Sakane, Yoriko. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Sakane, Yoriko. 2 Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital , Kyoto, Japan . IN - Fukuda, Yorihide. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Fujii, Toshihito. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Taura, Daisuke. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Hirata, Masakazu. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Hirota, Keisho. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Ueda, Yohei. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Kanai, Yugo. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Yamashita, Yui. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Kondo, Eri. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Sone, Masakatsu. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Yasoda, Akihiro. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . IN - Inagaki, Nobuya. 1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan . TI - Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study. SO - Thyroid. 27(7):894-901, 2017 Jul AS - Thyroid. 27(7):894-901, 2017 Jul NJ - Thyroid : official journal of the American Thyroid Association PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bjw, 9104317 IO - Thyroid CP - United States KW - PD-1; immune checkpoint inhibitor; nivolumab; painless thyroiditis; thyrotoxicosis AB - BACKGROUND: The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor and its two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved for malignant melanoma, advanced non-small cell lung cancer, and advanced renal cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been reported in international Phase 3 studies and national post-marketing surveillance of nivolumab in Japan. AB - METHODS: This study analyzed five consecutive cases with thyroid dysfunction associated with nivolumab therapy. Second, it examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse transcription polymerase chain reaction and Western blotting. AB - RESULTS: All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism. In addition, it was verified that normal thyroid tissue expresses PD-L1 and PD-L2 mRNA and those proteins. AB - CONCLUSIONS: In the present cases, nivolumab-induced thyrotoxicosis seemed to be associated with painless thyroiditis, while no patient with Graves' disease was observed. A transient and rapid course with subsequent hypothyroidism was observed in nivolumab-induced thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in normal thyroid tissue. This suggests that nivolumab therapy reduces immune tolerance, even in normal thyroid tissue, and leads to the development of thyroiditis. Treating thyrotoxicosis with only supportive care and considering levothyroxine replacement therapy once subsequent hypothyroidism occurs is proposed. Further investigations are required to confirm whether glucocorticoid therapy and discontinuation of nivolumab therapy prevent subsequent hypothyroidism. ES - 1557-9077 IL - 1050-7256 DO - https://dx.doi.org/10.1089/thy.2016.0562 PT - Journal Article ID - 10.1089/thy.2016.0562 [doi] PP - ppublish LG - English EP - 20170621 DP - 2017 Jul DC - 20170524 EZ - 2017/05/25 06:00 DA - 2017/05/26 06:00 DT - 2017/05/26 06:00 YR - 2017 RD - 20170706 UP - 20170707 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28537531 <382. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28043983 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Telo GH AU - Carvalhal GF AU - Cauduro CGS AU - Webber VS AU - Barrios CH AU - Fay AP FA - Telo, G H FA - Carvalhal, G F FA - Cauduro, C G S FA - Webber, V S FA - Barrios, C H FA - Fay, A P IN - Telo, G H. Endocrinology Department, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre. IN - Carvalhal, G F. School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90619-900, Brazil. IN - Cauduro, C G S. School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90619-900, Brazil. IN - Webber, V S. Clinical Research Center, PUCRS, Porto Alegre, Brazil. IN - Barrios, C H. School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90619-900, Brazil. IN - Barrios, C H. Clinical Research Center, PUCRS, Porto Alegre, Brazil. IN - Barrios, C H. Medical Oncology, Hospital do Cancer Mae de Deus, Porto Alegre, Brazil. IN - Barrios, C H. Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil. IN - Fay, A P. School of Medicine, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90619-900, Brazil. IN - Fay, A P. Clinical Research Center, PUCRS, Porto Alegre, Brazil. IN - Fay, A P. Medical Oncology, Hospital do Cancer Mae de Deus, Porto Alegre, Brazil. IN - Fay, A P. Latin American Cooperative Oncology Group (LACOG), Porto Alegre, Brazil. TI - Fulminant type 1 diabetes caused by dual immune checkpoint blockade in metastatic renal cell carcinoma. SO - Annals of Oncology. 28(1):191-192, 2017 01 01 AS - Ann Oncol. 28(1):191-192, 2017 01 01 NJ - Annals of oncology : official journal of the European Society for Medical Oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - ayf, 9007735 IO - Ann. Oncol. CP - England ES - 1569-8041 IL - 0923-7534 DI - mdw447 DO - https://dx.doi.org/10.1093/annonc/mdw447 PT - Journal Article ID - mdw447 [pii] ID - 10.1093/annonc/mdw447 [doi] PP - ppublish LG - English DP - 2017 01 01 DC - 20170103 EZ - 2017/01/04 06:00 DA - 2017/01/04 06:00 DT - 2017/01/04 06:00 YR - 2017 RD - 20170704 UP - 20170705 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28043983 <383. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27998967 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Osorio JC AU - Ni A AU - Chaft JE AU - Pollina R AU - Kasler MK AU - Stephens D AU - Rodriguez C AU - Cambridge L AU - Rizvi H AU - Wolchok JD AU - Merghoub T AU - Rudin CM AU - Fish S AU - Hellmann MD FA - Osorio, J C FA - Ni, A FA - Chaft, J E FA - Pollina, R FA - Kasler, M K FA - Stephens, D FA - Rodriguez, C FA - Cambridge, L FA - Rizvi, H FA - Wolchok, J D FA - Merghoub, T FA - Rudin, C M FA - Fish, S FA - Hellmann, M D IN - Osorio, J C. Department of Medicine, Weill Cornell Medical College, New York. IN - Ni, A. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington Ave., New York, NY 10017, USA. IN - Chaft, J E. Department of Medicine, Weill Cornell Medical College, New York. IN - Chaft, J E. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Pollina, R. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Kasler, M K. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Stephens, D. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Rodriguez, C. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Cambridge, L. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Rizvi, H. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Wolchok, J D. Department of Medicine, Weill Cornell Medical College, New York. IN - Wolchok, J D. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Wolchok, J D. Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering, New York. IN - Wolchok, J D. Ludwig Institute for Cancer Research, New York, USA. IN - Merghoub, T. Department of Medicine, Weill Cornell Medical College, New York. IN - Merghoub, T. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Merghoub, T. Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering, New York. IN - Merghoub, T. Ludwig Institute for Cancer Research, New York, USA. IN - Rudin, C M. Department of Medicine, Weill Cornell Medical College, New York. IN - Rudin, C M. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Fish, S. Department of Medicine, Weill Cornell Medical College, New York. IN - Fish, S. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Hellmann, M D. Department of Medicine, Weill Cornell Medical College, New York. IN - Hellmann, M D. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA IN - Hellmann, M D. Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering, New York. TI - Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. SO - Annals of Oncology. 28(3):583-589, 2017 03 01 AS - Ann Oncol. 28(3):583-589, 2017 03 01 NJ - Annals of oncology : official journal of the European Society for Medical Oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - ayf, 9007735 IO - Ann. Oncol. CP - England KW - *PD-1; *hypothyroidism; *non-small cell lung cancer; *pembrolizumab; *thyroid dysfunction AB - Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. AB - Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n=51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. AB - Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P<0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P=0.04). AB - Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity. ES - 1569-8041 IL - 0923-7534 DI - mdw640 DO - https://dx.doi.org/10.1093/annonc/mdw640 PT - Journal Article ID - mdw640 [pii] ID - 10.1093/annonc/mdw640 [doi] PP - ppublish LG - English DP - 2017 03 01 DC - 20161221 EZ - 2016/12/22 06:00 DA - 2016/12/22 06:00 DT - 2016/12/22 06:00 YR - 2017 RD - 20170704 UP - 20170705 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27998967 <384. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28554108 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Peng TR AU - Tsai FP AU - Wu TW FA - Peng, Tzu-Rong FA - Tsai, Fang-Pei FA - Wu, Ta-Wei IN - Peng, Tzu-Rong. Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan. IN - Tsai, Fang-Pei. Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan. IN - Wu, Ta-Wei. Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei City, Taiwan. Electronic address: tawei@tzuchi.com.tw. TI - Indirect comparison between pembrolizumab and nivolumab for the treatment of non-small cell lung cancer: A meta-analysis of randomized clinical trials. SO - International Immunopharmacology. 49:85-94, 2017 Aug AS - Int Immunopharmacol. 49:85-94, 2017 Aug NJ - International immunopharmacology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - d17, 100965259 IO - Int. Immunopharmacol. CP - Netherlands KW - Adverse effects; Nivolumab; Non-small cell lung cancer; Pembrolizumab; Pneumonitis AB - OBJECTIVE: The purpose of this study is to evaluate the efficacy and adverse effects of nivolumab and pembrolizumab for the treatment of advanced non-small-cell lung cancer (NSCLC) by meta-analysis. AB - MATERIALS AND METHODS: This meta-analysis of randomized controlled trials (RCTs) was performed after searching PubMed, EMBASE, and American Society of Clinical Oncology meeting abstracts, clinicaltrial gov, and Cochrane library databases. Two reviewers independently assessed the quality of the trials. Outcomes analysis was overall response rates (ORR), overall survival (OS), progression- free survival (PFS) and major adverse effects with odds ratio (OR) or hazard ratio (HR) and 95% confidence intervals (CI). AB - RESULTS: Results reported from three RCTs involving 1,887 patients are included in this analysis. Indirect comparison between pembrolizumab and nivolumab in advanced NSCLC shows no statistically significant difference in ORR (OR: 1.14, 95% CI, 0.60-2.01), OS (HR: 0.98, 95% CI, 0.35-2.74) and PFS (HR: 1.12, 95% CI, 0.70-1.77). The incidence of grades>=3 adverse effects is higher with pembrolizumab as compared with nivolumab (OR: 3.44, 95% CI, 1.87-6.32). There are no significant statistical differences between severe adverse effects, such as pneumonitis and hypothyroidism, of the two drugs. AB - CONCLUSIONS: This study has demonstrated that pembrolizumab and nivolumab have similar survival outcomes in patients with advanced NSCLC, but pembrolizumab has a higher incidence of grades>=3 adverse effects than nivolumab. Copyright © 2017 Elsevier B.V. All rights reserved. ES - 1878-1705 IL - 1567-5769 DI - S1567-5769(17)30191-1 DO - https://dx.doi.org/10.1016/j.intimp.2017.05.019 PT - Journal Article ID - S1567-5769(17)30191-1 [pii] ID - 10.1016/j.intimp.2017.05.019 [doi] PP - ppublish PH - 2017/03/17 [received] PH - 2017/05/11 [revised] PH - 2017/05/17 [accepted] LG - English EP - 20170527 DP - 2017 Aug DC - 20170529 EZ - 2017/05/30 06:00 DA - 2017/05/30 06:00 DT - 2017/05/30 06:00 YR - 2017 RD - 20170630 UP - 20170630 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28554108 <385. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28653941 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - van Kooten MJ AU - van den Berg G AU - Glaudemans AWJM AU - Hiltermann TJN AU - Groen HJM AU - Rutgers A AU - Links TP FA - van Kooten, M J FA - van den Berg, G FA - Glaudemans, A W J M FA - Hiltermann, T J N FA - Groen, H J M FA - Rutgers, A FA - Links, T P IN - van Kooten, M J. Department of Endocrinology, University of Groningen, University Medical CenterGroningen, Groningen, the Netherlands. TI - Transient thyrotoxicosis during nivolumab treatment. SO - Netherlands Journal of Medicine. 75(5):204-207, 2017 Jun AS - Neth J Med. 75(5):204-207, 2017 Jun NJ - The Netherlands journal of medicine PI - Journal available in: Print PI - Citation processed from: Internet JC - nwy, 0356133 IO - Neth J Med CP - Netherlands AB - Two patients presented with transient thyrotoxicosis within 2-4 weeks after starting treatment with nivolumab. This thyrotoxicosis turned into hypothyroidism within 6-8 weeks. Temporary treatment with a beta blocker may be sufficient. ES - 1872-9061 IL - 0300-2977 PT - Journal Article PP - ppublish LG - English DP - 2017 Jun DC - 20170627 EZ - 2017/06/28 06:00 DA - 2017/06/28 06:00 DT - 2017/06/28 06:00 YR - 2017 RD - 20170627 UP - 20170628 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28653941 <386. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28489679 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Yildirim S AU - Deniz K AU - Dogan E AU - Baskol M AU - Gursoy S AU - Ozkan M FA - Yildirim, Sumeyra FA - Deniz, Kemal FA - Dogan, Ender FA - Baskol, Mevlut FA - Gursoy, Sebnem FA - Ozkan, Metin IN - Yildirim, Sumeyra. Departments of aGastroenterology bPathology cOncology, Erciyes University, Kayseri, Turkey. TI - Ipilimumab-associated cholestatic hepatitis: a case report and literature review. SO - Melanoma Research. 27(4):380-382, 2017 Aug AS - Melanoma Res. 27(4):380-382, 2017 Aug NJ - Melanoma research PI - Journal available in: Print PI - Citation processed from: Internet JC - bjr, 9109623 IO - Melanoma Res. CP - England AB - Ipilimumab is a monoclonal antibody that exerts its effects by inhibiting the cytotoxic T-lymphocyte-associated protein 4 receptor on cytotoxic T lymphocytes. It is frequently used for the treatment of unresectable or metastatic melanoma. Ipilimumab may lead to several immune-related disease including colitis, thyroiditis, pneumonia, hepatitis, or pancreatitis as a side effect. Limited number of cases with hepatic damage as an ipilimumab-related adverse event has been reported in the literature. This agent has been implicated in causing acute hepatitis-like liver injury. Here, we presented a case in which cholestatic hepatitis developed during ipilimumab use for the treatment of metastatic melanoma. ES - 1473-5636 IL - 0960-8931 DO - https://dx.doi.org/10.1097/CMR.0000000000000366 PT - Journal Article ID - 10.1097/CMR.0000000000000366 [doi] PP - ppublish LG - English DP - 2017 Aug DC - 20170510 EZ - 2017/05/11 06:00 DA - 2017/05/11 06:00 DT - 2017/05/11 06:00 YR - 2017 RD - 20170627 UP - 20170628 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28489679 <387. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28434648 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - El-Khoueiry AB AU - Sangro B AU - Yau T AU - Crocenzi TS AU - Kudo M AU - Hsu C AU - Kim TY AU - Choo SP AU - Trojan J AU - Welling TH Rd AU - Meyer T AU - Kang YK AU - Yeo W AU - Chopra A AU - Anderson J AU - Dela Cruz C AU - Lang L AU - Neely J AU - Tang H AU - Dastani HB AU - Melero I FA - El-Khoueiry, Anthony B FA - Sangro, Bruno FA - Yau, Thomas FA - Crocenzi, Todd S FA - Kudo, Masatoshi FA - Hsu, Chiun FA - Kim, Tae-You FA - Choo, Su-Pin FA - Trojan, Jorg FA - Welling, Theodore H Rd FA - Meyer, Tim FA - Kang, Yoon-Koo FA - Yeo, Winnie FA - Chopra, Akhil FA - Anderson, Jeffrey FA - Dela Cruz, Christine FA - Lang, Lixin FA - Neely, Jaclyn FA - Tang, Hao FA - Dastani, Homa B FA - Melero, Ignacio IN - El-Khoueiry, Anthony B. USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA. Electronic address: elkhouei@med.usc.edu. IN - Sangro, Bruno. Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain. IN - Yau, Thomas. University of Hong Kong, Hong Kong Special Administrative Region, China. IN - Crocenzi, Todd S. Providence Cancer Center, Portland, OR, USA. IN - Kudo, Masatoshi. Kindai University Faculty of Medicine, Osaka, Japan. IN - Hsu, Chiun. National Taiwan University Hospital, Taipei, Taiwan. IN - Kim, Tae-You. Seoul National University Hospital, Seoul, South Korea. IN - Choo, Su-Pin. National Cancer Center, Singapore. IN - Trojan, Jorg. Goethe University Hospital and Cancer Center, Frankfurt, Germany. IN - Welling, Theodore H Rd. University of Michigan School of Medicine, Ann Arbor, MI, USA. IN - Meyer, Tim. Royal Free Hospital, London, UK. IN - Kang, Yoon-Koo. Asan Medical Center, University of Ulsan, Seoul, South Korea. IN - Yeo, Winnie. Chinese University of Hong Kong, Hong Kong Special Administrative Region, China. IN - Chopra, Akhil. Johns Hopkins Singapore International Medical Centre, Singapore. IN - Anderson, Jeffrey. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Dela Cruz, Christine. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Lang, Lixin. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Neely, Jaclyn. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Tang, Hao. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Dastani, Homa B. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Melero, Ignacio. Biomedical Research Network in Oncology (CIBERONC), Pamplona, Spain; Center for Applied Medical Research (CIMA), Pamplona, Spain. TI - Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. SO - Lancet. 389(10088):2492-2502, 2017 Jun 24 AS - Lancet. 389(10088):2492-2502, 2017 Jun 24 NJ - Lancet (London, England) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 2985213r, l0s, 0053266 IO - Lancet CP - England AB - BACKGROUND: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. AB - METHODS: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (>=18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. AB - FINDINGS: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. AB - INTERPRETATION: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. AB - FUNDING: Bristol-Myers Squibb. Copyright © 2017 Elsevier Ltd. All rights reserved. ES - 1474-547X IL - 0140-6736 DI - S0140-6736(17)31046-2 DO - https://dx.doi.org/10.1016/S0140-6736(17)31046-2 PT - Journal Article ID - S0140-6736(17)31046-2 [pii] ID - 10.1016/S0140-6736(17)31046-2 [doi] PP - ppublish PH - 2016/11/23 [received] PH - 2017/02/17 [revised] PH - 2017/02/23 [accepted] LG - English EP - 20170420 DP - 2017 Jun 24 DC - 20170424 EZ - 2017/04/25 06:00 DA - 2017/04/25 06:00 DT - 2017/04/25 06:00 YR - 2017 RD - 20170628 UP - 20170628 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28434648 <388. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28419059 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Diamantopoulos PT AU - Gaggadi M AU - Kassi E AU - Benopoulou O AU - Anastasopoulou A AU - Gogas H FA - Diamantopoulos, Panagiotis T FA - Gaggadi, Maria FA - Kassi, Eva FA - Benopoulou, Olga FA - Anastasopoulou, Amalia FA - Gogas, Helen IN - Diamantopoulos, Panagiotis T. aFirst Department of Internal Medicine, National and Kapodistrian University of Athens bDepartment of Pneumology, Laikon General Hospital, Athens, Greece. TI - Late-onset nivolumab-mediated pneumonitis in a patient with melanoma and multiple immune-related adverse events. SO - Melanoma Research. 27(4):391-395, 2017 Aug AS - Melanoma Res. 27(4):391-395, 2017 Aug NJ - Melanoma research PI - Journal available in: Print PI - Citation processed from: Internet JC - bjr, 9109623 IO - Melanoma Res. CP - England AB - Immune-related adverse effects (AEs) of PD-1 inhibitors can affect almost every organ, but the skin, intestine, lung, eye, and liver are the most commonly affected organs. Here, we present the case of a 62-year-old female patient with stage IIIc melanoma treated with nivolumab in an adjuvant setting who sequentially developed hyperthyroidism, hypothyroidism, acute hepatitis, and pneumonitis. Six months before the emergence of pneumonitis, the patient had discontinued treatment with nivolumab because of acute hepatitis. Information on pneumonitis after nivolumab discontinuation in the literature is scarce, whereas most of the cases emerge during the first 2.5 months of treatment. Patients with multiple immune-related AEs comprise a group of special interest as the identification of factors affecting the susceptibility of patients to immune-related AEs of PD-1 inhibitors may lead to a more rational use of these drugs. Human leukocyte antigen haplotype and Fcgamma receptor polymorphisms are possible targets of the relevant research. ES - 1473-5636 IL - 0960-8931 DO - https://dx.doi.org/10.1097/CMR.0000000000000355 PT - Journal Article ID - 10.1097/CMR.0000000000000355 [doi] PP - ppublish LG - English DP - 2017 Aug DC - 20170418 EZ - 2017/04/19 06:00 DA - 2017/04/19 06:00 DT - 2017/04/19 06:00 YR - 2017 RD - 20170627 UP - 20170628 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28419059 <389. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28363614 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Win MA AU - Thein KZ AU - Qdaisat A AU - Yeung SJ FA - Win, Myint Aung FA - Thein, Kyaw Zin FA - Qdaisat, Aiham FA - Yeung, Sai-Ching Jim IN - Win, Myint Aung. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. IN - Thein, Kyaw Zin. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Hematology Oncology, Texas Tech University Health Sciences Center, Lubbock, TX, United States. IN - Qdaisat, Aiham. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. IN - Yeung, Sai-Ching Jim. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address: syeung@mdanderson.org. TI - Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. SO - American Journal of Emergency Medicine. 35(7):1039.e5-1039.e7, 2017 Jul AS - Am J Emerg Med. 35(7):1039.e5-1039.e7, 2017 Jul NJ - The American journal of emergency medicine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - aa2, 8309942 IO - Am J Emerg Med CP - United States KW - Hypocalcemia; Hypoparathyroidism; Ipilimumab; Melanoma; Nivolumab; Thyroiditis AB - BACKGROUND: Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia. AB - CASE DESCRIPTION: A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia. AB - CONCLUSIONS: Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology. Copyright © 2017 Elsevier Inc. All rights reserved. ES - 1532-8171 IL - 0735-6757 DI - S0735-6757(17)30161-4 DO - https://dx.doi.org/10.1016/j.ajem.2017.02.048 PT - Journal Article ID - S0735-6757(17)30161-4 [pii] ID - 10.1016/j.ajem.2017.02.048 [doi] PP - ppublish PH - 2017/02/10 [received] PH - 2017/02/25 [accepted] LG - English EP - 20170227 DP - 2017 Jul DC - 20170401 EZ - 2017/04/02 06:00 DA - 2017/04/02 06:00 DT - 2017/04/02 06:00 YR - 2017 RD - 20170626 UP - 20170626 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28363614 <390. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28643173 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Lehman JM AU - Gwin ME AU - Massion PP FA - Lehman, Jonathan M FA - Gwin, Mary E FA - Massion, Pierre P IN - Lehman, Jonathan M. Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, 37232, USA. IN - Gwin, Mary E. Vanderbilt University, PMB 353746, 2301 Vanderbilt Place, Nashville, TN, 37235, USA. IN - Massion, Pierre P. Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building, 640, Nashville, TN, USA. pierre.massion@vanderbilt.edu. IN - Massion, Pierre P. Cancer Early Detection and Prevention Initiative, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN, 37232, USA. pierre.massion@vanderbilt.edu. IN - Massion, Pierre P. US Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue South, Nashville, TN, 37212, USA. pierre.massion@vanderbilt.edu. TI - Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope. [Review] SO - Current Oncology Reports. 19(7):49, 2017 Jul AS - Curr Oncol Rep. 19(7):49, 2017 Jul NJ - Current oncology reports PI - Journal available in: Print PI - Citation processed from: Internet JC - 100888967, dyp IO - Curr Oncol Rep CP - United States KW - Antibody drug conjugates; BCL2; CTLA4; Immunotherapy; PARP inhibitor; PDL1; Peptide receptor radionuclide therapy; Small cell lung cancer AB - Small cell lung cancer (SCLC) is a devastating and aggressive neuroendocrine carcinoma of the lung. It accounts for ~15% of lung cancer mortality and has had no improvement in standard treatment options for nearly 30 years. However, there is now hope for change with new therapies and modalities of therapy. Immunotherapies and checkpoint inhibitors are entering clinical practice, selected targeted therapies show promise, and "smart bomb"-based drug/radioconjugates have led to good response in early clinical trials. Additionally, new research insights into the genetics and tumor heterogeneity of SCLC alongside the availability of new tools such as patient-derived or circulating tumor cell xenografts offer the potential to shine light on this beshadowed cancer. ES - 1534-6269 IL - 1523-3790 DI - 10.1007/s11912-017-0609-2 DO - https://dx.doi.org/10.1007/s11912-017-0609-2 PT - Journal Article PT - Review ID - 10.1007/s11912-017-0609-2 [doi] ID - 10.1007/s11912-017-0609-2 [pii] PP - ppublish LG - English DP - 2017 Jul DC - 20170623 EZ - 2017/06/24 06:00 DA - 2017/06/24 06:00 DT - 2017/06/24 06:00 YR - 2017 RD - 20170623 UP - 20170626 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28643173 <391. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28550027 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Sharabi A AU - Kim SS AU - Kato S AU - Sanders PD AU - Patel SP AU - Sanghvi P AU - Weihe E AU - Kurzrock R FA - Sharabi, Andrew FA - Kim, Sangwoo Shawn FA - Kato, Shumei FA - Sanders, Philip D FA - Patel, Sandip Pravin FA - Sanghvi, Parag FA - Weihe, Elizabeth FA - Kurzrock, Razelle IN - Sharabi, Andrew. Department of Radiation Medicine and Applied Sciences, UC San Diego Moores Cancer Center, San Diego, California, USA sharabi@ucsd.edu. IN - Kim, Sangwoo Shawn. School of Medicine, University of California San Diego, California, USA. IN - Kato, Shumei. Division of Hematology & Oncology and Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, San Diego, California, USA. IN - Sanders, Philip D. Department of Radiation Medicine and Applied Sciences, UC San Diego Moores Cancer Center, San Diego, California, USA. IN - Patel, Sandip Pravin. Division of Hematology & Oncology and Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, San Diego, California, USA. IN - Sanghvi, Parag. Department of Radiation Medicine and Applied Sciences, UC San Diego Moores Cancer Center, San Diego, California, USA. IN - Weihe, Elizabeth. Department of Radiology, University of California San Diego, California, USA. IN - Kurzrock, Razelle. Division of Hematology & Oncology and Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, San Diego, California, USA. TI - Exceptional Response to Nivolumab and Stereotactic Body Radiation Therapy (SBRT) in Neuroendocrine Cervical Carcinoma with High Tumor Mutational Burden: Management Considerations from the Center For Personalized Cancer Therapy at UC San Diego Moores Cancer Center. SO - Oncologist. 22(6):631-637, 2017 Jun AS - Oncologist. 22(6):631-637, 2017 Jun NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist CP - United States AB - Neuroendocrine carcinoma of the cervix is an ultra-rare malignancy with a poor prognosis and limited treatment options. Checkpoint blockade immunotherapy has rapidly developed into an emerging standard of care for several common disease types. Interestingly, in preclinical and retrospective clinical data, radiation therapy has been demonstrated to synergize with checkpoint inhibitors. Here we report a patient with metastatic, chemotherapy-refractory neuroendocrine carcinoma who presented with partial bowel obstruction due to a large tumor burden. Genomic analysis demonstrated a high number of alterations on liquid biopsy (circulating tumor DNA [ctDNA]), which prompted treatment with stereotactic body radiation therapy (SBRT) combined with anti-programmed cell death protein 1 antibody. Tissue rebiopsy and comprehensive genomic profiling confirmed high tumor mutational burden and a mismatch repair gene defect. The patient manifested near-complete systemic resolution of disease, ongoing at 10+ months. We discuss the novel treatment modality of SBRT combined with a checkpoint inhibitor and the implications of molecular profiling and tumor mutational burden as potential predictors of response. AB - KEY POINTS: High-grade, large-cell neuroendocrine carcinoma of the cervix is an ultra-rare malignancy that carries a grim prognosis.Next-generation sequencing may reveal key mutations in MSH2 genes amongst others. MSH2 mutations target the DNA mismatch repair process and can predispose patients to malignancies with high mutational burdens.Immunotherapy combined with radiation therapy can elicit a significant response, both within and outside the field of radiation. The latter is termed the "abscopal" effect, perhaps mediated by radiation-induced cross presentation of tumor antigens resulting in immune activation.Sequencing of blood-derived ctDNA showed a high number of alterations, and tissue sequencing confirmed a high tumor mutational burden as a consequence of a mismatch repair gene defect. This observation led to a therapeutic "match" with an anti- programmed cell death protein 1 antibody combined with SBRT, resulting in a durable (10+ months), near-complete remission in a patient with advanced chemotherapy-refractory disease. AB - Copyright © AlphaMed Press 2017. CI - Disclosures of potential conflicts of interest may be found at the end of this article. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2016-0517 DO - https://dx.doi.org/10.1634/theoncologist.2016-0517 PT - Journal Article ID - theoncologist.2016-0517 [pii] ID - 10.1634/theoncologist.2016-0517 [doi] ID - PMC5469598 [pmc] PP - ppublish PH - 2016/12/28 [received] PH - 2017/03/20 [accepted] PH - 2017/12/01 [pmc-release] GI - No: P30 CA016672 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20170526 DP - 2017 Jun DC - 20170527 EZ - 2017/05/28 06:00 DA - 2017/05/28 06:00 DT - 2017/05/28 06:00 YR - 2017 RD - 20170621 UP - 20170621 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28550027 <392. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28625622 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Tsuruoka K AU - Horinouchi H AU - Goto Y AU - Kanda S AU - Fujiwara Y AU - Nokihara H AU - Yamamoto N AU - Asakura K AU - Nakagawa K AU - Sakurai H AU - Watanabe SI AU - Tsuta K AU - Ohe Y FA - Tsuruoka, Kenjiro FA - Horinouchi, Hidehito FA - Goto, Yasushi FA - Kanda, Shintaro FA - Fujiwara, Yutaka FA - Nokihara, Hiroshi FA - Yamamoto, Noboru FA - Asakura, Keisuke FA - Nakagawa, Kazuo FA - Sakurai, Hiroyuki FA - Watanabe, Shun-Ichi FA - Tsuta, Koji FA - Ohe, Yuichiro IN - Tsuruoka, Kenjiro. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Horinouchi, Hidehito. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: hhoriou@ncc.go.jp. IN - Goto, Yasushi. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Kanda, Shintaro. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Fujiwara, Yutaka. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Nokihara, Hiroshi. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Yamamoto, Noboru. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Asakura, Keisuke. Division of Thoracic Surgery, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Nakagawa, Kazuo. Division of Thoracic Surgery, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Sakurai, Hiroyuki. Division of Thoracic Surgery, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Watanabe, Shun-Ichi. Division of Thoracic Surgery, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. IN - Tsuta, Koji. Division of Pathology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan; Department of Pathology and Laboratory Medicine, Kansai Medical University, Shinmachi 2-3-1, Hirakata, Osaka 573-1191, Japan. IN - Ohe, Yuichiro. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. TI - PD-L1 expression in neuroendocrine tumors of the lung. SO - Lung Cancer. 108:115-120, 2017 Jun AS - Lung Cancer. 108:115-120, 2017 Jun NJ - Lung cancer (Amsterdam, Netherlands) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - b3u, 8800805 IO - Lung Cancer CP - Ireland KW - Carcinoid; Clone E1L3N; Immunohistochemistry; LCNEC; Neuroendocrine; PD-1; PD-L1; Small cell lung cancer AB - BACKGROUND: Various tumors express programmed cell death ligand 1 (PD-L1), an immune checkpoint ligand, the expression of which correlates with certain effects of anti-programmed cell death 1 (PD-1)/PD-L1 drugs. The aim of this study was to assess the frequency of PD-L1 expression in each of the types of neuroendocrine tumors of the lung. AB - METHODS: The subjects enrolled in this study were patients who had been diagnosed with neuroendocrine tumors of the lung and had been treated at the National Cancer Center Hospital (Tokyo, Japan) between 1982 and 2010. We performed immunohistochemical analysis on a tissue microarray (TMA) of the surgical specimens using the validated PD-L1 antibody clone, E1L3N. Tumor PD-L1 expression scores were calculated semiquantitatively (staining intensity [0-3]xstained area [0-100%]). A score of 1 was used as a cut-off to determine the presence or absence of PD-L1 expression. AB - RESULTS: Among the 227 patients included in this study, the patient demographics were as follows: median age (range), 65 years (19-84); sex (male/female), 168/59; pStage (IA, IB, IIA, IIB, IIIA, IIIB, IV): 79, 36, 25, 29, 47, 6, 5, respectively; and histology was typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), small cell lung cancer (SCLC): 46, 6, 106, 69, respectively. The numbers (proportions) of PD-L1-expression tumors were as follows: TC/AC/LCNEC/SCLC, 0/0/11 (10.4%)/4 (5.8%). AB - CONCLUSIONS: PD-L1 expression was apparent in 10.4% of LCNEC and 5.8% of SCLC tumors, and was not observed in carcinoid tumors. AB - Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved. ES - 1872-8332 IL - 0169-5002 DI - S0169-5002(17)30260-X DO - https://dx.doi.org/10.1016/j.lungcan.2017.03.006 PT - Journal Article ID - S0169-5002(17)30260-X [pii] ID - 10.1016/j.lungcan.2017.03.006 [doi] PP - ppublish PH - 2017/01/06 [received] PH - 2017/03/11 [revised] PH - 2017/03/14 [accepted] LG - English EP - 20170324 DP - 2017 Jun DC - 20170619 EZ - 2017/06/20 06:00 DA - 2017/06/20 06:00 DT - 2017/06/20 06:00 YR - 2017 RD - 20170619 UP - 20170620 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28625622 <393. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28424325 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Ning YM AU - Suzman D AU - Maher VE AU - Zhang L AU - Tang S AU - Ricks T AU - Palmby T AU - Fu W AU - Liu Q AU - Goldberg KB AU - Kim G AU - Pazdur R FA - Ning, Yang-Min FA - Suzman, Daniel FA - Maher, V Ellen FA - Zhang, Lijun FA - Tang, Shenghui FA - Ricks, Tiffany FA - Palmby, Todd FA - Fu, Wentao FA - Liu, Qi FA - Goldberg, Kirsten B FA - Kim, Geoffrey FA - Pazdur, Richard IN - Ning, Yang-Min. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA ningy@cder.fda.gov. IN - Suzman, Daniel. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Maher, V Ellen. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Zhang, Lijun. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Tang, Shenghui. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Ricks, Tiffany. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Palmby, Todd. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Fu, Wentao. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Liu, Qi. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Goldberg, Kirsten B. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Kim, Geoffrey. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. IN - Pazdur, Richard. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Springs, Maryland, USA. TI - FDA Approval Summary: Atezolizumab for the Treatment of Patients with Progressive Advanced Urothelial Carcinoma after Platinum-Containing Chemotherapy. SO - Oncologist. 22(6):743-749, 2017 Jun AS - Oncologist. 22(6):743-749, 2017 Jun NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist CP - United States KW - Atezolizumab; Bladder cancer; Immunotherapy; Locally advanced or metastatic urothelial carcinoma; Platinum-containing chemotherapy AB - Until recently in the United States, no products were approved for second-line treatment of advanced urothelial carcinoma. On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody and represents the first approved product directed against PD-L1. This accelerated approval was based on results of a single-arm trial in 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression after prior platinum-containing chemotherapy. Patients received atezolizumab 1,200 mg intravenously every 3 weeks until disease progression or unacceptable toxicity. Key efficacy measures were objective response rate (ORR), as assessed by Independent Review per RECIST 1.1, and duration of response (DoR). With a median follow-up of 14.4 months, confirmed ORR was 14.8% (95% CI: 11.1, 19.3) in all treated patients. Median DoR was not reached and response durations ranged from 2.1+ to 13.8+ months. Of the 46 responders, 37 patients had an ongoing response for >=6 months. The most common adverse reactions (>=20%) were fatigue, decreased appetite, nausea, urinary tract infection, pyrexia, and constipation. Infection and immune-related adverse events also occurred, including pneumonitis, hepatitis, colitis, endocrine disorders, and rashes. Overall, the benefit-risk assessment was favorable to support accelerated approval. The observed clinical benefits need to be verified in confirmatory trial(s). AB - IMPLICATIONS FOR PRACTICE: This accelerated approval of atezolizumab for second-line use in advanced urothelial carcinoma provides patients with an effective, novel treatment option for the management of their disease. This represents the first immunotherapy approved in this disease setting. AB - Copyright Published 2017. This article is a U.S. Government work and is in the public domain in the USA. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2017-0087 DO - https://dx.doi.org/10.1634/theoncologist.2017-0087 PT - Journal Article ID - theoncologist.2017-0087 [pii] ID - 10.1634/theoncologist.2017-0087 [doi] ID - PMC5469588 [pmc] PP - ppublish PH - 2017/02/14 [received] PH - 2017/02/16 [accepted] PH - 2018/06/01 [pmc-release] LG - English EP - 20170419 DP - 2017 Jun DC - 20170420 EZ - 2017/04/21 06:00 DA - 2017/04/21 06:00 DT - 2017/04/21 06:00 YR - 2017 RD - 20170620 UP - 20170620 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28424325 <394. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28031819 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Lowe JR AU - Perry DJ AU - Salama AK AU - Mathews CE AU - Moss LG AU - Hanks BA FA - Lowe, Jared R FA - Perry, Daniel J FA - Salama, April K S FA - Mathews, Clayton E FA - Moss, Larry G FA - Hanks, Brent A IN - Lowe, Jared R. Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA. IN - Perry, Daniel J. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610 USA. IN - Salama, April K S. Department of Medicine, Division of Medical Oncology, Melanoma Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710 USA. IN - Mathews, Clayton E. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610 USA. IN - Moss, Larry G. Department of Medicine, Division of Endocrinology, Metabolism, & Nutrition, Duke University Medical Center, Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Durham, NC 27701 USA. IN - Hanks, Brent A. Department of Medicine, Division of Medical Oncology, Melanoma Program, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710 USA. TI - Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. SO - Journal for Immunotherapy of Cancer. 4:89, 2016 AS - J Immunother Cancer. 4:89, 2016 NJ - Journal for immunotherapy of cancer PI - Journal available in: Electronic-eCollection PI - Citation processed from: Internet JC - 101620585 IO - J Immunother Cancer CP - England KW - Advanced melanoma; Autoimmune endocrinopathy; Genetic risk analysis; HLA risk allele; Ipilimumab; Nivolumab; Single nucleotide polymorphism; Type I diabetes AB - BACKGROUND: Checkpoint inhibitor immunotherapy is becoming an effective treatment modality for an increasing number of malignancies. As a result, autoinflammatory side-effects are also being observed more commonly in the clinic. We are currently unable to predict which patients will develop more severe toxicities associated with these treatment regimens. AB - CASE PRESENTATION: We present a patient with stage IV melanoma that developed rapid onset autoimmune type 1 diabetes (T1D) in response to combination ipilimumab and nivolumab immunotherapy. At the time of the patient's presentation with diabetes ketoacidosis, a confirmed anti-GAD antibody seroconversion was noted. Longer-term follow-up of this patient has demonstrated a durable complete response based on PET CT imaging along with a persistently undetectable C-peptide level. Single nucleotide polymorphism gene sequencing and HLA risk allele analysis has revealed the patient to lack any established genetic predisposition to the development of autoimmune T1D. AB - CONCLUSIONS: While larger studies are necessary to better understand the role of genetic risk factors for the development of autoimmune toxicities in those patients undergoing checkpoint inhibitor immunotherapy, these results suggest that pre-screening patients for known T1D risk alleles may not be indicated. Additional investigation is needed to determine whether an approach such as T cell receptor clonotypic analysis to identify the presence of autoreactive T cell clones may be an effective approach for predicting which patients are at risk for the development of autoinflammatory toxicities while undergoing checkpoint inhibitor immunotherapy. ES - 2051-1426 IL - 2051-1426 DI - 196 DO - https://dx.doi.org/10.1186/s40425-016-0196-z PT - Journal Article ID - 10.1186/s40425-016-0196-z [doi] ID - 196 [pii] ID - PMC5170902 [pmc] PP - epublish PH - 2016/08/15 [received] PH - 2016/11/17 [accepted] GI - No: K08 CA191063 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20161220 DP - 2016 DC - 20161229 EZ - 2016/12/30 06:00 DA - 2016/12/30 06:01 DT - 2016/12/30 06:00 YR - 2016 RD - 20170619 UP - 20170619 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28031819 <395. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28407743 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Kroschinsky F AU - Stolzel F AU - von Bonin S AU - Beutel G AU - Kochanek M AU - Kiehl M AU - Schellongowski P AU - Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group FA - Kroschinsky, Frank FA - Stolzel, Friedrich FA - von Bonin, Simone FA - Beutel, Gernot FA - Kochanek, Matthias FA - Kiehl, Michael FA - Schellongowski, Peter FA - Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group IN - Kroschinsky, Frank. Dresden University Hospital, Medical Department I, Fetscherstr. 74, 01307, Dresden, Germany. frank.kroschinsky@uniklinikum-dresden.de. IN - Stolzel, Friedrich. Dresden University Hospital, Medical Department I, Fetscherstr. 74, 01307, Dresden, Germany. IN - von Bonin, Simone. Dresden University Hospital, Medical Department I, Fetscherstr. 74, 01307, Dresden, Germany. IN - Beutel, Gernot. Department for Hematology/Oncology/Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. IN - Kochanek, Matthias. Department I of Internal Medicine, University Hospital Koln, Koln, Germany. IN - Kiehl, Michael. Medical Department I and Stem Cell Transplant Center, Hospital Frankfurt/Oder, Frankfurt/Oder, Germany. IN - Schellongowski, Peter. General Hospital Department of Medicine I, Medical University of Vienna, Vienna, Austria. TI - New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management. [Review] SO - Critical Care (London, England). 21(1):89, 2017 04 14 AS - Crit Care. 21(1):89, 2017 04 14 NJ - Critical care (London, England) PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 9801902 IO - Crit Care CP - England KW - *Cancer; *Immunotherapy; *Interdisciplinary management; *Targeted therapy; *Toxicity AB - Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms. ES - 1466-609X IL - 1364-8535 DI - 10.1186/s13054-017-1678-1 DO - https://dx.doi.org/10.1186/s13054-017-1678-1 PT - Journal Article PT - Review PT - Research Support, Non-U.S. Gov't ID - 10.1186/s13054-017-1678-1 [doi] ID - 10.1186/s13054-017-1678-1 [pii] ID - PMC5391608 [pmc] PP - epublish LG - English EP - 20170414 DP - 2017 04 14 DC - 20170414 EZ - 2017/04/15 06:00 DA - 2017/04/15 06:00 DT - 2017/04/15 06:00 YR - 2017 RD - 20170615 UP - 20170616 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28407743 <396. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28557813 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Leonardi GC AU - Oxnard GR AU - Haas A AU - Lang JP AU - Williams JS AU - Awad MM FA - Leonardi, Giulia C FA - Oxnard, Geoffrey R FA - Haas, Andrea FA - Lang, Joshua P FA - Williams, Jonathan S FA - Awad, Mark M IN - Leonardi, Giulia C. *Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute +Division of Endocrinology, Diabetes and Hypertension ++Department of Medicine, Brigham and Women's Hospital, Boston, MA. TI - Diabetic Ketoacidosis as an Immune-related Adverse Event from Pembrolizumab in Non-Small Cell Lung Cancer. SO - Journal of Immunotherapy. 40(6):249-251, 2017 Jul/Aug AS - J Immunother. 40(6):249-251, 2017 Jul/Aug NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. CP - United States AB - Programmed cell death protein 1 pathway inhibitors are now routinely administered to patients with non-small cell lung cancer, and prompt recognition of immune-related adverse events is critical to managing serious drug toxicities. Here, we describe a 66-year-old man with no known history of diabetes who presented with diabetic ketoacidosis after receiving 3 doses of pembrolizumab for lung adenocarcinoma. Autoimmune diabetes is a rare but potentially life-threatening complication of programmed cell death protein 1 inhibitors. ES - 1537-4513 IL - 1524-9557 DO - https://dx.doi.org/10.1097/CJI.0000000000000173 PT - Journal Article ID - 10.1097/CJI.0000000000000173 [doi] PP - ppublish LG - English DP - 2017 Jul/Aug DC - 20170530 EZ - 2017/05/31 06:00 DA - 2017/05/31 06:00 DT - 2017/05/31 06:00 YR - 2017 RD - 20170613 UP - 20170614 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28557813 <397. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28603207 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Okiyama N AU - Tanaka R FA - Okiyama, Naoko FA - Tanaka, Ryota IN - Okiyama, Naoko. Department of Dermatology, Faculty of Medicine, University of Tsukuba. IN - Tanaka, Ryota. Department of Dermatology, Faculty of Medicine, University of Tsukuba. TI - Varied immuno-related adverse events induced by immune-check point inhibitors - Nivolumab-associated psoriasiform dermatitis related with increased serum level of interleukin-6. SO - Nihon Rinsho Meneki Gakkai Kaishi. 40(2):95-101, 2017 AS - Nihon Rinsho Meneki Gakkai Kaishi. 40(2):95-101, 2017 NJ - Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology PI - Journal available in: Print PI - Citation processed from: Internet JC - ccm, 9505992 IO - Nihon Rinsho Meneki Gakkai Kaishi CP - Japan KW - immuno-related adverse events; interleukin-6; polyradiculoneuropathy; psoriasiform dermatitis; thyroiditis AB - Nivolumab is a standard recombinant antibody treatment for patients with malignant melanoma (MM), which functions as an immune checkpoint inhibitor by blocking the programmed cell death-1 (PD-1) pathway in T cells. However, it leads to various immune-related adverse events (irAEs), and also exacerbates underlying autoimmune diseases. Herein we report cases of MM with irAE. Case 1: A 69-year-old woman with MM developed destructive thyroiditis resulting in hypothyroidism after 3 doses of nivolumab, and had been treated with thyroid gland auxiliary therapy. Case 2: A 80-year-old man with MM developed an acute onset of hyperthyroidism after 4 doses of nivolumab. Case 3: A 85-year-old woman with MM developed polyradiculoneuropathy resulting in somatosensory disorder and muscle weakness after 2 doses of nivolumab, and had been treated with intravenous immunoglobulin and oral predonisolone (40 mg/day). Case 4: A 77-year-old man with MM developed psoriasiform dermatitis after local injections of IFN-beta and 11 doses of nivolumab. Case 5: Case 2 also developed psoriasiform dermatitis. We analyzed serum levels of inflammatory cytokines in MM patients before/after treatments with nivolumab. All six patients who developed psoriasiform dermatitis with/without anamnesis of psoriasis after treatment with nivolumab, and all seven patients with other irAE exhibited increased serum IL-6 levels after nivolumab treatment, while decreased serum levels of IL-6 were observed in 5 of 7 non-afflicted MM patients. In addition, MM patients who achieved good responses to nivolumab significantly exhibited decreased serum TNF-alpha levels after nivolumab treatment compared to progressive MM patients. ES - 1349-7413 IL - 0911-4300 DO - https://dx.doi.org/10.2177/jsci.40.95 PT - Journal Article ID - 10.2177/jsci.40.95 [doi] PP - ppublish LG - English DP - 2017 DC - 20170612 EZ - 2017/06/13 06:00 DA - 2017/06/13 06:00 DT - 2017/06/13 06:00 YR - 2017 RD - 20170612 UP - 20170613 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28603207 <398. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28603206 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Iwama S AU - Arima H FA - Iwama, Shintaro FA - Arima, Hiroshi IN - Iwama, Shintaro. Research Center of Health, Physical Fitness and Sports, Nagoya University. IN - Arima, Hiroshi. Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine. TI - Clinical practice and mechanism of endocrinological adverse events associated with immune checkpoint inhibitors. SO - Nihon Rinsho Meneki Gakkai Kaishi. 40(2):90-94, 2017 AS - Nihon Rinsho Meneki Gakkai Kaishi. 40(2):90-94, 2017 NJ - Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology PI - Journal available in: Print PI - Citation processed from: Internet JC - ccm, 9505992 IO - Nihon Rinsho Meneki Gakkai Kaishi CP - Japan KW - Hypophysitis; hypopituitarism; ipilimumab; nivolumab; pituitary AB - Immune checkpoint inhibitors, used for cancer immunotherapy, show anti-tumor effects through T cell activations. Monoclonal antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death (PD)-1, or PD-ligand 1 which is a ligand of PD-1 have been shown to be effective in the treatments of advanced cancers including malignant melanoma, non-small cell lung cancer, and renal cell carcinoma. However, these drugs also have immune-related adverse events (irAEs). The irAEs, which have unique characteristics different from those seen in conventional cytotoxic anti-tumor medicines, are observed in the several tissues such as skin, gastrointestinal tract, liver, lung, muscle, nerve and endocrine systems. To safely use immune checkpoint inhibitors, it is quite important to understand the characteristics of irAEs and to manage them in clinical practice. In this review, we focus on clinical characteristics and pathogenesis of adverse events in the pituitary gland. ES - 1349-7413 IL - 0911-4300 DO - https://dx.doi.org/10.2177/jsci.40.90 PT - Journal Article ID - 10.2177/jsci.40.90 [doi] PP - ppublish LG - English DP - 2017 DC - 20170612 EZ - 2017/06/13 06:00 DA - 2017/06/13 06:00 DT - 2017/06/13 06:00 YR - 2017 RD - 20170612 UP - 20170613 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28603206 <399. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28603205 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Kadono T FA - Kadono, Takafumi IN - Kadono, Takafumi. Department of Dermatology, St. Marianna University School of Medicine. TI - Immune-related adverse events by immune checkpoint inhibitors. SO - Nihon Rinsho Meneki Gakkai Kaishi. 40(2):83-89, 2017 AS - Nihon Rinsho Meneki Gakkai Kaishi. 40(2):83-89, 2017 NJ - Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology PI - Journal available in: Print PI - Citation processed from: Internet JC - ccm, 9505992 IO - Nihon Rinsho Meneki Gakkai Kaishi CP - Japan KW - immune checkpoint inhibitor; immune-related adverse event; ipilimumab; nivolumab; vitiligo AB - Recent introduction of immune checkpoint inhibitors represented by anti-PD-1 antibodies such as nivolumab and pembrolizumab, and anti-CTLA-4 antibody such as ipilimumab had a great impact on cancer immunotherapy especially for melanoma, non-small cell lung cancer, renal cell carcinoma, and Hodgkin's lymphoma. On the other hand, immune checkpoint inhibitors have their own distinctive adverse events, which are collectively named as "immune-related adverse events". Although immune-related adverse events may occur at any part of the body, interstitial pneumonia, colitis, hypothyroidism, liver dysfunction, skin rash, vitiligo, hypophysitis, type 1 diabetes, renal dysfunction, myasthenia gravis, neuropathy, myositis, and uveitis are representative. The onset of these immune-related adverse events varies. As for ipilimumab, cutaneous and mucous complications appear relatively early, and subsequently digestive symptoms emerge. As for nivolumab, most immune-related adverse events start around a few months after its administration. These immune-related adverse events are basically managed according to the algorism. Prompt consultation to the experts are of great importance and the grade of immune-related adverse events and patients' disease conditions need to be carefully evaluated to decide the optimal measures. As immune-related adverse events could affect various organs, cooperation with many experts from various fields is critical and it is important to organize a cooperative system within a hospital. ES - 1349-7413 IL - 0911-4300 DO - https://dx.doi.org/10.2177/jsci.40.83 PT - Journal Article ID - 10.2177/jsci.40.83 [doi] PP - ppublish LG - English DP - 2017 DC - 20170612 EZ - 2017/06/13 06:00 DA - 2017/06/13 06:00 DT - 2017/06/13 06:00 YR - 2017 RD - 20170612 UP - 20170613 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28603205 <400. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28595520 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Araujo M AU - Ligeiro D AU - Costa L AU - Marques F AU - Trindade H AU - Correia JM AU - Fonseca C FA - Araujo, Manuel FA - Ligeiro, Dario FA - Costa, Luis FA - Marques, Filipa FA - Trindade, Helder FA - Correia, Jose Manuel FA - Fonseca, Candida IN - Araujo, Manuel. Internal Medicine Department & Hospital Dia, Hospital Sao Francisco Xavier - Centro Hospitalar de Lisboa Ocidental, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal. IN - Ligeiro, Dario. Immunogenetics Laboratory - Centro de Sangue e Transplantacao de Lisboa, Instituto Portugues de Sangue e Transplantacao, IP, Lisbon, Portugal. IN - Costa, Luis. Internal Medicine Department & Hospital Dia, Hospital Sao Francisco Xavier - Centro Hospitalar de Lisboa Ocidental, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal. IN - Marques, Filipa. Internal Medicine Department & Hospital Dia, Hospital Sao Francisco Xavier - Centro Hospitalar de Lisboa Ocidental, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal. IN - Trindade, Helder. Immunogenetics Laboratory - Centro de Sangue e Transplantacao de Lisboa, Instituto Portugues de Sangue e Transplantacao, IP, Lisbon, Portugal. IN - Correia, Jose Manuel. Pneumology Department, Hospital Egas Moniz - Centro Hospitalar de Lisboa Ocidental, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal. IN - Fonseca, Candida. Internal Medicine Department & Hospital Dia, Hospital Sao Francisco Xavier - Centro Hospitalar de Lisboa Ocidental, NOVA Medical School, Faculdade de Ciencias Medicas, Universidade Nova de Lisboa, Lisbon, Portugal. TI - A case of fulminant Type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient. SO - Immunotherapy. 9(7):531-535, 2017 Jun AS - Immunotherapy. 9(7):531-535, 2017 Jun NJ - Immunotherapy PI - Journal available in: Print PI - Citation processed from: Internet JC - 101485158 IO - Immunotherapy CP - England AB - Programmed cell death-1 protein (PD-1) is an immune checkpoint that has gained popularity in the treatment of several advanced cancers. Inhibiting this checkpoint is known to enhance immune response, but is also known to diminish immune tolerance and to increase autoimmune toxicity. We discuss a case of rapid onset fulminant Type 1 diabetes induced by treatment with anti-programmed cell death-1 monoclonal antibody, nivolumab, in a patient with late-stage non-small-cell lung adenocarcinoma. The patient had no history of previous diabetes but did reveal a high-risk genotype for Type 1 diabetes development (DR3-DQ2; DR4-DQ8). This finding supports that acute Type 1 diabetes can be an important adverse effect of immunotherapies targeting T-cell activation regulation. Because of the severity of this adverse effect, physicians should be aware of it, and studies directed to the detection of new biomarkers for early risk stratification (e.g., HLA) should be sought. ES - 1750-7448 IL - 1750-743X DO - https://dx.doi.org/10.2217/imt-2017-0020 PT - Journal Article ID - 10.2217/imt-2017-0020 [doi] PP - ppublish LG - English DP - 2017 Jun DC - 20170609 EZ - 2017/06/10 06:00 DA - 2017/06/10 06:00 DT - 2017/06/10 06:00 YR - 2017 RD - 20170609 UP - 20170612 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28595520 <401. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28228726 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Kumar V AU - Chaudhary N AU - Garg M AU - Floudas CS AU - Soni P AU - Chandra AB FA - Kumar, Vivek FA - Chaudhary, Neha FA - Garg, Mohit FA - Floudas, Charalampos S FA - Soni, Parita FA - Chandra, Abhinav B IN - Kumar, Vivek. Department of Medicine, Maimonides Medical Center Brooklyn, NY, USA. IN - Chaudhary, Neha. Department of Pediatrics, Maimonides Medical Center Brooklyn, NY, USA. IN - Garg, Mohit. Department of Medicine, Maimonides Medical Center Brooklyn, NY, USA. IN - Floudas, Charalampos S. Department of Medicine, Maimonides Medical Center Brooklyn, NY, USA. IN - Soni, Parita. Department of Medicine, Maimonides Medical Center Brooklyn, NY, USA. IN - Chandra, Abhinav B. Medical Director, Yuma Regional Cancer Center Yuma, AZ, USA. TI - Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. [Review][Erratum appears in Front Pharmacol. 2017 May 31;8:311; PMID: 28579959] SO - Frontiers in Pharmacology. 8:49, 2017 AS - Front Pharmacol. 8:49, 2017 NJ - Frontiers in pharmacology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101548923 IO - Front Pharmacol CP - Switzerland KW - *checkpoint blockade; *immune related adverse events; *ipilimumab; *irAEs; *nivolumab; *pembrolizumab AB - The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agent like atezolimumab for use in patients with advanced stage urothelial carcinoma. More frequent use of ICIs has improved our understanding of their unique side effects, which are known as immune-related adverse events (irAEs). The spectrum of irAEs has expanded beyond more common manifestations such as dermatological, gastrointestinal and endocrine effects to rarer presentations involving nervous, hematopoietic and urinary systems. There are new safety data accumulating on ICIs in patients with previously diagnosed autoimmune conditions. It is challenging for clinicians to continuously update their working knowledge to diagnose and manage these events successfully. If diagnosed timely, the majority of events are completely reversible, and temporary immunosuppression with glucocorticoids, infliximab or other agents is warranted only in the most severe grade illnesses. The same principles of management will possibly apply as newer anti- cytotoxic T lymphocytes-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1/PD-L1) antibodies are introduced. The current focus of research is for prophylaxis and for biomarkers to predict the onset of these toxicities. In this review we summarize the irAEs of ICIs and emphasize their growing spectrum and their management algorithms, to update oncology practitioners. IL - 1663-9812 DO - https://dx.doi.org/10.3389/fphar.2017.00049 PT - Journal Article PT - Review ID - 10.3389/fphar.2017.00049 [doi] ID - PMC5296331 [pmc] PP - epublish PH - 2016/08/16 [received] PH - 2017/01/23 [accepted] LG - English EP - 20170208 DP - 2017 DC - 20170223 EZ - 2017/02/24 06:00 DA - 2017/02/24 06:00 DT - 2017/02/24 06:00 YR - 2017 RD - 20170609 UP - 20170609 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28228726 <402. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27943234 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Zarbo A AU - Belum VR AU - Sibaud V AU - Oudard S AU - Postow MA AU - Hsieh JJ AU - Motzer RJ AU - Busam KJ AU - Lacouture ME AI - Zarbo, A; ORCID: http://orcid.org/0000-0002-2256-7492 AI - Belum, V R; ORCID: http://orcid.org/0000-0003-3628-3412 FA - Zarbo, A FA - Belum, V R FA - Sibaud, V FA - Oudard, S FA - Postow, M A FA - Hsieh, J J FA - Motzer, R J FA - Busam, K J FA - Lacouture, M E IN - Zarbo, A. Department of Dermatology and Transitional Year Program, Henry Ford Hospital, Detroit, MI, 48202, U.S.A. IN - Belum, V R. Department of Dermatology Service, Memorial Sloan Kettering Cancer Center, 60th Street Outpatient Center, Suite 407, Room 4315 16 East 60th Street, New York, NY, 10022, U.S.A. IN - Sibaud, V. Department of Oncodermatology, Institut Universitaire du Cancer, Toulouse Oncopole, Toulouse, 31100, France. IN - Oudard, S. Department of Medical Oncology, Hopital Europeen Georges Pompidou, Assistance Publique Hopitaux de Paris, 75015, France. IN - Postow, M A. Melanoma & Immunotherapeutics Service, Weill Cornell Medical College, New York, NY, U.S.A. IN - Hsieh, J J. Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, 60th Street Outpatient Center, Suite 407, Room 4315 16 East 60th Street, New York, NY, 10022, U.S.A. IN - Motzer, R J. Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, 60th Street Outpatient Center, Suite 407, Room 4315 16 East 60th Street, New York, NY, 10022, U.S.A. IN - Busam, K J. Department of Pathology, Memorial Sloan Kettering Cancer Center, 60th Street Outpatient Center, Suite 407, Room 4315 16 East 60th Street, New York, NY, 10022, U.S.A. IN - Lacouture, M E. Department of Dermatology Service, Memorial Sloan Kettering Cancer Center, 60th Street Outpatient Center, Suite 407, Room 4315 16 East 60th Street, New York, NY, 10022, U.S.A. TI - Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors. SO - British Journal of Dermatology. 176(6):1649-1652, 2017 Jun AS - Br J Dermatol. 176(6):1649-1652, 2017 Jun NJ - The British journal of dermatology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - aw0, 0004041 IO - Br. J. Dermatol. CP - England AB - Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint inhibitors), are used to treat various malignancies. Their mechanism of action involves the inhibition of negative regulators of immune activation, resulting in immune-related adverse events (irAEs) including endocrinopathies, pneumonitis, colitis, hepatitis and dermatological events. Dermatological irAEs include maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia secondary to immune checkpoint inhibitors has been reported in 1.0-2.0% of treated patients. Our objective is to characterize for the first time the clinicopathology of patients with alopecia areata (AA) secondary to immune checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced AA, and review of the literature. Four cases of patients who developed partial or complete alopecia during treatment with immune checkpoint inhibitors for underlying cancer were identified from our clinics. Methods include the review of the history and clinicopathologic features. Three patients (75%) had AA and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy. This report describes a series of four patients who developed partial or complete alopecia (i.e. areata and universalis) during treatment with immune checkpoint inhibitor therapies for cancer. The recognition and management of hair-related irAEs are important for pretherapy counselling and interventions that contribute to maintaining optimal health-related quality of life in patients. AB - Copyright © 2016 British Association of Dermatologists. ES - 1365-2133 IL - 0007-0963 DO - https://dx.doi.org/10.1111/bjd.15237 PT - Case Reports ID - 10.1111/bjd.15237 [doi] ID - PMC5459625 [pmc] ID - NIHMS836795 [mid] PP - ppublish PH - 2016/12/02 [accepted] PH - 2018/06/01 [pmc-release] GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20170424 DP - 2017 Jun DC - 20161212 EZ - 2016/12/13 06:00 DA - 2016/12/13 06:00 DT - 2016/12/13 06:00 YR - 2017 RD - 20170607 UP - 20170609 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27943234 <403. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27442441 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Yu D AU - Leja-Jarblad J AU - Loskog A AU - Hellman P AU - Giandomenico V AU - Oberg K AU - Essand M FA - Yu, Di FA - Leja-Jarblad, Justyna FA - Loskog, Angelica FA - Hellman, Per FA - Giandomenico, Valeria FA - Oberg, Kjell FA - Essand, Magnus IN - Yu, Di. Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. TI - Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for Treatment of Liver Metastases from Neuroendocrine Cancer. SO - Neuroendocrinology. 105(1):54-66, 2017 AS - Neuroendocrinology. 105(1):54-66, 2017 NJ - Neuroendocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ny8, 0035665 IO - Neuroendocrinology CP - Switzerland KW - AdVince; Immunotherapy; Liver metastases; Neuroendocrine cancer; Oncolytic adenovirus AB - Cancer immunotherapy is becoming a cornerstone in the clinical care of cancer patients due to the breakthrough trials with immune checkpoint blockade antibodies and chimeric antigen receptor T cells. The next breakthrough in cancer immunotherapy is likely to be oncolytic viruses engineered to selectively kill tumor cells and deceive the immune system to believe that the tumor is a foreign entity that needs to be eradicated. We have developed AdVince, an oncolytic adenovirus for treatment of liver metastases from neuroendocrine tumor (NET). AdVince includes the gene promoter from human chromogranin A for selective replication in neuroendocrine cells, miR122 target sequences for reduced liver toxicity, and a cell-penetrating peptide in the capsid for increased infectivity of tumor cells and optimized spread within tumors. This paper describes the preclinical evaluation of AdVince on freshly isolated human gastrointestinal NET cells resected from liver metastases and freshly isolated human hepatocytes as well as in fresh human blood. AdVince selectively replicates in and kills NET cells. Approximately 73-fold higher concentration of AdVince is needed to induce a similar level of cytotoxicity in NET cells as in hepatocytes. AdVince did not activate complement or induce considerable amount of proinflammatory cytokines or chemokines in human blood. The data presented herein indicate that AdVince can be safely evaluated in a phase I/IIa clinical trial for patients with liver-dominant NET. AB - Copyright © 2016 S. Karger AG, Basel. ES - 1423-0194 IL - 0028-3835 DI - 000448430 DO - https://dx.doi.org/10.1159/000448430 PT - Journal Article ID - 000448430 [pii] ID - 10.1159/000448430 [doi] PP - ppublish PH - 2016/03/14 [received] PH - 2016/07/17 [accepted] LG - English EP - 20160721 DP - 2017 DC - 20160721 EZ - 2016/07/22 06:00 DA - 2016/07/22 06:00 DT - 2016/07/22 06:00 YR - 2017 RD - 20170606 UP - 20170608 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27442441 <404. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28267244 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Maruyama D AU - Hatake K AU - Kinoshita T AU - Fukuhara N AU - Choi I AU - Taniwaki M AU - Ando K AU - Terui Y AU - Higuchi Y AU - Onishi Y AU - Abe Y AU - Kobayashi T AU - Shirasugi Y AU - Tobinai K AI - Maruyama, Dai; ORCID: http://orcid.org/0000-0003-0654-6920 FA - Maruyama, Dai FA - Hatake, Kiyohiko FA - Kinoshita, Tomohiro FA - Fukuhara, Noriko FA - Choi, Ilseung FA - Taniwaki, Masafumi FA - Ando, Kiyoshi FA - Terui, Yasuhito FA - Higuchi, Yusuke FA - Onishi, Yasushi FA - Abe, Yasunobu FA - Kobayashi, Tsutomu FA - Shirasugi, Yukari FA - Tobinai, Kensei IN - Maruyama, Dai. Department of Hematology, National Cancer Center Hospital, Tokyo, Japan. IN - Hatake, Kiyohiko. Department of Hematology and Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. IN - Kinoshita, Tomohiro. Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan. IN - Fukuhara, Noriko. Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan. IN - Choi, Ilseung. Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. IN - Taniwaki, Masafumi. Department of Hematology and Oncology, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan. IN - Ando, Kiyoshi. Department of Hematology and Oncology, Tokai University, Isehara, Japan. IN - Terui, Yasuhito. Department of Hematology and Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. IN - Higuchi, Yusuke. Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan. IN - Onishi, Yasushi. Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan. IN - Abe, Yasunobu. Department of Hematology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. IN - Kobayashi, Tsutomu. Department of Hematology and Oncology, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan. IN - Shirasugi, Yukari. Department of Hematology and Oncology, Tokai University, Isehara, Japan. IN - Tobinai, Kensei. Department of Hematology, National Cancer Center Hospital, Tokyo, Japan. TI - Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. SO - Cancer Science. 108(5):1007-1012, 2017 May AS - Cancer Sci. 108(5):1007-1012, 2017 May NJ - Cancer science PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101168776 IO - Cancer Sci. CP - England KW - Hodgkin lymphoma; Japanese; immunotherapy; nivolumab; programmed death-1 AB - Overexpression of programmed death-1 (PD-1) ligands contributes to an immunosuppressive microenvironment. Nivolumab is a PD-1-blocking antibody that inhibits the PD-1 pathway and showed good efficacy in several types of malignancy. This phase II study examined the efficacy and safety of nivolumab in 17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma previously treated with brentuximab vedotin. Sixteen patients were included in efficacy analyses and 17 in safety analyses. The primary endpoint was the centrally assessed objective response rate (ORR). The study was commenced in March 2015. We report data obtained at a cutoff of 16 March 2016, at which time 11 patients were still receiving nivolumab. The median (range) duration of treatment and follow-up were 7.0 (1.4-10.6) months and 9.8 (6.0-11.1) months, respectively. All 17 patients had previously received brentuximab vedotin. The ORR was 81.3% (95% confidence interval [CI]: 54.4-96.0%; 13/16 patients), with complete remission and partial remission in 4 and 9 patients, respectively. The overall survival (OS) and progression-free survival (PFS) rates at 6 months were 100 and 60.0% (95% CI: 31.8-79.7%), respectively; the median OS and PFS were not reached. The most common adverse events (AE) were pyrexia (41.2%), pruritus (35.3%), rash (35.3%) and hypothyroidism (29.4%). Four patients (23.5%) experienced grade 3 or 4 AE, but most AE were of grade 1 or 2. In conclusion, nivolumab is a potentially effective and tolerable treatment option for Japanese patients with relapsed/refractory classical Hodgkin lymphoma previously treated with brentuximab vedotin. AB - Copyright © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. ES - 1349-7006 IL - 1347-9032 DO - https://dx.doi.org/10.1111/cas.13230 PT - Journal Article ID - 10.1111/cas.13230 [doi] ID - PMC5448600 [pmc] PP - ppublish PH - 2017/01/09 [received] PH - 2017/02/27 [revised] PH - 2017/03/01 [accepted] LG - English EP - 20170519 DP - 2017 May DC - 20170307 EZ - 2017/03/08 06:00 DA - 2017/03/08 06:00 DT - 2017/03/08 06:00 YR - 2017 RD - 20170602 UP - 20170605 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28267244 <405. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27852042 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Costa R AU - Carneiro BA AU - Agulnik M AU - Rademaker AW AU - Pai SG AU - Villaflor VM AU - Cristofanilli M AU - Sosman JA AU - Giles FJ FA - Costa, Ricardo FA - Carneiro, Benedito A FA - Agulnik, Mark FA - Rademaker, Alfred W FA - Pai, Sachin G FA - Villaflor, Victoria M FA - Cristofanilli, Massimo FA - Sosman, Jeffrey A FA - Giles, Francis J IN - Costa, Ricardo. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. IN - Costa, Ricardo. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. IN - Carneiro, Benedito A. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. IN - Carneiro, Benedito A. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. IN - Agulnik, Mark. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. IN - Agulnik, Mark. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. IN - Rademaker, Alfred W. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. IN - Rademaker, Alfred W. Northwestern University Department of Preventive Medicine, Chicago, Illinois, USA. IN - Pai, Sachin G. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. IN - Pai, Sachin G. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. IN - Villaflor, Victoria M. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. IN - Villaflor, Victoria M. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. IN - Cristofanilli, Massimo. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. IN - Cristofanilli, Massimo. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. IN - Sosman, Jeffrey A. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. IN - Sosman, Jeffrey A. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. IN - Giles, Francis J. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. IN - Giles, Francis J. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA. TI - Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. [Review] SO - Oncotarget. 8(5):8910-8920, 2017 Jan 31 AS - Oncotarget. 8(5):8910-8920, 2017 Jan 31 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget CP - United States KW - adverse events; anti-PD1 antibodies; hypothyroidism; meta-analysis; pruritus AB - PURPOSE: Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents. AB - METHODS: PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy. Data were analyzed using random effects meta-analysis for risk ratios. Heterogeneity across studies was analyzed using Q and I2 statistics. AB - RESULTS: Nine randomized trials and 5,353 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies. The pooled relative risk (RR) for treatment-related all grade AEs and grade 3/4 AEs was 0.88 (95% CI 0.81-0.95;P=0.002) and 0.39 (95% CI 0.29-0.53; P<0.001) respectively favoring anti-PD-1 therapy versus standard of care approach. The RR of treatment-related death was 0.45 (95% CI 0.19-1.09; P=0.076). Patients treated with PD-1 inhibitors had an increased risk of hyperthyroidism [RR of 3.44 (95% CI 1.98-5.99; P<0.001)] and hypothyroidism [RR of 6.79 (95% CI 3.10-14.84; P<0.001)]. All grade pruritus and vitiligo were also more common among these patients. The pooled absolute risks of pneumonitis and hypophysitis were 2.65% and 0.47% respectively. AB - CONCLUSION: Approved PD-1 inhibitors are well tolerated, associated with significant low risk of severe treatment-related AEs and increased risk of thyroid dysfunction, pruritus, and vitiligo. ES - 1949-2553 IL - 1949-2553 DI - 13315 DO - https://dx.doi.org/10.18632/oncotarget.13315 PT - Journal Article PT - Review ID - 13315 [pii] ID - 10.18632/oncotarget.13315 [doi] ID - PMC5352453 [pmc] PP - ppublish PH - 2016/09/20 [received] PH - 2016/10/13 [accepted] GI - No: P30 CA060553 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2017 Jan 31 DC - 20161116 EZ - 2016/11/17 06:00 DA - 2016/11/17 06:00 DT - 2016/11/17 06:00 YR - 2017 RD - 20170526 UP - 20170530 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27852042 <406. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28515940 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Godwin JL AU - Jaggi S AU - Sirisena I AU - Sharda P AU - Rao AD AU - Mehra R AU - Veloski C AI - Godwin, James Luke; ISNI: 0000 0004 0456 6466 AI - Godwin, James Luke; GRID: 0000 0004 0456 6466 AI - Jaggi, Shuchie; ISNI: 0000 0004 0456 652X AI - Jaggi, Shuchie; GRID: 0000 0004 0456 652X AI - Sirisena, Imali; ISNI: 0000 0004 0456 652X AI - Sirisena, Imali; GRID: 0000 0004 0456 652X AI - Sharda, Pankaj; ISNI: 0000 0004 0456 6466 AI - Sharda, Pankaj; GRID: 0000 0004 0456 6466 AI - Rao, Ajay D; ISNI: 0000 0004 0456 652X AI - Rao, Ajay D; GRID: 0000 0004 0456 652X AI - Veloski, Colleen; ISNI: 0000 0004 0456 6466 AI - Veloski, Colleen; GRID: 0000 0004 0456 6466 FA - Godwin, James Luke FA - Jaggi, Shuchie FA - Sirisena, Imali FA - Sharda, Pankaj FA - Rao, Ajay D FA - Mehra, Ranee FA - Veloski, Colleen IN - Godwin, James Luke. Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA USA. IN - Jaggi, Shuchie. Department of Medicine, Section of Metabolism, Diabetes and Endocrinology, Temple University Hospital, Philadelphia, PA USA. IN - Sirisena, Imali. Department of Medicine, Section of Metabolism, Diabetes and Endocrinology, Temple University Hospital, Philadelphia, PA USA. IN - Sharda, Pankaj. Department of Medicine, Section of Endocrinology, Fox Chase Cancer Center, Philadelphia, PA USA. IN - Rao, Ajay D. Department of Medicine, Section of Metabolism, Diabetes and Endocrinology, Temple University Hospital, Philadelphia, PA USA. IN - Mehra, Ranee. Department of Oncology, Johns Hopkins Hospital/Sidney Kimmel Comprehensive Cancer Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore, MD USA. IN - Veloski, Colleen. Department of Medicine, Section of Endocrinology, Fox Chase Cancer Center, Philadelphia, PA USA. TI - Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. SO - Journal for Immunotherapy of Cancer. 5:40, 2017 AS - J Immunother Cancer. 5:40, 2017 NJ - Journal for immunotherapy of cancer PI - Journal available in: Electronic-eCollection PI - Citation processed from: Internet JC - 101620585 IO - J Immunother Cancer CP - England KW - Autoimmune diabetes; Diabetic ketoacidosis (DKA); Immune related adverse events (irAE); Nivolumab; Non-small cell lung cancer (NSCLC); PD-1 inhibitor AB - BACKGROUND: Advances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10-20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM. AB - CASE PRESENTATION: A 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy. AB - CONCLUSION: New onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of<1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM after anti-PD-1 therapy occurred in patients with no detectable diabetes related autoantibodies. Further studies are needed to delineate genetic and immunologic biomarkers that may be useful in identifying patients at risk of developing ICI related autoimmune DM. ES - 2051-1426 IL - 2051-1426 DI - 245 DO - https://dx.doi.org/10.1186/s40425-017-0245-2 PT - Journal Article ID - 10.1186/s40425-017-0245-2 [doi] ID - 245 [pii] ID - PMC5433051 [pmc] PP - epublish PH - 2016/11/18 [received] PH - 2017/04/26 [accepted] LG - English EP - 20170516 DP - 2017 DC - 20170518 EZ - 2017/05/19 06:00 DA - 2017/05/19 06:00 DT - 2017/05/19 06:00 YR - 2017 RD - 20170521 UP - 20170523 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28515940 <407. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28512413 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Imafuku K AU - Yoshino K AU - Yamaguchi K AU - Tsuboi S AU - Ohara K AU - Hata H FA - Imafuku, Keisuke FA - Yoshino, Koji FA - Yamaguchi, Kei FA - Tsuboi, Satoshi FA - Ohara, Kuniaki FA - Hata, Hiroo IN - Imafuku, Keisuke. aTokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. IN - Yoshino, Koji. aTokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. IN - Yamaguchi, Kei. aTokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. IN - Tsuboi, Satoshi. aTokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. IN - Ohara, Kuniaki. aTokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan. IN - Hata, Hiroo. bDepartment of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. TI - Two Cases of Nivolumab Re-Administration after Pneumonitis as Immune-Related Adverse Events. SO - Case Reports Oncology. 10(1):296-300, 2017 Jan-Apr AS - Case rep., oncol.. 10(1):296-300, 2017 Jan-Apr NJ - Case reports in oncology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101517601 IO - Case Rep Oncol CP - Switzerland KW - Cryptogenic organizing pneumonia; Diffuse alveolar damage; Immune-related adverse event; Nivolumab; Pneumonitis; Re-administration; Unresectable malignant melanoma AB - Nivolumab is a recently approved medication for the treatment of unresectable malignant melanoma. Many immune-related adverse events (irAEs) associated with nivolumab have been reported, such as pneumonitis, hepatitis, dermatitis, and thyroiditis. Prednisolone can effectively treat irAEs. However, it is unclear how or if nivolumab should be administered to patients after they have experienced an irAE. Herein, we show 2 patients who underwent pneumonitis as irAE. Case 1 demonstrated a cryptogenic organizing pneumonia pattern in the CT scan and case 2 had a diffuse alveolar damage (DAD) pattern. Oral corticosteroids improved chest shadow of CT scan in both cases. However, when nivolumab was re-administrated, case 1 demonstrated no symptoms, but case 2 demonstrated pneumonia again. From our cases, it is difficult to re-administrate nivolumab for the patients with pneumonitis which shows a DAD pattern in CT, even if oral corticosteroids improve their symptoms. IL - 1662-6575 DI - cro-0010-0296 DO - https://dx.doi.org/10.1159/000463379 PT - Journal Article ID - 10.1159/000463379 [doi] ID - cro-0010-0296 [pii] ID - PMC5422733 [pmc] PP - epublish PH - 2017/02/13 [received] PH - 2017/02/13 [accepted] LG - English EP - 20170404 DP - 2017 Jan-Apr DC - 20170517 EZ - 2017/05/18 06:00 DA - 2017/05/18 06:01 DT - 2017/05/18 06:00 YR - 2017 RD - 20170521 UP - 20170523 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28512413 <408. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28476618 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Xiao ZX AU - Chen RQ AU - Hu DX AU - Xie XQ AU - Yu SB AU - Chen XQ FA - Xiao, Zui Xuan FA - Chen, Ruo Qiao FA - Hu, Dian Xing FA - Xie, Xiao Qiang FA - Yu, Shang Bin FA - Chen, Xiao Qian IN - Xiao, Zui Xuan. Department of Endocrinology, Jingzhou First People's Hospital, The First Clinical Medical College, Yangtze University, Jingzhou 434100, China. IN - Chen, Ruo Qiao. School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. IN - Hu, Dian Xing. Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. IN - Xie, Xiao Qiang. Department of Pathology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou 434020, China. Electronic address: slideabc@hotmail.com. IN - Yu, Shang Bin. Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: yushangbin@tjmu.edu.cn. IN - Chen, Xiao Qian. Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: chenxq@mails.tjmu.edu.cn. TI - Identification of repaglinide as a therapeutic drug for glioblastoma multiforme. SO - Biochemical & Biophysical Research Communications. 488(1):33-39, 2017 Jun 17 AS - Biochem Biophys Res Commun. 488(1):33-39, 2017 Jun 17 NJ - Biochemical and biophysical research communications PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9y8, 0372516 IO - Biochem. Biophys. Res. Commun. CP - United States KW - Bioinformatics; Brain tumor; Cancer therapy; Drug repositioning; Glioma; Repaglinide AB - Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a median survival time of only 14 months after treatment. It is urgent to find new therapeutic drugs that increase survival time of GBM patients. To achieve this goal, we screened differentially expressed genes between long-term and short-term survived GBM patients from Gene Expression Omnibus database and found gene expression signature for the long-term survived GBM patients. The signaling networks of all those differentially expressed genes converged to protein binding, extracellular matrix and tissue development as revealed in BiNGO and Cytoscape. Drug repositioning in Connectivity Map by using the gene expression signature identified repaglinide, a first-line drug for diabetes mellitus, as the most promising novel drug for GBM. In vitro experiments demonstrated that repaglinide significantly inhibited the proliferation and migration of human GBM cells. In vivo experiments demonstrated that repaglinide prominently prolonged the median survival time of mice bearing orthotopic glioma. Mechanistically, repaglinide significantly reduced Bcl-2, Beclin-1 and PD-L1 expression in glioma tissues, indicating that repaglinide may exert its anti-cancer effects via apoptotic, autophagic and immune checkpoint signaling. Taken together, repaglinide is likely to be an effective drug to prolong life span of GBM patients. AB - Copyright © 2017. Published by Elsevier Inc. ES - 1090-2104 IL - 0006-291X DI - S0006-291X(17)30846-X DO - https://dx.doi.org/10.1016/j.bbrc.2017.04.157 PT - Journal Article ID - S0006-291X(17)30846-X [pii] ID - 10.1016/j.bbrc.2017.04.157 [doi] PP - ppublish PH - 2017/04/26 [received] PH - 2017/04/30 [accepted] LG - English EP - 20170502 DP - 2017 Jun 17 DC - 20170506 EZ - 2017/05/07 06:00 DA - 2017/05/10 06:00 DT - 2017/05/10 06:00 YR - 2017 RD - 20170521 UP - 20170523 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28476618 <409. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28421272 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Koelzer VH AU - Glatz K AU - Bubendorf L AU - Weber A AU - Gaspert A AU - Cathomas G AU - Lugli A AU - Zippelius A AU - Kempf W AU - Mertz KD FA - Koelzer, V H FA - Glatz, K FA - Bubendorf, L FA - Weber, A FA - Gaspert, A FA - Cathomas, G FA - Lugli, A FA - Zippelius, A FA - Kempf, W FA - Mertz, K D IN - Koelzer, V H. Institut fur Pathologie, Kantonsspital Baselland, Muhlemattstrase 11, 4410, Liestal, Schweiz. IN - Koelzer, V H. Translational Research Unit (TRU), Institut fur Pathologie, Universitat Bern, Bern, Schweiz. IN - Glatz, K. Institut fur Pathologie, Universitatsspital Basel, Basel, Schweiz. IN - Bubendorf, L. Institut fur Pathologie, Universitatsspital Basel, Basel, Schweiz. IN - Weber, A. Institut fur Pathologie und Molekularpathologie, Universitat Zurich und Universitatsspital Zurich, Zurich, Schweiz. IN - Gaspert, A. Institut fur Pathologie und Molekularpathologie, Universitat Zurich und Universitatsspital Zurich, Zurich, Schweiz. IN - Cathomas, G. Institut fur Pathologie, Kantonsspital Baselland, Muhlemattstrase 11, 4410, Liestal, Schweiz. IN - Lugli, A. Klinische Pathologie, Institut fur Pathologie, Universitat Bern, Bern, Schweiz. IN - Zippelius, A. Klinik fur Onkologie, Universitatsspital Basel, Basel, Schweiz. IN - Kempf, W. Kempf und Pfaltz Histologische Diagnostik, Research Unit, Zurich, Schweiz. IN - Mertz, K D. Institut fur Pathologie, Kantonsspital Baselland, Muhlemattstrase 11, 4410, Liestal, Schweiz. kirsten.mertz@ksbl.ch. TI - [The pathology of adverse events with immune checkpoint inhibitors]. [German] OT - Pathologie der Nebenwirkungen von Immune-Checkpoint-Inhibitoren. SO - Pathologe. 38(3):197-208, 2017 May AS - Pathologe. 38(3):197-208, 2017 May NJ - Der Pathologe PI - Journal available in: Print PI - Citation processed from: Internet JC - plk, 8006541 IO - Pathologe CP - Germany KW - Adverse drug event; Autoimmunity; Immunotherapy; Personalized medicine AB - BACKGROUND: Immunotherapy has gained importance with the development of new effective cancer treatments. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote T-cell mediated tumor immune rejection. Checkpoint blockade also carries the risk of inducing autoimmune reactions ("immune related adverse events", irAEs). The diagnosis and classification of irAEs constitute a new and important field in pathology. AB - AIM: Practice-oriented review of the diagnosis and classification of irAEs. AB - MATERIALS AND METHODS: Structured, selective literature review based on PubMed und UpToDate online. AB - RESULTS: The most common irAEs affect the skin, the gastrointestinal tract, the liver, and the respiratory system. The correct diagnosis and classification of irAEs by an interdisciplinary care team is essential for appropriate therapy and the prevention of long-term sequelae. Other important irAEs affect the endocrine organs, the heart, the joints, the kidneys and the nervous system. Because of their rarity and/or limited options for bioptic diagnosis, only limited data on the morphology and pathophysiology of these irAEs are currently available. Autopsies carried out after ICI therapy constitute an important element of quality control and allow better documentation of the incidence and pathogenesis of irAEs. AB - DISCUSSION: Pathology plays a central role in the diagnosis and treatment of irAEs. Future studies may contribute to a better mechanistic understanding of irAEs for individualized knowledge-based risk assessment. ES - 1432-1963 IL - 0172-8113 DI - 10.1007/s00292-017-0281-1 DO - https://dx.doi.org/10.1007/s00292-017-0281-1 PT - English Abstract PT - Journal Article ID - 10.1007/s00292-017-0281-1 [doi] ID - 10.1007/s00292-017-0281-1 [pii] PP - ppublish LG - German DP - 2017 May DC - 20170419 EZ - 2017/04/20 06:00 DA - 2017/04/20 06:00 DT - 2017/04/20 06:00 YR - 2017 RD - 20170518 UP - 20170519 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28421272 <410. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27401894 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Weber JS AU - Postow M AU - Lao CD AU - Schadendorf D FA - Weber, Jeffrey S FA - Postow, Michael FA - Lao, Christopher D FA - Schadendorf, Dirk IN - Weber, Jeffrey S. Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York, USA jeffrey.weber2@nyumc.org. IN - Postow, Michael. Memorial Sloan Kettering Cancer Center, New York, New York, USA Weill Cornell Medical College, New York, New York, USA. IN - Lao, Christopher D. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. IN - Schadendorf, Dirk. University Hospital Essen, Essen, Germany. TI - Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents. [Review] SO - Oncologist. 21(10):1230-1240, 2016 Oct AS - Oncologist. 21(10):1230-1240, 2016 Oct NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist CP - United States KW - Drug-related side effects and adverse reactions; Melanoma; Nivolumab; Pembrolizumab; Programmed cell death 1 receptor AB - : Immune checkpoint inhibitors have emerged as a mainstay of melanoma therapy and are playing an increasingly important role in the treatment of other tumor types. The clinical benefit afforded by these treatments can be accompanied by a unique spectrum of adverse events, called immune-related adverse events (irAEs), which reflect the drug's immune-based mechanism of action. IrAEs typically originate in the skin, gastrointestinal tract, liver, and endocrine system, although other organ systems may also be affected. This article provides an overview of irAEs associated with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab and pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab), followed by a discussion of irAEs of special clinical interest based on the potential for morbidity, frequent steroid use, and inpatient admission. We review clinical trial data and provide recommendations on how to manage irAEs associated with anti-PD-1 agents based on clinical experience and established management guidelines. We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab. A better understanding of the identification and management of irAEs will help inform health care providers about the risks associated with anti-PD-1 treatment, to ensure the safe and appropriate use of these important new treatments. AB - IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitors have demonstrated significant clinical benefit in advanced melanoma and other tumor types. These treatments are associated with immune-related adverse events (irAEs), which most commonly affect the skin and gastrointestinal tract, and, to a lesser extent, the liver, endocrine system, and other organs. This review focuses on the management of irAEs after treatment with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab or pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab) in patients with advanced melanoma. A better understanding of the management of irAEs will help ensure the safe and appropriate use of anti-PD-1 agents in melanoma and other tumor types. AB - Copyright ©AlphaMed Press. CI - of potential conflicts of interest may be found at the end of this article. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2016-0055 DO - https://dx.doi.org/10.1634/theoncologist.2016-0055 PT - Review PT - Journal Article ID - theoncologist.2016-0055 [pii] ID - 10.1634/theoncologist.2016-0055 [doi] ID - PMC5061539 [pmc] PP - ppublish PH - 2016/02/12 [received] PH - 2016/05/02 [accepted] PH - 2017/10/01 [pmc-release] GI - No: P30 CA008748 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20160708 DP - 2016 Oct DC - 20160712 EZ - 2016/07/13 06:00 DA - 2016/07/13 06:00 DT - 2016/07/13 06:00 YR - 2016 RD - 20170518 UP - 20170519 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27401894 <411. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28499411 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Gambichler T AU - Strutzmann S AU - Tannapfel A AU - Susok L AI - Gambichler, Thilo; ORCID: http://orcid.org/0000-0001-7862-3695 FA - Gambichler, Thilo FA - Strutzmann, Stefanie FA - Tannapfel, Andrea FA - Susok, Laura IN - Gambichler, Thilo. Department of Dermatology, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. t.gambichler@klinikum-bochum.de. IN - Strutzmann, Stefanie. Department of Dermatology, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. IN - Tannapfel, Andrea. Institute of Pathology, Ruhr-University Bochum, Burkle-de-la-Camp-Platz 1, 44789, Bochum, Germany. IN - Susok, Laura. Department of Dermatology, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany. TI - Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma under immune checkpoint blockade. SO - BMC Cancer. 17(1):327, 2017 May 12 AS - BMC Cancer. 17(1):327, 2017 May 12 NJ - BMC cancer PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 100967800 IO - BMC Cancer CP - England KW - Digital ischemia; Gangrene; Immune-checkpoint blockade, ipilimumab, nivolumab; Melanoma AB - BACKGROUND: Paraneoplastic acral vascular syndrome (PAVS) is a rare phenomenon which is observed in patients with adenocarcinomas and other malignancies. Various potential pathogenic mechanisms such as tumour invasion of sympathetic nerves, hyperviscosity, hypercoagulability, vasoactive tumour-secreted substances, and immunological mechanisms have been suggested. AB - CASE PRESENTATION: We report a 60-year-old Caucasian male attended our hospital with a bulky lymph node mass in the right axilla. Extirpation of a lymph node conglomerate revealed 5 melanoma lymph node metastases. Computed tomography showed a liver metastasis (diameter: 3.8 cm), several retroperitoneal metastases, bilateral metastases in the lung hilus, and prepectoral subcutaneous metastases (Stage IV; pTx, N3, M1c). Lactate dehydrogenase and S100B were slightly elevated. Combination therapy of nivolumab (1 mg/kg BW) and ipilimumab (3 mg/kg BW) was started. Three weeks after the first combination therapy he developed progressive erythema, paraesthesia and pain on the fingertips of both hands. Both cold and warmth was not well tolerated by the patient. Complete work-up excluded associated conditions or factors such as haematological disorders, rheumatologic disorders, hypertension, diabetes or smoking. Treatment was initiated with prostacyclin 20 mug twice daily and oral prednisolone 50 mg in tapering dosage. However, prostacyclin was stopped after the first applications because the pain increased during infusion. The second course of nivolumab and ipilimumab was administered. About 2 weeks later, the patient presented with increased pain and small subungual necrosis. We treated the patient with oral analgetics and intravenous prednisolone 500 mg in tapering dosage. On digital substraction angiography occlusion of all arteries of the fingers was demonstrated. Further rheologic and anti-melanoma treatments were refused by the patient. About 2 months after the second course of nivolumab and ipilimumab combination therapy several fingers showed severe gangrene which finally led to amputations of end phalanges of several fingers. Histopathology did not reveal evidence for vasculitis or other primary vascular pathologies. During the following 2 months the patient experienced dramatic progress of his metastatic disease and finally died at multi-organ failure. AB - CONCLUSION: Presence of rapidly progressive digital ischemia in an elderly patient with cancer should always raise clinical suspicion of a paraneoplastic phenomenon when other possible causes have been excluded. In patients treated with immune checkpoint inhibitors such as CTLA-4 and PD-L1 blockers PVAS-like events have not been reported so far. However, it is debatable whether immune checkpoint blockade may play a pathogenetic role in the development of PAVS in patients with malignancies. ES - 1471-2407 IL - 1471-2407 DI - 10.1186/s12885-017-3313-6 DO - https://dx.doi.org/10.1186/s12885-017-3313-6 PT - Journal Article ID - 10.1186/s12885-017-3313-6 [doi] ID - 10.1186/s12885-017-3313-6 [pii] ID - PMC5429577 [pmc] PP - epublish PH - 2016/12/21 [received] PH - 2017/05/01 [accepted] LG - English EP - 20170512 DP - 2017 May 12 DC - 20170513 EZ - 2017/05/14 06:00 DA - 2017/05/14 06:00 DT - 2017/05/14 06:00 YR - 2017 RD - 20170516 UP - 20170518 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28499411 <412. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28438889 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Kasamon YL AU - de Claro RA AU - Wang Y AU - Shen YL AU - Farrell AT AU - Pazdur R FA - Kasamon, Yvette L FA - de Claro, R Angelo FA - Wang, Yaping FA - Shen, Yuan Li FA - Farrell, Ann T FA - Pazdur, Richard IN - Kasamon, Yvette L. Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA Yvette.Kasamon@fda.hhs.gov. IN - de Claro, R Angelo. Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Wang, Yaping. Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Shen, Yuan Li. Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Farrell, Ann T. Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Pazdur, Richard. Office of Hematology and Oncology Products and Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. TI - FDA Approval Summary: Nivolumab for the Treatment of Relapsed or Progressive Classical Hodgkin Lymphoma. SO - Oncologist. 22(5):585-591, 2017 May AS - Oncologist. 22(5):585-591, 2017 May NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist CP - United States KW - Hodgkin lymphoma; Nivolumab; Programmed cell death 1 inhibitor; Programmed death-ligand 1 AB - On May 17, 2016, after an expedited priority review, the U.S. Food and Drug Administration granted accelerated approval to nivolumab for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin (BV). Nivolumab in cHL had been granted breakthrough therapy designation. Accelerated approval was based on two single-arm, multicenter trials in adults with cHL. In 95 patients with relapsed or progressive cHL after autologous HSCT and post-transplantation BV, nivolumab, dosed at 3 mg/kg intravenously every 2 weeks, produced a 65% (95% confidence interval: 55%-75%) objective response rate (58% partial remission, 7% complete remission). The estimated median duration of response was 8.7 months, with 4.6-month median follow-up for response duration. The median time to response was 2.1 (range: 0.7-5.7) months. Among 263 patients with cHL treated with nivolumab, 21% reported serious adverse reactions (ARs). The most common all-grade ARs (reported in >=20%) were fatigue, upper respiratory tract infection, cough, pyrexia, diarrhea, elevated transaminases, and cytopenias. Infusion-related reaction and hypothyroidism or thyroiditis occurred in >10% of patients; other immune-mediated ARs, occurring in 1%-5%, included rash, pneumonitis, hepatitis, hyperthyroidism, and colitis. A new Warning and Precaution was issued for complications of allogeneic HSCT after nivolumab, including severe or hyperacute graft-versus-host disease, other immune-mediated ARs, and transplant-related mortality. Continued approval for the cHL indication may be contingent upon verification of clinical benefit in a randomized trial. The Oncologist 2017;22:585-591 IMPLICATIONS FOR PRACTICE: Based on response rate and duration in single-arm studies, nivolumab is a new treatment option for patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed despite autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin. This was the first U.S. Food and Drug Administration marketing application for a programmed cell death 1 inhibitor in hematologic malignancies. The use of immune checkpoint blockade in cHL represents a new treatment paradigm. The safety of allogeneic HSCT after nivolumab requires further evaluation, as does the safety of nivolumab after allogeneic HSCT. AB - Copyright © AlphaMed Press 2017. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2017-0004 DO - https://dx.doi.org/10.1634/theoncologist.2017-0004 PT - Journal Article ID - theoncologist.2017-0004 [pii] ID - 10.1634/theoncologist.2017-0004 [doi] ID - PMC5423515 [pmc] PP - ppublish PH - 2017/01/06 [received] PH - 2017/02/08 [accepted] PH - 2018/05/01 [pmc-release] LG - English EP - 20170424 DP - 2017 May DC - 20170425 EZ - 2017/04/26 06:00 DA - 2017/04/26 06:00 DT - 2017/04/26 06:00 YR - 2017 RD - 20170512 UP - 20170515 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28438889 <413. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28359784 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Ascierto PA AU - Del Vecchio M AU - Robert C AU - Mackiewicz A AU - Chiarion-Sileni V AU - Arance A AU - Lebbe C AU - Bastholt L AU - Hamid O AU - Rutkowski P AU - McNeil C AU - Garbe C AU - Loquai C AU - Dreno B AU - Thomas L AU - Grob JJ AU - Liszkay G AU - Nyakas M AU - Gutzmer R AU - Pikiel J AU - Grange F AU - Hoeller C AU - Ferraresi V AU - Smylie M AU - Schadendorf D AU - Mortier L AU - Svane IM AU - Hennicken D AU - Qureshi A AU - Maio M FA - Ascierto, Paolo A FA - Del Vecchio, Michele FA - Robert, Caroline FA - Mackiewicz, Andrzej FA - Chiarion-Sileni, Vanna FA - Arance, Ana FA - Lebbe, Celeste FA - Bastholt, Lars FA - Hamid, Omid FA - Rutkowski, Piotr FA - McNeil, Catriona FA - Garbe, Claus FA - Loquai, Carmen FA - Dreno, Brigitte FA - Thomas, Luc FA - Grob, Jean-Jacques FA - Liszkay, Gabriella FA - Nyakas, Marta FA - Gutzmer, Ralf FA - Pikiel, Joanna FA - Grange, Florent FA - Hoeller, Christoph FA - Ferraresi, Virginia FA - Smylie, Michael FA - Schadendorf, Dirk FA - Mortier, Laurent FA - Svane, Inge Marie FA - Hennicken, Delphine FA - Qureshi, Anila FA - Maio, Michele IN - Ascierto, Paolo A. Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. Electronic address: paolo.ascierto@gmail.com. IN - Del Vecchio, Michele. Medical Oncology, National Cancer Institute, Milan, Italy. IN - Robert, Caroline. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. IN - Mackiewicz, Andrzej. Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan Medical University, Poznan, Poland. IN - Chiarion-Sileni, Vanna. IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy. IN - Arance, Ana. Hospital Clinic and Institut d'Investigacions Biomediques August Pi I Sunyer, Barcelona, Spain. IN - Lebbe, Celeste. AP-HP Dermatology CIC Departments, Saint-Louis Hospital, INSERM U976, Universite Paris Diderot, Paris, France. IN - Bastholt, Lars. Odense University Hospital, Odense, Denmark. IN - Hamid, Omid. The Angeles Clinic and Research Institute, Los Angeles, CA, USA. IN - Rutkowski, Piotr. Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. IN - McNeil, Catriona. Chris O'Brien Lifehouse and Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Melanoma Institute Australia, Sydney, NSW, Australia. IN - Garbe, Claus. Eberhard Karls University, Tubingen, Germany. IN - Loquai, Carmen. University Medical Center, Mainz, Germany. IN - Dreno, Brigitte. Department of Oncodermatology, INSERM Research Unit 892, Nantes University Hospital, Nantes, France. IN - Thomas, Luc. Department of Dermatology, Centre Hospitalier Lyon-Sud, Pierre-Benite, France. IN - Grob, Jean-Jacques. Hospital de la Timone, Marseille, France. IN - Liszkay, Gabriella. National Institute of Oncology, Budapest, Hungary. IN - Nyakas, Marta. Oslo University Hospital, Oslo, Norway. IN - Gutzmer, Ralf. Medizinische Hochschule Hannover, Hannover, Germany. IN - Pikiel, Joanna. Wojewodzkie Centrum Oncologii, Gdansk, Poland. IN - Grange, Florent. Department of Dermatology, Reims University Hospital, Reims, France. IN - Hoeller, Christoph. Medical University of Vienna, Vienna, Austria. IN - Ferraresi, Virginia. Istituti Fisioterapici Ospitalieri, Rome, Italy. IN - Smylie, Michael. Cross Cancer Institute, Edmonton, AB, Canada. IN - Schadendorf, Dirk. University Hospital Essen, Essen, Germany. IN - Mortier, Laurent. Hospital Claude Huriez, Lille, France. IN - Svane, Inge Marie. Herlev Hospital, University of Copenhagen, Herlev, Denmark. IN - Hennicken, Delphine. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Qureshi, Anila. Bristol-Myers Squibb, Princeton, NJ, USA. IN - Maio, Michele. University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. TI - Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. SO - Lancet Oncology. 18(5):611-622, 2017 May AS - Lancet Oncol. 18(5):611-622, 2017 May NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. CP - England AB - BACKGROUND: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg. AB - METHODS: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. AB - FINDINGS: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14.5 months (IQR 4.6-42.3) for the ipilimumab 10 mg/kg group and 11.2 months (4.9-29.4) for the ipilimumab 3 mg/kg group. Median overall survival was 15.7 months (95% CI 11.6-17.8) for ipilimumab 10 mg/kg compared with 11.5 months (9.9-13.3) for ipilimumab 3 mg/kg (hazard ratio 0.84, 95% CI 0.70-0.99; p=0.04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events. AB - INTERPRETATION: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment. AB - FUNDING: Bristol-Myers Squibb. AB - Copyright © 2017 Elsevier Ltd. All rights reserved. ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(17)30231-0 DO - https://dx.doi.org/10.1016/S1470-2045(17)30231-0 PT - Journal Article ID - S1470-2045(17)30231-0 [pii] ID - 10.1016/S1470-2045(17)30231-0 [doi] PP - ppublish PH - 2016/12/09 [received] PH - 2017/01/31 [revised] PH - 2017/02/03 [accepted] LG - English EP - 20170327 DP - 2017 May DC - 20170331 EZ - 2017/04/01 06:00 DA - 2017/04/01 06:00 DT - 2017/04/01 06:00 YR - 2017 RD - 20170512 UP - 20170515 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28359784 <414. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28291584 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Alley EW AU - Lopez J AU - Santoro A AU - Morosky A AU - Saraf S AU - Piperdi B AU - van Brummelen E FA - Alley, Evan W FA - Lopez, Juanita FA - Santoro, Armando FA - Morosky, Anne FA - Saraf, Sanatan FA - Piperdi, Bilal FA - van Brummelen, Emilie IN - Alley, Evan W. Hematology and Oncology Division, Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, PA, USA. Electronic address: evan.alley@uphs.upenn.edu. IN - Lopez, Juanita. Drug Development Unit, Institute of Cancer Research, London, UK. IN - Santoro, Armando. Humanitas Cancer Center, Humanitas University, Milan, Italy. IN - Morosky, Anne. Merck, Kenilworth, NJ, USA. IN - Saraf, Sanatan. Merck, Kenilworth, NJ, USA. IN - Piperdi, Bilal. Merck, Kenilworth, NJ, USA. IN - van Brummelen, Emilie. Netherlands Cancer Institute, Amsterdam, Netherlands. TI - Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. SO - Lancet Oncology. 18(5):623-630, 2017 May AS - Lancet Oncol. 18(5):623-630, 2017 May NJ - The Lancet. Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 100957246 IO - Lancet Oncol. CP - England AB - BACKGROUND: Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis and few treatment options following progression on platinum-containing chemotherapy. We assessed the safety and efficacy of pembrolizumab (an anti-programmed cell death receptor 1 [PD-1] antibody) in advanced solid tumours expressing programmed cell death ligand 1 (PD-L1) and report here on the interim analysis of the malignant pleural mesothelioma cohort. AB - METHODS: Previously treated patients with PD-L1-positive malignant pleural mesothelioma were enrolled from 13 centres in six countries. Patients received pembrolizumab (10 mg/kg every 2 weeks) for up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria included measurable disease, failure of standard therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1. PD-L1 positivity was defined as expression in 1% or more of tumour cells by immunohistochemistry. Response was assessed based on investigator review using the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Primary endpoints were safety and tolerability, analysed in the all-patients-as-treated population, and objective response, analysed for the full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT02054806, and is ongoing but not recruiting participants. AB - FINDINGS: As of June 20, 2016, 25 patients received pembrolizumab. 16 (64%) patients reported a treatment-related adverse event; the most common adverse event were fatigue (six [24%]), nausea (six [24%]), and arthralgia (five [20%]). Five (20%) patients reported grade 3 treatment-related adverse events. Three (12%) patients required dose interruption because of immune-related adverse events: one (4%) of 25 each had grade 3 rhabdomyolysis and grade 2 hypothyroidism; grade 3 iridocyclitis, grade 1 erythema multiforme, and grade 3 erythema; and grade 2 infusion-related reaction. No treatment-related deaths or discontinuations occurred. Five (20%) patients had a partial response, for an objective response of 20% (95% CI 6.8-40.7), and 13 (52%) of 25 had stable disease. Responses were durable (median response duration 12.0 months [95% CI 3.7 to not reached]); two patients remained on treatment at data cutoff. AB - INTERPRETATION: Pembrolizumab appears to be well tolerated and might confer anti-tumour activity in patients with PD-L1-positive malignant pleural mesothelioma. Response durability and efficacy in this patient population warrants further investigation. AB - FUNDING: Merck. AB - Copyright © 2017 Elsevier Ltd. All rights reserved. ES - 1474-5488 IL - 1470-2045 DI - S1470-2045(17)30169-9 DO - https://dx.doi.org/10.1016/S1470-2045(17)30169-9 PT - Journal Article ID - S1470-2045(17)30169-9 [pii] ID - 10.1016/S1470-2045(17)30169-9 [doi] PP - ppublish PH - 2016/11/08 [received] PH - 2017/01/11 [revised] PH - 2017/01/18 [accepted] LG - English EP - 20170311 DP - 2017 May DC - 20170314 EZ - 2017/03/15 06:00 DA - 2017/03/16 06:00 DT - 2017/03/16 06:00 YR - 2017 RD - 20170512 UP - 20170515 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28291584 <415. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28246107 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - De Velasco G AU - Je Y AU - Bosse D AU - Awad MM AU - Ott PA AU - Moreira RB AU - Schutz F AU - Bellmunt J AU - Sonpavde GP AU - Hodi FS AU - Choueiri TK FA - De Velasco, Guillermo FA - Je, Youjin FA - Bosse, Dominick FA - Awad, Mark M FA - Ott, Patrick A FA - Moreira, Raphael B FA - Schutz, Fabio FA - Bellmunt, Joaquim FA - Sonpavde, Guru P FA - Hodi, F Stephen FA - Choueiri, Toni K IN - De Velasco, Guillermo. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. IN - De Velasco, Guillermo. Department of Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain. IN - Je, Youjin. Department of Food and Nutrition, College of Human Ecology, Kyung Hee University, Seoul, Korea. IN - Bosse, Dominick. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. IN - Awad, Mark M. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. IN - Ott, Patrick A. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. IN - Moreira, Raphael B. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. IN - Schutz, Fabio. Department of Medical Oncology, Hospital Sao Jose, Beneficencia Portuguesa de Sao Paulo, Brazil. IN - Bellmunt, Joaquim. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. IN - Sonpavde, Guru P. Division of Oncology and Hematology, University of Alabama, Birmingham, Alabama. IN - Hodi, F Stephen. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. IN - Choueiri, Toni K. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. toni_choueiri@dfci.harvard.edu. TI - Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients. SO - Cancer Immunology Research. 5(4):312-318, 2017 Apr AS - Cancer Immunol Res. 5(4):312-318, 2017 Apr NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res CP - United States AB - Immune-related adverse events (irAE) have been described with immune checkpoint inhibitors (ICI), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab, or pembrolizumab, and atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016. We calculated the incidence and RR of selected all-grade and high-grade gastrointestinal, liver, skin, endocrine, and pulmonary irAEs across the trials using random-effect models. Twenty-one trials were included, totaling 11,454 patients, of whom 6,528 received an ICI (nivolumab, 1,534; pembrolizumab, 1,522; atezolizumab, 751; and ipilimumab, 2,721) and 4,926 had not. Compared with non-ICI arms, ICIs were associated with more all-grade colitis (RR 7.66, P < 0.001), aspartate aminotransferase (AST) elevation (RR 1.80; P = 0.020), rash (RR 2.50; P = 0.001), hypothyroidism (RR 6.81; P < 0.001), and pneumonitis (RR 4.14; P = 0.012). Rates of high-grade colitis (RR 5.85; P < 0.001) and AST elevation (RR 2.79; P = 0.014) were higher in the ICI arms. Ipilimumab was associated with a higher risk of all-grade rash (P = 0.006) and high-grade colitis (P = 0.021) compared with PD-1/PD-L1 ICIs. Incidence of fatal irAE was < 1%. This meta-analysis offers substantial evidence that ICIs are associated with a small but significant increase in risk of selected all-grade irAEs and high-grade gastrointestinal and liver toxicities. Although fatal irAEs remain rare, AEs should be recognized promptly as early interventions may alleviate future complications. Cancer Immunol Res; 5(4); 312-8. ©2017 AACR. AB - Copyright ©2017 American Association for Cancer Research. ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-16-0237 DO - https://dx.doi.org/10.1158/2326-6066.CIR-16-0237 PT - Journal Article ID - 2326-6066.CIR-16-0237 [pii] ID - 10.1158/2326-6066.CIR-16-0237 [doi] ID - PMC5418853 [pmc] ID - NIHMS856814 [mid] PP - ppublish PH - 2016/09/12 [received] PH - 2016/10/17 [revised] PH - 2017/02/23 [accepted] PH - 2017/10/01 [pmc-release] GI - No: P50 CA101942 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20170228 DP - 2017 Apr DC - 20170301 EZ - 2017/03/02 06:00 DA - 2017/03/02 06:00 DT - 2017/03/02 06:00 YR - 2017 RD - 20170507 UP - 20170509 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28246107 <416. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28334791 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Kitajima K AU - Ashida K AU - Wada N AU - Suetsugu R AU - Takeichi Y AU - Sakamoto S AU - Uchi H AU - Matsushima T AU - Shiratsuchi M AU - Ohnaka K AU - Furue M AU - Nomura M FA - Kitajima, Keiko FA - Ashida, Kenji FA - Wada, Naoko FA - Suetsugu, Ryoko FA - Takeichi, Yukina FA - Sakamoto, Shohei FA - Uchi, Hiroshi FA - Matsushima, Takamitsu FA - Shiratsuchi, Motoaki FA - Ohnaka, Keizo FA - Furue, Masutaka FA - Nomura, Masatoshi IN - Kitajima, Keiko. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka. IN - Kitajima, Keiko. Department of Metabolism and Endocrinology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka. IN - Ashida, Kenji. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka. IN - Wada, Naoko. Department of Dermatology, Kyushu University Hospital, Fukuoka. IN - Suetsugu, Ryoko. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka. IN - Suetsugu, Ryoko. Department of Metabolism and Endocrinology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka. IN - Takeichi, Yukina. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka. IN - Sakamoto, Shohei. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka. IN - Uchi, Hiroshi. Department of Dermatology, Kyushu University Hospital, Fukuoka. IN - Matsushima, Takamitsu. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka. IN - Shiratsuchi, Motoaki. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka. IN - Ohnaka, Keizo. Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. IN - Furue, Masutaka. Department of Dermatology, Kyushu University Hospital, Fukuoka. IN - Nomura, Masatoshi. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka. TI - Isolated ACTH deficiency probably induced by autoimmune-related mechanism evoked with nivolumab. SO - Japanese Journal of Clinical Oncology. 47(5):463-466, 2017 May 01 AS - Jpn J Clin Oncol. 47(5):463-466, 2017 May 01 NJ - Japanese journal of clinical oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - kin, 0313225 IO - Jpn. J. Clin. Oncol. CP - England KW - dermatology; endocrine-med; immunotherapy AB - Nivolumab, an anti-programmed death-1 antibody, is a breakthrough treatment for several malignancies. Its specific adverse effects caused by autoimmunity are termed immune-related adverse events, which involve several endocrine dysfunctions. Herein, we report two cases of isolated adrenocorticotropic hormone (ACTH) deficiency induced by nivolumab for the treatment of metastatic malignant melanoma. Case 1 was a 39-year-old man and Case 2 was a 50-year-old woman, both of whom presented with progressive melanoma. After 13 courses of nivolumab administration, both cases were diagnosed with adrenal insufficiency. Despite their basal serum ACTH and cortisol levels being low with little response to corticotropin-releasing hormone loading, other anterior pituitary hormone levels were preserved. Based on these endocrinological data, isolated ACTH deficiency was diagnosed. Magnetic resonance imaging showed normal pituitary glands, excluding hypophysitis. Finally, hydrocortisone replacement enabled the patients to continue nivolumab treatment. Therefore, it is important to consider isolated ACTH syndrome as a possible and potentially severe immune-related adverse event of nivolumab, even when head magnetic resonance imaging of affected cases does not show enlargement. We should not misdiagnose hidden immune-related adverse events behind general complaints of malignancies such as general malaise and appetite loss, to allow successful treatment using this beneficial immune checkpoint inhibitor. AB - Copyright © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. ES - 1465-3621 IL - 0368-2811 DI - 3003225 DO - https://dx.doi.org/10.1093/jjco/hyx018 PT - Journal Article ID - 3003225 [pii] ID - 10.1093/jjco/hyx018 [doi] PP - ppublish PH - 2016/08/06 [received] PH - 2017/01/31 [accepted] LG - English DP - 2017 May 01 DC - 20170323 EZ - 2017/03/24 06:00 DA - 2017/03/24 06:00 DT - 2017/03/24 06:00 YR - 2017 RD - 20170505 UP - 20170508 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28334791 <417. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26068559 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Sheldon CA AU - Kharlip J AU - Tamhankar MA FA - Sheldon, Claire A FA - Kharlip, Julia FA - Tamhankar, Madhura A IN - Sheldon, Claire A. *Scheie Eye Institute, Department of Ophthalmology, and +Departments of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. TI - Inflammatory Orbitopathy Associated With Ipilimumab. SO - Ophthalmic Plastic & Reconstructive Surgery. 33(3S Suppl 1):S155-S158, 2017 May/Jun AS - Ophthal Plast Reconstr Surg. 33(3S Suppl 1):S155-S158, 2017 May/Jun NJ - Ophthalmic plastic and reconstructive surgery PI - Journal available in: Print PI - Citation processed from: Internet JC - ay2, 8508431 IO - Ophthal Plast Reconstr Surg CP - United States AB - In this case report, the clinical presentation of an inflammatory orbitopathy seen following treatment with ipilimumab is described. After 3 rounds of ipilimumab (10 mg/kg) treatment for Stage III metastatic melanoma, the subject of this case report developed acute eye pain and proptosis. At initial presentation, she had marked proptosis and diffuse severe ophthalmoparesis. After treatment with high-dose steroids, over a period of 6 months, the symptoms gradually resolved fully. Although the condition may mimic thyroid-associated orbitopathy, imaging and laboratory features suggest that the orbitopathy associated with ipilimumab is not a secondary effect of thyroid dysfunction but a distinct inflammatory condition. The authors conclude that immune-related side effects can occur with biologic agents used to treat malignancies and these side-effects can involve the eye. This case illustrates the occurrence of an inflammatory orbitopathy associated with ipilimumab treatment. ES - 1537-2677 IL - 0740-9303 DO - https://dx.doi.org/10.1097/IOP.0000000000000509 PT - Journal Article ID - 10.1097/IOP.0000000000000509 [doi] PP - ppublish LG - English DP - 2017 May/Jun DC - 20150612 EZ - 2015/06/13 06:00 DA - 2015/06/13 06:00 DT - 2015/06/13 06:00 YR - 2017 RD - 20170505 UP - 20170508 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26068559 <418. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27941003 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Scharping NE AU - Menk AV AU - Whetstone RD AU - Zeng X AU - Delgoffe GM FA - Scharping, Nicole E FA - Menk, Ashley V FA - Whetstone, Ryan D FA - Zeng, Xue FA - Delgoffe, Greg M IN - Scharping, Nicole E. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. IN - Scharping, Nicole E. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. IN - Menk, Ashley V. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. IN - Whetstone, Ryan D. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. IN - Whetstone, Ryan D. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. IN - Zeng, Xue. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. IN - Delgoffe, Greg M. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. delgoffeg@upmc.edu. IN - Delgoffe, Greg M. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. TI - Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. SO - Cancer Immunology Research. 5(1):9-16, 2017 Jan AS - Cancer Immunol Res. 5(1):9-16, 2017 Jan NJ - Cancer immunology research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101614637 IO - Cancer Immunol Res CP - United States AB - Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit. Cancer Immunol Res; 5(1); 9-16. ©2016 AACR. AB - Copyright ©2016 American Association for Cancer Research. ES - 2326-6074 IL - 2326-6066 DI - 2326-6066.CIR-16-0103 DO - https://dx.doi.org/10.1158/2326-6066.CIR-16-0103 PT - Journal Article ID - 2326-6066.CIR-16-0103 [pii] ID - 10.1158/2326-6066.CIR-16-0103 [doi] ID - PMC5340074 [pmc] ID - NIHMS835819 [mid] PP - ppublish PH - 2016/05/11 [received] PH - 2016/10/20 [revised] PH - 2016/11/10 [accepted] PH - 2018/01/01 [pmc-release] GI - No: P30 CA047904 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA097190 Organization: (CA) *NCI NIH HHS* Country: United States No: P50 CA121973 Organization: (CA) *NCI NIH HHS* Country: United States No: T32 CA082084 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20161209 DP - 2017 Jan DC - 20161212 EZ - 2016/12/13 06:00 DA - 2016/12/13 06:00 DT - 2016/12/13 06:00 YR - 2017 RD - 20170502 UP - 20170503 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27941003 <419. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28343398 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Zhao P AU - Atanackovic D AU - Dong S AU - Yagita H AU - He X AU - Chen M AI - Chen, Mingnan; ORCID: http://orcid.org/0000-0002-7080-9804 FA - Zhao, Peng FA - Atanackovic, Djordje FA - Dong, Shuyun FA - Yagita, Hideo FA - He, Xiao FA - Chen, Mingnan IN - Zhao, Peng. Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah , Salt Lake City, Utah 84112, United States. IN - Atanackovic, Djordje. University of Utah School of Medicine , Salt Lake City, Utah 84112, United States. IN - Dong, Shuyun. Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah , Salt Lake City, Utah 84112, United States. IN - Yagita, Hideo. Department of Immunology, Juntendo University School of Medicine , Tokyo, Japan. IN - He, Xiao. Department of Pathology, The University of Utah , Salt Lake City, Utah 84112, United States. IN - Chen, Mingnan. Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah , Salt Lake City, Utah 84112, United States. TI - An Anti-Programmed Death-1 Antibody (alphaPD-1) Fusion Protein That Self-Assembles into a Multivalent and Functional alphaPD-1 Nanoparticle. SO - Molecular Pharmaceutics. 14(5):1494-1500, 2017 May 01 AS - Mol Pharm. 14(5):1494-1500, 2017 May 01 NJ - Molecular pharmaceutics PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101197791 IO - Mol. Pharm. CP - United States KW - anti-programmed death-1 antibody; diabetes; multivalency; nanoparticle; recombinant anti-programmed death-1 antibody fusion AB - Cancer immune checkpoint therapy has achieved remarkable clinical successes in various cancers. However, current immune checkpoint inhibitors block the checkpoint of not only the immune cells that are important to cancer therapy but also the immune cells that are irrelevant to the therapy. Such an indiscriminate blockade limits the efficacy and causes the autoimmune toxicity of the therapy. It might be beneficial to use a carrier to target immune checkpoint inhibitors to cancer-reactive immune cells. Here, we explore a method to load the inhibitors into carriers. We used the anti-programmed death-1 antibody (alphaPD-1) as a model immune checkpoint inhibitor. First, we generated a recombinant single-chain variable fragment (scFv) of alphaPD-1. Then, we designed and generated a fusion protein consisting of the scFv and an amphiphilic immune-tolerant elastin-like polypeptide (iTEP). Because of the amphiphilic iTEP, the fusion was able to self-assemble into a nanoparticle (NP). The NP was proved to block the PD-1 immune checkpoint in vitro and in vivo. Particularly, the NP exacerbated diabetes development in nonobese diabetic mice as effectively as natural, intact alphaPD-1. In summary, we successfully expressed alphaPD-1 as a recombinant protein and linked alphaPD-1 to a NP, which lays a foundation to develop a delivery system to target alphaPD-1 to a subpopulation of immune cells. ES - 1543-8392 IL - 1543-8384 DO - https://dx.doi.org/10.1021/acs.molpharmaceut.6b01021 PT - Journal Article ID - 10.1021/acs.molpharmaceut.6b01021 [doi] PP - ppublish LG - English EP - 20170419 DP - 2017 May 01 DC - 20170327 EZ - 2017/03/28 06:00 DA - 2017/03/28 06:00 DT - 2017/03/28 06:00 YR - 2017 RD - 20170501 UP - 20170502 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28343398 <420. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28073132 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Alhusseini M AU - Samantray J FA - Alhusseini, M FA - Samantray, J IN - Alhusseini, M. Division of Endocrinology, University Health Center, Wayne State University School of Medicine, Detroit, USA. IN - Samantray, J. Division of Endocrinology, University Health Center, Wayne State University School of Medicine, Detroit, USA. TI - Hypothyroidism in Cancer Patients on Immune Checkpoint Inhibitors with anti-PD1 Agents: Insights on Underlying Mechanisms. SO - Experimental & Clinical Endocrinology & Diabetes. 125(4):267-269, 2017 Apr AS - Exp Clin Endocrinol Diabetes. 125(4):267-269, 2017 Apr NJ - Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ccv, 9505926 IO - Exp. Clin. Endocrinol. Diabetes CP - Germany AB - Background: Immune therapy using monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) for various cancers have been reported to cause thyroid dysfunction. Little is known, however, about the underlying pathogenic mechanisms and the course of hypothyroidism that subsequently develops. In this report, we use the change in thyroglobulin and thyroid antibody levels in patients on immune therapy who develop hypothyroidism to better understand its pathogenesis as well as examine the status of hypothyroidism in the long term. Methods: We report a case series of 10 patients who developed hypothyroidism after initiation of immune therapy (either anti-PD-1 alone or in combination with anti-CTLA-4). Available thyroid antibodies including anti-thyroglobulin (anti-Tg), anti-thyroid peroxidase (anti-TPO), and thyroid stimulating immunoglobulin (TSI) were noted during the initial thyroiditis phase as well as the hypothyroid phase. Persistence or remission of hypothyroidism was noted at 6 months. Summary: During the thyroiditis phase, 50% of the patients had elevated Tg titers, 40% had elevated anti-Tg, and 40% had elevated TSI. All of these titers decreased during the hypothyroid phase. Permanent hypothyroidism was noted in 80% of the cases. Conclusion: Hypothyroidism following initiation of immune therapy has immunologic and non-immunologic mediated mechanisms and is likely to be persistent. AB - Copyright © Georg Thieme Verlag KG Stuttgart . New York. ES - 1439-3646 IL - 0947-7349 DO - https://dx.doi.org/10.1055/s-0042-119528 PT - Journal Article ID - 10.1055/s-0042-119528 [doi] PP - ppublish LG - English EP - 20170110 DP - 2017 Apr DC - 20170110 EZ - 2017/01/11 06:00 DA - 2017/01/11 06:00 DT - 2017/01/11 06:00 YR - 2017 RD - 20170426 UP - 20170427 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28073132 <421. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28421161 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Maughan BL AU - Bailey E AU - Gill DM AU - Agarwal N FA - Maughan, Benjamin L FA - Bailey, Erin FA - Gill, David M FA - Agarwal, Neeraj IN - Maughan, Benjamin L. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. IN - Maughan, Benjamin L. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. IN - Bailey, Erin. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. IN - Gill, David M. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. IN - Agarwal, Neeraj. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. IN - Agarwal, Neeraj. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. TI - Incidence of Immune-Related Adverse Events with Program Death Receptor-1- and Program Death Receptor-1 Ligand-Directed Therapies in Genitourinary Cancers. [Review] SO - Frontiers in Oncology. 7:56, 2017 AS - Front. oncol.. 7:56, 2017 NJ - Frontiers in oncology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101568867 IO - Front Oncol CP - Switzerland KW - autoimmune; checkpoint blockade; immune-related adverse events; immunotherapy; toxicity; treatment AB - Program death receptor-1 (PD-1) and program death receptor-1 ligand (PD-L1) inhibitors are increasingly being used in the clinic to treat a growing number of malignancies, including many genitourinary (GU) malignancies. These immune-based therapies have demonstrated a distinct toxicity profile compared to traditional chemotherapy and the targeted therapies directed at the vascular endothelial growth factor pathway or the mammalian target of rapamycin pathway. Autoimmune toxicity targeting the skin, gastrointestinal tract, or the endocrine organs are some of the more common adverse events (AEs) noted with these therapies. Here in, we report the results of a systematic review of the incidence of toxicities in GU cancers reported in the phase II or phase III clinical trials using single-agent PD-1 or PD-L1 inhibitors. Overall, the rate of serious (grades 3-4) AEs was noted in approximately 15% of patients. The AEs noted were similar between all the agents tested, highlighting the overall class effect of these therapies. The incidence in GU cancers is similar to those seen in other malignancies. Given the widespread and high volume real-world use of these agents, it is important for oncologists to be familiar with these side effects to minimize the risks for patients while undergoing therapy. IL - 2234-943X DO - https://dx.doi.org/10.3389/fonc.2017.00056 PT - Journal Article PT - Review ID - 10.3389/fonc.2017.00056 [doi] ID - PMC5377000 [pmc] PP - epublish PH - 2017/01/30 [received] PH - 2017/03/14 [accepted] LG - English EP - 20170403 DP - 2017 DC - 20170419 EZ - 2017/04/20 06:00 DA - 2017/04/20 06:00 DT - 2017/04/20 06:00 YR - 2017 RD - 20170423 UP - 20170425 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28421161 <422. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28088513 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Karasaki T AU - Nagayama K AU - Kuwano H AU - Nitadori JI AU - Sato M AU - Anraku M AU - Hosoi A AU - Matsushita H AU - Morishita Y AU - Kashiwabara K AU - Takazawa M AU - Ohara O AU - Kakimi K AU - Nakajima J FA - Karasaki, Takahiro FA - Nagayama, Kazuhiro FA - Kuwano, Hideki FA - Nitadori, Jun-Ichi FA - Sato, Masaaki FA - Anraku, Masaki FA - Hosoi, Akihiro FA - Matsushita, Hirokazu FA - Morishita, Yasuyuki FA - Kashiwabara, Kosuke FA - Takazawa, Masaki FA - Ohara, Osamu FA - Kakimi, Kazuhiro FA - Nakajima, Jun IN - Karasaki, Takahiro. Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IN - Nagayama, Kazuhiro. Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IN - Kuwano, Hideki. Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IN - Nitadori, Jun-Ichi. Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IN - Sato, Masaaki. Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IN - Anraku, Masaki. Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IN - Hosoi, Akihiro. Department of Immunotherapeutics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Medinet Co. Ltd., Yokohama, Japan. IN - Matsushita, Hirokazu. Department of Immunotherapeutics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IN - Morishita, Yasuyuki. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IN - Kashiwabara, Kosuke. Department of Biostatistics, School of Public Health, The University of Tokyo, Tokyo, Japan. IN - Takazawa, Masaki. Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan. IN - Ohara, Osamu. Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan. IN - Kakimi, Kazuhiro. Department of Immunotherapeutics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: kakimi@m.u-tokyo.ac.jp. IN - Nakajima, Jun. Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. TI - An Immunogram for the Cancer-Immunity Cycle: Towards Personalized Immunotherapy of Lung Cancer. SO - Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer. 12(5):791-803, 2017 May AS - J Thorac Oncol. 12(5):791-803, 2017 May NJ - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101274235 IO - J Thorac Oncol CP - United States KW - Cancer-immunity cycle; Immunogram; Lung cancer; Neoantigen; Transcriptome AB - INTRODUCTION: The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of antitumor immunity as a dynamic spatiotemporal process is required for each individual patient. To this end, we developed an immunogram for the cancer-immunity cycle by using next-generation sequencing. AB - METHODS: Whole exome sequencing and RNA sequencing were performed in 20 patients with NSCLC (12 with adenocarcinoma, seven with squamous cell carcinoma, and one with large cell neuroendocrine carcinoma). Mutated neoantigens and cancer germline antigens expressed in the tumor were assessed for predicted binding to patients' human leukocyte antigen molecules. The expression of genes related to cancer immunity was assessed and normalized to construct a radar chart composed of eight axes reflecting seven steps in the cancer-immunity cycle. AB - RESULTS: Three immunogram patterns were observed in patients with lung cancer: T-cell-rich, T-cell-poor, and intermediate. The T-cell-rich pattern was characterized by gene signatures of abundant T cells, regulatory T cells, myeloid-derived suppressor cells, checkpoint molecules, and immune-inhibitory molecules in the tumor, suggesting the presence of antitumor immunity dampened by an immunosuppressive microenvironment. The T-cell-poor phenotype reflected lack of antitumor immunity, inadequate dendritic cell activation, and insufficient antigen presentation in the tumor. Immunograms for both the patients with adenocarcinoma and the patients with nonadenocarcinoma tumors included both T-cell-rich and T-cell-poor phenotypes, suggesting that histologic type does not necessarily reflect the cancer immunity status of the tumor. AB - CONCLUSIONS: The patient-specific landscape of the tumor microenvironment can be appreciated by using immunograms as integrated biomarkers, which may thus become a valuable resource for optimal personalized immunotherapy. AB - Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. ES - 1556-1380 IL - 1556-0864 DI - S1556-0864(17)30008-4 DO - https://dx.doi.org/10.1016/j.jtho.2017.01.005 PT - Journal Article ID - S1556-0864(17)30008-4 [pii] ID - 10.1016/j.jtho.2017.01.005 [doi] PP - ppublish PH - 2016/08/31 [received] PH - 2016/11/21 [revised] PH - 2017/01/04 [accepted] LG - English EP - 20170111 DP - 2017 May DC - 20170115 EZ - 2017/01/16 06:00 DA - 2017/01/16 06:00 DT - 2017/01/16 06:00 YR - 2017 RD - 20170424 UP - 20170425 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28088513 <423. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28017788 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Usui Y AU - Udagawa H AU - Matsumoto S AU - Imai K AU - Ohashi K AU - Ishibashi M AU - Kirita K AU - Umemura S AU - Yoh K AU - Niho S AU - Osame K AU - Goto K FA - Usui, Yuko FA - Udagawa, Hibiki FA - Matsumoto, Shingo FA - Imai, Kenjiro FA - Ohashi, Ken FA - Ishibashi, Masayuki FA - Kirita, Keisuke FA - Umemura, Shigeki FA - Yoh, Kiyotaka FA - Niho, Seiji FA - Osame, Keiichiro FA - Goto, Koichi IN - Usui, Yuko. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. Electronic address: yusui@east.ncc.go.jp. IN - Udagawa, Hibiki. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. IN - Matsumoto, Shingo. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. IN - Imai, Kenjiro. Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan. IN - Ohashi, Ken. Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan. IN - Ishibashi, Masayuki. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. IN - Kirita, Keisuke. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. IN - Umemura, Shigeki. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. IN - Yoh, Kiyotaka. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. IN - Niho, Seiji. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. IN - Osame, Keiichiro. Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan. IN - Goto, Koichi. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. TI - Association of Serum Anti-GAD Antibody and HLA Haplotypes with Type 1 Diabetes Mellitus Triggered by Nivolumab in Patients with Non-Small Cell Lung Cancer. SO - Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer. 12(5):e41-e43, 2017 May AS - J Thorac Oncol. 12(5):e41-e43, 2017 May NJ - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101274235 IO - J Thorac Oncol CP - United States ES - 1556-1380 IL - 1556-0864 DI - S1556-0864(16)33605-X DO - https://dx.doi.org/10.1016/j.jtho.2016.12.015 PT - Journal Article ID - S1556-0864(16)33605-X [pii] ID - 10.1016/j.jtho.2016.12.015 [doi] PP - ppublish PH - 2016/10/17 [received] PH - 2016/12/08 [revised] PH - 2016/12/16 [accepted] LG - English EP - 20161223 DP - 2017 May DC - 20161226 EZ - 2016/12/27 06:00 DA - 2016/12/27 06:00 DT - 2016/12/27 06:00 YR - 2017 RD - 20170424 UP - 20170425 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28017788 <424. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28344807 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - King J AU - de la Cruz J AU - Lutzky J AI - de la Cruz, Javier; ISNI: 0000 0004 0430 4458 AI - de la Cruz, Javier; GRID: 0000 0004 0430 4458 FA - King, Jeanelle FA - de la Cruz, Javier FA - Lutzky, Jose IN - King, Jeanelle. Mount Sinai Comprehensive Cancer Center, Division of Hematology/Oncology, 4306 Alton Road, Miami Beach, FL 33140 USA. IN - de la Cruz, Javier. Mount Sinai Medical Center, Department of Internal Medicine, 4300 Alton Road, Miami Beach, FL 33140 USA. IN - Lutzky, Jose. Mount Sinai Comprehensive Cancer Center, Division of Hematology/Oncology, 4306 Alton Road, Miami Beach, FL 33140 USA. TI - Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP). SO - Journal for Immunotherapy of Cancer. 5:19, 2017 AS - J Immunother Cancer. 5:19, 2017 NJ - Journal for immunotherapy of cancer PI - Journal available in: Electronic-eCollection PI - Citation processed from: Internet JC - 101620585 IO - J Immunother Cancer CP - England AB - BACKGROUND: CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first immune checkpoint receptor clinically targeted for use in cancer treatment. It is expressed exclusively on T-cells where its primary role is to regulate the amplitude of the early stages of T-cell activation.1 Ipilimumab, a CTLA-4 blocking antibody, has been widely used for the treatment of patients with high risk and metastatic melanoma. Given its mechanism of action and consequent immune activation, the side effect profile of this drug greatly differs from that of standard cytotoxic chemotherapy. Adverse events are from the most part immune-mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis. AB - CASE PRESENTATION: We describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a 68 year-old woman with high risk, stage III melanoma occurring after 3 cycles of adjuvant treatment with ipilimumab as part of a clinical trial. AB - CONCLUSION: The range of immune-mediated adverse events during treatment with ipilimumab is wide and varied and clinicians should have a high degree of suspicion when managing these patients. ES - 2051-1426 IL - 2051-1426 DI - 224 DO - https://dx.doi.org/10.1186/s40425-017-0224-7 PT - Journal Article ID - 10.1186/s40425-017-0224-7 [doi] ID - 224 [pii] ID - PMC5360069 [pmc] PP - epublish PH - 2016/07/26 [received] PH - 2017/02/13 [accepted] LG - English EP - 20170321 DP - 2017 DC - 20170327 EZ - 2017/03/28 06:00 DA - 2017/03/28 06:00 DT - 2017/03/28 06:00 YR - 2017 RD - 20170421 UP - 20170424 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28344807 <425. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28239466 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Khan U AU - Rizvi H AU - Sano D AU - Chiu J AU - Hadid T AI - Khan, Uqba; ORCID: https://orcid.org/0000-0002-4740-2256 AI - Khan, Uqba; GRID: grid.416413.5 AI - Rizvi, Humaira; GRID: grid.416413.5 AI - Sano, Dahlia; GRID: grid.416413.5 AI - Chiu, Jane; GRID: grid.416413.5 AI - Hadid, Tarik; GRID: grid.416413.5 FA - Khan, Uqba FA - Rizvi, Humaira FA - Sano, Dahlia FA - Chiu, Jane FA - Hadid, Tarik IN - Khan, Uqba. Department of Hematology/Oncology, St. John Hospital and Medical Center, 19229 Mack Ave Suite 23 Grosse Pointe Woods, Detroit, 48236 Michigan USA. IN - Rizvi, Humaira. Department of Hematology/Oncology, St. John Hospital and Medical Center, 19229 Mack Ave Suite 23 Grosse Pointe Woods, Detroit, 48236 Michigan USA. IN - Sano, Dahlia. Department of Hematology/Oncology, St. John Hospital and Medical Center, 19229 Mack Ave Suite 23 Grosse Pointe Woods, Detroit, 48236 Michigan USA. IN - Chiu, Jane. Department of Hematology/Oncology, St. John Hospital and Medical Center, 19229 Mack Ave Suite 23 Grosse Pointe Woods, Detroit, 48236 Michigan USA. IN - Hadid, Tarik. Department of Hematology/Oncology, St. John Hospital and Medical Center, 19229 Mack Ave Suite 23 Grosse Pointe Woods, Detroit, 48236 Michigan USA. TI - Nivolumab induced myxedema crisis. SO - Journal for Immunotherapy of Cancer. 5:13, 2017 AS - J Immunother Cancer. 5:13, 2017 NJ - Journal for immunotherapy of cancer PI - Journal available in: Electronic-eCollection PI - Citation processed from: Internet JC - 101620585 IO - J Immunother Cancer CP - England KW - Hyperthyroidism; Immunotherapy; Myxedema crisis; Nivolumab AB - BACKGROUND: Nivolumab is an anti-programmed cell death (anti-PD-1) monoclonal antibody that is approved by Food and Drug Administration for treatment of metastatic non-small cell lung cancer, metastatic melanoma, relapsed Hodgkin lymphoma and advanced renal cell cancer. We report a rare case of myxedema crisis induced by nivolumab in a patient with metastatic squamous cell carcinoma of lung. AB - CASE PRESENTATION: Fifty three-year old woman with metastatic squamous cell carcinoma currently on treatment with nivolumab presented with diffuse facial and tongue swelling, slurred speech, depressed mentation, fatigue and weakness. Initial evaluation revealed severe hypothyroidism with thyroid stimulating hormone of 237 micro Unit/mL (Normal Reference range: 0.27-4.20 micro unit/mL) and undetectable free T4. Patient was diagnosed with nivolumab induced myxedema crisis. She was treated successfully with levothyroxine with complete resolution of her symptoms. Nivolumab was safely restarted once the symptoms of myxedema resolved. AB - CONCLUSION: Nivolumab can cause immune-mediated endocrinopathies including thyroiditis, hypophysitis, adrenal insufficiency and type 1 diabetes mellitus. High index of suspicion and periodic measurement of thyroid function tests are recommended in patients receiving nivolumab therapy. Our case also suggests that once the myxedema crisis is treated and symptoms are resolved, nivolumab can be safely re-challenged. ES - 2051-1426 IL - 2051-1426 DI - 213 DO - https://dx.doi.org/10.1186/s40425-017-0213-x PT - Journal Article ID - 10.1186/s40425-017-0213-x [doi] ID - 213 [pii] ID - PMC5319087 [pmc] PP - epublish PH - 2016/09/30 [received] PH - 2017/01/23 [accepted] LG - English EP - 20170221 DP - 2017 DC - 20170227 EZ - 2017/02/28 06:00 DA - 2017/02/28 06:00 DT - 2017/02/28 06:00 YR - 2017 RD - 20170421 UP - 20170424 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28239466 <426. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28174665 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Paraghamian SE AU - Longoria TC AU - Eskander RN AI - Paraghamian, Sarah E; ISNI: 0000 0004 0434 883X AI - Paraghamian, Sarah E; GRID: 0000 0004 0434 883X AI - Longoria, Teresa C; ISNI: 0000 0004 0434 883X AI - Longoria, Teresa C; GRID: 0000 0004 0434 883X AI - Eskander, Ramez N; ISNI: 0000 0004 0434 883X AI - Eskander, Ramez N; GRID: 0000 0004 0434 883X FA - Paraghamian, Sarah E FA - Longoria, Teresa C FA - Eskander, Ramez N IN - Paraghamian, Sarah E. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California Irvine Medical Center, 33 City Blvd. West #1400, Orange, CA 92868 USA. IN - Longoria, Teresa C. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California Irvine Medical Center, 33 City Blvd. West #1400, Orange, CA 92868 USA. IN - Eskander, Ramez N. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of California Irvine Medical Center, 33 City Blvd. West #1400, Orange, CA 92868 USA. TI - Metastatic small cell neuroendocrine carcinoma of the cervix treated with the PD-1 inhibitor, nivolumab: a case report. SO - Gynecologic Oncology Research and Practice. 4:3, 2017 AS - Gynecol Oncol Res Pract. 4:3, 2017 NJ - Gynecologic oncology research and practice PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101676223 IO - Gynecol Oncol Res Pract CP - England KW - Cervical cancer; Immunotherapy; Nivolumab; PD-1 inhibitor; Small cell neuroendocrine carcinoma AB - BACKGROUND: Nivolumab is an immune checkpoint inhibitor specific for the programmed death 1 (PD-1) receptor that has led to clinical responses in many cancer types. Identifying biomarkers predictive of response to PD-1 blockade is an area of active investigation. AB - CASE PRESENTATION: We present a patient with recurrent, metastatic, PD-L1-negative small cell neuroendocrine carcinoma of the cervix (SCNEC) who experienced a complete response to nivolumab. Though nivolumab was discontinued over 4 months ago due to treatment-related adverse events, she continues to have no evidence of disease. AB - CONCLUSIONS: Immune checkpoint inhibitors may be active in neuroendocrine cervical cancer, with potential for dramatic responses in a modest subset of patients. IL - 2053-6844 DI - 38 DO - https://dx.doi.org/10.1186/s40661-017-0038-9 PT - Journal Article ID - 10.1186/s40661-017-0038-9 [doi] ID - 38 [pii] ID - PMC5290639 [pmc] PP - epublish PH - 2016/12/31 [received] PH - 2017/01/21 [accepted] LG - English EP - 20170202 DP - 2017 DC - 20170208 EZ - 2017/02/09 06:00 DA - 2017/02/09 06:00 DT - 2017/02/09 06:00 YR - 2017 RD - 20170421 UP - 20170424 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28174665 <427. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28275115 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Nishijima TF AU - Shachar SS AU - Nyrop KA AU - Muss HB FA - Nishijima, Tomohiro F FA - Shachar, Shlomit S FA - Nyrop, Kirsten A FA - Muss, Hyman B IN - Nishijima, Tomohiro F. UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA Tomohiro.Nishijima@unchealth.unc.edu. IN - Shachar, Shlomit S. Division of Oncology, Rambam Health Care Campus, Haifa, Israel. IN - Nyrop, Kirsten A. UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA. IN - Muss, Hyman B. UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA. TI - Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis. [Review] SO - Oncologist. 22(4):470-479, 2017 Apr AS - Oncologist. 22(4):470-479, 2017 Apr NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist CP - United States KW - Chemotherapy; Meta-analysis; PD-1/PD-L1 inhibitor; Systematic review; Toxicity AB - BACKGROUND: Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy. AB - METHODS: PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single-agent U.S. Food and Drug Administration-approved PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all-grade (1-4) or high-grade (3-4) adverse events (AEs), all- or high-grade treatment-related symptoms, hematologic toxicities and immune-related AEs, treatment discontinuation due to toxicities, or treatment-related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated. AB - RESULTS: A total of 3,450 patients from 7 RCTs were included in the meta-analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non-small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD-1/PD-L1 inhibitors had a significantly lower risk of all- and high-grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all-grade anorexia, nausea, and constipation, any all- and high-grade AEs, and treatment discontinuation. There was an increased risk of all-grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all- and high-grade pneumonitis with PD1/PD-L1 inhibitors. AB - CONCLUSION: PD-1/PD-L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD-1/PD-L1 inhibitors. The Oncologist 2017;22:470-479 IMPLICATIONS FOR PRACTICE: We conducted a systematic review and meta-analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy. PD1/PD-L1 inhibitors were associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune-related adverse events (AEs). Summary toxicity endpoints favor PD1/PD-L1 inhibitors (any all- and high-grade AEs and treatment discontinuation). PD1/PD-L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well-balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer. AB - Copyright © AlphaMed Press 2017. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2016-0419 DO - https://dx.doi.org/10.1634/theoncologist.2016-0419 PT - Journal Article PT - Review ID - theoncologist.2016-0419 [pii] ID - 10.1634/theoncologist.2016-0419 [doi] ID - PMC5388381 [pmc] PP - ppublish PH - 2016/10/22 [received] PH - 2016/12/16 [accepted] PH - 2018/04/01 [pmc-release] LG - English EP - 20170308 DP - 2017 Apr DC - 20170309 EZ - 2017/03/10 06:00 DA - 2017/03/10 06:00 DT - 2017/03/10 06:00 YR - 2017 RD - 20170416 UP - 20170418 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28275115 <428. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28393006 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Imakita T AU - Fujita K AU - Kanai O AU - Terashima T AU - Mio T FA - Imakita, Takuma FA - Fujita, Kohei FA - Kanai, Osamu FA - Terashima, Tsuyoshi FA - Mio, Tadashi IN - Imakita, Takuma. Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, Japan; Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan. IN - Fujita, Kohei. Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, Japan. IN - Kanai, Osamu. Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, Japan. IN - Terashima, Tsuyoshi. Division of Clinical Pathology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan. IN - Mio, Tadashi. Division of Respiratory Medicine, National Hospital Organization Kyoto Medical Center, Kyoto, Japan. TI - Small cell lung cancer transformation during immunotherapy with nivolumab: A case report. SO - Respiratory Medicine Case Reports. 21:52-55, 2017 AS - Respir Med Case Rep. 21:52-55, 2017 NJ - Respiratory medicine case reports PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101604463 IO - Respir Med Case Rep CP - England KW - Immune checkpoint inhibitor; NSCLC; Nivolumab; SCLC transformation AB - We report a rare case of transformation of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC), without epidermal growth factor receptor (EGFR) gene mutation, during immunotherapy treatment with nivolumab. A 75-year-old man was referred to our hospital following the observation of a 64 mm mass in a chest computed tomography (CT) scan. A transbronchial biopsy of the mass identified the pathological presence of poorly differentiated NSCLC, with no histological signs of SCLC. No mutations were identified in the EGFR gene. A clinical diagnosis of NSCLC (cT3N3M1a, stage IV) was made following a positron emission tomography (PET)-CT scan and enhanced brain magnetic resonance imaging. Docetaxel and bevacizumab were selected as the first-line chemotherapy regimen; however, after two cycles, the patient developed a gastrointestinal perforation, and discontinuation of cytotoxic chemotherapy was recommended. Owing to gradual disease progression, immunotherapy with nivolumab was selected as the second-line regimen. During the immunotherapy, the tumor continued to progress and some subcutaneous tumors emerged. Biopsy of a subcutaneous tumor revealed SCLC, with positive immunostaining for cluster of differentiation 56, synaptophysin, and thyroid transcription factor-1. Serum tumor markers of SCLC were also elevated. Based on these results, we concluded that in this case NSCLC had transformed to SCLC during immunotherapy with nivolumab. IL - 2213-0071 DI - S2213-0071(17)30096-5 DO - https://dx.doi.org/10.1016/j.rmcr.2017.03.019 PT - Journal Article ID - 10.1016/j.rmcr.2017.03.019 [doi] ID - S2213-0071(17)30096-5 [pii] ID - PMC5376266 [pmc] PP - epublish PH - 2017/03/14 [received] PH - 2017/03/26 [revised] PH - 2017/03/27 [accepted] LG - English EP - 20170329 DP - 2017 DC - 20170410 EZ - 2017/04/11 06:00 DA - 2017/04/11 06:00 DT - 2017/04/11 06:00 YR - 2017 RD - 20170413 UP - 20170417 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28393006 <429. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27934619 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Ishikawa K AU - Shono-Saito T AU - Yamate T AU - Kai Y AU - Sakai T AU - Shimizu F AU - Yamada Y AU - Mori H AU - Noso S AU - Ikegami H AU - Kojima H AU - Tanaka H AU - Fujiwara S AU - Hatano Y FA - Ishikawa, Kazushi FA - Shono-Saito, Tomoko FA - Yamate, Tomoko FA - Kai, Yoshitaka FA - Sakai, Takashi FA - Shimizu, Fumiaki FA - Yamada, Yasunari FA - Mori, Hiromu FA - Noso, Shinsuke FA - Ikegami, Hiroshi FA - Kojima, Hiroto FA - Tanaka, Hidenori FA - Fujiwara, Sakuhei FA - Hatano, Yutaka IN - Ishikawa, Kazushi. Department of Dermatology. IN - Shono-Saito, Tomoko. Department of Dermatology. IN - Yamate, Tomoko. Department of Dermatology. IN - Kai, Yoshitaka. Department of Dermatology. IN - Sakai, Takashi. Department of Dermatology. IN - Shimizu, Fumiaki. Department of Plastic Surgery. IN - Yamada, Yasunari. Department of Radiology Faculty of Medicine, Oita University 1-1 Idaigaoka, Hasama-machi Yufu 879-5593, Japan. IN - Mori, Hiromu. Department of Radiology Faculty of Medicine, Oita University 1-1 Idaigaoka, Hasama-machi Yufu 879-5593, Japan. IN - Noso, Shinsuke. Department of Endocrinology Metabolism and Diabetes, Kindai University Faculty of Medicine 377-2 Ohno-higashi, Osaka-sayama Osaka 589-8511, Japan. IN - Ikegami, Hiroshi. Department of Endocrinology Metabolism and Diabetes, Kindai University Faculty of Medicine 377-2 Ohno-higashi, Osaka-sayama Osaka 589-8511, Japan. IN - Kojima, Hiroto. HLA Foundation Laboratory Kyoto, Japan. IN - Tanaka, Hidenori. HLA Foundation Laboratory Kyoto, Japan. IN - Fujiwara, Sakuhei. Department of Dermatology. IN - Hatano, Yutaka. Department of Dermatology. TI - A case of fulminant type 1 diabetes mellitus, with a precipitous decrease in pancreatic volume, induced by nivolumab for malignant melanoma: analysis of HLA and CTLA-4 polymorphisms. SO - European Journal of Dermatology. 27(2):184-185, 2017 Apr 01 AS - Eur J Dermatol. 27(2):184-185, 2017 Apr 01 NJ - European journal of dermatology : EJD PI - Journal available in: Print PI - Citation processed from: Internet JC - c4s, 9206420 IO - Eur J Dermatol CP - France ES - 1952-4013 IL - 1167-1122 DI - ejd.2016.2923 DO - https://dx.doi.org/10.1684/ejd.2016.2923 PT - Journal Article ID - ejd.2016.2923 [pii] ID - 10.1684/ejd.2016.2923 [doi] PP - ppublish LG - English DP - 2017 Apr 01 DC - 20161209 EZ - 2016/12/10 06:00 DA - 2016/12/10 06:00 DT - 2016/12/10 06:00 YR - 2017 RD - 20170412 UP - 20170413 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27934619 <430. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28246759 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Foller S AU - Oppel-Heuchel H AU - Fetter I AU - Winkler Y AU - Grimm MO FA - Foller, S FA - Oppel-Heuchel, H FA - Fetter, I FA - Winkler, Y FA - Grimm, M-O IN - Foller, S. Urologische Klinik und Poliklinik, Universitatsklinikum Jena, Lessingstrase 1, 07743, Jena, Deutschland. Susan.Foller@med.uni-jena.de. IN - Oppel-Heuchel, H. Urologische Klinik und Poliklinik, Universitatsklinikum Jena, Lessingstrase 1, 07743, Jena, Deutschland. IN - Fetter, I. Urologische Klinik und Poliklinik, Universitatsklinikum Jena, Lessingstrase 1, 07743, Jena, Deutschland. IN - Winkler, Y. Urologische Klinik und Poliklinik, Universitatsklinikum Jena, Lessingstrase 1, 07743, Jena, Deutschland. IN - Grimm, M-O. Urologische Klinik und Poliklinik, Universitatsklinikum Jena, Lessingstrase 1, 07743, Jena, Deutschland. TI - [Adverse events of immune checkpoint inhibitors]. [German] OT - Nebenwirkungen der Immun-Checkpoint-Inhibitoren. SO - Urologe (Ausg. A). 56(4):486-491, 2017 Apr AS - Urologe A. 56(4):486-491, 2017 Apr NJ - Der Urologe. Ausg. A PI - Journal available in: Print PI - Citation processed from: Internet JC - wsj, 1304110 IO - Urologe A CP - Germany KW - Adverse events, immune-mediated; Corticosteroids; Immunotherapy; PD-1 inhibitor; PD-L1 inhibitor AB - After immune checkpoint inhibitor therapy was approved for renal cell carcinoma last year, this new immune therapy has spread to urology. Further approvals (atezolizumab, nivolumab, pembrolizumab) are expected in 2017 for metastatic urothelial carcinoma that has progressed following treatment with platinum-based chemotherapy. With expanding use of immune checkpoint inhibitors, experience in diagnosing and managing immune-mediated adverse events increases. Although of low incidence, grade 3/4 toxicities play a central role. Organs most common for immune-mediated adverse events are skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and colitis), lungs (pneumonitis), and endocrine organs (hyper-, hypothyroidism and hypophysitis). Diagnostic workup includes routine laboratory tests (including liver function tests) and may be supplemented with hormone values. In cases of pneumonitis or hypophysitis, imaging (high-resolution CT, MRI) can confirm diagnoses. Immune-mediated toxicities are treated with therapy interruption and administration of corticosteroids (and in individual cases additional immunosuppression). Dose modification is not intended! ES - 1433-0563 IL - 0340-2592 DI - 10.1007/s00120-017-0342-3 DO - https://dx.doi.org/10.1007/s00120-017-0342-3 PT - English Abstract PT - Journal Article ID - 10.1007/s00120-017-0342-3 [doi] ID - 10.1007/s00120-017-0342-3 [pii] PP - ppublish LG - German DP - 2017 Apr DC - 20170301 EZ - 2017/03/02 06:00 DA - 2017/03/02 06:00 DT - 2017/03/02 06:00 YR - 2017 RD - 20170408 UP - 20170410 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28246759 <431. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27825291 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Shi RL AU - Qu N AU - Luo TX AU - Xiang J AU - Liao T AU - Sun GH AU - Wang Y AU - Wang YL AU - Huang CP AU - Ji QH FA - Shi, Rong-Liang FA - Qu, Ning FA - Luo, Ting-Xian FA - Xiang, Jun FA - Liao, Tian FA - Sun, Guo-Hua FA - Wang, Yu FA - Wang, Yu-Long FA - Huang, Cai-Ping FA - Ji, Qing-Hai IN - Shi, Rong-Liang. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Shi, Rong-Liang. 2 Department of General Surgery, Minhang Hospital, Fudan University , Shanghai, China . IN - Qu, Ning. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Luo, Ting-Xian. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Xiang, Jun. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Liao, Tian. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Sun, Guo-Hua. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Wang, Yu. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Wang, Yu-Long. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Huang, Cai-Ping. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . IN - Ji, Qing-Hai. 1 Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University , Shanghai, China . TI - Programmed Death-Ligand 1 Expression in Papillary Thyroid Cancer and Its Correlation with Clinicopathologic Factors and Recurrence. SO - Thyroid. 27(4):537-545, 2017 Apr AS - Thyroid. 27(4):537-545, 2017 Apr NJ - Thyroid : official journal of the American Thyroid Association PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bjw, 9104317 IO - Thyroid CP - United States KW - biological marker; papillary thyroid cancer; programmed death-ligand 1; survival analysis AB - BACKGROUND: Programmed death-ligand 1 (PD-L1) expression has been reported in several malignancies, but the expression of PD-L1 in papillary thyroid cancer (PTC) has been characterized rarely. The aim of this study was to assess the significance of PD-L1 expression and its associations with clinicopathologic factors and disease outcome in PTC. AB - METHODS: Immunohistochemistry staining was conducted retrospectively to evaluate the expression of PD-L1 in a total of 260 PTC tumors and corresponding non-tumor tissues. The correlations between PD-L1 expressions with clinicopathologic features and recurrence-free survival (RFS) were analyzed. AB - RESULTS: PD-L1 expression was positive in 52.3% (136/260) of PTC tumor tissues, which was significantly higher than in corresponding non-tumor thyroid tissues. In clinicopathologic analyses, this positive staining of PD-L1 was positively linked to multifocality (p=0.001) and extrathyroidal extension (p=0.001). In multivariate Cox regression analysis, positive PD-L1 expression in tumor tissue was significantly associated with worse RFS (hazard ratio 2.825 [confidence interval 1.149-6.943], p=0.024). In subgroup analyses based on clinicopathologic factors, positive PD-L1 staining of tumor tissue was associated with worse RFS in males (p=0.001), older patients (>=45 years; p=0.001), and patients with a primary tumor size >4cm (p=0.002), multifocal tumors (p=0.031), extrathyroidal extension (p=0.012), and lymph node metastasis (p=0.004). In contrast, positive PD-L1 staining predicted worse RFS in the subgroup of patients without Hashimoto's thyroiditis (p=0.001) and treated with total thyroidectomy (p=0.019). AB - CONCLUSIONS: PD-L1 is important in determining aggressiveness of PTC and could predict the prognosis of patients. Therefore, inhibition of PD-L1 is suggested as a potential strategy for the treatment of advanced PTC with high expression of PD-L1. ES - 1557-9077 IL - 1050-7256 DO - https://dx.doi.org/10.1089/thy.2016.0228 PT - Journal Article ID - 10.1089/thy.2016.0228 [doi] PP - ppublish LG - English EP - 20170124 DP - 2017 Apr DC - 20161109 EZ - 2016/11/10 06:00 DA - 2016/11/09 06:00 DT - 2016/11/09 06:00 YR - 2017 RD - 20170404 UP - 20170406 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27825291 <432. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28345313 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Hwangbo Y AU - Lee EK AI - Lee, Eun Kyung; ORCID: http://orcid.org/0000-0003-0098-0873 FA - Hwangbo, Yul FA - Lee, Eun Kyung IN - Hwangbo, Yul. Department of Internal Medicine, Center for Thyroid Cancer, National Cancer Center, Goyang, Korea. IN - Lee, Eun Kyung. Department of Internal Medicine, Center for Thyroid Cancer, National Cancer Center, Goyang, Korea. waterfol@ncc.re.kr. TI - Acute Hyperglycemia Associated with Anti-Cancer Medication. [Review] SO - Endocrinology and Metabolism. 32(1):23-29, 2017 Mar AS - Endocrinol Metab (Seoul). 32(1):23-29, 2017 Mar NJ - Endocrinology and metabolism (Seoul, Korea) PI - Journal available in: Print PI - Citation processed from: Print JC - 101554139 IO - Endocrinol Metab (Seoul) CP - Korea (South) KW - Cytotoxic chemotherapy; Drug therapy; Hyperglycemia; Immunotherapy; Mammalian target of rapamycin inhibitor; Neoplasms AB - Hyperglycemia during chemotherapy occurs in approximately 10% to 30% of patients. Glucocorticoids and L-asparaginase are well known to cause acute hyperglycemia during chemotherapy. Long-term hyperglycemia is also frequently observed, especially in patients with hematologic malignancies treated with L-asparaginase-based regimens and total body irradiation. Glucocorticoid-induced hyperglycemia often develops because of increased insulin resistance, diminished insulin secretion, and exaggerated hepatic glucose output. Screening strategies for this condition include random glucose testing, hemoglobin A1c testing, oral glucose loading, and fasting plasma glucose screens. The management of hyperglycemia starts with insulin or sulfonylurea, depending on the type, dose, and delivery of the glucocorticoid formulation. Mammalian target of rapamycin (mTOR) inhibitors are associated with a high incidence of hyperglycemia, ranging from 13% to 50%. Immunotherapy, such as anti-programmed death 1 (PD-1) antibody treatment, induces hyperglycemia with a prevalence of 0.1%. The proposed mechanism of immunotherapy-induced hyperglycemia is an autoimmune process (insulitis). Withdrawal of the PD-1 inhibitor is the primary treatment for severe hyperglycemia. The efficacy of glucocorticoid therapy is not fully established and the decision to resume PD-1 inhibitor therapy depends on the severity of the hyperglycemia. Diabetic patients should achieve optimized glycemic control before initiating treatment, and glucose levels should be monitored periodically in patients initiating mTOR inhibitor or PD-1 inhibitor therapy. With regard to hyperglycemia caused by anti-cancer therapy, frequent monitoring and proper management are important for promoting the efficacy of anti-cancer therapy and improving patients' quality of life. AB - Copyright © 2017 Korean Endocrine Society. CI - No potential conflict of interest relevant to this article was reported. IS - 2093-596X IL - 2093-596X DI - 32.23 DO - https://dx.doi.org/10.3803/EnM.2017.32.1.23 PT - Journal Article PT - Review ID - 32.23 [pii] ID - 10.3803/EnM.2017.32.1.23 [doi] ID - PMC5368117 [pmc] PP - ppublish PH - 2017/01/16 [received] PH - 2017/02/01 [revised] PH - 2017/02/16 [accepted] LG - English DP - 2017 Mar DC - 20170327 EZ - 2017/03/28 06:00 DA - 2017/03/28 06:00 DT - 2017/03/28 06:00 YR - 2017 RD - 20170403 UP - 20170404 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28345313 <433. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28255845 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Hickmott L AU - De La Pena H AU - Turner H AU - Ahmed F AU - Protheroe A AU - Grossman A AU - Gupta A AI - Hickmott, Laura; ORCID: http://orcid.org/0000-0002-5119-6416 FA - Hickmott, Laura FA - De La Pena, Hugo FA - Turner, Helen FA - Ahmed, Fathelrahman FA - Protheroe, Andrew FA - Grossman, Ashley FA - Gupta, Avinash IN - Hickmott, Laura. Department of Oncology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK. laura.hickmott@nhs.net. IN - De La Pena, Hugo. Department of Oncology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK. IN - Turner, Helen. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK. IN - Ahmed, Fathelrahman. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK. IN - Protheroe, Andrew. Department of Oncology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK. IN - Grossman, Ashley. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK. IN - Gupta, Avinash. Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK. TI - Anti-PD-L1 atezolizumab-Induced Autoimmune Diabetes: a Case Report and Review of the Literature. [Review] SO - Targeted Oncology. 12(2):235-241, 2017 Apr AS - Target. oncol.. 12(2):235-241, 2017 Apr NJ - Targeted oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - 101270595 IO - Target Oncol CP - France AB - Programmed cell death-1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors trigger an immune-mediated anti-tumour response by promoting the activation of cytotoxic T lymphocytes. Although proven to be highly effective in the treatment of several malignancies they can induce significant immune-related adverse events (irAEs) including endocrinopathies, most commonly hypophysitis and thyroid dysfunction, and rarely autoimmune diabetes. Here we present the first case report of a patient with a primary diagnosis of urothelial cancer developing PD-L1 inhibitor-induced autoimmune diabetes. A euglycemic 57 year old male presented to clinic with dehydration after the fifth cycle of treatment with the novel PD-L1 inhibitor atezolizumab. Blood tests demonstrated rapid onset hyperglycaemia (BM 24 mmol/L), ketosis and a low C-peptide level (0.65 ng/mL) confirming the diagnosis of type 1 diabetes. He responded well to insulin therapy and was discharged with stable blood glucose levels. Due to the widening use of PD-1/PD-L1 inhibitors in cancer treatment clinicians need to be aware of this rare yet treatable irAE. Given the morbidity and mortality associated with undiagnosed autoimmune diabetes we recommend routine HbA1c and plasma glucose testing in all patients prior to and during treatment with PD-1/PD-L1 inhibitors until more evidence has accumulated on identifying those patients with a pre-treatment risk of such irAEs. ES - 1776-260X IL - 1776-2596 DI - 10.1007/s11523-017-0480-y DO - https://dx.doi.org/10.1007/s11523-017-0480-y PT - Journal Article PT - Review ID - 10.1007/s11523-017-0480-y [doi] ID - 10.1007/s11523-017-0480-y [pii] PP - ppublish LG - English DP - 2017 Apr DC - 20170303 EZ - 2017/03/04 06:00 DA - 2017/03/04 06:00 DT - 2017/03/04 06:00 YR - 2017 RD - 20170329 UP - 20170330 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28255845 <434. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28315541 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Vazquez A FA - Vazquez, Adrienne IN - Vazquez, Adrienne. University of Miami. TI - Hypophysitis: Nursing Management of Immune-Related Adverse Events. SO - Clinical Journal of Oncology Nursing. 21(2):154-156, 2017 Apr 01 AS - Clin J Oncol Nurs. 21(2):154-156, 2017 Apr 01 NJ - Clinical journal of oncology nursing PI - Journal available in: Print PI - Citation processed from: Internet JC - czm, 9705336 IO - Clin J Oncol Nurs CP - United States KW - hypophysitis; immune-related adverse events; immunotherapy; pituitary gland; steroids AB - Immunotherapy can treat cancer and prevent future cancer relapse by enhancing the body's immune system. With novel immunotherapeutic agents like checkpoint inhibitors come unique immune-related adverse events. Hypophysitis, one of the lesser known immune-related complications, may be observed in patients receiving checkpoint inhibitors. Although the acute symptoms of immune-related hypophysitis may be managed with attentive monitoring and high-dose corticosteroids, lifelong hormone substitution therapy may be warranted. Oncology nurses are responsible for educating themselves and their patients on the complications of immunotherapy.. ES - 1538-067X IL - 1092-1095 DO - https://dx.doi.org/10.1188/17.CJON.154-156 PT - Journal Article ID - 10.1188/17.CJON.154-156 [doi] PP - ppublish LG - English DP - 2017 Apr 01 DC - 20170318 EZ - 2017/03/19 06:00 DA - 2017/03/21 06:00 DT - 2017/03/21 06:00 YR - 2017 RD - 20170318 UP - 20170322 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28315541 <435. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28028828 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Morganstein DL AU - Lai Z AU - Spain L AU - Diem S AU - Levine D AU - Mace C AU - Gore M AU - Larkin J AI - Morganstein, D L; ORCID: http://orcid.org/0000-0003-1565-8617 FA - Morganstein, D L FA - Lai, Z FA - Spain, L FA - Diem, S FA - Levine, D FA - Mace, C FA - Gore, M FA - Larkin, J IN - Morganstein, D L. Skin Unit, Royal Marsden Hospital, London, UK. IN - Morganstein, D L. Department of Endocrinology, Chelsea and Westminster Hospital, London, UK. IN - Lai, Z. Skin Unit, Royal Marsden Hospital, London, UK. IN - Lai, Z. Department of Endocrinology, Chelsea and Westminster Hospital, London, UK. IN - Spain, L. Skin Unit, Royal Marsden Hospital, London, UK. IN - Diem, S. Skin Unit, Royal Marsden Hospital, London, UK. IN - Diem, S. Department of Oncology/Hematology, Cantonal Hospital St. Gallen, Switzerland, Switzerland. IN - Diem, S. Department of Oncology/Hematology, Hospital Grabs, Switzerland. IN - Levine, D. Department of Nuclear Medicine, Royal Marsden Hospital, London, UK. IN - Mace, C. Department of Endocrinology, Chelsea and Westminster Hospital, London, UK. IN - Gore, M. Skin Unit, Royal Marsden Hospital, London, UK. IN - Larkin, J. Skin Unit, Royal Marsden Hospital, London, UK. TI - Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. SO - Clinical Endocrinology. 86(4):614-620, 2017 Apr AS - Clin Endocrinol (Oxf). 86(4):614-620, 2017 Apr NJ - Clinical endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dci, 0346653 IO - Clin. Endocrinol. (Oxf) CP - England AB - CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy. AB - OBJECTIVE: To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course. AB - DESIGN AND PATIENTS: Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction. AB - RESULTS: Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13.0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22.2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13.0% treated with a PD-1 inhibitor, 15.9% following a PD-1 inhibitor, and 22.2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23.0% following ipilimumab, 39.1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients. AB - CONCLUSION: Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%. AB - Copyright © 2016 John Wiley & Sons Ltd. ES - 1365-2265 IL - 0300-0664 DO - https://dx.doi.org/10.1111/cen.13297 PT - Journal Article ID - 10.1111/cen.13297 [doi] PP - ppublish PH - 2016/08/15 [received] PH - 2016/11/14 [revised] PH - 2016/12/19 [revised] PH - 2016/12/20 [accepted] LG - English EP - 20170127 DP - 2017 Apr DC - 20161228 EZ - 2016/12/29 06:00 DA - 2016/12/29 06:00 DT - 2016/12/29 06:00 YR - 2017 RD - 20170316 UP - 20170317 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28028828 <436. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27879975 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Walocko FM AU - Scheier BY AU - Harms PW AU - Fecher LA AU - Lao CD FA - Walocko, Frances M FA - Scheier, Benjamin Y FA - Harms, Paul W FA - Fecher, Leslie A FA - Lao, Christopher D IN - Walocko, Frances M. University of Michigan Medical School, Ann Arbor, MI USA. IN - Scheier, Benjamin Y. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C451 Med Inn, 1500 East Medical Center Drive, Ann Arbor, MI 48109 USA. IN - Harms, Paul W. Department of Pathology, University of Michigan, Ann Arbor, MI USA ; Department of Dermatology, University of Michigan, Ann Arbor, MI USA. IN - Fecher, Leslie A. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C451 Med Inn, 1500 East Medical Center Drive, Ann Arbor, MI 48109 USA. IN - Lao, Christopher D. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C451 Med Inn, 1500 East Medical Center Drive, Ann Arbor, MI 48109 USA. TI - Metastatic Merkel cell carcinoma response to nivolumab.[Erratum appears in J Immunother Cancer. 2017 Mar 6;5:27; PMID: 28286652] SO - Journal for Immunotherapy of Cancer. 4:79, 2016 AS - J Immunother Cancer. 4:79, 2016 NJ - Journal for immunotherapy of cancer PI - Journal available in: Electronic-eCollection PI - Citation processed from: Internet JC - 101620585 IO - J Immunother Cancer CP - England KW - Case report; Immunotherapy; Merkel cell carcinoma; Nivolumab; PD-L1; Polyomavirus AB - BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with limited treatment options. Several lines of evidence support the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis as a likely contributor to immune evasion in MCC. AB - CASE PRESENTATION: We report a case of a patient with metastatic MCC with a significant and durable response to nivolumab, a humanized IgG4 monoclonal anti-PD-1 antibody. AB - CONCLUSION: Immunotherapy with PD-1/PD-L1 inhibitors has become a rational and promising treatment option for MCC in the advanced or metastatic disease. Clinical trials are currently in progress to further evaluate these novel therapeutic agents. ES - 2051-1426 IL - 2051-1426 DI - 186 DO - https://dx.doi.org/10.1186/s40425-016-0186-1 PT - Journal Article ID - 10.1186/s40425-016-0186-1 [doi] ID - 186 [pii] ID - PMC5109712 [pmc] PP - epublish PH - 2016/08/22 [received] PH - 2016/11/01 [accepted] LG - English EP - 20161115 DP - 2016 DC - 20161123 EZ - 2016/11/24 06:00 DA - 2016/11/24 06:00 DT - 2016/11/24 06:00 YR - 2016 RD - 20170313 UP - 20170314 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27879975 <437. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27829150 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Jiang TT AU - Martinov T AU - Xin L AU - Kinder JM AU - Spanier JA AU - Fife BT AU - Way SS FA - Jiang, Tony T FA - Martinov, Tijana FA - Xin, Lijun FA - Kinder, Jeremy M FA - Spanier, Justin A FA - Fife, Brian T FA - Way, Sing Sing IN - Jiang, Tony T. Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. IN - Martinov, Tijana. Center for Immunology, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA. IN - Xin, Lijun. Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. IN - Kinder, Jeremy M. Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. IN - Spanier, Justin A. Center for Immunology, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA. IN - Fife, Brian T. Center for Immunology, Department of Medicine, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA. Electronic address: bfife@umn.edu. IN - Way, Sing Sing. Division of Infectious Diseases and Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. Electronic address: singsing.way@cchmc.org. TI - Programmed Death-1 Culls Peripheral Accumulation of High-Affinity Autoreactive CD4 T Cells to Protect against Autoimmunity. SO - Cell Reports. 17(7):1783-1794, 2016 Nov 08 AS - Cell Rep. 17(7):1783-1794, 2016 Nov 08 NJ - Cell reports PI - Journal available in: Print PI - Citation processed from: Internet JC - 101573691 IO - Cell Rep CP - United States KW - T cell activation; autoimmunity; costimulation; peripheral immune tolerance AB - Self-reactive CD4 T cells are incompletely deleted during thymic development, and their peripheral seeding highlights the need for additional safeguards to avert autoimmunity. Here, we show an essential role for the coinhibitory molecule programmed death-1 (PD-1) in silencing the activation of high-affinity autoreactive CD4 T cells. Each wave of self-reactive CD4 T cells that escapes thymic deletion autonomously upregulates PD-1 to maintain self-tolerance. By tracking the progeny derived from individual autoreactive CD4 T cell clones, we demonstrate that self-reactive cells with the greatest autoimmune threat and highest self-antigen affinity express the most PD-1. Reciprocally, PD-1 deprivation unleashes high-affinity self-reactive CD4 T cells in target tissues to exacerbate neuronal inflammation and autoimmune diabetes. Reliance on PD-1 to actively maintain self-tolerance may explain why exploiting this pathway by cancerous cells and invasive microbes efficiently subverts protective immunity, and why autoimmune side effects can develop after PD-1-neutralizing checkpoint therapies. AB - Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved. ES - 2211-1247 DI - S2211-1247(16)31462-0 DO - https://dx.doi.org/10.1016/j.celrep.2016.10.042 PT - Journal Article ID - S2211-1247(16)31462-0 [pii] ID - 10.1016/j.celrep.2016.10.042 [doi] ID - PMC5108556 [pmc] ID - NIHMS824882 [mid] PP - ppublish PH - 2016/07/25 [received] PH - 2016/09/25 [revised] PH - 2016/10/13 [accepted] GI - No: R01 AI120202 Organization: (AI) *NIAID NIH HHS* Country: United States No: HHSN272201300006C Organization: (AI) *NIAID NIH HHS* Country: United States No: R01 AI106791 Organization: (AI) *NIAID NIH HHS* Country: United States No: F30 DK107199 Organization: (DK) *NIDDK NIH HHS* Country: United States No: T32 GM063483 Organization: (GM) *NIGMS NIH HHS* Country: United States No: T32 DK007203 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English DP - 2016 Nov 08 DC - 20161109 EZ - 2016/11/10 06:00 DA - 2016/11/10 06:00 DT - 2016/11/10 06:00 YR - 2016 RD - 20170311 UP - 20170313 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27829150 <438. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28231723 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Shang YH AU - Zhang Y AU - Li JH AU - Li P AU - Zhang X FA - Shang, Yan Hong FA - Zhang, Yu FA - Li, Jing Hua FA - Li, Peng FA - Zhang, Xi IN - Shang, Yan Hong. Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding 071000, P R China. IN - Zhang, Yu. Department of internal Medicine, Baoding Children's Hospital, Baoding 071000, P R China. IN - Li, Jing Hua. Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding 071000, P R China. IN - Li, Peng. Departments of Ultrasound, Affiliated Hospital of Hebei University, Baoding 071000, P R China. IN - Zhang, Xi. Department of Radiation Oncology, Affiliated Hospital of Hebei University, 212 East Yuhua Road, Baoding 071000, Hebei, P R China. TI - Risk of endocrine adverse events in cancer patients treated with PD-1 inhibitors: a systematic review and meta-analysis. SO - Immunotherapy. 9(3):261-272, 2017 Mar AS - Immunotherapy. 9(3):261-272, 2017 Mar NJ - Immunotherapy PI - Journal available in: Print PI - Citation processed from: Internet JC - 101485158 IO - Immunotherapy CP - England KW - PD-1 inhibitors; cancer; hyperthyroidism; hypophysitis; hypothyroidism AB - AIM: We conducted this meta-analysis to investigate the overall incidence and risk of endocrine complications in cancer patients treated with PD-1 inhibitors. AB - METHODS: Pubmed, Embase and oncology conference proceedings were searched for relevant studies. AB - RESULTS: In comparison with chemotherapy or everolimus or cetuximab control, PD-1 inhibitors significantly increased the risk of all grade hypothyroidism (relative risk: 6.38; 95% CI: 3.78-10.77; p < 0.001) and hyperthyroidism (relative risk: 5.08; 95% CI: 2.55-10.14; p < 0.001), but not for hypophysitis. When compared with ipilimumab control, the risk of all grade hyperthyroidism and hypothyroidism with PD-1 inhibitors monotherapy seemed to be higher than ipilimumab, while the risk of hypophysitis was lower than ipilimumab. AB - CONCLUSION: Treatment with PD-1 inhibitors is associated with an increased risk of developing hypothyroidism and hyperthyroidism, but not for hypophysitis. ES - 1750-7448 IL - 1750-743X DO - https://dx.doi.org/10.2217/imt-2016-0147 PT - Journal Article ID - 28231723 [pubmed] ID - 10.2217/imt-2016-0147 [doi] PP - ppublish LG - English DP - 2017 Mar DC - 20170224 EZ - 2017/02/25 06:00 DA - 2017/02/25 06:00 DT - 2017/02/25 06:00 YR - 2017 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28231723 <439. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28070057 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Cho KY AU - Miyoshi H AU - Nakamura A AU - Kurita T AU - Atsumi T FA - Cho, Kyu Yong FA - Miyoshi, Hideaki FA - Nakamura, Akinobu FA - Kurita, Takashi FA - Atsumi, Tatsuya IN - Cho, Kyu Yong. Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. TI - Hyponatremia can be a powerful predictor of the development of isolated ACTH deficiency associated with nivolumab treatment [Letter to the Editor]. SO - Endocrine Journal. 64(2):235-236, 2017 Feb 27 AS - Endocr J. 64(2):235-236, 2017 Feb 27 NJ - Endocrine journal PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bt5, 9313485 IO - Endocr. J. CP - Japan ES - 1348-4540 IL - 0918-8959 DO - https://dx.doi.org/10.1507/endocrj.EJ16-0596 PT - Journal Article ID - 28070057 [pubmed] ID - 10.1507/endocrj.EJ16-0596 [doi] PP - ppublish LG - English EP - 20170106 DP - 2017 Feb 27 DC - 20170110 EZ - 2017/01/11 06:00 DA - 2017/01/11 06:00 DT - 2017/01/11 06:00 YR - 2017 RD - 20170227 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28070057 <440. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28101034 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Mertz AT AU - Ojemuyiwa MA FA - Mertz, Andrew T FA - Ojemuyiwa, Michelle A IN - Mertz, Andrew T. Uniformed Services University of the Health Sciences, Bethesda, MD, USA. IN - Ojemuyiwa, Michelle A. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, MD, USA. TI - A Case of Poorly Differentiated Large-Cell Neuroendocrine Carcinoma of the Cecum: A Rare Malignancy, with Review of the Literature. SO - Case Reports Oncology. 9(3):847-853, 2016 Sep-Dec AS - Case rep., oncol.. 9(3):847-853, 2016 Sep-Dec NJ - Case reports in oncology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101517601 IO - Case Rep Oncol CP - Switzerland KW - Gastroenteropancreatic neuroendocrine tumors; Immunotherapy; Neuroendocrine carcinomas; Programmed death-ligand 1; Small-cell lung cancer AB - Poorly differentiated neuroendocrine carcinomas (NECs) are rare tumors that can arise anywhere along the gastrointestinal tract. They often present in advanced stage and portend a poor prognosis when compared to adenocarcinomas of the same stage. Characterization of these tumors is best accomplished with tissue biopsy, as peripheral tumor markers commonly used in NECs are of little utility. Therapeutic strategies often involve chemotherapeutic regimens that have been used to treat small-cell lung cancer. Recent studies have shown that programmed death-ligand 1 (PD-L1) expression within poorly differentiated NECs is a poor prognostic indicator. However, PD-L1 expression may represent a possible target for immunotherapy drugs, often called checkpoint inhibitors, such as anti-PD-1 inhibitors. CI - The authors declare no conflicts of interest and have no disclosures. IL - 1662-6575 DI - cro-0009-0847 DO - https://dx.doi.org/10.1159/000452655 PT - Journal Article ID - 28101034 [pubmed] ID - 10.1159/000452655 [doi] ID - cro-0009-0847 [pii] ID - PMC5216239 [pmc] PP - epublish PH - 2016/10/17 [received] PH - 2016/10/18 [accepted] LG - English EP - 20161214 DP - 2016 Sep-Dec DC - 20170119 EZ - 2017/01/20 06:00 DA - 2017/01/20 06:01 DT - 2017/01/20 06:00 YR - 2016 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28101034 <441. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28101032 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Khokhar MO AU - Kettle J AU - Palla AR FA - Khokhar, Muhammad O FA - Kettle, Jacob FA - Palla, Amruth R IN - Khokhar, Muhammad O. Division of Hematology and Oncology, Department of Medicine, Ellis Fischel Cancer Center, University of Missouri Columbia, Columbia, MO, USA. IN - Kettle, Jacob. Division of Hematology and Oncology, Department of Pharmacy, Ellis Fischel Cancer Center, University of Missouri Columbia, Columbia, MO, USA. IN - Palla, Amruth R. Division of Hematology and Oncology, Department of Medicine, Ellis Fischel Cancer Center, University of Missouri Columbia, Columbia, MO, USA. TI - Debilitating Skin Toxicity Associated with Pembrolizumab Therapy in an 81-Year-Old Female with Malignant Melanoma. SO - Case Reports Oncology. 9(3):833-839, 2016 Sep-Dec AS - Case rep., oncol.. 9(3):833-839, 2016 Sep-Dec NJ - Case reports in oncology PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101517601 IO - Case Rep Oncol CP - Switzerland KW - Immune checkpoint inhibitors; Pembrolizumab; Skin toxicity AB - Frequently described immune-mediated adverse effects of immune therapy include dermatological complications, hepatitis, colitis, pneumonitis, and endocrinopathies. As utilization of pembrolizumab and related agents continues to expand both in the available indications as well as duration of exposure, there remains a significant potential to uncover previously undescribed adverse events. From a dermatological standpoint, 39% of patients receiving pembrolizumab therapy experience some form of skin-related drug toxicity [Naidoo et al.: Ann Oncol 2015;26: 2375-2391]. We describe a case of pembrolizumab-induced disabling autoimmune ectodermal toxicity. CI - None of the authors have any conflicts of interest to disclose. All the authors have read the manuscript and agree to its publication in this form. We assure whoever is concerned that this paper is not under simultaneous consideration by any other publication. IL - 1662-6575 DI - cro-0009-0833 DO - https://dx.doi.org/10.1159/000452944 PT - Journal Article ID - 28101032 [pubmed] ID - 10.1159/000452944 [doi] ID - cro-0009-0833 [pii] ID - PMC5216251 [pmc] PP - epublish PH - 2016/10/31 [received] PH - 2016/10/31 [accepted] LG - English EP - 20161208 DP - 2016 Sep-Dec DC - 20170119 EZ - 2017/01/20 06:00 DA - 2017/01/20 06:01 DT - 2017/01/20 06:00 YR - 2016 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28101032 <442. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28085094 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Yu LY AU - Tang J AU - Zhang CM AU - Zeng WJ AU - Yan H AU - Li MP AU - Chen XP FA - Yu, Lin-Yu FA - Tang, Jie FA - Zhang, Cong-Min FA - Zeng, Wen-Jing FA - Yan, Han FA - Li, Mu-Peng FA - Chen, Xiao-Ping IN - Yu, Lin-Yu. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China. yulinhui19910530@163.com. IN - Yu, Lin-Yu. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, China. yulinhui19910530@163.com. IN - Tang, Jie. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China. jietang@csu.edu.cn. IN - Tang, Jie. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, China. jietang@csu.edu.cn. IN - Zhang, Cong-Min. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China. ZhangCM126126@126.com. IN - Zhang, Cong-Min. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, China. ZhangCM126126@126.com. IN - Zeng, Wen-Jing. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China. wenjinganne@126.com. IN - Zeng, Wen-Jing. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, China. wenjinganne@126.com. IN - Yan, Han. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China. yanhan501@126.com. IN - Yan, Han. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, China. yanhan501@126.com. IN - Li, Mu-Peng. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China. elskesunny@163.com. IN - Li, Mu-Peng. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, China. elskesunny@163.com. IN - Chen, Xiao-Ping. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China. chenxp74@hotmail.com. IN - Chen, Xiao-Ping. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, China. chenxp74@hotmail.com. TI - New Immunotherapy Strategies in Breast Cancer. [Review] SO - International Journal of Environmental Research & Public Health [Electronic Resource]. 14(1), 2017 Jan 12 AS - Int J Environ Res Public Health. 14(1), 2017 Jan 12 NJ - International journal of environmental research and public health PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101238455 IO - Int J Environ Res Public Health CP - Switzerland KW - bispecific antibodies; breast cancer; cancer vaccines; immune checkpoint inhibitors; immunotherapy; stimulatory molecule agonists AB - Breast cancer is the most commonly diagnosed cancer among women. Therapeutic treatments for breast cancer generally include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, immunotherapy becomes a promising new field in breast cancer therapies. In this review, we discussed recent progress in breast cancer immunotherapy, including cancer vaccines, bispecific antibodies, and immune checkpoint inhibitors. Several additional immunotherapy modalities in early stages of development are also highlighted. It is believed that these new immunotherapeutic strategies will ultimately change the current status of breast cancer therapies. CI - The authors declare no conflict of interest. ES - 1660-4601 IL - 1660-4601 DI - E68 DI - ijerph14010068 DO - https://dx.doi.org/10.3390/ijerph14010068 PT - Review PT - Journal Article ID - 28085094 [pubmed] ID - ijerph14010068 [pii] ID - 10.3390/ijerph14010068 [doi] ID - PMC5295319 [pmc] PP - epublish PH - 2016/10/09 [received] PH - 2017/01/05 [revised] PH - 2017/01/09 [accepted] LG - English EP - 20170112 DP - 2017 Jan 12 DC - 20170113 EZ - 2017/01/14 06:00 DA - 2017/01/14 06:00 DT - 2017/01/14 06:00 YR - 2017 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28085094 <443. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28068177 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Weber JS AU - Hodi FS AU - Wolchok JD AU - Topalian SL AU - Schadendorf D AU - Larkin J AU - Sznol M AU - Long GV AU - Li H AU - Waxman IM AU - Jiang J AU - Robert C FA - Weber, Jeffrey S FA - Hodi, F Stephen FA - Wolchok, Jedd D FA - Topalian, Suzanne L FA - Schadendorf, Dirk FA - Larkin, James FA - Sznol, Mario FA - Long, Georgina V FA - Li, Hewei FA - Waxman, Ian M FA - Jiang, Joel FA - Robert, Caroline IN - Weber, Jeffrey S. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Hodi, F Stephen. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Wolchok, Jedd D. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Topalian, Suzanne L. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Schadendorf, Dirk. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Larkin, James. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Sznol, Mario. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Long, Georgina V. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Li, Hewei. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Waxman, Ian M. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Jiang, Joel. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. IN - Robert, Caroline. Jeffrey S. Weber, H. Lee Moffitt Cancer Center, Tampa, FL; F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA; Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center, New York, NY; Suzanne L. Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Mario Sznol, Yale University School of Medicine and Smilow Cancer Center, Yale-New Haven Hospital, New Haven, CT; Hewei Li, Ian M. Waxman, and Joel Jiang, Bristol-Myers Squibb, Princeton, NJ; Dirk Schadendorf, University of Essen, Essen, Germany; James Larkin, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; Georgina V. Long, Melanoma Institute Australia and University of Sydney, Sydney, New South Wales, Australia; and Caroline Robert, Gustave Roussy and Paris-Sud University, Villejuif-Paris Sud, France. TI - Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. SO - Journal of Clinical Oncology. 35(7):785-792, 2017 Mar AS - J Clin Oncol. 35(7):785-792, 2017 Mar NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. CP - United States AB - Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit. ES - 1527-7755 IL - 0732-183X DI - 10.1200/JCO.2015.66.1389 DO - https://dx.doi.org/10.1200/JCO.2015.66.1389 PT - Journal Article ID - 28068177 [pubmed] ID - 10.1200/JCO.2015.66.1389 [doi] ID - 10.1200/JCO.2015.66.1389 [pii] PP - ppublish LG - English EP - 20161114 DP - 2017 Mar DC - 20170109 EZ - 2017/01/10 06:00 DA - 2017/01/10 06:00 DT - 2017/01/10 06:00 YR - 2017 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28068177 <444. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28029020 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - PubMed-not-MEDLINE AU - Topliss DJ AI - Topliss, Duncan J; ORCID: http://orcid.org/0000-0003-4763-3385 FA - Topliss, Duncan J IN - Topliss, Duncan J. Department of Endocrinology and Diabetes, The Alfred, Melbourne, Australia. IN - Topliss, Duncan J. Department of Medicine, Monash University, Melbourne, Australia. duncan.topliss@monash.edu. TI - Clinical Update in Aspects of the Management of Autoimmune Thyroid Diseases. [Review] SO - Endocrinology and Metabolism. 31(4):493-499, 2016 Dec AS - Endocrinol Metab (Seoul). 31(4):493-499, 2016 Dec NJ - Endocrinology and metabolism (Seoul, Korea) PI - Journal available in: Print PI - Citation processed from: Print JC - 101554139 IO - Endocrinol Metab (Seoul) CP - Korea (South) KW - Hashimoto disease; Immunoglobulin G; Immunomodulation; Iodine; Thyroxine AB - Aspects of autoimmune thyroid disease updated in this review include: immunoglobulin G4 (IgG4)-related thyroid disease (Riedel's thyroiditis, fibrosing variant of Hashimoto's thyroiditis, IgG4-related Hashimoto's thyroiditis, and Graves' disease with elevated IgG4 levels); recent epidemiological studies from China and Denmark indicating that excess iodine increases the incidence of Hashimoto's thyroiditis and hypothyroidism; immunomodulatory agents (ipilimumab, pembrolizumab, nivolumab) activate immune response by inhibiting T-cell surface receptors which down-regulate immune response, i.e., cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 pathways; alemtuzumab is a humanised monoclonal antibody to CD52 which causes immune depletion and thyroid autoimmune disease especially Graves' hyperthyroidism; small molecule ligand (SML) agonists which activate receptors, SML neutral antagonists, which inhibit receptor activation by agonists, and SML inverse agonists which inhibit receptor activation by agonists and inhibit constitutive agonist independent signaling have been identified. SML antagonism of thyroid-stimulating hormone-receptor stimulatory antibody could treat Graves' hyperthyroidism and Graves' ophthalmopathy; and thyroxine treatment of subclinical hypothyroidism can produce iatrogenic subclinical hyperthyroidism with the risk of atrial fibrillation and osteoporosis. The increased risk of harm from subclinical hyperthyroidism may be stronger than the potential benefit from treatment of subclinical hypothyroidism. CI - The author has been a presenter at a Sanofi-Aventis (Genzyme) seminar to neurologists on alemtuzumab (Lemtrada) and received an honorarium for this. IS - 2093-596X IL - 2093-596X DI - 31.493 DO - https://dx.doi.org/10.3803/EnM.2016.31.4.493 PT - Review PT - Journal Article ID - 28029020 [pubmed] ID - 31.493 [pii] ID - 10.3803/EnM.2016.31.4.493 [doi] ID - PMC5195823 [pmc] PP - ppublish PH - 2016/10/29 [received] PH - 2016/11/11 [revised] PH - 2016/11/17 [accepted] LG - English DP - 2016 Dec DC - 20161228 EZ - 2016/12/29 06:00 DA - 2016/12/29 06:01 DT - 2016/12/29 06:00 YR - 2016 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28029020 <445. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27904651 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Schmid TA AU - Gore ME FA - Schmid, Thomas A FA - Gore, Martin E IN - Schmid, Thomas A. Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK. IN - Gore, Martin E. Royal Marsden NHS Foundation Trust, London, UK. TI - Sunitinib in the treatment of metastatic renal cell carcinoma. [Review] SO - Therapeutic Advances in Urology. 8(6):348-371, 2016 Dec AS - Ther Adv Urol. 8(6):348-371, 2016 Dec NJ - Therapeutic advances in urology PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101487328 IO - Ther Adv Urol CP - England KW - renal cell cancer; sunitinib; targeted therapy; tyrosine kinase inhibitor AB - Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that targets various receptors, including vascular endothelial growth factor receptors (VEGFRs). Sunitinib received approval in 2006 and became a standard treatment option in the first-line treatment of metastatic renal cell cancer (mRCC) after a phase III trial showed superiority compared with interferon alpha (IFN-alpha). Sunitinib has also shown activity in second-line treatment in several trials. Most of the combination trials with sunitinib with various agents have led to considerable toxicity without improving efficacy. Sunitinib alone causes significant side effects and has a distinct profile with diarrhoea, hypertension, skin effects hypothyroidism, fatigue and nausea of special interest. The recommended dose of sunitinib in mRCC is 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment (4/2 schedule). An alternative 2 weeks on, 1 week off schedule (2/1 schedule) seems to be of similar efficacy and better tolerability and could be more widely used in the future. An intermittent treatment strategy with a stop in remission and re-induction after progression showed efficacy in smaller trials and is currently being evaluated in a phase III trial. Direct comparison of sunitinib with pazopanib in first-line treatment showed a similar efficacy for both TKIs with a distinct toxicity profile. Data from two phase II trials showed that sunitinib has also activity in non-clear cell cancer and is an option due to a lack of better alternatives. Currently, after immune checkpoint inhibitors have shown very promising results in the second-line treatment of RCC, they are being tested in a number of phase III trials in the first-line setting. The future will show the position of sunitinib in the first-line treatment of RCC in the era of the immune checkpoint inhibitors. CI - The authors declare that there is no conflict of interest. IS - 1756-2872 IL - 1756-2872 DI - 10.1177_1756287216663979 DO - https://dx.doi.org/10.1177/1756287216663979 PT - Review PT - Journal Article ID - 27904651 [pubmed] ID - 10.1177/1756287216663979 [doi] ID - 10.1177_1756287216663979 [pii] ID - PMC5117167 [pmc] PP - ppublish LG - English EP - 20160823 DP - 2016 Dec DC - 20161201 EZ - 2016/12/02 06:00 DA - 2016/12/03 06:00 DT - 2016/12/03 06:00 YR - 2016 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27904651 <446. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27429197 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Graff JN AU - Alumkal JJ AU - Drake CG AU - Thomas GV AU - Redmond WL AU - Farhad M AU - Cetnar JP AU - Ey FS AU - Bergan RC AU - Slottke R AU - Beer TM FA - Graff, Julie N FA - Alumkal, Joshi J FA - Drake, Charles G FA - Thomas, George V FA - Redmond, William L FA - Farhad, Mohammad FA - Cetnar, Jeremy P FA - Ey, Frederick S FA - Bergan, Raymond C FA - Slottke, Rachel FA - Beer, Tomasz M IN - Graff, Julie N. Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. IN - Graff, Julie N. VA Portland Health Care System, Portland, OR, USA. IN - Alumkal, Joshi J. Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. IN - Drake, Charles G. Sidney Kimmel Comprehensive Cancer Center and the Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. IN - Thomas, George V. Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA. IN - Redmond, William L. Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA. IN - Farhad, Mohammad. Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA. IN - Farhad, Mohammad. Cell, Developmental, and Cancer Biology Department, Oregon Health and Science University, Portland, OR, USA. IN - Cetnar, Jeremy P. Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. IN - Ey, Frederick S. Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. IN - Bergan, Raymond C. Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. IN - Slottke, Rachel. Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. IN - Beer, Tomasz M. Division of Hematology/Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. TI - Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. SO - Oncotarget. 7(33):52810-52817, 2016 Aug 16 AS - Oncotarget. 7(33):52810-52817, 2016 Aug 16 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget CP - United States KW - Immune response; Immunity; Immunology and Microbiology Section; PD-1; enzalutamide; immunotherapy; prostate cancer AB - While programmed cell death 1 (PD-1) inhibitors have shown clear anti-tumor efficacy in several solid tumors, prior results in men with metastatic castration resistant prostate cancer (mCRPC) showed no evidence of activity. Here we report unexpected antitumor activity seen in mCRPC patients treated with the anti-PD-1 antibody pembrolizumab. Patients with evidence of progression on enzalutamide were treated with pembrolizumab 200 mg IV every 3 weeks for 4 doses; pembrolizumab was added to standard dose enzalutamide. Three of the first ten patients enrolled in this ongoing phase II trial experienced rapid prostate specific antigen (PSA) reductions to <= 0.2 ng/ml. Two of these three patients had measurable disease upon study entry; both achieved a partial response. There were three patients with significant immune-related adverse events. One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response. Two of the three responders had a baseline tumor biopsy. Immunohistochemistry from those biopsies showed the presence of CD3+, CD8+, and CD163+ leukocyte infiltrates and PD-L1 expression. Genetic analysis of the two responders revealed markers of microsatellite instability in one. The surprising and robust responses seen in this study should lead to re-examination of PD-1 inhibition in prostate cancer. CI - JNG has received honoraria from Astellas/Medivation. She has received research funding from Astellas/Medivation and Merck. CGD has received research funding from Bristol Myers Squibb (BMS). He has received consulting fees from BMS, Merck, Astra Zeneca (AZ) and Medimmune. He has patents licensed to AZ, BMS and Medimmune. WLR has received research grants, consulting fees, and/or royalties from Bristol-Myers Squibb, Merck, Galectin Therapeutics, and Nektar Therapeutics. TMB Research funding from Astellas and Medivation; consulting fees from Astellas. JJA, GVT, MF, JPC, FSE, RCB and RS have no conflicts. This research was funded by Merck Sharp & Dohme Corporation. Funds from the Bloomberg Kimmel Institute (BKI) supported a portion of the laboratory work. Additional laboratory funding was funded by Merck. ES - 1949-2553 IL - 1949-2553 DI - 10547 DO - https://dx.doi.org/10.18632/oncotarget.10547 PT - Journal Article ID - 27429197 [pubmed] ID - 10547 [pii] ID - 10.18632/oncotarget.10547 [doi] ID - PMC5288150 [pmc] PP - ppublish PH - 2016/05/31 [received] PH - 2016/06/17 [accepted] LG - English DP - 2016 Aug 16 DC - 20160718 EZ - 2016/07/19 06:00 DA - 2016/07/19 06:00 DT - 2016/07/19 06:00 YR - 2016 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27429197 <447. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27418145 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Cives M AU - Simone V AU - Rizzo FM AU - Silvestris F FA - Cives, Mauro FA - Simone, Valeria FA - Rizzo, Francesca Maria FA - Silvestris, Franco IN - Cives, Mauro. Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro", Bari, Italy. IN - Simone, Valeria. Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro", Bari, Italy. IN - Rizzo, Francesca Maria. Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro", Bari, Italy. IN - Silvestris, Franco. Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro", Bari, Italy. TI - NETs: organ-related epigenetic derangements and potential clinical applications. [Review] SO - Oncotarget. 7(35):57414-57429, 2016 Aug 30 AS - Oncotarget. 7(35):57414-57429, 2016 Aug 30 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget CP - United States KW - ATRX; DAXX; DNA methylation; MEN1; carcinoid tumors AB - High-throughput next-generation sequencing methods have recently provided a detailed picture of the genetic landscape of neuroendocrine tumors (NETs), revealing recurrent mutations of chromatin-remodeling genes and little-to-no pathogenetic role for oncogenes commonly mutated in cancer. Concurrently, multiple epigenetic modifications have been described across the whole spectrum of NETs, and their putative function as tumorigenic drivers has been envisaged. As result, it is still unclear whether or not NETs are epigenetically-driven, rather than genetically-induced malignancies. Although the NET epigenome profiling has led to the identification of molecularly-distinct tumor subsets, validation studies in larger cohorts of patients are needed to translate the use of NET epitypes in clinical practice. In the precision medicine era, recognition of subpopulations of patients more likely to respond to therapeutic agents is critical, and future studies testing epigenetic biomarkers are therefore awaited. Restoration of the aberrant chromatin remodeling machinery is an attractive approach for future treatment of cancer and in several hematological malignancies a few epigenetic agents have been already approved. Although clinical outcomes of epigenetic therapies in NETs have been disappointing so far, further clinical trials are required to investigate the efficacy of these drugs. In this context, given the immune-stimulating effects of epidrugs, combination therapies with immune checkpoint inhibitors should be tested. In this review, we provide an overview of the epigenetic changes in both hereditary and sporadic NETs of the gastroenteropancreatic and bronchial tract, focusing on their diagnostic, prognostic and therapeutic implications. CI - The Authors declare no affiliation with industries or organizations with a financial interest, direct or indirect, that may affect the conduct or reporting of the work submitted. ES - 1949-2553 IL - 1949-2553 DI - 10598 DO - https://dx.doi.org/10.18632/oncotarget.10598 PT - Review PT - Journal Article ID - 27418145 [pubmed] ID - 10598 [pii] ID - 10.18632/oncotarget.10598 [doi] ID - PMC5302998 [pmc] PP - ppublish PH - 2016/04/06 [received] PH - 2016/06/30 [accepted] LG - English DP - 2016 Aug 30 DC - 20160726 EZ - 2016/07/16 06:00 DA - 2016/07/16 06:00 DT - 2016/07/16 06:00 YR - 2016 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27418145 <448. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27086918 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Chowdhury S AU - Veyhl J AU - Jessa F AU - Polyakova O AU - Alenzi A AU - MacMillan C AU - Ralhan R AU - Walfish PG FA - Chowdhury, Subrata FA - Veyhl, Joe FA - Jessa, Fatima FA - Polyakova, Olena FA - Alenzi, Ahmed FA - MacMillan, Christina FA - Ralhan, Ranju FA - Walfish, Paul G IN - Chowdhury, Subrata. Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Veyhl, Joe. Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Jessa, Fatima. Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Polyakova, Olena. Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Polyakova, Olena. Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto Medical School, Toronto, Ontario, Canada. IN - Alenzi, Ahmed. Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Alenzi, Ahmed. Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto Medical School, Toronto, Ontario, Canada. IN - MacMillan, Christina. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - MacMillan, Christina. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. IN - Ralhan, Ranju. Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Ralhan, Ranju. Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology-Head and Neck Surgery Program, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Ralhan, Ranju. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Ralhan, Ranju. Department of Otolaryngology-Head and Neck Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Ralhan, Ranju. Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada. IN - Ralhan, Ranju. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. IN - Walfish, Paul G. Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Walfish, Paul G. Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology-Head and Neck Surgery Program, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Walfish, Paul G. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. IN - Walfish, Paul G. Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto Medical School, Toronto, Ontario, Canada. IN - Walfish, Paul G. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. TI - Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. SO - Oncotarget. 7(22):32318-28, 2016 May 31 AS - Oncotarget. 7(22):32318-28, 2016 May 31 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget SB - Index Medicus CP - United States KW - benign nodule; programmed death-ligand 1; protein biomarkers; subcellular localization; thyroid cancer AB - Programmed death-ligand 1(PD-L1) expression on tumor cells is emerging as a potential predictive biomarker in anti-PD-L1 directed cancer immunotherapy. We analyzed PD-L1 expression in papillary thyroid carcinoma (PTC) and its variants and determined its prognostic potential to predict clinical outcome in these patients. This study was conducted at an academic oncology hospital which is a prime referral centre for thyroid diseases. Immunohistochemical subcellular localization (IHC) analyses of PD-L1 protein was retrospectively performed on 251 archived formalin fixed and paraffin embedded (FFPE) surgical tissues (66 benign thyroid nodules and 185 PTCs) using a rabbit monoclonal anti-PD-L1 antibody (E1L3N, Cell Signaling Technology) and detected using VECTASTAIN rapid protocol with diaminobenzidine (DAB) as the chromogen. The clinical-pathological factors and disease outcome over 190 months were assessed; immunohistochemical subcellular localization of PD-L1 was correlated with disease free survival (DFS) using Kaplan Meier survival and Cox multivariate regression analysis. Increased PD-L1 immunostaining was predominantly localized in cytoplasm and occasionally in plasma membrane of tumor cells. Among all combined stages of PTC, patients with increased PD-L1 membrane or cytoplasmic positivity had significantly shorter median DFS (36 months and 49 months respectively) as compared to those with PD-L1 negative tumors (DFS, both 186 months with p < 0.001 and p < 0.01 respectively). Comparison of PD-L1+ and PD-L1- patients with matched staging showed increased cytoplasmic positivity in all four stages of PTC that correlated with a greater risk of recurrence and a poor prognosis, but increased membrane positivity significantly correlated with a greater risk of metastasis or death only in Stage IV patients. In conclusion, PD-L1 positive expression in PTC correlates with a greater risk of recurrence and shortened disease free survival supporting its potential application as a prognostic marker for PTC. CI - PGW and RR are shareholders in Proteocyte Diagnostics Inc. All the other authors (SC, JV, FJ, OP, AA and CM) have nothing to disclose. ES - 1949-2553 IL - 1949-2553 DI - 8698 DO - https://dx.doi.org/10.18632/oncotarget.8698 PT - Journal Article ID - 27086918 [pubmed] ID - 8698 [pii] ID - 10.18632/oncotarget.8698 [doi] ID - PMC5078015 [pmc] PP - ppublish PH - 2016/03/23 [received] PH - 2016/03/26 [accepted] LG - English DP - 2016 May 31 DC - 20160915 EZ - 2016/04/19 06:00 DA - 2016/04/19 06:00 DT - 2016/04/19 06:00 YR - 2016 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27086918 <449. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27008709 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Soliman HH AU - Minton SE AU - Han HS AU - Ismail-Khan R AU - Neuger A AU - Khambati F AU - Noyes D AU - Lush R AU - Chiappori AA AU - Roberts JD AU - Link C AU - Vahanian NN AU - Mautino M AU - Streicher H AU - Sullivan DM AU - Antonia SJ FA - Soliman, Hatem H FA - Minton, Susan E FA - Han, Hyo Sook FA - Ismail-Khan, Roohi FA - Neuger, Anthony FA - Khambati, Fatema FA - Noyes, David FA - Lush, Richard FA - Chiappori, Alberto A FA - Roberts, John D FA - Link, Charles FA - Vahanian, Nicholas N FA - Mautino, Mario FA - Streicher, Howard FA - Sullivan, Daniel M FA - Antonia, Scott J IN - Soliman, Hatem H. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Minton, Susan E. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Han, Hyo Sook. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Ismail-Khan, Roohi. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Neuger, Anthony. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Khambati, Fatema. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Noyes, David. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Lush, Richard. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Chiappori, Alberto A. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Roberts, John D. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA. IN - Link, Charles. NewLink Genetics Inc., Ames, Iowa, USA. IN - Vahanian, Nicholas N. NewLink Genetics Inc., Ames, Iowa, USA. IN - Mautino, Mario. NewLink Genetics Inc., Ames, Iowa, USA. IN - Streicher, Howard. Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, Maryland, USA. IN - Sullivan, Daniel M. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. IN - Antonia, Scott J. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. TI - A phase I study of indoximod in patients with advanced malignancies. SO - Oncotarget. 7(16):22928-38, 2016 Apr 19 AS - Oncotarget. 7(16):22928-38, 2016 Apr 19 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008412 SB - Index Medicus CP - United States KW - 1-methyl-D-tryptophan; 3 dioxygenase; immunomodulator; indoleamine 2; indoximod AB - PURPOSE: Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates. AB - EXPERIMENTAL DESIGN: Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age >=18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy <= 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. AB - RESULTS: In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 muM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels. AB - CONCLUSIONS: Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed. CI - Charles Link, Nicholas Vahanian, W. Jay Ramsey, and Mario Mautino all have ownership/employment relationships with NewLink Genetics Inc., which is developing indoximod. Hatem Soliman is the lead investigator on a phase 2 clinical trial sponsored by NewLink Genetics. ES - 1949-2553 IL - 1949-2553 DI - 8216 DO - https://dx.doi.org/10.18632/oncotarget.8216 PT - Journal Article ID - 27008709 [pubmed] ID - 8216 [pii] ID - 10.18632/oncotarget.8216 [doi] ID - PMC5008412 [pmc] PP - ppublish PH - 2016/02/11 [received] PH - 2016/03/10 [accepted] GI - No: HHSN261201100100C Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA016059 Organization: (CA) *NCI NIH HHS* Country: United States No: P30 CA076292 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2016 Apr 19 DC - 20160725 EZ - 2016/03/24 06:00 DA - 2016/03/24 06:00 DT - 2016/03/24 06:00 YR - 2016 RD - 20170224 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27008709 <450. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27206299 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Anonymous TI - Programmed Death-1 Inhibition in Cancer With a Focus on Non-Small Cell Lung Cancer: Rationale, Nursing Implications, and Patient Management Strategies. SO - Clinical Journal of Oncology Nursing. 20(3):319-26, 2016 Jun 01 AS - Clin J Oncol Nurs. 20(3):319-26, 2016 Jun 01 NJ - Clinical journal of oncology nursing PI - Journal available in: Print PI - Citation processed from: Internet JC - czm, 9705336 IO - Clin J Oncol Nurs SB - Nursing Journal CP - United States KW - PD-1; immune checkpoint blockade; immuno-oncology; nivolumab; pembrolizumab AB - BACKGROUND: Programmed death-1 (PD-1) immune checkpoint inhibitors are novel immuno-oncology agents. Unlike chemotherapy or targeted agents, which inhibit tumor cell proliferation or induce tumor cell death, immune checkpoint inhibitors are designed to stimulate a patient's own immune system to eliminate tumors. As a result of their mechanism of action, PD-1 pathway inhibitors are associated with adverse events (AEs) with immunologic etiologies, termed immune-mediated AEs (imAEs). These include skin and gastrointestinal AEs, and endocrine, hepatic, renal, and respiratory AEs, including pneumonitis. Most imAEs can be effectively managed with treatment interruption/discontinuation and/or steroids or other immunosuppressive agents. A specialist consult may be required in some cases, and endocrine imAEs may require permanent hormone replacement therapy. AB - OBJECTIVES: This article provides an overview of PD-1 inhibitors, including the potential mechanism of action, key clinical trial data, and strategies for managing patients who may receive PD-1 inhibitors for the treatment of non-small cell lung cancer. AB - METHODS: Information in the article comes from PubMed literature searches and the author's experience with these agents in clinical trials. AB - FINDINGS: Oncology clinicians must thoroughly assess baseline functioning and symptoms and be vigilant for imAEs, which require prompt diagnosis and management. A good understanding of the clinical profile of PD-1 pathway inhibitors is instrumental in helping clinicians manage patients receiving these new therapies. ES - 1538-067X IL - 1092-1095 DO - https://dx.doi.org/10.1188/16.CJON.319-326 PT - Journal Article ID - 27206299 [pubmed] ID - 10.1188/16.CJON.319-326 [doi] PP - ppublish LG - English DP - 2016 Jun 01 DC - 20160521 EZ - 2016/05/21 06:00 DA - 2016/05/21 06:00 DT - 2016/05/21 06:00 YR - 2016 RD - 20170208 UP - 20170209 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27206299 <451. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28093480 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Ahn S AU - Kim TH AU - Kim SW AU - Ki CS AU - Jang HW AU - Kim JS AU - Kim JH AU - Choe JH AU - Shin JH AU - Hahn SY AU - Oh YL AU - Chung JH FA - Ahn, Soomin FA - Kim, Tae Hyuk FA - Kim, Sun Wook FA - Ki, Chang Seok FA - Jang, Hye Won FA - Kim, Jee Soo FA - Kim, Jung Han FA - Choe, Jun-Ho FA - Shin, Jung Hee FA - Hahn, Soo Yeon FA - Oh, Young Lyun FA - Chung, Jae Hoon IN - Ahn, Soomin. Department of PathologyEwha Womans University School of Medicine, Seoul, Korea. IN - Kim, Tae Hyuk. Division of Endocrinology and MetabolismDepartment of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Kim, Sun Wook. Division of Endocrinology and MetabolismDepartment of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Ki, Chang Seok. Department of Laboratory Medicine and GeneticsSamsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Jang, Hye Won. Department of Medical EducationSungkyunkwan University School of Medicine, Seoul, Korea. IN - Kim, Jee Soo. Division of Breast and Endocrine SurgeryDepartment of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Kim, Jung Han. Division of Breast and Endocrine SurgeryDepartment of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Choe, Jun-Ho. Division of Breast and Endocrine SurgeryDepartment of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Shin, Jung Hee. Department of Radiology and Center for Imaging ScienceSamsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Hahn, Soo Yeon. Department of Radiology and Center for Imaging ScienceSamsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. IN - Oh, Young Lyun. Department of Pathology and Translational genomicsSungkyunkwan University School of Medicine, Seoul, Korea bijou@skku.edu thyroid@skku.edu. IN - Chung, Jae Hoon. Division of Endocrinology and MetabolismDepartment of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea bijou@skku.edu thyroid@skku.edu. TI - Comprehensive screening for PD-L1 expression in thyroid cancer. SO - Endocrine-Related Cancer. 24(2):97-106, 2017 Feb AS - Endocr Relat Cancer. 24(2):97-106, 2017 Feb NJ - Endocrine-related cancer PI - Journal available in: Print PI - Citation processed from: Internet JC - 9436481, dgr IO - Endocr. Relat. Cancer CP - England KW - PD1; PDL1; TERT; anaplastic carcinoma; thyroid AB - PD-L1 expression is being considered a potential biomarker for response of anti-PD-1 or anti-PD-L1 agents in various tumors. The reported frequency of PD-L1 positivity varies in thyroid carcinomas, and multiple factors may contribute to the variability in PD-L1 positivity. We evaluated the PD-L1 expression in various thyroid cancers on a large scale. A total of 407 primary thyroid cancers with a median 13.7-year of follow-up were included. We evaluated the frequency of PD-L1 expression using a rabbit monoclonal antibody (clone SP142). In addition, we analyzed the relationships between PD-L1 expression and clinicopathologic factors, including TERT promoter, BRAF status and disease progression. Tumoral PD-L1 was expressed in 6.1% of papillary thyroid carcinomas, 7.6% of follicular thyroid carcinomas and 22.2% of anaplastic thyroid carcinomas. The distribution of PD-L1 positivity was different according to cancer histology types (P<0.001). All PD-L1-positive cases of follicular thyroid carcinoma and anaplastic thyroid carcinoma showed strong intensity. The proportions of positivity in PD-L1 positive anaplastic thyroid carcinomas were more than 80%. PD-L1 in immune cells was positive in 28.5% of papillary thyroid carcinoma, 9.1% of follicular thyroid carcinomas and 11.1% of anaplastic thyroid carcinomas. There was no significant association between clinicopathologic variables, disease progression, oncogenic mutation and PD-L1 expression. PD-L1 was highly expressed in a subset of patients with advanced thyroid cancer, such as follicular and anaplastic thyroid carcinoma. Identification of PD-L1 expression may have direct therapeutic relevance to patients with refractory thyroid cancer. AB - Copyright © 2017 Society for Endocrinology. ES - 1479-6821 IL - 1351-0088 DI - 24/2/97 DO - https://dx.doi.org/10.1530/ERC-16-0421 PT - Journal Article ID - 28093480 [pubmed] ID - 24/2/97 [pii] ID - 10.1530/ERC-16-0421 [doi] PP - ppublish PH - 2016/11/30 [received] PH - 2016/12/13 [accepted] LG - English DP - 2017 Feb DC - 20170117 EZ - 2017/01/18 06:00 DA - 2017/01/18 06:00 DT - 2017/01/18 06:00 YR - 2017 RD - 20170117 UP - 20170119 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=28093480 <452. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27761609 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Chae YK AU - Chiec L AU - Mohindra N AU - Gentzler R AU - Patel J AU - Giles F FA - Chae, Young Kwang FA - Chiec, Lauren FA - Mohindra, Nisha FA - Gentzler, Ryan FA - Patel, Jyoti FA - Giles, Francis IN - Chae, Young Kwang. Developmental Therapeutics Program of the Division of Hematology/Oncology, Northwestern University, Chicago, IL, 60611, USA. young.chae@northwestern.edu. IN - Chae, Young Kwang. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA. young.chae@northwestern.edu. IN - Chae, Young Kwang. Feinberg School of Medicine, Northwestern University, 645 N. Michigan Ave, Suite 1006, Chicago, IL, 60611, USA. young.chae@northwestern.edu. IN - Chiec, Lauren. Feinberg School of Medicine, Northwestern University, 645 N. Michigan Ave, Suite 1006, Chicago, IL, 60611, USA. IN - Mohindra, Nisha. Developmental Therapeutics Program of the Division of Hematology/Oncology, Northwestern University, Chicago, IL, 60611, USA. IN - Mohindra, Nisha. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA. IN - Mohindra, Nisha. Feinberg School of Medicine, Northwestern University, 645 N. Michigan Ave, Suite 1006, Chicago, IL, 60611, USA. IN - Gentzler, Ryan. University of Virginia School of Medicine, Charlottesville, VA, 22908-0395, USA. IN - Patel, Jyoti. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA. IN - Patel, Jyoti. Feinberg School of Medicine, Northwestern University, 645 N. Michigan Ave, Suite 1006, Chicago, IL, 60611, USA. IN - Patel, Jyoti. The University of Chicago Medicine, Chicago, IL, 60637, USA. IN - Giles, Francis. Developmental Therapeutics Program of the Division of Hematology/Oncology, Northwestern University, Chicago, IL, 60611, USA. IN - Giles, Francis. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA. IN - Giles, Francis. Feinberg School of Medicine, Northwestern University, 645 N. Michigan Ave, Suite 1006, Chicago, IL, 60611, USA. TI - A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. SO - Cancer Immunology, Immunotherapy. 66(1):25-32, 2017 Jan AS - Cancer Immunol Immunother. 66(1):25-32, 2017 Jan NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. CP - Germany KW - Diabetes mellitus; Immune-related adverse effect; Immunomodulatory; Ipilimumab; Nivolumab; Pembrolizumab AB - Immune checkpoint inhibitors such as pembrolizumab, ipilimumab, and nivolumab, now FDA-approved for use in treating several types of cancer, have been associated with immune-related adverse effects. Specifically, the antibodies targeting the programmed-cell death-1 immune checkpoint, pembrolizumab and nivolumab, have been rarely reported to induce the development of type 1 diabetes mellitus. Here we describe a case of a patient who developed antibody-positive type 1 diabetes mellitus following treatment with pembrolizumab in combination with systemic chemotherapy for metastatic adenocarcinoma of the lung. We will also provide a brief literature review of other rarely reported cases of type 1 diabetes presenting after treatment with pembrolizumab and nivolumab, as well as discussion regarding potential mechanisms of this adverse effect and its importance as these drugs continue to become even more widespread. ES - 1432-0851 IL - 0340-7004 DI - 10.1007/s00262-016-1913-7 DO - https://dx.doi.org/10.1007/s00262-016-1913-7 PT - Journal Article ID - 27761609 [pubmed] ID - 10.1007/s00262-016-1913-7 [doi] ID - 10.1007/s00262-016-1913-7 [pii] PP - ppublish PH - 2016/03/29 [received] PH - 2016/10/01 [accepted] LG - English EP - 20161019 DP - 2017 Jan DC - 20161020 EZ - 2016/10/21 06:00 DA - 2016/10/21 06:00 DT - 2016/10/21 06:00 YR - 2017 RD - 20170110 UP - 20170111 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27761609 <453. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27913998 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Spellman A AU - Tang SC FA - Spellman, Alison FA - Tang, Shou-Ching IN - Spellman, Alison. Georgia Regents University Cancer Center, 1411 Laney Walker Boulevard, Augusta, GA, 30912, USA. IN - Tang, Shou-Ching. Georgia Regents University Cancer Center, 1411 Laney Walker Boulevard, Augusta, GA, 30912, USA. stang@gru.edu. IN - Tang, Shou-Ching. Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin, 300060, China. stang@gru.edu. TI - Immunotherapy for breast cancer: past, present, and future. SO - Cancer & Metastasis Reviews. 35(4):525-546, 2016 Dec AS - Cancer Metastasis Rev. 35(4):525-546, 2016 Dec NJ - Cancer metastasis reviews PI - Journal available in: Print PI - Citation processed from: Internet JC - c9h, 8605731 IO - Cancer Metastasis Rev. CP - Netherlands KW - Biomarkers; Breast cancer; Checkpoint inhibitor; Clinical trials; Immunotherapy; Review AB - Immunotherapy has shown promise in many solid tumors including melanoma and non-small cell lung cancer with an evolving role in breast cancer. Immunotherapy encompasses a wide range of therapies including immune checkpoint inhibition, monoclonal antibodies, bispecific antibodies, vaccinations, antibody-drug conjugates, and identifying other emerging interventions targeting the tumor microenvironment. Increasing efficacy of these treatments in breast cancer patients requires identification of better biomarkers to guide patient selection; recognizing when to initiate these therapies in multi-modality treatment plans; establishing novel assays to monitor immune-mediated responses; and creating combined systemic therapy options incorporating conventional treatments such as chemotherapy and endocrine therapy. This review will focus on the current role and future directions of many of these immunotherapies in breast cancer, as well as highlighting clinical trials that are investigating several of these active issues. ES - 1573-7233 IL - 0167-7659 DI - 10.1007/s10555-016-9654-9 DO - https://dx.doi.org/10.1007/s10555-016-9654-9 PT - Journal Article ID - 27913998 [pubmed] ID - 10.1007/s10555-016-9654-9 [doi] ID - 10.1007/s10555-016-9654-9 [pii] PP - ppublish LG - English DP - 2016 Dec DC - 20161203 EZ - 2016/12/04 06:00 DA - 2016/12/04 06:00 DT - 2016/12/04 06:00 YR - 2016 RD - 20170105 UP - 20170106 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27913998 <454. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27966604 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Zhou J AU - Jin JO AU - Kawai T AU - Yu Q FA - Zhou, Jing FA - Jin, Jun-O FA - Kawai, Toshihisa FA - Yu, Qing IN - Zhou, Jing. Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA. IN - Zhou, Jing. Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. IN - Jin, Jun-O. Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA. IN - Kawai, Toshihisa. Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA. IN - Kawai, Toshihisa. Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. IN - Yu, Qing. Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA. IN - Yu, Qing. Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. TI - Endogenous programmed death ligand-1 restrains the development and onset of Sjogren's syndrome in non-obese diabetic mice. SO - Scientific Reports. 6:39105, 2016 Dec 14 AS - Sci. rep.. 6:39105, 2016 Dec 14 NJ - Scientific reports PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 101563288 IO - Sci Rep CP - England AB - Programmed death-ligand 1 (PD-L1) down-modulates various immune responses by engaging the co-inhibitory receptor programmed death-1. Expression of PD-L1 and programmed death-1 is elevated in the salivary glands of patients with Sjogren's syndrome (SS). The objective of this study is to define the role of endogenous PD-L1 in SS pathogenesis in non-obese diabetic (NOD) mouse model of this disease. We inhibited endogenous PD-L1 function by intraperitoneal administration of a blocking antibody to 6 week-old female NOD/ShiLtJ mice repeatedly during a 9-day period. PD-L1 blockade accelerated leukocyte infiltration and caspase-3 activation in the submandibular gland (SMG), production of antinuclear and anti-M3 muscarinic acetylcholine receptor (M3R) autoantibodies and impairment of saliva secretion, indicative of accelerated development and onset of SS. The effect of PD-L1 blockade was associated with increased T- and B cells and T helper 1 cytokine IFN-gamma in the SMG. Local administration of exogenous IFN-gamma to the SMG led to impaired salivary secretion accompanied by down-regulation of aquaporin 5 and an increase in anti-M3R autoantibodies. Conversely, neutralization of IFN-gamma markedly improved salivary secretion and aquaporin 5 expression in anti-PD-L1-treated NOD/ShiLtJ mice. Hence, endogenous PD-L1 hinders the development and onset of SS in NOD mice, in part by suppressing IFN-gamma production. ES - 2045-2322 IL - 2045-2322 DI - srep39105 DO - https://dx.doi.org/10.1038/srep39105 PT - Journal Article ID - 27966604 [pubmed] ID - srep39105 [pii] ID - 10.1038/srep39105 [doi] ID - PMC5155421 [pmc] PP - epublish PH - 2016/07/22 [received] PH - 2016/11/17 [accepted] GI - No: P30 DE020751 Organization: (DE) *NIDCR NIH HHS* Country: United States No: R01 DE023838 Organization: (DE) *NIDCR NIH HHS* Country: United States LG - English EP - 20161214 DP - 2016 Dec 14 DC - 20161214 EZ - 2016/12/15 06:00 DA - 2016/12/15 06:00 DT - 2016/12/15 06:00 YR - 2016 RD - 20161222 UP - 20161223 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27966604 <455. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27373241 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Kahler KC AU - Hassel JC AU - Heinzerling L AU - Loquai C AU - Mossner R AU - Ugurel S AU - Zimmer L AU - Gutzmer R AU - "Cutaneous Side Effects" Committee of the Work Group Dermatological Oncology (ADO) FA - Kahler, Katharina C FA - Hassel, Jessica C FA - Heinzerling, Lucie FA - Loquai, Carmen FA - Mossner, Rotraut FA - Ugurel, Selma FA - Zimmer, Lisa FA - Gutzmer, Ralf FA - "Cutaneous Side Effects" Committee of the Work Group Dermatological Oncology (ADO) IN - Kahler, Katharina C. Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. IN - Hassel, Jessica C. Department of Dermatology, and National Cancer Center, University Hospital Heidelberg, Heidelberg, Germany. IN - Heinzerling, Lucie. Department of Dermatology, University Hospital Erlangen, Erlangen, Germany. IN - Loquai, Carmen. Department of Dermatology, Medical Faculty, University of Mainz, Mainz, Germany. IN - Mossner, Rotraut. Department of Dermatology, Venereology, and Allergology, University Medicine Gottingen, Gottingen, Germany. IN - Ugurel, Selma. Department of Dermatology, Venereology and Allergology, University Hospital Essen, Essen, Germany. IN - Zimmer, Lisa. Department of Dermatology, Venereology and Allergology, University Hospital Essen, Essen, Germany. IN - Gutzmer, Ralf. Hanover Skin Cancer Center, Department of Dermatology, Venereology, and Allergology, Hanover Medical College, Hanover, Germany. TI - Management of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma. SO - Journal der Deutschen Dermatologischen Gesellschaft. 14(7):662-81, 2016 Jul AS - J.Deutschen Dermatologischen Gesellschaft. 14(7):662-81, 2016 Jul NJ - Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG PI - Journal available in: Print PI - Citation processed from: Internet JC - 101164708 IO - J Dtsch Dermatol Ges SB - Index Medicus CP - Germany KW - CTLA-4 antibody; PD-1 antibody; autoimmune side effects; immune checkpoint blockade; melanoma; side effect management AB - CTLA-4 and PD-1 are potential targets for tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint-modifying monoclonal antibodies oppose these effects, inducing T cell-mediated immune responses to various tumors including melanoma. Both anti-CTLA-4 and anti-PD-1 antibodies modify the interaction between tumor, antigen-presenting cells, and T lymphocytes. With respect to overall survival, clinical studies have shown a major benefit for the anti-CTLA-4 antibody ipilimumab as well as the two anti-PD-1 antibodies nivolumab and pembrolizumab. Following approval of ipilimumab in 2011, the latter two achieved market authorization in the summer of 2015. Immune responses thus induced and enhanced inevitably entail autoimmune phenomena, affecting various organs to varying degrees. Knowledge of these side effects is crucial with regard to prevention and management by treating physicians. Typically occurring early on and presenting with pronounced and persistent diarrhea, colitis represents a major and severe side effect. Other immune-mediated disorders include dermatitis, hypophysitis, thyroiditis, hepatitis, iridocyclitis as well as other less common autoimmune phenomena. Early recognition and initiation of treatment can reduce risks and sequelae for patients. This review describes the mechanisms of action of immune checkpoint blockade as well as its clinical effects in metastatic melanoma, with a detailed focus on the spectrum of adverse events and their therapeutic management. AB - Copyright © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. ES - 1610-0387 IL - 1610-0379 DO - https://dx.doi.org/10.1111/ddg.13047 PT - Journal Article ID - 27373241 [pubmed] ID - 10.1111/ddg.13047 [doi] PP - ppublish LG - English DP - 2016 Jul DC - 20160704 EZ - 2016/07/05 06:00 DA - 2016/07/05 06:00 DT - 2016/07/05 06:00 YR - 2016 RD - 20161219 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27373241 <456. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27229364 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Bonnet C AU - Beinse G AU - Cabel L AU - Cochereau D AU - Lavaud P AU - Rochefort P AU - Tabouret E AU - Turpin A AU - Verlingue L AU - Vicier C AU - Massard C FA - Bonnet, Clement FA - Beinse, Guillaume FA - Cabel, Luc FA - Cochereau, Delphine FA - Lavaud, Pernelle FA - Rochefort, Pauline FA - Tabouret, Emeline FA - Turpin, Anthony FA - Verlingue, Loic FA - Vicier, Cecile FA - Massard, Christophe IN - Bonnet, Clement. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Beinse, Guillaume. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Cabel, Luc. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Cochereau, Delphine. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Lavaud, Pernelle. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Rochefort, Pauline. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Tabouret, Emeline. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Turpin, Anthony. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Verlingue, Loic. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Vicier, Cecile. AERIO, 149, avenue du Maine, 75014 Paris, France. IN - Massard, Christophe. AERIO, 149, avenue du Maine, 75014 Paris, France; DITEP, Gustave-Roussy, 94805 Villejuif, France. Electronic address: christophe.massard@gustaveroussy.fr. TI - [ESMO ECCO 2015: The highlights of immunotherapy and targeted therapies]. [French] OT - ESMO ECCO 2015 : les temps forts de l'immunotherapie et des therapies ciblees. SO - Bulletin du Cancer. 103(6):594-603, 2016 Jun AS - Bull Cancer. 103(6):594-603, 2016 Jun NJ - Bulletin du cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0072416 IO - Bull Cancer SB - Index Medicus CP - France KW - Early phase studies; Essai de phases precoces; Immunotherapies; Immunotherapies; Medecine personnalisee; Personalized medicine; Targeted therapies; Therapies ciblees AB - The ESMO/ECC congress (European Society for Medical Oncology/European Cancer Congress) took place in Vienna, Austria, September 25-29. The main topic of the conference was immunotherapies especially in advanced kidney cancer with nivolumab in phase III and in metastatic lung cancer with atezolizumab in phase II. Targeted therapies were also highlighted with cabozantinib proposed in advanced renal cancer or everolimus in differenciated neuroendocrine tumors grade 1 or 2. Furthermore the current challenges remain unchanged: improving patients' care through better selection and finding biomarkers using simple samples (blood or urine). Also early phases and personalized medicine found their place in the different presentations and were highlighted largely bringing new approaches in the treatment of metastatic patients. AB - Copyright © 2016. ES - 1769-6917 IL - 0007-4551 DI - S0007-4551(16)30039-X DO - https://dx.doi.org/10.1016/j.bulcan.2016.04.001 PT - English Abstract PT - Journal Article ID - 27229364 [pubmed] ID - S0007-4551(16)30039-X [pii] ID - 10.1016/j.bulcan.2016.04.001 [doi] PP - ppublish PH - 2016/04/01 [received] PH - 2016/04/09 [accepted] LG - French EP - 20160524 DP - 2016 Jun DC - 20160617 EZ - 2016/05/28 06:00 DA - 2016/05/28 06:00 DT - 2016/05/28 06:00 YR - 2016 RD - 20161219 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27229364 <457. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27146870 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Oppel-Heuchel H AU - Grimm MO FA - Oppel-Heuchel, H FA - Grimm, M-O IN - Oppel-Heuchel, H. Urologische Klinik und Poliklinik, Universitatsklinikum Jena, Lessingsstrase 1, 07743, Jena, Deutschland. Harriet.Oppel@med.uni-jena.de. IN - Grimm, M-O. Urologische Klinik und Poliklinik, Universitatsklinikum Jena, Lessingsstrase 1, 07743, Jena, Deutschland. TI - [Therapy monitoring and management of adverse events in PD-1/PD-L1 immune checkpoint inhibition]. [German] OT - Therapiemonitoring und Nebenwirkungsmanagement bei PD-1/PD-L1-Immuncheckpoint-Inhibition. SO - Urologe (Ausg. A). 55(5):677-90, 2016 May AS - Urologe A. 55(5):677-90, 2016 May NJ - Der Urologe. Ausg. A PI - Journal available in: Print PI - Citation processed from: Internet JC - wsj, 1304110 IO - Urologe A SB - Index Medicus CP - Germany KW - Immune-mediated adverse events; Immunotherapy; Nivolumab; PD-1 inhibitor; PD-L1 inhibitor AB - Nivolumab was recently approved as the first inhibitor of the programmed death 1 (PD-1) receptor and its ligand (PD-L1) for the treatment of urological cancer, namely metastasized renal cell carcinoma after prior therapy. The use of this new immunotherapy requires special therapy monitoring and management of side effects. An increase of immune cells around the tumor can initially mimic progression (so-called pseudoprogression). Treatment-associated side effects of higher grade according to the common terminology criteria for adverse events (CTCAE grades 3 or 4) are relatively rare; however, new immune-mediated side effects can occur and affect the skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and colitis), lungs (pneumonitis) and endocrine organs (hyperthyroidism, hypothyroidism and hypophysitis). Treatment has to be delayed or discontinued depending on the kind and degree of side effects; furthermore, corticosteroids can be administered as immunosuppressants. When recognized in time and with correct management, immune-mediated side effects are basically reversible. ES - 1433-0563 IL - 0340-2592 DI - 10.1007/s00120-016-0109-2 DO - https://dx.doi.org/10.1007/s00120-016-0109-2 PT - English Abstract PT - Journal Article ID - 27146870 [pubmed] ID - 10.1007/s00120-016-0109-2 [doi] ID - 10.1007/s00120-016-0109-2 [pii] PP - ppublish LG - German DP - 2016 May DC - 20160514 EZ - 2016/05/06 06:00 DA - 2016/05/06 06:00 DT - 2016/05/06 06:00 YR - 2016 RD - 20161219 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27146870 <458. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25712627 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Abdallah AO AU - Herlopian A AU - Ravilla R AU - Bansal M AU - Chandra-Reddy S AU - Mahmoud F AU - Ong S AU - Gokden M AU - Hutchins L FA - Abdallah, Al-Ola FA - Herlopian, Aline FA - Ravilla, Rahul FA - Bansal, Meghana FA - Chandra-Reddy, Sowmya FA - Mahmoud, Fade FA - Ong, Shirley FA - Gokden, Murat FA - Hutchins, Laura IN - Abdallah, Al-Ola. Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA. IN - Herlopian, Aline. Department of Internal Medicine, Division of Neurology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA. IN - Ravilla, Rahul. Department of Internal Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA. IN - Bansal, Meghana. Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA. IN - Chandra-Reddy, Sowmya. Department of Internal Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA. IN - Mahmoud, Fade. Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA. IN - Ong, Shirley. Department of Internal Medicine, Division of Neurology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA. IN - Gokden, Murat. Department of Pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA. IN - Hutchins, Laura. Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA HutchinsLauraF@uams.edu. TI - Ipilimumab-induced necrotic myelopathy in a patient with metastatic melanoma: A case report and review of literature. SO - Journal of Oncology Pharmacy Practice. 22(3):537-42, 2016 Jun AS - J Oncol Pharm Pract. 22(3):537-42, 2016 Jun NJ - Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9511372 IO - J Oncol Pharm Pract SB - Index Medicus CP - England KW - Ipilimumab; immune-related adverse events; progressive necrotic myelopathy AB - Ipilimumab is a novel humanized monoclonal antibody directed against cytotoxic T lymphocyte antigen 4, a T-cell surface molecule involved in down-regulation and suppression of the T cell response to stimuli. Patients treated with ipilimumab are at risk for immune-related adverse events involving the skin, digestive tract, liver and endocrine organs. Few case reports of immune-related adverse effects involving central or peripheral nervous system due to ipilimumab are published. These include inflammatory myopathy, aseptic meningitis, severe meningo-radiculo-neuritis, temporal arteritis, Guillain-Barre syndrome, and posterior reversible encephalopathy syndrome. We report the first case of ipilimumab-induced progressive necrotic myelopathy. AB - Copyright © The Author(s) 2015. ES - 1477-092X IL - 1078-1552 DI - 1078155215572932 DO - https://dx.doi.org/10.1177/1078155215572932 PT - Journal Article ID - 25712627 [pubmed] ID - 1078155215572932 [pii] ID - 10.1177/1078155215572932 [doi] PP - ppublish LG - English EP - 20150223 DP - 2016 Jun DC - 20160423 EZ - 2015/02/26 06:00 DA - 2015/02/26 06:00 DT - 2015/02/26 06:00 YR - 2016 RD - 20161219 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=25712627 <459. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 25694346 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Eryilmaz MK AU - Mutlu H AU - Salim DK AU - Musri FY AU - Tural D AU - Bassorgun I AU - Coskun HS FA - Eryilmaz, Melek Karakurt FA - Mutlu, Hasan FA - Salim, Derya Kivrak FA - Musri, Fatma Yalcin FA - Tural, Deniz FA - Bassorgun, Ibrahim FA - Coskun, Hasan Senol IN - Eryilmaz, Melek Karakurt. Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey drangelkarakurt@hotmail.com. IN - Mutlu, Hasan. Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey. IN - Salim, Derya Kivrak. Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey. IN - Musri, Fatma Yalcin. Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey. IN - Tural, Deniz. Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey. IN - Bassorgun, Ibrahim. Department of Pathology, Akdeniz University School of Medicine, Antalya, Turkey. IN - Coskun, Hasan Senol. Department of Medical Oncology, Akdeniz University School of Medicine, Antalya, Turkey. TI - Ipilimumab may increase the severity of cutenaous toxicity related to radiotherapy. SO - Journal of Oncology Pharmacy Practice. 22(3):533-6, 2016 Jun AS - J Oncol Pharm Pract. 22(3):533-6, 2016 Jun NJ - Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9511372 IO - J Oncol Pharm Pract SB - Index Medicus CP - England KW - Melanoma; cytotoxic T-lymphocyte antigen-4; dermatitis; ipilimumab; radiotherapy AB - Ipilimumab, monoclonal antibody against cytotoxic T-lymphocyte antigen-4 and, radiotherapy are commonly used to treat unresectable and metastatic melanoma. As a result of upregulation of immune system with ipilimumab, many immune-related adverse effects, such as dermatitis, colitis, hepatitis, and hypophysitis, have been previously reported in literature. Typically, these effects are treated with high-dose steroids and mostly heal up. Here, we report a case who was receiving radiotherapy due to metastatic malignant melanoma with atypical generalized rash, which was enlarged with concurrent ipilimumab treatment. AB - Copyright © The Author(s) 2015. ES - 1477-092X IL - 1078-1552 DI - 1078155215572930 DO - https://dx.doi.org/10.1177/1078155215572930 PT - Journal Article ID - 25694346 [pubmed] ID - 1078155215572930 [pii] ID - 10.1177/1078155215572930 [doi] PP - ppublish LG - English EP - 20150217 DP - 2016 Jun DC - 20160423 EZ - 2015/02/20 06:00 DA - 2015/02/20 06:00 DT - 2015/02/20 06:00 YR - 2016 RD - 20161219 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=25694346 <460. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27554835 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Kushnir I AU - Wolf I FA - Kushnir, Igal FA - Wolf, Ido IN - Kushnir, Igal. Oncology Division, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. TI - Nivolumab-Induced Pericardial Tamponade: A Case Report and Discussion. SO - Cardiology. 136(1):49-51, 2017 AS - Cardiology. 136(1):49-51, 2017 NJ - Cardiology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - coi, 1266406 IO - Cardiology CP - Switzerland AB - Nivolumab, a programmed death 1 (PD1) inhibitor, belongs to a family of drugs known as immune checkpoint inhibitors that share a similar toxicity profile, which includes rash, pruritus, colitis, hepatitis, pneumonitis and thyroid dysfunction. Nivolumab has a proven efficacy in the treatment of malignant melanoma, non-small cell lung cancer and renal cell carcinoma. We present the case of a 67-year-old male patient with metastatic squamous cell carcinoma of the lung who suffered from a massive pericardial effusion secondary to treatment with nivolumab, which he began in June 2015. After five cycles the patient was hospitalized due to acute respiratory failure requiring mechanical ventilation. An echocardiogram revealed a massive pericardial effusion with tamponade. After pericardiocentesis and corticosteroid treatment, the patient's condition improved rapidly. A CT scan revealed a response of the tumor. Although anti-PD1 treatment is usually regarded as less toxic than chemotherapy, a wide spectrum of life-threatening immune-related side effects may still occur and clinical vigilance is required. AB - Copyright © 2016 S. Karger AG, Basel. ES - 1421-9751 IL - 0008-6312 DI - 000447053 DO - https://dx.doi.org/10.1159/000447053 PT - Journal Article ID - 27554835 [pubmed] ID - 000447053 [pii] ID - 10.1159/000447053 [doi] PP - ppublish PH - 2016/05/23 [received] PH - 2016/05/24 [accepted] LG - English EP - 20160824 DP - 2017 DC - 20160824 EZ - 2016/08/25 06:00 DA - 2016/08/25 06:00 DT - 2016/08/25 06:00 YR - 2017 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27554835 <461. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27117582 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Duchnowska R AU - Peksa R AU - Radecka B AU - Mandat T AU - Trojanowski T AU - Jarosz B AU - Czartoryska-Arlukowicz B AU - Olszewski WP AU - Och W AU - Kalinka-Warzocha E AU - Kozlowski W AU - Kowalczyk A AU - Loi S AU - Biernat W AU - Jassem J AU - Polish Brain Metastasis Consortium FA - Duchnowska, Renata FA - Peksa, Rafal FA - Radecka, Barbara FA - Mandat, Tomasz FA - Trojanowski, Tomasz FA - Jarosz, Bozena FA - Czartoryska-Arlukowicz, Bogumila FA - Olszewski, Wojciech P FA - Och, Waldemar FA - Kalinka-Warzocha, Ewa FA - Kozlowski, Wojciech FA - Kowalczyk, Anna FA - Loi, Sherene FA - Biernat, Wojciech FA - Jassem, Jacek FA - Polish Brain Metastasis Consortium IN - Duchnowska, Renata. Department of Oncology, Military Institute of Medicine, Szaserow St 128, 04-141, Warsaw, Poland. rdtt@wp.pl. IN - Peksa, Rafal. Department of Pathology, Medical University of Gdansk, 7 Debinki St, 80-211, Gdansk, Poland. IN - Radecka, Barbara. Department of Oncology, Regional Oncology Center, 66a Katowicka St, 45-060, Opole, Poland. IN - Mandat, Tomasz. Department of Neurosurgery, Oncology Center-Institute, 5 Roentgena St, 02-781, Warsaw, Poland. IN - Trojanowski, Tomasz. Department of Neurosurgery, Medical University of Lublin, 1 Al. Raclawickie, 20-059, Lublin, Poland. IN - Jarosz, Bozena. Department of Neurosurgery, Medical University of Lublin, 1 Al. Raclawickie, 20-059, Lublin, Poland. IN - Czartoryska-Arlukowicz, Bogumila. Department of Oncology, Regional Oncology Center, 12 Ogrodowa St, 15-027, Bialystok, Poland. IN - Olszewski, Wojciech P. Department of Pathology, Oncology Center-Institute, 5 Roentgena St, 02-781, Warsaw, Poland. IN - Och, Waldemar. Department of Neurosurgery, Regional Hospital, 18 Zolnierska St, 10-561, Olsztyn, Poland. IN - Kalinka-Warzocha, Ewa. Department of Oncology, Regional Oncology Center, 62 Pabianicka St, 93-513, Lodz, Poland. IN - Kozlowski, Wojciech. Department of Pathology, Military Institute of Medicine, Szaserow St 128, 04-141, Warsaw, Poland. IN - Kowalczyk, Anna. Department of Oncology and Radiotherapy, Medical University of Gdansk, 7 Debinki St, 80-211, Gdansk, Poland. IN - Loi, Sherene. Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, East Melbourne, VIC, 8006, Australia. IN - Biernat, Wojciech. Department of Pathology, Medical University of Gdansk, 7 Debinki St, 80-211, Gdansk, Poland. IN - Jassem, Jacek. Department of Oncology and Radiotherapy, Medical University of Gdansk, 7 Debinki St, 80-211, Gdansk, Poland. TI - Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. SO - Breast Cancer Research. 18(1):43, 2016 Apr 27 AS - Breast Cancer Res. 18(1):43, 2016 Apr 27 NJ - Breast cancer research : BCR PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 100927353, dyz IO - Breast Cancer Res. PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847231 SB - Index Medicus CP - England KW - Brain metastases; Breast cancer; Lymphocytes; PD-1; PD-L AB - BACKGROUND: A better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies. AB - METHODS: Immunohistochemical expression of stromal tumor-infiltrating lymphocytes (TILs: CD4, CD8, CTLA4), macrophage/microglial cells (CD68), programmed cell death protein 1 receptor (PD-1), programmed cell death protein 1 receptor ligand (PD-L)1, PD-L2 and glial fibrillary acid protein was assessed in 84 BCBM and their microenvironment. AB - RESULTS: Median survival after BCBM excision was 18.3 months (range 0-99). Median number of CD4+, CD8+ TILs and CD68+ was 49, 69 and 76 per 1 mm(2), respectively. PD-L1 and PD-L2 expression in BCBM was present in 53 % and 36 % of cases, and was not related to BCBM phenotype. PD-1 expression on TILs correlated positively with CD4+ and CD8+ TILs (r=0.26 and 0.33), and so did CD68+ (r=0.23 and 0.27, respectively). In the multivariate analysis, survival after BCBM excision positively correlated with PD-1 expression on TILs (hazard ratio (HR)=0.3, P=0.003), CD68+ infiltration (HR=0.2, P<0.001), brain radiotherapy (HR=0.1, P<0.001), endocrine therapy (HR=0.1, P<0.001), and negatively with hormone-receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive phenotype of primary tumor (HR=2.6, P=0.01), HER2 expression in BCBM (HR=4.9, P=0.01). AB - CONCLUSIONS: PD-L1 and PD-L2 expression is a common occurrence in BCBM, irrespective of primary tumor and BCBM phenotype. Favorable prognostic impact of PD-1 expression on TILs suggests a beneficial effect of preexisting immunity and implies a potential therapeutic role of immune checkpoint inhibitors in BCBM. ES - 1465-542X IL - 1465-5411 DI - 10.1186/s13058-016-0702-8 DO - https://dx.doi.org/10.1186/s13058-016-0702-8 PT - Journal Article ID - 27117582 [pubmed] ID - 10.1186/s13058-016-0702-8 [doi] ID - 10.1186/s13058-016-0702-8 [pii] ID - PMC4847231 [pmc] PP - epublish PH - 2015/12/08 [received] PH - 2016/04/04 [accepted] LG - English EP - 20160427 DP - 2016 Apr 27 DC - 20160427 EZ - 2016/04/28 06:00 DA - 2016/04/28 06:00 DT - 2016/04/28 06:00 YR - 2016 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27117582 <462. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27000274 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Shimizu T AU - Seto T AU - Hirai F AU - Takenoyama M AU - Nosaki K AU - Tsurutani J AU - Kaneda H AU - Iwasa T AU - Kawakami H AU - Noguchi K AU - Shimamoto T AU - Nakagawa K FA - Shimizu, Toshio FA - Seto, Takashi FA - Hirai, Fumihiko FA - Takenoyama, Mitsuhiro FA - Nosaki, Kaname FA - Tsurutani, Junji FA - Kaneda, Hiroyasu FA - Iwasa, Tsutomu FA - Kawakami, Hisato FA - Noguchi, Kazuo FA - Shimamoto, Takashi FA - Nakagawa, Kazuhiko IN - Shimizu, Toshio. Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka, 589-8511, Japan. jcog9511@hotmail.co.jp. IN - Seto, Takashi. Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan. IN - Hirai, Fumihiko. Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan. IN - Takenoyama, Mitsuhiro. Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan. IN - Nosaki, Kaname. Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan. IN - Tsurutani, Junji. Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka, 589-8511, Japan. IN - Kaneda, Hiroyasu. Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka, 589-8511, Japan. IN - Iwasa, Tsutomu. Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka, 589-8511, Japan. IN - Kawakami, Hisato. Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka, 589-8511, Japan. IN - Noguchi, Kazuo. MSD K.K., Kitanomaru square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo, 102-8667, Japan. IN - Shimamoto, Takashi. MSD K.K., Kitanomaru square, 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo, 102-8667, Japan. IN - Nakagawa, Kazuhiko. Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Osaka, 589-8511, Japan. TI - Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors. SO - Investigational New Drugs. 34(3):347-54, 2016 Jun AS - Invest New Drugs. 34(3):347-54, 2016 Jun NJ - Investigational new drugs PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - gwj, 8309330 IO - Invest New Drugs PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859860 SB - Index Medicus CP - United States KW - Anti-PD-1 therapy; PD-L1; Pembrolizumab; Pharmacokinetics; Phase I study AB - Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n=2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n=1), grade 3 AST elevation (n=1), grade 1 pneumonitis (n=1), and grade 1 thyroid-stimulating hormone elevation (n=1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC. ES - 1573-0646 IL - 0167-6997 DI - 10.1007/s10637-016-0347-6 DO - https://dx.doi.org/10.1007/s10637-016-0347-6 PT - Journal Article ID - 27000274 [pubmed] ID - 10.1007/s10637-016-0347-6 [doi] ID - 10.1007/s10637-016-0347-6 [pii] ID - PMC4859860 [pmc] PP - ppublish PH - 2016/03/09 [received] PH - 2016/03/16 [accepted] LG - English EP - 20160322 DP - 2016 Jun DC - 20160507 EZ - 2016/03/23 06:00 DA - 2016/03/24 06:00 DT - 2016/03/24 06:00 YR - 2016 RD - 20161215 UP - 20161222 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27000274 <463. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27842767 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Bunchorntavakul C AU - Reddy KR FA - Bunchorntavakul, Chalermrat FA - Reddy, K Rajender IN - Bunchorntavakul, Chalermrat. Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, HUP, Philadelphia, PA 19104, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand. IN - Reddy, K Rajender. Liver Transplantation, Viral Hepatitis Center, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, HUP, Liver Transplant Office, Philadelphia, PA 19104, USA. Electronic address: rajender.reddy@uphs.upenn.edu. TI - Drug Hepatotoxicity: Newer Agents. [Review] SO - Clinics in Liver Disease. 21(1):115-134, 2017 Feb AS - Clin Liver Dis. 21(1):115-134, 2017 Feb NJ - Clinics in liver disease PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dw6, 9710002 IO - Clin Liver Dis CP - United States KW - Antibiotics; Anticoagulants; Antiplatelet; Antiretrovirals; Drug-induced liver injury; Hepatotoxicity; Monoclonal antibodies; Tyrosine kinase inhibitors AB - Idiosyncratic hepatotoxicity is one of the most common reasons for an approved drug being restricted. This article focuses on hepatotoxicity of selected and recently introduced agents, such as, tyrosine kinase inhibitors, monoclonal antibodies, novel oral anticoagulants, newer antiplatelets, antibiotics, anti-diabetics, anti-epileptics, anti-depressants, anti-psychotics and anti-retrovirals. Overall, the incidence of clinically relevant hepatotoxicity from newer agents seems to be lower than that of the older agents. Nevertheless, cases of severe hepatotoxicity have been reported due to some of these newer agents, including, trastuzumab, ipilimumab, infliximab, imatinib, bosutinib, dasatinib, gefitinib, erlotinib, sunitinib, ponatinib, lapatinib, vemurafenib, dabigatran, rivaroxaban, felbamate, lamotrigine, levetiracetam, venlafaxine, duloxetine, darunavir, and maraviroc. AB - Copyright © 2016 Elsevier Inc. All rights reserved. ES - 1557-8224 IL - 1089-3261 DI - S1089-3261(16)30068-X DO - https://dx.doi.org/10.1016/j.cld.2016.08.009 PT - Review PT - Journal Article ID - 27842767 [pubmed] ID - S1089-3261(16)30068-X [pii] ID - 10.1016/j.cld.2016.08.009 [doi] PP - ppublish LG - English EP - 20161014 DP - 2017 Feb DC - 20161115 EZ - 2016/11/16 06:00 DA - 2016/11/16 06:00 DT - 2016/11/16 06:00 YR - 2017 RD - 20161116 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27842767 <464. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27818005 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Wachsmann JW AU - Ganti R AU - Peng F FA - Wachsmann, Jason W FA - Ganti, Ramapriya FA - Peng, Fangyu IN - Wachsmann, Jason W. Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9140. Electronic address: Jason.Wachsmann@UTSouthwestern.edu. IN - Ganti, Ramapriya. Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9140. IN - Peng, Fangyu. Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9140; Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas. TI - Immune-mediated Disease in Ipilimumab Immunotherapy of Melanoma with FDG PET-CT. [Review] SO - Academic Radiology. 24(1):111-115, 2017 Jan AS - Acad Radiol. 24(1):111-115, 2017 Jan NJ - Academic radiology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - clv, 9440159 IO - Acad Radiol CP - United States KW - FDG; PET-CT; immune-related adverse events; ipilimumab; melanoma AB - RATIONALE AND OBJECTIVES: The purposes of this study were to provide a case-based overview of various immune-mediated side effects detected by 18F-Fluorodeoxyglucose (F-18 FDG) positron emission tomography-computed tomography (PET-CT) in the patients receiving ipilimumab immunotherapy for treatment of malignant melanoma, and discuss the importance of recognizing immune-mediated side effects in the use of F-18 FDG PET-CT for monitoring therapeutic effects of ipilimumab on metastatic melanoma. AB - MATERIALS AND METHODS: This is a retrospective case series study of the patients diagnosed with melanoma who were subjected to immunomodulating therapy with ipilimumab. F-18 FDG PET-CT findings were reviewed, and the patients with immune-mediated side effects were selected for further analysis, in conjunction with review of clinical progress notes, the results of laboratory tests, and findings of other imaging tests. AB - RESULTS: Four patients with immune-mediated side effects were identified among the patients being treated with ipilimumab and subjected to F-18 FDG PET-CT for monitoring therapeutic effects. These immune mediated side effects include new findings of abnormal increased FDG uptake associated with immune-mediated pancreatitis and hypophysitis, as well as immune-mediated thyroiditis and colitis reported previously. AB - CONCLUSIONS: Various immune-mediated side effects were detected by F-18 FDG PET-CT in the patients subjected to immunomodulating therapy with ipilimumab. It is essential for the interpreting provider to recognize and differentiate abnormal FDG uptake associated with immune-mediated side effects from hypermetabolic malignant lesions when using F-18 FDG PET-CT for monitoring therapeutic effects of ipilimumab on melanoma lesions. AB - Copyright A© 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved. ES - 1878-4046 IL - 1076-6332 DI - S1076-6332(16)30180-5 DO - https://dx.doi.org/10.1016/j.acra.2016.08.005 PT - Review PT - Journal Article ID - 27818005 [pubmed] ID - S1076-6332(16)30180-5 [pii] ID - 10.1016/j.acra.2016.08.005 [doi] PP - ppublish PH - 2015/11/25 [received] PH - 2016/08/05 [revised] PH - 2016/08/07 [accepted] LG - English EP - 20161104 DP - 2017 Jan DC - 20161107 EZ - 2016/11/08 06:00 DA - 2016/11/08 06:00 DT - 2016/11/08 06:00 YR - 2017 RD - 20161205 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27818005 <465. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27876011 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Jung K AU - Zeng X AU - Bilusic M AI - Jung, Kyungsuk; ORCID: http://orcid.org/0000-0003-1306-5180 FA - Jung, Kyungsuk FA - Zeng, Xu FA - Bilusic, Marijo IN - Jung, Kyungsuk. Department of Medicine, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA. Kyungsuk.Jung@fccc.edu. IN - Zeng, Xu. Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, 3500N Broad St, Philadelphia, PA, 19140, USA. IN - Bilusic, Marijo. Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, 19111, USA. TI - Nivolumab-associated acute glomerulonephritis: a case report and literature review. SO - BMC Nephrology. 17(1):188, 2016 Nov 22 AS - BMC Nephrol. 17(1):188, 2016 Nov 22 NJ - BMC nephrology PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 100967793 IO - BMC Nephrol CP - England KW - Acute kidney injury; Autoimmune nephritis; Case report; Immunotherapy; Nivolumab; Renal cell carcinoma AB - BACKGROUND: Immune checkpoint inhibitors are changing the landscape of oncology treatment as they are significantly improving treatment for multiple malignancies. Nivolumab, an anti-programmed death 1 antibody, is a US Food and Drug Administration-approved treatment for melanoma, non-small cell lung cancer, and kidney cancer but can result in a spectrum of autoimmune side effects. Adverse effects can occur within any organ system in the body including the colon, lung, liver, endocrine systems, or kidneys. AB - CASE PRESENTATION: A 70-year-old male with clear cell kidney cancer was admitted with acute kidney injury while on nivolumab. A kidney biopsy revealed diffuse tubular injury and immune complex-mediated glomerulonephritis. Electron microscopy of the specimen showed hump-like subepithelial deposits. Nivolumab was discontinued and the patient was started on a high dose of steroids. After 5 months of systemic corticosteroids and hemodialysis, the patient's kidney function improved to his baseline level. Despite a prolonged interruption to treatment, immunosuppressive therapy did not compromise the anticancer effects of nivolumab. AB - CONCLUSION: Immune-related adverse effects in the kidney can cause autoimmune glomerulonephritis as well as tubulointerstitial injury. In the literature, immune-related nephritis generally responded well to systemic corticosteroid treatment. Based on our experience, a prolonged course of a high dose of steroids and hemodialysis may be required to achieve an adequate treatment effect. ES - 1471-2369 IL - 1471-2369 DI - 10.1186/s12882-016-0408-2 DO - https://dx.doi.org/10.1186/s12882-016-0408-2 PT - Journal Article ID - 27876011 [pubmed] ID - 10.1186/s12882-016-0408-2 [doi] ID - 10.1186/s12882-016-0408-2 [pii] ID - PMC5120473 [pmc] PP - epublish PH - 2016/06/10 [received] PH - 2016/11/15 [accepted] LG - English EP - 20161122 DP - 2016 Nov 22 DC - 20161123 EZ - 2016/11/24 06:00 DA - 2016/11/24 06:00 DT - 2016/11/24 06:00 YR - 2016 RD - 20161129 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27876011 <466. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27857838 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Trainer H AU - Hulse P AU - Higham CE AU - Trainer P AU - Lorigan P FA - Trainer, Harris FA - Hulse, Paul FA - Higham, Claire E FA - Trainer, Peter FA - Lorigan, Paul IN - Trainer, Harris. Departments of Endocrinology. IN - Hulse, Paul. Departments of Radiology. IN - Higham, Claire E. Departments of Endocrinology. IN - Trainer, Peter. Departments of Endocrinology. IN - Lorigan, Paul. Departments of Medical Oncology , The Christie NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester , UK. TI - Hyponatraemia secondary to nivolumab-induced primary adrenal failure. SO - Endocrinology, Diabetes & Metabolism Case Reports. 2016, 2016 AS - Endocrinol Diabetes Metab Case Rep. 2016, 2016 NJ - Endocrinology, diabetes & metabolism case reports PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 101618943 IO - Endocrinol Diabetes Metab Case Rep CP - England AB - : Checkpoint inhibitors, such as ipilimumab and pembrolizumab, have transformed the prognosis for patients with advanced malignant melanoma and squamous non-small-cell lung cancer, and their use will only expand as experience is gained in a variety of other malignancies, for instance, renal and lymphoma. As the use of checkpoint inhibitors increases, so too will the incidence of their unique side effects, termed immune-related adverse events (irAEs), which can affect dermatological, gastrointestinal, hepatic, endocrine and other systems. Nivolumab is a monoclonal antibody that blocks the human programmed death receptor-1 ligand (PD-L1) found on many cancer cells and is licensed for the treatment of advanced malignant melanoma. We describe the first case of nivolumab-induced adrenalitis resulting in primary adrenal failure presenting with hyponatraemia in a 43-year-old man with malignant melanoma. The case highlights the potentially life-threatening complications of checkpoint inhibitors and the need for patient education and awareness of irAEs among the wider clinical community because such side effects require prompt recognition and treatment. AB - LEARNING POINTS: Nivolumab can cause primary adrenal insufficiency.Not all cases of hyponatraemia in patients with malignancy are due to SIADH.Any patient on a checkpoint inhibitor becoming unwell should have serum cortisol urgently measured and if in doubt hydrocortisone therapy should be initiated.Although hyponatraemia can occur in patients with ACTH deficiency, the possibility of primary adrenal failure should also be considered and investigated by measurement of renin, aldosterone and ACTH.Patients receiving checkpoint inhibitors require education on the potential risks of hypocortisolaemia.PET imaging demonstrated bilateral increased activity consistent with an autoimmune adrenalitis. IL - 2052-0573 DI - 16-0108 DI - EDM160108 DO - https://dx.doi.org/10.1530/EDM-16-0108 PT - Journal Article ID - 27857838 [pubmed] ID - 10.1530/EDM-16-0108 [doi] ID - EDM160108 [pii] ID - PMC5097140 [pmc] PP - ppublish PH - 2016/10/04 [received] PH - 2016/10/14 [accepted] LG - English EP - 20161101 DP - 2016 DC - 20161118 EZ - 2016/11/19 06:00 DA - 2016/11/20 06:00 DT - 2016/11/20 06:00 YR - 2016 RD - 20161121 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27857838 <467. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27777775 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Wilson MA AU - Guld K AU - Galetta S AU - Walsh RD AU - Kharlip J AU - Tamhankar M AU - McGettigan S AU - Schuchter LM AU - Fecher LA FA - Wilson, Melissa A FA - Guld, Kelly FA - Galetta, Steven FA - Walsh, Ryan D FA - Kharlip, Julia FA - Tamhankar, Madhura FA - McGettigan, Suzanne FA - Schuchter, Lynn M FA - Fecher, Leslie A IN - Wilson, Melissa A. Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA ; Present address: Division of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY USA. IN - Guld, Kelly. Department of Medicine, University of Pennsylvania, Philadelphia, PA USA ; Present address: Department of Cardiology, UCSF Medical Center, San Francisco, CA USA. IN - Galetta, Steven. Department of Neurology, NYU Langone Medical Center, New York, NY USA. IN - Walsh, Ryan D. Departments of Ophthalmology and Neurology, Medical College of Wisconsin, Milwaukee, WI USA. IN - Kharlip, Julia. Division of Endocrinology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA. IN - Tamhankar, Madhura. Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania Health System, Philadelphia, PA USA. IN - McGettigan, Suzanne. Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA. IN - Schuchter, Lynn M. Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA. IN - Fecher, Leslie A. Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA USA ; Present address: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C366 MIB 1500 E. Medical Center Drive, SPC5848, Ann Arbor, MI 48109 USA. TI - Acute visual loss after ipilimumab treatment for metastatic melanoma. SO - Journal for Immunotherapy of Cancer. 4:66, 2016 AS - J Immunother Cancer. 4:66, 2016 NJ - Journal for immunotherapy of cancer PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101620585 IO - J Immunother Cancer CP - England KW - Checkpoint inhibitors; Immune; Ipilimumab; Melanoma; Optic neuritis; Side effects AB - BACKGROUND: Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs). AB - CASE PRESENTATION: Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs. AB - CONCLUSIONS: This case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab. IL - 2051-1426 DI - 170 DO - https://dx.doi.org/10.1186/s40425-016-0170-9 PT - Journal Article ID - 27777775 [pubmed] ID - 10.1186/s40425-016-0170-9 [doi] ID - 170 [pii] ID - PMC5067900 [pmc] PP - epublish PH - 2016/03/24 [received] PH - 2016/09/29 [accepted] GI - No: T32 CA009615 Organization: (CA) *NCI NIH HHS* Country: United States LG - English EP - 20161018 DP - 2016 DC - 20161025 EZ - 2016/10/26 06:00 DA - 2016/10/26 06:00 DT - 2016/10/26 06:00 YR - 2016 RD - 20161202 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27777775 <468. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27777773 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Ong M AU - Ibrahim AM AU - Bourassa-Blanchette S AU - Canil C AU - Fairhead T AU - Knoll G FA - Ong, Michael FA - Ibrahim, Andrea Marie FA - Bourassa-Blanchette, Samuel FA - Canil, Christina FA - Fairhead, Todd FA - Knoll, Greg IN - Ong, Michael. Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada ; The Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada. IN - Ibrahim, Andrea Marie. The Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada. IN - Bourassa-Blanchette, Samuel. Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada. IN - Canil, Christina. Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada. IN - Fairhead, Todd. Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada. IN - Knoll, Greg. Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada. TI - Antitumor activity of nivolumab on hemodialysis after renal allograft rejection. SO - Journal for Immunotherapy of Cancer. 4:64, 2016 AS - J Immunother Cancer. 4:64, 2016 NJ - Journal for immunotherapy of cancer PI - Journal available in: Electronic-eCollection PI - Citation processed from: Print JC - 101620585 IO - J Immunother Cancer CP - England KW - Acute allograft rejection; Anti-PD-1 therapy; Hemodialysis; Melanoma; Nivolumab; Organ transplant AB - BACKGROUND: Nivolumab (OpdivoTM) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer. AB - CASE PRESENTATION: We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient's immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response. AB - CONCLUSIONS: This case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis. IL - 2051-1426 DI - 171 DO - https://dx.doi.org/10.1186/s40425-016-0171-8 PT - Journal Article ID - 27777773 [pubmed] ID - 10.1186/s40425-016-0171-8 [doi] ID - 171 [pii] ID - PMC5067882 [pmc] PP - epublish PH - 2016/08/03 [received] PH - 2016/09/29 [accepted] LG - English EP - 20161018 DP - 2016 DC - 20161025 EZ - 2016/10/26 06:00 DA - 2016/10/26 06:00 DT - 2016/10/26 06:00 YR - 2016 RD - 20161102 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27777773 <469. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27755140 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Dawood S AU - Rugo HS FA - Dawood, Shaheenah FA - Rugo, Hope S IN - Dawood, Shaheenah. aDepartment of Medical Oncology, Dubai Hospital, UAE bUniversity of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA. TI - Targeting the host immune system: PD-1 and PD-L1 antibodies and breast cancer. SO - Current Opinion in Supportive & Palliative Care. 10(4):336-342, 2016 Dec AS - Curr. opin. support. palliat. care. 10(4):336-342, 2016 Dec NJ - Current opinion in supportive and palliative care PI - Journal available in: Print PI - Citation processed from: Internet JC - 101297402 IO - Curr Opin Support Palliat Care CP - United States AB - PURPOSE OF REVIEW: This article describes the role of the PD-1 axis and reviews current data and future directions inhibiting PD-1 and PD-L1 in breast cancer. AB - RECENT FINDINGS: Four phase I monotherapy expansion trials in patients with metastatic breast cancer have demonstrated low but durable single agent responses to PD-1 and PD-L1 inhibitors, ranging from 4.8 to 19%. Higher response rates are seen in triple negative breast cancer, compared with hormone receptor positive disease. Variability in requirements for tumor PD-L1 expression, and variations in testing complicate cross trial comparisons. A fifth phase Ib trial reported a 38% response rate in metastatic triple negative breast cancer treated with the combination of a PD-L1 inhibitor and nab-paclitaxel chemotherapy. Treatment is generally well tolerated, with low rates of immune toxicity including hypothyroidism, pneumonitis, hepatitis, colitis, and hypophysitis, occurring even months after the end of therapy. AB - SUMMARY: Immune checkpoint inhibitor therapy has recently been shown to have clinical efficacy in the treatment of breast cancer. The most compelling data are in the triple negative subtype, with responses documented in hormone receptor positive disease as well. Numerous trials are evaluating various combination strategies and biomarkers in early and late stage disease to enhance immunogenicity and response. ES - 1751-4266 IL - 1751-4258 DO - https://dx.doi.org/10.1097/SPC.0000000000000243 PT - Journal Article ID - 27755140 [pubmed] ID - 10.1097/SPC.0000000000000243 [doi] PP - ppublish LG - English DP - 2016 Dec DC - 20161018 EZ - 2016/10/27 06:00 DA - 2016/10/27 06:00 DT - 2016/10/27 06:00 YR - 2016 RD - 20161027 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27755140 <470. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27662340 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Diem S AU - Keller F AU - Ruesch R AU - Maillard SA AU - Speiser DE AU - Dummer R AU - Siano M AU - Urner-Bloch U AU - Goldinger SM AU - Flatz L FA - Diem, Stefan FA - Keller, Fabienne FA - Ruesch, Reinhard FA - Maillard, Samia A FA - Speiser, Daniel E FA - Dummer, Reinhard FA - Siano, Marco FA - Urner-Bloch, Ursula FA - Goldinger, Simone M FA - Flatz, Lukas IN - Diem, Stefan. Departments of *Oncology ++Ophthalmology #Dermatology/Allergology **Institute of Immunobiology, Kantonal Hospital St Gallen, St Gallen +Department of Oncology, Hospital Grabs, Grabs Ludwig Cancer Research Center, University of Lausanne, Lausanne Department of Dermatology PPrivate Ophthalmic Practice in Cooperation with the Skin Cancer Unit, University Hospital of Zurich, Zurich, Switzerland. TI - Pembrolizumab-triggered Uveitis: An Additional Surrogate Marker for Responders in Melanoma Immunotherapy?. SO - Journal of Immunotherapy. 39(9):379-382, 2016 Nov/Dec AS - J Immunother. 39(9):379-382, 2016 Nov/Dec NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. CP - United States AB - Immunotherapy leads to significantly prolonged survival of patients with metastatic melanoma. Autoimmune side effects including colitis, dermatitis, and endocrine abnormalities are common in patients treated with ipilimumab [anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4)]. Antibodies such as pembrolizumab that interfere with the PD-1 (programmed cell death 1)/PD-L1 pathway show greater efficacy and less toxicity than ipilimumab. Here we report 2 cases of pembrolizumab-induced uveitis associated with complete or partial tumor response. We suggest that uveitis may serve as a surrogate marker for a tumor response to therapy with pembrolizumab. ES - 1537-4513 IL - 1524-9557 DO - https://dx.doi.org/10.1097/CJI.0000000000000143 PT - Journal Article ID - 27662340 [pubmed] ID - 10.1097/CJI.0000000000000143 [doi] PP - ppublish LG - English DP - 2016 Nov/Dec DC - 20160923 EZ - 2016/09/24 06:00 DA - 2016/09/24 06:00 DT - 2016/09/24 06:00 YR - 2016 RD - 20161014 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27662340 <471. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27653290 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Hottinger AF FA - Hottinger, Andreas F IN - Hottinger, Andreas F. Department of Clinical Neurosciences; Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland. TI - Neurologic complications of immune checkpoint inhibitors. SO - Current Opinion in Neurology. 29(6):806-812, 2016 Dec AS - Curr Opin Neurol. 29(6):806-812, 2016 Dec NJ - Current opinion in neurology PI - Journal available in: Print PI - Citation processed from: Internet JC - bx4, 9319162 IO - Curr. Opin. Neurol. CP - England AB - PURPOSE OF REVIEW: In recent years, advances in the understanding of the regulatory mechanisms of the immune system has led to the development of new approaches for cancer treatment. Currently, immune checkpoint inhibitors are the first successful examples of this approach and several agents that target cytotoxic lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) have been approved for various oncologic situations. The aim of this review is to describe the neurologic adverse event profiles for these new immune therapeutic approaches and to discuss their appropriate management. AB - RECENT FINDINGS: The immune checkpoint inhibitor ipilimumab against CTLA-4 and nivolumab or pembrolizumab against PD-1 show a unique spectrum of toxic effects. The most common toxicities include rash, colitis, hepatitis, endocrinopathies, and pneumonitis. Neurologic side-effects are rare but include cases of immune polyneuropathies, Guillain Barre syndrome, myasthenia gravis, posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis as well as immune encephalitis. AB - SUMMARY: It is essential that neurologic immune-related adverse events are recognized and treated as soon as possible, as early treatment increases the odds of a complete recovery. ES - 1473-6551 IL - 1350-7540 DO - https://dx.doi.org/10.1097/WCO.0000000000000391 PT - Journal Article ID - 27653290 [pubmed] ID - 10.1097/WCO.0000000000000391 [doi] PP - ppublish LG - English DP - 2016 Dec DC - 20160922 EZ - 2016/09/23 06:00 DA - 2016/11/03 06:00 DT - 2016/11/03 06:00 YR - 2016 RD - 20161103 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27653290 <472. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27565924 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Semper H AU - Muehlberg F AU - Schulz-Menger J AU - Allewelt M AU - Grohe C FA - Semper, H FA - Muehlberg, F FA - Schulz-Menger, J FA - Allewelt, M FA - Grohe, C IN - Semper, H. ELK Thorax Center, Lindenberger Weg 27, 13125 Berlin, Germany. IN - Muehlberg, F. Working Group on Cardiovascular Magnetic Resonance, Experimental and Clinical Research Center, A Joint Cooperation Between the Charite Medical Faculty and the Max-Delbruck Center for Molecular Medicine and HELIOS Hospital Berlin Buch, Department of Cardiology and Nephrology, Schwanebecker Chaussee 50, 13125 Berlin, Germany. IN - Schulz-Menger, J. Working Group on Cardiovascular Magnetic Resonance, Experimental and Clinical Research Center, A Joint Cooperation Between the Charite Medical Faculty and the Max-Delbruck Center for Molecular Medicine and HELIOS Hospital Berlin Buch, Department of Cardiology and Nephrology, Schwanebecker Chaussee 50, 13125 Berlin, Germany. IN - Allewelt, M. ELK Thorax Center, Lindenberger Weg 27, 13125 Berlin, Germany. IN - Grohe, C. ELK Thorax Center, Lindenberger Weg 27, 13125 Berlin, Germany. Electronic address: Christian.grohe@pgdiakonie.de. TI - Drug-induced myocarditis after nivolumab treatment in a patient with PDL1- negative squamous cell carcinoma of the lung. SO - Lung Cancer. 99:117-9, 2016 Sep AS - Lung Cancer. 99:117-9, 2016 Sep NJ - Lung cancer (Amsterdam, Netherlands) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - b3u, 8800805 IO - Lung Cancer SB - Index Medicus CP - Ireland KW - Drug-induced myocarditis; Immunotherapy; Nivolumab; PDL-1; Pulmonary squamous cell carcinoma AB - Immunotherapy such as nivolumab is a new promising therapeutic option for advanced stage non small cell lung cancer (NSCLC). Due to the interference with the immune system previously unknown side effects are observed both in clinical studies and experience. Autoimmune phenomena effecting skin, gastrointestinal tract, endocrine glands, kidney and lung have been described. Up to now there is only limited information regarding potential cardiac side effects. We present a case of symptomatic drug induced myocarditis after nine cycles of nivolumab in a patient with efficient anticancer response. AB - Copyright © 2016 Elsevier Ireland Ltd. All rights reserved. ES - 1872-8332 IL - 0169-5002 DI - S0169-5002(16)30394-4 DO - https://dx.doi.org/10.1016/j.lungcan.2016.06.025 PT - Journal Article ID - 27565924 [pubmed] ID - S0169-5002(16)30394-4 [pii] ID - 10.1016/j.lungcan.2016.06.025 [doi] PP - ppublish PH - 2016/04/26 [received] PH - 2016/06/28 [revised] PH - 2016/06/30 [accepted] LG - English EP - 20160701 DP - 2016 Sep DC - 20160827 EZ - 2016/08/28 06:00 DA - 2016/08/28 06:00 DT - 2016/08/28 06:00 YR - 2016 RD - 20160827 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27565924 <473. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27543082 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Bickel A AU - Koneth I AU - Enzler-Tschudy A AU - Neuweiler J AU - Flatz L AU - Fruh M FA - Bickel, Angelika FA - Koneth, Irene FA - Enzler-Tschudy, Annette FA - Neuweiler, Jorg FA - Flatz, Lukas FA - Fruh, Martin IN - Bickel, Angelika. Department of Oncology and Haematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007, St. Gallen, Switzerland. angelika.bickel@kssg.ch. IN - Koneth, Irene. Division of Nephrology and Transplantation Medicine, Cantonal Hospital St.Gallen, St. Gallen, Switzerland. IN - Enzler-Tschudy, Annette. Institute of Pathology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. IN - Neuweiler, Jorg. Institute of Pathology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. IN - Flatz, Lukas. Department of Dermatology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. IN - Fruh, Martin. Department of Oncology and Haematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, 9007, St. Gallen, Switzerland. TI - Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma. SO - BMC Cancer. 16:656, 2016 Aug 19 AS - BMC Cancer. 16:656, 2016 Aug 19 NJ - BMC cancer PI - Journal available in: Electronic PI - Citation processed from: Internet JC - 100967800 IO - BMC Cancer PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992260 SB - Index Medicus CP - England KW - Immunotherapy; Malignant Pleural Mesothelioma; Minimal change disease; PD-1 antibody; Pembrolizumab AB - BACKGROUND: Pembrolizumab is an anti- Programmed Death 1 (PD-1) antibody approved in melanoma, non-small cell lung cancer and investigated in malignant pleural mesothelioma. The most frequent immunotherapy related autoimmune reactions include dermatitis, pneumonitis, colitis, hypophysitis, uveitis, hypothyreodism, hepatitis and interstitial nephritis. AB - CASE PRESENTATION: We describe a 62-year old patient diagnosed with malignant pleural mesothelioma who experienced ten days after the second dose of third line therapy with pembrolizumab sudden onset of generalized edema including legs and eyelids and weight gain of 15 kg resulting from nephrotic syndrome and acute renal failure. Pembrolizumab was discontinued and prednisone, diuretics and angiotensin II receptor blocker were initiated with full recovery of symptoms and renal function. Pembrolizumab-associated minimal change disease (MCD) was confirmed by electron microscopy in the renal biopsy. AB - CONCLUSION: We are the first to describe pembrolizumab-related minimal change disease (MCD). Physicians should be aware of this side effect in patients presenting with edema and weight gain and initiate prompt renal function testing, serum albumin and urinalysis followed by steroid treatment if pembrolizumab-related MCD is suspected. ES - 1471-2407 IL - 1471-2407 DI - 10.1186/s12885-016-2718-y DO - https://dx.doi.org/10.1186/s12885-016-2718-y PT - Journal Article ID - 27543082 [pubmed] ID - 10.1186/s12885-016-2718-y [doi] ID - 10.1186/s12885-016-2718-y [pii] ID - PMC4992260 [pmc] PP - epublish PH - 2016/04/28 [received] PH - 2016/08/14 [accepted] LG - English EP - 20160819 DP - 2016 Aug 19 DC - 20160820 EZ - 2016/08/21 06:00 DA - 2016/08/21 06:00 DT - 2016/08/21 06:00 YR - 2016 RD - 20160822 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27543082 <474. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27521108 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Perazella MA FA - Perazella, Mark A IN - Perazella, Mark A. Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Section of Nephrology, Department of Medicine, VA Medical Center, West Haven, Connecticut, USA. Electronic address: Mark.perazella@yale.edu. TI - Checkmate: kidney injury associated with targeted cancer immunotherapy. SO - Kidney International. 90(3):474-6, 2016 Sep AS - Kidney Int. 90(3):474-6, 2016 Sep NJ - Kidney international PI - Journal available in: Print PI - Citation processed from: Internet JC - kvb, 0323470 IO - Kidney Int. SB - Index Medicus CP - United States AB - Immune checkpoint inhibitors are a class of drugs that utilizes immunotherapy to target various cancers. Included are the anti-CTLA-4 and anti-PD-1 receptor antibodies. By reprogramming the immune system, these agents provide a therapy that destroys cancer cells. However, this approach runs the risk of allowing pathologic autoimmunity and organ injury to develop. Unsurprisingly, immune-related adverse effects are described including pneumonitis, colitis, and various endocrinopathies. Now added to this list is AKI, primarily due to ATIN. AB - Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved. ES - 1523-1755 IL - 0085-2538 DI - S0085-2538(16)30265-4 DO - https://dx.doi.org/10.1016/j.kint.2016.05.024 PT - Journal Article ID - 27521108 [pubmed] ID - S0085-2538(16)30265-4 [pii] ID - 10.1016/j.kint.2016.05.024 [doi] PP - ppublish PH - 2016/05/04 [received] PH - 2016/05/19 [revised] PH - 2016/05/20 [accepted] LG - English DP - 2016 Sep DC - 20160813 EZ - 2016/08/14 06:00 DA - 2016/08/16 06:00 DT - 2016/08/16 06:00 YR - 2016 RD - 20160813 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27521108 <475. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27517638 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Tripathi A AU - Kaymakcalan MD AU - LeBoeuf NR AU - Harshman LC FA - Tripathi, Abhishek FA - Kaymakcalan, Marina D FA - LeBoeuf, Nicole R FA - Harshman, Lauren C IN - Tripathi, Abhishek. aLank Center for Genitourinary Oncology, Dana-Farber Cancer Institute bThe Center for Cutaneous Oncology, Department of Dermatology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. TI - Programmed cell death-1 pathway inhibitors in genitourinary malignancies: specific side-effects and their management. SO - Current Opinion in Urology. 26(6):548-55, 2016 Nov AS - Curr Opin Urol. 26(6):548-55, 2016 Nov NJ - Current opinion in urology PI - Journal available in: Print PI - Citation processed from: Internet JC - dgp, 9200621 IO - Curr Opin Urol SB - Index Medicus CP - United States AB - PURPOSE OF REVIEW: Immune checkpoint inhibitors such as those that target the programmed cell death (PD)-1 pathway harness the host immune system to elicit an antitumor response. Their remarkable clinical benefit has led to regulatory approvals in several malignancies including the genitourinary cancers, renal cell carcinoma, and urothelial carcinoma. This review will focus on the management of the toxicities encountered with these agents. AB - RECENT FINDINGS: Although generally well tolerated, a small proportion of patients (10-20%) treated with PD-1 directed agents as monotherapy can develop severe autoimmune manifestations, also known as, immune-related adverse events. These include but are not limited to rashes, pneumonitis, endocrinopathy, colitis, and immune-mediated hepatic dysfunction. Combining these agents with the anti-CTLA-4 antibody ipilimumab can be associated with a higher incidence of these toxicities. Early initiation of immunosuppression with corticosteroids and other agents when needed can help mitigate these toxicities and to date has not been shown to compromise their clinical benefit. AB - SUMMARY: The development of immune checkpoint inhibitors represents significant advances in anticancer therapy but their efficacy may come at the cost of autoimmune toxicities secondary to their induction of the immune system. Early recognition of these effects and aggressive upfront management is essential to safely administer these agents in routine clinical practice. ES - 1473-6586 IL - 0963-0643 DO - https://dx.doi.org/10.1097/MOU.0000000000000332 PT - Journal Article ID - 27517638 [pubmed] ID - 10.1097/MOU.0000000000000332 [doi] PP - ppublish LG - English DP - 2016 Nov DC - 20160928 EZ - 2016/08/13 06:00 DA - 2016/08/16 06:00 DT - 2016/08/16 06:00 YR - 2016 RD - 20160928 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27517638 <476. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27485460 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Latteyer S AU - Tiedje V AU - Schilling B AU - Fuhrer D FA - Latteyer, S FA - Tiedje, V FA - Schilling, B FA - Fuhrer, D IN - Latteyer, S. Department of Endocrinology and MetabolismUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany Endocrine Tumour Center at West German Cancer Center (WTZ)Essen, Germany. IN - Tiedje, V. Department of Endocrinology and MetabolismUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany Endocrine Tumour Center at West German Cancer Center (WTZ)Essen, Germany. IN - Schilling, B. Department of DermatologyVenereology and Allergology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany German Cancer Consortium (DKTK)Heidelberg, Germany. IN - Fuhrer, D. Department of Endocrinology and MetabolismUniversity Hospital Essen, University of Duisburg-Essen, Essen, Germany Endocrine Tumour Center at West German Cancer Center (WTZ)Essen, Germany Dagmar.fuehrer@uk-essen.de. TI - Perspectives for immunotherapy in endocrine cancer. [Review] SO - Endocrine-Related Cancer. 23(10):R469-84, 2016 Oct AS - Endocr Relat Cancer. 23(10):R469-84, 2016 Oct NJ - Endocrine-related cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9436481, dgr IO - Endocr. Relat. Cancer SB - Index Medicus CP - England KW - anti-CTLA-4; anti-PD-1; endocrine and neuroendocrine cancer; immune checkpoint blockade; immunooncology; tumor microenvironment AB - The fight against cancer has seen major breakthroughs in recent years. More than a decade ago, tyrosine kinase inhibitors targeting constitutively activated signaling cascades within the tumor inaugurated a new era of oncological therapy. Recently, immunotherapy with immune checkpoint inhibitors has started to revolutionize the treatment of several malignancies, most notably malignant melanoma, leading to the renaissance and the long-awaited breakthrough of immunooncology. This review provides an overview of the basis of immunotherapy from its initial concepts of anti-tumor immunity and cell-based therapy to the development of immune checkpoint inhibitors and discusses published studies and the perspectives of immunooncology for the treatment of endocrine malignancies. AB - Copyright © 2016 Society for Endocrinology. ES - 1479-6821 IL - 1351-0088 DI - ERC-16-0169 DO - https://dx.doi.org/10.1530/ERC-16-0169 PT - Journal Article PT - Review ID - 27485460 [pubmed] ID - ERC-16-0169 [pii] ID - 10.1530/ERC-16-0169 [doi] PP - ppublish PH - 2016/06/28 [received] PH - 2016/08/02 [accepted] LG - English EP - 20160802 DP - 2016 Oct DC - 20160909 EZ - 2016/08/04 06:00 DA - 2016/08/04 06:00 DT - 2016/08/04 06:00 YR - 2016 RD - 20160909 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27485460 <477. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27472273 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Abdel-Wahab N AU - Shah M AU - Suarez-Almazor ME FA - Abdel-Wahab, Noha FA - Shah, Mohsin FA - Suarez-Almazor, Maria E IN - Abdel-Wahab, Noha. Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. IN - Abdel-Wahab, Noha. Rheumatology and Rehabilitation Department, Assiut University Hospitals, Assiut, Egypt. IN - Shah, Mohsin. Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. IN - Suarez-Almazor, Maria E. Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. TI - Adverse Events Associated with Immune Checkpoint Blockade in Patients with Cancer: A Systematic Review of Case Reports. SO - PLoS ONE [Electronic Resource]. 11(7):e0160221, 2016 AS - PLoS ONE. 11(7):e0160221, 2016 NJ - PloS one PI - Journal available in: Electronic-eCollection PI - Citation processed from: Internet JC - 101285081 IO - PLoS ONE PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4966895 SB - Index Medicus CP - United States AB - BACKGROUND: Three checkpoint inhibitor drugs have been approved by the US Food and Drug Administration for use in specific types of cancers. While the results are promising, severe immunotherapy-related adverse events (irAEs) have been reported. AB - OBJECTIVES: To conduct a systematic review of case reports describing the occurrence of irAEs in patients with cancer following checkpoint blockade therapy, primarily to identify potentially unrecognized or unusual clinical findings and toxicity. AB - DATA SOURCES: We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane CENTRAL with no restriction through August 2015. AB - STUDY SELECTION: Studies reporting cases of cancer develop irAEs following treatment with anti CTLA-4 (ipilimumab) or anti PD-1 (nivolumab or pembrolizumab) antibodies were included. AB - DATA EXTRACTION: We extracted data on patient characteristics, irAEs characteristics, how irAEs were managed, and their outcomes. AB - DATA SYNTHESIS: 191 publications met inclusion criteria, reporting on 251 cases. Most patients had metastatic melanoma (95.6%), and the majority were treated with ipilimumab (93.2%). Autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported irAEs in ipilimumab treated patients. A broad spectrum of toxicities were reported for almost every body system. Moreover, well-defined diseases such as sarcoidosis, polyarthritis, polymyalgia rheumatica/arteritis, lupus, celiac disease, dermatomyositis, and Vogt-Koyanagi-like syndrome were reported. The most frequent irAEs reported with anti-PD1 agents were dermatitis for pembrolizumab, and thyroid disease and pneumonitis for nivolumab. Complete resolution of adverse events occurred in most cases. However, persistent irAEs and death were reported, mainly in patients treated with ipilimumab. AB - LIMITATIONS: Our study is limited by information available in the original reports. AB - CONCLUSIONS: Evidence from case reports shows that cancer patients develop irAEs following checkpoint blockade therapy, and can occasionally develop clearly defined autoimmune systemic diseases. While discontinuation of therapy and/or treatment can result in resolution of irAEs, long-term sequelae and death have been reported. ES - 1932-6203 IL - 1932-6203 DI - PONE-D-16-14449 DO - https://dx.doi.org/10.1371/journal.pone.0160221 PT - Journal Article ID - 27472273 [pubmed] ID - 10.1371/journal.pone.0160221 [doi] ID - PONE-D-16-14449 [pii] ID - PMC4966895 [pmc] PP - epublish PH - 2016/04/25 [received] PH - 2016/07/17 [accepted] LG - English EP - 20160729 DP - 2016 DC - 20160730 EZ - 2016/07/30 06:00 DA - 2016/07/30 06:00 DT - 2016/07/30 06:00 YR - 2016 RD - 20160819 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27472273 <478. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27438388 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Steenbruggen TG AU - van den Heuvel MM AU - Blank CU AU - van Dieren JM AU - Haanen JB AU - Kok M FA - Steenbruggen, T G FA - van den Heuvel, M M FA - Blank, C U FA - van Dieren, J M FA - Haanen, J B A G FA - Kok, M IN - Steenbruggen, T G. Nederlands Kanker Instituut/Antoni van Leeuwenhoek, Amsterdam. TI - [No hair loss, but colitis or pneumonitis: unique side effects of immune checkpoint inhibitors for cancer]. [Dutch] OT - Geen haaruitval, maar wel colitis of pneumonitis. SO - Nederlands Tijdschrift voor Geneeskunde. 160(0):A9873, 2016 AS - Ned Tijdschr Geneeskd. 160(0):A9873, 2016 NJ - Nederlands tijdschrift voor geneeskunde PI - Journal available in: Print PI - Citation processed from: Internet JC - nuk, 0400770 IO - Ned Tijdschr Geneeskd SB - Index Medicus CP - Netherlands AB - Immunotherapy with checkpoint inhibitors is an effective strategy for several cancers. In some patients long-term remissions are seen. However, enhancement of the immune response can be accompanied by immune-related adverse events (irAEs). These patients often present with nonspecific symptoms. The most common irAEs are dermatitis, colitis, pneumonitis, hepatitis and endocrinopathies. IrAEs can occur in every organ, even simultaneously. Furthermore, irAEs can occur weeks or months after discontinuation of checkpoint inhibitors. Most irAEs can be well managed, but life-threatening situations do occur. General management involves supportive care, glucocorticoids and sometimes immunomodulatory drugs, such as infliximab. Early diagnosis and adequate team management can improve the course of irAEs without compromising the cancer treatment. Here, we present two cases: a melanoma patient with an ipilimumab-induced colitis and a lung cancer patient with pneumonitis after anti-PD-1.We then summarise the most common toxicities of checkpoint inhibitors, emphasising the need to familiarise the practitioner with irAEs of approved and emerging immunotherapies. ES - 1876-8784 IL - 0028-2162 PT - English Abstract PT - Journal Article ID - 27438388 [pubmed] PP - ppublish LG - Dutch DP - 2016 DC - 20160721 EZ - 2016/07/21 06:00 DA - 2016/07/22 06:00 DT - 2016/07/22 06:00 YR - 2016 RD - 20160721 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27438388 <479. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27407160 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Banks PD AU - Sandhu S AU - Gyorki DE AU - Johnston ML AU - Rischin D FA - Banks, Patricia D FA - Sandhu, Shahneen FA - Gyorki, David E FA - Johnston, Meredith L FA - Rischin, Danny IN - Banks, Patricia D. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. IN - Sandhu, Shahneen. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. IN - Gyorki, David E. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. IN - Johnston, Meredith L. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. IN - Rischin, Danny. Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia danny.rischin@petermac.org. TI - Recent Insights and Advances in the Management of Merkel Cell Carcinoma. [Review] SO - Journal of oncology practice/American Society of Clinical Oncology. 12(7):637-46, 2016 Jul AS - J Oncol Pract. 12(7):637-46, 2016 Jul NJ - Journal of oncology practice PI - Journal available in: Print PI - Citation processed from: Internet JC - 101261852 IO - J Oncol Pract SB - Index Medicus CP - United States AB - Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy with a propensity for recurrence and a poor prognosis. Incidence of MCC is on the rise and is known to increase with advanced age, immunosuppression, and UV exposure. Merkel cell polyomavirus is implicated in the pathogenesis of virus-positive MCC and accounts for 80% of MCCs in the northern hemisphere and 25% in southern latitudes. In contrast, tumorigenesis of virus-negative MCC is linked to UV-induced DNA damage. Interplay between ubiquitous Merkel cell polyomavirus skin infections that commonly occur in healthy skin and other established risk factors, such as immunosuppression and UV exposure, remains poorly understood. Surgery and radiotherapy achieves excellent locoregional control; however, invariably, a significant proportion of patients develop disseminated disease that is incurable. Chemotherapy offers a high response rate for metastatic disease, but responses are short-lived and the impact on survival is not established. Recent advances in our understanding of the genetic landscape and immunobiology of MCC has led to investigation of novel treatments, including immune checkpoint inhibitors, which are likely to rapidly transform the way we manage these patients. We review epidemiologic, clinical, and histopathologic features of MCC; describe recent insights in MCC biology; and discuss novel therapeutic approaches. AB - Copyright © 2016 by American Society of Clinical Oncology. ES - 1935-469X IL - 1554-7477 DI - 12/7/637 DO - https://dx.doi.org/10.1200/JOP.2016.013367 PT - Journal Article PT - Review ID - 27407160 [pubmed] ID - 12/7/637 [pii] ID - 10.1200/JOP.2016.013367 [doi] PP - ppublish LG - English DP - 2016 Jul DC - 20160713 EZ - 2016/07/14 06:00 DA - 2016/07/14 06:00 DT - 2016/07/14 06:00 YR - 2016 RD - 20161020 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27407160 <480. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27306502 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Kottschade L AU - Brys A AU - Peikert T AU - Ryder M AU - Raffals L AU - Brewer J AU - Mosca P AU - Markovic S AU - Midwest Melanoma Partnership FA - Kottschade, Lisa FA - Brys, Adam FA - Peikert, Tobias FA - Ryder, Mabel FA - Raffals, Laura FA - Brewer, Jerry FA - Mosca, Paul FA - Markovic, Svetomir FA - Midwest Melanoma Partnership IN - Kottschade, Lisa. Division of aMedical Oncology bPulmonary and Critical Care Medicine cEndocrinology dGastroenterology and Hepatology eDermatology fHematology, Mayo Clinic, Rochester, Minnesota gDuke University School of Medicine hDivision of Advance Oncologic and GI Surgery, Duke University, Durham, North Carolina, USA. TI - A multidisciplinary approach to toxicity management of modern immune checkpoint inhibitors in cancer therapy. SO - Melanoma Research. 26(5):469-80, 2016 Oct AS - Melanoma Res. 26(5):469-80, 2016 Oct NJ - Melanoma research PI - Journal available in: Print PI - Citation processed from: Internet JC - bjr, 9109623 IO - Melanoma Res. SB - Index Medicus CP - England AB - Immune-related Adverse Events (irAEs) are the most significant toxicities associated with the use of checkpoint inhibitors, and result from disinhibition of the host's immune homeostasis. The adverse effects experienced from immunotherapy are significantly different from those of chemotherapy and, to a lesser extent, targeted therapy. Early recognition and diagnosis of these toxicities is often challenging, but is critically important because of the potentially life-threatening nature and associated morbidity. Gastrointestinal, dermatologic, endocrine, and liver toxicities are the most commonly observed. Less commonly, the eyes, pancreas, kidneys, lungs, bone marrow, or nervous system may be affected. Although most irAEs may resolve with supportive care or discontinuation of drug, in severe cases, they may require hospitalization and immune suppressants, such as steroids, and/or may even cause death. The management of immune-related side effects requires a multidisciplinary approach. ES - 1473-5636 IL - 0960-8931 DO - https://dx.doi.org/10.1097/CMR.0000000000000273 PT - Journal Article ID - 27306502 [pubmed] ID - 10.1097/CMR.0000000000000273 [doi] PP - ppublish LG - English DP - 2016 Oct DC - 20160901 EZ - 2016/06/17 06:00 DA - 2016/06/17 06:00 DT - 2016/06/17 06:00 YR - 2016 RD - 20160901 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27306502 <481. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27262710 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Cassler NM AU - Merrill D AU - Bichakjian CK AU - Brownell I FA - Cassler, Nicole M FA - Merrill, Dean FA - Bichakjian, Christopher K FA - Brownell, Isaac IN - Cassler, Nicole M. Department of Dermatology, Walter Reed National Military Medical Center, Bethesda, MD, USA. IN - Merrill, Dean. University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA. IN - Bichakjian, Christopher K. Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI, USA. IN - Brownell, Isaac. Dermatology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892-1908, USA. Isaac.brownell@nih.gov. TI - Merkel Cell Carcinoma Therapeutic Update. [Review] SO - Current Treatment Options in Oncology. 17(7):36, 2016 Jul AS - Curr Treat Options Oncol. 17(7):36, 2016 Jul NJ - Current treatment options in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - 100900946 IO - Curr Treat Options Oncol SB - Index Medicus CP - United States KW - AKT; Avelumab; CM2B4; Cabozantinib; FDG-PET; Idelalisib; Imatinib; MCV; MLN0128; Merkel cell carcinoma; Neuroendocrine; Octreotide; PD-1; PD-L1; PI3K; Pazopanib; Pembrolizumab; Polyomavirus; VP1; Vaccine; mTOR AB - OPINION STATEMENT: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations. ES - 1534-6277 IL - 1534-6277 DI - 10.1007/s11864-016-0409-1 DO - https://dx.doi.org/10.1007/s11864-016-0409-1 PT - Journal Article PT - Review ID - 27262710 [pubmed] ID - 10.1007/s11864-016-0409-1 [doi] ID - 10.1007/s11864-016-0409-1 [pii] PP - ppublish LG - English DP - 2016 Jul DC - 20160606 EZ - 2016/06/06 06:00 DA - 2016/06/06 06:00 DT - 2016/06/06 06:00 YR - 2016 RD - 20160606 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27262710 <482. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27138570 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Tabchi S AU - Messier C AU - Blais N FA - Tabchi, Samer FA - Messier, Christine FA - Blais, Normand IN - Tabchi, Samer. aDepartment of Hematology - Oncology bDepartment of Pharmacy, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada. TI - Immune-mediated respiratory adverse events of checkpoint inhibitors. SO - Current Opinion in Oncology. 28(4):269-77, 2016 Jul AS - Curr Opin Oncol. 28(4):269-77, 2016 Jul NJ - Current opinion in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - a1v, 9007265 IO - Curr Opin Oncol SB - Index Medicus CP - United States AB - PURPOSE OF REVIEW: Immune checkpoint inhibitors have demonstrated remarkable efficacy with durable responses in the treatment of various malignancies. This new class of therapeutic agents is associated with a toxicity profile that differs from conventional cytotoxic therapy. The present review is focused on one of these toxicities affecting the respiratory system. AB - RECENT FINDINGS: Many types of immune-related adverse events (irAEs) have been identified since the emergence of checkpoint inhibitors including colitis, nephritis, myasthenia gravis-like syndromes, acute interstitial nephritis, pneumonitis, and endocrinopathies. Although pneumonitis is relatively less frequent than other irAEs, this toxicity is by no means inconsequential as it has led to treatment-related deaths during the initial testing phases. AB - SUMMARY: Immune-mediated pneumonitis is a potentially serious but relatively infrequent adverse event associated with the use of immune checkpoint inhibitors. IrAEs can be challenging for oncologists who are still unfamiliar with the early presenting symptoms and subsequent management of these toxicities, especially in the context of a rapidly expanding science. A high index of suspicion for pneumonitis must be maintained in patients receiving checkpoint inhibitors and who present new onset respiratory symptoms because this type of toxicity can be severe and potentially fatal. ES - 1531-703X IL - 1040-8746 DO - https://dx.doi.org/10.1097/CCO.0000000000000291 PT - Journal Article ID - 27138570 [pubmed] ID - 10.1097/CCO.0000000000000291 [doi] PP - ppublish LG - English DP - 2016 Jul DC - 20160603 EZ - 2016/05/04 06:00 DA - 2016/05/04 06:00 DT - 2016/05/04 06:00 YR - 2016 RD - 20160603 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27138570 <483. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27136136 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Torino F AU - Corsello SM AU - Salvatori R FA - Torino, Francesco FA - Corsello, Salvatore M FA - Salvatori, Roberto IN - Torino, Francesco. aDepartment of Systems Medicine, Chair of Medical Oncology, Tor Vergata University of Rome bEndocrinology Unit, Catholic University of Sacred Heart, Rome, Italy cDivision of Endocrinology and Metabolism and Pituitary Center, Johns Hopkins University, Baltimore, Maryland, USA. TI - Endocrinological side-effects of immune checkpoint inhibitors. SO - Current Opinion in Oncology. 28(4):278-87, 2016 Jul AS - Curr Opin Oncol. 28(4):278-87, 2016 Jul NJ - Current opinion in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - a1v, 9007265 IO - Curr Opin Oncol SB - Index Medicus CP - United States AB - PURPOSE OF REVIEW: Three mAbs targeting immune checkpoint proteins are available for the treatment of patients with melanoma, lung, and kidney cancer, and their use will likely expand in the future to additional tumor types. We here update the literature on the incidence and pathophysiology of endocrine toxicities induced by these agents, and discuss management guidance. AB - RECENT FINDINGS: Immune checkpoint inhibition may trigger autoimmune syndromes involving different organs, including several endocrine glands (pituitary, thyroid, adrenals, and endocrine pancreas). Hypophysitis is more frequently associated with ipilimumab, whereas the incidence of thyroid dysfunction is higher with nivolumab/pembrolizumab. Primary adrenal insufficiency can rarely occur with either treatment. Autoimmune diabetes is very rare. As hypophysitis and adrenalitis may be life-threatening, endocrinological evaluation is essential particularly in patients developing fatigue and other symptoms consistent with adrenal insufficiency. Corticosteroids should be promptly used when hypophysitis-induced adrenal insufficiency or adrenalitis are diagnosed, but not in thyroiditis or diabetes. No impact of corticosteroids on the efficacy/activity of immune checkpoint-inhibiting drugs is reported. Hormonal deficiencies are often permanent. AB - SUMMARY: In absence of predicting factors, accurate information to patients provided by the oncology care team is essential for early diagnosis and to limit the consequences of checkpoint inhibition-related endocrine toxicity. ES - 1531-703X IL - 1040-8746 DO - https://dx.doi.org/10.1097/CCO.0000000000000293 PT - Journal Article ID - 27136136 [pubmed] ID - 10.1097/CCO.0000000000000293 [doi] PP - ppublish LG - English DP - 2016 Jul DC - 20160603 EZ - 2016/05/03 06:00 DA - 2016/05/03 06:00 DT - 2016/05/03 06:00 YR - 2016 RD - 20160603 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27136136 <484. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27136135 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Antoun J AU - Titah C AU - Cochereau I FA - Antoun, Joelle FA - Titah, Cherif FA - Cochereau, Isabelle IN - Antoun, Joelle. aSaint Joseph University, Faculty of Medicine, Beirut, Lebanon bFondation ophtalmologique Adolphe de Rothschild cHopital Bichat Claude Bernard, Faculte de Medecine Diderot Paris 7, France. TI - Ocular and orbital side-effects of checkpoint inhibitors: a review article. SO - Current Opinion in Oncology. 28(4):288-94, 2016 Jul AS - Curr Opin Oncol. 28(4):288-94, 2016 Jul NJ - Current opinion in oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - a1v, 9007265 IO - Curr Opin Oncol SB - Index Medicus CP - United States AB - PURPOSE OF REVIEW: Checkpoint inhibitors have been increasingly considered as new targets for cancer therapies. Patients receiving checkpoint inhibitors develop many immune-related adverse events (IRAEs). However, ophthalmic IRAEs are rare and have been reported in less than 1% of patients. To date, few case reports evaluating the ophthalmological side-effects of checkpoint inhibitors have been published. In this review, we plan to report the different ocular and orbital side-effects of the checkpoint inhibitors, and to help guide ophthalmologists and oncologists in their management. AB - RECENT FINDINGS: Ocular side-effects of checkpoint inhibitors include peripheral ulcerative keratitis, uveitis, Vogt-Koyanagi-Harada syndrome, choroidal neovascularization and melanoma-associated retinopathy. Both thyroid-associated orbitopathy and idiopathic orbital inflammation have also been reported in association with checkpoint inhibitors. Mild IRAE can be treated with topical steroids, whereas systemic corticosteroids and discontinuation of checkpoint inhibitors are indicated in more severe ocular and orbital inflammation. AB - SUMMARY: Physicians involved in the care of oncologic patients should be aware of the ocular and orbital IRAEs that may develop with checkpoint inhibitors. A strong cooperation between oncologists and ophthalmologists is required in the diagnosis and prompt management of these IRAEs. ES - 1531-703X IL - 1040-8746 DO - https://dx.doi.org/10.1097/CCO.0000000000000296 PT - Journal Article ID - 27136135 [pubmed] ID - 10.1097/CCO.0000000000000296 [doi] PP - ppublish LG - English DP - 2016 Jul DC - 20160603 EZ - 2016/05/03 06:00 DA - 2016/05/03 06:00 DT - 2016/05/03 06:00 YR - 2016 RD - 20160603 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27136135 <485. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27116334 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Wen X AU - Wang Y AU - Ding Y AU - Li D AU - Li J AU - Guo Y AU - Peng R AU - Zhao J AU - Zhang X AU - Zhang XS FA - Wen, Xizhi FA - Wang, Yao FA - Ding, Ya FA - Li, Dandan FA - Li, Jingjing FA - Guo, Yiqun FA - Peng, Ruiqing FA - Zhao, Jingjing FA - Zhang, Xing FA - Zhang, Xiao-Shi IN - Wen, Xizhi. State Key Laboratory of Oncology in South China, Biotherapy Center, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China. TI - Safety of immune checkpoint inhibitors in Chinese patients with melanoma. SO - Melanoma Research. 26(3):284-9, 2016 Jun AS - Melanoma Res. 26(3):284-9, 2016 Jun NJ - Melanoma research PI - Journal available in: Print PI - Citation processed from: Internet JC - bjr, 9109623 IO - Melanoma Res. SB - Index Medicus CP - England AB - This study aimed to determine the tolerability of Chinese melanoma patients, particularly those with hepatitis B virus (HBV) infection, to immune checkpoint inhibitor therapy. Patients with metastatic melanoma who received anti-cytotoxic T lymphocyte-associated antigen-4 antibody (ipilimumab) or anti-programmed death 1 antibody (pembrolizumab) therapy at our hospital between August 2012 and July 2015 were retrospectively reviewed. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Twenty-three patients with advanced melanoma were included; nine and 10 patients received infusions of ipilimumab and pembrolizumab, respectively, whereas four patients received concurrent ipilimumab and pembrolizumab therapy. There was no cessation of treatment because of agent-related adverse events in any patient. Immune-related adverse events were observed in 44% (4/9), 60% (6/10), 100% (4/4), and 61% (14/23) of patients receiving ipilimumab, pembrolizumab, concomitant ipilimumab and pembrolizumab, and any treatment, respectively. The most frequent immune-related adverse events were endocrine disorders (39%, 9/23), liver function abnormalities (22%, 5/23), and dermatological events (17%, 4/23). There were no gastrointestinal reactions. Toxicities were usually mild and easily managed; only 13% (3/23) of patients had grade 3 adverse events and none experienced grade 4 events or treatment-related death. No additional toxicity nor severe hepatotoxicity was observed in 11 patients who had previous HBV infection. The recommended anti-cytotoxic T lymphocyte-associated antigen-4 and anti-programmed death 1 antibody doses were well tolerated by Chinese patients. Thus, immune checkpoint inhibitors appear to be effective and safe in metastatic melanoma patients, including those with pre-existing HBV infection. ES - 1473-5636 IL - 0960-8931 DI - 00008390-201606000-00010 DO - https://dx.doi.org/10.1097/CMR.0000000000000256 PT - Journal Article ID - 27116334 [pubmed] ID - 10.1097/CMR.0000000000000256 [doi] ID - 00008390-201606000-00010 [pii] PP - ppublish LG - English DP - 2016 Jun DC - 20160427 EZ - 2016/04/27 06:00 DA - 2016/04/27 06:00 DT - 2016/04/27 06:00 YR - 2016 RD - 20160427 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27116334 <486. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27026676 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Sul J AU - Blumenthal GM AU - Jiang X AU - He K AU - Keegan P AU - Pazdur R FA - Sul, Joohee FA - Blumenthal, Gideon M FA - Jiang, Xiaoping FA - He, Kun FA - Keegan, Patricia FA - Pazdur, Richard IN - Sul, Joohee. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA joohee.sul@fda.hhs.gov. IN - Blumenthal, Gideon M. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Jiang, Xiaoping. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - He, Kun. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Keegan, Patricia. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. IN - Pazdur, Richard. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA. TI - FDA Approval Summary: Pembrolizumab for the Treatment of Patients With Metastatic Non-Small Cell Lung Cancer Whose Tumors Express Programmed Death-Ligand 1. SO - Oncologist. 21(5):643-50, 2016 May AS - Oncologist. 21(5):643-50, 2016 May NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861368 SB - Index Medicus CP - United States KW - Lung cancer; Pembrolizumab; Programmed death-ligand 1; U.S. Food and Drug Administration AB - UNLABELLED: : On October 2, 2015, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab, a breakthrough therapy-designated drug, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test, and who have disease progression on or after platinum-containing chemotherapy or targeted therapy against anaplastic lymphoma kinase or epidermal growth factor receptor, if appropriate. This indication was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx, a companion diagnostic test for patient selection based on PD-L1 tumor expression. The accelerated approval was granted based on durable objective response rate (ORR) and an acceptable toxicity profile demonstrated in a multicenter, open-label trial enrolling 550 patients with metastatic NSCLC. The efficacy population comprised 61 patients with tumors identified as strongly positive for PD-L1, and the confirmed ORR as determined by blinded independent central review was 41% (95% confidence interval: 28.6%, 54.3%); all were partial responses. At the time of the analysis, responses were ongoing in 21 of 25 patients (84%), with 11 patients (44%) having response duration of >=6 months. The most commonly occurring (>=20%) adverse reactions included fatigue, decreased appetite, dyspnea, and cough. The most frequent (>=2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Immune-mediated adverse reactions occurred in 13% of patients and included pneumonitis, colitis, hypophysitis, and thyroid disorders. The accelerated approval regulations describe approval of drugs and biologic products for serious and life-threatening illnesses based on a surrogate endpoint likely to predict clinical benefit. Under these regulations, a confirmatory trial or trials is required to verify and describe the benefit of pembrolizumab for patients with metastatic NSCLC. AB - IMPLICATIONS FOR PRACTICE: This report presents key information on the U.S. Food and Drug Administration (FDA) accelerated approval of pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1, as determined by an FDA-approved test, and who have disease progression on or after platinum-containing chemotherapy or targeted therapy against anaplastic lymphoma kinase or epidermal growth factor receptor, if appropriate. The report discusses the data supporting the approval decision, specifically highlighting the incorporation of a companion diagnostic in the key study and the optimal dose of pembrolizumab. AB - Copyright ©AlphaMed Press. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2015-0498 DO - https://dx.doi.org/10.1634/theoncologist.2015-0498 PT - Journal Article ID - 27026676 [pubmed] ID - theoncologist.2015-0498 [pii] ID - 10.1634/theoncologist.2015-0498 [doi] ID - PMC4861368 [pmc] PP - ppublish PH - 2015/12/08 [received] PH - 2016/01/15 [accepted] LG - English EP - 20160329 DP - 2016 May DC - 20160510 EZ - 2016/03/31 06:00 DA - 2016/03/31 06:00 DT - 2016/03/31 06:00 YR - 2016 RD - 20160517 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27026676 <487. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26998595 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Joshi MN AU - Whitelaw BC AU - Palomar MT AU - Wu Y AU - Carroll PV FA - Joshi, M N FA - Whitelaw, B C FA - Palomar, M T P FA - Wu, Y FA - Carroll, P V IN - Joshi, M N. Departments of Endocrinology, Guy's & St Thomas NHS Foundation Trust, London, UK. IN - Whitelaw, B C. Department of Endocrinology, Kings College London NHS Foundation Trust, London, UK. IN - Palomar, M T P. Medical Oncology, Guy's & St Thomas NHS Foundation Trust, London, UK. IN - Wu, Y. Medical Oncology, Guy's & St Thomas NHS Foundation Trust, London, UK. IN - Carroll, P V. Departments of Endocrinology, Guy's & St Thomas NHS Foundation Trust, London, UK. TI - Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review. [Review] SO - Clinical Endocrinology. 85(3):331-9, 2016 Sep AS - Clin Endocrinol (Oxf). 85(3):331-9, 2016 Sep NJ - Clinical endocrinology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dci, 0346653 IO - Clin. Endocrinol. (Oxf) SB - Index Medicus CP - England AB - Immune checkpoint inhibitors are a new and effective class of cancer therapy, with ipilimumab being the most established drug in this category. The drugs' mechanism of action includes promoting the effector T cell response to tumours and therefore increased autoimmunity is a predictable side effect. The endocrine effects of these drugs include hypophysitis and thyroid dysfunction, with rare reports of adrenalitis. The overall incidence of hypophysitis with these medications is up to 9%. Primary thyroid dysfunction occurs in up to 15% of patients, with adrenalitis reported in approximately 1%. The mean onset of endocrine side effects is 9 weeks after initiation (range 5-36 weeks). Investigation and/or screening for hypophysitis requires biochemical and radiological assessment. Hypopituitarism is treated with replacement doses of deficient hormones. Since the endocrine effects of immune checkpoint inhibitors are classed as toxic adverse events, most authors recommend both discontinuation of the immune checkpoint inhibiting medication and 'high-dose' glucocorticoid treatment. However, this has been challenged by some authors, particularly if the endocrine effects can be managed (e.g. pituitary hormone deficiency), and the therapy is proving effective as an anticancer agent. This review describes the mechanism of action of immune checkpoint inhibitors and details the key clinical endocrine-related consequences of this novel class of immunotherapies. AB - Copyright © 2016 John Wiley & Sons Ltd. ES - 1365-2265 IL - 0300-0664 DO - https://dx.doi.org/10.1111/cen.13063 PT - Journal Article PT - Review ID - 26998595 [pubmed] ID - 10.1111/cen.13063 [doi] PP - ppublish PH - 2015/11/26 [received] PH - 2015/12/23 [revised] PH - 2016/02/08 [revised] PH - 2016/03/06 [accepted] LG - English EP - 20160413 DP - 2016 Sep DC - 20160817 EZ - 2016/03/22 06:00 DA - 2016/03/22 06:00 DT - 2016/03/22 06:00 YR - 2016 RD - 20160817 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26998595 <488. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26943572 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Brauner E AU - Gunda V AU - Vanden Borre P AU - Zurakowski D AU - Kim YS AU - Dennett KV AU - Amin S AU - Freeman GJ AU - Parangi S FA - Brauner, Eran FA - Gunda, Viswanath FA - Vanden Borre, Pierre FA - Zurakowski, David FA - Kim, Yon Seon FA - Dennett, Kate Virginia FA - Amin, Salma FA - Freeman, Gordon James FA - Parangi, Sareh IN - Brauner, Eran. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. IN - Gunda, Viswanath. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. IN - Vanden Borre, Pierre. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. IN - Zurakowski, David. Departments of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. IN - Zurakowski, David. Departments of Anesthesia, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. IN - Kim, Yon Seon. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. IN - Kim, Yon Seon. Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea. IN - Dennett, Kate Virginia. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. IN - Amin, Salma. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. IN - Freeman, Gordon James. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. IN - Parangi, Sareh. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. TI - Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer. SO - Oncotarget. 7(13):17194-211, 2016 Mar 29 AS - Oncotarget. 7(13):17194-211, 2016 Mar 29 NJ - Oncotarget PI - Journal available in: Print PI - Citation processed from: Internet JC - 101532965 IO - Oncotarget PM - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941380 SB - Index Medicus CP - United States KW - BRAF inhibitor; MEK inhibitor; anaplastic thyroid cancer; programmed cell death-1; programmed cell death-ligand 1 AB - The interaction of programmed cell death-1 and its ligand is widely studied in cancer. Monoclonal antibodies blocking these molecules have had great success but little is known about them in thyroid cancer. We investigated the role of PD-L1 in thyroid cancer with respect to BRAF mutation and MAP kinase pathway activity and the effect of anti PD-L1 antibody therapy on tumor regression and intra-tumoral immune response alone or in combination with BRAF inhibitor (BRAFi). BRAFV600E cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAFWT cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAFV600E cells, but paradoxically increased its expression in BRAFWT cells. BRAFV600E mutated patients samples had a higher level of PD-L1 mRNA compared to BRAFWT (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAFV600E/WT P53-/- murine tumor cells were randomized to control, PLX4720, anti PD-L1 antibody and their combination. In this model of aggressive thyroid cancer, control tumor volume reached 782.3+/-174.6mm3 at two weeks. The combination dramatically reduced tumor volume to 147.3+/-60.8, compared to PLX4720 (439.3+/-188.4 mm3, P=0.023) or PD-L1 antibody (716.7+/-62.1, P<0.001) alone. Immunohistochemistry analysis revealed intense CD8+ CTL infiltration and cytotoxicity and favorable CD8+:Treg ratio compared to each individual treatment. Our results show anti PD-L1 treatment potentiates the effect of BRAFi on tumor regression and intensifies anti tumor immune response in an immunocompetent model of ATC. Clinical trials of this therapeutic combination may be of benefit in patients with ATC. ES - 1949-2553 IL - 1949-2553 DI - 7839 DO - https://dx.doi.org/10.18632/oncotarget.7839 PT - Journal Article ID - 26943572 [pubmed] ID - 7839 [pii] ID - 10.18632/oncotarget.7839 [doi] ID - PMC4941380 [pmc] PP - ppublish PH - 2015/11/25 [received] PH - 2016/02/06 [accepted] GI - No: P01 AI054456 Organization: (AI) *NIAID NIH HHS* Country: United States No: P50 CA101942 Organization: (CA) *NCI NIH HHS* Country: United States No: R01 CA149738 Organization: (CA) *NCI NIH HHS* Country: United States LG - English DP - 2016 Mar 29 DC - 20160524 EZ - 2016/03/05 06:00 DA - 2016/03/05 06:00 DT - 2016/03/05 06:00 YR - 2016 RD - 20161019 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=26943572 <489. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27265913 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Process AU - Marques P AU - Grossman A FA - Marques, Pedro FA - Grossman, Ashley TI - Ipilimumab-Induced Autoimmune Hypophysitis: Diagnostic and Management Challenges Illustrated by a Clinical Case. SO - Acta Medica Portuguesa. 28(6):775-9, 2015 Nov-Dec AS - Acta Med Port. 28(6):775-9, 2015 Nov-Dec NJ - Acta medica portuguesa PI - Journal available in: Print PI - Citation processed from: Internet JC - 7906803 IO - Acta Med Port SB - Index Medicus CP - Portugal AB - Autoimmune hypophysitis has been described in patients on ipilimumab, a humanised monoclonal antibody increasingly used in the treatment of metastatic melanoma. A 67-year-old woman presented with severe fatigue, nausea and headaches following the third dose of ipilimumab, which was being given as treatment for metastatic melanoma (four administrations at three-weekly intervals). Hormonal evaluation confirmed hypocortisolism, with low gonadotrophins and a low thyroid-stimulating hormone with normal free T4 (she was on long-standing levothyroxine because of past surgery for a multinodular goitre). Magnetic resonance imaging scanning revealed pituitary enlargement compatible with autoimmune hypophysitis. She was commenced on replacement with hydrocortisone with significant improvement of her symptoms. The enlarged pituitary was reduced in size 4 months later. The patient is currently asymptomatic on glucocorticoid and levothyroxine replacement. This case highlights relevant clinical, diagnostic and management aspects of ipilimumab-induced autoimmune hypophysitis, and emphasises the need for increasing awareness for potential side-effects of these new immunomodulatory therapies, including autoimmune hypophysitis. ES - 1646-0758 IL - 0870-399X PT - Journal Article ID - 27265913 [pubmed] PP - ppublish LG - English DP - 2015 Nov-Dec DC - 20160605 EZ - 2016/06/07 06:00 DA - 2016/06/07 06:00 DT - 2016/06/07 06:00 YR - 2015 RD - 20160605 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27265913 <490. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27950718 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - O'Day SJ AU - Ibrahim R AU - DePril V AU - Maio M AU - Chiarion-Sileni V AU - Gajewski TF AU - Pehamberger H AU - Hoos A AU - Humphrey R AU - Wolchock J FA - O'Day, S J FA - Ibrahim, R FA - DePril, V FA - Maio, M FA - Chiarion-Sileni, V FA - Gajewski, T F FA - Pehamberger, H FA - Hoos, A FA - Humphrey, R FA - Wolchock, J IN - O'Day, S J. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - Ibrahim, R. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - DePril, V. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - Maio, M. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - Chiarion-Sileni, V. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - Gajewski, T F. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - Pehamberger, H. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - Hoos, A. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - Humphrey, R. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. IN - Wolchock, J. The Angeles Clinic and Research Institute, Santa Monica, CA; Bristol- Myers Squibb; Bristol-Myers Squibb; University Hospital of Siena; Istituto Oncologico del Veneto IOV-IRCSS; University of Chicago; University of Vienna; Memorial Sloan- Kettering Cancer Center. TI - Efficacy and safety of ipilimumab induction and maintenance dosing in patients with advanced melanoma who progressed on one or more prior therapies. SO - Journal of Clinical Oncology. 26(15_suppl):9021, 2008 May 20 AS - J Clin Oncol. 26(15_suppl):9021, 2008 May 20 NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. CP - United States AB - 9021 Background: Ipilimumab (ipi) is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4. The current study was designed to determine the efficacy and safety of ipi in patients (pts) with advanced melanoma who developed progressive disease (PD) on prior therapies. AB - METHODS: Advanced melanoma pts with PD during or after >1 prior therapeutic regimen were eligible for enrollment into this single-arm, multicenter, phase II study. Ipi induction was given at 10 mg/kg every 3 weeks (Q3W)x4; eligible pts received maintenance Q12W starting at Week (Wk) 24. The primary objective was to evaluate the best overall response rate (BORR, complete + partial response [CR+PR]). Efficacy endpoints were assessed with modified World Health Organization (mWHO) criteria; the first assessment was at Wk 12. Follow-up tumor evaluation beyond PD (defined by an overall tumor burden increase of >25%) by mWHO and before the administration of non-ipi anticancer therapy was permitted as per protocol. AB - RESULTS: The study included 155 treated pts. The median number of prior therapies was 2. The BORR as per an Independent Review Committee (IRC) was 5.8% (9/155) [95% CI, 2.7 - 10.7]. The disease control rate (DCR, best response of CR + PR + stable disease [SD]) was 27.1% (42/155) [95% CI, 20.3 - 34.8]. New exploratory response criteria revealed a >25% reduction of measurable total tumor burden in 25.8% of patients. The progression free survival rate at Wk 24 was 49.1% [95% CI 41.2, 57.9]. Immune-related adverse events (irAEs) occurred in 70.3% of pts. Most patients (46.5%) had Grade 1/2 irAEs. The rates of patients with Grade 3/4 irAEs were: gastrointestinal 8.4%; hepatobiliary 7.1%; endocrine 1.3%; and skin 3.2%. Most irAEs were medically manageable. There were no bowel perforations. AB - CONCLUSIONS: Ipi 10 mg/kg induction/maintenance dosing is effective and well tolerated in pts with PD on prior therapies. Clinical activity, in the form of either objective response or SD occurred in 27% of patients. Based on preliminary results from previous studies (eg, MDX010-15), we expect pts with a BOR of SD or better to remain progression free for months to years. Follow up of these pts is ongoing; survival data will be presented at the meeting. [Table: see text]. ES - 1527-7755 IL - 0732-183X DI - 10.1200/jco.2008.26.15_suppl.9021 PT - Journal Article ID - 27950718 [pubmed] ID - 10.1200/jco.2008.26.15_suppl.9021 [pii] PP - ppublish LG - English DP - 2008 May 20 DC - 20161212 EZ - 2016/12/13 06:00 YR - 2008 RD - 20161212 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27950718 <491. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27948611 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Beer TM AU - Slovin SF AU - Higano CS AU - Tejwani S AU - Dorff TB AU - Stankevich E AU - Lowy I AU - Prostate Cancer Clinical Trials Consortium FA - Beer, T M FA - Slovin, S F FA - Higano, C S FA - Tejwani, S FA - Dorff, T B FA - Stankevich, E FA - Lowy, I FA - Prostate Cancer Clinical Trials Consortium IN - Beer, T M. Oregon Health & Science University, Portland, OR; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Washington School of Medicine, Seattle, WA; Henry Ford Health System, Detroit, MI; The Angeles Clinic and Research Institute, Santa Monica, CA; Medarex, Inc., Bloomsbury, NJ. IN - Slovin, S F. Oregon Health & Science University, Portland, OR; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Washington School of Medicine, Seattle, WA; Henry Ford Health System, Detroit, MI; The Angeles Clinic and Research Institute, Santa Monica, CA; Medarex, Inc., Bloomsbury, NJ. IN - Higano, C S. Oregon Health & Science University, Portland, OR; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Washington School of Medicine, Seattle, WA; Henry Ford Health System, Detroit, MI; The Angeles Clinic and Research Institute, Santa Monica, CA; Medarex, Inc., Bloomsbury, NJ. IN - Tejwani, S. Oregon Health & Science University, Portland, OR; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Washington School of Medicine, Seattle, WA; Henry Ford Health System, Detroit, MI; The Angeles Clinic and Research Institute, Santa Monica, CA; Medarex, Inc., Bloomsbury, NJ. IN - Dorff, T B. Oregon Health & Science University, Portland, OR; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Washington School of Medicine, Seattle, WA; Henry Ford Health System, Detroit, MI; The Angeles Clinic and Research Institute, Santa Monica, CA; Medarex, Inc., Bloomsbury, NJ. IN - Stankevich, E. Oregon Health & Science University, Portland, OR; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Washington School of Medicine, Seattle, WA; Henry Ford Health System, Detroit, MI; The Angeles Clinic and Research Institute, Santa Monica, CA; Medarex, Inc., Bloomsbury, NJ. IN - Lowy, I. Oregon Health & Science University, Portland, OR; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Washington School of Medicine, Seattle, WA; Henry Ford Health System, Detroit, MI; The Angeles Clinic and Research Institute, Santa Monica, CA; Medarex, Inc., Bloomsbury, NJ. TI - Phase I trial of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration resistant prostate cancer (mCRPC). SO - Journal of Clinical Oncology. 26(15_suppl):5004, 2008 May 20 AS - J Clin Oncol. 26(15_suppl):5004, 2008 May 20 NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. CP - United States AB - 5004 Background: IPI is a fully human, anti-CTLA 4 monoclonal antibody capable of enhancing anti-tumor immunity. In preclinical models, XRT results in tumor antigen release and enhances anti-tumor activity of CTLA-4 blockade. AB - METHODS: Pts with mCRPC and ECOG PS of 0-1 were treated with escalating doses of IPI every 3 weeks X 4 doses in cohorts of 6 pts at dose levels of 3, 5, and 10 mg/kg. After the 10 mg/kg cohort was completed, a protocol amendment added single fraction XRT prior to IPI starting at the 3 mg/kg dose level. The primary endpoint was safety. Imaging was repeated every 3 months and serum PSA was monitored monthly. AB - RESULTS: Between 1/2006 and 12/2007, 8, 6, and 6 pts were treated at the 3, 5, and 10 mg/kg dose levels respectively; 6 pts were then treated in the first XRT cohort for a total of 26 pts. 19 pts experienced 29 immune-related adverse events (irAEs) including diarrhea/colitis (14), rash (9), hepatitis (4), endocrinopathy (2). irAEs were >= Grade 3 in 9 pts: GI (6), hepatitis (2), and rash (1) and were generally responsive to immunosuppression. One pt died of opportunistic infections (OI) after 3 months of immunosuppression for colitis; this prompted inclusion of OI prophylaxis within the treatment algorithms. Another pt continues (1yr+) on immunosuppression to suppress colitis. Six pts (23%, 95% CI: 9-44%), all with irAEs, had a confirmed >50% PSA decline (median duration 140d, range 49 to 269+; median time to PSA decline 84d, range 41 to 147). 1 of 7 pts with measurable disease had a PR in nodal metastases and the prostate and achieved an undetectable PSA after treatment with 10 mg/kg IPI. Measurable disease response and PSA decline are both ongoing for 185+, 269+ d, respectively. AB - CONCLUSIONS: The irAEs seen in this trial are similar in type to those seen in melanoma trials with IPI. Antitumor activity appears associated with irAEs. Both irAEs and PSA declines were seen across dose levels. Addition of XRT to 3 mg/kg appears feasible, and evaluation of radiation with 10 mg/kg of IPI is underway. [Table: see text]. ES - 1527-7755 IL - 0732-183X DI - 10.1200/jco.2008.26.15_suppl.5004 PT - Journal Article ID - 27948611 [pubmed] ID - 10.1200/jco.2008.26.15_suppl.5004 [pii] PP - ppublish LG - English DP - 2008 May 20 DC - 20161212 EZ - 2016/12/13 06:00 YR - 2008 RD - 20161212 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27948611 <492. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27948191 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - In-Data-Review AU - Gerritsen W AU - van den Eertwegh AJ AU - de Gruijl T AU - van den Berg HP AU - Scheper RJ AU - Sacks N AU - Lowy I AU - Stankevich E AU - Hege K FA - Gerritsen, W FA - van den Eertwegh, A J FA - de Gruijl, T FA - van den Berg, H P FA - Scheper, R J FA - Sacks, N FA - Lowy, I FA - Stankevich, E FA - Hege, K IN - Gerritsen, W. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. IN - van den Eertwegh, A J. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. IN - de Gruijl, T. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. IN - van den Berg, H P. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. IN - Scheper, R J. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. IN - Sacks, N. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. IN - Lowy, I. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. IN - Stankevich, E. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. IN - Hege, K. VU Medical Center, Amsterdam, The Netherlands; Cell Genesys, Inc., South San Francisco, CA; Medarex, Bloomsbury, NJ. TI - Expanded phase I combination trial of GVAX immunotherapy for prostate cancer and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHPRC). SO - Journal of Clinical Oncology. 26(15_suppl):5146, 2008 May 20 AS - J Clin Oncol. 26(15_suppl):5146, 2008 May 20 NJ - Journal of clinical oncology : official journal of the American Society of Clinical Oncology PI - Journal available in: Print PI - Citation processed from: Internet JC - jco, 8309333 IO - J. Clin. Oncol. CP - United States AB - 5146 Background: A Phase 1 trial is underway to study GVAX immunotherapy for prostate cancer [GVAX immunotherapy (GVAX IT)] and ipilimumab (Ipi) in chemonaive mHRPC patients (pts). AB - METHODS: Twelve pts were treated in a dose-escalation phase for 24 weeks (wks) with bi-weekly intradermal injections of GVAX IT and monthly Ipi. Pts were enrolled in cohorts of 3; each cohort received an escalating dose of Ipi: 0.3, 1, 3 or 5 mg/kg. Sixteen pts were then enrolled in an expansion cohort to be treated with GVAX IT and 3 mg/kg Ipi. AB - RESULTS: Escalation Cohort: Median follow-up of 12 pts is 21.2 months (m). Five of six pts at the higher Ipi doses (3 and 5 mg/kg) developed Grade 2 or 3 immune-related adverse events (irAEs), including Grade 2 or 3 hypophysitis and Grade 3 alveolitis. Late onset PSA responses (declines > 50%) were seen in these 5 pts with response durations of 6.7, 8.6, 9.5, 13.8 (on-going), and 23.1 m. Four of these pts had stable disease on bone scan for at least 12 m, and up to 21 m. Multiple tumor-reactive antibodies (abs) induced by treatment were identified by serologic analysis (SEREX), including abs to filamin B, PSMA and NY-ESO-1. Biopsies of injection sites showed T cell infiltration and Granzyme B expression; these T cells are being tested for antigen-specific lytic activity. Expansion Cohort: Sixteen pts were enrolled, 6 have completed treatment, 10 are on-going. Three pts have experienced irAEs of Grade 1 diarrhea, Grade 3 adrenal insufficiency, and a Grade 3 hepatitis that resolved with steroids. With median follow-up of 6.5 months in the 6 pts who have completed treatment, 1 pt had a PSA response (> 50% decline) and 3 obtained stable PSA, accompanied in one pt by pain relief and decrease in alkaline phosphatase. AB - CONCLUSIONS: The GVAX IT and ipilimumab combination is active in mHRPC in this trial. IrAEs appear manageable and may correlate with anti-tumor activity. The maximum tolerated dose of the combination is not established. Follow-up on the 16 expansion cohort pts will provide data on safety, clinical activity and immunologic correlates. [Table: see text]. ES - 1527-7755 IL - 0732-183X DI - 10.1200/jco.2008.26.15_suppl.5146 PT - Journal Article ID - 27948191 [pubmed] ID - 10.1200/jco.2008.26.15_suppl.5146 [pii] PP - ppublish LG - English DP - 2008 May 20 DC - 20161212 EZ - 2016/12/13 06:00 YR - 2008 RD - 20161212 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=prem&AN=27948191 <493. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28707167 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Rapoport BL AU - van Eeden R AU - Sibaud V AU - Epstein JB AU - Klastersky J AU - Aapro M AU - Moodley D FA - Rapoport, Bernardo Leon FA - van Eeden, Ronwyn FA - Sibaud, Vincent FA - Epstein, Joel B FA - Klastersky, Jean FA - Aapro, Matti FA - Moodley, Devan IN - Rapoport, Bernardo Leon. The Medical Oncology Centre of Rosebank129 Oxford Road, Saxonwold 2196, Johannesburg, South Africa. brapoport@rosebankoncology.co.za. IN - Rapoport, Bernardo Leon. Department of Immunology, Faculty of Health Sciences, University of Pretoria, PO Box 2040, Parklands 2121, Pretoria, 0001, South Africa. brapoport@rosebankoncology.co.za. IN - van Eeden, Ronwyn. The Medical Oncology Centre of Rosebank129 Oxford Road, Saxonwold 2196, Johannesburg, South Africa. IN - Sibaud, Vincent. Department of Medical Oncology and Clinical Research Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse Oncopole, France. IN - Sibaud, Vincent. Department of Oncodermatology, Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse Oncopole, France. IN - Epstein, Joel B. Cedars-Sinai Health System, Samuel Oshin Comprehensive Cancer Institute, Los Angeles, CA, USA. IN - Klastersky, Jean. Institut Jules Bordet, Universite Libre de Bruxelles, Centre des Tumeurs de l'ULB, Rue Heger Bordet, 1, 1000, Brussels, Belgium. IN - Aapro, Matti. Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, Genolier, Switzerland. IN - Moodley, Devan. University of the Witwatersrand and Wits Donald Gordon Medical Center, Johannesburg, South Africa. TI - Supportive care for patients undergoing immunotherapy. SO - Supportive Care in Cancer. , 2017 Jul 13 AS - Support Care Cancer. , 2017 Jul 13 NJ - Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9302957, b1l IO - Support Care Cancer CP - Germany KW - Anti-CTLA-4; Anti-PD-1; Anti-PDL-1; Colitis; Endocrinopathy; Immune checkpoint inhibitors; Immune-related adverse events; Nephritis; Pneumonitis; Skin rash; Vitiligo; irAE AB - Immune checkpoint inhibitors, a new class of cancer therapeutic agents, play an important role in the management of melanoma, NSCLC, and other malignancies. A workshop organized by three MASCC Study Groups: Oral Care, Skin Toxicities, and Neutropenia, Infection, and Myelosuppression during the MASCC Annual Meeting held in Adelaide, Australia on 23-25 June, 2016 focused on the new class of anti-cancer therapeutic agents. Topics in the workshop included the mechanism of action and clinical uses of immune anti-CTL4 and anti-PD1 antibodies, checkpoint inhibitor toxicities, including skin adverse events, gastrointestinal toxicities, oral complications, pulmonary toxicities, and endocrinological and immune-related infections. Checkpoint inhibitors have been approved for use in different malignancies including metastatic melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, refractory Hodgkin's lymphoma, metastatic bladder cancer, and advanced head and neck cancer, and the list continues to grow. In general, these agents seem to be better tolerated in most patients and less toxic compared to conventional chemotherapy. However, the toxicities here, termed immune-related adverse events (irAEs), are unique and different from what we have seen in the past. There is no prospective data on these toxicities, and guidelines or recommendations are currently based on symptomatic management from the ongoing clinical trials. Treating oncologists need to be aware and alert themselves to the subtleties in presentation and the big difference in the way we manage the irAEs. Although most irAEs are low-grade and manageable, they have the potential to be life-threatening and extremely severe if not promptly treated. Additionally, irAEs could even lead to death, if managed incorrectly. The MASCC workshop addressed the various irAEs, per organ system, clinical presentation, management recommendations, and individual toxicities. ES - 1433-7339 IL - 0941-4355 DI - 10.1007/s00520-017-3802-9 DO - https://dx.doi.org/10.1007/s00520-017-3802-9 PT - Journal Article ID - 10.1007/s00520-017-3802-9 [doi] ID - 10.1007/s00520-017-3802-9 [pii] PP - aheadofprint PH - 2017/03/31 [received] PH - 2017/06/18 [accepted] LG - English EP - 20170713 DP - 2017 Jul 13 DC - 20170714 EZ - 2017/07/15 06:00 DA - 2017/07/15 06:00 DT - 2017/07/15 06:00 YR - 2017 RD - 20170714 UP - 20170717 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28707167 <494. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28689073 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Sznol M AU - Postow MA AU - Davies MJ AU - Pavlick AC AU - Plimack ER AU - Shaheen M AU - Veloski C AU - Robert C FA - Sznol, Mario FA - Postow, Michael A FA - Davies, Marianne J FA - Pavlick, Anna C FA - Plimack, Elizabeth R FA - Shaheen, Montaser FA - Veloski, Colleen FA - Robert, Caroline IN - Sznol, Mario. Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA. Electronic address: mario.sznol@yale.edu. IN - Postow, Michael A. Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. IN - Davies, Marianne J. Yale School of Nursing, West Haven, CT, USA. IN - Pavlick, Anna C. New York University, New York, NY, USA. IN - Plimack, Elizabeth R. Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA. IN - Shaheen, Montaser. University of New Mexico, Albuquerque, NM, USA. IN - Veloski, Colleen. Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA. IN - Robert, Caroline. Gustave Roussy and Paris-Sud University, Villejuif, France. TI - Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. [Review] SO - Cancer Treatment Reviews. 58:70-76, 2017 Jun 22 AS - Cancer Treat Rev. 58:70-76, 2017 Jun 22 NJ - Cancer treatment reviews PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cnn, 7502030 IO - Cancer Treat. Rev. CP - Netherlands KW - Hypophysitis; Immune-related adverse events; Ipilimumab; Melanoma; Nivolumab; Thyroiditis AB - Agents that modulate immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1), have become a mainstay in cancer treatment. The clinical benefit afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events (irAE) that affect the skin, gastrointestinal tract, liver, and endocrine system. The types of irAEs associated with immune checkpoint inhibitors are generally consistent across tumor types. Immune-related endocrine events can affect the pituitary, thyroid, and adrenal glands, as well as other downstream target organs. These events are unique when compared with other irAEs because the manifestations are often irreversible. Immune-related endocrine events are typically grade 1/2 in severity and often present with non-specific symptoms, making them difficult to diagnose. The mechanisms underlying immune-related target organ damage in select individuals remain mostly undefined. Management includes close patient monitoring, appropriate laboratory testing for endocrine function, replacement of hormones, and consultation with an endocrinologist when appropriate. An awareness of the symptoms and management of immune-related endocrine events may aid in the safe and appropriate use of immune checkpoint inhibitors in clinical practice. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved. ES - 1532-1967 IL - 0305-7372 DI - S0305-7372(17)30100-7 DO - https://dx.doi.org/10.1016/j.ctrv.2017.06.002 PT - Journal Article PT - Review ID - S0305-7372(17)30100-7 [pii] ID - 10.1016/j.ctrv.2017.06.002 [doi] PP - aheadofprint PH - 2017/01/27 [received] PH - 2017/06/13 [revised] PH - 2017/06/14 [accepted] LG - English EP - 20170622 DP - 2017 Jun 22 DC - 20170709 EZ - 2017/07/10 06:00 DA - 2017/07/10 06:00 DT - 2017/07/10 06:00 YR - 2017 RD - 20170709 UP - 20170710 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28689073 <495. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28666240 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Makarious D AU - Horwood K AU - Coward JIG FA - Makarious, D FA - Horwood, K FA - Coward, J I G IN - Makarious, D. Bond University, School of Medicine, Robina, Australia. IN - Horwood, K. ICON Cancer Care, Brisbane, Australia. IN - Coward, J I G. ICON Cancer Care, Brisbane, Australia; Faculty of Medicine, University of Queensland, Australia; Princess Alexandra Hospital, Brisbane, Australia. Electronic address: jim.coward@gmail.com. TI - Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors. [Review] SO - European Journal of Cancer. 82:128-136, 2017 Jun 27 AS - Eur J Cancer. 82:128-136, 2017 Jun 27 NJ - European journal of cancer (Oxford, England : 1990) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - arv, 9005373 IO - Eur. J. Cancer CP - England KW - Autoimmunity; CTLA-4; Immune checkpoint inhibitors; Immune-related adverse events; Ipilimumab; Myasthenia gravis; Nivolumab; PD-1; Pembrolizumab AB - The advent of immunotherapy has heralded a number of significant advances in the treatment of particular malignancies associated with poor prognosis (melanoma, non-small-cell lung, renal and head/neck cancers). The success witnessed with therapeutic agents targeting cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and programmed cell death ligand 1 immune checkpoints has inevitably led to an explosion in their clinical application and the subsequent recognition of specific toxicity profiles distinct from those long recognised with chemotherapy. Consequently, as the utility of such therapies broaden, understanding the nature, timing and management of these immune-related adverse events (irAEs) becomes increasingly significant. Although neurological irAEs are considered relatively rare in comparison with hepatitis, colitis, pneumonitis and endocrinopathies, one emerging side-effect is myasthenia gravis (MG). Among the 23 reported cases of immune checkpoint inhibitor-associated MG, 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG. The average onset of symptoms was within 6 weeks (range 2-12 weeks) of treatment initiation. In addition, there was no consistent association with elevated acetylcholine antibody titres and the development of immune checkpoint inhibitor-related MG. Significantly, there was a 30.4% MG-specific-related mortality, which further emphasises the importance of early recognition and robust treatment of this toxicity. In addition to a review of the existing literature, we present a new case of pembrolizumab-induced MG and provide insights into the underlying mechanisms of action of this phenomenon. Copyright © 2017 Elsevier Ltd. All rights reserved. ES - 1879-0852 IL - 0959-8049 DI - S0959-8049(17)31017-1 DO - https://dx.doi.org/10.1016/j.ejca.2017.05.041 PT - Journal Article PT - Review ID - S0959-8049(17)31017-1 [pii] ID - 10.1016/j.ejca.2017.05.041 [doi] PP - aheadofprint PH - 2017/03/27 [received] PH - 2017/05/06 [revised] PH - 2017/05/19 [accepted] LG - English EP - 20170627 DP - 2017 Jun 27 DC - 20170630 EZ - 2017/07/01 06:00 DA - 2017/07/01 06:00 DT - 2017/07/01 06:00 YR - 2017 RD - 20170630 UP - 20170703 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28666240 <496. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28661915 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Konda B AU - Nabhan F AU - Shah MH FA - Konda, Bhavana FA - Nabhan, Fadi FA - Shah, Manisha H IN - Konda, Bhavana. aDivision of Medical Oncology, Department of Internal Medicine bDivision of Endocrinology, Diabetes, and Metabolism, The Ohio State University and Arthur G. James Cancer Center, Columbus, Ohio, USA *Bhavana Konda and Fadi Nabhan contributed equally to the article. TI - Endocrine dysfunction following immune checkpoint inhibitor therapy. SO - Current Opinion in Endocrinology, Diabetes & Obesity. , 2017 Jun 28 AS - Curr. opin. endocrinol. diabetes obes.. , 2017 Jun 28 NJ - Current opinion in endocrinology, diabetes, and obesity PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101308636 IO - Curr Opin Endocrinol Diabetes Obes CP - England AB - PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) represent an important milestone in the modern era of antineoplastic therapy and have ushered optimism amongst oncologists and patients alike. These agents, however, are associated with significant potential toxicities, the importance of which cannot be overstated. The clinical presentation, diagnosis, and management strategies of immune-related endocrinopathies associated with ICI use are described in this case-based review. AB - RECENT FINDINGS: An increasing number of ICI have shown promise in the management of various malignancies in the recent years. These include cytotoxic T lymphocyte antigen-4 inhibitors, programed death 1 antibodies, and programed death-ligand 1 antibodies. Several endocrinopathies, including hypophysitis, thyroid dysfunction, hyperglycemia, and primary adrenal insufficiency, have been associated with the use of these agents. Toxicities may range from mild transient laboratory abnormalities to potentially life-threatening ones, warranting immediate therapeutic intervention. Combination ICI therapies may be associated with a greater risk of endocrine dysfunction when compared with monotherapy. The clinical presentation and laboratory assessment of these patients often pose a diagnostic challenge as they may be confused by the symptoms related to their underlying malignancy or potential associated acute illnesses. AB - SUMMARY: ICI use is associated with serious endocrinopathies that may have a nonspecific initial presentation. A constant eye for these symptoms and a systematic approach to diagnosis are essential for prompt initiation of therapy and prevention of significant complications. ES - 1752-2978 IL - 1752-296X DO - https://dx.doi.org/10.1097/MED.0000000000000357 PT - Journal Article ID - 10.1097/MED.0000000000000357 [doi] PP - aheadofprint LG - English EP - 20170628 DP - 2017 Jun 28 DC - 20170629 EZ - 2017/06/30 06:00 DA - 2017/07/01 06:00 DT - 2017/07/01 06:00 YR - 2017 RD - 20170629 UP - 20170703 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28661915 <497. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28661901 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Han TS AU - Gleeson HK FA - Han, Thang S FA - Gleeson, Helena K IN - Han, Thang S. aInstitute of Cardiovascular Research, Royal Holloway, University of London & Ashford and St Peter's Hospitals NHS Foundation Trust, Egham bUniversity Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. TI - Long-term and late treatment consequences: endocrine and metabolic effects. SO - Current Opinion in Supportive & Palliative Care. , 2017 Jun 28 AS - Curr. opin. support. palliat. care. , 2017 Jun 28 NJ - Current opinion in supportive and palliative care PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101297402 IO - Curr Opin Support Palliat Care CP - United States AB - PURPOSE OF REVIEW: Cancer therapies often result in the 'late effect of cancer treatment' whereby secondary health complications emerge years after radiotherapy and chemotherapy. This review focuses on endocrine and metabolic consequences in adult cancer survivors as late treatment effects. AB - RECENT FINDINGS: Endocrine and metabolic disorders are among the most common late effects. Endocrine disorders include hypopituitarism, which leads to growth hormone deficiency, hypogonadism, adrenal insufficiency and hypothyroidism and related clinical manifestations. Hypogonadism in particular is associated with a wide range of health complications requiring input from the like of endocrine and fertility specialists. Immune checkpoint inhibitors are novel anticancer agents, some of which are uniquely associated with hypophysitis which requires early recognition and management, including steroid replacement. Metabolic syndrome, a significant risk for cardiovascular disease, is highly prevalent. Although the effects of cranial irradiation on the hypothalamic-pituitary system are more apparent, the relationship between chemotherapy and endocrine/metabolic disorders remains to be elucidated. There exist published guidelines for monitoring endocrine and cardiometabolic risk in cancer survivors, but the extent of monitoring appears insufficient. AB - SUMMARY: Regular monitoring and early management of endocrine/metabolic disorders is required to prevent the elevated rates of health complications after cancer treatment, and thereby improve cancer survivorship. ES - 1751-4266 IL - 1751-4258 DO - https://dx.doi.org/10.1097/SPC.0000000000000289 PT - Journal Article ID - 10.1097/SPC.0000000000000289 [doi] PP - aheadofprint LG - English EP - 20170628 DP - 2017 Jun 28 DC - 20170629 EZ - 2017/06/30 06:00 DA - 2017/07/01 06:00 DT - 2017/07/01 06:00 YR - 2017 RD - 20170629 UP - 20170703 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28661901 <498. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28640512 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Chan PY AU - Hall P AU - Hay G AU - Cohen VML AU - Szlosarek PW FA - Chan, Pui Ying FA - Hall, Peter FA - Hay, Gordon FA - Cohen, Victoria M L FA - Szlosarek, Peter W IN - Chan, Pui Ying. Department of Medical Oncology, St Bartholomew's Hospital, London, UK. IN - Hall, Peter. Department of Medical Oncology, St Bartholomew's Hospital, London, UK. IN - Hay, Gordon. Department of Ocular Oncology, Moorfields Eye Hospital, London, UK. IN - Hay, Gordon. UCL Institute of Ophthalmology, London, UK. IN - Cohen, Victoria M L. Department of Ocular Oncology, Moorfields Eye Hospital, London, UK. IN - Cohen, Victoria M L. Department of Ocular Oncology, St Bartholomew's Hospital, London, UK. IN - Szlosarek, Peter W. Department of Medical Oncology, St Bartholomew's Hospital, London, UK. IN - Szlosarek, Peter W. Centre for Molecular Oncology, Barts Cancer Institute, London, UK. TI - A major responder to ipilimumab and nivolumab in metastatic uveal melanoma with concomitant autoimmunity. SO - Pigment Cell & Melanoma Research. , 2017 Jun 22 AS - Pigment Cell Melanoma Res. , 2017 Jun 22 NJ - Pigment cell & melanoma research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101318927 IO - Pigment Cell Melanoma Res CP - England KW - Autoimmunity; immunotherapy; ipilimumab; metastasis; nivolumab; ocular; uveal melanoma AB - The use of immune checkpoint inhibition has led to major improvements in outcome for patients with metastatic cutaneous melanoma. The combination of ipilimumab and nivolumab has demonstrated greater activity over single agent immunotherapy in phase III trials. Clinical trials of combination CTLA-4 and PD-1 inhibition are underway in uveal melanoma, for which there are currently no data. Here, we present the case of a 74-year-old male patient with metastatic uveal melanoma, who was treated with a combination of ipilimumab and nivolumab. He developed sequential autoimmune transaminitis, diabetes and uveitis, which necessitated discontinuation of maintenance nivolumab 3 months after commencement of treatment. The patient continues to demonstrate an ongoing partial response 10 months from the initial combination immunotherapy, with evidence of depigmentation of the primary ocular tumour. This article is protected by copyright. All rights reserved. Copyright This article is protected by copyright. All rights reserved. ES - 1755-148X IL - 1755-1471 DO - https://dx.doi.org/10.1111/pcmr.12607 PT - Journal Article ID - 10.1111/pcmr.12607 [doi] PP - aheadofprint LG - English EP - 20170622 DP - 2017 Jun 22 DC - 20170622 EZ - 2017/06/23 06:00 DA - 2017/06/24 06:00 DT - 2017/06/24 06:00 YR - 2017 RD - 20170622 UP - 20170626 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28640512 <499. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28634815 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Gauci ML AU - Laly P AU - Vidal-Trecan T AU - Baroudjian B AU - Gottlieb J AU - Madjlessi-Ezra N AU - Da Meda L AU - Madelaine-Chambrin I AU - Bagot M AU - Basset-Seguin N AU - Pages C AU - Mourah S AU - Boudou P AU - Lebbe C AU - Gautier JF FA - Gauci, Marie-Lea FA - Laly, Pauline FA - Vidal-Trecan, Tiphaine FA - Baroudjian, Barouyr FA - Gottlieb, Jeremy FA - Madjlessi-Ezra, Nika FA - Da Meda, Laetitia FA - Madelaine-Chambrin, Isabelle FA - Bagot, Martine FA - Basset-Seguin, Nicole FA - Pages, Cecile FA - Mourah, Samia FA - Boudou, Philippe FA - Lebbe, Celeste FA - Gautier, Jean-Francois IN - Gauci, Marie-Lea. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. marie-lea.gauci@hotmail.fr. IN - Gauci, Marie-Lea. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. marie-lea.gauci@hotmail.fr. IN - Laly, Pauline. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Laly, Pauline. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Vidal-Trecan, Tiphaine. AP-HP Diabetology Department, Lariboisiere Hospital, Paris, France. IN - Vidal-Trecan, Tiphaine. INSERM U1138, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Baroudjian, Barouyr. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Baroudjian, Barouyr. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Gottlieb, Jeremy. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Gottlieb, Jeremy. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Madjlessi-Ezra, Nika. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Madjlessi-Ezra, Nika. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Da Meda, Laetitia. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Da Meda, Laetitia. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Madelaine-Chambrin, Isabelle. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Madelaine-Chambrin, Isabelle. AP-HP Pharmacology Department, Saint-Louis Hospital, Paris, France. IN - Bagot, Martine. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Bagot, Martine. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Basset-Seguin, Nicole. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Basset-Seguin, Nicole. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Pages, Cecile. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Pages, Cecile. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Mourah, Samia. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Mourah, Samia. AP-HP Pharmacogenomic Laboratory, Saint-Louis Hospital, Paris, France. IN - Boudou, Philippe. AP-HP Hormonology Department, Saint-Louis Hospital, Paris, France. IN - Boudou, Philippe. Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Lebbe, Celeste. AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue Claude Vellefaux, 75475, Paris Cedex 10, France. IN - Lebbe, Celeste. INSERM U976, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. IN - Gautier, Jean-Francois. AP-HP Diabetology Department, Lariboisiere Hospital, Paris, France. IN - Gautier, Jean-Francois. INSERM U1138, Universite Paris Diderot-Paris VII, Sorbonne Paris Cite, Paris, France. TI - Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. SO - Cancer Immunology, Immunotherapy. , 2017 Jun 20 AS - Cancer Immunol Immunother. , 2017 Jun 20 NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. CP - Germany KW - Adverse events; Anti-PD-1 antibody; Autoimmune diabetes; Melanoma AB - Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect. ES - 1432-0851 IL - 0340-7004 DI - 10.1007/s00262-017-2033-8 DO - https://dx.doi.org/10.1007/s00262-017-2033-8 PT - Journal Article ID - 10.1007/s00262-017-2033-8 [doi] ID - 10.1007/s00262-017-2033-8 [pii] PP - aheadofprint PH - 2017/01/25 [received] PH - 2017/06/12 [accepted] LG - English EP - 20170620 DP - 2017 Jun 20 DC - 20170621 EZ - 2017/06/22 06:00 DA - 2017/06/22 06:00 DT - 2017/06/22 06:00 YR - 2017 RD - 20170621 UP - 20170622 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28634815 <500. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28383817 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Zwaenepoel K AU - Jacobs J AU - De Meulenaere A AU - Silence K AU - Smits E AU - Siozopoulou V AU - Hauben E AU - Rolfo C AU - Rottey S AU - Pauwels P AI - Zwaenepoel, Karen; ORCID: http://orcid.org/0000-0001-9122-0639 FA - Zwaenepoel, Karen FA - Jacobs, Julie FA - De Meulenaere, Astrid FA - Silence, Karen FA - Smits, Evelien FA - Siozopoulou, Vasiliki FA - Hauben, Esther FA - Rolfo, Christian FA - Rottey, Sylvie FA - Pauwels, Patrick IN - Zwaenepoel, Karen. Department of Pathology, Antwerp University Hospital, Edegem, Belgium. IN - Zwaenepoel, Karen. Center for Oncological Research Antwerp, University of Antwerp, Wilrijk, Belgium. IN - Jacobs, Julie. Department of Pathology, Antwerp University Hospital, Edegem, Belgium. IN - Jacobs, Julie. Center for Oncological Research Antwerp, University of Antwerp, Wilrijk, Belgium. IN - De Meulenaere, Astrid. Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium. IN - Silence, Karen. arGEN-X BVBA, Ghent, Belgium. IN - Smits, Evelien. Center for Oncological Research Antwerp, University of Antwerp, Wilrijk, Belgium. IN - Smits, Evelien. Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute, University of Antwerp, Wilrijk, Belgium. IN - Siozopoulou, Vasiliki. Department of Pathology, Antwerp University Hospital, Edegem, Belgium. IN - Siozopoulou, Vasiliki. Center for Oncological Research Antwerp, University of Antwerp, Wilrijk, Belgium. IN - Hauben, Esther. Translational Cell and Tissue Research, Leuven University Hospital, Leuven, Belgium. IN - Rolfo, Christian. Department of Oncology, Antwerp University Hospital, Edegem, Belgium. IN - Rolfo, Christian. Phase 1-Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium. IN - Rottey, Sylvie. Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium. IN - Pauwels, Patrick. Department of Pathology, Antwerp University Hospital, Edegem, Belgium. IN - Pauwels, Patrick. Center for Oncological Research Antwerp, University of Antwerp, Wilrijk, Belgium. TI - CD70 and PD-L1 in anaplastic thyroid cancer - promising targets for immunotherapy. SO - Histopathology. , 2017 Apr 06 AS - Histopathology. , 2017 Apr 06 NJ - Histopathology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - gb4, 7704136 IO - Histopathology CP - England KW - BRAF; CD70; PDL1; anaplastic thyroid cancer; immunotherapy AB - AIMS: During recent years, immune checkpoint inhibition has proved to be effective in several solid malignancies. The aim of this study was to identify novel targets for immunotherapy in anaplastic thyroid cancer by analysis of the expression of tumour antigens for which therapeutic agents are available. AB - METHOD AND RESULTS: By immunohistochemistry we observed tumoral expression of CD70 in 49% of cases. Expression of its receptor, CD27, was present mainly in lymphocytes surrounding and infiltrating the tumour and observed only rarely in tumour cells. CD70 expression was associated with the presence of a precursor papillary thyroid carcinoma and the presence of BRAF V600E mutations in the anaplastic thyroid cancer lesion. Furthermore, the expression of CD70 seems stable during progression of the disease. Tumoral expression of programmed cell death ligand 1 (PD-L1) was found in 28.6% of the anaplastic thyroid cancer cases. Programmed cell death 1 (PD-1), the receptor of PD-L1, was not expressed on the tumour cells. No association between CD70 expression and PD-L1 expression could be demonstrated. AB - CONCLUSION: These data suggest that targeted immunotherapy for CD70/CD27 and PD-L1/PD-1 might be promising in anaplastic thyroid cancer. However, as a low amount of tumour-infiltrating lymphocytes was observed in most lesions, combined therapy with agents enhancing the invasion of lymphocytes in the tumour region needs to be considered. AB - Copyright © 2017 John Wiley & Sons Ltd. ES - 1365-2559 IL - 0309-0167 DO - https://dx.doi.org/10.1111/his.13230 PT - Journal Article ID - 10.1111/his.13230 [doi] PP - aheadofprint PH - 2017/03/01 [received] PH - 2017/04/04 [accepted] LG - English EP - 20170406 DP - 2017 Apr 06 DC - 20170406 EZ - 2017/04/07 06:00 DA - 2017/04/07 06:00 DT - 2017/04/07 06:00 YR - 2017 RD - 20170616 UP - 20170616 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28383817 <501. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28611199 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Weinstock C AU - Khozin S AU - Suzman D AU - Zhang L AU - Tang S AU - Wahby S AU - Goldberg KB AU - Kim G AU - Pazdur R FA - Weinstock, Chana FA - Khozin, Sean FA - Suzman, Daniel FA - Zhang, Lijun FA - Tang, Shenghui FA - Wahby, Sakar FA - Goldberg, Kirsten B FA - Kim, Geoffrey FA - Pazdur, Richard IN - Weinstock, Chana. Center for Drug Evaluation and Research, FDA Chana.Weinstock@fda.hhs.gov. IN - Khozin, Sean. Center for Drug Evaluation and Research, FDA. IN - Suzman, Daniel. Center for Drug Evaluation and Research, FDA. IN - Zhang, Lijun. Office of Biostatistics, FDA. IN - Tang, Shenghui. CDER, FDA. IN - Wahby, Sakar. Center for Drug Evaluation and Research, FDA. IN - Goldberg, Kirsten B. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. IN - Kim, Geoffrey. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. IN - Pazdur, Richard. Office of Oncology Drug Products, U.S. Food and Drug Administration. TI - U.S. Food and Drug Administration Approval Summary: Atezolizumab for Metastatic Non-Small Cell Lung Cancer. SO - Clinical Cancer Research. , 2017 Jun 13 AS - Clin Cancer Res. , 2017 Jun 13 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. CP - United States AB - On October 18 2016, the U.S. Food and Drug Administration approved atezolizumab (TECENTRIQ, Genentech Inc.) for treatment of patients with metastatic non-small cell lung cancer (mNSCLC) whose disease progressed during or following platinum-containing chemotherapy. Approval was based on demonstration of clinically meaningful improvements in overall survival (OS) and an acceptable safety profile in two randomized clinical trials (OAK and POPLAR). Median OS in OAK, a phase III trial, was 13.8 months (95% confidence interval [CI] 11.8,15.7) in the atezolizumab arm compared with 9.6 months (95% CI 8.6,11.2) in the docetaxel arm (HR=0.74 [95% CI 0.63,0.87]; p=0.0004). Median OS in POPLAR, a phase II trial, was 12.6 months (95% CI 9.7, 16.0) and 9.7 months (95% CI 8.6, 12.0) (HR=0.69 [95% CI 0.52, 0.92]) for the atezolizumab and docetaxel arms, respectively. In patients treated with atezolizumab, the most common (>=20%) adverse reactions were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation; the most common (>=2%) grade 3-4 adverse events were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, AST increase, ALT increase, dysphagia, and arthralgia. Clinically significant immune-related adverse events for patients receiving atezolizumab included 1.4% incidence each of Grade 3-4 pneumonitis, hepatitis, colitis, and thyroid disease. AB - Copyright ©2017, American Association for Cancer Research. IS - 1078-0432 IL - 1078-0432 DI - clincanres.0540.2017 DI - 1078-0432.CCR-17-0540 DO - https://dx.doi.org/10.1158/1078-0432.CCR-17-0540 PT - Journal Article ID - 1078-0432.CCR-17-0540 [pii] ID - 10.1158/1078-0432.CCR-17-0540 [doi] PP - aheadofprint PH - 2017/06/07 [accepted] PH - 2017/03/09 [received] PH - 2017/05/01 [revised] LG - English EP - 20170613 DP - 2017 Jun 13 DC - 20170614 EZ - 2017/06/15 06:00 DA - 2017/06/15 06:00 DT - 2017/06/15 06:00 YR - 2017 RD - 20170614 UP - 20170615 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28611199 <502. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28609832 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Delivanis DA AU - Gustafson MP AU - Bornschlegl S AU - Merten MM AU - Kottschade L AU - Withers S AU - Dietz AB AU - Ryder M FA - Delivanis, Danae A FA - Gustafson, Michael P FA - Bornschlegl, Svetlana FA - Merten, Michele M FA - Kottschade, Lisa FA - Withers, Sarah FA - Dietz, Allan B FA - Ryder, Mabel IN - Delivanis, Danae A. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA IN - Gustafson, Michael P. Human Cell Therapy Laboratory, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA IN - Bornschlegl, Svetlana. Department of Laboratory Medicine & Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA IN - Merten, Michele M. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA IN - Kottschade, Lisa. Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA IN - Withers, Sarah. Department of Laboratory Medicine & Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA IN - Dietz, Allan B. Human Cell Therapy Laboratory, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA IN - Ryder, Mabel. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA IN - Ryder, Mabel. Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA TI - Pembrolizumab-induced thyroiditis. Comprehensive clinical review and insights into underlying involved mechanisms. SO - Journal of Clinical Endocrinology & Metabolism. , 2017 05 09 AS - J Clin Endocrinol Metab. , 2017 05 09 NJ - The Journal of clinical endocrinology and metabolism PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - hrb, 0375362 IO - J. Clin. Endocrinol. Metab. CP - United States KW - *hypothyroidism; *fluorodeoxyglucose f18; *cd14 antigen; *cancer; *flow cytometry; *cd56 antigens; *color; *hla-dr antigens; *iodide peroxidase; *natural killer cells; *monocytes; *neural cell adhesion molecules; *thyroid diseases; *thyroiditis; *t-lymphocyte; *antibodies; *thryoxine; *malignant neoplasm of thyroid; *cd16; *radionuclide; *thyroid imaging study; *destructive behavior; *thyroid autoantibodies; *advanced; *adverse event; *laboratory test finding; *infusion procedures; *pembrolizumab AB - Context: Thyroid immune-related adverse events (irAEs) in patients treated with programmed death receptor-1 (PD-1) blockade are increasingly recognized as one of the most common adverse effects. Our aim was to determine the incidence and examine the potential mechanisms of anti-PD-1 induced thyroid irAEs. AB - Design: Single center, retrospective cohort study. AB - Patients and Measurements: We studied 93 patients with advanced cancer (aged 24-82 years; 60% males) who received at least one infusion of pembrolizumab. Thyroid test results and thyroid imaging modalities were reviewed. Comprehensive 10-color flow cytometry of peripheral blood was performed. AB - Results: Thirteen (14%) thyroid irAEs were observed. Thyroiditis occurred in 7 patients (54%), from which 4 recovered. New onset of hypothyroidism overt/subclinical developed in 3 patients. Levothyroxine dosing required doubling in 3 patients with known history of hypothyroidism. Thyroperoxidase (TPO) antibodies-(abs) were positive in the minority of the patients 4/13 (31%) and diffuse increased 18FDG uptake of the thyroid gland was observed in the majority 7/11 (64%) of patients. We observed an increased number of circulating CD56+CD16+ NK cells and an elevated HLA-DR surface expression in the inflammatory intermediate CD14+CD16+ monocytes in anti-PD-1 treated patients. AB - Conclusions: Thyroid dysfunction is common in cancer patients treated with pembrolizumab. Reversible destructive thyroiditis as well as overt hypothyroidism are the most common clinical presentations. The mechanism of thyroid destruction appears independent of thyroid autoantibodies and may include T-cell, NK cell, and/or monocyte mediated pathways. As the thyroid is a frequent target of anti-PD-1 therapies, patients with therapeutically refractory thyroid cancer may be ideal candidates for this treatment. AB - Copyright © 2017 by the Endocrine Society ES - 1945-7197 IL - 0021-972X DO - https://dx.doi.org/10.1210/jc.2017-00448 PT - Journal Article ID - 10.1210/jc.2017-00448 [doi] PP - aheadofprint PH - 2017/05/02 [accepted] PH - 2017/02/16 [received] LG - English EP - 20170509 DP - 2017 05 09 DC - 20170613 EZ - 2017/06/15 06:00 DA - 2017/06/15 06:00 DT - 2017/06/15 06:00 YR - 2017 RD - 20170613 UP - 20170615 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28609832 <503. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28604555 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Tchapyjnikov D AU - Borst AJ FA - Tchapyjnikov, Dmitry FA - Borst, Alexandra J IN - Tchapyjnikov, Dmitry. *Division of Pediatric Neurology +Division of Pediatric Hematology-Oncology, Duke University Medical Center, Durham, NC. TI - Immune-related Neurological Symptoms in an Adolescent Patient Receiving the Checkpoint Inhibitor Nivolumab. SO - Journal of Immunotherapy. , 2017 Jun 09 AS - J Immunother. , 2017 Jun 09 NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. CP - United States AB - Immune checkpoint inhibitors are a novel group of immunotherapeutic agents for the treatment of cancer. Immune-related adverse events, including neurological symptoms, have been associated with these agents. We present the case of an adolescent with refractory Hodgkin lymphoma treated with nivolumab, a PD1 inhibitor, who developed Hashimoto thyroiditis, posterior reversible encephalopathy syndrome causing seizures, as well as urinary retention, truncal/appendicular spasticity, dysphagia, and a progressive encephalopathy that was clinically consistent with a diagnosis of progressive encephalopathy with rigidity and myoclonus, a stiff-person-syndrome spectrum disorder. He showed response and ultimately full recovery to a combination of intravenous steroids, intravenous immunoglobulin, and plasma exchange. To our knowledge, this is the first documented report of an immune-related neurological reaction to nivolumab in an adolescent patient and expands the spectrum of known nivolumab-associated toxicities. ES - 1537-4513 IL - 1524-9557 DO - https://dx.doi.org/10.1097/CJI.0000000000000177 PT - Journal Article ID - 10.1097/CJI.0000000000000177 [doi] PP - aheadofprint LG - English EP - 20170609 DP - 2017 Jun 09 DC - 20170612 EZ - 2017/06/13 06:00 DA - 2017/06/13 06:00 DT - 2017/06/13 06:00 YR - 2017 RD - 20170612 UP - 20170613 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28604555 <504. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28604554 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Pushkarevskaya A AU - Neuberger U AU - Dimitrakopoulou-Strauss A AU - Enk A AU - Hassel JC FA - Pushkarevskaya, Anna FA - Neuberger, Ulf FA - Dimitrakopoulou-Strauss, Antonia FA - Enk, Alexander FA - Hassel, Jessica C IN - Pushkarevskaya, Anna. Departments of *Dermatology and National Center for Tumor Diseases (NCT) +Diagnostic Radiology, University Hospital Heidelberg ++German Cancer Research Center, Clinical Cooperation Unit Nuclear Medicine, Heidelberg, Germany. TI - Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of 2 Cases. SO - Journal of Immunotherapy. , 2017 Jun 09 AS - J Immunother. , 2017 Jun 09 NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. CP - United States AB - Ipilimumab binds and blocks cytotoxic T-lymphocyte-associated antigen-4, causing enhanced T-cell reaction, antitumor response, and significant improvement of the overall survival of patients with metastatic melanoma. Patients treated with ipilimumab can develop immune-related adverse effects, primarily dermatitis, colitis, hepatitis, and hypophysitis. Although, in phase I-III studies, 64.2% of all patients suffered from immune-related adverse effects, ocular adverse effects occurred in 1.3% only. In the cases reported below, 2 patients with metastatic melanoma developed severe ocular myositis after treatment with ipilimumab. These are the first 2 reports of successful treatment of this condition by use of a combination of methylprednisolone and mycophenolate mofetil, and, in 1 of the cases, additional medication with intravenous immunoglobulin. ES - 1537-4513 IL - 1524-9557 DO - https://dx.doi.org/10.1097/CJI.0000000000000178 PT - Journal Article ID - 10.1097/CJI.0000000000000178 [doi] PP - aheadofprint LG - English EP - 20170609 DP - 2017 Jun 09 DC - 20170612 EZ - 2017/06/13 06:00 DA - 2017/06/13 06:00 DT - 2017/06/13 06:00 YR - 2017 RD - 20170612 UP - 20170613 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28604554 <505. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28418115 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Matsumura K AU - Nagasawa K AU - Oshima Y AU - Kikuno S AU - Hayashi K AU - Nishimura A AU - Okubo M AU - Uruga H AU - Kishi K AU - Kobayashi T AU - Mori Y AI - Matsumura, Kimio; ORCID: http://orcid.org/0000-0001-7031-5014 FA - Matsumura, Kimio FA - Nagasawa, Kaoru FA - Oshima, Yoichi FA - Kikuno, Shouta FA - Hayashi, Kyohei FA - Nishimura, Akihiro FA - Okubo, Minoru FA - Uruga, Hironori FA - Kishi, Kazuma FA - Kobayashi, Tetsuro FA - Mori, Yasumichi IN - Matsumura, Kimio. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. IN - Nagasawa, Kaoru. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. IN - Oshima, Yoichi. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. IN - Kikuno, Shouta. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. IN - Hayashi, Kyohei. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. IN - Nishimura, Akihiro. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. IN - Okubo, Minoru. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. IN - Okubo, Minoru. Okinaka Memorial Institute for Medical Research, Tokyo, Japan. IN - Uruga, Hironori. Okinaka Memorial Institute for Medical Research, Tokyo, Japan. IN - Uruga, Hironori. Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, Tokyo, Japan. IN - Kishi, Kazuma. Okinaka Memorial Institute for Medical Research, Tokyo, Japan. IN - Kishi, Kazuma. Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, Tokyo, Japan. IN - Kobayashi, Tetsuro. Okinaka Memorial Institute for Medical Research, Tokyo, Japan. IN - Mori, Yasumichi. Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan. IN - Mori, Yasumichi. Okinaka Memorial Institute for Medical Research, Tokyo, Japan. TI - Aggravation of diabetes, and incompletely deficient insulin secretion in a case with type 1 diabetes-resistant human leukocyte antigen DRB1*15:02 treated with nivolumab. SO - Journal of Diabetes Investigation. , 2017 Apr 18 AS - J. diabetes investig.. , 2017 Apr 18 NJ - Journal of diabetes investigation PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 101520702 IO - J Diabetes Investig CP - Japan KW - Anti-programmed death 1 antibody; Nivolumab; Type 1 Diabetes AB - Anti-programmed cell death-1 (PD-1) antibody therapy induces various adverse effects, especially in the endocrine system. Several cases of acute-onset insulin-dependent diabetes after anti-PD-1 antibody therapy have been reported. Many of these cases have a susceptible human leukocyte antigen (HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be involved in the onset of diabetes with anti-PD-1 therapy. We describe an atypical case of hyperglycemia after anti-PD-1 antibody administration. A 68-year-old Japanese man with pancreatic diabetes and steroid diabetes was given nivolumab three times for chemoresistant adenocarcinoma of the lung. On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with incompletely deficient insulin secretion. The patient had both type 1 diabetes susceptible (HLA-A*24:02 and -DRB1*09:01) and resistant (HLA-DRB1*15:02) HLA genotypes. These HLA genotypes differ from those previously reported in anti-PD-1 antibody-induced diabetes, and might have influenced the preservation of insulin secretion after nivolumab administration in the present case. AB - Copyright © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd. ES - 2040-1124 IL - 2040-1116 DO - https://dx.doi.org/10.1111/jdi.12679 PT - Case Reports ID - 10.1111/jdi.12679 [doi] PP - aheadofprint PH - 2017/02/23 [received] PH - 2017/03/30 [revised] PH - 2017/04/11 [accepted] LG - English EP - 20170418 DP - 2017 Apr 18 DC - 20170418 EZ - 2017/04/19 06:00 DA - 2017/04/19 06:00 DT - 2017/04/19 06:00 YR - 2017 RD - 20170613 UP - 20170613 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28418115 <506. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28598870 VI - 1 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Allen RC FA - Allen, Richard C IN - Allen, Richard C. Section of Ophthalmology, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. TI - Molecularly targeted agents in oculoplastic surgery. SO - Current Opinion in Ophthalmology. , 2017 Jun 08 AS - Curr Opin Ophthalmol. , 2017 Jun 08 NJ - Current opinion in ophthalmology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bb4, 9011108 IO - Curr Opin Ophthalmol CP - United States AB - PURPOSE OF REVIEW: Significant advances have been made in oncology and rheumatology with the introduction of molecularly targeted agents (MTAs). MTAs consist of monoclonal antibodies and small molecule inhibitors. The purpose of this manuscript is to review the recent applications of MTAs to orbital, lacrimal, and eyelid disease. AB - RECENT FINDINGS: The use of monoclonal antibodies has been described in the treatment of orbital vascular lesions, lymphoma, and squamous cell carcinoma. Inflammatory conditions treated with monoclonal antibodies include thyroid eye disease, IgG4 disease, and granulomatosis with polyangiitis. Immunotherapy with checkpoint inhibitors has also found applications to orbital disease. Use of small molecule inhibitors has been described in the treatment of basal cell carcinoma, squamous cell carcinoma, and Erdheim-Chester disease. There are many orbital, lacrimal, and eyelid side effects of MTAs with which the oculoplastic surgeon should be familiar, including hypertrichosis, edema, and orbital and eyelid inflammation. AB - SUMMARY: MTAs represent the future of treatment of oncologic and inflammatory conditions. Application of these agents to orbital, lacrimal, and eyelid disease will continue to expand. Elucidating the molecular mechanisms of oculoplastic disorders will facilitate additional potential pathways that could be targeted for therapy. ES - 1531-7021 IL - 1040-8738 DO - https://dx.doi.org/10.1097/ICU.0000000000000403 PT - Journal Article ID - 10.1097/ICU.0000000000000403 [doi] PP - aheadofprint LG - English EP - 20170608 DP - 2017 Jun 08 DC - 20170609 EZ - 2017/06/10 06:00 DA - 2017/06/10 06:00 DT - 2017/06/10 06:00 YR - 2017 RD - 20170609 UP - 20170612 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28598870 <507. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28433543 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Kim SH AU - Li M AU - Trousil S AU - Zhang Y AU - Pasca di Magliano M AU - Swanson KD AU - Zheng B FA - Kim, Sun Hye FA - Li, Man FA - Trousil, Sebastian FA - Zhang, Yaqing FA - Pasca di Magliano, Marina FA - Swanson, Kenneth D FA - Zheng, Bin IN - Kim, Sun Hye. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. IN - Li, Man. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. IN - Trousil, Sebastian. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. IN - Zhang, Yaqing. Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA. IN - Pasca di Magliano, Marina. Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA. IN - Swanson, Kenneth D. Department of Neurology, Brain Tumor Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. IN - Zheng, Bin. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. Electronic address: bin.zheng@cbrc2.mgh.harvard.edu. TI - Phenformin Inhibits Myeloid-Derived Suppressor Cells and Enhances the Anti-Tumor Activity of PD-1 Blockade in Melanoma. SO - Journal of Investigative Dermatology. , 2017 Apr 19 AS - J Invest Dermatol. , 2017 Apr 19 NJ - The Journal of investigative dermatology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ihz, 0426720 IO - J. Invest. Dermatol. CP - United States AB - Biguanides, such as the diabetes therapeutics metformin and phenformin, have shown antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin selectively inhibits granulocytic myeloid-derived suppressor cells in spleens of tumor-bearing mice and ex vivo. Phenformin induces production of reactive oxygen species in granulocytic myeloid-derived suppressor cells, whereas the antioxidant N-acetylcysteine attenuates the inhibitory effects of phenformin. Co-treatment of phenformin enhances the effect of anti-PD-1 antibody therapy on inhibiting tumor growth in the BRAF V600E/PTEN-null melanoma mouse model. Combination of phenformin and anti PD-1 cooperatively induces CD8⁺ T-cell infiltration and decreases levels of proteins that are critical for immune suppressive activities of myeloid-derived suppressor cells. Our findings show a selective, inhibitory effect of phenformin on granulocytic myeloid-derived suppressor cell-driven immune suppression and support that phenformin improves the anti-tumor activity of PD-1 blockade immunotherapy in melanoma. AB - Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved. ES - 1523-1747 IL - 0022-202X DI - S0022-202X(17)31420-3 DO - https://dx.doi.org/10.1016/j.jid.2017.03.033 PT - Journal Article ID - S0022-202X(17)31420-3 [pii] ID - 10.1016/j.jid.2017.03.033 [doi] PP - aheadofprint PH - 2016/08/19 [received] PH - 2017/02/27 [revised] PH - 2017/03/13 [accepted] LG - English EP - 20170419 DP - 2017 Apr 19 DC - 20170423 EZ - 2017/04/24 06:00 DA - 2017/04/24 06:00 DT - 2017/04/24 06:00 YR - 2017 RD - 20170531 UP - 20170601 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28433543 <508. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28478512 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Jagersberg M AU - El Rahal A AU - Dammann P AU - Merkler D AU - Weber DC AU - Schaller K AI - Jagersberg, Max; ORCID: http://orcid.org/0000-0002-6208-5121 FA - Jagersberg, Max FA - El Rahal, Amir FA - Dammann, Philipp FA - Merkler, Doron FA - Weber, Damien Charles FA - Schaller, Karl IN - Jagersberg, Max. Division of Neurosurgery, Geneva University Hospitals and University of Geneva, 4, rue Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland. max.jaegersberg@hcuge.ch. IN - El Rahal, Amir. Division of Neurosurgery, Geneva University Hospitals and University of Geneva, 4, rue Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland. IN - Dammann, Philipp. Division of Neurosurgery, Geneva University Hospitals and University of Geneva, 4, rue Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland. IN - Dammann, Philipp. Department of Neurosurgery, Essen University Hospital, University of Duisburg-Essen, Essen, Germany. IN - Merkler, Doron. Department of Pathology and Immunology, Division of Clinical Pathology, Geneva University Hospitals of Geneva, Geneva, Switzerland. IN - Weber, Damien Charles. Centre for Proton Therapy, Paul Scherrer Institute, Villigen, Switzerland. IN - Schaller, Karl. Division of Neurosurgery, Geneva University Hospitals and University of Geneva, 4, rue Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland. TI - Clival chordoma: a single-centre outcome analysis. SO - Acta Neurochirurgica. , 2017 May 07 AS - Acta Neurochir (Wien). , 2017 May 07 NJ - Acta neurochirurgica PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 0151000 IO - Acta Neurochir (Wien) CP - Austria KW - Chemotherapy; Clival chordoma; Maximal safe resection; Multimodal treatment; Radiosurgery; Systemic therapy AB - BACKGROUND: The treatment of clival chordomas remains challenging. Total tumour resection is often impossible without hampering adjacent anatomical structures and causing functional sequelae. On the other hand, chordomas show limited response to non-surgical treatment modalities. Up to now, no well-established interdisciplinary treatment algorithms for clival chordomas exist. In this regard, we analysed the data from all patients that underwent interdisciplinary treatment for clival chordoma in our institution over the last 10 years. AB - METHOD: Retrospective report of all patients treated at the authors' institution from 2005 to 2015. AB - RESULTS: Thirteen patients underwent 24 surgeries, of which 2 (8%) were gross total resections and 22 (92%) incomplete resections. Neurological deterioration, endocrinological disturbances and other surgical complications were observed in six (25%), three (13%) and nine (38%) cases, respectively. Three surgeries (13%) led to an improvement of the initial preoperative neurological condition. All patients were discussed on the interdisciplinary tumour board and all underwent one type of radiotherapy following initial surgery: proton beam in 11 cases (85%) and photon beam in two (15%) cases. In the course of their recurrent disease, three patients (23%) received systemic therapy (imatinib, pazopanib and nivolumab). One patient received a personalised cellular immunotherapy. One patient (8%) was lost to follow-up. Of the remaining 12 patients, four patients (33%) died in the period of analysis; all deaths were chordoma-related. The 5-year cumulative survival rate was 83% (52-97%, CI 95%), 5-year progression-free survival rate was 53% (26-79%, CI 95%). The eight patients (66%) still alive had favourable outcome (KPS, 90 +/- 10.7%). SF36 analysis among the survivors revealed 43 points for the Physical Component Summary (12% above, 38% at and 50% below the general population norm) and 47 points for the Mental Component Summary (25% above, 38% at and 38% below). AB - CONCLUSIONS: Our patients show a low rate of gross total resection but an outcome well comparable to other published results. This emphasises the importance of interdispiplinary treatment strategies, with surgery supplying maximal safe resection and avoiding severe neurological deficit, allowing patients to undergo adjusted radiotherapy and other treatment options in a good condition. ES - 0942-0940 IL - 0001-6268 DI - 10.1007/s00701-017-3163-7 DO - https://dx.doi.org/10.1007/s00701-017-3163-7 PT - Journal Article ID - 10.1007/s00701-017-3163-7 [doi] ID - 10.1007/s00701-017-3163-7 [pii] PP - aheadofprint PH - 2016/11/09 [received] PH - 2017/03/27 [accepted] LG - English EP - 20170507 DP - 2017 May 07 DC - 20170507 EZ - 2017/05/08 06:00 DA - 2017/05/10 06:00 DT - 2017/05/10 06:00 YR - 2017 RD - 20170507 UP - 20170511 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28478512 <509. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28476944 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Betof AS AU - Nipp RD AU - Giobbie-Hurder A AU - Johnpulle RAN AU - Rubin K AU - Rubinstein SM AU - Flaherty KT AU - Lawrence DP AU - Johnson DB AU - Sullivan RJ FA - Betof, Allison S FA - Nipp, Ryan D FA - Giobbie-Hurder, Anita FA - Johnpulle, Romany A N FA - Rubin, Krista FA - Rubinstein, Samuel M FA - Flaherty, Keith T FA - Lawrence, Donald P FA - Johnson, Douglas B FA - Sullivan, Ryan J IN - Betof, Allison S. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, Massachusetts, USA. IN - Nipp, Ryan D. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, Massachusetts, USA. IN - Giobbie-Hurder, Anita. Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. IN - Johnpulle, Romany A N. Vanderbilt University Medical Center, Nashville, Tennessee, USA. IN - Rubin, Krista. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, Massachusetts, USA. IN - Rubinstein, Samuel M. Vanderbilt University Medical Center, Nashville, Tennessee, USA. IN - Flaherty, Keith T. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, Massachusetts, USA. IN - Lawrence, Donald P. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, Massachusetts, USA. IN - Johnson, Douglas B. Vanderbilt University Medical Center, Nashville, Tennessee, USA. IN - Sullivan, Ryan J. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, Massachusetts, USA RSULLIVAN7@mgh.harvard.edu. TI - Impact of Age on Outcomes with Immunotherapy for Patients with Melanoma. SO - Oncologist. , 2017 May 05 AS - Oncologist. , 2017 May 05 NJ - The oncologist PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - dd5, 9607837 IO - Oncologist CP - United States KW - Geriatrics; Immunotherapy; Melanoma; Toxicity AB - BACKGROUND: Monoclonal antibodies (mAb) targeting PD-1/PD-L1 have revolutionized melanoma treatment, yet data regarding effectiveness and tolerability across age groups is limited. We sought to determine the impact of age on overall survival (OS), progression-free survival (PFS), and rates of immune-mediated toxicities in patients treated with anti-PD-1/anti-PD-L1 mAb at two academic medical centers. AB - METHODS: We retrospectively collected data on all patients with metastatic melanoma treated with anti-PD-1/PD-L1 mAb between May 2009 and April 2015. We used Kaplan-Meier and Cox regression analyses to assess OS and PFS and identify factors associated with these outcomes. We also compared rates of autoimmune toxicity across age groups. AB - RESULTS: Of 254 patients, 57 (22.4%) were <50 years old, 85 (33.5%) were age 50-64, 65 (25.6%) were age 65-74, and 47 (18.5%) were >=75 years. Across age groups, no differences existed in median OS (age <50: 22.9 months, age 50-64: 25.3 months, age 65-74: 22.0 months, age >=75: 24.3 months) or PFS (age <50: 4.1 months, age 50-64: 6.5 months, age 65-74: 5.4 months, age >=75: 7.9 months). The presence of liver metastases and elevated pre-treatment lactate dehydrogenase (LDH) were associated with reduced OS. Presence of liver metastasis, pretreatment LDH, BRAF mutation, and type of melanoma correlated with PFS. Overall, 110 patients (43.3%) experienced immune-mediated toxicities; 25 (9.8%) had colitis and 26 (10.2%) had endocrine toxicity. Rates of colitis, hepatitis, and pneumonitis did not differ across age groups. AB - CONCLUSION: We demonstrated that patients could safely tolerate anti-PD1/PDL-1 mAb therapy and achieve similar outcomes regardless of their age. The Oncologist 2017;22:1-8Implications for Practice: Immunotherapy has revolutionized treatment for patients with metastatic melanoma, yet data are lacking regarding the effectiveness and tolerability of these treatments for older patients. In this study, we demonstrated that patients with melanoma safely tolerate immunotherapy and achieve similar outcomes regardless of their age. Specifically, we utilized data from two academic cancer centers and found no significant difference in overall survival, progression free survival, or immune-related toxicities, other than arthritis, across age groups. As the population ages, studies such as this will become critical to help us understand how best to treat older adults with cancer. AB - Copyright © AlphaMed Press 2017. CI - Disclosures of potential conflicts of interest may be found at the end of this article. ES - 1549-490X IL - 1083-7159 DI - theoncologist.2016-0450 DO - https://dx.doi.org/10.1634/theoncologist.2016-0450 PT - Journal Article ID - theoncologist.2016-0450 [pii] ID - 10.1634/theoncologist.2016-0450 [doi] PP - aheadofprint PH - 2016/11/12 [received] PH - 2017/03/03 [accepted] LG - English EP - 20170505 DP - 2017 May 05 DC - 20170506 EZ - 2017/05/07 06:00 DA - 2017/05/10 06:00 DT - 2017/05/10 06:00 YR - 2017 RD - 20170506 UP - 20170511 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28476944 <510. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28461396 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Badros A AU - Hyjek E AU - Ma N AU - Lesokhin A AU - Dogan A AU - Rapoport AP AU - Kocoglu M AU - Lederer E AU - Philip S AU - Milliron T AU - Dell C AU - Goloubeva O AU - Singh Z AI - Badros, Ashraf; ORCID: http://orcid.org/0000-0003-1690-0188 AI - Lesokhin, Alexander; ORCID: http://orcid.org/0000-0001-9321-702X FA - Badros, Ashraf FA - Hyjek, Elizabeth FA - Ma, Ning FA - Lesokhin, Alexander FA - Dogan, Ahmet FA - Rapoport, Aaron P FA - Kocoglu, Mehmet FA - Lederer, Emily FA - Philip, Sunita FA - Milliron, Todd FA - Dell, Cameron FA - Goloubeva, Olga FA - Singh, Zeba IN - Badros, Ashraf. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States; abadros@umm.edu. IN - Hyjek, Elizabeth. Department of Pathology, University of Chicago, United States. IN - Ma, Ning. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. IN - Lesokhin, Alexander. Memorial Sloan Kettering Cancer Center, New York, NY, United States. IN - Dogan, Ahmet. Memorial Sloan Kettering Cancer Center, New York, NY, United States. IN - Rapoport, Aaron P. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. IN - Kocoglu, Mehmet. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. IN - Lederer, Emily. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. IN - Philip, Sunita. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. IN - Milliron, Todd. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. IN - Dell, Cameron. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. IN - Goloubeva, Olga. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. IN - Singh, Zeba. University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States. TI - Pembrolizumab, pomalidomide and low dose dexamethasone for relapsed/refractory multiple myeloma. SO - Blood. , 2017 May 01 AS - Blood. , 2017 May 01 NJ - Blood PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - a8g, 7603509 IO - Blood CP - United States AB - Programmed death 1 (PD-1) receptor and its ligand (PD-L1) facilitate immune evasion in multiple myeloma (MM). We hypothesized that pembrolizumab, PD-1-antibody, can enhance anti-myeloma cellular immunity generated by pomalidomide leading to improved clinical responses. In this single-center, phase II study, 48 patients with relapsed/refractory MM (RRMM) received 28-days cycles of pembrolizumab, 200 mg intravenously every 2 weeks, pomalidomide 4 mg daily for 21 days and dexamethasone 40 mg weekly. Patients had a median of 3 (range: 2-5) lines of therapy, median age 64 (range: 35-83) years and had received both immune modulatory agent and proteasome inhibitor; (35 [73%] of 48) were refractory to both; (31 [70%]) had received an autologous transplant and (30 [62%]) had high-risk cytogenetics. Adverse events grade 3-4 occurred in (19 [40%] of 48 patients) including hematologic toxicities (19 [40%]), hyperglycemia (12 [25%] and pneumonia (7 [15%]). Autoimmune events included pneumonitis (6 [13%]) and hypothyroidism (5[10%]), mostly <= grade 2. Objective responses occurred in (29 [60%] of 48) patients including: sCR/CR (4 [8%]), VGPR (9 [19%]) and PR (16 [33%]); median duration of response was 14.7 months (95% CI 7.9-17.5). At median follow-up of 15.6 months (95% CI 9.2-17.5), progression free survival (PFS) was 17.4 months (95% CI 11.7-18.8) and overall survival was not reached (95% CI 18.9-NR). Analyses of pretreatment marrow samples revealed a trend for increased expression of PD-L1 in responding patients and longer PFS with increased T-lymphocyte infiltrates, irrespective of PD-1 expression. Pembrolizumab, pomalidomide and low-dose dexamethasone has acceptable safety and durable responses in RRMM patients. This trial was registered at www.clincialtrials.gov as # NCT02289222. AB - Copyright © 2017 American Society of Hematology. ES - 1528-0020 IL - 0006-4971 DI - blood-2017-03-775122 DO - https://dx.doi.org/10.1182/blood-2017-03-775122 PT - Journal Article ID - blood-2017-03-775122 [pii] ID - 10.1182/blood-2017-03-775122 [doi] PP - aheadofprint PH - 2017/03/23 [received] PH - 2017/04/25 [accepted] LG - English EP - 20170501 DP - 2017 May 01 DC - 20170502 EZ - 2017/05/03 06:00 DA - 2017/05/04 06:00 DT - 2017/05/04 06:00 YR - 2017 RD - 20170502 UP - 20170505 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28461396 <511. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28444424 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Wen X AU - Ding Y AU - Li J AU - Zhao J AU - Peng R AU - Li D AU - Zhu B AU - Wang Y AU - Zhang X AU - Zhang X FA - Wen, Xizhi FA - Ding, Ya FA - Li, Jingjing FA - Zhao, Jingjing FA - Peng, Ruiqing FA - Li, Dandan FA - Zhu, Baoyan FA - Wang, Yao FA - Zhang, Xing FA - Zhang, Xiaoshi IN - Wen, Xizhi. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Ding, Ya. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Li, Jingjing. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Zhao, Jingjing. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Peng, Ruiqing. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Li, Dandan. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Zhu, Baoyan. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Wang, Yao. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Zhang, Xing. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. IN - Zhang, Xiaoshi. Biotherapy Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, People's Republic of China. zhangxsh@sysucc.org.cn. TI - The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series. SO - Cancer Immunology, Immunotherapy. , 2017 Apr 25 AS - Cancer Immunol Immunother. , 2017 Apr 25 NJ - Cancer immunology, immunotherapy : CII PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cn3, 8605732 IO - Cancer Immunol. Immunother. CP - Germany KW - Acral melanoma; Biomarkers; Chinese patients; Ipilimumab; Mucosal melanoma; Pembrolizumab AB - Melanomas in Chinese patients show relatively higher rates of acral and mucosal types than in other populations. However, the efficacy of checkpoint inhibitor therapies against these melanoma subtypes is not well defined. We analyzed 52 patients treated with ipilimumab, pembrolizumab, or a combination of both to evaluate the efficacy and safety of checkpoint inhibitors in Chinese patients with advanced melanoma, particularly those with acral and mucosal types. The objective response rates (ORRs) were 0, 25, and 20% for ipilimumab, pembrolizumab, and pembrolizumab plus ipilimumab, respectively. Pembrolizumab contained therapy was as effective in acral and mucosal melanoma patients (ORR 26.7 and 20%, respectively) as in non-acral cutaneous melanoma patients (ORR 26.7%). Baseline lactate dehydrogenase levels and relative lymphocyte counts were independent prognostic factors for PFS and OS. The incidences of grade 3-4 adverse events were 14% in the two monotherapy groups and 30% in the combined therapy group. The most frequent adverse events were elevation of aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue. Treatment-related rash or vitiligo was associated with a better prognosis. In summary, pembrolizumab-based therapy resulted in meaningful efficacy and good tolerability in Chinese patients with melanoma, including those with acral and mucosal types. ES - 1432-0851 IL - 0340-7004 DI - 10.1007/s00262-017-1989-8 DO - https://dx.doi.org/10.1007/s00262-017-1989-8 PT - Journal Article ID - 10.1007/s00262-017-1989-8 [doi] ID - 10.1007/s00262-017-1989-8 [pii] PP - aheadofprint PH - 2016/09/24 [received] PH - 2017/03/16 [accepted] LG - English EP - 20170425 DP - 2017 Apr 25 DC - 20170426 EZ - 2017/04/27 06:00 DA - 2017/04/27 06:00 DT - 2017/04/27 06:00 YR - 2017 RD - 20170426 UP - 20170428 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28444424 <512. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28431010 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Gay CL AU - Bosch RJ AU - Ritz J AU - Hataye JM AU - Aga E AU - Tressler RL AU - Mason SW AU - Hwang CK AU - Grasela DM AU - Ray N AU - Cyktor JC AU - Coffin JM AU - Acosta EP AU - Koup RA AU - Mellors JW AU - Eron JJ AU - AIDS Clinical Trials 5326 Study Team FA - Gay, Cynthia L FA - Bosch, Ronald J FA - Ritz, Justin FA - Hataye, Jason M FA - Aga, Evgenia FA - Tressler, Randall L FA - Mason, Stephen W FA - Hwang, Carey K FA - Grasela, Dennis M FA - Ray, Neelanjana FA - Cyktor, Josh C FA - Coffin, John M FA - Acosta, Edward P FA - Koup, Richard A FA - Mellors, John W FA - Eron, Joseph J FA - AIDS Clinical Trials 5326 Study Team IN - Gay, Cynthia L. The University of North Carolina at Chapel Hill, Chapel Hill, NC. IN - Bosch, Ronald J. Harvard T.H. Chan School of Public Health, Boston, MA. IN - Ritz, Justin. Harvard T.H. Chan School of Public Health, Boston, MA. IN - Hataye, Jason M. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD. IN - Aga, Evgenia. Harvard T.H. Chan School of Public Health, Boston, MA. IN - Tressler, Randall L. Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD. IN - Tressler, Randall L. Columbus Technologies, El Segundo, CA. IN - Mason, Stephen W. Bristol-Myers Squibb, Wallingford, CT. IN - Hwang, Carey K. Bristol-Myers Squibb, Princeton, NJ. IN - Grasela, Dennis M. Bristol-Myers Squibb, Princeton, NJ. IN - Ray, Neelanjana. Bristol-Myers Squibb, Princeton, NJ. IN - Cyktor, Josh C. University of Pittsburgh, Pittsburgh, PA. IN - Coffin, John M. Tufts University School of Medicine, Boston, MA. IN - Acosta, Edward P. University of Alabama School of Medicine, Birmingham, AL. IN - Koup, Richard A. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD. IN - Mellors, John W. University of Pittsburgh, Pittsburgh, PA. IN - Eron, Joseph J. The University of North Carolina at Chapel Hill, Chapel Hill, NC. TI - Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants on Suppressive Antiretroviral Therapy. SO - Journal of Infectious Diseases. , 2017 Apr 18 AS - J Infect Dis. , 2017 Apr 18 NJ - The Journal of infectious diseases PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - ih3, 0413675 IO - J. Infect. Dis. CP - United States KW - BMS-936559.; HIV cure; HIV eradication; HIV-1; anti-PD-L1; checkpoint inhibitors; immune response AB - Background.: Reversing immune exhaustion with an anti-PD-L1 antibody may improve HIV-1-specific immunity and increase clearance of HIV-1 expressing cells. AB - Methods.: Phase I, randomized, double-blind, placebo-controlled dose-escalating study of BMS-936559including HIV-1-infected adults >=18 to <=70 years on suppressive antiretroviral therapy with CD4+ counts >=350 cells/muL and detectable plasma HIV-1 RNA by single copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any >=Grade 3 or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cells responses from baseline to day 28 post-infusion. AB - Results.: Eight men enrolled; six received 0.3 mg/kg of BMS-936559 and two received placebo infusions. There were no BMS-936559 related >Grade 3 AEs. In one participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days following BMS-936559 infusion that resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing IFN-gamma increased from baseline (0.09%) through day 28 (0.20%; p=0.14), driven by substantial increases in two participants who received BMS-936559. AB - Discussion.: In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single low dose BMS-936559 infusions appeared to enhance HIV-1 specific immunity in a subset of participants. ES - 1537-6613 IL - 0022-1899 DI - 3738530 DO - https://dx.doi.org/10.1093/infdis/jix191 PT - Journal Article ID - 3738530 [pii] ID - 10.1093/infdis/jix191 [doi] PP - aheadofprint PH - 2017/02/07 [received] LG - English EP - 20170418 DP - 2017 Apr 18 DC - 20170421 EZ - 2017/04/22 06:00 DA - 2017/04/22 06:00 DT - 2017/04/22 06:00 YR - 2017 RD - 20170421 UP - 20170424 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28431010 <513. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28401443 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Brilli L AU - Danielli R AU - Ciuoli C AU - Calabro L AU - Di Giacomo AM AU - Cerase A AU - Paffetti P AU - Sestini F AU - Porcelli B AU - Maio M AU - Pacini F FA - Brilli, Lucia FA - Danielli, Riccardo FA - Ciuoli, Cristina FA - Calabro, Luana FA - Di Giacomo, Anna Maria FA - Cerase, Alfonso FA - Paffetti, Patrizia FA - Sestini, Fausta FA - Porcelli, Brunetta FA - Maio, Michele FA - Pacini, Furio IN - Brilli, Lucia. Section of Endocrinology, Department of Medical, Surgical and Neurological sciences, University of Siena, Siena, Italy. IN - Danielli, Riccardo. Medical Oncology and Immunotherapy Unit, Department of Oncology, Istituto Toscano Tumori, University of Siena, Siena, Italy. IN - Ciuoli, Cristina. Section of Endocrinology, Department of Medical, Surgical and Neurological sciences, University of Siena, Siena, Italy. IN - Calabro, Luana. Medical Oncology and Immunotherapy Unit, Department of Oncology, Istituto Toscano Tumori, University of Siena, Siena, Italy. IN - Di Giacomo, Anna Maria. Medical Oncology and Immunotherapy Unit, Department of Oncology, Istituto Toscano Tumori, University of Siena, Siena, Italy. IN - Cerase, Alfonso. Unit of Neuroimaging and Neurointervention, Department of Neurological and Sensorineural Sciences, Azienda Ospedaliera Universitaria Senese, Siena, Italy. IN - Paffetti, Patrizia. Section of Endocrinology, Department of Medical, Surgical and Neurological sciences, University of Siena, Siena, Italy. IN - Sestini, Fausta. Section of Endocrinology, Department of Medical, Surgical and Neurological sciences, University of Siena, Siena, Italy. IN - Porcelli, Brunetta. Department of Medical Biotechnologies, Biochemistry Division, University of Siena, UOC Laboratorio Patologia Clinica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. IN - Maio, Michele. Medical Oncology and Immunotherapy Unit, Department of Oncology, Istituto Toscano Tumori, University of Siena, Siena, Italy. IN - Pacini, Furio. Section of Endocrinology, Department of Medical, Surgical and Neurological sciences, University of Siena, Siena, Italy. pacini8@unisi.it. TI - Prevalence of hypophysitis in a cohort of patients with metastatic melanoma and prostate cancer treated with ipilimumab. SO - Endocrine. , 2017 Apr 12 AS - Endocrine. , 2017 Apr 12 NJ - Endocrine PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9434444, CV9 IO - Endocrine CP - United States KW - CTLA-4; Hypophysitis; Ipilimumab; Melanoma AB - OBJECTIVE: Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4, that has been shown to significantly improve survival in patients with metastatic melanoma. Blocking cytotoxic T-lymphocyte antigen-4 elicits T cell activation, proliferation and anti-tumor response, but can also trigger immune-related adverse events. Among immune-related endocrinopathies, hypophysitis represents the most frequent, with an incidence up to 17% in patients treated with ipilimumab. AB - DESIGN AND METHODS: We report nine cases of ipilimumab-induced hypophysitis in a cohort of 273 patients treated with ipilimumab between 2006 and 2015, as part of clinical trials or after its marketing. Thyroid function tests were scheduled at screening and during follow up (every 21days) in all patients. Cortisol, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, and estradiol (for females) or testosterone (for males), prolactin, growth hormone, insulin-like growth factor 1 were measured only in case of clinical suspicion. AB - RESULTS: The incidence of hypophysitis was 3.3%. The most frequent pituitary failure was adrenocorticotropic hormone and thyroid stimulating hormone secretion with a complete recovery of thyroid stimulating hormone, but not of adrenocorticotropic hormone during follow up. All patients had negative pituitary antibodies. The main symptoms at diagnosis were fatigue and headache. AB - CONCLUSION: Clinicians should be aware about the risk of hypophysitis during treatment with immune check-point inhibitors and the necessity of investigating pituitary function during therapy. Pituitary magnetic resonance imaging does not seem pivotal for a definite diagnosis if not performed at the onset of disease. ES - 1559-0100 IL - 1355-008X DI - 10.1007/s12020-017-1289-2 DO - https://dx.doi.org/10.1007/s12020-017-1289-2 PT - Journal Article ID - 10.1007/s12020-017-1289-2 [doi] ID - 10.1007/s12020-017-1289-2 [pii] PP - aheadofprint PH - 2016/11/11 [received] PH - 2017/03/21 [accepted] LG - English EP - 20170412 DP - 2017 Apr 12 DC - 20170412 EZ - 2017/04/13 06:00 DA - 2017/04/13 06:00 DT - 2017/04/13 06:00 YR - 2017 RD - 20170412 UP - 20170414 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28401443 <514. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28355971 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Mahmoud F AU - Wilkinson JT AU - Gizinski A AU - Viswamitra S AU - Gokden N AU - Vander Schilden J FA - Mahmoud, Fade FA - Wilkinson, John T FA - Gizinski, Alison FA - Viswamitra, Sanjaya FA - Gokden, Neriman FA - Vander Schilden, John IN - Mahmoud, Fade. 1 Department of Internal Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. IN - Wilkinson, John T. 2 Department of Orthopedics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. IN - Gizinski, Alison. 3 Department of Rheumatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. IN - Viswamitra, Sanjaya. 4 Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. IN - Gokden, Neriman. 5 Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. IN - Vander Schilden, John. 2 Department of Orthopedics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. TI - Could knee inflammatory synovitis be induced by pembrolizumab?. SO - Journal of Oncology Pharmacy Practice. :1078155217701292, 2017 Jan 01 AS - J Oncol Pharm Pract. :1078155217701292, 2017 Jan 01 NJ - Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9511372 IO - J Oncol Pharm Pract CP - England KW - Pemprolizumab; autoimmune arthritis; melanoma; synovitis AB - Pembrolizumab, a selective anti-PD-1 humanized monoclonal antibody, reactivates T cells to fight cancer. Immune-related adverse events such as autoimmune colitis, pneumonitis, hepatitis, nephritis, hypophysitis, and thyroiditis may occur during, or weeks to months after therapy. Pemprolizumab-induced synovitis is rarely reported. With the wide use of immunotherapy to treat cancers, physicians need to be aware of this rare immune-related adverse event and provide immediate treatment to avoid permanent joint damage. ES - 1477-092X IL - 1078-1552 DO - https://dx.doi.org/10.1177/1078155217701292 PT - Journal Article ID - 10.1177/1078155217701292 [doi] PP - aheadofprint LG - English EP - 20170101 DP - 2017 Jan 01 DC - 20170330 EZ - 2017/03/31 06:00 DA - 2017/03/31 06:00 DT - 2017/03/31 06:00 YR - 2017 RD - 20170330 UP - 20170403 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28355971 <515. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28280929 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Tafe LJ FA - Tafe, Laura J IN - Tafe, Laura J. One Medical Center Drive, Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03754, USA. Laura.J.Tafe@hitchcock.org. TI - Molecular mechanisms of therapy resistance in solid tumors: chasing "moving" targets. [Review] SO - Virchows Archiv. , 2017 Mar 10 AS - Virchows Arch. , 2017 Mar 10 NJ - Virchows Archiv : an international journal of pathology PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - bzd, 9423843 IO - Virchows Arch. CP - Germany KW - Breast cancer; Castration-resistant prostate cancer; Checkpoint inhibitors; Drug resistance; EGFR T790M; ESR1 mutation; Epithelial-mesenchymal transition; Non-small cell lung cancer; Resistance mechanisms; Small cell transformation; TKI resistance AB - The goal of personalized cancer therapy is to treat tumors based on genomic aberrations that drive their survival and progression. Most patients who receive targeted therapies typically develop resistance and disease progression within a year's time. This review focuses on the heterogeneous mechanisms of therapy resistance to tyrosine kinase inhibitors, endocrine/hormone therapy and checkpoint blockade using non-small cell lung cancer, breast and castration-resistant prostate cancer, and melanoma as classical examples, respectively. In addition, testing for resistance mechanisms and therapeutic approaches to overcoming resistance is addressed. ES - 1432-2307 IL - 0945-6317 DI - 10.1007/s00428-017-2101-7 DO - https://dx.doi.org/10.1007/s00428-017-2101-7 PT - Journal Article PT - Review ID - 10.1007/s00428-017-2101-7 [doi] ID - 10.1007/s00428-017-2101-7 [pii] PP - aheadofprint PH - 2017/01/24 [received] PH - 2017/02/23 [accepted] LG - English EP - 20170310 DP - 2017 Mar 10 DC - 20170310 EZ - 2017/03/11 06:00 DA - 2017/03/11 06:00 DT - 2017/03/11 06:00 YR - 2017 RD - 20170310 UP - 20170313 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28280929 <516. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27656680 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Martinov T AU - Spanier JA AU - Pauken KE AU - Fife BT FA - Martinov, Tijana FA - Spanier, Justin A FA - Pauken, Kristen E FA - Fife, Brian T IN - Martinov, Tijana. Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, 55455, USA. IN - Spanier, Justin A. Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, 55455, USA. IN - Pauken, Kristen E. Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, 55455, USA. IN - Fife, Brian T. Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, 55455, USA. TI - PD-1 pathway-mediated regulation of islet-specific CD4⁺ T cell subsets in autoimmune diabetes. SO - Immunoendocrinology. 3, 2016 AS - Immunoendocrinology (Houst). 3, 2016 NJ - Immunoendocrinology (Houston, Tex.) PI - Journal available in: Print PI - Citation processed from: Print JC - 101686763 IO - Immunoendocrinology (Houst) CP - United States KW - CD4+ T cells; PD-1; anergy; checkpoint blockade; insulin; type 1 diabetes AB - Type 1 diabetes (T1D) is a CD4⁺ T cell-driven autoimmune disease resulting from the destruction of insulin-producing pancreatic beta cells. Clinical evidence and studies in non-obese diabetic (NOD) mice suggest that insulin is a major autoantigen. With this in mind, we developed insulin B_10-23:IA^g7 tetramer reagents to track insulin-specific CD4⁺ T cells in mice and interrogated the role of Programmed death-1 (PD-1) for peripheral tolerance. PD-1 is a T cell inhibitory receptor necessary to maintain tolerance and prevent T1D in NOD mice. PD-1 pathway inhibitors are increasingly used in the clinic for treating malignancies, and while many patients benefit, some develop adverse autoimmune events, including T1D. We therefore sought to understand the role of PD-1 in maintaining islet-specific tolerance in diabetes-resistant strains. B6.g7 mice express the same MHC Class II allele as NOD mice, have predominantly naive insulin-specific CD4⁺ T cells in the periphery, and remain diabetes-free even after PD-1 pathway blockade. Here, we examined the trafficking potential of insulin-specific CD4⁺ T cells in NOD and B6.g7 mice with or without anti-PD-L1 treatment, and found that PD-L1 blockade preferentially increased the number of CD44^highCXCR3⁺ insulin-specific cells in NOD but not B6.g7 mice. Additionally, we investigated whether pancreatic islets in NOD and B6.g7 mice expressed CXCL10, a lymphocyte homing chemokine and ligand for CXCR3. Anti-PD-L1 treated and control NOD mice had detectable CXCL10 expression in the islets, while B6.g7 islets did not. These data suggest that islet tolerance may be in part attributed to the pancreatic environment and in the absence of pancreas inflammation, chemotactic cytokines may be missing. This, together with our previous data showing that PD-1 pathway blockade preferentially affects effector but not anergic self-specific T cells has implications for the use of checkpoint blockade in treating tumor patients. Our work suggests that determining tumor- and self-specific CD4⁺ T cell activation status (naive, effector or anergic) prior to initiation of immunotherapy would likely help to stratify individuals who would benefit from this therapy versus those who might have adverse effects or incomplete tumor control. CI - Conflicting Interests The authors have declared that no conflict of interests exist. IL - 2378-3079 DI - e1164 DO - https://dx.doi.org/10.14800/ie.1164 PT - Journal Article ID - 10.14800/ie.1164 [doi] ID - PMC5027981 [pmc] ID - NIHMS784558 [mid] PP - ppublish GI - No: P01 AI035296 Organization: (AI) *NIAID NIH HHS* Country: United States No: R01 AI106791 Organization: (AI) *NIAID NIH HHS* Country: United States No: T32 DK007203 Organization: (DK) *NIDDK NIH HHS* Country: United States LG - English DP - 2016 DC - 20160922 EZ - 2016/09/23 06:00 DA - 2016/09/23 06:00 DT - 2016/09/23 06:00 YR - 2016 RD - 20170311 UP - 20170313 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=27656680 <517. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28267050 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Bernier M AU - Guillaume C AU - Leon N AU - Alexandre J AU - Hamel-Senecal L AU - Chretien B AU - Lecaignec F AU - Humbert X AU - Fedrizzi S AU - Madelaine J AU - Sassier M FA - Bernier, Marjorie FA - Guillaume, Cyril FA - Leon, Nathalie FA - Alexandre, Joachim FA - Hamel-Senecal, Lea FA - Chretien, Basile FA - Lecaignec, Florian FA - Humbert, Xavier FA - Fedrizzi, Sophie FA - Madelaine, Jeannick FA - Sassier, Marion IN - Bernier, Marjorie. Departments of *Pharmacology +Pain and Palliative Care ++Rheumatology Pneumology, CHU of Caen Department of General Medicine, Medical School, Normandie University, Caen, France. TI - Nivolumab Causing a Polymyalgia Rheumatica in a Patient With a Squamous Non-Small Cell Lung Cancer. SO - Journal of Immunotherapy. , 2017 Mar 06 AS - J Immunother. , 2017 Mar 06 NJ - Journal of immunotherapy (Hagerstown, Md. : 1997) PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - cuq, 9706083 IO - J. Immunother. CP - United States AB - The anti-programmed cell-death-1 antibody, nivolumab, has been recently approved for the treatment of advanced non-small cell lung cancer. Although, today, immune-related adverse effects such as dermatologic, digestive, hepatic, and endocrine toxicities are well-known with immune checkpoint inhibitors, rheumatic diseases are less well described. Herein, we report the case of a patient without a history of arthritis who developed polymyalgia rheumatica after 13 cycles of nivolumab used for the treatment of advanced non-small cell lung cancer. Laboratory evidence of inflammatory syndrome, articular echography, and clinical presentation with classical symptoms and also distal manifestations were suggestive of this chronic inflammatory disorder. Because of a relevant pain, clinicians were forced to suspend immunotherapy. Nevertheless, due to glucocorticoid therapy, the patient's symptoms have decreased progressively. Moreover, nivolumab was reintroduced 8 weeks later, whereas prednisone (10 mg) was continued, without any recurrence symptoms. To conclude, our case suggests that polymyalgia rheumatica might be a very disabling anti-programmed cell-death-1 immune-related adverse effect. ES - 1537-4513 IL - 1524-9557 DO - https://dx.doi.org/10.1097/CJI.0000000000000163 PT - Journal Article ID - 10.1097/CJI.0000000000000163 [doi] PP - aheadofprint LG - English EP - 20170306 DP - 2017 Mar 06 DC - 20170307 EZ - 2017/03/08 06:00 DA - 2017/03/08 06:00 DT - 2017/03/08 06:00 YR - 2017 RD - 20170308 UP - 20170309 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28267050 <518. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28235882 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Chuk MK AU - Chang JT AU - Theoret MR AU - Sampene E AU - He K AU - Weis SL AU - Helms WS AU - Jin R AU - Li H AU - Yu J AU - Zhao H AU - Zhao L AU - Paciga M AU - Schmiel D AU - Rawat R AU - Keegan P AU - Pazdur R FA - Chuk, Meredith K FA - Chang, Jennie T FA - Theoret, Marc R FA - Sampene, Emmanuel FA - He, Kun FA - Weis, Shawna L FA - Helms, Whitney S FA - Jin, Runyan FA - Li, Hongshan FA - Yu, Jingyu FA - Zhao, Hong FA - Zhao, Liang FA - Paciga, Mark FA - Schmiel, Deborah FA - Rawat, Rashmi FA - Keegan, Patricia FA - Pazdur, Richard IN - Chuk, Meredith K. Office of Hematology and Oncology Products, FDA Meredith.Chuk@fda.hhs.gov. IN - Chang, Jennie T. Office of Hematology and Oncology Products, U.S. Food and Drug Administration. IN - Theoret, Marc R. Surgery Branch, National Cancer Institute. IN - Sampene, Emmanuel. Office of Biostatistics, U.S. Food and Drug Administration. IN - He, Kun. Office of Biostatistics, U.S. Food and Drug Administration. IN - Weis, Shawna L. Office of Hematology and Oncology Products, U.S. Food and Drug Administration. IN - Helms, Whitney S. Office of Hematology and Oncology Products, Food & Drug Administration/CDER. IN - Jin, Runyan. OCP, FDA. IN - Li, Hongshan. OCP, FDA. IN - Yu, Jingyu. Office of Translational Sciences, U.S. Food and Drug Administration. IN - Zhao, Hong. Office of Clinical Pharmacology, Food and Drug Administration. IN - Zhao, Liang. FDA. IN - Paciga, Mark. Office of Biotechnology Products, U.S. Food and Drug Administration. IN - Schmiel, Deborah. Office of Biotechnology Products, FDA. IN - Rawat, Rashmi. Office of Biotechnology Products, U.S. Food and Drug Administration. IN - Keegan, Patricia. Office of Oncology Drug Products, Office of New Drugs, Food and Drug Administration. IN - Pazdur, Richard. Office of Oncology Drug Products, U.S. Food and Drug Administration. TI - FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. SO - Clinical Cancer Research. , 2017 Feb 24 AS - Clin Cancer Res. , 2017 Feb 24 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. CP - United States AB - On September 4, 2014, FDA approved pembrolizumab (KEYTRUDA, Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating Phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% CI: 15, 34); with 6 months of follow-up, 86% of responses were ongoing. The most common (>= 20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease, and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. AB - Copyright ©2017, American Association for Cancer Research. IS - 1078-0432 IL - 1078-0432 DI - clincanres.0663.2016 DI - 1078-0432.CCR-16-0663 DO - https://dx.doi.org/10.1158/1078-0432.CCR-16-0663 PT - Journal Article ID - 28235882 [pubmed] ID - 1078-0432.CCR-16-0663 [pii] ID - 10.1158/1078-0432.CCR-16-0663 [doi] PP - aheadofprint PH - 2017/02/20 [accepted] PH - 2016/10/12 [received] PH - 2017/01/27 [revised] LG - English EP - 20170224 DP - 2017 Feb 24 DC - 20170225 EZ - 2017/02/26 06:00 DA - 2017/02/27 06:00 DT - 2017/02/27 06:00 YR - 2017 RD - 20170225 UP - 20170228 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28235882 <519. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28207422 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Nandavaram S AU - Nadkarni A FA - Nandavaram, Sravanthi FA - Nadkarni, Anupa IN - Nandavaram, Sravanthi. Division of Pulmonary Critical Care, SUNY Upstate Medical University, Syracuse, NY. TI - Ipilimumab-Induced Sarcoidosis and Thyroiditis. SO - American Journal of Therapeutics. , 2017 Feb 15 AS - Am J Ther. , 2017 Feb 15 NJ - American journal of therapeutics PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - db7, 9441347 IO - Am J Ther CP - United States ES - 1536-3686 IL - 1075-2765 DO - https://dx.doi.org/10.1097/MJT.0000000000000545 PT - Journal Article ID - 28207422 [pubmed] ID - 10.1097/MJT.0000000000000545 [doi] PP - aheadofprint LG - English EP - 20170215 DP - 2017 Feb 15 DC - 20170216 EZ - 2017/02/17 06:00 DA - 2017/02/17 06:00 DT - 2017/02/17 06:00 YR - 2017 RD - 20170216 UP - 20170221 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28207422 <520. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28179454 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Barone A AU - Hazarika M AU - Theoret MR AU - Mishra-Kalyani P AU - Chen H AU - He K AU - Sridhara R AU - Subramaniam S AU - Pfuma E AU - Wang Y AU - Li H AU - Zhao H AU - Fourie Zirkelbach J AU - Keegan P AU - Pazdur R FA - Barone, Amy FA - Hazarika, Maitreyee FA - Theoret, Marc R FA - Mishra-Kalyani, Pallavi FA - Chen, Huanyu FA - He, Kun FA - Sridhara, Rajeshwari FA - Subramaniam, Sriram FA - Pfuma, Elimika FA - Wang, Yaning FA - Li, Hongshan FA - Zhao, Hong FA - Fourie Zirkelbach, Jeanne FA - Keegan, Patricia FA - Pazdur, Richard IN - Barone, Amy. Office of Hematology and Oncology Products, U.S. Food and Drug Administration amy.barone@fda.hhs.gov. IN - Hazarika, Maitreyee. Office of Oncology Drug Products, FDA. IN - Theoret, Marc R. Surgery Branch, National Cancer Institute. IN - Mishra-Kalyani, Pallavi. Office of Biostatistics, U.S. Food and Drug Administration. IN - Chen, Huanyu. Office of Biostatistics, FDA. IN - He, Kun. Office of Biostatistics, U.S. Food and Drug Administration. IN - Sridhara, Rajeshwari. Office of Biostatistics, FDA. IN - Subramaniam, Sriram. Office of Clinical Pharmacology, U.S. Food and Drug Administration. IN - Pfuma, Elimika. Office of Clinical Pharmacology, Food and Drug Administration. IN - Wang, Yaning. Office of Clinical Pharmacology, Division of Pharmacometrics, FDA. IN - Li, Hongshan. OCP, FDA. IN - Zhao, Hong. Office of Clinical Pharmacology, Food and Drug Administration. IN - Fourie Zirkelbach, Jeanne. DOP1/OHOP/CDER, Food and Drug Administration. IN - Keegan, Patricia. Office of Oncology Drug Products, Office of New Drugs, Food and Drug Administration. IN - Pazdur, Richard. Office of Oncology Drug Products, U.S. Food and Drug Administration. TI - FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. SO - Clinical Cancer Research. , 2017 Feb 08 AS - Clin Cancer Res. , 2017 Feb 08 NJ - Clinical cancer research : an official journal of the American Association for Cancer Research PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - c2h, 9502500 IO - Clin. Cancer Res. CP - United States AB - On December 18, 2015, the U.S. Food and Drug Administration (FDA) granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma, based on results of two randomized, open-label, active-controlled clinical trials. In Trial PN006, 834 patients with ipilimumab-naive metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg intravenously (IV) every 2 (q2w) or 3 (q3w) weeks until disease progression or ipilimumab 3 mg/kg q3w for up to four doses. In Trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg IV q3w or to investigator's choice of chemotherapy. In Trial PN006, patients randomized to pembrolizumab demonstrated statistically significant improvement in overall survival compared to ipilimumab (q2w arm, HR= 0.63 [95%CI: 0.47, 0.83; p<0.001]; q3w arm, HR=0.67 [95%CI: 0.52, 0.90; p=0.004]). In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (>=2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response-based endpoints using Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST (irRC). AB - Copyright ©2017, American Association for Cancer Research. IS - 1078-0432 IL - 1078-0432 DI - clincanres.0664.2016 DI - 1078-0432.CCR-16-0664 DO - https://dx.doi.org/10.1158/1078-0432.CCR-16-0664 PT - Journal Article ID - 28179454 [pubmed] ID - 1078-0432.CCR-16-0664 [pii] ID - 10.1158/1078-0432.CCR-16-0664 [doi] PP - aheadofprint PH - 2016/12/21 [accepted] PH - 2016/10/26 [received] PH - 2016/12/19 [revised] LG - English EP - 20170208 DP - 2017 Feb 08 DC - 20170209 EZ - 2017/02/10 06:00 DA - 2017/02/10 06:00 DT - 2017/02/10 06:00 YR - 2017 RD - 20170209 UP - 20170213 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28179454 <521. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 28147928 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - March KL AU - Samarin MJ AU - Sodhi A AU - Owens RE FA - March, Katherine L FA - Samarin, Michael J FA - Sodhi, Amik FA - Owens, Ryan E IN - March, Katherine L. 1 Department of Pharmacy, Methodist University Hospital, Memphis, TN, USA. IN - March, Katherine L. 2 Department of Clinical Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA. IN - Samarin, Michael J. 1 Department of Pharmacy, Methodist University Hospital, Memphis, TN, USA. IN - Sodhi, Amik. 1 Department of Pharmacy, Methodist University Hospital, Memphis, TN, USA. IN - Sodhi, Amik. 3 Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, University of Tennessee Health Science Center at Memphis, Memphis, TN, USA. IN - Owens, Ryan E. 4 Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma Health Sciences Center, OK, USA. TI - Pembrolizumab-induced myasthenia gravis: A fatal case report. SO - Journal of Oncology Pharmacy Practice. :1078155216687389, 2017 Jan 01 AS - J Oncol Pharm Pract. :1078155216687389, 2017 Jan 01 NJ - Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners PI - Journal available in: Print-Electronic PI - Citation processed from: Internet JC - 9511372 IO - J Oncol Pharm Pract CP - England KW - Myasthenia gravis; monoclonal antibody; neurology; oncology; pembrolizumab AB - Purpose Pembrolizumab, a monoclonal antibody which inhibits the programmed cell death 1 receptor, has been shown to efficaciously enhance pre-existing immune responses to malignancies. However, safety concerns must also be considered as pembrolizumab use has been associated with several life-threatening immune-related adverse events (irAEs). We report a fatal case of pembrolizumab-induced myasthenia gravis in a patient with no prior myasthenia gravis history. Case report A 63-year-old male presented with right eyelid drooping, puffiness, blurred vision, and shortness of breath two weeks after an initial infusion of pembrolizumab. He was subsequently diagnosed with new onset acetylcholine-receptor positive myasthenia gravis. Despite aggressive treatment with corticosteroids, pyridostigmine, intravenous immunoglobulin, and plasmapheresis, the patient clinically deteriorated and ultimately expired from acute respiratory failure after a 12-day hospitalization. Discussion Current package labeling for pembrolizumab warns against various irAEs associated with its use including pneumonitis, colitis, and endocrinopathies. To date, only one case of new onset myasthenia gravis and two case reports of myasthenia gravis exacerbation have been identified. This case further highlights the mortality risk associated with development of irAEs. Conclusion While rare, evidence for the development of MG associated with pembrolizumab is growing. Prompt recognition of symptoms and discontinuation of pembrolizumab is necessary to help improve prognosis. ES - 1477-092X IL - 1078-1552 DO - https://dx.doi.org/10.1177/1078155216687389 PT - Journal Article ID - 28147928 [pubmed] ID - 10.1177/1078155216687389 [doi] PP - aheadofprint LG - English EP - 20170101 DP - 2017 Jan 01 DC - 20170202 EZ - 2017/02/03 06:00 DA - 2017/02/06 06:00 DT - 2017/02/06 06:00 YR - 2017 RD - 20170202 UP - 20170207 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=28147928 <522. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 27849378 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - McElduff A FA - McElduff, Aidan IN - McElduff, Aidan. From: The Discipline of Medicine, The University of Sydney, Sydney, NSW, Australia. TI - THE EFFECT ON PD-1 INHIBITORS ON ENDOCRINE FUNCTION. SO - Endocrine Practice. , 2016 Nov 16 AS - Endocr Pract. , 2016 Nov 16 NJ - Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - 9607439, dy1 IO - Endocr Pract CP - United States IS - 1530-891X IL - 1530-891X DO - https://dx.doi.org/10.4158/EP161636.ED PT - Journal Article ID - 27849378 [pubmed] ID - 10.4158/EP161636.ED [doi] PP - aheadofprint LG - English EP - 20161116 DP - 2016 Nov 16 DC - 20161116 EZ - 2016/11/17 06:00 DA - 2016/11/17 06:00 DT - 2016/11/17 06:00 YR - 2016 RD - 20161117 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=27849378 <523. > VN - Ovid Technologies DB - Ovid MEDLINE(R) UI - 26893783 RO - From MEDLINE, a database of the U.S. National Library of Medicine. ST - Publisher AU - Khoja L AU - Atenafu EG AU - Ye Q AU - Gedye C AU - Chappell M AU - Hogg D AU - Butler MO AU - Joshua AM FA - Khoja, Leila FA - Atenafu, Eshetu G FA - Ye, Qian FA - Gedye, Craig FA - Chappell, Maryanne FA - Hogg, David FA - Butler, Marcus O FA - Joshua, Anthony M IN - Khoja, Leila. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. IN - Atenafu, Eshetu G. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. IN - Ye, Qian. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. IN - Gedye, Craig. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. IN - Chappell, Maryanne. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. IN - Hogg, David. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. IN - Butler, Marcus O. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. IN - Joshua, Anthony M. Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. TI - Real-world efficacy, toxicity and clinical management of ipilimumab treatment in metastatic melanoma. SO - Oncology Letters. 11(2):1581-1585, 2016 Feb AS - Oncol. Lett.. 11(2):1581-1585, 2016 Feb NJ - Oncology letters PI - Journal available in: Print-Electronic PI - Citation processed from: Print JC - ovftdb,1408060, 101531236 IO - Oncol Lett CP - Greece KW - checkpoint inhibitors; immune-related adverse events; ipilimumab; melanoma; pembrolizumab; toxicity AB - Approved by the Food and Drug Administration in 2011, the anti-cytotoxic T-lymphocyte-associated protein 4 checkpoint inhibitor ipilimumab has delivered a survival benefit of >=3 years in a subset of metastatic melanoma patients. After participating in the registration trial, patients were treated with this agent in routine practice. Toxicity and efficacy of agents in "real world" settings may differ from trials. The present study aimed to evaluate, with respect to toxicity and outcome, all patients treated with ipilimumab to date at the Princess Margaret Hospital (Toronto, Canada). Patients treated with ipilimumab between 2008 and 2013 were identified, and patient characteristics (age, gender, tumour burden, oncogenic mutation status, number of treatments received and toxicities from treatment) were collected. Progression-free survival (PFS) and overall survival (OS) were calculated from the commencement of ipilimumab treatment. Associations between clinical characteristics and outcome or toxicity were assessed. Between 2008 and 2013, 129 patients with metastatic cutaneous melanoma were treated. Since, during this period, ipilimumab was approved in the second line setting, ipilimumab was delivered in the second or subsequent line in all patients, and 70% did not receive any further anticancer therapy. Immune-related toxicities were observed, the onset of which varied from 1 to 162 days. The majority resolved within 6 weeks of the final treatment, with the exception of endocrinopathies and bowel related toxicity. The median PFS and OS were 2.83 and 8.44 months, respectively. No pre-treatment factor independently predicted toxicity. The number of infusions (4 vs. <=3) and presence of toxicity were significantly associated with superior survival. The onset of toxicity secondary to ipilimumab could occur later than previously reported. Toxicities were manageable, but required long-term vigilance. IS - 1792-1074 IL - 1792-1074 DI - OL-0-0-4069 DO - https://dx.doi.org/10.3892/ol.2015.4069 PT - Journal Article ID - 26893783 [pubmed] ID - 10.3892/ol.2015.4069 [doi] ID - OL-0-0-4069 [pii] ID - PMC4734313 [pmc] PP - ppublish PH - 2014/10/09 [received] PH - 2015/09/30 [accepted] LG - English EP - 20151231 DP - 2016 Feb DC - 20160219 EZ - 2016/02/20 06:00 DA - 2016/02/20 06:00 DT - 2016/02/20 06:00 YR - 2016 RD - 20160222 UP - 20161215 XL - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=26893783