446 Records downloaded  - Fri Apr 06 13:51:48 UTC 2018


RECORD 1
TITLE
  Diabetic ketoacidosis after treatment with pembrolizumab
AUTHOR NAMES
  Abdul Aziz M.H.F.
  Fernando I.P.
  Lenkanpally A.
  Fernando D.J.S.
AUTHOR ADDRESSES
  (Abdul Aziz M.H.F.; Fernando I.P.; Lenkanpally A.; Fernando D.J.S., 
devaka.fernando@sfh-tr.nhs.uk) Department of Diabetes and Endocrinology, 
Sherwood Forest Hospitals NHS Foundation Trust, Sutton in Ashfield, 
Nottinghamshire, United Kingdom.
(Fernando I.P.) Western Sydney University, Cambeltown, Australia.
(Fernando D.J.S., devaka.fernando@sfh-tr.nhs.uk) Centre for Health Services 
Studies, University of Kent, George Allen Wing, Cornwallis Building, 
Canterbury, United Kingdom.
CORRESPONDENCE ADDRESS
  D.J.S. Fernando, Department of Diabetes and Endocrinology, Sherwood Forest 
Hospitals NHS Foundation Trust, Sutton in Ashfield, Nottinghamshire, United 
Kingdom. Email: devaka.fernando@sfh-tr.nhs.uk
SOURCE
  Journal of Clinical and Translational Endocrinology: Case Reports (2017) 5 
(4-5). Date of Publication: 1 Sep 2017
ISSN
  2214-6245 (electronic)
BOOK PUBLISHER
  Elsevier Inc
ABSTRACT
  Immune checkpoint inhibiting agents have been shown to precipitate type 1 
diabetes. We report a case of acute severe diabetic ketoacidosis in a 
patient with no history of diabetes who developed ketoacidosis after 
starting anti-PD1 immunotherapy with Pembrolizumab. Key Words Immune 
Checkpoint inhibitors, Pembrolizumab, Diabetic Ketoacidosis, Melanoma, 
Programmed Cell Death receptor, Anti PD1, PD 1 Inhibitor Introduction 
Pembrolizumab is a monoclonal antibody mainly used in the treatment of 
advanced/metastatic malignant melanoma (and also historically less 
responsive tumour types) [1] that acts by blocking the inhibitory ligand 
(PDL1) of the PD1 (programmed cell death 1) receptor. Anti-PD-1 therapy has 
been shown to precipitate type 1 diabetes in non-obese diabetic mice models 
[2] and only recently has diabetic keto-acidosis (DKA) secondary to PD1 
antibody use been reported in humans [3–5].
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  bicarbonate (endogenous compound)
  chloride (endogenous compound)
  glucose (endogenous compound)
  glutamate decarboxylase antibody (endogenous compound)
  hemoglobin A1c (endogenous compound)
  insulin (drug therapy)
  insulin antibody (endogenous compound)
  ketone (endogenous compound)
  lactic acid (endogenous compound)
  potassium (endogenous compound)
  sodium (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  diabetic ketoacidosis (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  anion gap
  antibody blood level
  article
  breathing disorder
  cancer immunotherapy
  case report
  chloride blood level
  clinical examination
  dehydration
  drug withdrawal
  dyspnea
  emergency ward
  female
  glucose blood level
  hemoglobin blood level
  hospital admission
  hospital discharge
  human
  insulin treatment
  lactate blood level
  melanoma (drug therapy)
  middle aged
  mucosal dryness
  potassium blood level
  priority journal
  skin turgor
  sodium blood level
  thirst
  urinary frequency
  urine level
  urine pH
CAS REGISTRY NUMBERS
  bicarbonate (144-55-8, 71-52-3)
  chloride (16887-00-6)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
  lactic acid (113-21-3, 50-21-5)
  pembrolizumab (1374853-91-4)
  potassium (7440-09-7)
  sodium (7440-23-5)
EMBASE CLASSIFICATIONS
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170466142
PUI
  L616989326
DOI
  10.1016/j.jecr.2017.05.002
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.jecr.2017.05.002
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 2
TITLE
  Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors
AUTHOR NAMES
  Makarious D.
  Horwood K.
  Coward J.I.G.
AUTHOR ADDRESSES
  (Makarious D.) Bond University, School of Medicine, Robina, Australia.
(Horwood K.; Coward J.I.G., jim.coward@gmail.com) ICON Cancer Care, 
Brisbane, Australia.
(Coward J.I.G., jim.coward@gmail.com) Faculty of Medicine, University of 
Queensland, Australia.
(Coward J.I.G., jim.coward@gmail.com) Princess Alexandra Hospital, Brisbane, 
Australia.
CORRESPONDENCE ADDRESS
  J.I.G. Coward, ICON Cancer Care, Level 5 Mater Medical Centre, 298 Vulture 
Street, South Brisbane, Australia. Email: jim.coward@gmail.com
SOURCE
  European Journal of Cancer (2017) 82 (128-136). Date of Publication: 1 Sep 
2017
ISSN
  1879-0852 (electronic)
  0959-8049
BOOK PUBLISHER
  Elsevier Ltd
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immune checkpoint inhibitor (adverse drug reaction)
  immunomodulating agent (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  immunoglobulin (drug therapy, intravenous drug administration)
  pembrolizumab (adverse drug reaction, drug therapy)
  prednisone (drug therapy)
  programmed death 1 receptor (endogenous compound)
  pyridostigmine (drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug induced disease (drug therapy, side effect, drug therapy, side effect)
  immunotoxicity (drug therapy, side effect, drug therapy, side effect)
  myasthenia gravis (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  aged
  axillary lymph node
  cardiovascular mortality
  case report
  diplopia
  drug tolerability
  drug withdrawal
  female
  human
  lymphadenopathy (drug therapy)
  maintenance therapy
  metastatic melanoma (drug therapy)
  multiple cycle treatment
  priority journal
  ptosis
  review
  systemic therapy
  treatment response
  very elderly
CAS REGISTRY NUMBERS
  immunoglobulin (9007-83-4)
  pembrolizumab (1374853-91-4)
  prednisone (53-03-2)
  pyridostigmine (101-26-8, 155-97-5)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170459314
MEDLINE PMID
  28666240 (http://www.ncbi.nlm.nih.gov/pubmed/28666240)
PUI
  L616943814
DOI
  10.1016/j.ejca.2017.05.041
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ejca.2017.05.041
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 3
TITLE
  Accelerating drug development for neuroblastoma - New Drug Development 
Strategy: an Innovative Therapies for Children with Cancer, European Network 
for Cancer Research in Children and Adolescents and International Society of 
Paediatric Oncology Europe Neuroblastoma project
AUTHOR NAMES
  Moreno L.
  Caron H.
  Geoerger B.
  Eggert A.
  Schleiermacher G.
  Brock P.
  Valteau-Couanet D.
  Chesler L.
  Schulte J.H.
  De Preter K.
  Molenaar J.
  Schramm A.
  Eilers M.
  Van Maerken T.
  Johnsen J.I.
  Garrett M.
  George S.L.
  Tweddle D.A.
  Kogner P.
  Berthold F.
  Koster J.
  Barone G.
  Tucker E.R.
  Marshall L.
  Herold R.
  Sterba J.
  Norga K.
  Vassal G.
  Pearson A.D.
AUTHOR ADDRESSES
  (Moreno L., lucas.moreno@salud.madrid.org) Paediatric Phase I-II Clinical 
Trials Unit, Paediatric Haematology & Oncology, Hospital Niño Jesus, Madrid, 
Spain.
(Moreno L., lucas.moreno@salud.madrid.org) Instituto de Investigación 
Sanitaria La Princesa, Madrid, Spain.
(Moreno L., lucas.moreno@salud.madrid.org; Chesler L.; George S.L.; Barone 
G.; Tucker E.R.; Marshall L.; Pearson A.D.) Paediatric Drug Development, 
Children and Young People’s Unit, Royal Marsden Hospital, London, United 
Kingdom.
(Caron H.) Emma Children’s Hospital, Amsterdam, Netherlands.
(Caron H.) Hoffman-La Roche, Basel, Switzerland.
(Geoerger B.; Valteau-Couanet D.) Department of Paediatric and Adolescent 
Oncology, Institut Gustave Roussy, Villejuif, France.
(Eggert A.; Schulte J.H.) Department of Pediatric Oncology and Hematology, 
Charite University Hospital, Berlin, Germany.
(Schleiermacher G.) Department of Paediatric, Adolescents and Young Adults 
Oncology and INSERM U830, Institut Curie, Paris, France.
(Brock P.) Department Paediatric Oncology, Great Ormond Street Hospital, 
London, United Kingdom.
(Chesler L.; George S.L.; Barone G.; Tucker E.R.; Marshall L.; Pearson A.D.) 
Division of Clinical Studies, Institute of Cancer Research, London, United 
Kingdom.
(De Preter K.; Van Maerken T.) Centre for Medical Genetic, Ghent University, 
Ghent, Belgium.
(Molenaar J.; Koster J.) Princess Maxima Center for Pediatric Oncology, 
University of Amsterdam, Amsterdam, Netherlands.
(Schramm A.) Department of Pediatric Oncology, University of Essen, Essen, 
Germany.
(Eilers M.) Theodor Boveri Institute and Comprehensive Cancer Center 
Mainfranken, Biocenter, University of Wurzburg, Wurzburg, Germany.
(Johnsen J.I.; Kogner P.) Department of Women’s and Children’s Health, 
Karolinska Institute, Stockholm, Sweden.
(Garrett M.) School of Biosciences, University of Kent, Canterbury, United 
Kingdom.
(Tweddle D.A.) Wolfson Childhood Cancer Research Centre, Newcastle 
University, Newcastle, United Kingdom.
(Berthold F.) Department of Pediatric Oncology and Hematology, University of 
Cologne, Cologne, Germany.
(Herold R.) European Medicines Agency, London, United Kingdom.
(Sterba J.) Masaryk University, University Hospital, Brno, Czech Republic.
(Sterba J.) Department of Pediatric Oncology, International Clinical 
Research Center, St. Anne’s University Hospital, Brno, Czech Republic.
(Sterba J.) RECAMO, Masaryk Memorial Cancer Centre, Brno, Czech Republic.
(Norga K.) Pediatric Hematology/Oncology Unit, Antwerp University Hospital, 
Antwerp, Belgium.
(Vassal G.) Department of Clinical Research, Gustave Roussy, Paris-Sud 
University, Paris, France.
CORRESPONDENCE ADDRESS
  L. Moreno, Paediatric Phase I-II Clinical Trials Unit, Paediatric 
Haematology & Oncology, Hospital Niño Jesus, Madrid, Spain. Email: 
lucas.moreno@salud.madrid.org
SOURCE
  Expert Opinion on Drug Discovery (2017) 12:8 (801-811). Date of Publication: 
3 Aug 2017
ISSN
  1746-045X (electronic)
  1746-0441
BOOK PUBLISHER
  Taylor and Francis Ltd, healthcare.enquiries@informa.com
ABSTRACT
  Introduction: Neuroblastoma, the commonest paediatric extra-cranial tumour, 
remains a leading cause of death from cancer in children. There is an urgent 
need to develop new drugs to improve cure rates and reduce long-term 
toxicity and to incorporate molecularly targeted therapies into treatment. 
Many potential drugs are becoming available, but have to be prioritised for 
clinical trials due to the relatively small numbers of patients. Areas 
covered: The current drug development model has been slow, associated with 
significant attrition, and few new drugs have been developed for 
neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 
1) established a group with expertise in drug development; 2) prioritised 
targets and drugs according to tumour biology (target expression, 
dependency, pre-clinical data; potential combinations; biomarkers), 
identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by 
BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) 
promoted clinical trials with target-prioritised drugs. Drugs showing 
activity can be rapidly transitioned via parallel randomised trials into 
front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the 
premise that optimal drug development is reliant on knowledge of tumour 
biology and prioritisation. This approach will accelerate neuroblastoma drug 
development and other poor prognosis childhood malignancies.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug therapy)
EMTREE DRUG INDEX TERMS
  4 (4 chlorophenyl) 2,3,9 trimethyl 6h thieno[3,2 f][1,2,4]triazolo[4,3 
a][1,4]diazepine 6 acetic acid tert butyl ester (drug therapy)
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide (drug 
therapy)
  abemaciclib (drug therapy)
  alisertib (drug therapy)
  aurora kinase (endogenous compound)
  azd 8055 (drug therapy)
  cct 137690 (drug therapy)
  cct 245737 (drug therapy)
  checkpoint kinase 1 (endogenous compound)
  checkpoint kinase 3 (endogenous compound)
  cobimetinib (drug therapy)
  crizotinib (drug therapy)
  cyclin dependent kinase 4 (endogenous compound)
  cyclin dependent kinase 6 (endogenous compound)
  dabrafenib (drug therapy)
  gsk 1324726a (drug therapy)
  mammalian target of rapamycin complex 1 (endogenous compound)
  mammalian target of rapamycin complex 2 (endogenous compound)
  mitogen activated protein kinase kinase (endogenous compound)
  mk 8776 (drug therapy)
  N Myc proto oncogene protein (endogenous compound)
  palbociclib (drug therapy)
  protein MDM2 (endogenous compound)
  protein serine threonine kinase (endogenous compound)
  ribociclib (drug therapy)
  selumetinib (drug therapy)
  survivin (endogenous compound)
  trametinib (drug therapy)
  unclassified drug
  vorinostat (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug development
  neuroblastoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adolescent
  cancer prognosis
  child
  childhood cancer
  drug activity
  experimental therapy
  human
  nonhuman
  phase 1 clinical trial (topic)
  priority journal
  review
DRUG TRADE NAMES
  azd 7762
  azd 8055
  cct 137690
  cct 244747
  cct 245737
  gsk 1324726a
  jq 1
  ldk 378
  lee 011
  ly 2835219
  mk 8776
  mln 8237
  sch 900776
  ym 155
CAS REGISTRY NUMBERS
  4 (4 chlorophenyl) 2,3,9 trimethyl 6h thieno[3,2 f][1,2,4]triazolo[4,3 
a][1,4]diazepine 6 acetic acid tert butyl ester (1268524-70-4)
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide 
(1019773-80-8, 860352-01-8)
  abemaciclib (1231929-97-7)
  alisertib (1028486-01-2, 1208255-63-3)
  cobimetinib (934660-93-2, 1369665-02-0)
  crizotinib (877399-52-5)
  cyclin dependent kinase 4 (147014-97-9)
  dabrafenib (1195765-45-7, 1195768-06-9)
  mitogen activated protein kinase kinase (142805-58-1)
  palbociclib (571190-30-2, 827022-33-3)
  protein serine threonine kinase ()
  ribociclib (1211441-98-3, 1374639-75-4)
  selumetinib (606143-52-6, 865610-79-3, 943332-08-9)
  survivin (195263-98-0)
  trametinib (1187431-43-1, 871700-17-3)
  vorinostat (149647-78-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Pediatrics and Pediatric Surgery (7)
  Neurology and Neurosurgery (8)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02813135)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170503863
MEDLINE PMID
  28604107 (http://www.ncbi.nlm.nih.gov/pubmed/28604107)
PUI
  L617310291
DOI
  10.1080/17460441.2017.1340269
FULL TEXT LINK
  http://dx.doi.org/10.1080/17460441.2017.1340269
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 4
TITLE
  Indirect comparison between pembrolizumab and nivolumab for the treatment of 
non-small cell lung cancer: A meta-analysis of randomized clinical trials
AUTHOR NAMES
  Peng T.-R.
  Tsai F.-P.
  Wu T.-W.
AUTHOR ADDRESSES
  (Peng T.-R.; Tsai F.-P.; Wu T.-W., tawei@tzuchi.com.tw) Department of 
Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New 
Taipei City, Taiwan.
(Wu T.-W., tawei@tzuchi.com.tw) School of Pharmacy, College of Pharmacy, 
Taipei Medical University, Taipei City, Taiwan.
CORRESPONDENCE ADDRESS
  T.-W. Wu, #289, Jianguo Road, Xindian City, New Taipei City, Taiwan. Email: 
tawei@tzuchi.com.tw
SOURCE
  International Immunopharmacology (2017) 49 (85-94). Date of Publication: 1 
Aug 2017
ISSN
  1878-1705 (electronic)
  1567-5769
BOOK PUBLISHER
  Elsevier B.V.
ABSTRACT
  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. 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). 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. 
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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug comparison, drug 
therapy)
  pembrolizumab (adverse drug reaction, clinical trial, drug comparison, drug 
therapy)
EMTREE DRUG INDEX TERMS
  docetaxel (drug comparison)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  article
  asthenia (side effect)
  cancer chemotherapy
  cancer patient
  cancer survival
  decreased appetite (side effect)
  diarrhea (side effect)
  fatigue (side effect)
  human
  hypothyroidism (side effect)
  meta analysis
  nausea (side effect)
  overall survival
  pneumonia (side effect)
  priority journal
  progression free survival
  randomized controlled trial (topic)
  systematic review
  treatment response
CAS REGISTRY NUMBERS
  docetaxel (114977-28-5)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170377960
PUI
  L616371330
DOI
  10.1016/j.intimp.2017.05.019
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.intimp.2017.05.019
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 5
TITLE
  Elevated tumor mutational burden and prolonged clinical response to 
anti-PD-L1 antibody in platinum-resistant recurrent ovarian cancer
AUTHOR NAMES
  Morse C.B.
  Elvin J.A.
  Gay L.M.
  Liao J.B.
AUTHOR ADDRESSES
  (Morse C.B.; Liao J.B., johnliao@uw.edu) Department of Obstetrics and 
Gynecology, University of Washington, Seattle, United States.
(Elvin J.A.; Gay L.M.) Foundation Medicine, Cambridge, United States.
CORRESPONDENCE ADDRESS
  J.B. Liao, University of Washington Medical Center, Department of Obstetrics 
and Gynecology, Box 356460, Seattle, United States. Email: johnliao@uw.edu
SOURCE
  Gynecologic Oncology Reports (2017) 21 (78-80). Date of Publication: 1 Aug 
2017
ISSN
  2352-5789 (electronic)
BOOK PUBLISHER
  Elsevier B.V.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  avelumab (adverse drug reaction, clinical trial, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  CA 125 antigen (endogenous compound)
  carboplatin (drug combination, drug therapy)
  paclitaxel (drug combination, drug therapy)
  prednisone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer recurrence
  ovary cancer (drug therapy, diagnosis, drug resistance, drug therapy, 
surgery)
  somatic mutation
  treatment response
  tumor volume
EMTREE MEDICAL INDEX TERMS
  abdominal hysterectomy
  abdominal pain
  advanced cancer
  article
  ascites
  bloating
  bronchoscopy
  cancer immunotherapy
  carcinomatous peritonitis
  case report
  comorbidity
  computer assisted tomography
  cytology
  cytoreductive surgery
  drug withdrawal
  dyspnea
  female
  genetic counseling
  human
  laparotomy
  lavage
  lung alveolitis
  lung diffusion capacity
  lung embolism
  lung function test
  lymphocyte
  Muellerian duct
  multiple cycle treatment
  neoadjuvant chemotherapy
  omentectomy
  paracentesis
  pleura effusion
  pneumonia (drug therapy, side effect)
  salpingooophorectomy
  thoracocentesis
  treatment duration
CAS REGISTRY NUMBERS
  avelumab (1537032-82-8)
  carboplatin (41575-94-4)
  paclitaxel (33069-62-4)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170507622
PUI
  L617292858
DOI
  10.1016/j.gore.2017.06.013
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.gore.2017.06.013
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 6
TITLE
  Tremelimumab-Induced Graves Hyperthyroidism

AUTHOR NAMES
  Gan E.H.
  Mitchell A.L.
  Plummer R.
  Pearce S.
  Perros P.
AUTHOR ADDRESSES
  (Gan E.H., earn.gan1@ncl.ac.uk; Mitchell A.L.; Plummer R.; Pearce S.; Perros 
P.) Institute of Genetic Medicine, International Centre for Life, Centre 
Parkway, Newcastle upon Tyne, United Kingdom.
SOURCE
  European Thyroid Journal (2017) 6:3 (167-170). Date of Publication: 1 Jul 
2017
ISSN
  2235-0802 (electronic)
  2235-0640
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  Tremelimumab and ipilimumab are monoclonal antibodies directed against the 
extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) 
and have been used as immunotherapies against immune checkpoints that 
suppress T-cell activation. Anti-CTLA-4 antibody-based therapies have been 
shown to be effective in treating various cancers including metastatic 
melanoma. However, a few immune-related adverse events including 
hypophysitis and thyroid disorder have been reported, mostly developed 
within the first year of receiving treatment. We report a case of 
tremelimumab-induced Graves hyperthyroidism in a 55-year-old man who was 
diagnosed with metastatic melanoma after 8 years of tremelimumab therapy. He 
had no personal or family history of thyroid or autoimmune diseases. His 
biochemical profile was in keeping with Graves disease, with raised serum 
free thyroid hormones, suppressed thyroid-stimulating hormone concentration, 
and raised thyrotropin receptor antibody level. He was treated with 
carbimazole as part of the block and replace therapy, without complications. 
Tremelimumab therapy was temporarily discontinued and recommenced when he 
was rendered biochemically euthyroid. There has been no further relapse of 
Graves hyperthyroidism since the discontinuation of block and replace 
therapy. The mechanistic profile of anti-CTLA-4-induced thyroid dysfunction 
and the long-term endocrine safety of this therapeutic approach remain 
unclear. It is important to monitor thyroid functions in patients receiving 
anti-CTLA-4 therapies, as their effects on endocrine systems could be more 
latent or prolonged than the data from current clinical trials suggest. 
Antithyroid drug therapy was safe and effective alongside anti-CTLA-4 
therapy without compromising antitumour treatment efficacy.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ticilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  carbimazole
  cytotoxic T lymphocyte antigen 4 antibody
  levothyroxine
  liothyronine (endogenous compound)
  thyroid peroxidase antibody (endogenous compound)
  thyrotropin (endogenous compound)
  thyrotropin receptor antibody (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug induced disease (side effect, side effect)
  Graves disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  body weight loss
  case report
  disease duration
  drug withdrawal
  hormone substitution
  human
  male
  metastatic melanoma (drug therapy)
  middle aged
  priority journal
  side effect
  sinus rhythm
  thyroid function
CAS REGISTRY NUMBERS
  carbimazole (22232-54-8)
  levothyroxine (51-48-9)
  liothyronine (6138-47-2, 6893-02-3)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170498327
PUI
  L617282352
DOI
  10.1159/000464285
FULL TEXT LINK
  http://dx.doi.org/10.1159/000464285
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 7
TITLE
  Endocrine-related adverse events associated with immune checkpoint blockade 
and expert insights on their management
AUTHOR NAMES
  Sznol M.
  Postow M.A.
  Davies M.J.
  Pavlick A.C.
  Plimack E.R.
  Shaheen M.
  Veloski C.
  Robert C.
AUTHOR ADDRESSES
  (Sznol M., mario.sznol@yale.edu) Yale University School of Medicine and Yale 
Cancer Center, New Haven, United States.
(Postow M.A.) Memorial Sloan Kettering Cancer Center, New York, United 
States.
(Postow M.A.) Weill Cornell Medical College, New York, United States.
(Davies M.J.) Yale School of Nursing, West Haven, United States.
(Pavlick A.C.) New York University, New York, United States.
(Plimack E.R.; Veloski C.) Fox Chase Cancer Center, Temple Health, 
Philadelphia, United States.
(Shaheen M.) University of New Mexico, Albuquerque, United States.
(Robert C.) Gustave Roussy and Paris-Sud University, Villejuif, France.
CORRESPONDENCE ADDRESS
  M. Sznol, Department of Internal Medicine and Melanoma Unit, Yale University 
School of Medicine and Yale Cancer Center, 333 Cedar Street, FMP #126, PO 
Box 208032, New Haven, United States. Email: mario.sznol@yale.edu
SOURCE
  Cancer Treatment Reviews (2017) 58 (70-76). Date of Publication: 1 Jul 2017
ISSN
  1532-1967 (electronic)
  0305-7372
BOOK PUBLISHER
  W.B. Saunders Ltd
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
  nivolumab (adverse drug reaction, drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  endocrine disease
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  autoimmune thyroiditis (side effect)
  consultation
  diabetes mellitus (side effect)
  drug safety
  endocrine function
  endocrinologist
  hormone substitution
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  laboratory test
  melanoma (drug therapy)
  non small cell lung cancer (drug therapy)
  nonhuman
  patient monitoring
  review
  side effect (side effect)
  thyroiditis (side effect)
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170483477
MEDLINE PMID
  28689073 (http://www.ncbi.nlm.nih.gov/pubmed/28689073)
PUI
  L617159782
DOI
  10.1016/j.ctrv.2017.06.002
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ctrv.2017.06.002
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 8
TITLE
  Clinical Features of Nivolumab-Induced Thyroiditis: A Case Series Study
AUTHOR NAMES
  Yamauchi I.
  Sakane Y.
  Fukuda Y.
  Fujii T.
  Taura D.
  Hirata M.
  Hirota K.
  Ueda Y.
  Kanai Y.
  Yamashita Y.
  Kondo E.
  Sone M.
  Yasoda A.
  Inagaki N.
AUTHOR ADDRESSES
  (Yamauchi I., ichiroy@kuhp.kyoto-u.ac.jp; Sakane Y.; Fukuda Y.; Fujii T.; 
Taura D.; Hirata M.; Hirota K.; Ueda Y.; Kanai Y.; Yamashita Y.; Kondo E.; 
Sone M.; Yasoda A.; Inagaki N.) Department of Diabetes, Endocrinology and 
Nutrition, Kyoto University Graduate School of Medicine, 54 Kawaharacho, 
Shogoin Sakyo-ku Kyoto, Japan.
(Sakane Y.) Preemptive Medicine and Lifestyle Disease Research Center, Kyoto 
University Hospital, Kyoto, Japan.
CORRESPONDENCE ADDRESS
  I. Yamauchi, Department of Diabetes, Endocrinology and Nutrition, Kyoto 
University Graduate School of Medicine, 54 Kawaharacho, Shogoin Sakyo-ku 
Kyoto, Japan. Email: ichiroy@kuhp.kyoto-u.ac.jp
SOURCE
  Thyroid (2017) 27:7 (894-901). Date of Publication: 1 Jul 2017
ISSN
  1557-9077 (electronic)
  1050-7256
BOOK PUBLISHER
  Mary Ann Liebert Inc., info@liebertpub.com
ABSTRACT
  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. 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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  beta interferon (drug combination, drug therapy)
  capecitabine (drug therapy)
  carboplatin (drug combination, drug therapy)
  dacarbazine (drug combination, drug therapy)
  gemcitabine (drug combination, drug therapy)
  gimeracil plus oteracil potassium plus tegafur (drug therapy)
  glucocorticoid (drug therapy)
  levothyroxine (drug therapy)
  liothyronine (endogenous compound)
  messenger RNA (endogenous compound)
  nedaplatin (drug combination, drug therapy)
  nimustine (drug combination, drug therapy)
  paclitaxel (drug combination, drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 ligand 2 (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
  UFT (drug therapy)
  vincristine (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  clinical feature
  thyroiditis (drug therapy, side effect, drug therapy, side effect)
  thyrotoxicosis (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  breast cancer (drug therapy)
  clinical article
  drug dose increase
  drug withdrawal
  female
  free liothyronine index
  free thyroxine index
  Hashimoto disease (drug therapy)
  HeLa cell line
  hormonal therapy
  human
  human tissue
  hypothyroidism (side effect)
  liothyronine blood level
  lung cancer (drug therapy)
  male
  MCF-7 cell line
  medical record review
  melanoma (drug therapy)
  middle aged
  priority journal
  protein expression
  reverse transcription polymerase chain reaction
  thyroid gland tissue
  thyrotropin blood level
  thyroxine blood level
  Western blotting
DRUG TRADE NAMES
  s 1
  UFT
CAS REGISTRY NUMBERS
  capecitabine (154361-50-9)
  carboplatin (41575-94-4)
  dacarbazine (4342-03-4)
  gemcitabine (103882-84-4)
  levothyroxine (51-48-9)
  liothyronine (6138-47-2, 6893-02-3)
  nedaplatin (95734-82-0)
  nimustine (42471-28-3, 55661-38-6)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
  UFT (74578-38-4)
  vincristine (57-22-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170499660
PUI
  L617286789
DOI
  10.1089/thy.2016.0562
FULL TEXT LINK
  http://dx.doi.org/10.1089/thy.2016.0562
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 9
TITLE
  Epitope-specific antitumor immunity suppresses tumor spread in papillary 
thyroid cancer
AUTHOR NAMES
  Ehlers M.
  Kuebart A.
  Hautzel H.
  Enczmann J.
  Reis A.-C.
  Haase M.
  Allelein S.
  Dringenberg T.
  Schmid C.
  Schott M.
AUTHOR ADDRESSES
  (Ehlers M., margret.ehlers@med.uni-duesseldorf.de; Kuebart A.; Haase M.; 
Allelein S.; Dringenberg T.; Schmid C.; Schott M.) Division for Specific 
Endocrinology, Medical Faculty, University of Duesseldorf, Moorenstrasse 5, 
Duesseldorf, Germany.
(Hautzel H.) Clinic for Nuclear Medicine, University Hospital Duesseldorf, 
Duesseldorf, Germany.
(Enczmann J.) Institute for Transplantation Diagnostics and Cell 
Therapeutics, Germany.
(Reis A.-C.) Institute of Pathology, Medical School, Heinrich Heine 
University, Duesseldorf, Germany.
(Reis A.-C.) Institute of Pathology, University Hospital of Essen, 
University of Duisburg-Essen, Essen, Germany.
CORRESPONDENCE ADDRESS
  M. Ehlers, Division for Specific Endocrinology, Medical Faculty, University 
of Duesseldorf, Moorenstrasse 5, Duesseldorf, Germany. Email: 
margret.ehlers@med.uni-duesseldorf.de
SOURCE
  Journal of Clinical Endocrinology and Metabolism (2017) 102:7 (2154-2161). 
Date of Publication: 1 Jul 2017
ISSN
  1945-7197 (electronic)
  0021-972X
BOOK PUBLISHER
  Endocrine Society, mzendell@endo-society.org
ABSTRACT
  Context: Papillary thyroid cancer (PTC) is characterized by a lymphocytic 
infiltration. PTC patients with lymphocytic infiltration may have a better 
clinical outcome. Objective: Characterization of tumor epitope-specific 
immunity and correlation analyses with the clinical outcome. Patients: 150 
PTC patients; 40 Hashimoto thyroiditis (HT) patients; 21 healthy controls; 
27,239 healthy whites (for HLA typing). Main Outcome Measures: HLA class I 
restricted thyroperoxidase (TPO) and thyroglobulin (Tg) epitope-specific T 
cells (tetramer analyses), correlation analyses between HLA class II 
phenotypes, T cell immunity, and the clinical course. Results: The frequency 
of TPO-and Tg-specific CD8+ T cells in PTC patients was largely increased 
compared with healthy controls (TPO and Tg, P,0.005 and P,0.005) and was 
similar to those in HT patients. HLA-DQB103-positive PTC patients had a 
significantly lower risk [risk ratio (RR), 0.170; 95% confidence interval 
(CI), 0.037 to 0.755; P < 0.05] and HLA-DRB103-positive and 
HLADQB1∗02-positive PTC patients a significantly higher risk (HLA-DRB103: 
RR, 4.400; 95% CI, 1.378 to 14.05; P < 0.05; HLA-DQB102: RR, 3.692; 95% CI, 
1.102 to 12.38; P < 0.05) for distant metastases, compared with patients 
with other haplotypes. HLA-DQB103-positive PTC patients revealed an 
increased responsiveness of tumor epitopes in vitro. These tumor 
epitope-specific CD8+ T cells were also found in lymph node metastases of 
HLA-DQB103-positive PTC patients. Conclusion: We demonstrate a tumor 
epitope-specific immunity in PTC patients and the protective role of 
HLA-DQB103 against metastatic spread. These results have direct implications 
for new treatment options with immune checkpoint inhibitors.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  epitope (endogenous compound)
EMTREE DRUG INDEX TERMS
  HLA antigen class 1 (endogenous compound)
  HLA DQB1 antigen (endogenous compound)
  thyroglobulin (endogenous compound)
  thyroid peroxidase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer inhibition
  thyroid papillary carcinoma
  tumor immunity
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer localization
  cellular immunity
  controlled study
  distant metastasis
  female
  genetic association
  haplotype
  Hashimoto disease
  high risk population
  human
  in vitro study
  lymph node metastasis
  major clinical study
  male
  outcome assessment
  phenotype
  prevalence
  priority journal
  risk factor
  T lymphocyte
CAS REGISTRY NUMBERS
  thyroglobulin (9010-34-8)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170504364
MEDLINE PMID
  27860539 (http://www.ncbi.nlm.nih.gov/pubmed/27860539)
PUI
  L617314487
DOI
  10.1210/jc.2016-2469
FULL TEXT LINK
  http://dx.doi.org/10.1210/jc.2016-2469
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 10
TITLE
  Clinical Use of Programmed Cell Death-1 and Its Ligand Expression as 
Discriminatory and Predictive Markers in Ovarian Cancer
AUTHOR NAMES
  Chatterjee J.
  Dai W.
  Aziz N.H.A.
  Teo P.Y.
  Wahba J.
  Phelps D.L.
  Maine C.J.
  Whilding L.M.
  Dina R.
  Trevisan G.
  Flower K.J.
  George A.J.
  Ghaem-Maghami S.
AUTHOR ADDRESSES
  (Chatterjee J.; Dai W.; Aziz N.H.A.; Teo P.Y.; Wahba J.; Phelps D.L.; Maine 
C.J.; Whilding L.M.; Dina R.; Trevisan G.; Flower K.J.; George A.J.; 
Ghaem-Maghami S., s.ghaem-maghami@imperial.ac.uk) Imperial College London, 
4th Floor IRDB Du Cane Road, London, United Kingdom.
(George A.J.) Brunel University London, London, United Kingdom.
(Aziz N.H.A.) National University of Malaysia, Kuala Lumpur, Malaysia.
CORRESPONDENCE ADDRESS
  S. Ghaem-Maghami, Imperial College London, 4th Floor IRDB Du Cane Road, 
London, United Kingdom. Email: s.ghaem-maghami@imperial.ac.uk
SOURCE
  Clinical Cancer Research (2017) 23:13 (3453-3460). Date of Publication: 1 
Jul 2017
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  Purpose: We aimed to establish whether programmed cell death-1 (PD-1) and 
programmed cell death ligand 1 (PD-L1) expression, in ovarian cancer tumor 
tissue and blood, could be used as biomarkers for discrimination of tumor 
histology and prognosis of ovarian cancer. Experimental Design: Immune cells 
were separated from blood, ascites, and tumor tissue obtained from women 
with suspected ovarian cancer and studied for the differential expression of 
possible immune biomarkers using flow cytometry. PD-L1 expression on 
tumor-associated inflammatory cells was assessed by immunohistochemistry and 
tissue microarray. Plasma soluble PD-L1 was measured using sandwich ELISA. 
The relationships among immune markers were explored using hierarchical 
cluster analyses. Results: Biomarkers from the discovery cohort that 
associated with PD-L1(þ) cells were found. PD-L1(þ) CD14(þ) cells and 
PD-L1(þ) CD11c(þ) cells in the monocyte gate showed a distinct expression 
pattern when comparing benign tumors and epithelial ovarian cancers 
(EOCs)—confirmed in the validation cohort. Receiver operating characteristic 
curves showed PD-L1(þ) and PD-L1(þ) CD14(þ) cells in the monocyte gate 
performed better than the well-established tumor marker CA-125 alone. Plasma 
soluble PD-L1 was elevated in patients with EOC compared with healthy women 
and patients with benign ovarian tumors. Low total PD-1(þ) expression on 
lymphocytes was associated with improved survival. Conclusions: Differential 
expression of immunological markers relating to the PD-1/PD-L1 pathway in 
blood can be used as potential diagnostic and prognostic markers in EOC. 
These data have implications for the development and trial of 
anti–PD-1/PD-L1 therapy in ovarian cancer.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer (diagnosis)
  protein expression
EMTREE MEDICAL INDEX TERMS
  article
  ascites
  cancer prognosis
  cell survival
  cluster analysis
  cohort analysis
  controlled study
  disease marker
  enzyme linked immunosorbent assay
  female
  flow cytometry
  human
  human cell
  human tissue
  immunogenicity
  immunohistochemistry
  lymphocyte
  major clinical study
  priority journal
  progression free survival
  protein phosphorylation
  receiver operating characteristic
  tissue microarray
  validation study
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170482653
PUI
  L617109740
DOI
  10.1158/1078-0432.CCR-16-2366
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-16-2366
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 11
TITLE
  Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope
AUTHOR NAMES
  Lehman J.M.
  Gwin M.E.
  Massion P.P.
AUTHOR ADDRESSES
  (Lehman J.M., jonathan.m.lehman@vanderbilt.edu) Division of 
Hematology/Oncology, Department of Medicine, Vanderbilt University Medical 
Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, United 
States.
(Gwin M.E., mary.gwin@vanderbilt.edu) Vanderbilt University, PMB 353746, 
2301 Vanderbilt Place, Nashville, United States.
(Massion P.P., pierre.massion@vanderbilt.edu) Division of Allergy, 
Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt 
University Medical Center, 2220 Pierce Avenue, Preston Research Building, 
640, Nashville, United States.
(Massion P.P., pierre.massion@vanderbilt.edu) Cancer Early Detection and 
Prevention Initiative, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, 
Nashville, United States.
(Massion P.P., pierre.massion@vanderbilt.edu) US Department of Veterans 
Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue South, 
Nashville, United States.
CORRESPONDENCE ADDRESS
  P.P. Massion, Cancer Early Detection and Prevention Initiative, 
Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, United 
States. Email: pierre.massion@vanderbilt.edu
SOURCE
  Current Oncology Reports (2017) 19:7 Article Number: 49. Date of 
Publication: 1 Jul 2017
ISSN
  1534-6269 (electronic)
  1523-3790
BOOK PUBLISHER
  Current Medicine Group LLC 1, info@phl.cursci.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  alisertib (clinical trial, drug therapy)
  amrubicin (clinical trial, drug therapy)
  atezolizumab (clinical trial, drug therapy)
  barasertib (clinical trial, drug therapy)
  carboplatin (clinical trial, drug therapy)
  cisplatin (clinical trial, drug therapy)
  danusertib (clinical trial, drug therapy)
  durvalumab (clinical trial, drug therapy)
  etoposide (clinical trial, drug therapy)
  ipilimumab (clinical trial, drug therapy)
  navitoclax (clinical trial, drug therapy)
  nivolumab (clinical trial, drug therapy)
  obatoclax (clinical trial, drug therapy)
  olaparib (clinical trial, drug therapy)
  paclitaxel (clinical trial, drug therapy)
  pembrolizumab (clinical trial, drug therapy)
  rovalpituzumab tesirine (clinical trial, drug therapy)
  ticilimumab (clinical trial, drug therapy)
  topotecan (clinical trial, drug therapy)
  venetoclax (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  apoptosis
  cancer chemotherapy
  cancer mortality
  cancer radiotherapy
  carcinogenesis
  human
  immunohistochemistry
  in vitro study
  in vivo study
  multicenter study (topic)
  nonhuman
  overall survival
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  randomized controlled trial (topic)
  review
  single cell analysis
  treatment response
  tumor microenvironment
DRUG TRADE NAMES
  abt 199
  abt 263
  rova T
CAS REGISTRY NUMBERS
  alisertib (1028486-01-2, 1208255-63-3)
  amrubicin (110311-30-3)
  atezolizumab (1380723-44-3)
  barasertib (722543-31-9)
  carboplatin (41575-94-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  danusertib (827318-97-8)
  durvalumab (1428935-60-7)
  etoposide (33419-42-0, 433304-61-1)
  ipilimumab (477202-00-9)
  navitoclax (923564-51-6, 1000696-69-4, 1093851-28-5)
  nivolumab (946414-94-4)
  obatoclax (803712-67-6, 803712-79-0)
  olaparib (763113-22-0)
  paclitaxel (33069-62-4)
  pembrolizumab (1374853-91-4)
  rovalpituzumab tesirine (1613313-09-9)
  ticilimumab (745013-59-6)
  topotecan (119413-54-6, 123948-87-8)
  venetoclax (1257044-40-8)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01638546, NCT02046733, NCT02481830, NCT02538666, NCT02551432, NCT02628067, NCT02701400, NCT02734004, NCT02763579)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170456851
MEDLINE PMID
  28643173 (http://www.ncbi.nlm.nih.gov/pubmed/28643173)
PUI
  L616954875
DOI
  10.1007/s11912-017-0609-2
FULL TEXT LINK
  http://dx.doi.org/10.1007/s11912-017-0609-2
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 12
TITLE
  Safety & clinical activity of the programmed death-ligand 1 inhibitor 
durvalumab in combination with Poly (ADP-Ribose) polymerase inhibitor 
olaparib or vascular endothelial growth factor Receptor 1-3 Inhibitor 
Cediranib in Women's Cancers: A dose-escalation, phase I study
AUTHOR NAMES
  Lee J.-M.
  Cimino-Mathews A.
  Peer C.J.
  Zimmer A.
  Lipkowitz S.
  Annunziata C.M.
  Cao L.
  Harrell M.I.
  Swisher E.M.
  Houston N.
  Botesteanu D.-A.
  Taube J.M.
  Thompson E.
  Ogurtsova A.
  Xu H.
  Nguyen J.
  Ho T.W.
  Figg W.D.
  Kohn E.C.
AUTHOR ADDRESSES
  (Lee J.-M., leej6@mail.nih.gov; Peer C.J.; Zimmer A.; Lipkowitz S.; 
Annunziata C.M.; Cao L.; Houston N.; Botesteanu D.-A.; Nguyen J.; Figg W.D.; 
Kohn E.C.) Center for Cancer Research, National Cancer Institute, Bethesda, 
United States.
(Cimino-Mathews A.; Taube J.M.; Thompson E.; Ogurtsova A.; Xu H.) Johns 
Hopkins Medical Institution, Baltimore, United States.
(Ho T.W.) AstraZeneca, Gaithersburg, United States.
(Harrell M.I.; Swisher E.M.) University of Washington, Seattle, United 
States.
(Lee J.-M., leej6@mail.nih.gov) National Cancer Institute, 10 Center Dr, 
Building 10, MSC1906, Room 4B54, Bethesda, United States.
CORRESPONDENCE ADDRESS
  J.-M. Lee, National Cancer Institute, 10 Center Dr, Building 10, MSC1906, 
Room 4B54, Bethesda, United States. Email: leej6@mail.nih.gov
SOURCE
  Journal of Clinical Oncology (2017) 35:19 (2193-2202). Date of Publication: 
1 Jul 2017
ISSN
  1527-7755 (electronic)
  0732-183X
BOOK PUBLISHER
  American Society of Clinical Oncology, jcoservice@asco.org
ABSTRACT
  Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition 
and/or reduced vascular endothelial growth factor signaling by vascular 
endothelial growth factor receptor inhibition may complement antitumor 
activity of immune checkpoint blockade. We hypothesize the programmed 
death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib 
combinations are tolerable and active in recurrent women's cancers. Patients 
and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 
dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 
1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib 
on two schedules. The primary end point was the recommended phase II dose 
(RP2D). Response rate and pharmacokinetic analysis were secondary end 
points. Results Between June 2015 andMay 2016, 26womenwere enrolled. The 
RP2Dwas durvalumab 1,500mg every 4 weeks with olaparib 300 mg twice a day, 
or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was 
recorded with durvalumab plus olaparib. The cediranib intermittent schedule 
(n = 6) was examined because of recurrent grade 2 and non-dose-limiting 
toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). 
Treatment-emergent AEs included hypertension (two of eight), diarrhea (two 
of eight), pulmonary embolism(two of eight), pulmonary hypertension (one of 
eight), and lymphopenia (one of eight). Durvalumab plus intermittent 
cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one 
of six). Exposure to durvalumab increased cediranib area under the curve and 
maximum plasma concentration on the daily, but not intermittent, schedules. 
Two partial responses ($15 months and$11 months) and eight stable 
diseases$4months (median, 8 months [4 to 14.5months]) were seen in patients 
who received durvalumab plus olaparib, yielding an 83% disease control rate. 
Six partial responses ($ 5 to $ 8 months) and three stable diseases $ 
4months (4 to $ 8 months) were seen in 12 evaluable patients who received 
durvalumab plus cediranib, for a 50%response rate and a 75% disease control 
rate. Response to therapy was independent of PD-L1 expression. Conclusion To 
our knowledge, this is the first reported anti-PD-L1 plus olaparib or 
cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and 
durvalumab plus intermittent cediranib are tolerable and active. Phase II 
studies with biomarker evaluation are ongoing.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cediranib (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy, pharmacokinetics, pharmacology)
  durvalumab (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy, intravenous drug administration, pharmacokinetics, 
pharmacology)
  olaparib (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy, pharmacokinetics, pharmacology)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  alkaline phosphatase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  BRCA1 protein (endogenous compound)
  BRCA2 protein (endogenous compound)
  creatinine (endogenous compound)
  gamma interferon (endogenous compound)
  interleukin 6 (endogenous compound)
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
(endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  Rad51 protein (endogenous compound)
  vasculotropin (endogenous compound)
  vasculotropin receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antineoplastic activity
  breast cancer (drug therapy, drug therapy)
  drug safety
  ovary cancer (drug therapy, drug therapy)
  uterine cervix cancer (drug therapy, drug therapy)
  uterus cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adverse outcome
  anemia (side effect)
  anorexia (side effect)
  article
  cancer patient
  clearance at steady-state
  clinical article
  colitis (side effect)
  constipation (side effect)
  creatinine blood level
  diarrhea (side effect)
  disease course
  DNA damage
  drug withdrawal
  dysgeusia (side effect)
  dyspnea (side effect)
  fatigue (side effect)
  female
  gastroesophageal reflux (side effect)
  headache (side effect)
  histology
  hoarseness (side effect)
  homologous recombination
  human
  hypertension (side effect)
  hyperthyroidism (side effect)
  hypothyroidism (side effect)
  immunohistochemistry
  limit of quantitation
  lung embolism (side effect)
  lymphocytopenia (side effect)
  maximum tolerated dose
  nausea (side effect)
  neutropenia (side effect)
  oral mucositis (side effect)
  outcome assessment
  phase 1 clinical trial
  phenotype
  priority journal
  protein expression
  pruritus (side effect)
  pulmonary hypertension (side effect)
  rash (side effect)
  response evaluation criteria in solid tumors
  somatic mutation
  tablet
  thrombocytopenia (side effect)
  tumor associated leukocyte
  tumor differentiation
  vomiting (side effect)
DRUG TRADE NAMES
  medi 4736
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  alkaline phosphatase (9001-78-9)
  aspartate aminotransferase (9000-97-9)
  cediranib (288383-20-0, 857036-77-2)
  creatinine (19230-81-0, 60-27-5)
  durvalumab (1428935-60-7)
  gamma interferon (82115-62-6)
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
(58319-92-9)
  olaparib (763113-22-0)
  vasculotropin (127464-60-2)
  vasculotropin receptor (301253-48-5)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02484404)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170487653
MEDLINE PMID
  28471727 (http://www.ncbi.nlm.nih.gov/pubmed/28471727)
PUI
  L617109652
DOI
  10.1200/JCO.2016.72.1340
FULL TEXT LINK
  http://dx.doi.org/10.1200/JCO.2016.72.1340
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 13
TITLE
  Acute symptomatic hypocalcemia from immune checkpoint therapy-induced 
hypoparathyroidism
AUTHOR NAMES
  Win M.A.
  Thein K.Z.
  Qdaisat A.
  Yeung S.-C.J.
AUTHOR ADDRESSES
  (Win M.A.; Thein K.Z.; Qdaisat A.; Yeung S.-C.J., syeung@mdanderson.org) 
Department of Emergency Medicine, The University of Texas MD Anderson Cancer 
Center, Houston, United States.
(Thein K.Z.) Department of Hematology Oncology, Texas Tech University Health 
Sciences Center, Lubbock, United States.
(Yeung S.-C.J., syeung@mdanderson.org) Department of Endocrine Neoplasia and 
Hormonal Disorders, The University of Texas MD Anderson Cancer Center, 
Houston, United States.
CORRESPONDENCE ADDRESS
  S.-C.J. Yeung, Department of Emergency Medicine, Unit 1468, The University 
of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, United 
States. Email: syeung@mdanderson.org
SOURCE
  American Journal of Emergency Medicine (2017) 35:7 (1039.e5-1039.e7). Date 
of Publication: 1 Jul 2017
ISSN
  1532-8171 (electronic)
  0735-6757
BOOK PUBLISHER
  W.B. Saunders
ABSTRACT
  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. 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 1.5 months 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 4 months 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. 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.
EMTREE DRUG INDEX TERMS
  calcifediol (endogenous compound)
  calcitriol (drug therapy)
  calcium carbonate (drug therapy, oral drug administration)
  calcium ion (endogenous compound)
  ergocalciferol (drug therapy, oral drug administration)
  gluconate calcium (drug therapy, intravenous drug administration)
  ipilimumab (drug therapy)
  levothyroxine (oral drug administration)
  magnesium sulfate (intravenous drug administration)
  nivolumab (drug therapy)
  parathyroid hormone (endogenous compound)
  thyroid peroxidase antibody (endogenous compound)
  thyrotropin (endogenous compound)
  vitamin D (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypocalcemia (drug therapy, drug therapy)
  hypoparathyroidism
EMTREE MEDICAL INDEX TERMS
  abdominal cramp
  abdominal pain
  abdominal radiography
  aged
  anxiety
  article
  ataxia
  autoimmune thyroiditis
  cancer immunotherapy
  case report
  electrocardiography
  emergency ward
  free thyroxine index
  Graves disease
  heart right bundle branch block
  hormone substitution
  hospitalization
  human
  hypercalciuria
  hyperphosphatemia
  hypomagnesemia
  hypothyroidism
  laboratory test
  male
  metastatic melanoma (drug therapy)
  muscle weakness
  neuroimaging
  nuclear magnetic resonance imaging
  parathyroid function
  parathyroid hormone blood level
  paresthesia
  priority journal
  QTc interval
  tachycardia
  thyrotoxicosis
  urine sampling
CAS REGISTRY NUMBERS
  calcifediol (19356-17-3)
  calcitriol (32222-06-3, 32511-63-0, 66772-14-3)
  calcium carbonate (13397-26-7, 13701-58-1, 14791-73-2, 471-34-1)
  calcium ion (14127-61-8)
  ergocalciferol (50-14-6, 50809-47-7, 8042-78-2)
  gluconate calcium (299-28-5)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  magnesium sulfate (7487-88-9)
  nivolumab (946414-94-4)
  parathyroid hormone (12584-96-2, 68893-82-3, 9002-64-6)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170249724
MEDLINE PMID
  28363614 (http://www.ncbi.nlm.nih.gov/pubmed/28363614)
PUI
  L615174347
DOI
  10.1016/j.ajem.2017.02.048
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ajem.2017.02.048
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 14
TITLE
  Prolactin as a Potential Early Predictive Factor in Metastatic Non-Small 
Cell Lung Cancer Patients Treated with Nivolumab
AUTHOR NAMES
  Caponnetto S.
  Iannantuono G.M.
  Barchiesi G.
  Magri V.
  Gelibter A.
  Cortesi E.
AUTHOR ADDRESSES
  (Caponnetto S., salvo.caponnetto@uniroma1.it; Iannantuono G.M.; Barchiesi 
G.; Magri V.; Gelibter A.; Cortesi E.) Division of Medical Oncology, 
Department of Radiological, Oncological, and Pathological Sciences, Sapienza 
University, Viale del Policlinico 155, Rome, Italy.
SOURCE
  Oncology (Switzerland) (2017) 93:1 (62-66). Date of Publication: 1 Jul 2017
ISSN
  1423-0232 (electronic)
  0030-2414
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  Background/Aims: Prolactin (PRL) is a peptide hormone and several studies 
have demonstrated its role as a cytokine in human T cell-mediated immunity. 
We are unaware if PRL is a positive or negative immunomodulator, but its 
effects on the regulation of T cells could inhibit the antitumor activity 
elicited by nivolumab (NIVO). We aimed to assess whether the occurrence of 
hyperprolactinemia in metastatic non-small cell lung cancer (mNSCLC) 
patients treated with NIVO is associated with poor clinical outcomes. 
Methods: We evaluated 26 mNSCLC patients treated with NIVO. Blood samples 
were collected in every patient to evaluate PRL basal levels before starting 
the therapy with NIVO and before each following administration of NIVO. All 
patients underwent a conventional CT to investigate the effect of therapy 
according to Immune-related Response Evaluation Criteria in Solid Tumors 
(IrRECIST). Results: Twenty patients (77%) developed hyperprolactinemia 
during the treatment, whereas 6 patients (23%) had stable levels of PRL 
during the therapy (p = 0.001). A total of 95% of the 20 patients with 
hyperprolactinemia had progressive disease (PD), according to CT results, 
whereas only 2 patients (33%) out of 6 with stable PRL levels had PD (p = 
0.004). Conclusions: Hyperprolactinemia in mNSCLC patients treated with NIVO 
could potentially represent a negative early predictive factor for poor 
clinical outcomes, thus anticipating PD shown by CT scan.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
  prolactin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hyperprolactinemia (side effect, side effect)
  metastatic non small cell lung cancer (drug therapy, drug therapy)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer growth
  cancer prognosis
  clinical article
  computer assisted tomography
  female
  human
  male
  observational study
  priority journal
  prospective study
  risk factor
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170288225
PUI
  L615577067
DOI
  10.1159/000464328
FULL TEXT LINK
  http://dx.doi.org/10.1159/000464328
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 15
TITLE
  Nivolumab-induced myasthenia gravis in a patient with squamous cell lung 
carcinoma
AUTHOR NAMES
  Chen Y.-H.
  Liu F.-C.
  Hsu C.-H.
  Chian C.-F.
AUTHOR ADDRESSES
  (Chen Y.-H.; Liu F.-C.) Division of Rheumatology/Immunology/Allergy, 
Department of Medicine, Tri-Service General Hospital, National Defense 
Medical Center, Mexico.
(Hsu C.-H.) Department of Neurology, Tri-Service General Hospital, National 
Defense Medical Center, Taiwan.
(Chian C.-F., sonice3982@gmail.com) Division of Pulmonary Medicine, 
Department of Medicine, Tri-Service General Hospital, National Defense 
Medical Center, No. 325 Cheng-Gong Rd, Taipei, Taiwan.
CORRESPONDENCE ADDRESS
  C.-F. Chian, Division of Pulmonary Medicine, Department of Medicine, 
Tri-Service General Hospital, National Defense Medical Center, No. 325 
Cheng-Gong Rd, Taipei, Taiwan. Email: sonice3982@gmail.com
SOURCE
  Medicine (United States) (2017) 96:27 Article Number: e7350. Date of 
Publication: 1 Jul 2017
ISSN
  1536-5964 (electronic)
  0025-7974
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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. 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. 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. 
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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  carbon dioxide
  CD4 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  cholinergic receptor antibody (endogenous compound)
  cisplatin (drug combination, drug therapy)
  creatine kinase (endogenous compound)
  gemcitabine (drug combination, drug therapy)
  lactate dehydrogenase (endogenous compound)
  methylprednisolone (drug therapy)
  muscle enzyme (endogenous compound)
  paclitaxel (drug combination, drug therapy)
  pyridostigmine
  steroid
  troponin I (endogenous compound)
  vinorelbine tartrate (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  myasthenia gravis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
  squamous cell lung carcinoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal radiography
  aged
  article
  blood gas analysis
  botulism
  cancer combination chemotherapy
  cancer immunotherapy
  cancer radiotherapy
  cancer staging
  case report
  cause of death
  chemoradiotherapy
  chronic obstructive lung disease (diagnosis)
  diplopia (side effect)
  disease course
  drug exposure
  drug infusion
  drug treatment failure
  dysphagia
  electromyography
  eye movement disorder
  hospital admission
  human
  hypercapnia (side effect)
  hypersalivation
  limb weakness (side effect)
  lymphadenopathy
  male
  mechanical ventilator
  medical history
  muscle strength
  muscle weakness (side effect)
  myasthenia
  myositis (diagnosis, side effect)
  nerve conduction velocity test
  neuroimaging
  neuromuscular junction disorder
  nuclear magnetic resonance imaging
  outcome assessment
  partial pressure
  peripheral lymphocyte
  physical examination
  plasma exchange
  polyneuropathy
  priority journal
  provocation test
  ptosis (side effect)
  respiratory failure
  side effect (side effect)
  smoking
  thoracic aorta
  transthoracic echocardiography
  treatment duration
  treatment planning
  treatment refusal
  treatment response
DRUG TRADE NAMES
  gemzar
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  carbon dioxide (124-38-9, 58561-67-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  creatine kinase (9001-15-4)
  gemcitabine (103882-84-4)
  lactate dehydrogenase (9001-60-9)
  methylprednisolone (6923-42-8, 83-43-2)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  pyridostigmine (101-26-8, 155-97-5)
  troponin I (77108-40-8)
  vinorelbine tartrate (125317-39-7, 71486-22-1)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170491556
MEDLINE PMID
  28682883 (http://www.ncbi.nlm.nih.gov/pubmed/28682883)
PUI
  L617243433
DOI
  10.1097/MD.0000000000007350
FULL TEXT LINK
  http://dx.doi.org/10.1097/MD.0000000000007350
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 16
TITLE
  FDA approval summary: Pembrolizumab for the treatment of recurrent 
ormetastatic head and neck squamous cell carcinoma with disease progression 
on or after platinum-containing chemotherapy
AUTHOR NAMES
  Larkins E.
  Blumenthal G.M.
  Yuan W.
  He K.
  Sridhara R.
  Subramaniam S.
  Zhao H.
  Liu C.
  Yu J.
  Goldberg K.B.
  McKee A.E.
  Keegan P.
  Pazdur R.
AUTHOR ADDRESSES
  (Larkins E., erin.larkins@fda.hhs.gov; Blumenthal G.M.; Yuan W.; He K.; 
Sridhara R.; Subramaniam S.; Zhao H.; Liu C.; Yu J.; Goldberg K.B.; McKee 
A.E.; Keegan P.; Pazdur R.) Office of Hematology and Oncology Products, 
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 
Silver Spring, United States.
CORRESPONDENCE ADDRESS
  E. Larkins, U.S. Food and Drug Administration, WO22/2346, 10903 New 
Hampshire Avenue, Silver Spring, United States. Email: 
erin.larkins@fda.hhs.gov
SOURCE
  Oncologist (2017) 22:7 (873-878). Date of Publication: 1 Jul 2017
ISSN
  1549-490X (electronic)
  1083-7159
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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 2.41 months to 27.71 
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 
benefitrisk 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy, 
intravenous drug administration)
  platinum
EMTREE DRUG INDEX TERMS
  cetuximab
  methotrexate
  taxane derivative
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer chemotherapy
  head and neck squamous cell carcinoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adjuvant therapy
  adrenal insufficiency (side effect)
  adult
  aged
  article
  asthenia (side effect)
  clinical trial
  confusion (side effect)
  controlled study
  decreased appetite (side effect)
  diabetes mellitus (side effect)
  disease course
  drug efficacy
  drug safety
  drug withdrawal
  dyspnea (side effect)
  face edema (side effect)
  fatigue (side effect)
  female
  hepatitis (side effect)
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  incidence
  major clinical study
  male
  metastatic melanoma
  multicenter study
  myositis (side effect)
  nephritis (side effect)
  pleura effusion (side effect)
  pneumonia (side effect)
  priority journal
  respiratory failure (side effect)
  risk management
  skin toxicity (side effect)
  thyroiditis (side effect)
  vomiting (side effect)
DRUG TRADE NAMES
  keytruda  , United StatesMerck Sharp and Dohme

DRUG MANUFACTURERS
   (United States)Merck Sharp and Dohme
CAS REGISTRY NUMBERS
  cetuximab (205923-56-4)
  methotrexate (15475-56-6, 59-05-2, 7413-34-5)
  pembrolizumab (1374853-91-4)
  platinum (7440-06-4)
EMBASE CLASSIFICATIONS
  Otorhinolaryngology (11)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01848834, NCT02252042, NCT02255097)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170513679
MEDLINE PMID
  28533473 (http://www.ncbi.nlm.nih.gov/pubmed/28533473)
PUI
  L617280300
DOI
  10.1634/theoncologist.2016-0496
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2016-0496
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 17
TITLE
  A case of secondary adrenocortical insufficiency developed due to ACTH 
deficiency after nivolumab treatment
AUTHOR NAMES
  Saijo T.
  Tanaka A.
  Ito T.
  Ikeda N.
AUTHOR ADDRESSES
  (Saijo T.; Tanaka A.) Department of Internal Medicine, Toda Central General 
Hospital, Japan.
(Ito T.) Department of Thoracic Surgery, Toda Central General Hospital, 
Japan.
(Ikeda N.) Department of Thoracic Surgery, Tokyo Medical University 
Hospital, Japan.
CORRESPONDENCE ADDRESS
  T. Saijo, Department of Internal Medicine, Toda Central General Hospital, 
Japan.
SOURCE
  Japanese Journal of Lung Cancer (2017) 57:3 (226-231). Date of Publication: 
20 Jun 2017
ISSN
  0386-9628
BOOK PUBLISHER
  Japan Lung Cancer Society, office@haigan.gr.jp
ABSTRACT
  Background. Nivolumab, an anti-programmed death-1 specific monoclonal 
antibody, has become a standard second-line chemotherapy agent for 
metastatic non-small cell lung cancer (NSCLC). Nivolumab induces several 
autoimmune adverse events, defined as immune-related adverse events (irAEs). 
Two cases of adrenocortical insufficiency have been experienced in Japanese 
investigational drug trials against NSCLC, but the details have not yet been 
published. No such cases have been reported in global clinical trials. This 
is the first case report of ACTH deficiency associated with secondary 
adrenocortical insufficiency induced by nivolumab in practical use for 
metastatic NSCLC. Case. A 65-year-old man with stage HIB lung squamous cell 
carcinoma was treated with nivolumab as second-line therapy. After 12 cycles 
of nivolumab, the patient developed appetite loss, general fatigue, low 
blood pressure and body weight loss. These symptoms were strongly suggested 
to be related to adrenocortical insufficiency. Endocrinological examinations 
suggested isolated ACTH deficiency. The symptoms of appetite loss and 
general fatigue were improved, and the blood pressure was normalized soon 
after the initiation of treatment with prednisolone. Two weeks later, the 
performance status (PS) dramatically improved when the patient was 
discharged. Conclusion. This is the first report of nivolumab-induced ACTH 
deficiency associated with secondary adrenocortical insufficiency 
demonstrated by endocrinological tests in practical use for metastatic 
NSCLC. irAEs, which are associated with immune checkpoint inhibitors, vary 
in presentation and can be difficult to diagnose. Such events should be 
carefully checked for in order to ensure their timely management. It may be 
wise to perform blood biochemical examinations at baseline and before the 
administration of each nivolumab dose.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  prednisolone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adrenal cortex insufficiency (complication)
  corticotropin deficiency (drug therapy, side effect, diagnosis, drug 
therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  body weight loss
  cancer staging
  case report
  endocrine system examination
  fatigue (side effect)
  functional status assessment
  human
  hypotension (side effect)
  loss of appetite (side effect)
  male
  multiple cycle treatment
  side effect (side effect)
  squamous cell lung carcinoma (drug therapy)
  treatment duration
  treatment outcome
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
  prednisolone (50-24-8)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170483059
PUI
  L617187010
DOI
  10.2482/haigan.57.226
FULL TEXT LINK
  http://dx.doi.org/10.2482/haigan.57.226
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 18
TITLE
  Identification of repaglinide as a therapeutic drug for glioblastoma 
multiforme
AUTHOR NAMES
  Xiao Z.X.
  Chen R.Q.
  Hu D.X.
  Xie X.Q.
  Yu S.B.
  Chen X.Q.
AUTHOR ADDRESSES
  (Xiao Z.X.) Department of Endocrinology, Jingzhou First People's Hospital, 
The First Clinical Medical College, Yangtze University, Jingzhou, China.
(Chen R.Q.) School of Basic Medicine, Tongji Medical College, Huazhong 
University of Science and Technology, Wuhan, China.
(Hu D.X.; Yu S.B., yushangbin@tjmu.edu.cn; Chen X.Q.) 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, China.
(Xie X.Q.) Department of Pathology, Jingzhou Central Hospital, The Second 
Clinical Medical College, Yangtze University, Jingzhou, China.
CORRESPONDENCE ADDRESS
  X.Q. Xie, Department of Pathology, Jingzhou Central Hospital, The Second 
Clinical Medical College, Yangtze University, Jingzhou, China. Email: 
slideabc@hotmail.com
SOURCE
  Biochemical and Biophysical Research Communications (2017) 488:1 (33-39). 
Date of Publication: 17 Jun 2017
ISSN
  1090-2104 (electronic)
  0006-291X
BOOK PUBLISHER
  Elsevier B.V., apjcs@harcourt.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  repaglinide (drug analysis, drug therapy, intraperitoneal drug 
administration, pharmacology)
EMTREE DRUG INDEX TERMS
  beclin 1 (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  protein bcl 2 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug identification
  glioblastoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  animal experiment
  animal model
  antineoplastic activity
  apoptosis
  article
  autophagy
  cell migration
  cell proliferation
  diabetes mellitus (drug therapy)
  drug repositioning
  drug screening
  extracellular matrix
  gene expression
  glioma
  human
  human cell
  in vitro study
  in vivo study
  major clinical study
  median survival time
  mouse
  nonhuman
  priority journal
  protein binding
CAS REGISTRY NUMBERS
  protein bcl 2 (219306-68-0)
  repaglinide (135062-02-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170325058
PUI
  L615952396
DOI
  10.1016/j.bbrc.2017.04.157
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.bbrc.2017.04.157
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 19
TITLE
  PD-1 blockade with nivolumab in relapsed/refractory primary central nervous 
system and testicular lymphoma
AUTHOR NAMES
  Nayak L.
  Iwamoto F.M.
  Lacasce A.
  Mukundan S.
  Roemer M.G.M.
  Chapuy B.
  Armand P.
  Rodig S.J.
  Shipp M.A.
AUTHOR ADDRESSES
  (Nayak L., lakshmi_nayak@dfci.harvard.edu; Lacasce A.; Mukundan S.; Roemer 
M.G.M.; Chapuy B.; Armand P.; Rodig S.J.; Shipp M.A.) Dana-Farber Cancer 
Institute, 450 Brookline Ave, DA 2120, Boston, United States.
(Nayak L., lakshmi_nayak@dfci.harvard.edu; Lacasce A.; Mukundan S.; Armand 
P.; Rodig S.J.; Shipp M.A.) Brigham and Women’s Hospital, Boston, United 
States.
(Iwamoto F.M.) New York Presbyterian Hospital, New York, United States.
CORRESPONDENCE ADDRESS
  L. Nayak, Dana-Farber Cancer Institute, 450 Brookline Ave, DA 2120, Boston, 
United States. Email: lakshmi_nayak@dfci.harvard.edu
SOURCE
  Blood (2017) 129:23 (3071-3073). Date of Publication: 8 Jun 2017
ISSN
  1528-0020 (electronic)
  0006-4971
BOOK PUBLISHER
  American Society of Hematology, publishing@hematology.org
ABSTRACT
  Primary central nervous system (CNS) lymphoma (PCNSL) and primary testicular 
lymphoma (PTL) are rare extranodal large B-cell lymphomas with similar 
genetic signatures. There are no standard-of-care treatment options for 
patients with relapsed and refractory PCNSL and PTL, and the overall 
prognosis is poor. PCNSLs and PTLs exhibit frequent 9p24.1 copy-number 
alterations and infrequent translocations of 9p24.1 and associated increased 
expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and 
PD-L2. The activity of PD-1 blockade in other lymphomas with 9p24.1 
alterations prompted us to test the efficacy of the anti–PD1 antibody, 
nivolumab, in 4 patients with relapsed/refractory PCNSL and 1 patient with 
CNS relapse of PTL. All 5 patients had clinical and radiographic responses 
to PD-1 blockade, and 3 patients remain progression-free at 13(1) to 17(1) 
months. Our data suggest that nivolumab is active in relapsed/refractory 
PCNSL and PTL and support further investigation of PD-1 blockade in these 
diseases. (Blood. 2017;129(23): 3071-3073)
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy, intraocular drug 
administration, intravenous drug administration)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  cytarabine (drug therapy)
  dexamethasone (drug therapy, oral drug administration)
  methotrexate (drug therapy)
  pemetrexed (drug therapy)
  rituximab (drug therapy)
  thiotepa (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer chemotherapy
  large cell lymphoma (drug therapy, drug therapy, therapy)
  primary central nervous system lymphoma (drug therapy, drug therapy, 
radiotherapy)
  primary testicular lymphoma (drug therapy, drug therapy, therapy)
  testis cancer (drug therapy, drug therapy, therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  autologous stem cell transplantation
  brain radiography
  cancer radiotherapy
  cancer recurrence
  cancer surgery
  cancer survival
  cancer transplantation
  clinical article
  corticosteroid therapy
  dose response
  drug dose reduction
  drug efficacy
  drug megadose
  drug safety
  drug targeting
  drug withdrawal
  fatigue (side effect)
  hemodialysis
  human
  human tissue
  intraocular lymphoma (radiotherapy, surgery)
  kidney biopsy
  kidney failure (side effect, therapy)
  male
  off label drug use
  priority journal
  progression free survival
  pruritus (side effect)
  treatment response
  urogenital tract radiography
  vitrectomy
  whole brain radiotherapy
CAS REGISTRY NUMBERS
  cytarabine (147-94-4, 69-74-9)
  dexamethasone (50-02-2)
  methotrexate (15475-56-6, 59-05-2, 7413-34-5)
  nivolumab (946414-94-4)
  pemetrexed (137281-23-3, 150399-23-8)
  rituximab (174722-31-7)
  thiotepa (52-24-4)
EMBASE CLASSIFICATIONS
  Hematology (25)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170430050
MEDLINE PMID
  28356247 (http://www.ncbi.nlm.nih.gov/pubmed/28356247)
PUI
  L616780322
DOI
  10.1182/blood-2017-01-764209
FULL TEXT LINK
  http://dx.doi.org/10.1182/blood-2017-01-764209
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 20
TITLE
  Immune-related alopecia (areata and universalis) in cancer patients 
receiving immune checkpoint inhibitors
AUTHOR NAMES
  Zarbo A.
  Belum V.R.
  Sibaud V.
  Oudard S.
  Postow M.A.
  Hsieh J.J.
  Motzer R.J.
  Busam K.J.
  Lacouture M.E.
AUTHOR ADDRESSES
  (Zarbo A.) Department of Dermatology and Transitional Year Program, Henry 
Ford Hospital, Detroit, United States.
(Belum V.R.; Lacouture M.E., lacoutum@mskcc.org) Department of Dermatology 
Service, Memorial Sloan Kettering Cancer Center, 60th Street Outpatient 
Center, Suite 407, Room 4315 16 East 60th Street, New York, United States.
(Sibaud V.) Department of Oncodermatology, Institut Universitaire du Cancer, 
Toulouse Oncopole, Toulouse, France.
(Oudard S.) Department of Medical Oncology, Hôpital Européen Georges 
Pompidou, Assistance Publique Hôpitaux de Paris, , France.
(Postow M.A.) Melanoma & Immunotherapeutics Service, Weill Cornell Medical 
College, New York, United States.
(Hsieh J.J.; 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, United States.
(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, United States.
CORRESPONDENCE ADDRESS
  M.E. Lacouture, Department of Dermatology Service, Memorial Sloan Kettering 
Cancer Center, 60th Street Outpatient Center, Suite 407, Room 4315 16 East 
60th Street, New York, United States. Email: lacoutum@mskcc.org
SOURCE
  British Journal of Dermatology (2017) 176:6 (1649-1652). Date of 
Publication: 1 Jun 2017
ISSN
  1365-2133 (electronic)
  0007-0963
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction, drug therapy)
  cytotoxic T lymphocyte antigen 4 receptor inhibitor (adverse drug reaction, 
drug therapy)
  pd 1 receptor inhibitor (adverse drug reaction, drug therapy)
  vasculotropin inhibitor (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  biotin
  clobetasol (drug therapy, topical drug administration)
  hemoglobin (endogenous compound)
  infliximab (drug therapy)
  manganese (endogenous compound)
  silicic acid
  steroid (drug therapy)
  thyroxine (endogenous compound)
  triamcinolone (drug therapy, intralesional drug administration)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  alopecia (drug therapy, side effect, drug therapy, side effect)
  alopecia areata (side effect, side effect)
  alopecia universalis (side effect, side effect)
  cancer patient
  immunotherapy
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  anemia
  article
  case report
  colitis (drug therapy)
  diabetes mellitus (complication)
  erythrocyte sedimentation rate
  female
  follow up
  hair growth
  hematocrit
  hemoglobin blood level
  human
  human tissue
  hypertransaminasemia (side effect)
  hypervitaminosis
  kidney carcinoma (drug therapy)
  liver metastasis (drug therapy)
  lung metastasis (drug therapy)
  male
  manganese blood level
  metastatic melanoma (drug therapy)
  middle aged
  multiple cycle treatment
  nail dystrophy
  onycholysis (side effect)
  pancreas metastasis (drug therapy)
  priority journal
  pruritus (side effect)
  rash (side effect)
  skin biopsy
  steroid therapy
  thyroxine blood level
  topical treatment
CAS REGISTRY NUMBERS
  biotin (58-85-5)
  clobetasol (25122-41-2)
  hemoglobin (9008-02-0)
  infliximab (170277-31-3)
  manganese (16397-91-4, 7439-96-5)
  silicic acid (10193-36-9, 1343-98-2)
  thyroxine (7488-70-2)
  triamcinolone (124-94-7)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170297071
PUI
  L615654893
DOI
  10.1111/bjd.15237
FULL TEXT LINK
  http://dx.doi.org/10.1111/bjd.15237
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 21
TITLE
  Exceptional response to nivolumab and stereotactic body radiation therapy 
(SBRT) in neuroendocrine cervical carcinoma with high tumormutational 
burden: Management considerations from the center for personalized cancer 
therapy at UC San Diego moores cancer center
AUTHOR NAMES
  Sharabi A.
  Kim S.S.
  Kato S.
  Sanders P.D.
  Patel S.P.
  Sanghvi P.
  Weihe E.
  Kurzrock R.
AUTHOR ADDRESSES
  (Sharabi A., sharabi@ucsd.edu; Sanders P.D.; Sanghvi P.) Department of 
Radiation Medicine and Applied Sciences, San Diego, United States.
(Kato S.; Patel S.P.; Kurzrock R.) Division of Hematology & Oncology and 
Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, 
San Diego, United States.
(Kim S.S.) School of Medicine, University of California, San Diego, United 
States.
(Weihe E.) Department of Radiology, University of California, San Diego, 
United States.
CORRESPONDENCE ADDRESS
  A. Sharabi, Department of Radiation Medicine and Applied Sciences, 
University of California San Diego, 3960 Health Sciences Dr., La Jolla, 
United States. Email: sharabi@ucsd.edu
SOURCE
  Oncologist (2017) 22:6 (631-637). Date of Publication: 1 Jun 2017
ISSN
  1549-490X (electronic)
  1083-7159
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (drug combination, drug therapy, intravenous drug administration)
  octreotide (drug combination, drug therapy, subcutaneous drug 
administration)
EMTREE DRUG INDEX TERMS
  CD99 antigen
  cisplatin
  etoposide
  programmed death 1 receptor
  synaptophysin
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  neuroendocrine disease (drug therapy, drug therapy)
  uterine cervix carcinoma
EMTREE MEDICAL INDEX TERMS
  adult
  article
  case report
  cell death
  computer assisted tomography
  female
  Hodgkin disease
  human
  hydronephrosis
  intestine obstruction
  liquid biopsy
  lymphadenopathy
  microsatellite instability
  middle aged
  mismatch repair
  next generation sequencing
  priority journal
  retrospective study
  stereotactic body radiation therapy
  tumor regression
  tumor volume
  uterus myoma
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  etoposide (33419-42-0, 433304-61-1)
  nivolumab (946414-94-4)
  octreotide (83150-76-9, 1607842-55-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Neurology and Neurosurgery (8)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02257528, NCT02478931, NCT02834013, NCT02843165)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170441751
MEDLINE PMID
  28550027 (http://www.ncbi.nlm.nih.gov/pubmed/28550027)
PUI
  L616783030
DOI
  10.1634/theoncologist.2016-0517
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2016-0517
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 22
TITLE
  FDA approval summary: Atezolizumab for the treatment of patients with 
progressive advanced urothelial carcinoma after platinum-containing 
chemotherapy
AUTHOR NAMES
  Ning Y.-M.
  Suzman D.
  Maher V.E.
  Zhang L.
  Tang S.
  Ricks T.
  Palmby T.
  Fu W.
  Liu Q.
  Goldberg K.B.
  Kim G.
  Pazdur R.
AUTHOR ADDRESSES
  (Ning Y.-M., ningy@cder.fda.gov; Suzman D.; Maher V.E.; Zhang L.; Tang S.; 
Ricks T.; Palmby T.; Fu W.; Liu Q.; Goldberg K.B.; Kim G.; Pazdur R.) Center 
for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver 
Springs, United States.
CORRESPONDENCE ADDRESS
  Y.-M. Ning, Office of Hematology and Oncology Products, Center for Drug 
Evaluation and Research, Food and Drug Administration, Building 22, Room 
2139, 10903 New Hampshire Avenue, Silver Spring, United States. Email: 
ningy@cder.fda.gov
SOURCE
  Oncologist (2017) 22:6 (743-748). Date of Publication: 1 Jun 2017
ISSN
  1549-490X (electronic)
  1083-7159
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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 
platinumcontaining 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).
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  atezolizumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
  platinum
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  alkaline phosphatase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  carboplatin
  cisplatin
  prednisolone
  programmed death 1 ligand 1
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  food and drug administration
  transitional cell carcinoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adjuvant chemotherapy
  aged
  anemia (side effect)
  article
  backache (side effect)
  cancer infiltration
  clinical outcome
  colitis (side effect)
  constipation (side effect)
  creatinine clearance
  diabetes mellitus (side effect)
  diarrhea (side effect)
  disease course
  drug efficacy
  drug megadose
  drug safety
  drug withdrawal
  dyspnea (side effect)
  fatigue (side effect)
  female
  fever (side effect)
  hematuria (side effect)
  hepatitis (side effect)
  human
  hypersensitivity (side effect)
  hypoalbuminemia (side effect)
  hyponatremia (side effect)
  hypothyroidism (side effect)
  immunotherapy
  intestine obstruction (side effect)
  loss of appetite (side effect)
  lymph node metastasis
  lymphocytopenia (side effect)
  major clinical study
  male
  nausea (side effect)
  neck pain (side effect)
  open study
  osteomyelitis (side effect)
  pneumonia (side effect)
  priority journal
  protein expression
  rash (side effect)
  risk management
  sepsis (side effect)
  side effect (side effect)
  skin infection (side effect)
  thyroid function
  thyroiditis (side effect)
  treatment duration
  urinary tract infection (side effect)
  visceral metastasis
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  alkaline phosphatase (9001-78-9)
  aspartate aminotransferase (9000-97-9)
  atezolizumab (1380723-44-3)
  carboplatin (41575-94-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  platinum (7440-06-4)
  prednisolone (50-24-8)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02108652)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170441752
MEDLINE PMID
  28424325 (http://www.ncbi.nlm.nih.gov/pubmed/28424325)
PUI
  L616783052
DOI
  10.1634/theoncologist.2017-0087
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2017-0087
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 23
TITLE
  Biologics in gastrointestinal and pancreatic neuroendocrine tumors
AUTHOR NAMES
  Liu I.H.
  Kunz P.L.
AUTHOR ADDRESSES
  (Liu I.H.; Kunz P.L., pkunz@stanford.edu) Stanford University School of 
Medicine, Stanford, United States.
CORRESPONDENCE ADDRESS
  P.L. Kunz, Stanford Cancer Institute, 875 Blake Wilbur Drive, Stanford, 
United States. Email: pkunz@stanford.edu
SOURCE
  Journal of Gastrointestinal Oncology (2017) 8:3 (457-465). Date of 
Publication: 1 Jun 2017
ISSN
  2219-679X (electronic)
  2078-6891
BOOK PUBLISHER
  AME Publishing Company, jtd@thepbpc.org
ABSTRACT
  The development of biologic agents has ushered in a new era of precision 
medicine, opening the door to new therapeutic options designed to 
intelligently target cancer cells and their promoting factors, while leaving 
normal cells relatively unharmed. Biologics for the treatment of 
neuroendocrine tumors (NETs) have followed in the footsteps of regimens 
targeting pathways upregulated in other cancers, including the vascular 
endothelial growth factor (VEGF) and the mammalian target of rapamycin 
(mTOR). Through a number of clinical trials, the mTOR inhibitor everolimus 
and the receptor tyrosine kinase (RTK) inhibitor sunitinib were recently 
approved for NETs. Other biologics such as the VEGF-A inhibitor bevacizumab 
have also demonstrated promising clinical activity in NETs. Interestingly, 
though trials have demonstrated the efficacy of everolimus and sunitinib in 
extending progression-free survival (PFS) in NETs, objective response rates 
(RR) are uniformly low, indicating that the primary effect of these drugs is 
maintenance of stable disease. Due to the relatively indolent nature of the 
more common, well-differentiated variety of NETs, stable disease is often a 
reasonable goal for NET patients. Well-differentiated NETs have been shown 
to be poor responders to cytotoxic chemotherapy, underlining the important 
role of biologics in treating and managing NETs and their hormonal symptoms. 
Ongoing and future trials are investigating a wide variety of biologic 
compounds in NETs, including other RTK inhibitors, mTOR pathway inhibitors, 
and immune checkpoint inhibitors. Within this review, we will discuss major 
trials leading up to the FDA approval of everolimus and sunitinib for NETs, 
as well as other promising biologics currently under investigation in NET 
clinical trials
EMTREE DRUG INDEX TERMS
  alpha interferon (adverse drug reaction, drug therapy)
  bevacizumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  capecitabine (clinical trial, drug combination, drug therapy)
  everolimus (adverse drug reaction, clinical trial, drug combination, drug 
comparison - placebo, drug therapy, pharmacology)
  fluorouracil (drug combination, drug therapy)
  folinic acid (drug combination, drug therapy)
  mammalian target of rapamycin (endogenous compound)
  octreotide (adverse drug reaction, drug combination, drug comparison - 
placebo, intramuscular drug administration)
  oxaliplatin (clinical trial, drug combination, drug therapy)
  placebo
  sunitinib (adverse drug reaction, clinical trial, drug comparison - placebo, 
drug therapy, oral drug administration, pharmacology)
  temsirolimus (intravenous drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gastroenteropancreatic neuroendocrine tumor (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  asthenia (side effect)
  cancer combination chemotherapy
  cancer prognosis
  cancer survival
  cell growth
  clinical trial (topic)
  diarrhea (side effect)
  drug approval
  drug efficacy
  drug mechanism
  drug response
  fatigue (side effect)
  food and drug administration
  growth inhibition
  human
  hyperglycemia (side effect)
  hypertension (side effect)
  hyponatremia (side effect)
  hypophosphatemia (side effect)
  lymphocytopenia (side effect)
  nausea (side effect)
  neutropenia (side effect)
  overall survival
  phase 3 clinical trial (topic)
  protein expression
  proteinuria (side effect)
  randomized controlled trial (topic)
  rash (side effect)
  review
  stomatitis (side effect)
  survival rate
  thrombocytopenia (side effect)
  treatment outcome
  vomiting (side effect)
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  capecitabine (154361-50-9)
  everolimus (159351-69-6)
  fluorouracil (51-21-8)
  folinic acid (58-05-9)
  octreotide (83150-76-9, 1607842-55-6)
  oxaliplatin (61825-94-3)
  sunitinib (341031-54-7, 557795-19-4)
  temsirolimus (162635-04-3, 343261-52-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170454209
PUI
  L616963899
DOI
  10.21037/jgo.2016.12.09
FULL TEXT LINK
  http://dx.doi.org/10.21037/jgo.2016.12.09
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 24
TITLE
  PD-L1 expression in neuroendocrine tumors of the lung
AUTHOR NAMES
  Tsuruoka K.
  Horinouchi H.
  Goto Y.
  Kanda S.
  Fujiwara Y.
  Nokihara H.
  Yamamoto N.
  Asakura K.
  Nakagawa K.
  Sakurai H.
  Watanabe S.-I.
  Tsuta K.
  Ohe Y.
AUTHOR ADDRESSES
  (Tsuruoka K.; Horinouchi H., hhoriou@ncc.go.jp; Goto Y.; Kanda S.; Fujiwara 
Y.; Nokihara H.; Yamamoto N.; Ohe Y.) Department of Thoracic Oncology, 
National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan.
(Asakura K.; Nakagawa K.; Sakurai H.; Watanabe S.-I.) Division of Thoracic 
Surgery, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 
Japan.
(Tsuta K.) Division of Pathology, National Cancer Center Hospital, Tsukiji 
5-1-1, Chuo-ku, Tokyo, Japan.
(Tsuta K.) Department of Pathology and Laboratory Medicine, Kansai Medical 
University, Shinmachi 2-3-1, Hirakata, Osaka, Japan.
CORRESPONDENCE ADDRESS
  H. Horinouchi, Department of Thoracic Oncology, National Cancer Center 
Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan. Email: hhoriou@ncc.go.jp
SOURCE
  Lung Cancer (2017) 108 (115-120). Date of Publication: 1 Jun 2017
ISSN
  1872-8332 (electronic)
  0169-5002
BOOK PUBLISHER
  Elsevier Ireland Ltd
ABSTRACT
  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. 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] × stained area [0–100%]). A 
score of 1 was used as a cut-off to determine the presence or absence of 
PD-L1 expression. Results Among the 227 patients included in this study, the 
patient demographics were as followsmedian 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 followsTC/AC/LCNEC/SCLC, 
0/0/11 (10.4%)/4 (5.8%). Conclusions PD-L1 expression was apparent in 10.4% 
of LCNEC and 5.8% of SCLC tumors, and was not observed in carcinoid tumors.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  large cell neuroendocrine carcinoma (surgery)
  neuroendocrine tumor
  small cell lung cancer (surgery)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer staging
  cancer surgery
  female
  human
  immunohistochemistry
  major clinical study
  male
  priority journal
  protein expression
  smoking
  thorax surgery
  tissue microarray
  very elderly
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170241797
MEDLINE PMID
  28625622 (http://www.ncbi.nlm.nih.gov/pubmed/28625622)
PUI
  L615071073
DOI
  10.1016/j.lungcan.2017.03.006
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.lungcan.2017.03.006
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 25
TITLE
  Preclinical Evaluation of AdVince, an Oncolytic Adenovirus Adapted for 
Treatment of Liver Metastases from Neuroendocrine Cancer
AUTHOR NAMES
  Yu D.
  Leja-Jarblad J.
  Loskog A.
  Hellman P.
  Giandomenico V.
  Oberg K.
  Essand M.
AUTHOR ADDRESSES
  (Yu D.; Leja-Jarblad J.; Loskog A.; Essand M., magnus.essand@igp.uu.se) 
Science for Life Laboratory, Department of Immunology Genetics and 
Pathology, Uppsala University, Uppsala, Sweden.
(Hellman P.) Departments of Surgical Sciences, Uppsala University, Uppsala, 
Sweden.
(Giandomenico V.; Oberg K.) Departments of Medical Sciences, Uppsala 
University, Uppsala, Sweden.
CORRESPONDENCE ADDRESS
  M. Essand, Science for Life Laboratory, Department of Immunology Genetics 
and Pathology, Uppsala University, Uppsala, Sweden. Email: 
magnus.essand@igp.uu.se
SOURCE
  Neuroendocrinology (2017) 105:1 (54-66). Date of Publication: 1 Jun 2017
ISSN
  1423-0194 (electronic)
  0028-3835
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  advince (drug development, drug therapy, drug toxicity, intratumoral drug 
administration, pharmacology)
  oncolytic adenovirus (drug development, drug therapy, drug toxicity, 
intratumoral drug administration, pharmacology)
EMTREE DRUG INDEX TERMS
  cell penetrating peptide (endogenous compound)
  chromogranin A (endogenous compound)
  E1A protein (endogenous compound)
  eotaxin (endogenous compound)
  eotaxin 3 (endogenous compound)
  gamma interferon (endogenous compound)
  gamma interferon inducible protein 10 (endogenous compound)
  interleukin 10 (endogenous compound)
  interleukin 12p70 (endogenous compound)
  interleukin 13 (endogenous compound)
  interleukin 1beta (endogenous compound)
  interleukin 2 (endogenous compound)
  interleukin 4 (endogenous compound)
  interleukin 6 (endogenous compound)
  interleukin 8 (endogenous compound)
  macrophage derived chemokine (endogenous compound)
  macrophage inflammatory protein 1alpha (endogenous compound)
  macrophage inflammatory protein 1beta (endogenous compound)
  microRNA 122 (endogenous compound)
  monocyte chemotactic protein 1 (endogenous compound)
  monocyte chemotactic protein 4 (endogenous compound)
  protein (endogenous compound)
  protein hexon (endogenous compound)
  RANTES (endogenous compound)
  thymus and activation regulated chemokine (endogenous compound)
  tumor necrosis factor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  liver metastasis
  neuroendocrine tumor (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  animal experiment
  animal model
  article
  cell division
  cell specificity
  controlled study
  cytolysis
  cytotoxicity
  drug cytotoxicity
  drug efficacy
  human
  human cell
  human tissue
  in vivo study
  liver cell
  mouse
  neurosecretory cell
  nonhuman
  priority journal
  promoter region
  protein expression
  virus recombinant
  virus replication
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
  gamma interferon inducible protein 10 (97741-20-3)
  interleukin 13 (148157-34-0)
  interleukin 2 (85898-30-2)
  interleukin 8 (114308-91-7)
  macrophage inflammatory protein 1alpha (155075-84-6)
  macrophage inflammatory protein 1beta (122071-81-2)
  monocyte chemotactic protein 4 (173146-42-4, 177346-98-4)
  protein (67254-75-5)
  thymus and activation regulated chemokine (181532-29-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Gastroenterology (48)
  Toxicology (52)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160547151
MEDLINE PMID
  27442441 (http://www.ncbi.nlm.nih.gov/pubmed/27442441)
PUI
  L611348207
DOI
  10.1159/000448430
FULL TEXT LINK
  http://dx.doi.org/10.1159/000448430
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 26
TITLE
  Hypopituitarism and hypothyroidism following atrioventricular block during 
nivolumab treatment
AUTHOR NAMES
  Oda T.
  Sawada Y.
  Okada E.
  Yamaguchi T.
  Ohmori S.
  Haruyama S.
  Yoshioka M.
  Nakamura M.
AUTHOR ADDRESSES
  (Oda T.; Sawada Y., long-ago@med.uoeh-u.ac.jp; Okada E.; Yamaguchi T.; 
Ohmori S.; Haruyama S.; Yoshioka M.; Nakamura M.) Department of Dermatology, 
University of Occupational and Environmental Health, Kitakyushu, Japan.
CORRESPONDENCE ADDRESS
  Y. Sawada, Department of Dermatology, University of Occupational and 
Environmental Health, Kitakyushu, Japan. Email: long-ago@med.uoeh-u.ac.jp
SOURCE
  Journal of Dermatology (2017) 44:6 (e144-e145). Date of Publication: 1 Jun 
2017
ISSN
  1346-8138 (electronic)
  0385-2407
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy, intravenous drug 
administration, pharmacology)
EMTREE DRUG INDEX TERMS
  hydrocortisone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  atrioventricular block (side effect, diagnosis, side effect, therapy)
  hypopituitarism (side effect, diagnosis, side effect)
  hypothyroidism (side effect, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (drug therapy)
  aged
  case report
  computer assisted tomography
  fatigue
  forehead
  histopathology
  human
  laboratory test
  letter
  loss of appetite
  lung metastasis
  male
  melanoma (diagnosis, drug therapy)
  outcome assessment
  patient referral
  skin biopsy
  skin manifestation (diagnosis)
  very elderly
CAS REGISTRY NUMBERS
  hydrocortisone (50-23-7)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Cardiovascular Diseases and Cardiovascular Surgery (18)
  Endocrinology (3)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170197741
PUI
  L614844204
DOI
  10.1111/1346-8138.13797
FULL TEXT LINK
  http://dx.doi.org/10.1111/1346-8138.13797
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 27
TITLE
  A case of fulminant Type 1 diabetes following anti-PD1 immunotherapy in a 
genetically susceptible patient
AUTHOR NAMES
  Araújo M.
  Ligeiro D.
  Costa L.
  Marques F.
  Trindade H.
  Correia J.M.
  Fonseca C.
AUTHOR ADDRESSES
  (Araújo M., drmanuelbaraujo@gmail.com; Costa L.; Marques F.; Fonseca C.) 
Internal Medicine Department and Hospital Dia, Hospital São Francisco 
Xavier, Centro Hospitalar de Lisboa Ocidental, NOVA Medical School, 
Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, 
Portugal.
(Ligeiro D.; Trindade H.) Immunogenetics Laboratory, Centro de Sangue e 
Transplantação de Lisboa, Instituto Português de Sangue e Transplantação, 
IP, Lisbon, Portugal.
(Correia J.M.) Pneumology Department, Hospital Egas Moniz, Centro Hospitalar 
de Lisboa Ocidental, NOVA Medical School, Faculdade de Ciências Médicas, 
Universidade Nova de Lisboa, Lisbon, Portugal.
CORRESPONDENCE ADDRESS
  M. Araújo, Internal Medicine Department and Hospital Dia, Hospital São 
Francisco Xavier, Centro Hospitalar de Lisboa Ocidental, NOVA Medical 
School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, 
Portugal. Email: drmanuelbaraujo@gmail.com
SOURCE
  Immunotherapy (2017) 9:7 (531-535). Date of Publication: 1 Jun 2017
ISSN
  1750-7448 (electronic)
  1750-743X
BOOK PUBLISHER
  Future Medicine Ltd., info@futuremedicine.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  alpha adrenergic receptor stimulating agent
  angiotensin receptor antagonist
  beta adrenergic receptor blocking agent
  C peptide (endogenous compound)
  C reactive protein (endogenous compound)
  carboplatin (drug combination, drug therapy)
  glutamate decarboxylase (endogenous compound)
  hemoglobin A1c (endogenous compound)
  hydroxymethylglutaryl coenzyme A reductase inhibitor
  insulin (drug therapy, intravenous drug administration)
  nivolumab (adverse drug reaction, drug therapy)
  noradrenalin
  pemetrexed (drug combination, drug therapy)
  thiazide diuretic agent
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  insulin dependent diabetes mellitus (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure
  aged
  article
  cancer staging
  capillary electrophoresis
  case report
  Caucasian
  confusion
  diabetic ketoacidosis (drug therapy)
  echography
  female
  hemodynamics
  human
  hyperglycemia
  insulin treatment
  ketoacidosis
  multiple cycle treatment
  non small cell lung cancer (drug therapy)
  polydipsia
  polymerase chain reaction
  polyuria
  priority journal
  protein blood level
  Sanger sequencing
  urinalysis
  vomiting
CAS REGISTRY NUMBERS
  C peptide (59112-80-0)
  C reactive protein (9007-41-4)
  carboplatin (41575-94-4)
  glutamate decarboxylase (9024-58-2)
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
  nivolumab (946414-94-4)
  noradrenalin (1407-84-7, 51-41-2)
  pemetrexed (137281-23-3, 150399-23-8)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170420982
MEDLINE PMID
  28595520 (http://www.ncbi.nlm.nih.gov/pubmed/28595520)
PUI
  L616744325
DOI
  10.2217/imt-2017-0020
FULL TEXT LINK
  http://dx.doi.org/10.2217/imt-2017-0020
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 28
TITLE
  Histologic Remission following Neoadjuvant Immunotherapy in a Patient with 
Lynch-Syndrome and Primarily Unresectable Relapse of Rectum Carcinoma
ORIGINAL (NON-ENGLISH) TITLE
  Histologische Vollremission nach neoadjuvanter Immuntherapie bei einem 
Patienten mit Lynch-Syndrom und primär inoperablem Rezidiv eines 
Rektumkarzinoms
AUTHOR NAMES
  Micheel A.
  Aigner F.
  Henke O.
AUTHOR ADDRESSES
  (Micheel A.; Henke O., oliver.henke@charite.de) Bundeswehrkrankenhaus 
Berlin, Abteilung für Innere Medizin, Berlin, Germany.
(Aigner F.) Charité - Universitätsmedizin Berlin, Chirurgische Klinik, 
Campus Virchow Klinikum, Berlin, Germany.
(Henke O., oliver.henke@charite.de) C/o Cancer Care Centre, Kilimanjaro 
Christian Medical Centre, P.O. Box 3010, Moshi, Tanzania.
CORRESPONDENCE ADDRESS
  O. Henke, C/o Cancer Care Centre, Kilimanjaro Christian Medical Centre, P.O. 
Box 3010, Moshi, Tanzania. Email: oliver.henke@charite.de
SOURCE
  Deutsche Medizinische Wochenschrift (2017) 142:11 (842-846). Date of 
Publication: 1 Jun 2017
ISSN
  1439-4413 (electronic)
  0012-0472
BOOK PUBLISHER
  Georg Thieme Verlag, iaorl@iaorl.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug combination, drug therapy)
  bevacizumab (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer recurrence
  cancer regression
  hereditary nonpolyposis colorectal cancer
  rectum carcinoma (drug therapy, drug therapy, radiotherapy, surgery)
EMTREE MEDICAL INDEX TERMS
  adjuvant chemoradiotherapy
  adult
  autoimmune thyroiditis (side effect)
  cancer immunotherapy
  cancer surgery
  case report
  disease course
  human
  inoperable cancer
  male
  multimodality cancer therapy
  multiple cycle treatment
  off label drug use
  pelvis exenteration
  positron emission tomography-computed tomography
  reoperation
  review
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  German
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  20170411574
MEDLINE PMID
  28564739 (http://www.ncbi.nlm.nih.gov/pubmed/28564739)
PUI
  L616574332
DOI
  10.1055/s-0043-101212
FULL TEXT LINK
  http://dx.doi.org/10.1055/s-0043-101212
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 29
TITLE
  Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic 
ketoacidosis in a patient with metastatic lung cancer
AUTHOR NAMES
  Godwin J.L.
  Jaggi S.
  Sirisena I.
  Sharda P.
  Rao A.D.
  Mehra R.
  Veloski C.
AUTHOR ADDRESSES
  (Godwin J.L., james.godwin@tuhs.temple.edu) Fox Chase Cancer Center, 
Department of Hematology/Oncology, Philadelphia, United States.
(Jaggi S., Shuchie.Jain@tuhs.temple.edu; Sirisena I., 
Imali.Sirisena@tuhs.temple.edu; Rao A.D., ajay.rao@temple.edu) Temple 
University Hospital, Department of Medicine, Section of Metabolism, Diabetes 
and Endocrinology, Philadelphia, United States.
(Sharda P., Pankaj.Sharda@fccc.edu; Veloski C., colleen.veloski@fccc.edu) 
Fox Chase Cancer Center, Department of Medicine, Section of Endocrinology, 
Philadelphia, United States.
(Mehra R., rmehra1@jhmi.edu) Johns Hopkins Hospital/Sidney Kimmel 
Comprehensive Cancer Center, BloombergKimmel Institute for Cancer 
Immunotherapy, Department of Oncology, Baltimore, United States.
CORRESPONDENCE ADDRESS
  C. Veloski, Fox Chase Cancer Center, Department of Medicine, Section of 
Endocrinology, Philadelphia, United States. Email: colleen.veloski@fccc.edu
SOURCE
  Journal for ImmunoTherapy of Cancer (2017) 5:1 Article Number: 40. Date of 
Publication: 16 May 2017
ISSN
  2051-1426 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. Case Presentation: A 34year 
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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  C peptide (endogenous compound)
  HLA antigen (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  diabetic ketoacidosis (side effect, side effect)
  drug induced disease
  non small cell lung cancer (drug therapy, drug resistance, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  biopsy
  bone scintiscanning
  bronchoscopy
  cancer immunotherapy
  case report
  chemoradiotherapy
  computer assisted tomography
  corticotropin blood level
  disease course
  female
  glucose blood level
  hemoglobin blood level
  human
  hyperglycemia
  lymphadenopathy
  nuclear magnetic resonance imaging
  positron emission tomography
  priority journal
  risk factor
  thorax radiography
  thyrotropin blood level
CAS REGISTRY NUMBERS
  C peptide (59112-80-0)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170353418
MEDLINE PMID
  28515940 (http://www.ncbi.nlm.nih.gov/pubmed/28515940)
PUI
  L616162255
DOI
  10.1186/s40425-017-0245-2
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40425-017-0245-2
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 30
TITLE
  Paraneoplastic acral vascular syndrome in a patient with metastatic melanoma 
under immune checkpoint blockade
AUTHOR NAMES
  Gambichler T.
  Strutzmann S.
  Tannapfel A.
  Susok L.
AUTHOR ADDRESSES
  (Gambichler T., t.gambichler@klinikum-bochum.de; Strutzmann S., 
s.strutzmann@klinikum-bochum.de; Susok L., l.susok@klinikum-bochum.de) 
Ruhr-University Bochum, Department of Dermatology, Gudrunstr. 56, Bochum, 
Germany.
(Tannapfel A., andrea.tannapfel@rub.de) Ruhr-University Bochum, Institute of 
Pathology, Bürkle-de-la-Camp-Platz 1, Bochum, Germany.
CORRESPONDENCE ADDRESS
  T. Gambichler, Ruhr-University Bochum, Department of Dermatology, Gudrunstr. 
56, Bochum, Germany. Email: t.gambichler@klinikum-bochum.de
SOURCE
  BMC Cancer (2017) 17:1 Article Number: 327. Date of Publication: 12 May 2017
ISSN
  1471-2407 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 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: 3.8cm), 
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 (1mg/kg BW) and ipilimumab (3mg/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 20μg twice daily and oral prednisolone 50mg 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 2weeks later, the patient presented with 
increased pain and small subungual necrosis. We treated the patient with 
oral analgetics and intravenous prednisolone 500mg 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 2months 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 2months the patient experienced 
dramatic progress of his metastatic disease and finally died at multi-organ 
failure. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  analgesic agent (drug combination, drug therapy, oral drug administration)
  lactate dehydrogenase (endogenous compound)
  prednisolone (drug combination, drug dose, drug therapy, intravenous drug 
administration, oral drug administration)
  prostacyclin (adverse drug reaction, drug combination, drug therapy)
  protein S100B (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
  paraneoplastic acral vascular syndrome (drug therapy, side effect, 
complication, diagnosis, drug therapy, etiology, side effect)
  paraneoplastic syndrome (drug therapy, side effect, complication, diagnosis, 
drug therapy, etiology, side effect)
  vascular disease (drug therapy, side effect, complication, diagnosis, drug 
therapy, etiology, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer staging
  case report
  Caucasian
  computer assisted tomography
  death
  digital subtraction angiography
  drug dose reduction
  drug withdrawal
  erythema (side effect)
  finger amputation
  finger phalanx
  gangrene (side effect, surgery)
  hand disease (drug therapy, side effect)
  hand pain (side effect)
  hand paresthesia (side effect)
  heat intolerance (side effect)
  histopathology
  human
  human tissue
  inflammatory infiltrate
  injection site pain (side effect)
  liver metastasis (complication, diagnosis)
  lung metastasis (complication, diagnosis)
  lymph node metastasis (complication, diagnosis)
  male
  middle aged
  multiple cycle treatment
  multiple organ failure
  pain (drug therapy)
  pathogenesis
  retroperitoneal cancer (complication, diagnosis)
  skin metastasis (complication, diagnosis)
  subungual necrosis (drug therapy, side effect)
  subungual necrosis (drug therapy, side effect)
  treatment duration
  treatment refusal
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  lactate dehydrogenase (9001-60-9)
  nivolumab (946414-94-4)
  prednisolone (50-24-8)
  prostacyclin (35121-78-9, 61849-14-7)
  protein S100B (357701-89-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Cardiovascular Diseases and Cardiovascular Surgery (18)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170350167
MEDLINE PMID
  28499411 (http://www.ncbi.nlm.nih.gov/pubmed/28499411)
PUI
  L616104559
DOI
  10.1186/s12885-017-3313-6
FULL TEXT LINK
  http://dx.doi.org/10.1186/s12885-017-3313-6
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 31
TITLE
  Multicenter phase II study of nivolumab in Japanese patients with relapsed 
or refractory classical Hodgkin lymphoma
AUTHOR NAMES
  Maruyama D.
  Hatake K.
  Kinoshita T.
  Fukuhara N.
  Choi I.
  Taniwaki M.
  Ando K.
  Terui Y.
  Higuchi Y.
  Onishi Y.
  Abe Y.
  Kobayashi T.
  Shirasugi Y.
  Tobinai K.
AUTHOR ADDRESSES
  (Maruyama D., dmaruyam@ncc.go.jp; Tobinai K.) Department of Hematology, 
National Cancer Center Hospital, Tokyo, Japan.
(Hatake K.; Terui Y.) Department of Hematology and Oncology, Cancer 
Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
(Kinoshita T.; Higuchi Y.) Department of Hematology and Cell Therapy, Aichi 
Cancer Center, Nagoya, Japan.
(Fukuhara N.; Onishi Y.) Department of Hematology and Rheumatology, Tohoku 
University Graduate School of Medicine, Sendai, Japan.
(Choi I.; Abe Y.) Department of Hematology, National Hospital Organization 
Kyushu Cancer Center, Fukuoka, Japan.
(Taniwaki M.; Kobayashi T.) Department of Hematology and Oncology, 
University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan.
(Ando K.; Shirasugi Y.) Department of Hematology and Oncology, Tokai 
University, Isehara, Japan.
CORRESPONDENCE ADDRESS
  D. Maruyama, Department of Hematology, National Cancer Center Hospital, 
Tokyo, Japan. Email: dmaruyam@ncc.go.jp
SOURCE
  Cancer Science (2017) 108:5 (1007-1012). Date of Publication: 1 May 2017
ISSN
  1349-7006 (electronic)
  1347-9032
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  brentuximab vedotin (drug therapy)
  drug antibody (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  classical Hodgkin lymphoma (drug therapy, drug therapy)
  drug efficacy
  drug safety
EMTREE MEDICAL INDEX TERMS
  acne (side effect)
  adult
  aged
  anemia (side effect)
  antibody detection
  article
  backache (side effect)
  cancer regression
  cancer survival
  cataract (side effect)
  clinical article
  constipation (side effect)
  diarrhea (side effect)
  dizziness (side effect)
  drug fatality (side effect)
  drug withdrawal
  edema (side effect)
  enterocolitis (side effect)
  fatigue (side effect)
  female
  fever (side effect)
  follow up
  headache (side effect)
  human
  hyponatremia (side effect)
  hypothyroidism (side effect)
  insulin dependent diabetes mellitus (side effect)
  interstitial lung disease (side effect)
  Japanese (people)
  lymphocytopenia (side effect)
  malaise (side effect)
  male
  multicenter study
  myalgia (side effect)
  overall survival
  peripheral neuropathy (side effect)
  phase 2 clinical trial
  pneumonia (side effect)
  priority journal
  progression free survival
  pruritus (side effect)
  rash (side effect)
  rhinopharyngitis (side effect)
  side effect (side effect)
  skin cyst (side effect)
  thrombocytopenia (side effect)
  treatment duration
  treatment response
  tumor volume
  upper respiratory tract infection (side effect)
CAS REGISTRY NUMBERS
  brentuximab vedotin (914088-09-8)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Hematology (25)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170390961
MEDLINE PMID
  28267244 (http://www.ncbi.nlm.nih.gov/pubmed/28267244)
PUI
  L616519566
DOI
  10.1111/cas.13230
FULL TEXT LINK
  http://dx.doi.org/10.1111/cas.13230
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 32
TITLE
  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
AUTHOR NAMES
  Usui Y.
  Udagawa H.
  Matsumoto S.
  Imai K.
  Ohashi K.
  Ishibashi M.
  Kirita K.
  Umemura S.
  Yoh K.
  Niho S.
  Osame K.
  Goto K.
AUTHOR ADDRESSES
  (Usui Y., yusui@east.ncc.go.jp; Udagawa H.; Matsumoto S.; Ishibashi M.; 
Kirita K.; Umemura S.; Yoh K.; Niho S.; Goto K.) Department of Thoracic 
Oncology, National Cancer Center Hospital East, Chiba, Japan.
(Imai K.; Ohashi K.; Osame K.) Department of Internal Medicine, National 
Cancer Center Hospital, Tokyo, Japan.
CORRESPONDENCE ADDRESS
  Y. Usui, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, 
Japan. Email: yusui@east.ncc.go.jp
SOURCE
  Journal of Thoracic Oncology (2017) 12:5 (e41-e43). Date of Publication: 1 
May 2017
ISSN
  1556-1380 (electronic)
  1556-0864
BOOK PUBLISHER
  Elsevier Inc, agents@lww.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  glutamate decarboxylase antibody (endogenous compound)
  HLA antigen (endogenous compound)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  C peptide (endogenous compound)
  glucose (endogenous compound)
  glycosylated hemoglobin (endogenous compound)
  HLA DQB1 antigen (endogenous compound)
  HLA DRB1 antigen (endogenous compound)
  infusion fluid (intravenous drug administration)
  insulin (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  insulin dependent diabetes mellitus (drug therapy, side effect, diagnosis, 
drug therapy, side effect)
  non small cell lung cancer (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer
  antibody blood level
  antibody titer
  article
  case report
  computer assisted tomography
  continuous infusion
  disease association
  disease course
  fatigue
  female
  glucose blood level
  haplotype
  HLA typing
  human
  hyperglycemia (drug therapy)
  Japanese (people)
  ketoacidosis
  male
  medical history
  metabolic acidosis
  metastasis (drug therapy)
  middle aged
  nausea
  polydipsia
  polyuria
  postprandial state
  protein blood level
CAS REGISTRY NUMBERS
  C peptide (59112-80-0)
  glucose (50-99-7, 84778-64-3)
  glycosylated hemoglobin (9062-63-9)
  insulin (9004-10-8)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170287151
PUI
  L615546356
DOI
  10.1016/j.jtho.2016.12.015
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.jtho.2016.12.015
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 33
TITLE
  An Immunogram for the Cancer-Immunity Cycle: Towards Personalized 
Immunotherapy of Lung Cancer
AUTHOR NAMES
  Karasaki T.
  Nagayama K.
  Kuwano H.
  Nitadori J.-I.
  Sato M.
  Anraku M.
  Hosoi A.
  Matsushita H.
  Morishita Y.
  Kashiwabara K.
  Takazawa M.
  Ohara O.
  Kakimi K.
  Nakajima J.
AUTHOR ADDRESSES
  (Karasaki T.; Nagayama K.; Kuwano H.; Nitadori J.-I.; Sato M.; Anraku M.; 
Nakajima J.) Department of Thoracic Surgery, Graduate School of Medicine, 
The University of Tokyo, Tokyo, Japan.
(Hosoi A.; Matsushita H.; Kakimi K., kakimi@m.u-tokyo.ac.jp) Department of 
Immunotherapeutics, Graduate School of Medicine, The University of Tokyo, 
Tokyo, Japan.
(Hosoi A.) Medinet Co. Ltd., Yokohama, Japan.
(Morishita Y.) Department of Molecular Pathology, Graduate School of 
Medicine, The University of Tokyo, Tokyo, Japan.
(Kashiwabara K.) Department of Biostatistics, School of Public Health, The 
University of Tokyo, Tokyo, Japan.
(Takazawa M.; Ohara O.) Department of Technology Development, Kazusa DNA 
Research Institute, Kisarazu, Japan.
CORRESPONDENCE ADDRESS
  K. Kakimi, Department of Immunotherapeutics, Graduate School of Medicine, 
The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, Japan. Email: 
kakimi@m.u-tokyo.ac.jp
SOURCE
  Journal of Thoracic Oncology (2017) 12:5 (791-803). Date of Publication: 1 
May 2017
ISSN
  1556-1380 (electronic)
  1556-0864
BOOK PUBLISHER
  Elsevier Inc, agents@lww.com
ABSTRACT
  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. 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. 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. 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.
EMTREE DRUG INDEX TERMS
  HLA A antigen (endogenous compound)
  HLA antigen class 1 (endogenous compound)
  HLA B antigen (endogenous compound)
  HLA C antigen (endogenous compound)
  tumor antigen (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunogram
  immunological procedures
  non small cell lung cancer
  tumor immunity
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  antigen binding
  antigen expression
  antigenicity
  article
  cancer immunotherapy
  cell cycle checkpoint
  cell infiltration
  cell interaction
  cell killing
  cell migration
  cellular immunity
  clinical article
  dendritic cell
  female
  germline mutation
  human
  human tissue
  large cell neuroendocrine carcinoma
  lung adenocarcinoma
  male
  middle aged
  myeloid-derived suppressor cell
  next generation sequencing
  personalized medicine
  phenotype
  regulatory T lymphocyte
  RNA sequence
  squamous cell lung carcinoma
  T lymphocyte activation
  tumor microenvironment
  very elderly
  whole exome sequencing
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Human Genetics (22)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170287154
MEDLINE PMID
  28088513 (http://www.ncbi.nlm.nih.gov/pubmed/28088513)
PUI
  L615546362
DOI
  10.1016/j.jtho.2017.01.005
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.jtho.2017.01.005
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 34
TITLE
  FDA approval summary: Nivolumab for the treatment of relapsed or progressive 
classical hodgkin lymphoma
AUTHOR NAMES
  Kasamon Y.L.
  De Claro R.A.
  Wang Y.
  Shen Y.L.
  Farrell A.T.
  Pazdur R.
AUTHOR ADDRESSES
  (Kasamon Y.L., Yvette.Kasamon@fda.hhs.gov; De Claro R.A.; Wang Y.; Shen 
Y.L.; Farrell A.T.; Pazdur R.) Office of Hematology and Oncology Products, 
Office of Biostatistics, Center for Drug Evaluation and Research, U.S. Food 
and Drug Administration, Silver Spring, United States.
CORRESPONDENCE ADDRESS
  Y.L. Kasamon, White Oak Campus, Building 22, Room 2163, 10903 New Hampshire 
Avenue, Silver Spring, United States. Email: Yvette.Kasamon@fda.hhs.gov
SOURCE
  Oncologist (2017) 22:5 (585-591). Date of Publication: 1 May 2017
ISSN
  1549-490X (electronic)
  1083-7159
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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 posttransplantation 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 immunemediated 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-versushost disease, other immune-mediated ARs, and transplantrelated 
mortality. Continued approval for the cHL indication may be contingent upon 
verification of clinical benefit in a randomized trial.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug therapy, intravenous 
drug administration, pharmacoeconomics)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  bilirubin (endogenous compound)
  brentuximab vedotin (drug therapy)
  creatinine (endogenous compound)
  triacylglycerol lipase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  classical Hodgkin lymphoma (drug therapy, disease management, drug therapy)
  drug approval
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adult
  anemia (side effect)
  arthralgia (side effect)
  article
  autologous hematopoietic stem cell transplantation
  cancer regression
  clinical trial (topic)
  colitis (side effect)
  constipation (side effect)
  controlled study
  coughing (side effect)
  drug efficacy
  drug safety
  dyspnea (side effect)
  fatigue (side effect)
  female
  fever (side effect)
  headache (side effect)
  human
  hyperglycemia (side effect)
  hypocalcemia (side effect)
  hypokalemia (side effect)
  hypomagnesemia (side effect)
  hyponatremia (side effect)
  hypothyroidism (side effect)
  lymphocytopenia (side effect)
  major clinical study
  male
  multicenter study (topic)
  musculoskeletal pain (side effect)
  nausea (side effect)
  neutropenia (side effect)
  peripheral neuropathy (side effect)
  pneumonia (side effect)
  priority journal
  pruritus (side effect)
  rash (side effect)
  thrombocytopenia (side effect)
  treatment duration
  treatment response
  tumor volume
  upper respiratory tract infection (side effect)
  vomiting (side effect)
DRUG TRADE NAMES
  adcetris  Seattle Genetics

  opdivo  Bristol Myers Squibb

DRUG MANUFACTURERS
  Bristol Myers Squibb
  Seattle Genetics
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  bilirubin (18422-02-1, 635-65-4)
  brentuximab vedotin (914088-09-8)
  creatinine (19230-81-0, 60-27-5)
  nivolumab (946414-94-4)
  triacylglycerol lipase (9001-62-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Hematology (25)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01592370, NCT02181738)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170345530
MEDLINE PMID
  28438889 (http://www.ncbi.nlm.nih.gov/pubmed/28438889)
PUI
  L616021874
DOI
  10.1634/theoncologist.2017-0004
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2017-0004
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 35
TITLE
  Vitiligo-like lesions occurring in patients receiving anti-programmed cell 
death–1 therapies are clinically and biologically distinct from vitiligo
AUTHOR NAMES
  Larsabal M.
  Marti A.
  Jacquemin C.
  Rambert J.
  Thiolat D.
  Dousset L.
  Taieb A.
  Dutriaux C.
  Prey S.
  Boniface K.
  Seneschal J.
AUTHOR ADDRESSES
  (Larsabal M.; Marti A.; Dousset L.; Taieb A.; Dutriaux C.; Prey S.; Boniface 
K.; Seneschal J., julien.seneschal@chu-bordeaux.fr) Department of 
Dermatology and Pediatric Dermatology, National Reference Center for Rare 
Skin Disorders, Hôpital Saint-André, Bordeaux, France.
(Jacquemin C.; Rambert J.; Thiolat D.; Taieb A.; Boniface K.; Seneschal J., 
julien.seneschal@chu-bordeaux.fr) Institut National de la Santé Et de la 
Recherche Médicale (INSERM) U1035, Biothérapies de Maladies Génétiques, 
Inflammatoires et Cancers (BMGIC), Immuno-dermatology ATIP-AVENIR, 
University of Bordeaux, Bordeaux, France.
CORRESPONDENCE ADDRESS
  J. Seneschal, Department of Dermatology and Pediatric Dermatology, National 
Reference Center for Rare Skin Disorders, Hôpital Saint-André, 1 rue Jean 
Burguet, Bordeaux, Cedex, France. Email: julien.seneschal@chu-bordeaux.fr
SOURCE
  Journal of the American Academy of Dermatology (2017) 76:5 (863-870). Date 
of Publication: 1 May 2017
ISSN
  1097-6787 (electronic)
  0190-9622
BOOK PUBLISHER
  Mosby Inc., customerservice@mosby.com
ABSTRACT
  Background The use of anti-programmed cell death (PD)-1 therapies in 
metastatic tumors is associated with cutaneous side effects including 
vitiligo-like lesions. 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. 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. 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-γ and tumor necrosis factor-alfa. Limitations This 
cross-sectional study concerned a single center. Conclusions Clinical and 
biological patterns of vitiligo-like lesions occurring in patients receiving 
anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  gamma interferon (endogenous compound)
  gamma interferon inducible protein 10 (endogenous compound)
  tumor necrosis factor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  metastasis
  vitiligo (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  autoimmune thyroiditis
  blood sampling
  CD8+ T lymphocyte
  clinical article
  clinical feature
  cohort analysis
  controlled study
  cross-sectional study
  family history
  female
  human
  human cell
  human tissue
  lung metastasis (drug therapy)
  lymphocytic infiltration
  male
  medical history
  metastatic melanoma (drug therapy)
  photography
  priority journal
  prospective study
  protein blood level
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
  gamma interferon inducible protein 10 (97741-20-3)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170051141
MEDLINE PMID
  28094061 (http://www.ncbi.nlm.nih.gov/pubmed/28094061)
PUI
  L614102821
DOI
  10.1016/j.jaad.2016.10.044
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.jaad.2016.10.044
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 36
TITLE
  Inflammatory Orbitopathy Associated with Ipilimumab
AUTHOR NAMES
  Sheldon C.A.
  Kharlip J.
  Tamhankar M.A.
AUTHOR ADDRESSES
  (Sheldon C.A., claire.a.sheldon@gmail.com; Tamhankar M.A.) Scheie Eye 
Institute, Department of Ophthalmology, University of Pennsylvania, 
Pennsylvania, United States.
(Kharlip J.) Departments of Endocrinology, Diabetes and Metabolism, 
Department of Medicine, University of Pennsylvania, Philadelphia, United 
States.
CORRESPONDENCE ADDRESS
  C.A. Sheldon, Scheie Eye Institute, Department of Ophthalmology, University 
of Pennsylvania, Pennsylvania, United States. Email: 
claire.a.sheldon@gmail.com
SOURCE
  Ophthalmic Plastic and Reconstructive Surgery (2017) 33:3S Supplement 1 
(S155-S158). Date of Publication: 1 May 2017
ISSN
  1537-2677 (electronic)
  0740-9303
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  methylprednisolone (drug therapy, intravenous drug administration)
  prednisone (drug therapy, oral drug administration)
  steroid (drug dose, drug therapy, oral drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  orbit inflammation (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer staging
  case report
  clinical feature
  disease association
  disease course
  disease severity
  drug dose reduction
  drug megadose
  echography
  exophthalmos
  eye pain
  female
  human
  hypothyroidism
  metastatic melanoma (drug therapy)
  multiple cycle treatment
  nuclear magnetic resonance imaging
  ophthalmoplegia
  orbit disease (drug therapy)
  priority journal
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170379549
MEDLINE PMID
  26068559 (http://www.ncbi.nlm.nih.gov/pubmed/26068559)
PUI
  L616442630
DOI
  10.1097/IOP.0000000000000509
FULL TEXT LINK
  http://dx.doi.org/10.1097/IOP.0000000000000509
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 37
TITLE
  Fulminant type 1 diabetes mellitus associated with pembrolizumab
ORIGINAL (NON-ENGLISH) TITLE
  Diabetes fulminante secundaria a tratamiento con pembrolizumab
AUTHOR NAMES
  Mizab Mellah C.
  Sánchez Pérez M.
  Santos Rey M.D.
  Hernández García M.
AUTHOR ADDRESSES
  (Mizab Mellah C.; Sánchez Pérez M.; Santos Rey M.D.; Hernández García M., 
martahernandezg@gmail.com) Servei d'Endocrinología y Nutrició, Hospital 
Universitari Arnau de Vilanova, Lleida, Spain.
(Hernández García M., martahernandezg@gmail.com) Institut de Recerca 
Biomèdica de Lleida, IRB Lleida, Lleida, Spain.
CORRESPONDENCE ADDRESS
  M. Hernández García, Institut de Recerca Biomèdica de Lleida, IRB Lleida, 
Lleida, Spain. Email: martahernandezg@gmail.com
SOURCE
  Endocrinologia, Diabetes y Nutricion (2017) 64:5 (272-273). Date of 
Publication: 1 May 2017
ISSN
  2530-0164
BOOK PUBLISHER
  Elsevier Doyma, editorial@elsevier.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  insulin dependent diabetes mellitus (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  article
  human
CAS REGISTRY NUMBERS
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English, Spanish
EMBASE ACCESSION NUMBER
  20170321231
PUI
  L615855771
DOI
  10.1016/j.endinu.2017.01.005
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.endinu.2017.01.005
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 38
TITLE
  Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable 
or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 
trial
AUTHOR NAMES
  Ascierto P.A.
  Del Vecchio M.
  Robert C.
  Mackiewicz A.
  Chiarion-Sileni V.
  Arance A.
  Lebbé C.
  Bastholt L.
  Hamid O.
  Rutkowski P.
  McNeil C.
  Garbe C.
  Loquai C.
  Dreno B.
  Thomas L.
  Grob J.-J.
  Liszkay G.
  Nyakas M.
  Gutzmer R.
  Pikiel J.
  Grange F.
  Hoeller C.
  Ferraresi V.
  Smylie M.
  Schadendorf D.
  Mortier L.
  Svane I.M.
  Hennicken D.
  Qureshi A.
  Maio M.
AUTHOR ADDRESSES
  (Ascierto P.A., paolo.ascierto@gmail.com) Istituto Nazionale Tumori 
Fondazione Pascale, Naples, Italy.
(Del Vecchio M.) Medical Oncology, National Cancer Institute, Milan, Italy.
(Robert C.) Gustave Roussy Cancer Campus Grand Paris, Villejuif, France.
(Mackiewicz A.) Department of Diagnostics and Cancer Immunology, Greater 
Poland Cancer Centre, Poznan Medical University, Poznan, Poland.
(Chiarion-Sileni V.) IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy.
(Arance A.) Hospital Clinic and Institut d'Investigacions Biomèdiques August 
Pi I Sunyer, Barcelona, Spain.
(Lebbé C.) AP-HP Dermatology CIC Departments, Saint-Louis Hospital, INSERM 
U976, Université Paris Diderot, Paris, France.
(Bastholt L.) Odense University Hospital, Odense, Denmark.
(Hamid O.) The Angeles Clinic and Research Institute, Los Angeles, United 
States.
(Rutkowski P.) Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, 
Poland.
(McNeil C.) Chris O'Brien Lifehouse and Royal Prince Alfred Hospital, 
Camperdown, Australia.
(McNeil C.) Melanoma Institute Australia, Sydney, Australia.
(Garbe C.) Eberhard Karls University, Tübingen, Germany.
(Loquai C.) University Medical Center, Mainz, Germany.
(Dreno B.) Department of Oncodermatology, INSERM Research Unit 892, Nantes 
University Hospital, Nantes, France.
(Thomas L.) Department of Dermatology, Centre Hospitalier Lyon-Sud, 
Pierre-Bénite, France.
(Grob J.-J.) Hospital de la Timone, Marseille, France.
(Liszkay G.) National Institute of Oncology, Budapest, Hungary.
(Nyakas M.) Oslo University Hospital, Oslo, Norway.
(Gutzmer R.) Medizinische Hochschule Hannover, Hannover, Germany.
(Pikiel J.) Wojewodzkie Centrum Oncologii, Gdańsk, Poland.
(Grange F.) Department of Dermatology, Reims University Hospital, Reims, 
France.
(Hoeller C.) Medical University of Vienna, Vienna, Austria.
(Ferraresi V.) Istituti Fisioterapici Ospitalieri, Rome, Italy.
(Smylie M.) Cross Cancer Institute, Edmonton, Canada.
(Schadendorf D.) University Hospital Essen, Essen, Germany.
(Mortier L.) Hôspital Claude Huriez, Lille, France.
(Svane I.M.) Herlev Hospital, University of Copenhagen, Herlev, Denmark.
(Hennicken D.; Qureshi A.) Bristol-Myers Squibb, Princeton, United States.
(Maio M.) University Hospital of Siena, Istituto Toscano Tumori, Siena, 
Italy.
CORRESPONDENCE ADDRESS
  P.A. Ascierto, Melanoma Cancer Immunotherapy and Innovative Therapy Unit, 
Istituto Nazionale Tumori Fondazione “G. Pascale”, Via Mariano Semmola, 
Naples, Italy. Email: paolo.ascierto@gmail.com
SOURCE
  The Lancet Oncology (2017) 18:5 (611-622). Date of Publication: 1 May 2017
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  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. 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. 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. 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. Funding Bristol-Myers Squibb.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug dose, drug therapy, 
intravenous drug administration)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  alkaline phosphatase (endogenous compound)
  aminotransferase (endogenous compound)
  amylase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  gamma glutamyltransferase (endogenous compound)
  liver enzyme (endogenous compound)
  triacylglycerol lipase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  abnormally low substrate concentration in blood (side effect)
  acute hepatitis (side effect)
  acute kidney failure (side effect)
  acute liver failure (side effect)
  adrenal cortex insufficiency (side effect)
  adrenal insufficiency (side effect)
  adult
  advanced cancer
  aged
  alanine aminotransferase blood level
  alkaline phosphatase blood level
  aminotransferase blood level
  amylase blood level
  anemia (side effect)
  arthralgia (side effect)
  article
  aspartate aminotransferase blood level
  asthenia (side effect)
  autoimmune colitis (side effect)
  autoimmune colitis (side effect)
  autoimmune disease (side effect)
  autoimmune hepatitis (side effect)
  bicytopenia (side effect)
  bicytopenia (side effect)
  body weight loss
  cancer growth
  cause of death
  colitis (side effect)
  confusion (side effect)
  constipation (side effect)
  controlled study
  corticotropin deficiency (side effect)
  cytomegalovirus colitis (side effect)
  cytomegalovirus colitis (side effect)
  cytomegalovirus infection (side effect)
  cytopenia (side effect)
  decreased appetite (side effect)
  dehydration (side effect)
  diarrhea (side effect)
  digestive system perforation (side effect)
  diseases (side effect)
  double blind procedure
  drug dose comparison
  drug efficacy
  drug safety
  drug tolerability
  dyspnea (side effect)
  enzyme blood level
  erysipelas (side effect)
  erythema nodosum (side effect)
  facial nerve paralysis (side effect)
  fatigue (side effect)
  febrile neutropenia (side effect)
  female
  fever (side effect)
  flu like syndrome (side effect)
  follow up
  gamma glutamyl transferase blood level
  gastrointestinal pain (side effect)
  Guillain Barre syndrome (side effect)
  headache (side effect)
  heart arrest (side effect)
  hepatitis (side effect)
  human
  hyperbilirubinemia (side effect)
  hyperglycemia (side effect)
  hyperlipasemia (side effect)
  hyperlipasemia (side effect)
  hypersensitivity (side effect)
  hypertension (side effect)
  hyponatremia (side effect)
  hypophosphatemia (side effect)
  hypophysis disease (side effect)
  hypophysitis (side effect)
  hypopituitarism (side effect)
  hypothalamopituitary disorder (side effect)
  hypothalamopituitary disorder (side effect)
  hypothalamus disease (side effect)
  hypothyroidism (side effect)
  infection (side effect)
  infusion related reaction (side effect)
  intention to treat analysis
  kidney failure (side effect)
  large intestine perforation (side effect)
  liver cell damage (side effect)
  liver function test
  liver toxicity (side effect)
  lower abdominal pain (side effect)
  lung disease (side effect)
  lymphocytic hypophysitis (side effect)
  lymphocytic hypophysitis (side effect)
  maculopapular rash (side effect)
  major clinical study
  male
  motor neuropathy (side effect)
  multicenter study
  nausea (side effect)
  neutrophil count
  overall survival
  pancytopenia (side effect)
  pericarditis (side effect)
  peripheral neuropathy (side effect)
  peritonitis (side effect)
  phase 3 clinical trial
  pneumonia (side effect)
  population research
  prostatitis (side effect)
  pruritus (side effect)
  randomized controlled trial
  rash (side effect)
  rectum hemorrhage (side effect)
  rheumatic polymyalgia (side effect)
  sensory neuropathy (side effect)
  skin toxicity (side effect)
  small intestine obstruction (side effect)
  small intestine perforation (side effect)
  thrombocytopenia (side effect)
  thyroid crisis (side effect)
  thyroiditis (side effect)
  treatment response
  triacylglycerol lipase blood level
  ulcerative colitis (side effect)
  uveitis (side effect)
  vomiting (side effect)
DRUG TRADE NAMES
  bms 734016
  mdx 010
  mdx 101
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  alkaline phosphatase (9001-78-9)
  aminotransferase (9031-66-7)
  amylase (9000-90-2, 9000-92-4, 9001-19-8)
  aspartate aminotransferase (9000-97-9)
  gamma glutamyltransferase (85876-02-4)
  ipilimumab (477202-00-9)
  triacylglycerol lipase (9001-62-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01515189)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170249796
MEDLINE PMID
  28359784 (http://www.ncbi.nlm.nih.gov/pubmed/28359784)
PUI
  L615174500
DOI
  10.1016/S1470-2045(17)30231-0
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(17)30231-0
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 39
TITLE
  Case of type 1 diabetes associated with less-dose nivolumab therapy in a 
melanoma patient
AUTHOR NAMES
  Teramoto Y.
  Nakamura Y.
  Asami Y.
  Imamura T.
  Takahira S.
  Nemoto M.
  Sakai G.
  Shimada A.
  Noda M.
  Yamamoto A.
AUTHOR ADDRESSES
  (Teramoto Y., y_tera@saitama-med.ac.jp; Nakamura Y.; Asami Y.; Imamura T.; 
Yamamoto A.) Department of Skin Oncology/Dermatology, Saitama Medical 
University International Medical Center, Saitama, Japan.
(Takahira S.; Nemoto M.) Division of Traumatology and Emergency Acute 
Medicine, Saitama Medical University International Medical Center, Saitama, 
Japan.
(Sakai G.; Shimada A.; Noda M.) Department of Endocrinology and Diabetes, 
Saitama Medical University, Saitama, Japan.
CORRESPONDENCE ADDRESS
  Y. Teramoto, Department of Skin Oncology/Dermatology, Saitama Medical 
University International Medical Center, Saitama, Japan. Email: 
y_tera@saitama-med.ac.jp
SOURCE
  Journal of Dermatology (2017) 44:5 (605-606). Date of Publication: 1 May 
2017
ISSN
  1346-8138 (electronic)
  0385-2407
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  amylase (endogenous compound)
  bicarbonate (endogenous compound)
  C peptide (endogenous compound)
  dacarbazine (drug therapy)
  elastase (endogenous compound)
  elastase I (endogenous compound)
  glucose (endogenous compound)
  hemoglobin A1c (endogenous compound)
  insulin (drug therapy)
  ketone body (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  insulin dependent diabetes mellitus (drug therapy, side effect, diagnosis, 
drug therapy, side effect)
  melanoma (drug therapy, drug therapy)
  vulvar melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  amylase blood level
  cancer growth
  cancer patient
  case report
  diabetic ketoacidosis (complication, diagnosis)
  disease association
  drug withdrawal
  fatigue (complication)
  female
  glucose blood level
  glycemic control
  human
  insulin release
  insulin treatment
  letter
  middle aged
  pH
  polydipsia (complication)
  polyuria (complication)
CAS REGISTRY NUMBERS
  amylase (9000-90-2, 9000-92-4, 9001-19-8)
  bicarbonate (144-55-8, 71-52-3)
  C peptide (59112-80-0)
  dacarbazine (4342-03-4)
  elastase (9004-06-2)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170302735
PUI
  L615706972
DOI
  10.1111/1346-8138.13486
FULL TEXT LINK
  http://dx.doi.org/10.1111/1346-8138.13486
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 40
TITLE
  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
AUTHOR NAMES
  Alley E.W.
  Lopez J.
  Santoro A.
  Morosky A.
  Saraf S.
  Piperdi B.
  van Brummelen E.
AUTHOR ADDRESSES
  (Alley E.W., evan.alley@uphs.upenn.edu) Hematology and Oncology Division, 
Penn Presbyterian Medical Center, University of Pennsylvania Health System, 
Philadelphia, United States.
(Lopez J.) Drug Development Unit, Institute of Cancer Research, London, 
United Kingdom.
(Santoro A.) Humanitas Cancer Center, Humanitas University, Milan, Italy.
(Morosky A.; Saraf S.; Piperdi B.) Merck, Kenilworth, United States.
(van Brummelen E.) Netherlands Cancer Institute, Amsterdam, Netherlands.
CORRESPONDENCE ADDRESS
  E.W. Alley, Hematology and Oncology Division, Penn Presbyterian Medical 
Center, University of Pennsylvania Health System, Philadelphia, United 
States. Email: evan.alley@uphs.upenn.edu
SOURCE
  The Lancet Oncology (2017) 18:5 (623-630). Date of Publication: 1 May 2017
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  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. 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. 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. 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. Funding 
Merck.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug dose, drug 
therapy, intravenous drug administration, pharmacology)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  alkaline phosphatase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  gamma glutamyltransferase (endogenous compound)
  hemoglobin (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antineoplastic activity
  drug safety
  pleura mesothelioma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  arthralgia (side effect)
  article
  asthenia (side effect)
  balance disorder (side effect)
  burning sensation (side effect)
  cancer pain (side effect)
  clinical article
  constipation (side effect)
  coughing (side effect)
  decreased appetite (side effect)
  diarrhea (side effect)
  drug efficacy
  drug fatality (side effect)
  drug response
  drug tolerability
  drug treatment failure
  dry skin (side effect)
  dysgeusia (side effect)
  dyspnea (side effect)
  erythema (side effect)
  erythema multiforme (side effect)
  fatigue (side effect)
  female
  fever (side effect)
  headache (side effect)
  human
  hypocalcemia (side effect)
  hypothyroidism (side effect)
  immunohistochemistry
  infusion related reaction (side effect)
  iridocyclitis (side effect)
  joint stiffness (side effect)
  leukocyte count
  maculopapular rash (side effect)
  male
  middle aged
  mucosa inflammation (side effect)
  multicenter study
  musculoskeletal stiffness (side effect)
  myalgia (side effect)
  nausea (side effect)
  neutrophil count
  outcome assessment
  overall survival
  paresthesia (side effect)
  phase 1 clinical trial
  progression free survival
  pruritus (side effect)
  rash (side effect)
  rhabdomyolysis (side effect)
  side effect (side effect)
  thorax pain (side effect)
  thrombocytopenia (side effect)
  thrombosis (side effect)
  xerostomia (side effect)
DRUG MANUFACTURERS
   (United States)Merck
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  alkaline phosphatase (9001-78-9)
  aspartate aminotransferase (9000-97-9)
  gamma glutamyltransferase (85876-02-4)
  hemoglobin (9008-02-0)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02054806)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170188979
MEDLINE PMID
  28291584 (http://www.ncbi.nlm.nih.gov/pubmed/28291584)
PUI
  L614767417
DOI
  10.1016/S1470-2045(17)30169-9
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(17)30169-9
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 41
TITLE
  Maintenance therapy of metastatic breast cancer
ORIGINAL (NON-ENGLISH) TITLE
  Erhaltungstherapie bei metastasiertem Mammakarzinom
AUTHOR NAMES
  Aivazova-Fuchs V.
  Friese K.
AUTHOR ADDRESSES
  (Aivazova-Fuchs V., viktoria.aivazova@klinik-bad-trissl.de; Friese K.) 
Gynäkologie, Klinikum Bad Trissl, Bad-Trissl-Str. 73, Oberaudorf, Germany.
CORRESPONDENCE ADDRESS
  V. Aivazova-Fuchs, Gynäkologie, Klinikum Bad Trissl, Bad-Trissl-Str. 73, 
Oberaudorf, Germany. Email: viktoria.aivazova@klinik-bad-trissl.de
SOURCE
  Gynakologe (2017) 50:5 (312-319). Date of Publication: 1 May 2017
ISSN
  1433-0393 (electronic)
  0017-5994
BOOK PUBLISHER
  Springer Verlag, service@springer.de
ABSTRACT
  Maintenance therapy is started after the initial therapy and it is an 
important element in the treatment of patients with metastatic gynecological 
tumors. A safe clinical symptom control can be achieved by maintenance 
therapy in cases of metastatic disease after good primary response to the 
initial therapy and can also have a positive influence on the quality of 
life and even on survival. This therapy is mostly continued until renewed 
progression of the disease or the appearance of intolerable side effects. 
Drugs, such as endocrine substances, CDK4/6 inhibitors, anti-HER 2 
substances in cases of HER 2 positive metastatic breast cancer, various 
cytostatic therapeutic drugs beyond best response and angiogenesis 
inhibitors are well-established in the daily clinical routine as maintenance 
therapy of metastatic breast cancer. Checkpoint inhibitors are currently the 
subject of intensive clinical studies. The antiresorptive long-term therapy 
with osteoprotective substances also has a special importance in the therapy 
of bone metastases in breast cancer.
EMTREE DRUG INDEX TERMS
  angiogenesis inhibitor (drug therapy)
  cyclin dependent kinase inhibitor (drug therapy)
  cytostatic agent (drug therapy)
  epidermal growth factor receptor 2 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  maintenance therapy
  metastatic breast cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  bone metastasis
  cancer growth
  cancer survival
  human
  quality of life
CAS REGISTRY NUMBERS
  epidermal growth factor receptor 2 (137632-09-8)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  German
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  20170308336
PUI
  L615772590
DOI
  10.1007/s00129-017-4072-9
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00129-017-4072-9
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 42
TITLE
  Small cell lung cancer: Pathology and biology
ORIGINAL (NON-ENGLISH) TITLE
  Kleinzelliges Lungenkarzinom: Pathologie und Biologie
AUTHOR NAMES
  Reu S.
  Huber R.M.
AUTHOR ADDRESSES
  (Reu S., simone.reu@med.uni-muenchen.de) Pathologisches Institut, 
Ludwig-Maximilians Universität München, Thalkirchner Straße 36, München, 
Germany.
(Huber R.M.) Medizinische Klinik V, Klinikum der Universität München, 
München, Germany.
CORRESPONDENCE ADDRESS
  S. Reu, Pathologisches Institut, Ludwig-Maximilians Universität München, 
Thalkirchner Straße 36, München, Germany. Email: 
simone.reu@med.uni-muenchen.de
SOURCE
  Onkologe (2017) 23:5 (340-346). Date of Publication: 1 May 2017
ISSN
  1433-0415 (electronic)
  0947-8965
BOOK PUBLISHER
  Springer Verlag, service@springer.de
ABSTRACT
  Background: Small cell lung cancer is an aggressive malignant neoplasm with 
a strong tendency to early and widespread metastastic lesions and is 
associated with a dismal prognosis. It has the strongest association with 
a smoking history of all subtypes of pulmonary carcinomas. Together with 
large cell neuroendocrine carcinoma of the lungs and pulmonary carcinoid 
tumors it comprises the pulmonary neuroendocrine tumors as a histogenetic 
group. Results: It is defined by its characteristic morphology consisting of 
small cells with scant cytoplasm, neuroendocrine differentiation, high 
proliferative activity and tumor cell necrosis that is typically extensive. 
On morphological features it is indistinguishable from small cell carcinomas 
originating in other organs than the lungs. Inactivating alterations of the 
tumor suppressor TP53 and RB1 genes constitute the main and ubiquitous 
drivers of tumor development and growth. They generate a genomic instability 
of the tumor cells that together with abundant numbers of mutations induced 
by carcinogens of tobacco smoke add to the remarkable mutational load of 
this tumor type. The large numbers of genetic and epigenetic alterations 
hinder the identification of molecular targets for targeted therapy but may 
provide a basis for immune checkpoint inhibition. Conclusion: Small cell 
lung cancer is an undifferentiated tumor that can be clearly separated from 
other histological types of lung cancer by specific clinical, prognostic, 
biological and morphological features and for which there are still a 
restricted number of therapeutic options.
EMTREE DRUG INDEX TERMS
  protein p53 (endogenous compound)
  RB1 protein (endogenous compound)
  tobacco smoke
  tumor marker (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  small cell lung cancer
EMTREE MEDICAL INDEX TERMS
  article
  cell differentiation
  cell proliferation
  cell structure
  cytoplasm
  epigenetics
  gene identification
  gene mutation
  gene targeting
  genomic instability
  lung cancer cell line
  necrosis
  pathology
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  German
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  20170162114
PUI
  L614644049
DOI
  10.1007/s00761-017-0203-0
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00761-017-0203-0
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 43
TITLE
  New drugs, new toxicities: Severe side effects of modern targeted and 
immunotherapy of cancer and their management
AUTHOR NAMES
  Kroschinsky F.
  Stölzel F.
  von Bonin S.
  Beutel G.
  Kochanek M.
  Kiehl M.
  Schellongowski P.
AUTHOR ADDRESSES
  (Kroschinsky F., frank.kroschinsky@uniklinikum-dresden.de; Stölzel F., 
friedrich.stoelzel@uniklinikum-dresden.de; von Bonin S., 
simone.vonbonin@uniklinikum-dresden.de) Medical Department I, Dresden 
University Hospital, Fetscherstr. 74, Dresden, Germany.
(Beutel G., beutel.gernot@mh-hannover.de) Hannover Medical School, 
Department for Hematology/Oncology/Stem Cell Transplantation, Hannover, 
Germany.
(Kochanek M., matthias.kochanek@uk-koeln.de) University Hospital Köln, 
Department I of Internal Medicine, Köln, Germany.
(Kiehl M., michael.kiehl@klinikumffo.de) Hospital Frankfurt/Oder, Medical 
Department I and Stem Cell Transplant Center, Frankfurt/Oder, Germany.
(Schellongowski P., peter.schellongowski@meduniwien.ac.at) Medical 
University of Vienna, General Hospital Department of Medicine I, Vienna, 
Austria.
()
CORRESPONDENCE ADDRESS
  F. Kroschinsky, Medical Department I, Dresden University Hospital, 
Fetscherstr. 74, Dresden, Germany. Email: 
frank.kroschinsky@uniklinikum-dresden.de
SOURCE
  Critical Care (2017) 21:1 Article Number: 89. Date of Publication: 14 Apr 
2017
ISSN
  1466-609X (electronic)
  1364-8535
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  aflibercept (adverse drug reaction, drug therapy)
  antihistaminic agent (drug therapy)
  antipyretic agent (drug therapy)
  axitinib (adverse drug reaction, drug therapy)
  bevacizumab (adverse drug reaction, drug therapy)
  blinatumomab (adverse drug reaction, clinical trial, drug therapy)
  cetuximab (adverse drug reaction, drug therapy)
  chimeric antigen receptor
  corticosteroid (drug therapy)
  dasatinib (adverse drug reaction, drug therapy)
  dexamethasone (drug therapy, intravenous drug administration)
  erlotinib (adverse drug reaction, drug therapy)
  idelalisib (adverse drug reaction, drug therapy)
  imatinib (adverse drug reaction, drug therapy)
  ipilimumab (adverse drug reaction, drug therapy)
  nivolumab (adverse drug reaction, drug therapy)
  obinutuzumab (adverse drug reaction, drug therapy)
  ofatumumab (adverse drug reaction, drug therapy)
  OKT 3 (adverse drug reaction)
  pazopanib (drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
  ponatinib (adverse drug reaction, drug therapy)
  ramucirumab (drug therapy)
  rituximab (adverse drug reaction, drug therapy)
  sorafenib (adverse drug reaction, drug therapy)
  sunitinib (adverse drug reaction, drug therapy)
  tocilizumab (drug therapy, intravenous drug administration)
  trametinib (adverse drug reaction, drug therapy)
  trastuzumab (adverse drug reaction, drug therapy)
  unindexed drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction
  cancer immunotherapy
  molecularly targeted therapy
EMTREE MEDICAL INDEX TERMS
  acute lymphoblastic leukemia (drug therapy)
  arterial thromboembolism (side effect)
  B cell lymphoma (drug therapy)
  brain disease (side effect)
  brain edema (side effect)
  breast cancer (drug therapy)
  central nervous system
  cerebellum disease (side effect)
  chronic myeloid leukemia (drug therapy)
  colitis (side effect)
  colorectal cancer (drug therapy)
  congestive heart failure (side effect)
  continuous infusion
  convulsion (side effect)
  cytokine release syndrome (drug therapy, side effect)
  diarrhea (side effect)
  digestive system perforation (side effect)
  drug safety
  edema (side effect)
  gastrointestinal hemorrhage (side effect)
  gastrointestinal stromal tumor (drug therapy)
  heart disease (side effect)
  hepatitis (side effect)
  Hodgkin disease (drug therapy)
  human
  hyperglycemia (side effect)
  hyperlipidemia (side effect)
  hypertension (side effect)
  hypertransaminasemia (side effect)
  hypophysitis (side effect)
  immune deficiency (side effect)
  immunopathology (side effect)
  infusion related reaction (side effect)
  intensive care unit
  interstitial pneumonia
  kidney carcinoma (drug therapy)
  leukemia (drug therapy)
  liver toxicity (side effect)
  melanoma (drug therapy)
  neurotoxicity (drug therapy, side effect)
  non small cell lung cancer (drug therapy)
  pericardial effusion (side effect)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pleura effusion (side effect)
  pneumonia (drug therapy, side effect)
  polyarthritis (side effect)
  posterior reversible encephalopathy syndrome (side effect)
  pulmonary hypertension (side effect)
  rash (side effect)
  respiratory distress
  review
  seizure (side effect)
  side effect (side effect)
  soft tissue sarcoma (drug therapy)
  stomach cancer (drug therapy)
  T lymphocyte
  thromboembolism (drug therapy, side effect)
  tremor (side effect)
  tumor vascularization
CAS REGISTRY NUMBERS
  aflibercept (845771-78-0, 862111-32-8)
  axitinib (319460-85-0)
  bevacizumab (216974-75-3)
  blinatumomab (853426-35-4)
  cetuximab (205923-56-4)
  dasatinib (302962-49-8, 863127-77-9)
  dexamethasone (50-02-2)
  erlotinib (183319-69-9, 183321-74-6)
  idelalisib (1146702-54-6, 870281-82-6)
  imatinib (152459-95-5, 220127-57-1)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  obinutuzumab (949142-50-1)
  ofatumumab (679818-59-8)
  OKT 3 (140608-64-6)
  pazopanib (444731-52-6, 635702-64-6)
  pembrolizumab (1374853-91-4)
  ponatinib (943319-70-8, 1114544-31-8)
  ramucirumab (947687-13-0)
  rituximab (174722-31-7)
  sorafenib (284461-73-0)
  sunitinib (341031-54-7, 557795-19-4)
  tocilizumab (375823-41-9)
  trametinib (1187431-43-1, 871700-17-3)
  trastuzumab (180288-69-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170296243
PUI
  L615547739
DOI
  10.1186/s13054-017-1678-1
FULL TEXT LINK
  http://dx.doi.org/10.1186/s13054-017-1678-1
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 44
TITLE
  Incidence of immune-related adverse events with program death receptor-1- 
and program death receptor-1 ligand-directed therapies in genitourinary 
cancers
AUTHOR NAMES
  Maughan B.L.
  Bailey E.
  Gill D.M.
  Agarwal N.
AUTHOR ADDRESSES
  (Maughan B.L.; Bailey E.; Agarwal N., neeraj.agarwal@hci.utah.edu) Huntsman 
Cancer Institute, University of Utah, Salt Lake City, United States.
(Maughan B.L.; Gill D.M.; Agarwal N., neeraj.agarwal@hci.utah.edu) 
Department of Internal Medicine, University of Utah, Salt Lake City, United 
States.
CORRESPONDENCE ADDRESS
  N. Agarwal, Huntsman Cancer Institute, University of Utah, Salt Lake City, 
United States. Email: neeraj.agarwal@hci.utah.edu
SOURCE
  Frontiers in Oncology (2017) 7:APR Article Number: 56. Date of Publication: 
3 Apr 2017
ISSN
  2234-943X (electronic)
BOOK PUBLISHER
  Frontiers Research Foundation, info@frontiersin.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent
  programmed death 1 ligand 1 inhibitor (drug development, drug toxicity, 
pharmacology)
  programmed death 1 receptor inhibitor
EMTREE DRUG INDEX TERMS
  atezolizumab (adverse drug reaction, drug therapy)
  avelumab
  durvalumab (adverse drug reaction, intravenous drug administration)
  everolimus
  mammalian target of rapamycin (endogenous compound)
  nivolumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
  pdr001
  pembrolizumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
  T lymphocyte receptor (endogenous compound)
  unclassified drug
  vascular endothelial growth factor receptor tyrosine kinase inhibitor
  vasculotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug induced disease
  urogenital tract cancer (therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  arthralgia (side effect)
  arthritis (side effect)
  autoimmune hepatitis (side effect)
  autoimmunity
  cancer immunotherapy
  castration resistant prostate cancer (drug therapy)
  chronic kidney failure (side effect)
  clinical trial (topic)
  colitis (side effect)
  cytokine release syndrome (side effect)
  dendritic cell
  diabetes mellitus (side effect)
  diarrhea (side effect)
  dry skin (side effect)
  dyspnea (side effect)
  encephalitis
  endocrine disease (side effect)
  fever (side effect)
  hepatitis (side effect)
  human
  hyperbilirubinemia (side effect)
  hyperglycemia (side effect)
  hypersensitivity (side effect)
  hyperthyroidism (side effect)
  hypertransaminasemia (side effect)
  hypophysitis (side effect)
  hypotension (side effect)
  hypothyroidism (side effect)
  infusion related reaction (side effect)
  kidney carcinoma (drug therapy)
  liver disease (side effect)
  maculopapular rash (side effect)
  major histocompatibility complex
  muscle spasm (side effect)
  musculoskeletal pain (side effect)
  myositis (side effect)
  natural killer cell
  nephritis (side effect)
  paraplegia (side effect)
  pericardial effusion (side effect)
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  pneumonia (side effect)
  pruritus (side effect)
  randomized controlled trial (topic)
  rash (side effect)
  rhabdomyolysis (side effect)
  rheumatoid arthritis (side effect)
  sepsis (side effect)
  short survey
  systematic review (topic)
  T lymphocyte activation
  tenosynovitis (side effect)
  thyroiditis
  transitional cell carcinoma (drug therapy)
  tumor associated leukocyte
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  avelumab (1537032-82-8)
  durvalumab (1428935-60-7)
  everolimus (159351-69-6)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  vasculotropin (127464-60-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170333335
PUI
  L615927970
DOI
  10.3389/fonc.2017.00056
FULL TEXT LINK
  http://dx.doi.org/10.3389/fonc.2017.00056
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 45
TITLE
  Deep exploration of the immune infiltrate and outcome prediction in 
testicular cancer by quantitative multiplexed immunohistochemistry and gene 
expression profiling
AUTHOR NAMES
  Siska P.J.
  Johnpulle R.A.N.
  Zhou A.
  Bordeaux J.
  Kim J.Y.
  Dabbas B.
  Dakappagari N.
  Rathmell J.C.
  Rathmell W.K.
  Morgans A.K.
  Balko J.M.
  Johnson D.B.
AUTHOR ADDRESSES
  (Siska P.J., peter.siska@ukr.de; Rathmell J.C.) Department of Internal 
Medicine III, University Hospital Regensburg, Regensburg, Germany.
(Siska P.J., peter.siska@ukr.de) Department of Pathology, Microbiology, and 
Immunology, Vanderbilt University Medical Center and Vanderbilt Ingram 
Cancer Center, Nashville, United States.
(Johnpulle R.A.N.; Rathmell W.K.; Morgans A.K.; Balko J.M.; Johnson D.B.) 
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt 
Ingram Cancer Center, Nashville, United States.
(Zhou A.) School of Medicine, Vanderbilt University Medical Center and 
Vanderbilt Ingram Cancer Center, Nashville, United States.
(Bordeaux J.; Kim J.Y.; Dakappagari N.) Navigate BioPharma Services, Inc., a 
Novartis Company, Carlsbad, United States.
(Dabbas B.) Genoptix, Inc., Carlsbad, United States.
(Rathmell J.C.; Balko J.M.) Department of Cancer Biology, Vanderbilt 
University Medical Center, Nashville, United States.
CORRESPONDENCE ADDRESS
  P.J. Siska, Department of Internal Medicine III, University Hospital 
Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany. Email: 
peter.siska@ukr.de
SOURCE
  OncoImmunology (2017) 6:4 Article Number: e1305535. Date of Publication: 3 
Apr 2017
ISSN
  2162-402X (electronic)
  2162-4011
BOOK PUBLISHER
  Taylor and Francis Inc., 325 Chestnut St, Suite 800, Philadelphia, United 
States.
ABSTRACT
  Platinum-based chemotherapy is usually curative for patients with testicular 
germ cell tumors (TGCT), but a subset of patients experience disease 
progression and poor clinical outcomes. Here, we tested whether immune 
profiling of TGCT could identify novel prognostic markers and therapeutic 
targets for this patient cohort. We obtained primary and metastatic TGCT 
samples from one center. We performed immune profiling using multiplexed 
fluorescence immunohistochemistry (FIHC) for T-cell subsets and immune 
checkpoints, and targeted gene expression profiling (Nanostring nCounter 
Immune panel). Publically available data sets were used to validate primary 
sample analyses. Nearly all samples had some degree of T-cell infiltration 
and immune checkpoint expression. Seminomas were associated with increased 
CD3(+) T-cell infiltration, decreased Regulatory T-cells, increased PD-L1, 
and increased PD-1/PD-L1 spatial interaction compared with non-seminomas 
using FIHC. Gene expression profiling confirmed these findings and also 
demonstrated increased expression of T-cell markers (e.g., IFNγ, and LAG3) 
and cancer/testis antigens (e.g., PRAME) in seminomas, whereas non-seminomas 
demonstrated high neutrophil and macrophage gene signatures. Irrespective of 
histology, advanced TGCT stage was associated with decreased T-cell and 
NK-cell signatures, while Treg, neutrophil, mast cell and macrophage 
signatures increased with advanced stage. Importantly, cancer/testis 
antigen, neutrophil, and CD8(+)/regulatory T-cell signatures correlated with 
recurrence free survival. Thus, deep immune characterization of TGCT using 
IHC and gene expression profiling identified activated T-cell infiltration 
which correlated with seminoma histology and good prognosis. These results 
may provide a rationale for testing of anti-PD-1/PD-L1 agents and suggest 
prognostic markers.
EMTREE DRUG INDEX TERMS
  cancer testis antigen (endogenous compound)
  CD24 antigen (endogenous compound)
  CXCL9 chemokine (endogenous compound)
  gamma interferon (endogenous compound)
  HLA DRB4 antigen (endogenous compound)
  interleukin 2 receptor alpha (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  transcription factor FOXP3 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cell infiltration
  gene expression profiling
  germ cell cancer
  immunohistochemistry
  multiplexed fluorscence immunohistochemistry
  testis cancer
EMTREE MEDICAL INDEX TERMS
  article
  cancer staging
  CD3+ T lymphocyte
  CD8+ T lymphocyte
  clinical article
  controlled study
  gene expression
  histology
  human
  human tissue
  image analysis
  outcome assessment
  progression free survival
  recurrence free survival
  regulatory T lymphocyte
  seminoma
  tumor biopsy
  tumor microenvironment
  tumor recurrence
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170312306
PUI
  L615822655
DOI
  10.1080/2162402X.2017.1305535
FULL TEXT LINK
  http://dx.doi.org/10.1080/2162402X.2017.1305535
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 46
TITLE
  Cancer immunotherapy-immune checkpoint blockade and associated 
endocrinopathies
AUTHOR NAMES
  Byun D.J.
  Wolchok J.D.
  Rosenberg L.M.
  Girotra M.
AUTHOR ADDRESSES
  (Byun D.J.; Wolchok J.D., wolchokj@mskcc.org; Girotra M., 
girotram@mskcc.org) Memorial Sloan Kettering Cancer Center, 1275 York 
Avenue, New York, United States.
(Byun D.J.; Wolchok J.D., wolchokj@mskcc.org; Rosenberg L.M.; Girotra M., 
girotram@mskcc.org) Weill Cornell Medical College, 1300 York Avenue, New 
York, United States.
CORRESPONDENCE ADDRESS
  J.D. Wolchok, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New 
York, United States. Email: wolchokj@mskcc.org
SOURCE
  Nature Reviews Endocrinology (2017) 13:4 (195-207). Date of Publication: 1 
Apr 2017
ISSN
  1759-5037 (electronic)
  1759-5029
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  atezolizumab (adverse drug reaction, clinical trial, drug therapy)
  bevacizumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  bms 936559 (adverse drug reaction, clinical trial, drug therapy)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  nivolumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy)
  ticilimumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  corticosteroid (drug therapy)
  corticotropin (endogenous compound)
  hydrocortisone (endogenous compound)
  levothyroxine (drug therapy)
  somatomedin C (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adrenal insufficiency (side effect, side effect)
  autoimmune hypophysitis (drug therapy, side effect, drug therapy, side 
effect)
  cancer immunotherapy
  hyperthyroidism (side effect, side effect)
  hypopituitarism (side effect, side effect)
  hypothyroidism (drug therapy, side effect, drug therapy, side effect)
  insulin dependent diabetes mellitus (side effect, side effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  anorexia (side effect)
  arthralgia (side effect)
  body weight loss
  cohort analysis
  dehydration (complication)
  drug efficacy
  drug safety
  electrolyte disturbance (complication)
  fatigue (side effect)
  follow up
  headache (side effect)
  human
  hypotension (complication)
  mental health
  muscle weakness (side effect)
  nausea (side effect)
  nuclear magnetic resonance imaging
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  retrospective study
  review
  side effect (side effect)
  temperature measurement
  thyroiditis (side effect)
  treatment response
  vision
DRUG TRADE NAMES
  mdx 010
  mdx 1105
  mdx 1106
  mk 3476
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  bevacizumab (216974-75-3)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  somatomedin C (67763-96-6)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170064499
MEDLINE PMID
  28106152 (http://www.ncbi.nlm.nih.gov/pubmed/28106152)
PUI
  L614164429
DOI
  10.1038/nrendo.2016.205
FULL TEXT LINK
  http://dx.doi.org/10.1038/nrendo.2016.205
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 47
TITLE
  Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 
and programmed death receptor protein-1 inhibitors in the treatment of 
melanoma
AUTHOR NAMES
  Morganstein D.L.
  Lai Z.
  Spain L.
  Diem S.
  Levine D.
  Mace C.
  Gore M.
  Larkin J.
AUTHOR ADDRESSES
  (Morganstein D.L., d.morganstein@ic.ac.uk; Lai Z.; Spain L.; Diem S.; Gore 
M.; Larkin J.) Skin Unit, Royal Marsden Hospital, London, United Kingdom.
(Morganstein D.L., d.morganstein@ic.ac.uk; Lai Z.; Mace C.) Department of 
Endocrinology, Chelsea and Westminster Hospital, London, United Kingdom.
(Diem S.) Department of Oncology/Hematology, Cantonal Hospital St. Gallen, 
Switzerland.
(Diem S.) Department of Oncology/Hematology, Hospital Grabs, Switzerland.
(Levine D.) Department of Nuclear Medicine, Royal Marsden Hospital, London, 
United Kingdom.
CORRESPONDENCE ADDRESS
  D.L. Morganstein, Skin Unit, Royal Marsden Hospital, London, United Kingdom. 
Email: d.morganstein@ic.ac.uk
SOURCE
  Clinical Endocrinology (2017) 86:4 (614-620). Date of Publication: 1 Apr 
2017
ISSN
  1365-2265 (electronic)
  0300-0664
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
  Context: Checkpoint inhibitors are emerging as important cancer therapies 
but are associated with a high rate of immune side effects, including 
endocrinopathy. Objective: To determine the burden of thyroid dysfunction in 
patients with melanoma treated with immune checkpoint inhibitors and 
describe the clinical course. 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. 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. Conclusion: Thyroid dysfunction 
occurs commonly in patients with melanoma treated with immune checkpoint 
inhibitors, with rates, including subclinical dysfunction, occurring in up 
to 50%.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  beta adrenergic receptor blocking agent (drug therapy)
  corticosteroid
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  pertechnetic acid tc 99m (intravenous drug administration, pharmacokinetics)
  programmed death 1 receptor (endogenous compound)
  thyroid peroxidase antibody (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  thyroid disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer combination chemotherapy
  collimator
  corticosteroid therapy
  drug uptake
  drug use
  female
  Graves disease (side effect)
  human
  hypothyroidism (side effect)
  major clinical study
  male
  medical record review
  middle aged
  priority journal
  subclinical hyperthyroidism (side effect)
  supraventricular tachycardia (drug therapy)
  thyroid function
  thyrotropin blood level
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  pertechnetic acid tc 99m (23288-60-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170095820
MEDLINE PMID
  28028828 (http://www.ncbi.nlm.nih.gov/pubmed/28028828)
PUI
  L614311707
DOI
  10.1111/cen.13297
FULL TEXT LINK
  http://dx.doi.org/10.1111/cen.13297
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 48
TITLE
  Anti-PD-L1 atezolizumab-Induced Autoimmune Diabetes: a Case Report and 
Review of the Literature
AUTHOR NAMES
  Hickmott L.
  De La Peña H.
  Turner H.
  Ahmed F.
  Protheroe A.
  Grossman A.
  Gupta A.
AUTHOR ADDRESSES
  (Hickmott L., laura.hickmott@nhs.net; De La Peña H.; Protheroe A.) 
Department of Oncology, Churchill Hospital, Oxford University Hospitals NHS 
Foundation Trust, Oxford, United Kingdom.
(Turner H.; Ahmed F.; Grossman A.) Oxford Centre for Diabetes, Endocrinology 
and Metabolism, Churchill Hospital, Oxford University Hospitals NHS 
Foundation Trust, Oxford, United Kingdom.
(Gupta A.) Department of Medical Oncology, The Christie NHS Foundation 
Trust, Manchester, United Kingdom.
CORRESPONDENCE ADDRESS
  L. Hickmott, Department of Oncology, Churchill Hospital, Oxford University 
Hospitals NHS Foundation Trust, Oxford, United Kingdom. Email: 
laura.hickmott@nhs.net
SOURCE
  Targeted Oncology (2017) 12:2 (235-241). Date of Publication: 1 Apr 2017
ISSN
  1776-260X (electronic)
  1776-2596
BOOK PUBLISHER
  Springer-Verlag France, 22, Rue de Palestro, Paris, France. 
york@springer-paris.fr
ABSTRACT
  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.[Figure 
not available: see fulltext.]
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  atezolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  C peptide (endogenous compound)
  cisplatin (drug therapy)
  gemcitabine (drug therapy)
  glucose (endogenous compound)
  hemoglobin A1c (endogenous compound)
  HLA DQB1 antigen (endogenous compound)
  HLA DRB1 antigen (endogenous compound)
  infusion fluid
  insulin (drug therapy, subcutaneous drug administration)
  ketone (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune diabetes (side effect, diagnosis, side effect)
  diabetes mellitus (side effect, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult
  blood examination
  blood gas
  body weight loss
  cancer chemotherapy
  cancer palliative therapy
  cancer staging
  case report
  comorbidity
  dehydration (side effect)
  diabetic ketoacidosis (diagnosis, drug therapy)
  disease duration
  disease predisposition
  drug dose titration
  family history
  fatigue
  glucose blood level
  hemoglobin blood level
  hormone blood level
  human
  hyperglycemia (diagnosis)
  hypophysitis (diagnosis, side effect)
  insulin dependent diabetes mellitus (diagnosis, drug therapy)
  insulin treatment
  lymph node metastasis (drug therapy)
  male
  middle aged
  multiple cycle treatment
  muscle tumor
  nuclear magnetic resonance imaging
  polydipsia
  review
  risk assessment
  skin metastasis (drug therapy)
  thyroiditis (side effect)
  treatment response
  urogenital tract cancer (drug therapy)
DRUG TRADE NAMES
  mpdl 3280a
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  C peptide (59112-80-0)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  gemcitabine (103882-84-4)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170161785
MEDLINE PMID
  28255845 (http://www.ncbi.nlm.nih.gov/pubmed/28255845)
PUI
  L614643310
DOI
  10.1007/s11523-017-0480-y
FULL TEXT LINK
  http://dx.doi.org/10.1007/s11523-017-0480-y
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 49
TITLE
  Programmed Death-Ligand 1 Expression in Papillary Thyroid Cancer and Its 
Correlation with Clinicopathologic Factors and Recurrence
AUTHOR NAMES
  Shi R.-L.
  Qu N.
  Luo T.-X.
  Xiang J.
  Liao T.
  Sun G.-H.
  Wang Y.
  Wang Y.-L.
  Huang C.-P.
  Ji Q.-H.
AUTHOR ADDRESSES
  (Shi R.-L.; Qu N.; Luo T.-X.; Xiang J.; Liao T.; Sun G.-H.; Wang Y.; Wang 
Y.-L., wangyulong@shca.org.cn; Huang C.-P., huangcaiping@shca.org.cn; Ji 
Q.-H., jiqinghai@shca.org.cn) Department of Head and Neck Surgery, Fudan 
University Shanghai Cancer Center, Department of Oncology, Shanghai Medical 
College, Fudan University, No. 270 Dong'An Road, Shanghai, China.
(Shi R.-L.) Department of General Surgery, Minhang Hospital, Fudan 
University, Shanghai, China.
(Wang Y.-L., wangyulong@shca.org.cn) Department of Ultrasonography, Fudan 
University Shanghai Cancer Center, Department of Oncology, Shanghai Medical 
College, Fudan University, No. 270 Dong'An Road, Shanghai, China.
CORRESPONDENCE ADDRESS
  Q.-H. Ji, Department of Head and Neck Surgery, Fudan University Shanghai 
Cancer Center, Department of Oncology, Shanghai Medical College, Fudan 
University, No. 270 Dong'An Road, Shanghai, China. Email: 
jiqinghai@shca.org.cn
SOURCE
  Thyroid (2017) 27:4 (537-545). Date of Publication: 1 Apr 2017
ISSN
  1557-9077 (electronic)
  1050-7256
BOOK PUBLISHER
  Mary Ann Liebert Inc., info@liebertpub.com
ABSTRACT
  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. 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. 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 >4 cm (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). 
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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer recurrence
  thyroid papillary carcinoma (etiology)
EMTREE MEDICAL INDEX TERMS
  adolescent
  adult
  aged
  article
  cancer survival
  cancer tissue
  clinical feature
  controlled study
  female
  follow up
  human
  human tissue
  immunohistochemistry
  lymph node metastasis
  major clinical study
  male
  outcome assessment
  priority journal
  protein expression
  recurrence free survival
  retrospective study
  staining
  thyroidectomy
  tumor volume
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170261570
MEDLINE PMID
  27825291 (http://www.ncbi.nlm.nih.gov/pubmed/27825291)
PUI
  L615260092
DOI
  10.1089/thy.2016.0228
FULL TEXT LINK
  http://dx.doi.org/10.1089/thy.2016.0228
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 50
TITLE
  Immune checkpoint inhibitors-related orchitis
AUTHOR NAMES
  Brunet-Possenti F.
  Opsomer M.A.
  Gomez L.
  Ouzaid I.
  Descamps V.
AUTHOR ADDRESSES
  (Brunet-Possenti F., florence.brunet-possenti@aphp.fr; Descamps V.) 
Department of Dermatology, Bichat Claude Bernard Hospital, AP-HP, Paris, 
France.
(Opsomer M.A.) Department of Pharmacology, Bichat Claude Bernard Hospital, 
AP-HP, Paris, France.
(Gomez L.) Department of Nuclear Medicine, Bichat Claude Bernard Hospital, 
AP-HP, Paris, France.
(Ouzaid I.) Department of Urology, Bichat Claude Bernard Hospital, AP-HP, 
Paris, France.
CORRESPONDENCE ADDRESS
  F. Brunet-Possenti, Department of Dermatology, Bichat Claude Bernard 
Hospital, AP-HP, Paris, France. Email: florence.brunet-possenti@aphp.fr
SOURCE
  Annals of Oncology (2017) 28:4 (906-907) Article Number: mdw696. Date of 
Publication: 1 Apr 2017
ISSN
  1569-8041 (electronic)
  0923-7534
BOOK PUBLISHER
  Oxford University Press, jnl.info@oup.co.uk
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  fluorodeoxyglucose
  luteinizing hormone (endogenous compound)
  testosterone (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  orchitis (side effect, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  blood examination
  bone lesion (diagnosis)
  bone metastasis (diagnosis)
  cancer combination chemotherapy
  cancer localization
  cancer staging
  case report
  clinical examination
  drug efficacy
  drug infusion
  drug tolerability
  human
  hypogonadism (diagnosis)
  immune response
  letter
  male
  melanoma (drug therapy)
  middle aged
  positron emission tomography
  priority journal
  scrotal swelling (diagnosis, side effect)
  testosterone blood level
  treatment response
CAS REGISTRY NUMBERS
  fluorodeoxyglucose (29702-43-0)
  ipilimumab (477202-00-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  nivolumab (946414-94-4)
  testosterone (58-22-0)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Nuclear Medicine (23)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170339657
PUI
  L616106162
DOI
  10.1093/annonc/mdw696
FULL TEXT LINK
  http://dx.doi.org/10.1093/annonc/mdw696
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 51
TITLE
  Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 
and PD-1/PD-L1 inhibitors in cancer patients
AUTHOR NAMES
  De Velasco G.
  Je Y.
  Bossé D.
  Awad M.M.
  Ott P.A.
  Moreira R.B.
  Schutz F.
  Bellmunt J.
  Sonpavde G.P.
  Hodi F.S.
  Choueiri T.K.
AUTHOR ADDRESSES
  (De Velasco G.; Bossé D.; Awad M.M.; Ott P.A.; Moreira R.B.; Bellmunt J.; 
Hodi F.S.; Choueiri T.K., toni_choueiri@dfci.harvard.edu) Department of 
Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 
Brookline Avenue (DANA 1230), Boston, United States.
(De Velasco G.) Department of Medical Oncology, University Hospital, Madrid, 
Spain.
(Je Y.) Department of Food and Nutrition, College of Human Ecology, Kyung 
Hee University, Seoul, South Korea.
(Schutz F.) Department of Medical Oncology, Hospital São José, Benefiçencia 
Portuguesa de São Paulo, Brazil.
(Sonpavde G.P.) Division of Oncology and Hematology, University of Alabama, 
Birmingham, United States.
CORRESPONDENCE ADDRESS
  T.K. Choueiri, Department of Medical Oncology, Dana-Farber Cancer Institute, 
Harvard Medical School, 450 Brookline Avenue (DANA 1230), Boston, United 
States. Email: toni_choueiri@dfci.harvard.edu
SOURCE
  Cancer Immunology Research (2017) 5:4 (312-318). Date of Publication: 1 Apr 
2017
ISSN
  2326-6074 (electronic)
  2326-6066
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  atezolizumab (adverse drug reaction)
  ipilimumab (adverse drug reaction)
  nivolumab (adverse drug reaction)
  pembrolizumab (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  aspartate aminotransferase
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
EMTREE MEDICAL INDEX TERMS
  article
  aspartate aminotransferase blood level
  cancer patient
  colitis (side effect)
  controlled study
  human
  hypertransaminasemia (side effect)
  hypothyroidism (side effect)
  incidence
  meta analysis
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pneumonia (side effect)
  randomized controlled trial (topic)
  rash (side effect)
  risk factor
CAS REGISTRY NUMBERS
  aspartate aminotransferase (9000-97-9)
  atezolizumab (1380723-44-3)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170264652
PUI
  L615230199
DOI
  10.1158/2326-6066.CIR-16-0237
FULL TEXT LINK
  http://dx.doi.org/10.1158/2326-6066.CIR-16-0237
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 52
TITLE
  Combining immunotherapy and radiation therapy for small cell lung cancer and 
thymic tumors
AUTHOR NAMES
  Patel S.H.
  Rimner A.
  Cohen R.B.
AUTHOR ADDRESSES
  (Patel S.H.; Rimner A., rimnera@mskcc.org) Department of Radiation Oncology, 
Memorial Sloan Kettering Cancer Center, New York, United States.
(Cohen R.B.) Division of Hematology-Oncology, Perelman Center for Advanced 
Medicine, Philadelphia, United States.
CORRESPONDENCE ADDRESS
  A. Rimner, Department of Radiation Oncology, Memorial Sloan Kettering Cancer 
Center, 1275 York Avenue, New York, United States. Email: rimnera@mskcc.org
SOURCE
  Translational Lung Cancer Research (2017) 6:2 (186-195). Date of 
Publication: 1 Apr 2017
ISSN
  2226-4477 (electronic)
  2218-6751
BOOK PUBLISHER
  AME Publishing Company, info@amepc.org
ABSTRACT
  Recent work with immunotherapy has shown promising results with treatment of 
several solid malignancies, and there are several reports of good systemic 
responses with the combination of immunotherapy and radiation therapy (RT), 
most notably in advanced melanoma. Given the rapid increase in the use of 
checkpoint blockade as well as anti-tumor vaccines, we review here the 
preclinical rationale and ongoing clinical work in combining immunotherapy 
with RT for small cell lung cancer (SCLC) and thymic tumors. While there are 
several reports of promising results with the combination of immunotherapy 
and conventional systemic treatment, we focus here on the ongoing clinical 
studies that combine immunotherapy with RT, and highlight the emerging data 
for this multimodality approach as well as key preclinical and clinical 
issues that remain to be addressed. With regards to SCLC, trials exploring 
to the combination of immunotherapy and RT are already ongoing, but clinical 
studies for this combination in thymoma are lacking.
EMTREE DRUG INDEX TERMS
  tumor vaccine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  cancer radiotherapy
  small cell lung cancer (radiotherapy)
  thymus cancer (radiotherapy)
EMTREE MEDICAL INDEX TERMS
  clinical outcome
  clinical trial (topic)
  human
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  review
  systemic therapy
  treatment response
EMBASE CLASSIFICATIONS
  Radiology (14)
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Hematology (25)
  Immunology, Serology and Transplantation (26)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00045617)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170323098
PUI
  L615948878
DOI
  10.21037/tlcr.2017.03.04
FULL TEXT LINK
  http://dx.doi.org/10.21037/tlcr.2017.03.04
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 53
TITLE
  Nivolumab for previously treated unresectable metastatic anal cancer 
(NCI9673): a multicentre, single-arm, phase 2 study
AUTHOR NAMES
  Morris V.K.
  Salem M.E.
  Nimeiri H.
  Iqbal S.
  Singh P.
  Ciombor K.
  Polite B.
  Deming D.
  Chan E.
  Wade J.L.
  Xiao L.
  Bekaii-Saab T.
  Vence L.
  Blando J.
  Mahvash A.
  Foo W.C.
  Ohaji C.
  Pasia M.
  Bland G.
  Ohinata A.
  Rogers J.
  Mehdizadeh A.
  Banks K.
  Lanman R.
  Wolff R.A.
  Streicher H.
  Allison J.
  Sharma P.
  Eng C.
AUTHOR ADDRESSES
  (Morris V.K.; Xiao L.; Vence L.; Blando J.; Mahvash A.; Foo W.C.; Ohaji C.; 
Pasia M.; Bland G.; Ohinata A.; Rogers J.; Mehdizadeh A.; Wolff R.A.; 
Allison J.; Sharma P.; Eng C., ceng@mdanderson.org) The University of 
Texas—MD Anderson Cancer Center, Houston, United States.
(Salem M.E.) Lombardi Comprehensive Cancer Center, Georgetown University, 
Washington, United States.
(Nimeiri H.) Northwestern University, Chicago, United States.
(Iqbal S.) University of Southern California, Los Angeles, United States.
(Singh P.) Washington University, St Louis, United States.
(Ciombor K.; Bekaii-Saab T.) The Ohio State University, Columbus, United 
States.
(Polite B.) University of Chicago, Chicago, United States.
(Deming D.) University of Wisconsin, Madison, United States.
(Chan E.) Vanderbilt-Ingram Cancer Center, Nashville, United States.
(Wade J.L.) Decatur Memorial Hospital, Decatur, United States.
(Banks K.; Lanman R.) Guardant Health, Redwood City, United States.
(Streicher H.) National Cancer Institute, Bethesda, United States.
CORRESPONDENCE ADDRESS
  C. Eng, The University of Texas—MD Anderson Cancer Center, Houston, United 
States. Email: ceng@mdanderson.org
SOURCE
  The Lancet Oncology (2017) 18:4 (446-453). Date of Publication: 1 Apr 2017
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  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. 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. 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. 
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. 
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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug therapy, intravenous 
drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  anus carcinoma (drug therapy, drug therapy)
  metastasis (drug therapy, drug therapy)
  metastastic squamous cell carcinoma of the anal canal (drug therapy, drug 
therapy)
EMTREE MEDICAL INDEX TERMS
  absence of side effects (side effect)
  adult
  anemia (side effect)
  article
  cancer growth
  clinical article
  controlled study
  disease severity
  drug efficacy
  drug safety
  drug tolerability
  fatigue (side effect)
  female
  human
  hypothyroidism (side effect)
  informed consent
  intention to treat analysis
  male
  multicenter study
  overall survival
  phase 2 clinical trial
  population research
  progression free survival
  rash (side effect)
  treatment response
  United States
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02314169)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170134429
MEDLINE PMID
  28223062 (http://www.ncbi.nlm.nih.gov/pubmed/28223062)
PUI
  L614502725
DOI
  10.1016/S1470-2045(17)30104-3
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(17)30104-3
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 54
TITLE
  Nivolumab-induced autoimmune diabetes
AUTHOR NAMES
  Chan J.T.K.
  Jones E.
AUTHOR ADDRESSES
  (Chan J.T.K., jenny.chan@health.qld.gov.au; Jones E.) Pharmacy Department, 
Redcliffe Hospital, Redcliffe, Australia.
CORRESPONDENCE ADDRESS
  J.T.K. Chan, Pharmacy Department, Redcliffe Hospital, Redcliffe, Australia. 
Email: jenny.chan@health.qld.gov.au
SOURCE
  Journal of Pharmacy Practice and Research (2017) 47:2 (136-139). Date of 
Publication: 1 Apr 2017
ISSN
  1445-937X
BOOK PUBLISHER
  Society of Hospital Pharmacists of Australia, shpa@shpa.org.au
ABSTRACT
  Background: Advances in research on lung cancer treatment have extended to 
manipulating the immune system for cancer treatment. A new class of 
monoclonal antibodies, which inhibit the programmed cell death 1 
(PD-1)/PD-ligand1 (PD-L1) immune checkpoint alliance, is being used for 
treatment in lung cancer, especially in heavily pretreated patients. An 
example of this class is nivolumab. Here we report an incident of autoimmune 
diabetes thought to have been induced by nivolumab. Clinical details: A 
78-year-old woman with no prior history of diabetes presented to the 
emergency department (ED) with a 3-day history of lethargy, anorexia, 
dyspnoea, polyuria and polydipsia, following her third treatment of 
nivolumab infusion for her metastatic lung cancer. Her pathology results and 
clinical symptoms were consistent with a diagnosis of diabetic ketoacidosis. 
Outcomes: The patient’s symptoms resolved after interventions of the ED, 
medical and endocrinology teams. She was eventually discharged from the 
hospital with insulin for her diabetes. Despite good disease response, the 
patient declined further nivolumab treatment. Manipulation of the immune 
checkpoint molecules may disrupt immunologic haemostasis and lead to 
autoimmune-like side effects. Similar adverse events have previously been 
reported with this drug class in the treatment of various cancers. 
Conclusion: This case report highlights a probable causal relationship 
between nivolumab and diabetes. The adverse effects associated with 
nivolumab may not be fully familiar to all. This case report serves to raise 
awareness among healthcare professionals about this rare 
nivolumab-associated adverse effect.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  carboplatin (drug therapy)
  gemcitabine (drug therapy)
  insulin
  insulin aspart (drug therapy)
  insulin glargine (drug therapy)
  pemetrexed (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune diabetic ketoacidosis (drug therapy, side effect, drug therapy, 
side effect)
  autoimmune disease (drug therapy, side effect, drug therapy, side effect)
  diabetic ketoacidosis (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal metastasis
  aged
  anorexia
  article
  brain metastasis
  case report
  drug withdrawal
  dyspnea
  evening dosage
  female
  hemostasis
  human
  lethargy
  liver metastasis
  morning dosage
  multiple cycle treatment
  non small cell lung cancer (drug therapy)
  polydipsia
  polyuria
DRUG TRADE NAMES
  lantus solostar
  novorapid flexpen
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  gemcitabine (103882-84-4)
  insulin (9004-10-8)
  insulin aspart (116094-23-6)
  insulin glargine (160337-95-1)
  nivolumab (946414-94-4)
  pemetrexed (137281-23-3, 150399-23-8)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170269026
PUI
  L615330800
DOI
  10.1002/jppr.1247
FULL TEXT LINK
  http://dx.doi.org/10.1002/jppr.1247
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 55
TITLE
  Adverse events of immune checkpoint inhibitors
ORIGINAL (NON-ENGLISH) TITLE
  Nebenwirkungen der Immun-Checkpoint-Inhibitoren
AUTHOR NAMES
  Foller S.
  Oppel-Heuchel H.
  Fetter I.
  Winkler Y.
  Grimm M.-O.
AUTHOR ADDRESSES
  (Foller S., Susan.Foller@med.uni-jena.de; Oppel-Heuchel H.; Fetter I.; 
Winkler Y.; Grimm M.-O.) Urologische Klinik und Poliklinik, 
Universitätsklinikum Jena, Lessingstraße 1, Jena, Germany.
CORRESPONDENCE ADDRESS
  S. Foller, Urologische Klinik und Poliklinik, Universitätsklinikum Jena, 
Lessingstraße 1, Jena, Germany. Email: Susan.Foller@med.uni-jena.de
SOURCE
  Urologe (2017) 56:4 (486-491). Date of Publication: 1 Apr 2017
ISSN
  1433-0563 (electronic)
  0340-2592
BOOK PUBLISHER
  Springer Verlag, service@springer.de
ABSTRACT
  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!
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction)
  immune checkpoint inhibitor (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  atezolizumab
  corticosteroid
  nivolumab
  pembrolizumab
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction
EMTREE MEDICAL INDEX TERMS
  article
  cancer chemotherapy
  cancer immunotherapy
  hepatitis (side effect)
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  liver function test
  liver toxicity (side effect)
  nephritis (side effect)
  nephrotoxicity (side effect)
  nuclear magnetic resonance imaging
  pneumonia (side effect)
  skin toxicity (side effect)
  x-ray computed tomography
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  German
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  20170156686
MEDLINE PMID
  28246759 (http://www.ncbi.nlm.nih.gov/pubmed/28246759)
PUI
  L614612308
DOI
  10.1007/s00120-017-0342-3
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00120-017-0342-3
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 56
TITLE
  Hypothyroidism in Cancer Patients on Immune Checkpoint Inhibitors with 
anti-PD1 Agents: Insights on Underlying Mechanisms
AUTHOR NAMES
  Alhusseini M.
  Samantray J.
AUTHOR ADDRESSES
  (Alhusseini M., malhusseini29@gmail.com; Samantray J.) Division of 
Endocrinology, University Health Center, Wayne State University, School of 
Medicine, 4201 St. Antoine, Detroit, United States.
CORRESPONDENCE ADDRESS
  M. Alhusseini, Division of Endocrinology, University Health Center, Wayne 
State University, School of Medicine, 4201 St. Antoine, Detroit, United 
States. Email: malhusseini29@gmail.com
SOURCE
  Experimental and Clinical Endocrinology and Diabetes (2017) 125:4 (267-269). 
Date of Publication: 1 Apr 2017
ISSN
  1439-3646 (electronic)
  0947-7349
BOOK PUBLISHER
  Georg Thieme Verlag, kunden.service@thieme.de
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
  pembrolizumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  levothyroxine (drug therapy)
  prednisone (drug therapy)
  thyroglobulin (endogenous compound)
  thyroid antibody (endogenous compound)
  thyroid peroxidase antibody (endogenous compound)
  thyroid stimulating immunoglobulin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  hypothyroidism (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult
  aged
  antibody blood level
  article
  cancer patient
  case study
  clinical article
  combination drug therapy
  female
  Hodgkin disease (drug therapy)
  human
  hyperthyroidism (side effect)
  male
  middle aged
  non small cell lung cancer (drug therapy)
  priority journal
  remission
  thyroglobulin blood level
  thyroiditis (drug therapy, side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  prednisone (53-03-2)
  thyroglobulin (9010-34-8)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Hematology (25)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170045952
MEDLINE PMID
  28073132 (http://www.ncbi.nlm.nih.gov/pubmed/28073132)
PUI
  L614085348
DOI
  10.1055/s-0042-119528
FULL TEXT LINK
  http://dx.doi.org/10.1055/s-0042-119528
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 57
TITLE
  Phase 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in 
Japanese patients with advanced melanoma (KEYNOTE-041)
AUTHOR NAMES
  Yamazaki N.
  Takenouchi T.
  Fujimoto M.
  Ihn H.
  Uchi H.
  Inozume T.
  Kiyohara Y.
  Uhara H.
  Nakagawa K.
  Furukawa H.
  Wada H.
  Noguchi K.
  Shimamoto T.
  Yokota K.
AUTHOR ADDRESSES
  (Yamazaki N., nyamazaki@ncc.go.jp) Department of Dermatologic Oncology, 
National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan.
(Takenouchi T.) Department of Dermatology, Niigata Cancer Center Hospital, 
Niigata, Japan.
(Fujimoto M.) Department of Dermatology, Faculty of Medicine, University of 
Tsukuba, Tsukuba, Japan.
(Ihn H.) Department of Dermatology and Plastic Surgery, Faculty of Life 
Sciences, Kumamoto University, Kumamoto, Japan.
(Uchi H.) Department of Dermatology, Kyushu University School of Medicine, 
Fukuoka, Japan.
(Inozume T.) Department of Dermatology, Faculty of Medicine, University of 
Yamanashi, Yamanashi, Japan.
(Kiyohara Y.) Department of Dermatology, Shizuoka Cancer Center, Shizuoka, 
Japan.
(Uhara H.) Department of Dermatology, Sapporo Medical University School of 
Medicine, Sapporo, Japan.
(Nakagawa K.) Department of Medical Oncology, Kindai University Faculty of 
Medicine, Osaka-sayama, Japan.
(Furukawa H.) Department of Plastic and Reconstructive Surgery, Graduate 
School of Medicine, Hokkaido University, Sapporo, Japan.
(Wada H.) Department of Dermatology, Yokohama City University School of 
Medicine, Yokohama, Japan.
(Noguchi K.; Shimamoto T.) MSD K.K., Tokyo, Japan.
(Yokota K.) Department of Dermatology, Nagoya University Graduate School of 
Medicine, Nagoya, Japan.
CORRESPONDENCE ADDRESS
  N. Yamazaki, Department of Dermatologic Oncology, National Cancer Center 
Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan. Email: nyamazaki@ncc.go.jp
SOURCE
  Cancer Chemotherapy and Pharmacology (2017) 79:4 (651-660). Date of 
Publication: 1 Apr 2017
ISSN
  1432-0843 (electronic)
  0344-5704
BOOK PUBLISHER
  Springer Verlag, service@springer.de
ABSTRACT
  Purpose: This phase I b study evaluated the safety and anti-tumor activity 
of pembrolizumab in Japanese patients with advanced melanoma. 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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy, 
intravenous drug administration)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  cancer chemotherapy
  cutaneous melanoma (drug therapy, drug therapy)
  mucosal melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adult
  aged
  alanine aminotransferase blood level
  anemia (side effect)
  antineoplastic activity
  article
  aspartate aminotransferase blood level
  brain disease (side effect)
  brain hemorrhage (side effect)
  cancer survival
  cholestasis (side effect)
  clinical article
  colitis (side effect)
  diarrhea (side effect)
  drug eruption (side effect)
  drug safety
  dry skin (side effect)
  eosinophil count
  female
  histopathology
  human
  human tissue
  hyperglycemia (side effect)
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypopigmentation (side effect)
  hypothyroidism (side effect)
  Japanese (people)
  lymphocytopenia (side effect)
  maculopapular rash (side effect)
  malaise (side effect)
  male
  multicenter study
  nausea (side effect)
  open study
  overall survival
  phase 1 clinical trial
  priority journal
  pruritus (side effect)
  side effect (side effect)
  survival rate
  survival time
  treatment outcome
  treatment response
  upper abdominal pain (side effect)
  vitiligo (side effect)
DRUG TRADE NAMES
  mk 3475
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02180061)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170184749
MEDLINE PMID
  28283736 (http://www.ncbi.nlm.nih.gov/pubmed/28283736)
PUI
  L614745039
DOI
  10.1007/s00280-016-3237-x
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00280-016-3237-x
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 58
TITLE
  Isolated adrenocorticotropic hormone deficiency associated with nivolumab 
therapy
AUTHOR NAMES
  Narahira A.
  Yanagi T.
  Cho K.Y.
  Nakamura A.
  Miyoshi H.
  Hata H.
  Imafuku K.
  Kitamura S.
  Shimizu H.
AUTHOR ADDRESSES
  (Narahira A.; Yanagi T., yanagi@med.hokudai.ac.jp; Hata H.; Imafuku K.; 
Kitamura S.; Shimizu H.) Department of Dermatology, Hokkaido University 
Graduate School of Medicine, Sapporo, Japan.
(Cho K.Y.; Nakamura A.; Miyoshi H.) Division of Rheumatology, Endocrinology 
and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, 
Japan.
CORRESPONDENCE ADDRESS
  T. Yanagi, Department of Dermatology, Hokkaido University Graduate School of 
Medicine, Sapporo, Japan. Email: yanagi@med.hokudai.ac.jp
SOURCE
  Journal of Dermatology (2017) 44:4 (e70). Date of Publication: 1 Apr 2017
ISSN
  1346-8138 (electronic)
  0385-2407
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  corticotropin releasing factor (endogenous compound)
  follitropin (endogenous compound)
  growth hormone (endogenous compound)
  hydrocortisone (drug therapy)
  luteinizing hormone (endogenous compound)
  prolactin (endogenous compound)
  sodium (endogenous compound)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  corticotropin deficiency (drug therapy, side effect, drug therapy, side 
effect)
  isolated ACTH deficiency (drug therapy, side effect, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  aged
  anterior pituitary stimulation test
  bradykinesia
  case report
  corticotropin blood level
  disease association
  endocrine function test
  fatigue
  female
  human
  hydrocortisone blood level
  hyponatremia
  letter
  loss of appetite
  metastatic melanoma (drug therapy)
  multiple cycle treatment
  sodium blood level
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  corticotropin releasing factor (9015-71-8, 178359-01-8, 79804-71-0, 
86297-72-5, 86784-80-7)
  follitropin (9002-68-0)
  growth hormone (36992-73-1, 37267-05-3, 66419-50-9, 9002-72-6)
  hydrocortisone (50-23-7)
  luteinizing hormone (39341-83-8, 9002-67-9)
  nivolumab (946414-94-4)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
  sodium (7440-23-5)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170258312
PUI
  L615243911
DOI
  10.1111/1346-8138.13571
FULL TEXT LINK
  http://dx.doi.org/10.1111/1346-8138.13571
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 59
TITLE
  Safety and tolerability of PD-1/PD-L1 inhibitors compared with chemotherapy 
in patients with advanced cancer: A meta-analysis
AUTHOR NAMES
  Nishijima T.F.
  Shachar S.S.
  Nyrop K.A.
  Muss H.B.
AUTHOR ADDRESSES
  (Nishijima T.F., Tomohiro.Nishijima@unchealth.unc.edu; Nyrop K.A.; Muss 
H.B.) UNC Lineberger Comprehensive Cancer Center, Chapel Hill, United 
States.
(Shachar S.S.) Division of Oncology, Rambam Health Care Campus, Haifa, 
Israel.
CORRESPONDENCE ADDRESS
  T.F. Nishijima, 170 Manning Drive, Campus Box 7305, Chapel Hill, United 
States. Email: Tomohiro.Nishijima@unchealth.unc.edu
SOURCE
  Oncologist (2017) 22:4 (470-479). Date of Publication: 1 Apr 2017
ISSN
  1549-490X (electronic)
  1083-7159
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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. 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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 receptor
EMTREE DRUG INDEX TERMS
  atezolizumab
  nivolumab
  pembrolizumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  chemotherapy
  drug safety
  drug tolerability
  malignant neoplasm
EMTREE MEDICAL INDEX TERMS
  anorexia
  colitis
  constipation
  diarrhea
  dyspnea
  fatigue
  hematologic disease
  human
  immunopathology
  insomnia
  melanoma
  meta analysis
  nausea
  non small cell lung cancer
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pneumonia
  priority journal
  quality of life
  randomized controlled trial (topic)
  review
  sensory neuropathy
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170276681
MEDLINE PMID
  28275115 (http://www.ncbi.nlm.nih.gov/pubmed/28275115)
PUI
  L615296951
DOI
  10.1634/theoncologist.2016-0419
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2016-0419
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 60
TITLE
  Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP)
AUTHOR NAMES
  King J.
  de la Cruz J.
  Lutzky J.
AUTHOR ADDRESSES
  (King J.; Lutzky J., jose.lutzky@msmc.com) Division of Hematology/Oncology, 
Mount Sinai Comprehensive Cancer Center, 4306 Alton Road, Miami Beach, 
United States.
(de la Cruz J.) Mount Sinai Medical Center, Department of Internal Medicine, 
4300 Alton Road, Miami Beach, United States.
CORRESPONDENCE ADDRESS
  J. Lutzky, Division of Hematology/Oncology, Mount Sinai Comprehensive Cancer 
Center, 4306 Alton Road, Miami Beach, United States. Email: 
jose.lutzky@msmc.com
SOURCE
  Journal for ImmunoTherapy of Cancer (2017) 5:1 Article Number: 19. Date of 
Publication: 21 Mar 2017
ISSN
  2051-1426 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  bilirubin (endogenous compound)
  C reactive protein (endogenous compound)
  ciprofloxacin plus dexamethasone (drug therapy, topical drug administration)
  clindamycin (drug therapy, oral drug administration)
  creatinine (endogenous compound)
  haptoglobin (endogenous compound)
  hemoglobin (endogenous compound)
  immunoglobulin (drug therapy)
  methylprednisolone sodium succinate (drug therapy, intravenous drug 
administration)
  prednisone (drug therapy)
  rituximab (drug therapy)
  von Willebrand factor cleaving proteinase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug induced disease
  thrombotic thrombocytopenic purpura (drug therapy, side effect, diagnosis, 
drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure
  adjuvant therapy
  aged
  article
  case report
  clinical trial (topic)
  diarrhea
  drug dose reduction
  enzyme activity
  erythrocyte transfusion
  external otitis (drug therapy)
  fatigue
  female
  fever
  human
  hyperglycemia
  immunotoxicity
  kidney function
  leukocytosis
  melanoma (drug therapy)
  mental disease
  microcytic anemia
  multiple cycle treatment
  nausea and vomiting
  oliguria
  plasma exchange
  plasmapheresis
  platelet count
  priority journal
  pruritus (drug therapy, side effect)
  rash (side effect)
  thrombocytopenia
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  bilirubin (18422-02-1, 635-65-4)
  C reactive protein (9007-41-4)
  clindamycin (18323-44-9)
  creatinine (19230-81-0, 60-27-5)
  haptoglobin (9087-69-8)
  hemoglobin (9008-02-0)
  immunoglobulin (9007-83-4)
  ipilimumab (477202-00-9)
  methylprednisolone sodium succinate (2375-03-3, 2921-57-5)
  prednisone (53-03-2)
  rituximab (174722-31-7)
  von Willebrand factor cleaving proteinase (334869-10-2)
EMBASE CLASSIFICATIONS
  Hematology (25)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170211086
PUI
  L614884912
DOI
  10.1186/s40425-017-0224-7
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40425-017-0224-7
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 61
TITLE
  Management of toxicities of immune checkpoint inhibitors
AUTHOR NAMES
  Horio Y.
AUTHOR ADDRESSES
  (Horio Y.) Department of Outpatient Services, Aichi Cancer Center Hospital, 
1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, Japan.
CORRESPONDENCE ADDRESS
  Y. Horio, Department of Outpatient Services, Aichi Cancer Center Hospital, 
1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, Japan.
SOURCE
  Japanese Journal of Cancer and Chemotherapy (2017) 44:3 (185-190). Date of 
Publication: 1 Mar 2017
ISSN
  0385-0684
BOOK PUBLISHER
  Japanese Journal of Cancer and Chemotherapy Publishers Inc., 
ccp@blue.ocn.ne.jp
ABSTRACT
  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 
malignan-cies. Immune-related Adverse Events (irAEs) which are different 
from adverse events of conventional chemotherapy and molecular targeted 
therapy, occur as a consequence of impaired seif-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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent
  immune checkpoint inhibitor (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  atezolizumab (adverse drug reaction, drug comparison)
  ipilimumab (adverse drug reaction, drug comparison)
  nivolumab (adverse drug reaction, drug comparison)
  pembrolizumab (adverse drug reaction, drug comparison)
  unclassified drug
EMTREE MEDICAL INDEX TERMS
  drug tolerance
  endocrine disease (side effect)
  gastrointestinal symptom (side effect)
  human
  liver toxicity (side effect)
  lung toxicity (side effect)
  nephrotoxicity (side effect)
  review
  side effect (side effect)
  skin toxicity (side effect)
  T lymphocyte
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English, Japanese
EMBASE ACCESSION NUMBER
  20170415653
MEDLINE PMID
  28292987 (http://www.ncbi.nlm.nih.gov/pubmed/28292987)
PUI
  L616692686
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 62
TITLE
  PD-L1 Expression in Premalignant and Malignant Trophoblasts From Gestational 
Trophoblastic Diseases Is Ubiquitous and Independent of Clinical Outcomes
AUTHOR NAMES
  Bolze P.-A.
  Patrier S.
  Massardier J.
  Hajri T.
  Abbas F.
  Schott A.M.
  Allias F.
  Devouassoux-Shisheboran M.
  Freyer G.
  Golfier F.
  You B.
AUTHOR ADDRESSES
  (Bolze P.-A., pierre-adrien.bolze@chu-lyon.fr; Golfier F.) Department of 
Gynecological Surgery, Oncology and Obstetrics, Pierre-Bénite, France.
(Bolze P.-A., pierre-adrien.bolze@chu-lyon.fr; Massardier J.; Hajri T.; 
Abbas F.; Schott A.M.; Allias F.; Devouassoux-Shisheboran M.; Freyer G.; 
Golfier F.; You B.) French Center for Trophoblastic Diseases, University 
Hospitals of Lyon, Centre Hospitalier Lyon Sud, 165, Chemin du Grand 
Revoyet, 2Ème Étage, Pierre-Bénite, France.
(Bolze P.-A., pierre-adrien.bolze@chu-lyon.fr; Patrier S.) Joint Unit 
Hospices Civils de Lyon-bioMerieux, University Hospital Lyon Sud, 
Pierre-Bénite, France.
(Patrier S.) Department of Pathology, University Hospital of Rouen, Rouen, 
France.
(Massardier J.) University Hospital Femme Mere Enfant, Department of 
Prenatal Diagnosis, Bron, France.
(Hajri T.; Abbas F.; Schott A.M.) Pôle Information Médicale Evaluation 
Recherche, Hospices Civils de Lyon, Bron, France.
(Allias F.; Devouassoux-Shisheboran M.) Department of Pathology, University 
Hospital La Croix Rousse, Lyon, France.
(Freyer G.; You B.) Department of Medical Oncology, HCL Cancer Institute, 
University Hospitals of Lyon, Lyon, France.
(You B.) Lyon 1 University, Lyon, France.
CORRESPONDENCE ADDRESS
  P.-A. Bolze, French Center for Trophoblastic Diseases, University Hospitals 
of Lyon, Centre Hospitalier Lyon Sud, 165, Chemin du Grand Revoyet, 2Ème 
Étage, Pierre-Bénite, France. Email: pierre-adrien.bolze@chu-lyon.fr
SOURCE
  International Journal of Gynecological Cancer (2017) 27:3 (554-561). Date of 
Publication: 1 Mar 2017
ISSN
  1525-1438 (electronic)
  1048-891X
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  Objective: Recently reported expression of programmed cell death 1 ligand 1 
(PD-L1) in gestational trophoblastic diseases (GTDs) suggests that the 
immune tolerance of pregnancy might be hijacked during neoplastic process. 
We assessed PD-L1 protein expression in premalignant and malignant GTD 
lesions and analyzed associations with disease severity and chemotherapy 
outcomes. Methods: We included 83 GTD whole-tissue sections from 76 patients 
in different treatment settings. PD-L1 protein expression was assessed with 
immunohistochemistry in each trophoblast subtype with the Allred total score 
(ATS), which combines intensity and proportion expression on a 0- to 8-point 
scale. Peritumoral immune infiltrate was scored on 
hematoxylin-eosin-safran-stained slides. Results: PD-L1 expression was 
ubiquitous and strong in all GTD trophoblast subtypes. For invasive moles, 
ATS scores were maximal at 8 in 100%, 100%, and 75% of syncytiotrophoblast, 
villous cytotrophoblast, and extravillous cytotrophoblast specimens, 
respectively. For choriocarcinomas, ATS was 8 in 80% of specimens. Immune 
infiltrates were moderate to severe in 61%, 100%, and 100% of peritumoral 
zones of choriocarcinoma, epithelioid trophoblastic tumor, and invasive 
moles, respectively. Because of the homogeneous pathological findings, no 
significant differences in PD-L1 expression profiles or peritumoral immune 
infiltrates were found regarding FIGO (International Federation of 
Gynecology Obstetrics) prognostic score, fatal outcome, or chemosensitivity. 
Conclusions: We confirm that PD-L1 is constitutively expressed in all GTD 
premalignant and malignant trophoblast subtypes, independently from FIGO 
score, chemoresistance, or fatal outcomes, thereby suggesting a crucial role 
for PD-L1 in the development and tolerance of GTD. Assessment of anti-PD-L1 
drug in GTD patients has been activated.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy)
  chorionic gonadotropin (drug therapy)
  eosin
  hematoxylin
  methotrexate (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  trophoblastic tumor (drug therapy, drug resistance, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer chemotherapy
  cancer hormone therapy
  cancer resistance
  choriocarcinoma (drug therapy)
  clinical outcome
  controlled study
  cytotrophoblast
  disease severity
  female
  human
  human tissue
  immunohistochemistry
  major clinical study
  metastasis (drug therapy)
  priority journal
  protein expression
  syncytiotrophoblast
  tissue section
  trophoblast
CAS REGISTRY NUMBERS
  chorionic gonadotropin (9002-61-3)
  eosin (17372-87-1, 51395-88-1, 548-26-5)
  hematoxylin (517-28-2)
  methotrexate (15475-56-6, 59-05-2, 7413-34-5)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Endocrinology (3)
  Drug Literature Index (37)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170175233
MEDLINE PMID
  28060141 (http://www.ncbi.nlm.nih.gov/pubmed/28060141)
PUI
  L614704009
DOI
  10.1097/IGC.0000000000000892
FULL TEXT LINK
  http://dx.doi.org/10.1097/IGC.0000000000000892
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 63
TITLE
  Isolated adrenocorticotropic hormone deficiency possibly caused by nivolumab 
in a metastatic melanoma patient
AUTHOR NAMES
  Fujimura T.
  Kambayashi Y.
  Furudate S.
  Kakizaki A.
  Hidaka T.
  Haga T.
  Hashimoto A.
  Morimoto R.
  Aiba S.
AUTHOR ADDRESSES
  (Fujimura T., tfujimura1@mac.com; Kambayashi Y.; Furudate S.; Kakizaki A.; 
Hidaka T.; Haga T.; Hashimoto A.; Aiba S.) Department of Dermatology, Tohoku 
University Graduate School of Medicine, Sendai, Japan.
(Morimoto R.) Division of Nephrology, Endocrinology and Vascular Medicine, 
Department of Medicine, Tohoku University Hospital, Sendai, Japan.
CORRESPONDENCE ADDRESS
  T. Fujimura, Department of Dermatology, Tohoku University Graduate School of 
Medicine, Sendai, Japan. Email: tfujimura1@mac.com
SOURCE
  Journal of Dermatology (2017) 44:3 (e13-e14). Date of Publication: 1 Mar 
2017
ISSN
  1346-8138 (electronic)
  0385-2407
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  CD163 antigen (endogenous compound)
  corticotropin (endogenous compound)
  epithelial derived neutrophil activating factor 78 (endogenous compound)
  thyrotropin (endogenous compound)
  tumor necrosis factor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  corticotropin deficiency (side effect, diagnosis, side effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  acral lentiginous melanoma (surgery)
  aged
  brain metastasis (diagnosis, radiotherapy)
  case report
  cutaneous melanoma (surgery)
  CyberKnife
  human
  human tissue
  hypopituitarism
  letter
  male
  nuclear magnetic resonance imaging
  skin nodule
  thyrotropin blood level
DEVICE TRADE NAMES
  CyberKnife  , United StatesAccuray

DEVICE MANUFACTURERS
   (United States)Accuray
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  epithelial derived neutrophil activating factor 78 (136956-40-6)
  nivolumab (946414-94-4)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Biophysics, Bioengineering and Medical Instrumentation (27)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20160553134
PUI
  L611375839
DOI
  10.1111/1346-8138.13532
FULL TEXT LINK
  http://dx.doi.org/10.1111/1346-8138.13532
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 64
TITLE
  Multiplatform-based molecular subtypes of non-small-cell lung cancer
AUTHOR NAMES
  Chen F.
  Zhang Y.
  Parra E.
  Rodriguez J.
  Behrens C.
  Akbani R.
  Lu Y.
  Kurie J.M.
  Gibbons D.L.
  Mills G.B.
  Wistuba I.I.
  Creighton C.J.
AUTHOR ADDRESSES
  (Chen F.; Zhang Y.; Creighton C.J., creighto@bcm.edu) Dan L. Duncan 
Comprehensive Cancer Center, Division of Biostatistics, Baylor College of 
Medicine, Houston, United States.
(Parra E.; Rodriguez J.; Behrens C.; Wistuba I.I.) Department of 
Translational Molecular Pathology, University of Texas MD Anderson Cancer, 
Houston, United States.
(Akbani R.; Creighton C.J., creighto@bcm.edu) Department of Bioinformatics 
and Computational Biology, University of Texas MD Anderson Cancer Center, 
Houston, United States.
(Lu Y.; Mills G.B.) Department of Systems Biology, University of Texas MD 
Anderson Cancer Center, Houston, United States.
(Kurie J.M.; Gibbons D.L.; Wistuba I.I.) Department of Thoracic/Head and 
Neck Medical Oncology, University of Texas MD Anderson Cancer Center, 
Houston, United States.
(Gibbons D.L.) Department of Molecular and Cellular Oncology, University of 
Texas MD Anderson Cancer Center, Houston, United States.
(Creighton C.J., creighto@bcm.edu) Department of Medicine, Baylor College of 
Medicine, Houston, United States.
CORRESPONDENCE ADDRESS
  C.J. Creighton, Dan L. Duncan Comprehensive Cancer Center, Division of 
Biostatistics, Baylor College of Medicine, Houston, United States. Email: 
creighto@bcm.edu
SOURCE
  Oncogene (2017) 36:10 (1384-1393). Date of Publication: 1 Mar 2017
ISSN
  1476-5594 (electronic)
  0950-9232
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  cancer testis antigen (endogenous compound)
  CD3 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  mammalian target of rapamycin (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 ligand 2 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  protein p63 (endogenous compound)
  synaptophysin (endogenous compound)
  transcription factor Sox2 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer classification
  lung adenocarcinoma
  non small cell lung cancer
  squamous cell lung carcinoma
EMTREE MEDICAL INDEX TERMS
  article
  cancer genetics
  cancer prognosis
  cell infiltration
  clinical feature
  CpG island
  DNA methylation
  gene expression
  human
  human genome
  immunocompetent cell
  immunohistochemistry
  major clinical study
  molecular pathology
  neuroendocrine tumor
  priority journal
  reference database
  tumor differentiation
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170193351
MEDLINE PMID
  27775076 (http://www.ncbi.nlm.nih.gov/pubmed/27775076)
PUI
  L614715376
DOI
  10.1038/onc.2016.303
FULL TEXT LINK
  http://dx.doi.org/10.1038/onc.2016.303
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 65
TITLE
  Erratum: Evaluation of efficacy and safety of different pembrolizumab 
dose/schedules in treatment of non-small-cell lung cancer and melanoma: A 
systematic reviewAbdel-RahmanEfficacy & safety of different pembrolizumab 
dose/schedules in treatment of NSCLC & melanoma (Immunotherapy (2016) 8:12 
(1383-1391))
AUTHOR ADDRESSES
  SOURCE
  Immunotherapy (2017) 9:4 (111). Date of Publication: 1 Mar 2017
ISSN
  1750-7448 (electronic)
  1750-743X
BOOK PUBLISHER
  Future Medicine Ltd., info@futuremedicine.com
ABSTRACT
  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). 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. Selection criteria: Prospective clinical trials 
reporting the outcomes of more than one dose schedule of pembrolizumab in 
the treatment of advanced NSCLC and melanoma. Data collection & analysis: 
The review author extracted information on the outcomes of the study for 
this review, and presented the results. 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). Conclusions: Given the 
equivalence in efficacy and safety between lower doses and higher doses of 
pembrolizumab, 2 mg/kg every 3 weeks seems to be an appropriate dose for 
routine practice in advanced pretreated NSCLC and melanoma. The Authors and 
Editors would like to sincerely apologize for any inconvenience or confusion 
this may have caused.
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  error
EMTREE MEDICAL INDEX TERMS
  erratum
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170213187
PUI
  L614944892
DOI
  10.2217/imt-2016-0075c1
FULL TEXT LINK
  http://dx.doi.org/10.2217/imt-2016-0075c1
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 66
TITLE
  Acute hyperglycemia associated with anti-cancer medication
AUTHOR NAMES
  Hwangbo Y.
  Lee E.K.
AUTHOR ADDRESSES
  (Hwangbo Y.; Lee E.K., waterfol@ncc.re.kr) Department of Internal Medicine, 
Center for Thyroid Cancer, National Cancer Center, Goyang, South Korea.
CORRESPONDENCE ADDRESS
  E.K. Lee, Department of Internal Medicine, Center for Thyroid Cancer, 
National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, South Korea. 
Email: waterfol@ncc.re.kr
SOURCE
  Endocrinology and Metabolism (2017) 32:1 (23-29). Date of Publication: 1 Mar 
2017
ISSN
  2093-5978 (electronic)
  2093-596X
BOOK PUBLISHER
  Korean Endocrine Society, endo@endocrinololgy.or.kr
ABSTRACT
  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 anticancer 
therapy, frequent monitoring and proper management are important for 
promoting the efficacy of anti-cancer therapy and improving patients' 
quality of life.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  acarbose
  asparaginase (adverse drug reaction)
  bms 936559 (adverse drug reaction)
  cyclophosphamide (adverse drug reaction)
  doxorubicin (adverse drug reaction)
  everolimus (adverse drug reaction)
  fluorouracil (adverse drug reaction)
  glucocorticoid (adverse drug reaction)
  glucose (endogenous compound)
  hemoglobin A1c (endogenous compound)
  mammalian target of rapamycin inhibitor
  metformin
  pembrolizumab (adverse drug reaction)
  prednisolone (adverse drug reaction)
  prednisone (adverse drug reaction)
  sulfonylurea
  temsirolimus (adverse drug reaction)
  vincristine (adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hyperglycemia (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  cancer immunotherapy
  cancer patient
  diabetic patient
  disease severity
  drug monitoring
  glucose blood level
  glycemic control
  human
  impaired glucose tolerance
  insulin dependent diabetes mellitus
  insulin release
  insulin resistance
  medical decision making
  prevalence
  quality of life
  review
  whole body radiation
DRUG TRADE NAMES
  bms 936559
CAS REGISTRY NUMBERS
  acarbose (56180-94-0)
  asparaginase (9015-68-3, 1349719-22-7)
  cyclophosphamide (50-18-0)
  doxorubicin (23214-92-8, 25316-40-9)
  everolimus (159351-69-6)
  fluorouracil (51-21-8)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  metformin (1115-70-4, 657-24-9)
  pembrolizumab (1374853-91-4)
  prednisolone (50-24-8)
  prednisone (53-03-2)
  temsirolimus (162635-04-3, 343261-52-9)
  vincristine (57-22-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170234050
PUI
  L615058621
DOI
  10.3803/EnM.2017.32.1.23
FULL TEXT LINK
  http://dx.doi.org/10.3803/EnM.2017.32.1.23
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 67
TITLE
  Hypothyroidism associated with nivolumab treatment of unresectable malignant 
melanoma
AUTHOR NAMES
  Imafuku K.
  Yoshino K.
  Yamaguchi K.
  Tsuboi S.
  Ohara K.
  Hata H.
AUTHOR ADDRESSES
  (Imafuku K., imafukukeisuke@gmail.com; Yoshino K.; Yamaguchi K.; Tsuboi S.; 
Ohara K.) Department of Dermatology, Tokyo Metropolitan Cancer and 
Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagoame, 
Bunkyo-ku, Tokyo, Tokyo, Japan.
(Hata H.) Department of Dermatology, Hokkaido University Graduate School of 
Medicine, Sapporo, Japan.
SOURCE
  Clinical and Experimental Dermatology (2017) 42:2 (217-218). Date of 
Publication: 1 Mar 2017
ISSN
  1365-2230 (electronic)
  0307-6938
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  thyroid hormone (drug therapy)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug induced disease (drug therapy, side effect, drug therapy, side effect)
  hypothyroidism (drug therapy, side effect, drug therapy, side effect)
  inoperable cancer (drug therapy, drug therapy)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  cancer immunotherapy
  case report
  disease exacerbation
  drug withdrawal
  heart failure
  hormonal therapy
  human
  letter
  male
  multiple cycle treatment
  patient care
  priority journal
  thyrotropin blood level
  thyroxine blood level
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170052142
MEDLINE PMID
  28052364 (http://www.ncbi.nlm.nih.gov/pubmed/28052364)
PUI
  L614107353
DOI
  10.1111/ced.13028
FULL TEXT LINK
  http://dx.doi.org/10.1111/ced.13028
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 68
TITLE
  Tumor-associated macrophage expression of PD-L1 in implants of high grade 
serous ovarian carcinoma: A comparison of matched primary and metastatic 
tumors
AUTHOR NAMES
  Gottlieb C.E.
  Mills A.M.
  Cross J.V.
  Ring K.L.
AUTHOR ADDRESSES
  (Gottlieb C.E., CEG2KC@hscmail.mcc.virginia.edu; Mills A.M., 
AMM7R@hscmail.mcc.virginia.edu; Cross J.V., jvc5b@eservices.virginia.edu) 
Department of Pathology, University of Virginia Health System, PO Box 
800712, Charlottesville, United States.
(Ring K.L., kel7j@hscmail.mcc.virginia.edu) Division of Gynecologic 
Oncology, Department of Obstetrics and Gynecology, University of Virginia 
Health System, PO Box 800712, Charlottesville, United States.
CORRESPONDENCE ADDRESS
  K.L. Ring, Department of Obstetrics and Gynecology, Division of Gynecologic 
Oncology, University of Virginia Health System, Box 800712, Charlottesville, 
United States. Email: kel7j@hscmail.mcc.virginia.edu
SOURCE
  Gynecologic Oncology (2017) 144:3 (607-612). Date of Publication: 1 Mar 2017
ISSN
  1095-6859 (electronic)
  0090-8258
BOOK PUBLISHER
  Academic Press Inc., apjcs@harcourt.com
ABSTRACT
  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 naïve tumors. We investigated PD-L1 
expression in primary ovarian tumors and matched metastatic implants from 
predominantly treatment-naïve HGSOC. 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. Results Eight percent of primary HGSOC demonstrated PD-L1 expression. 
In contrast, 74% showed PD-L1 + TAM. In the 16 treatment naïve 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 naïve cases. 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 naïve specimens. Clinical trials 
are needed to determine whether tumor-associated staining correlates with 
clinical response to PD-1/PD-L1 inhibition.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  bevacizumab (drug therapy)
  carboplatin (drug therapy)
  CD68 antigen (endogenous compound)
  paclitaxel (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  implant
  metastasis
  ovary carcinoma (drug therapy, drug therapy, surgery)
  primary tumor
  tumor associated leukocyte
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer adjuvant therapy
  cancer cell
  cancer grading
  clinical article
  cytoreductive surgery
  female
  human
  human tissue
  immunohistochemistry
  priority journal
  protein expression
  tissue microarray
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  carboplatin (41575-94-4)
  paclitaxel (33069-62-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170027519
MEDLINE PMID
  28065619 (http://www.ncbi.nlm.nih.gov/pubmed/28065619)
PUI
  L614009938
DOI
  10.1016/j.ygyno.2016.12.021
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ygyno.2016.12.021
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 69
TITLE
  Fulminant type I diabetes mellitus associated with nivolumab in a patient 
with relapsed classical Hodgkin lymphoma
AUTHOR NAMES
  Munakata W.
  Ohashi K.
  Yamauchi N.
  Tobinai K.
AUTHOR ADDRESSES
  (Munakata W., wmunakat@ncc.go.jp; Yamauchi N.; Tobinai K.) Department of 
Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 
Japan.
(Ohashi K.) Department of General Internal Medicine, National Cancer Center 
Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan.
CORRESPONDENCE ADDRESS
  W. Munakata, Department of Hematology, National Cancer Center Hospital, 
5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan. Email: wmunakat@ncc.go.jp
SOURCE
  International Journal of Hematology (2017) 105:3 (383-386). Date of 
Publication: 1 Mar 2017
ISSN
  1865-3774 (electronic)
  0925-5710
BOOK PUBLISHER
  Springer Tokyo, orders@springer.jp
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  bleomycin (drug combination, drug therapy)
  brentuximab vedotin (drug therapy)
  C peptide (endogenous compound)
  dacarbazine (drug combination, drug therapy)
  doxorubicin (drug combination, drug therapy)
  glucose (endogenous compound)
  hemoglobin A1c (endogenous compound)
  HLA B antigen (endogenous compound)
  insulin (drug therapy, endogenous compound)
  vinblastine (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer recurrence
  classical Hodgkin lymphoma (drug therapy, drug therapy)
  insulin dependent diabetes mellitus (drug therapy, side effect, diagnosis, 
drug therapy, etiology, side effect)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  case report
  computer assisted tomography
  disease course
  disease severity
  fatigue (side effect)
  genetic background
  genetic susceptibility
  glucose blood level
  haplotype
  human
  hyperglycemia (side effect)
  insulin release
  Japanese (people)
  laboratory test
  male
  multiple cycle treatment
  nuclear magnetic resonance imaging
  pancreatitis (diagnosis)
  polyuria (side effect)
  thirst
CAS REGISTRY NUMBERS
  bleomycin (11056-06-7, 9041-93-4)
  brentuximab vedotin (914088-09-8)
  C peptide (59112-80-0)
  dacarbazine (4342-03-4)
  doxorubicin (23214-92-8, 25316-40-9)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
  nivolumab (946414-94-4)
  vinblastine (865-21-4)
EMBASE CLASSIFICATIONS
  Human Genetics (22)
  Hematology (25)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160703230
MEDLINE PMID
  27696192 (http://www.ncbi.nlm.nih.gov/pubmed/27696192)
PUI
  L612449185
DOI
  10.1007/s12185-016-2101-4
FULL TEXT LINK
  http://dx.doi.org/10.1007/s12185-016-2101-4
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 70
TITLE
  Risk of endocrine adverse events in cancer patients treated with PD-1 
inhibitors: A systematic review and meta-analysis
AUTHOR NAMES
  Shang Y.H.
  Zhang Y.
  Li J.H.
  Li P.
  Zhang X.
AUTHOR ADDRESSES
  (Zhang X., xizhang1225@foxmail.com) Department of Radiation Oncology, 
Affiliated Hospital of Hebei University, 212 East Yuhua Road, Baoding, 
Hebei, China.
(Shang Y.H.) Department of Medical Oncology, Affiliated Hospital of Hebei 
University, Baoding, China.
(Zhang Y.) Department of Internal Medicine, Baoding Children's Hospital, 
Baoding, China.
(Li J.H.) Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei 
University, Baoding, China.
(Li P.) Departments of Ultrasound, Affiliated Hospital of Hebei University, 
Baoding, China.
CORRESPONDENCE ADDRESS
  X. Zhang, Department of Radiation Oncology, Affiliated Hospital of Hebei 
University, 212 East Yuhua Road, Baoding, Hebei, China. Email: 
xizhang1225@foxmail.com
SOURCE
  Immunotherapy (2017) 9:3 (261-272). Date of Publication: 1 Mar 2017
ISSN
  1750-7448 (electronic)
  1750-743X
BOOK PUBLISHER
  Future Medicine Ltd., info@futuremedicine.com
ABSTRACT
  Aim: We conducted this meta-analysis to investigate the overall incidence 
and risk of endocrine complications in cancer patients treated with PD-1 
inhibitors. Methods: Pubmed, Embase and oncology conference proceedings were 
searched for relevant studies. 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. Conclusion: Treatment with PD-1 
inhibitors is associated with an increased risk of developing hypothyroidism 
and hyperthyroidism, but not for hypophysitis.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug therapy)
  pembrolizumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug therapy)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (clinical trial, drug comparison, drug therapy)
  carboplatin (drug combination, drug therapy)
  cetuximab (clinical trial, drug comparison, drug therapy)
  docetaxel (clinical trial, drug comparison, drug therapy)
  everolimus (clinical trial, drug comparison, drug therapy)
  ipilimumab (clinical trial, drug comparison, drug therapy)
  methotrexate (clinical trial, drug comparison, drug therapy)
  pemetrexed (drug combination, drug therapy)
  programmed death 1 receptor (endogenous compound)
  programmed death 1 receptor inhibitor (adverse drug reaction, clinical 
trial, drug combination, drug comparison, drug therapy)
  protein inhibitor (adverse drug reaction, clinical trial, drug combination, 
drug comparison, drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction
  hyperthyroidism (side effect, side effect)
  hypophysitis (drug therapy, side effect, drug therapy, side effect)
  hypothyroidism (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  cancer chemotherapy
  cancer patient
  head and neck squamous cell carcinoma (drug therapy)
  high risk patient
  human
  incidence
  kidney carcinoma (drug therapy)
  malignant neoplasm (drug therapy)
  melanoma (drug therapy)
  meta analysis
  monotherapy
  non small cell lung cancer (drug therapy)
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  prospective study
  randomized controlled trial (topic)
  review
  risk assessment
  systematic review
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  cetuximab (205923-56-4)
  docetaxel (114977-28-5)
  everolimus (159351-69-6)
  ipilimumab (477202-00-9)
  methotrexate (15475-56-6, 59-05-2, 7413-34-5)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  pemetrexed (137281-23-3, 150399-23-8)
EMBASE CLASSIFICATIONS
  Otorhinolaryngology (11)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170157524
MEDLINE PMID
  28231723 (http://www.ncbi.nlm.nih.gov/pubmed/28231723)
PUI
  L614614280
DOI
  10.2217/imt-2016-0147
FULL TEXT LINK
  http://dx.doi.org/10.2217/imt-2016-0147
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 71
TITLE
  Neuroendocrine Cancer, Therapeutic Strategies in G3 Cancers
AUTHOR NAMES
  Rinke A.
  Gress T.M.
AUTHOR ADDRESSES
  (Rinke A., sprengea@staff.uni-marburg.de; Gress T.M.) Department of 
Gastroenterology and Endocrinology, University Hospital Marburg, Baldinger 
Strasse, Marburg, Germany.
SOURCE
  Digestion (2017) 95:2 (109-114). Date of Publication: 1 Mar 2017
ISSN
  1421-9867 (electronic)
  0012-2823
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS
  carboplatin (drug therapy)
  cisplatin (drug therapy)
  etoposide (drug therapy)
  irinotecan (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gastrointestinal carcinoma (drug therapy, drug therapy)
  gastrointestinal neuroendocrine carcinoma (drug therapy, drug therapy)
  neuroendocrine tumor (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  cancer chemotherapy
  cancer growth
  cancer localization
  cancer prognosis
  human
  pancreas
  practice guideline
  priority journal
  treatment planning
  tumor differentiation
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  etoposide (33419-42-0)
  irinotecan (100286-90-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170107549
MEDLINE PMID
  28161703 (http://www.ncbi.nlm.nih.gov/pubmed/28161703)
PUI
  L614368315
DOI
  10.1159/000454761
FULL TEXT LINK
  http://dx.doi.org/10.1159/000454761
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 72
TITLE
  Systematic drug sensitivity testing reveals synergistic growth inhibition by 
dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor 
cells
AUTHOR NAMES
  Haltia U.-M.
  Andersson N.
  Yadav B.
  Färkkilä A.
  Kulesskiy E.
  Kankainen M.
  Tang J.
  Bützow R.
  Riska A.
  Leminen A.
  Heikinheimo M.
  Kallioniemi O.
  Unkila-Kallio L.
  Wennerberg K.
  Aittokallio T.
  Anttonen M.
AUTHOR ADDRESSES
  (Haltia U.-M.; Andersson N.; Färkkilä A., anniina.farkkila@helsinki.fi; 
Heikinheimo M.) Children's Hospital, University of Helsinki and Helsinki 
University Hospital, PO Box 20, 00014 University of Helsinki, Finland.
(Haltia U.-M.; Färkkilä A., anniina.farkkila@helsinki.fi; Riska A.; Leminen 
A.; Unkila-Kallio L.) Obstetrics and Gynecology, University of Helsinki and 
Helsinki University Hospital, PO Box 140, Helsinki, Finland.
(Yadav B.; Kulesskiy E.; Kankainen M.; Tang J.; Kallioniemi O.; Wennerberg 
K.; Aittokallio T.) Institute for Molecular Medicine Finland (FIMM), 
University of Helsinki, PO Box 20, Helsinki, Finland.
(Bützow R.) Pathology, University of Helsinki and HUSLAB, Helsinki 
University Hospital, PO Box 400, Helsinki, Finland.
(Heikinheimo M.) Department of Pediatrics, Washington University School of 
Medicine, St Louis Children's Hospital, St Louis, United States.
(Anttonen M.) Clinical Chemistry and Hematology, University of Helsinki and 
HUSLAB, Helsinki University Hospital, PO Box 400, Helsinki, Finland.
(Aittokallio T.) Department of Mathematics and Statistics, University of 
Turku, Turku, Finland.
CORRESPONDENCE ADDRESS
  A. Färkkilä, Department of Obstetrics and Gynecology, Helsinki University 
Hospital, PO Box 400, Helsinki, Finland. Email: anniina.farkkila@helsinki.fi
SOURCE
  Gynecologic Oncology (2017) 144:3 (621-630). Date of Publication: 1 Mar 2017
ISSN
  1095-6859 (electronic)
  0090-8258
BOOK PUBLISHER
  Academic Press Inc., apjcs@harcourt.com
ABSTRACT
  Objective Resistance to standard chemotherapy poses a major clinical problem 
in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor 
(AGCT) is a unique ovarian cancer subtype for which efficient treatment 
options are lacking in advanced disease. To this end, systematic drug 
response and transcriptomics profiling were performed to uncover new therapy 
options for AGCTs. Methods The responses of three primary and four recurrent 
AGCTs to 230 anticancer compounds were screened in vitro using a systematic 
drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA 
sequencing. The responses of the AGCTs were compared with those of human 
granulosa luteal cells and bone marrow mononuclear cells. Results 
Patient-derived AGCT cells showed selective sensitivity to the Src family 
tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an 
mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition 
of AGCT cell viability. The key kinase targets of dasatinib and members of 
the mTOR pathway were constantly expressed at mRNA and protein levels, 
indicating multikinase signal addictions in the AGCT cells. Transcriptomic 
characterization of the tumors revealed no known oncogenic mutations, 
suggesting that the drug sensitivity of AGCTs was rather conveyed by 
selective target expression. Conclusions We used a systematic functional 
approach to reveal novel treatment options for a unique gynecological 
cancer. The selective synergy found between taxanes and dasatinib or mTOR 
inhibitors warrants further clinical investigations of these combinations in 
relapsed or aggressive AGCTs and demonstrate that high-throughput drug 
screening and molecular profiling can provide an effective approach to 
uncover new therapy options.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  dasatinib (drug combination, drug interaction, pharmacology)
  everolimus (drug combination, drug interaction, pharmacology)
  paclitaxel (drug combination, drug interaction, pharmacology)
EMTREE DRUG INDEX TERMS
  2 amino 8 [4 (2 hydroxyethoxy)cyclohexyl] 6 (6 methoxy 3 pyridinyl) 4 
methylpyrido[2,3 d]pyrimidin 7(8h) one (drug combination, drug interaction)
  alpha amino n [5,6 dihydro 2 (1 methyl 1h pyrazol 4 yl) 6 oxo 1h 
pyrrolo[4,3,2 ef][2,3]benzodiazepin 8 yl]cyclohexaneacetamide (pharmacology)
  antimitotic agent
  azd 8055 (drug combination, drug interaction)
  docetaxel (pharmacology)
  ephrin receptor A5 (endogenous compound)
  ephrin receptor B3 (endogenous compound)
  forkhead box protein L2 (endogenous compound)
  gyrase inhibitor
  heat shock protein 90 (endogenous compound)
  kit protein (endogenous compound)
  obatoclax (pharmacology)
  pdgfra protein (endogenous compound)
  protein (endogenous compound)
  sepantronium bromide (pharmacology)
  survivin (endogenous compound)
  temsirolimus
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer inhibition
  drug sensitivity
  granulosa cell tumor
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  bone marrow derived mononuclear cell
  cancer survival
  cell viability
  clinical article
  codon
  controlled study
  drug efficacy
  drug potentiation
  drug screening
  drug selectivity
  female
  gene expression
  gene mutation
  granulosa lutein cell
  high throughput screening
  human
  human cell
  in vitro study
  middle aged
  priority journal
  protein expression
  RNA sequence
  tissue microarray
  transcriptomics
  very elderly
  wild type
DRUG TRADE NAMES
  azd 8055
  pf 04691502
  pf 477736
  ym 155
CAS REGISTRY NUMBERS
  2 amino 8 [4 (2 hydroxyethoxy)cyclohexyl] 6 (6 methoxy 3 pyridinyl) 4 
methylpyrido[2,3 d]pyrimidin 7(8h) one (1013101-36-4)
  alpha amino n [5,6 dihydro 2 (1 methyl 1h pyrazol 4 yl) 6 oxo 1h 
pyrrolo[4,3,2 ef][2,3]benzodiazepin 8 yl]cyclohexaneacetamide (952021-60-2)
  dasatinib (302962-49-8, 863127-77-9)
  docetaxel (114977-28-5)
  everolimus (159351-69-6)
  obatoclax (803712-67-6, 803712-79-0)
  paclitaxel (33069-62-4)
  protein (67254-75-5)
  sepantronium bromide (781661-94-7)
  survivin (195263-98-0)
  temsirolimus (162635-04-3, 343261-52-9)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170054975
MEDLINE PMID
  28104295 (http://www.ncbi.nlm.nih.gov/pubmed/28104295)
PUI
  L614118899
DOI
  10.1016/j.ygyno.2016.12.016
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ygyno.2016.12.016
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 73
TITLE
  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
AUTHOR NAMES
  Coens C.
  Suciu S.
  Chiarion-Sileni V.
  Grob J.-J.
  Dummer R.
  Wolchok J.D.
  Schmidt H.
  Hamid O.
  Robert C.
  Ascierto P.A.
  Richards J.M.
  Lebbé C.
  Ferraresi V.
  Smylie M.
  Weber J.S.
  Maio M.
  Bottomley A.
  Kotapati S.
  de Pril V.
  Testori A.
  Eggermont A.M.M.
AUTHOR ADDRESSES
  (Coens C., corneel.coens@eortc.be; Suciu S.; Bottomley A.) EORTC 
Headquarters, Brussels, Belgium.
(Chiarion-Sileni V.) IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy.
(Grob J.-J.) Hôpital de la Timone, Marseille, France.
(Dummer R.) University of Zürich Hospital, Zürich, Switzerland.
(Wolchok J.D.) Memorial Sloan Kettering Cancer Center, New York, United 
States.
(Schmidt H.) Aarhus University Hospital, Aarhus, Denmark.
(Hamid O.) The Angeles Clinic and Research Institute, Los Angeles, United 
States.
(Robert C.; Eggermont A.M.M.) Gustave Roussy Cancer Campus Grand Paris, 
Villejuif, France.
(Ascierto P.A.) Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, 
Italy.
(Richards J.M.) Oncology Specialists S C, Park Ridge, United States.
(Lebbé C.) Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital 
Saint-Louis, Paris, United Kingdom.
(Ferraresi V.) Istituti Fisioterapici Ospitalieri, Rome, Italy.
(Smylie M.) Cross Cancer Institute, Edmonton, Canada.
(Weber J.S.) H Lee Moffitt Cancer Center, Tampa, United States.
(Maio M.) University Hospital of Siena, Istituto Toscano Tumori, Siena, 
Italy.
(Kotapati S.) Bristol-Myers Squibb, Wallingford, United States.
(de Pril V.) Bristol-Myers Squibb, Braine-l'Alleud, Belgium.
(Testori A.) European Institute of Oncology, Milan, Italy.
CORRESPONDENCE ADDRESS
  C. Coens, EORTC Headquarters, Brussels, Belgium. Email: 
corneel.coens@eortc.be
SOURCE
  The Lancet Oncology (2017) 18:3 (393-403). Date of Publication: 1 Mar 2017
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  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. 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. 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]). 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. Funding Bristol-Myers Squibb.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug comparison - 
placebo, drug therapy, intravenous drug administration)
EMTREE DRUG INDEX TERMS
  placebo
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer staging
  cancer surgery
  cutaneous melanoma (drug therapy, disease management, drug therapy, surgery)
  quality of life
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer adjuvant therapy
  cancer survival
  controlled study
  diarrhea (side effect)
  double blind procedure
  drug efficacy
  drug safety
  drug tolerability
  drug withdrawal
  EORTC QLQ C30
  fatigue (side effect)
  female
  geographic distribution
  high risk population
  human
  insomnia (side effect)
  longitudinal study
  loss of appetite (side effect)
  major clinical study
  male
  multicenter study
  nausea (side effect)
  patient compliance
  patient-reported outcome
  phase 3 clinical trial
  quality of life assessment
  randomized controlled trial
  recurrence free survival
  treatment duration
  vomiting (side effect)
DRUG MANUFACTURERS
  Bristol Myers Squibb
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Public Health, Social Medicine and Epidemiology (17)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00636168)
  EudraCT (2007-001974-10)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170093070
MEDLINE PMID
  28162999 (http://www.ncbi.nlm.nih.gov/pubmed/28162999)
PUI
  L614299805
DOI
  10.1016/S1470-2045(17)30015-3
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(17)30015-3
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 74
TITLE
  Systemic treatment for thymic malignancies
AUTHOR NAMES
  Girard N.
  Merveilleux Du Vignaux C.
AUTHOR ADDRESSES
  (Girard N., nicolas.girard@chu-lyon.fr; Merveilleux Du Vignaux C.) 
Department of Respiratory Medicine, National Expert Centre for Thymic 
Malignancies, Hôpital Louis Pradel, Lyon, France.
(Girard N., nicolas.girard@chu-lyon.fr) Department of Medical Oncology, 
Institut Curie, Paris, France.
(Girard N., nicolas.girard@chu-lyon.fr) Institut du Thorax Curie-Montsouris, 
Institut Curie, Institut Mutualiste Montsouris, Paris, France.
(Girard N., nicolas.girard@chu-lyon.fr) Départment dOncologie Médicale, 
Institut Curie, 26 rue dUlm, Paris Cedex 05, France.
CORRESPONDENCE ADDRESS
  N. Girard, Départment dOncologie Médicale, Institut Curie, 26 rue dUlm, 
Paris Cedex 05, France. Email: nicolas.girard@chu-lyon.fr
SOURCE
  Current Opinion in Oncology (2017) 29:2 (112-117). Date of Publication: 1 
Mar 2017
ISSN
  1531-703X (electronic)
  1040-8746
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  Purpose of review The management of thymic epithelial tumors is a paradigm 
of multidisciplinary collaboration. Chemotherapy may be administered as part 
of curative-intent sequential strategy integrating subsequent surgery or 
radiotherapy, or as an exclusive treatment if local treatment is not 
achievable. Recurrences of thymic epithelial tumors should be managed 
according to the same strategy as newly diagnosed tumors. Recent findings 
More options have become available for advanced, refractory, and recurrent 
thymic epithelial tumors, which include cytotoxic agents such as 
carboplatin-paclitaxel, pemetrexed, and oral etoposide. Angiogenesis 
targeting is a standard in advanced lines of treatment, after results of a 
phase II trial with sunitinib were reported. Ongoing studies are assessing 
the opportunity of targeting the immune-response checkpoint programmed 
death-1/programmed death ligand-1, with preliminary promising results 
whereas safety, with a higher risk of auto-immunity, may represent a 
concern. Summary Overall, a dramatic improvement in our knowledge of the 
management of thymic tumors has occurred in the past few years, resulting in 
the development of databases, translational research programmes, and 
clinical trials. Although access to innovative strategies represents a major 
challenge, as the rarity of the tumor precludes specific approval of drugs 
to be obtained, patient-centered initiatives, such as the establishment of 
dedicated networks, are warranted.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug therapy)
EMTREE DRUG INDEX TERMS
  angiogenesis inhibitor (drug therapy)
  carboplatin
  etoposide
  mammalian target of rapamycin inhibitor (drug therapy)
  paclitaxel
  pemetrexed
  programmed death 1 ligand 1
  sunitinib (clinical trial)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer chemotherapy
  systemic therapy
  thymoma (drug therapy, drug therapy, radiotherapy)
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  antiangiogenic therapy
  autoimmunity
  chemoradiotherapy
  drug safety
  epithelium tumor
  gene mutation
  human
  KIT gene
  phase 2 clinical trial (topic)
  postoperative care
  priority journal
  review
  tumor gene
  tumor recurrence
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  etoposide (33419-42-0)
  paclitaxel (33069-62-4)
  pemetrexed (137281-23-3, 150399-23-8)
  sunitinib (341031-54-7, 557795-19-4)
EMBASE CLASSIFICATIONS
  Hematology (25)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170002862
MEDLINE PMID
  28027106 (http://www.ncbi.nlm.nih.gov/pubmed/28027106)
PUI
  L613924494
DOI
  10.1097/CCO.0000000000000355
FULL TEXT LINK
  http://dx.doi.org/10.1097/CCO.0000000000000355
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 75
TITLE
  Safety profile of nivolumab monotherapy: A pooled analysis of patients with 
advanced melanoma
AUTHOR NAMES
  Weber J.S.
  Hodi F.S.
  Wolchok J.D.
  Topalian S.L.
  Schadendorf D.
  Larkin J.
  Sznol M.
  Long G.V.
  Li H.
  Waxman I.M.
  Jiang J.
  Robert C.
AUTHOR ADDRESSES
  (Weber J.S., jeffrey.weber2@nyumc.org) H. Lee Moffitt Cancer Center, Tampa, 
United States.
(Hodi F.S.) Dana-Farber Cancer Institute, Boston, United States.
(Wolchok J.D.) Memorial Sloan Kettering Cancer Center, New York, United 
States.
(Topalian S.L.) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 
Baltimore, United States.
(Sznol M.) Yale University School of Medicine, Smilow Cancer Center, 
Yale-New Haven Hospital, New Haven, United States.
(Li H.; Waxman I.M.; Jiang J.) Bristol-Myers Squibb, Princeton, United 
States.
(Schadendorf D.) University of Essen, Essen, Germany.
(Larkin J.) Royal Marsden National Health Service Foundation Trust, London, 
United Kingdom.
(Long G.V.) Melanoma Institute Australia, University of Sydney, Sydney, 
Australia.
(Robert C.) Gustave Roussy, Paris-Sud University, Villejuif-Paris Sud, 
France.
CORRESPONDENCE ADDRESS
  J.S. Weber, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical 
Center, 522 First Ave, 1310 Smilow Building, New York, United States. Email: 
jeffrey.weber2@nyumc.org
SOURCE
  Journal of Clinical Oncology (2017) 35:7 (785-792). Date of Publication: 1 
Mar 2017
ISSN
  1527-7755 (electronic)
  0732-183X
BOOK PUBLISHER
  American Society of Clinical Oncology, jcoservice@asco.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  corticosteroid (clinical trial, drug therapy)
  gamma glutamyltransferase (endogenous compound)
  immunomodulating agent (clinical trial, drug therapy)
  infliximab (clinical trial, drug therapy)
  ipilimumab (clinical trial, drug therapy)
  mycophenolic acid (clinical trial, drug therapy)
  triacylglycerol lipase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure (side effect)
  adult
  aged
  allergic neuropathy (side effect)
  arthralgia (side effect)
  arthritis (drug therapy, side effect)
  article
  asthenia (side effect)
  brain metastasis (side effect)
  colitis (side effect)
  constipation (side effect)
  creatinine blood level
  decreased appetite (side effect)
  demyelinating disease (side effect)
  diarrhea (side effect)
  drug efficacy
  drug safety
  drug withdrawal
  endocrine disease (side effect)
  fatigue (side effect)
  female
  gastrointestinal symptom (side effect)
  Guillain Barre syndrome (side effect)
  hepatitis (drug therapy, side effect)
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  interstitial nephritis (side effect)
  liver disease (side effect)
  liver function test
  maculopapular rash (side effect)
  major clinical study
  male
  monotherapy
  muscle contracture (side effect)
  nausea (side effect)
  neurologic disease (side effect)
  phase 1 clinical trial
  phase 3 clinical trial
  pneumonia (side effect)
  practice guideline
  priority journal
  pruritus (drug therapy, side effect)
  rash (drug therapy, side effect)
  side effect (drug therapy)
  skin disease (side effect)
  treatment response
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  gamma glutamyltransferase (85876-02-4)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  mycophenolic acid (23047-11-2, 24280-93-1)
  nivolumab (946414-94-4)
  triacylglycerol lipase (9001-62-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00730639)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170158310
MEDLINE PMID
  28068177 (http://www.ncbi.nlm.nih.gov/pubmed/28068177)
PUI
  L614587181
DOI
  10.1200/JCO.2015.66.1389
FULL TEXT LINK
  http://dx.doi.org/10.1200/JCO.2015.66.1389
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 76
TITLE
  Programmed death ligand 1 (PD-L1) tumor expression is associated with a 
better prognosis and diabetic disease in triple negative breast cancer 
patients
AUTHOR NAMES
  Botti G.
  Collina F.
  Scognamiglio G.
  Rao F.
  Peluso V.
  De Cecio R.
  Piezzo M.
  Landi G.
  De Laurentiis M.
  Cantile M.
  Di Bonito M.
AUTHOR ADDRESSES
  (Botti G., g.botti@istitutotumori.na.it; Collina F., 
francescacollina84@gmail.com; Scognamiglio G., giosco80@gmail.com; Rao F., 
federica.rao@gmail.com; Peluso V., valent.peluso@gmail.com; De Cecio R., 
r.dececio@istitutotumori.na.it; Cantile M., m.cantile@istitutotumori.na.it; 
Di Bonito M., mauriziodibonito@libero.it) Pathology Unit, Istituto Nazionale 
Tumori Fondazione “G. Pascale”, via Mariano Semmola, Napoli, Italy.
(Piezzo M., m.piezzo@breastunit.org; Landi G., g.landi@istitutotumori.na.it; 
De Laurentiis M., m.delaurentiis@istitutotumori.na.it) Department of Breast 
Surgery and Cancer Prevention, Istituto Nazionale Tumori Fondazione “G. 
Pascale”, via Mariano Semmola, Napoli, Italy.
CORRESPONDENCE ADDRESS
  M. Cantile, Pathology Unit, Istituto Nazionale Tumori Fondazione “G. 
Pascale”, via Mariano Semmola, Napoli, Italy. Email: 
m.cantile@istitutotumori.na.it
SOURCE
  International Journal of Molecular Sciences (2017) 18:2 Article Number: 459. 
Date of Publication: 21 Feb 2017
ISSN
  1422-0067 (electronic)
  1661-6596
BOOK PUBLISHER
  MDPI AG, Postfach, Basel, Switzerland.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  epidermal growth factor receptor 2 (endogenous compound)
  estrogen receptor (endogenous compound)
  Ki 67 antigen (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antigen expression
  cancer prognosis
  diabetes mellitus
  triple negative breast cancer
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  controlled study
  disease free survival
  female
  glucose blood level
  human
  human tissue
  immune response
  immunohistochemistry
  lymph node metastasis
  major clinical study
  menopause
  overall survival
  protein expression
  protein microarray
  tumor associated leukocyte
CAS REGISTRY NUMBERS
  epidermal growth factor receptor 2 (137632-09-8)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170151945
MEDLINE PMID
  28230773 (http://www.ncbi.nlm.nih.gov/pubmed/28230773)
PUI
  L614514762
DOI
  10.3390/ijms18020459
FULL TEXT LINK
  http://dx.doi.org/10.3390/ijms18020459
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 77
TITLE
  Nivolumab induced myxedema crisis
AUTHOR NAMES
  Khan U.
  Rizvi H.
  Sano D.
  Chiu J.
  Hadid T.
AUTHOR ADDRESSES
  (Khan U., uqba.md@gmail.com; Rizvi H., humaira.r@hotmail.com; Sano D., 
dahlia.sano@stjohn.org; Chiu J., jane.chiu@stjohn.org; Hadid T., 
tarik.hadid@stjohn.org) St. John Hospital and Medical Center, Department of 
Hematology/Oncology, 19229 Mack Ave Suite 23 Grosse Pointe Woods, Detroit, 
United States.
CORRESPONDENCE ADDRESS
  U. Khan, St. John Hospital and Medical Center, Department of 
Hematology/Oncology, 19229 Mack Ave Suite 23 Grosse Pointe Woods, Detroit, 
United States. Email: uqba.md@gmail.com
SOURCE
  Journal for ImmunoTherapy of Cancer (2017) 5:1 Article Number: 13. Date of 
Publication: 21 Feb 2017
ISSN
  2051-1426 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  creatine kinase (endogenous compound)
  hydrocortisone (drug combination, intravenous drug administration)
  levothyroxine (drug combination, drug therapy, intravenous drug 
administration, oral drug administration)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  myxedema (drug therapy, side effect, diagnosis, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  add on therapy
  adult
  amnesia
  article
  body temperature disorder
  case report
  cold intolerance
  constipation
  depression
  drug withdrawal
  dry skin
  dyspnea
  face edema
  fatigue
  female
  human
  middle aged
  multiple cycle treatment
  priority journal
  slurred speech
  squamous cell lung carcinoma (drug therapy)
  thinking
  tongue swelling
  voice disorder
  weakness
CAS REGISTRY NUMBERS
  creatine kinase (9001-15-4)
  hydrocortisone (50-23-7)
  levothyroxine (51-48-9)
  nivolumab (946414-94-4)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170139855
PUI
  L614478247
DOI
  10.1186/s40425-017-0213-x
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40425-017-0213-x
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 78
TITLE
  Ipilimumab-Induced Sarcoidosis and Thyroiditis
AUTHOR NAMES
  Nandavaram S.
  Nadkarni A.
AUTHOR ADDRESSES
  (Nandavaram S.) Division of Pulmonary Critical Care, SUNY Upstate Medical 
University, Syracuse, NY
(Nadkarni A.)
CORRESPONDENCE ADDRESS
  S. Nandavaram, Division of Pulmonary Critical Care, SUNY Upstate Medical 
University, Syracuse, NY
SOURCE
  American Journal of Therapeutics (2017). Date of Publication: 15 Feb 2017
ISSN
  1536-3686 (electronic)
  1075-2765
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  sarcoidosis
  thyroiditis
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170130902
PUI
  L614484926
DOI
  10.1097/MJT.0000000000000545
FULL TEXT LINK
  http://dx.doi.org/10.1097/MJT.0000000000000545
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 79
TITLE
  Neoadjuvant chemotherapy of ovarian cancer results in three patterns of 
tumor-infiltrating lymphocyte response with distinct implications for 
immunotherapy
AUTHOR NAMES
  Lo C.S.
  Sanii S.
  Kroeger D.R.
  Milne K.
  Talhouk A.
  Chiu D.S.
  Rahimi K.
  Shaw P.A.
  Clarke B.A.
  Nelson B.H.
AUTHOR ADDRESSES
  (Lo C.S.; Kroeger D.R.; Milne K.; Nelson B.H., bnelson@bccrc.ca) Deeley 
Research Centre, British Columbia Cancer Agency, Victoria, Canada.
(Lo C.S.) Interdisciplinary Oncology Program, Faculty of Medicine, 
University of British Columbia, Vancouver, Canada.
(Lo C.S.) British Columbia Cancer Research Centre, British Columbia Cancer 
Agency, Vancouver, Canada.
(Sanii S.; Shaw P.A.; Clarke B.A.) Department of Laboratory Medicine and 
Pathobiology, University of Toronto, University Health Network, Toronto 
General Hospital, Toronto, Canada.
(Talhouk A.) Department of Pathology and Laboratory Medicine, University of 
British Columbia, Vancouver, Canada.
(Chiu D.S.) Department of Statistics, University of British Columbia, 
Vancouver, Canada.
(Rahimi K.) Département de Pathologie et Biologie Cellulaire, Université de 
Montreal, Montréal, Canada.
(Nelson B.H., bnelson@bccrc.ca) Department of Biochemistry and Microbiology, 
University of Victoria, Victoria, Canada.
(Nelson B.H., bnelson@bccrc.ca) Department of Medical Genetics, University 
of British Columbia, Vancouver, Canada.
CORRESPONDENCE ADDRESS
  B.H. Nelson, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, 
Canada. Email: bnelson@bccrc.ca
SOURCE
  Clinical Cancer Research (2017) 23:4 (925-934). Date of Publication: 15 Feb 
2017
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  Purpose: Some forms of chemotherapy can enhance antitumor immunity through 
immunogenic cell death, resulting in increased T-cell activation and tumor 
infiltration. Such effects could potentially sensitize tumors to 
immunotherapies, including checkpoint blockade. We investigated whether 
platinum- and taxane-based chemotherapy for ovarian cancer induces 
immunologic changes consistent with this possibility. Experimental Design: 
Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 
high-grade serous carcinoma (HGSC) patients were analyzed by 
immunohistochemistry (IHC) for a large panel of immune cells and associated 
factors. The prognostic significance of post-chemotherapy TIL patterns was 
assessed in an expanded cohort (n = 90). Results: Neoadjuvant chemotherapy 
was associated with increased densities of CD3(+), CD8(+), CD8(+) TIA-1(+), 
PD-1(+) and CD20(+) TIL. Other immune subsets and factors were unchanged, 
including CD79a(+) CD138(+) plasma cells, CD68(+) macrophages, and MHC class 
I on tumor cells. Immunosuppressive cell types were also unchanged, 
including FoxP3(+) PD-1(+) cells (putative regulatory T cells), IDO-1(+) 
cells, and PD-L1(+) cells (both macrophages and tumor cells). Hierarchical 
clustering revealed three response patterns: (i) TIL(high) tumors showed 
increases in multiple immune markers after chemotherapy; (ii) TIL(low) 
tumors underwent similar increases, achieving patterns indistinguishable 
from the first group; and (iii) TIL(negative) cases generally remained 
negative. Despite the dramatic increases seen in the first two patterns, 
post-chemotherapy TIL showed limited prognostic significance. Conclusions: 
Chemotherapy augments pre-existing TIL responses but fails to relieve major 
immune-suppressive mechanisms or confer significant prognostic benefit. Our 
findings provide rationale for multipronged approaches to immunotherapy 
tailored to the baseline features of the tumor microenvironment.
EMTREE DRUG INDEX TERMS
  CD20 antigen (endogenous compound)
  CD3 antigen (endogenous compound)
  CD68 antigen (endogenous compound)
  CD79a antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  major histocompatibility antigen class 1 (endogenous compound)
  nucleolysin TIA 1 isoform p40 (endogenous compound)
  peptides and proteins (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  protein IDO 1 (endogenous compound)
  syndecan 1 (endogenous compound)
  transcription factor FOXP3 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer adjuvant therapy
  ovary cancer
  tumor associated leukocyte
  tumor immunity
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer immunotherapy
  cancer prognosis
  cohort analysis
  human
  immune deficiency
  immunohistochemistry
  macrophage
  major clinical study
  plasma cell
  regulatory T lymphocyte
CAS REGISTRY NUMBERS
  syndecan 1 (128559-86-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170125138
MEDLINE PMID
  27601594 (http://www.ncbi.nlm.nih.gov/pubmed/27601594)
PUI
  L614416508
DOI
  10.1158/1078-0432.CCR-16-1433
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-16-1433
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 80
TITLE
  Current diagnosis and management of immune related adverse events (irAEs) 
induced by immune checkpoint inhibitor therapy
AUTHOR NAMES
  Kumar V.
  Chaudhary N.
  Garg M.
  Floudas C.S.
  Soni P.
  Chandra A.B.
AUTHOR ADDRESSES
  (Kumar V.; Garg M.; Floudas C.S.; Soni P.) Department of Medicine, 
Maimonides Medical Center, Brooklyn, United States.
(Chaudhary N.) Department of Pediatrics, Maimonides Medical Center, 
Brooklyn, United States.
(Chandra A.B., abhinavbck@hotmail.com) Yuma Regional Cancer Center, Yuma, 
United States.
CORRESPONDENCE ADDRESS
  A.B. Chandra, Yuma Regional Cancer Center, Yuma, United States. Email: 
abhinavbck@hotmail.com
SOURCE
  Frontiers in Pharmacology (2017) 8:FEB Article Number: 49. Date of 
Publication: 8 Feb 2017
ISSN
  1663-9812 (electronic)
BOOK PUBLISHER
  Frontiers Media S.A., info@frontiersin.org
ABSTRACT
  The indications of immune checkpoint inhibitors (ICIs) are set to rise 
further with the approval of newer agents like tremelimumab and atezolimumab 
for use in patients with advanced stage mesothelioma and urothelial 
carcinoma respectively. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  atezolizumab (adverse drug reaction, clinical trial, drug therapy)
  durvalumab (adverse drug reaction, clinical trial)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  nivolumab (adverse drug reaction, clinical trial, drug therapy)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy)
  pidilizumab (adverse drug reaction, clinical trial)
  ticilimumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  antinuclear antibody (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  cyclophosphamide (drug therapy)
  infliximab (drug therapy)
  methylprednisolone (drug therapy)
  mycophenolate mofetil (drug therapy)
  prednisone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  colitis (drug therapy, side effect, diagnosis, drug therapy, side effect)
  dermatitis (drug therapy, diagnosis, drug therapy)
  drug induced disease (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
  endocrine disease (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
  hepatitis (drug therapy, side effect, diagnosis, drug therapy, side effect)
  immune mediated colitis (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
  immune mediated dermatitis (drug therapy, diagnosis, drug therapy)
  immune mediated endocrinopathy (drug therapy, side effect, diagnosis, drug 
therapy, side effect)
  immune mediated hepatitis (drug therapy, side effect, diagnosis, drug 
therapy, side effect)
  immune mediated injury (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
  immune mediated neurological disease (drug therapy, side effect, diagnosis, 
drug therapy, side effect)
  immune mediated pneumonitis (drug therapy, side effect, diagnosis, drug 
therapy, side effect)
  immune mediated renal dysfunction (drug therapy, side effect, diagnosis, 
drug therapy, side effect)
  kidney dysfunction (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
  neurologic disease (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
  pneumonia (drug therapy, side effect, diagnosis, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure (side effect)
  advanced cancer
  alanine aminotransferase blood level
  anemia (side effect)
  aspartate aminotransferase blood level
  bloody diarrhea (side effect)
  cancer recurrence
  computer assisted tomography
  conjunctivitis (side effect)
  disease exacerbation (side effect)
  drug efficacy
  drug safety
  episcleritis (side effect)
  gastrointestinal obstruction (side effect)
  Guillain Barre syndrome (side effect)
  head and neck cancer (drug therapy)
  hemophilia A (side effect)
  Hodgkin disease (drug therapy)
  human
  hyperbilirubinemia (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  immune mediated nephritis (side effect)
  immune mediated nephritis (side effect)
  immunosuppressive treatment
  interstitial nephritis (side effect)
  intestine perforation (side effect)
  kidney metastasis (drug therapy)
  liver toxicity (side effect)
  melanoma (drug therapy)
  mesothelioma (drug therapy)
  mucosa inflammation (side effect)
  myasthenia gravis (side effect)
  myelitis (side effect)
  nephritis (side effect)
  neuropathy (side effect)
  neurotoxicity (side effect)
  neutropenia (side effect)
  non small cell lung cancer (drug therapy)
  overall survival
  phase 3 clinical trial (topic)
  polymyositis (side effect)
  posterior reversible encephalopathy syndrome (side effect)
  pruritus (side effect)
  rash (side effect)
  rhabdomyolysis (side effect)
  rheumatoid arthritis (side effect)
  short survey
  side effect (side effect)
  Sjoegren syndrome (side effect)
  thrombocytopenia (side effect)
  transitional cell carcinoma (drug therapy)
  uveitis (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  atezolizumab (1380723-44-3)
  cyclophosphamide (50-18-0)
  durvalumab (1428935-60-7)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  pidilizumab (1036730-42-3)
  prednisone (53-03-2)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Radiology (14)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170166907
PUI
  L614619169
DOI
  10.3389/fphar.2017.00049
FULL TEXT LINK
  http://dx.doi.org/10.3389/fphar.2017.00049
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 81
TITLE
  Signal transducer and activator of transcription 1 plays a pivotal role in 
RET/PTC3 oncogene-induced expression of indoleamine 2,3-dioxygenase 1
AUTHOR NAMES
  Moretti S.
  Menicali E.
  Nucci N.
  Voce P.
  Colella R.
  Melillo R.M.
  Liotti F.
  Morelli S.
  Fallarino F.
  Macchiarulo A.
  Santoro M.
  Avenia N.
  Puxeddu E.
AUTHOR ADDRESSES
  (Moretti S.; Menicali E.; Nucci N.; Voce P.; Morelli S.; Puxeddu E., 
efisio.puxeddu@unipg.it) Department of Medicine, University of Perugia, 
Perugia, Italy.
(Moretti S.; Menicali E.; Nucci N.; Voce P.; Morelli S.; Avenia N.; Puxeddu 
E., efisio.puxeddu@unipg.it) Research Centre of Thyroid Proteomics and 
Genomics (CRiProGeT), University of Perugia, Terni, Italy.
(Colella R.; Fallarino F.) Department of Experimental Medicine, University 
of Perugia, Perugia, Italy.
(Melillo R.M.; Liotti F.; Santoro M.) Department of Molecular Medicine and 
Medical Biotechnology, University of Naples Federico II, Naples, Italy.
(Melillo R.M.) Istituto per l'Endocrinologia e l'Oncologia Sperimentale, 
CNR, Naples, Italy.
(Macchiarulo A.) Department of Pharmaceutical Sciences, University of 
Perugia, Perugia, Italy.
(Avenia N.) Department of Surgical and Biomedical Sciences, University of 
Perugia, Perugia, Italy.
CORRESPONDENCE ADDRESS
  E. Puxeddu, Edificio D, piano +2, Piazza L. Severi 1, Perugia, Italy. Email: 
efisio.puxeddu@unipg.it
SOURCE
  Journal of Biological Chemistry (2017) 292:5 (1785-1797). Date of 
Publication: 3 Feb 2017
ISSN
  1083-351X (electronic)
  0021-9258
BOOK PUBLISHER
  American Society for Biochemistry and Molecular Biology Inc., 9650 Rockville 
Pike, Bethesda, United States.
ABSTRACT
  Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxidoreductase that 
catalyzes tryptophan degradation to kynurenine. In cancer, it exerts an 
immunosuppressive function as part of an acquired mechanism of immune 
escape. Recently, we demonstrated that IDO1 expression is significantly 
higher in all thyroid cancer histotypes compared with normal thyroid and 
that its expression levels correlate with T regulatory (Treg) lymphocyte 
densities in the tumor microenvironment. BRAF(V600E) - and 
RET/PTC3-expressing PcCL3 cells were used as cellular models for the 
evaluation of IDO1 expression in thyroid carcinoma cells and for the study 
of involved signal transduction pathways. BRAF(V600E) -expressing PcCL3 
cells did not show IDO1 expression. Conversely, RET/PTC3-expressing cells 
were characterized by a high IDO1 expression. Moreover, we found that, the 
STAT1-IRF1 pathway was instrumental for IDO1 expression in RET/PTC3 
expressing cells. In detail, RET/PTC3 induced STAT1 overexpression and 
phosphorylation at Ser-727 and Tyr-701. STAT1 transcriptional regulation 
appeared to require activation of the canonical NF-κB pathway. Conversely, 
activation of the MAPK and PI3K-AKT pathways primarily regulated Ser-727 
phosphorylation, whereas a physical interaction between RET/PTC3 and STAT1, 
followed by a direct tyrosine phosphorylation event, was necessary for STAT1 
Tyr-701 phosphorylation. These data provide the first evidence of a direct 
link between IDO1 expression and the oncogenic activation of RET in thyroid 
carcinoma and describe the involved signal transduction pathways. Moreover, 
they suggest possible novel molecular targets for the abrogation of tumor 
microenvironment immunosuppression. The detection of those targets is 
becoming increasingly important to yield the full function of novel immune 
checkpoint inhibitors.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  indoleamine 2,3 dioxygenase (endogenous compound)
  STAT1 protein (endogenous compound)
EMTREE DRUG INDEX TERMS
  immunoglobulin enhancer binding protein (endogenous compound)
  interferon regulatory factor 1 (endogenous compound)
  Janus kinase 2 (endogenous compound)
  mitogen activated protein kinase (endogenous compound)
  phosphatidylinositol 3 kinase (endogenous compound)
  protein kinase B (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  oncogene
  protein expression
  PTC3 gene
  RET gene
EMTREE MEDICAL INDEX TERMS
  article
  carcinoma cell
  chromatin immunoprecipitation
  controlled study
  human
  human cell
  immunoblotting
  in vitro study
  plasmid
  polymerase chain reaction
  protein interaction
  protein phosphorylation
  regulatory T lymphocyte
  signal transduction
  thyroid carcinoma
  transcription regulation
  tumor microenvironment
CAS REGISTRY NUMBERS
  indoleamine 2,3 dioxygenase ()
  mitogen activated protein kinase (142243-02-5)
  phosphatidylinositol 3 kinase (115926-52-8)
  protein kinase B (148640-14-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170096230
MEDLINE PMID
  27994058 (http://www.ncbi.nlm.nih.gov/pubmed/27994058)
PUI
  L614287447
DOI
  10.1074/jbc.M116.745448
FULL TEXT LINK
  http://dx.doi.org/10.1074/jbc.M116.745448
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 82
TITLE
  Metastatic small cell neuroendocrine carcinoma of the cervix treated with 
the PD-1 inhibitor, nivolumab: A case report
AUTHOR NAMES
  Paraghamian S.E.
  Longoria T.C.
  Eskander R.N.
AUTHOR ADDRESSES
  (Paraghamian S.E., paraghas@uci.edu; Longoria T.C., longoria@uci.edu; 
Eskander R.N., eskander@uci.edu) Department of Obstetrics and Gynecology, 
Division of Gynecologic Oncology, University of California, Irvine Medical 
Center, 33 City Blvd. West #1400, Orange, United States.
CORRESPONDENCE ADDRESS
  R.N. Eskander, Department of Obstetrics and Gynecology, Division of 
Gynecologic Oncology, University of California, Irvine Medical Center, 33 
City Blvd. West #1400, Orange, United States. Email: eskander@uci.edu
SOURCE
  Gynecologic Oncology Research and Practice (2017) 4:1 Article Number: 3. 
Date of Publication: 2 Feb 2017
ISSN
  2053-6844 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 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. Conclusions: Immune checkpoint inhibitors may be active in 
neuroendocrine cervical cancer, with potential for dramatic responses in a 
modest subset of patients.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  cisplatin (adverse drug reaction, drug therapy, intravenous drug 
administration)
  etoposide (adverse drug reaction, drug therapy, intravenous drug 
administration)
  paclitaxel (drug therapy, intravenous drug administration)
  topotecan (drug therapy, intravenous drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastasis (drug therapy, drug therapy)
  neuroendocrine carcinoma (drug therapy, diagnosis, drug therapy, 
radiotherapy, surgery)
  small cell neuroendocrine carcinoma of the cervix (drug therapy, diagnosis, 
drug therapy, radiotherapy, surgery)
  uterine cervix carcinoma (drug therapy, diagnosis, drug therapy, 
radiotherapy, surgery)
EMTREE MEDICAL INDEX TERMS
  abdominal hysterectomy
  adult
  anemia (side effect)
  article
  bone marrow biopsy
  cancer radiotherapy
  case report
  drug response
  drug tolerability
  drug withdrawal
  dry eye (side effect)
  eye toxicity (side effect)
  fatigue (side effect)
  female
  glaucoma (side effect)
  human
  human tissue
  lymphocytopenia (side effect)
  multiple cycle treatment
  nausea (side effect)
  nephrostomy tube
  obstructive uropathy (surgery)
  pancytopenia (side effect)
  Papanicolaou test
  pelvic pain
  pelvis abscess (complication)
  pelvis lymphadenectomy
  positron emission tomography-computed tomography
  priority journal
  salpingooophorectomy
  small intestine obstruction
  thrombocytopenia (side effect)
  unspecified side effect (side effect)
  uterine cervix biopsy
  vagina discharge
  Wart virus
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  etoposide (33419-42-0, 433304-61-1)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  topotecan (119413-54-6, 123948-87-8)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02257528, NCT02488759)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170400621
PUI
  L616535597
DOI
  10.1186/s40661-017-0038-9
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40661-017-0038-9
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 83
TITLE
  PD-L1, PD-1, CD4, and CD8 expression in neoplastic and nonneoplastic thymus
AUTHOR NAMES
  Marchevsky A.M.
  Walts A.E.
AUTHOR ADDRESSES
  (Marchevsky A.M., Alberto.Marchevsky@cshs.org; Walts A.E., 
Ann.Walts@cshs.org) Department of Pathology and Laboratory Medicine, 
Cedars-Sinai Medical Center, Los Angeles, Greece.
CORRESPONDENCE ADDRESS
  A.M. Marchevsky, Department of Pathology and Laboratory Medicine, 
Cedars-Sinai Medical Center, 8700 Beverly Blvd, South Tower Room 8709, Los 
Angeles, United States. Email: Alberto.Marchevsky@cshs.org
SOURCE
  Human Pathology (2017) 60 (16-23). Date of Publication: 1 Feb 2017
ISSN
  1532-8392 (electronic)
  0046-8177
BOOK PUBLISHER
  W.B. Saunders
ABSTRACT
  The checkpoint protein programmed cell death ligand-1 protein (PD-L1) binds 
to its receptor (PD-1) activating the PD-L1/PD-1 pathway, an important 
therapeutic target. There is limited information regarding PD-L1 and PD-1 
expression in thymic lesions. Sections from nonneoplastic thymi (n = 20), 
thymomas World Health Organization types A, AB, B1, B2, and B3 (n = 38) and 
thymic squamous cell carcinoma (n = 8) were stained for PD-L1 (clone SP142; 
Spring BioScience), PD-1 (MRQ22; Cell Marque), CD4 (clone SPO32; Cell 
Marque), and CD8 (JCB117; Ventana). Immunoreactivity for each antibody was 
classified as focal or diffuse and scored as follows: 0, negative; 1%-5%, 
1+; 6%-20%, 2+; and >20%, 3+. The proportions of cases expressing PD-L1, 
PD-1, CD4, and C8 at score ≥1+ were compared by diagnosis, using χ(2) 
statistics. PD-L1 was expressed in 90% of nonneoplastic thymi, 92% of 
thymomas, and 50% of carcinomas, with significantly higher scores (P <.01) 
in B2 and B3 thymomas and carcinomas than in AB and B1 thymomas; PD-L1 was 
diffuse in most B2 and B3 thymomas and focal in carcinomas. PD-1 was focally 
expressed, and mostly with scores 1+, in 55% of nonneoplastic thymi, 63% of 
thymomas, and 37.5% of carcinomas. CD4+ and CD8+ cells were diffusely 
distributed with scores 3+ in all lesions other than B3 thymomas and 
carcinomas. The latter showed CD4+ cells mostly at the interface between 
neoplastic cells and stroma. PD-L1 and PD-1 are not expressed in similar 
locations and cellular proportions in thymic lesions, raising a question as 
to whether the PD-L1/PD-1 pathway is an actionable therapeutic target in 
these lesions.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  CD4 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  antibody
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thymus cancer
  thymus disease
EMTREE MEDICAL INDEX TERMS
  adolescent
  adult
  aged
  article
  child
  controlled study
  female
  human
  human tissue
  immunoreactivity
  lymphoid hyperplasia
  major clinical study
  male
  protein expression
  scoring system
  squamous cell carcinoma
  thymoma
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160877448
MEDLINE PMID
  27746267 (http://www.ncbi.nlm.nih.gov/pubmed/27746267)
PUI
  L613365653
DOI
  10.1016/j.humpath.2016.09.023
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.humpath.2016.09.023
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 84
TITLE
  The immune infiltrate in prostate, bladder and testicular tumors: An old 
friend for new challenges
AUTHOR NAMES
  Solinas C.
  Chanzá N.M.
  Awada A.
  Scartozzi M.
AUTHOR ADDRESSES
  (Solinas C., czsolinas@gmail.com) Molecular Immunology Unit, Université 
Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium.
(Chanzá N.M., nieves.martinez-chanza@bordet.be; Awada A., 
ahmad.awada@bordet.be) Medical Oncology, Université Libre de Bruxelles, 
Institut Jules Bordet, Brussels, Belgium.
(Chanzá N.M., nieves.martinez-chanza@bordet.be) Medical Oncology, Université 
Libre de Bruxelles, Erasme Hospital, Brussels, Belgium.
(Scartozzi M., marioscartozzi@gmail.com) Medical Oncology, University of 
Cagliari, Cagliari, Italy.
CORRESPONDENCE ADDRESS
  M. Scartozzi, Medical Oncology, University of Cagliari, Cagliari, Italy. 
Email: marioscartozzi@gmail.com
SOURCE
  Cancer Treatment Reviews (2017) 53 (138-145). Date of Publication: 1 Feb 
2017
ISSN
  1532-1967 (electronic)
  0305-7372
BOOK PUBLISHER
  W.B. Saunders Ltd
ABSTRACT
  In genito-urinary tumors immunotherapy has been administered for a long 
time: Calmette–Guèrin Bacillus as adjuvant treatment in high risk patients 
with non muscle invasive urothelial bladder cancer and interleukin-2 and 
interferon-α 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  BCG vaccine (drug therapy)
EMTREE DRUG INDEX TERMS
  alpha interferon (endogenous compound)
  cabozantinib (drug therapy)
  immunomodulating agent
  interleukin 2 (endogenous compound)
  lenvatinib (drug therapy)
  nivolumab (drug therapy)
  pembrolizumab (drug therapy)
  prostate specific antigen (endogenous compound)
  sipuleucel T
  transcription factor FOXP3 (endogenous compound)
  vasculotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  bladder cancer (drug therapy, drug therapy, surgery, therapy)
  prostate cancer (drug therapy, drug therapy, surgery, therapy)
  testis tumor (drug therapy, drug therapy, surgery, therapy)
EMTREE MEDICAL INDEX TERMS
  advanced cancer
  antineoplastic activity
  bone marrow cell
  cancer patient
  castration resistant prostate cancer (drug therapy)
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  Gleason score
  high risk patient
  human
  immune response
  immunotherapy
  mortality
  non muscle invasive bladder cancer (drug therapy, surgery, therapy)
  prostate hypertrophy
  prostatectomy
  recurrence free survival
  review
  risk reduction
  solid malignant neoplasm
  tumor associated leukocyte
  urogenital tract tumor
CAS REGISTRY NUMBERS
  cabozantinib (942407-59-2, 1140909-48-3, 849217-68-1)
  interleukin 2 (85898-30-2)
  lenvatinib (417716-92-8, 857890-39-2)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  sipuleucel T (917381-47-6)
  vasculotropin (127464-60-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Urology and Nephrology (28)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170063895
MEDLINE PMID
  28113097 (http://www.ncbi.nlm.nih.gov/pubmed/28113097)
PUI
  L614116826
DOI
  10.1016/j.ctrv.2016.12.004
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ctrv.2016.12.004
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 85
TITLE
  Clear cell ovarian cancers with microsatellite instability: A unique subset 
of ovarian cancers with increased tumor-infiltrating lymphocytes and 
PD-1/PD-L1 expression
AUTHOR NAMES
  Howitt B.E.
  Strickland K.C.
  Sholl L.M.
  Rodig S.
  Ritterhouse L.L.
  Chowdhury D.
  D'Andrea A.D.
  Matulonis U.A.
  Konstantinopoulos P.A.
AUTHOR ADDRESSES
  (Howitt B.E.; Strickland K.C.; Sholl L.M.; Rodig S.; Ritterhouse L.L.) 
Department of Pathology, Brigham and Women's Hospital, Harvard Medical 
School, Boston, United States.
(Chowdhury D.; D'Andrea A.D.) Division of Genomic Stability and DNA Repair, 
Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
(Matulonis U.A.; Konstantinopoulos P.A., 
panagiotis_konstantinopoulos@dfci.harvard.edu) Medical Gynecologic Oncology 
Program, Dana Farber Cancer Institute, Harvard Medical School, Boston, 
United States.
CORRESPONDENCE ADDRESS
  P.A. Konstantinopoulos, Medical Gynecologic Oncology Program, Dana Farber 
Cancer Institute, Harvard Medical School, Boston, United States. Email: 
panagiotis_konstantinopoulos@dfci.harvard.edu
SOURCE
  OncoImmunology (2017) 6:2 Article Number: e1277308. Date of Publication: 1 
Feb 2017
ISSN
  2162-402X (electronic)
  2162-4011
BOOK PUBLISHER
  Taylor and Francis Inc., 325 Chestnut St, Suite 800, Philadelphia, United 
States.
ABSTRACT
  Clear cell ovarian carcinoma (CCOC) represents a distinct histologic subtype 
of ovarian cancer associated with significantly worse prognosis across all 
stages and no effective therapeutic options. Here, we report a rare but 
clinically important cohort of CCOCs with microsatellite instability (MSI) 
(MSI-CCOCs), which are highly immunogenic and may thus be very responsive to 
immune checkpoint blockade. CCOCs with MSI exhibit a significantly higher 
number of CD8(+) TILs, higher CD8(+)/CD4(+) ratio, and higher PD-1(+) TILs 
compared with microsatellite stable (MSS) CCOCs and compared with high grade 
serous ovarian cancers, which are the most common histologic subtype of 
ovarian cancer. Of note, PD-L1 expression in tumor cells or immune cells was 
noted in all cases of CCOCs with MSI. These observations open an alternative 
therapeutic avenue for a fraction of patients with CCOC and argue for the 
routine testing of CCOCs for MSI, a test that is not currently routinely 
performed.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  arid1a protein (endogenous compound)
  baf250a protein (endogenous compound)
  peptides and proteins (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  clear cell carcinoma
  microsatellite instability
  ovary cancer
  tumor associated leukocyte
EMTREE MEDICAL INDEX TERMS
  article
  CD4 CD8 ratio
  CD8+ T lymphocyte
  clinical article
  controlled study
  disease association
  endometriosis
  female
  human
  human tissue
  immunohistochemistry
  protein depletion
  protein expression
  serous ovarian cancer
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170112823
PUI
  L614398836
DOI
  10.1080/2162402X.2016.1277308
FULL TEXT LINK
  http://dx.doi.org/10.1080/2162402X.2016.1277308
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 86
TITLE
  Advances in Small Cell Lung Cancer
AUTHOR NAMES
  Kalemkerian G.P.
  Schneider B.J.
AUTHOR ADDRESSES
  (Kalemkerian G.P., kalemker@umich.edu) Division of Hematology/Oncology, 
Department of Internal Medicine, University of Michigan, C350 Med Inn–SPC 
5848, 1500 East Medical Center Drive, Ann Arbor, United States.
(Schneider B.J.) Division of Hematology/Oncology, Department of Internal 
Medicine, University of Michigan, C411 Med Inn–SPC 5848, 1500 East Medical 
Center Drive, Ann Arbor, United States.
CORRESPONDENCE ADDRESS
  G.P. Kalemkerian, Division of Hematology/Oncology, Department of Internal 
Medicine, University of Michigan, C350 Med Inn–SPC 5848, 1500 East Medical 
Center Drive, Ann Arbor, United States. Email: kalemker@umich.edu
SOURCE
  Hematology/Oncology Clinics of North America (2017) 31:1 (143-156). Date of 
Publication: 1 Feb 2017
ISSN
  1558-1977 (electronic)
  0889-8588
BOOK PUBLISHER
  W.B. Saunders
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  angiogenesis inhibitor (drug therapy)
  carboplatin (drug comparison, drug therapy)
  cisplatin (drug comparison, drug therapy)
  cyclophosphamide (drug therapy)
  doxorubicin (drug therapy)
  epirubicin (drug therapy)
  etoposide (drug therapy)
  ipilimumab (drug therapy)
  irinotecan (drug therapy)
  nivolumab (drug therapy)
  pembrolizumab (drug therapy)
  platinum complex (drug therapy)
  sunitinib (drug therapy)
  topotecan (drug therapy)
  vincristine (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, diagnosis, drug therapy, radiotherapy)
  small cell lung cancer (drug therapy, diagnosis, drug therapy, radiotherapy)
EMTREE MEDICAL INDEX TERMS
  cancer chemotherapy
  cancer diagnosis
  cancer immunotherapy
  cancer radiotherapy
  cancer recurrence
  cancer staging
  cancer survival
  chemoradiotherapy
  diagnostic imaging
  differential diagnosis
  human
  molecularly targeted therapy
  patient assessment
  priority journal
  review
  skull irradiation
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  cyclophosphamide (50-18-0)
  doxorubicin (23214-92-8, 25316-40-9)
  epirubicin (56390-09-1, 56420-45-2)
  etoposide (33419-42-0, 433304-61-1)
  ipilimumab (477202-00-9)
  irinotecan (100286-90-6)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  sunitinib (341031-54-7, 557795-19-4)
  topotecan (119413-54-6, 123948-87-8)
  vincristine (57-22-7)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160875422
MEDLINE PMID
  27912830 (http://www.ncbi.nlm.nih.gov/pubmed/27912830)
PUI
  L613484421
DOI
  10.1016/j.hoc.2016.08.005
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.hoc.2016.08.005
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 87
TITLE
  Drug Hepatotoxicity: Newer Agents
AUTHOR NAMES
  Bunchorntavakul C.
  Reddy K.R.
AUTHOR ADDRESSES
  (Bunchorntavakul C.) Division of Gastroenterology and Hepatology, Department 
of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, HUP, 
Philadelphia, United States.
(Bunchorntavakul C.) Division of Gastroenterology and Hepatology, Department 
of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, 
Rajavithi Road, Ratchathewi, Bangkok, Thailand.
(Reddy K.R., rajender.reddy@uphs.upenn.edu) Liver Transplantation, Viral 
Hepatitis Center, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, 
HUP, Liver Transplant Office, Philadelphia, United States.
CORRESPONDENCE ADDRESS
  K.R. Reddy, Liver Transplantation, Viral Hepatitis Center, University of 
Pennsylvania, 2 Dulles, 3400 Spruce Street, HUP, Liver Transplant Office, 
Philadelphia, United States. Email: rajender.reddy@uphs.upenn.edu
SOURCE
  Clinics in Liver Disease (2017) 21:1 (115-134). Date of Publication: 1 Feb 
2017
ISSN
  1557-8224 (electronic)
  1089-3261
BOOK PUBLISHER
  W.B. Saunders
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  amoxicillin plus clavulanic acid (adverse drug reaction)
  anticoagulant agent (adverse drug reaction, clinical trial, drug therapy, 
oral drug administration)
  anticonvulsive agent (adverse drug reaction, drug therapy, pharmacokinetics)
  antidepressant agent (adverse drug reaction, clinical trial)
  antiretrovirus agent (adverse drug reaction, clinical trial)
  apixaban (adverse drug reaction, oral drug administration, pharmacokinetics)
  azithromycin (adverse drug reaction, clinical trial)
  cefazolin (adverse drug reaction, drug dose, intravenous drug 
administration)
  cephalosporin derivative (adverse drug reaction)
  clopidogrel (adverse drug reaction, clinical trial, drug therapy)
  dabigatran (adverse drug reaction, oral drug administration, 
pharmacokinetics)
  dipeptidyl peptidase IV inhibitor (adverse drug reaction, clinical trial, 
drug therapy)
  edoxaban (adverse drug reaction, oral drug administration, pharmacokinetics)
  glucagon like peptide 1 receptor agonist (adverse drug reaction, drug 
therapy)
  infliximab (adverse drug reaction)
  ipilimumab (adverse drug reaction)
  neuroleptic agent (adverse drug reaction)
  paroxetine (adverse drug reaction)
  prasugrel (adverse drug reaction, clinical trial, drug therapy)
  protein tyrosine kinase inhibitor (adverse drug reaction, clinical trial)
  quinoline derived antiinfective agent (adverse drug reaction)
  rituximab (adverse drug reaction)
  rivaroxaban (adverse drug reaction, oral drug administration, 
pharmacokinetics)
  sertraline (adverse drug reaction)
  sodium glucose cotransporter 2 inhibitor (adverse drug reaction, clinical 
trial, drug therapy)
  trastuzumab (adverse drug reaction)
  trastuzumab emtansine (adverse drug reaction)
  tumor necrosis factor inhibitor (adverse drug reaction, drug therapy)
  unindexed drug
  ximelagatran (adverse drug reaction, clinical trial, oral drug 
administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  liver toxicity (side effect, etiology, side effect)
EMTREE MEDICAL INDEX TERMS
  acute liver failure (side effect)
  alanine aminotransferase blood level
  arthralgia (side effect)
  autoimmune hepatitis (side effect)
  body weight gain
  cholestasis (side effect)
  chronic hepatitis B (side effect)
  clinical trial (topic)
  deep vein thrombosis (drug therapy)
  diabetes mellitus (drug therapy)
  disease severity
  disorders of mitochondrial functions (side effect)
  DRESS syndrome (side effect)
  drug efficacy
  drug exposure
  drug fatality (side effect)
  drug metabolism
  drug safety
  drug tolerability
  drug withdrawal
  embolism (drug therapy)
  eosinophilia (side effect)
  epilepsy (drug therapy)
  extrapyramidal symptom (side effect)
  fatty liver (side effect)
  fever (side effect)
  genetic association
  heart infarction (drug therapy)
  hepatitis (side effect)
  hepatitis B (side effect)
  high risk population
  human
  hyperplasia (side effect)
  hypersensitivity (side effect)
  hypertransaminasemia (side effect)
  immunopathogenesis
  interstitial nephritis (side effect)
  jaundice (side effect)
  liver cell damage (side effect)
  liver failure (side effect)
  liver injury (side effect)
  lung embolism (drug therapy)
  meta analysis (topic)
  multiple cycle treatment
  nodular regenerative hyperplasia (side effect)
  nodular regenerative hyperplasia (side effect)
  non insulin dependent diabetes mellitus (drug therapy)
  nonalcoholic fatty liver (side effect)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  portal hypertension (side effect)
  postmarketing surveillance
  prognosis
  randomized controlled trial (topic)
  rash (side effect)
  review
  rheumatoid arthritis (drug therapy)
  sialoadenitis (side effect)
  side effect (side effect)
  single drug dose
  single nucleotide polymorphism
  skin disease (side effect)
  Stevens Johnson syndrome (side effect)
  systematic review (topic)
  systemic inflammatory response syndrome (side effect)
  toxic epidermal necrolysis (side effect)
  toxic hepatitis (side effect)
  treatment duration
CAS REGISTRY NUMBERS
  amoxicillin plus clavulanic acid (74469-00-4, 79198-29-1)
  apixaban (503612-47-3)
  azithromycin (83905-01-5, 117772-70-0, 121470-24-4)
  cefazolin (25953-19-9, 27164-46-1)
  clopidogrel (113665-84-2, 120202-66-6, 90055-48-4, 94188-84-8)
  edoxaban (480449-70-5, 480449-71-6, 912273-65-5)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  paroxetine (61869-08-7)
  prasugrel (389574-19-0, 150322-43-3)
  rituximab (174722-31-7)
  rivaroxaban (366789-02-8)
  sertraline (79617-96-2)
  trastuzumab (180288-69-1)
  trastuzumab emtansine (1018448-65-1)
  ximelagatran (192939-46-1, 260790-58-7)
EMBASE CLASSIFICATIONS
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160744121
MEDLINE PMID
  27842767 (http://www.ncbi.nlm.nih.gov/pubmed/27842767)
PUI
  L612772690
DOI
  10.1016/j.cld.2016.08.009
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.cld.2016.08.009
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 88
TITLE
  Targeting TNFR2, an immune checkpoint stimulator and oncoprotein, is a 
promising treatment for cancer
AUTHOR NAMES
  Chen X.
  Oppenheim J.J.
AUTHOR ADDRESSES
  (Chen X., xchen@umac.mo) State Key Laboratory of Quality Research in Chinese 
Medicine, Institute of Chinese Medical Sciences, University of Macau, , 
Macao.
(Chen X., xchen@umac.mo; Oppenheim J.J., oppenhej@mail.nih.gov) Cancer and 
Inflammation Program, Center for Cancer Research, National Cancer Institute, 
Frederick, United States.
CORRESPONDENCE ADDRESS
  X. Chen, State Key Laboratory of Quality Research in Chinese Medicine, 
Institute of Chinese Medical Sciences, University of Macau, , Macao. Email: 
xchen@umac.mo
SOURCE
  Science Signaling (2017) 10:462 Article Number: eaal2328. Date of 
Publication: 17 Jan 2017
ISSN
  1937-9145 (electronic)
  1945-0877
BOOK PUBLISHER
  American Association for the Advancement of Science
ABSTRACT
  Tumor necrosis factor receptor type II (TNFR2) is expressed both by some 
cancer cells and by tumor-infiltrating immunosuppressive CD4+FoxP3+ 
regulatory T cells (T(regs)). TNFR2 stimulates the activation and 
proliferation of T(regs), a major checkpoint of antitumor immune responses, 
and promotes cancer cell survival and tumor growth. In this issue of Science 
Signaling, Torrey et al. found that dominant antagonistic antibodies against 
human TNFR2 may be a potential therapy for ovarian cancer patients by 
simultaneously suppressing Treg activity and inducing the death of the 
cancer cells.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytokine receptor antagonist (pharmacology)
  tumor necrosis factor receptor 2 (endogenous compound)
EMTREE DRUG INDEX TERMS
  cleavage and polyadenylation specificity factor (endogenous compound)
  lymphotoxin (endogenous compound)
  OX40 ligand (endogenous compound)
  protein (endogenous compound)
  protein TL1A (endogenous compound)
  T lymphocyte receptor (endogenous compound)
  tumor necrosis factor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  drug targeting
  ovary cancer
  regulatory T lymphocyte
EMTREE MEDICAL INDEX TERMS
  cancer cell
  cancer patient
  CD4+ T lymphocyte
  cell death
  effector cell
  female
  human
  nonhuman
  ovarian cancer cell line
  priority journal
  protein expression
  review
CAS REGISTRY NUMBERS
  protein (67254-75-5)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170073263
PUI
  L614206579
DOI
  10.1126/scisignal.aal2328
FULL TEXT LINK
  http://dx.doi.org/10.1126/scisignal.aal2328
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 89
TITLE
  New immunotherapy strategies in breast cancer
AUTHOR NAMES
  Yu L.-Y.
  Tang J.
  Zhang C.-M.
  Zeng W.-J.
  Yan H.
  Li M.-P.
  Chen X.-P.
AUTHOR ADDRESSES
  (Yu L.-Y., yulinhui19910530@163.com; Tang J., jietang@csu.edu.cn; Zhang 
C.-M., ZhangCM126126@126.com; Zeng W.-J., wenjinganne@126.com; Yan H., 
yanhan501@126.com; Li M.-P., elskesunny@163.com; Chen X.-P., 
chenxp74@hotmail.com) Department of Clinical Pharmacology, Xiangya Hospital, 
Central South University, Changsha, China.
(Yu L.-Y., yulinhui19910530@163.com; Tang J., jietang@csu.edu.cn; Zhang 
C.-M., ZhangCM126126@126.com; Zeng W.-J., wenjinganne@126.com; Yan H., 
yanhan501@126.com; Li M.-P., elskesunny@163.com; Chen X.-P., 
chenxp74@hotmail.com) Institute of Clinical Pharmacology, Central South 
University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
CORRESPONDENCE ADDRESS
  X.-P. Chen, Department of Clinical Pharmacology, Xiangya Hospital, Central 
South University, Changsha, China. Email: chenxp74@hotmail.com
SOURCE
  International Journal of Environmental Research and Public Health (2017) 
14:1 Article Number: 68. Date of Publication: 12 Jan 2017
ISSN
  1660-4601 (electronic)
  1661-7827
BOOK PUBLISHER
  MDPI AG, Postfach, Basel, Switzerland.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  4 1BB antibody
  antigen specific vaccine (drug therapy)
  antineoplastic agent (drug therapy)
  bispecific antibody (drug therapy)
  cancer vaccine (drug therapy)
  catumaxomab (drug therapy)
  CD134 antibody
  CD40 antibody
  cytotoxic T lymphocyte antigen 4 inhibitor (drug therapy)
  dendritic cell vaccine (drug therapy)
  epidermal growth factor receptor 2 (drug therapy)
  estrogen receptor
  immune checkpoint inhibitor (drug therapy)
  immunomodulating agent (drug therapy)
  lymphocyte activation gene 3 receptor
  mucin 1 (drug therapy)
  progesterone receptor
  programmed cell death 1 inhibitor (drug therapy)
  receptor
  stimulatory molecule agonist (drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  breast cancer (drug therapy, drug therapy)
  cancer immunotherapy
EMTREE MEDICAL INDEX TERMS
  cancer chemotherapy
  cancer growth
  cancer prognosis
  cancer staging
  cancer tissue
  drug efficacy
  human
  immune response
  immunosurveillance
  nonhuman
  protein expression
  review
  treatment response
  tumor microenvironment
CAS REGISTRY NUMBERS
  catumaxomab (509077-98-9)
  epidermal growth factor receptor 2 (137632-09-8)
  mucin 1 (212255-06-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01376505, NCT01570036, NCT01730118, NCT01730612, NCT01862900, NCT02018458, NCT02061332, NCT02129556, NCT02140996, NCT02309177, NCT02381314, NCT02404441, NCT02425891, NCT02427581, NCT02453620, NCT02478099, NCT02536794, NCT02554812, NCT02614833, NCT02628132, NCT02643303, NCT02649686, NCT02661100, NCT02685059, NCT02708680, NCT02725489)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170065008
MEDLINE PMID
  28085094 (http://www.ncbi.nlm.nih.gov/pubmed/28085094)
PUI
  L614088322
DOI
  10.3390/ijerph14010068
FULL TEXT LINK
  http://dx.doi.org/10.3390/ijerph14010068
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 90
TITLE
  Autoimmune Diabetes and Thyroiditis Complicating Treatment with Nivolumab
AUTHOR NAMES
  Li L.
  Masood A.
  Bari S.
  Yavuz S.
  Grosbach A.B.
AUTHOR ADDRESSES
  (Li L., li.li@medicine.ufl.edu; Grosbach A.B.) Division of Hematology and 
Oncology, Department of Medicine, University of Florida, 1600 SW Archer 
Road, Gainesville, United States.
(Masood A.; Yavuz S.) Division of Endocrinology, Diabetes and Metabolism, 
Department of Medicine, University of Florida, Gainesville, United States.
(Bari S.) Department of Medicine, University of Florida, Gainesville, United 
States.
(Li L., li.li@medicine.ufl.edu; Grosbach A.B.) Division of Hematology and 
Oncology, Malcom Randall VA Medical Center, Gainesville, United States.
(Masood A.; Yavuz S.) Division of Endocrinology, Malcom Randall VA Medical 
Center, Gainesville, United States.
CORRESPONDENCE ADDRESS
  L. Li, Division of Hematology and Oncology, Department of Medicine, 
University of Florida, 1600 SW Archer Road, Gainesville, United States. 
Email: li.li@medicine.ufl.edu
SOURCE
  Case Reports in Oncology (2017) 10:1 (230-234). Date of Publication: 6 Jan 
2017
ISSN
  1662-6575 (electronic)
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab
EMTREE DRUG INDEX TERMS
  carboplatin
  glutamate decarboxylase antibody (endogenous compound)
  insulin
  levothyroxine
  paclitaxel
  thyroid peroxidase antibody (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  latent autoimmune diabetes in adults
  thyroiditis
EMTREE MEDICAL INDEX TERMS
  adult
  article
  bronchus biopsy
  cancer staging
  case report
  chemoradiotherapy
  computer assisted tomography
  diabetic ketoacidosis
  disease course
  glucose blood level
  human
  human tissue
  hypothyroidism
  male
  middle aged
  priority journal
  squamous cell lung carcinoma
  treatment response
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  insulin (9004-10-8)
  levothyroxine (51-48-9)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170161968
PUI
  L614643713
DOI
  10.1159/000456540
FULL TEXT LINK
  http://dx.doi.org/10.1159/000456540
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 91
TITLE
  Two Cases of Nivolumab Re-Administration after Pneumonitis as Immune-Related 
Adverse Events
AUTHOR NAMES
  Imafuku K.
  Yoshino K.
  Yamaguchi K.
  Tsuboi S.
  Ohara K.
  Hata H.
AUTHOR ADDRESSES
  (Imafuku K., imafukukeisuke@gmail.com; Yoshino K.; Yamaguchi K.; Tsuboi S.; 
Ohara K.) Department of Dermatology, Tokyo Metropolitan Cancer and 
Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, 
Bunkyo-ku, Tokyo, Japan.
(Hata H.) Department of Dermatology, Hokkaido University Graduate School of 
Medicine, Sapporo, Japan.
CORRESPONDENCE ADDRESS
  K. Imafuku, Department of Dermatology, Tokyo Metropolitan Cancer and 
Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, 
Bunkyo-ku, Tokyo, Japan. Email: imafukukeisuke@gmail.com
SOURCE
  Case Reports in Oncology (2017) 10:1 (296-300). Date of Publication: 6 Jan 
2017
ISSN
  1662-6575 (electronic)
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticosteroid (drug therapy, oral drug administration)
  methylprednisolone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug administration
  pneumonia
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  bone metastasis (drug therapy)
  bronchiolitis obliterans organizing pneumonia
  case report
  computer assisted tomography
  dyspnea
  human
  interstitial pneumonia (diagnosis, drug therapy, side effect)
  liver metastasis
  lung diffusion
  lung metastasis
  male
  melanoma (drug therapy)
  middle aged
  priority journal
CAS REGISTRY NUMBERS
  methylprednisolone (6923-42-8, 83-43-2)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170256220
PUI
  L615240415
DOI
  10.1159/000463379
FULL TEXT LINK
  http://dx.doi.org/10.1159/000463379
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 92
TITLE
  A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of 
immune checkpoint inhibitor-induced type 1 diabetes
AUTHOR NAMES
  Chae Y.K.
  Chiec L.
  Mohindra N.
  Gentzler R.
  Patel J.
  Giles F.
AUTHOR ADDRESSES
  (Chae Y.K., young.chae@northwestern.edu; Mohindra N.; Giles F.) 
Developmental Therapeutics Program of the Division of Hematology/Oncology, 
Northwestern University, Chicago, United States.
(Chae Y.K., young.chae@northwestern.edu; Mohindra N.; Patel J.; Giles F.) 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 
Chicago, United States.
(Chae Y.K., young.chae@northwestern.edu; Chiec L.; Mohindra N.; Patel J.; 
Giles F.) Feinberg School of Medicine, Northwestern University, 645 N. 
Michigan Ave, Suite 1006, Chicago, United States.
(Gentzler R.) University of Virginia School of Medicine, Charlottesville, 
United States.
(Patel J.) The University of Chicago Medicine, Chicago, United States.
CORRESPONDENCE ADDRESS
  Y.K. Chae, Feinberg School of Medicine, Northwestern University, 645 N. 
Michigan Ave, Suite 1006, Chicago, United States. Email: 
young.chae@northwestern.edu
SOURCE
  Cancer Immunology, Immunotherapy (2017) 66:1 (25-32). Date of Publication: 1 
Jan 2017
ISSN
  1432-0851 (electronic)
  0340-7004
BOOK PUBLISHER
  Springer Science and Business Media Deutschland GmbH, info@springer-sbm.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  anaplastic lymphoma kinase
  carboplatin (adverse drug reaction, drug combination, drug therapy)
  epidermal growth factor receptor
  glucose (endogenous compound)
  hemoglobin A1c (endogenous compound)
  insulin glargine
  K ras protein
  nivolumab
  paclitaxel (adverse drug reaction, drug combination, drug therapy)
  prednisone
  short acting insulin
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  insulin dependent diabetes mellitus (side effect, side effect)
  lung adenocarcinoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  cancer combination chemotherapy
  case report
  computer assisted tomography
  cytology
  drug tolerance
  drug withdrawal
  dyspnea
  glucose blood level
  glycemic control
  hospital admission
  human
  hyperglycemia
  immunohistochemistry
  insulin treatment
  lung nodule
  maintenance chemotherapy
  male
  metastasis
  multiple cycle treatment
  neutropenia (side effect)
  pleura effusion
  priority journal
  robot assisted surgery
  smoking
  systemic therapy
  thoracocentesis
  thrombocytopenia (side effect)
  video assisted thoracoscopic surgery
  wedge resection
CAS REGISTRY NUMBERS
  anaplastic lymphoma kinase (166433-56-3)
  carboplatin (41575-94-4)
  epidermal growth factor receptor (79079-06-4)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  insulin glargine (160337-95-1)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  pembrolizumab (1374853-91-4)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160759275
MEDLINE PMID
  27761609 (http://www.ncbi.nlm.nih.gov/pubmed/27761609)
PUI
  L612864388
DOI
  10.1007/s00262-016-1913-7
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00262-016-1913-7
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 93
TITLE
  Immune-related adverse events by immune checkpoint inhibitors
AUTHOR NAMES
  Kadono T.
AUTHOR ADDRESSES
  (Kadono T.) Department of Dermatology, St. Marianna University School of 
Medicine, Japan.
CORRESPONDENCE ADDRESS
  T. Kadono, Department of Dermatology, St. Marianna University School of 
Medicine, Japan.
SOURCE
  Japanese Journal of Clinical Immunology (2017) 40:2 (83-89). Date of 
Publication: 2017
ISSN
  1349-7413 (electronic)
  0911-4300
BOOK PUBLISHER
  Japan Society for Clinical Immunology, jsci@nifty.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  checkpoint kinase inhibitor (adverse drug reaction)
  immune checkpoint inhibitor (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  ipilimumab (adverse drug reaction)
  nivolumab (adverse drug reaction)
  pembrolizumab (adverse drug reaction)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  immunopathology
EMTREE MEDICAL INDEX TERMS
  article
  colitis
  human
  hypophysitis
  hypothyroidism
  insulin dependent diabetes mellitus
  interstitial pneumonia
  kidney failure
  liver dysfunction
  mucosal disease
  myasthenia gravis
  myositis
  neuropathy
  rash
  skin disease
  unspecified side effect (side effect)
  uveitis
  vitiligo
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English, Japanese
EMBASE ACCESSION NUMBER
  20170427398
MEDLINE PMID
  28603205 (http://www.ncbi.nlm.nih.gov/pubmed/28603205)
PUI
  L616788151
DOI
  10.2177/jsci.40.83
FULL TEXT LINK
  http://dx.doi.org/10.2177/jsci.40.83
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 94
TITLE
  Nivolumab Causing a Polymyalgia Rheumatica in a Patient with a Squamous 
Non-Small Cell Lung Cancer
AUTHOR NAMES
  Bernier M.
  Guillaume C.
  Leon N.
  Alexandre J.
  Hamel-Senecal L.
  Chretien B.
  Lecaignec F.
  Humbert X.
  Fedrizzi S.
  Madelaine J.
  Sassier M.
AUTHOR ADDRESSES
  (Bernier M.; Alexandre J.; Hamel-Senecal L.; Chretien B.; Lecaignec F.; 
Humbert X.; Fedrizzi S.; Sassier M., marion.sassier@hotmail.fr) Department 
of Pharmacology, CHU de Caen, Caen, France.
(Guillaume C.) Department of Pain and Palliative Care, CHU of Caen, France.
(Leon N.) Department of Rheumatology, CHU of Caen, France.
(Madelaine J.) Department of Pneumology, CHU of Caen, France.
(Humbert X.) Department of General Medicine, Medical School, Normandie 
University, Caen, France.
CORRESPONDENCE ADDRESS
  M. Sassier, Department of Pharmacology, CHU de Caen, Caen, France. Email: 
marion.sassier@hotmail.fr
SOURCE
  Journal of Immunotherapy (2017) 40:4 (129-131). Date of Publication: 2017
ISSN
  1537-4513 (electronic)
  1524-9557
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  amitriptyline (drug therapy)
  carboplatin (drug combination, drug therapy)
  cisplatin (drug combination, drug therapy)
  gemcitabine (drug combination, drug therapy)
  ketoprofen (drug therapy)
  methylprednisolone (drug therapy)
  paclitaxel (drug combination, drug therapy)
  paracetamol (drug therapy)
  prednisone (drug therapy, oral drug administration)
  tramadol (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  rheumatic polymyalgia (drug therapy, side effect, drug therapy, side effect)
  squamous cell lung carcinoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  arthralgia (drug therapy)
  arthritis
  article
  bone scintiscanning
  cancer immunotherapy
  case report
  disease course
  echography
  human
  inflammation
  male
  medical history
  multiple cycle treatment
  outcome assessment
  priority journal
  spinal pain (drug therapy)
  treatment response
  x-ray computed tomography
CAS REGISTRY NUMBERS
  amitriptyline (50-48-6, 549-18-8)
  carboplatin (41575-94-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  gemcitabine (103882-84-4)
  ketoprofen (22071-15-4, 57495-14-4)
  methylprednisolone (6923-42-8, 83-43-2)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  paracetamol (103-90-2)
  prednisone (53-03-2)
  tramadol (27203-92-5, 36282-47-0)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Arthritis and Rheumatism (31)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170177070
PUI
  L614708899
DOI
  10.1097/CJI.0000000000000163
FULL TEXT LINK
  http://dx.doi.org/10.1097/CJI.0000000000000163
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 95
TITLE
  Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in 
patients with non-small-cell lung cancer
AUTHOR NAMES
  Osorio J.C.
  Ni A.
  Chaft J.E.
  Pollina R.
  Kasler M.K.
  Stephens D.
  Rodriguez C.
  Cambridge L.
  Rizvi H.
  Wolchok J.D.
  Merghoub T.
  Rudin C.M.
  Fish S.
  Hellmann M.D.
AUTHOR ADDRESSES
  (Osorio J.C.; Chaft J.E.; Wolchok J.D.; Merghoub T.; Rudin C.M.; Fish S.; 
Hellmann M.D., hellmanm@mskcc.org) Department of Medicine, Weill Cornell 
Medical College, New York, United States.
(Ni A.) Department of Biostatistics, Parker Institute for Cancer 
Immunotherapy at Memorial Sloan Kettering, New York, United States.
(Chaft J.E.; Pollina R.; Kasler M.K.; Stephens D.; Rodriguez C.; Cambridge 
L.; Rizvi H.; Wolchok J.D.; Merghoub T.; Rudin C.M.; Fish S.; Hellmann M.D., 
hellmanm@mskcc.org) Department of Medicine, Parker Institute for Cancer 
Immunotherapy at Memorial Sloan Kettering, New York, United States.
(Wolchok J.D.; Merghoub T.; Hellmann M.D., hellmanm@mskcc.org) Department of 
Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering, New 
York, United States.
(Wolchok J.D.; Merghoub T.) Department of Ludwig Institute for Cancer 
Research, New York, United States.
CORRESPONDENCE ADDRESS
  M.D. Hellmann, Department of Medicine, Memorial Sloan Kettering Cancer 
Center, 300 East 66th St., New York, United States. Email: 
hellmanm@mskcc.org
SOURCE
  Annals of Oncology (2017) 28:3 (583-589). Date of Publication: 2017
ISSN
  1569-8041 (electronic)
  0923-7534
BOOK PUBLISHER
  Oxford University Press, jnl.info@oup.co.uk
ABSTRACT
  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. 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 
antithyroid 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. 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). 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.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy)
  checkpoint inhibitor
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  cytotoxic T lymphocyte antigen 4 inhibitor (drug therapy)
  liothyronine (endogenous compound)
  pembrolizumab (adverse drug reaction, drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 ligand 1 inhibitor (drug therapy)
  programmed death 1 receptor (endogenous compound)
  programmed death 1 receptor inhibitor (drug therapy)
  thyroid antibody (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  non small cell lung cancer (drug therapy, drug therapy)
  T lymphocyte
  thyroid disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  article
  blood sampling
  cancer staging
  disease severity
  human
  hyperthyroidism
  hypothyroidism
  kidney carcinoma
  major clinical study
  melanoma (drug therapy)
  meta analysis
  monotherapy
  overall survival
  priority journal
  progression free survival
  systematic review
  thyroid function test
CAS REGISTRY NUMBERS
  liothyronine (6138-47-2, 6893-02-3)
  pembrolizumab (1374853-91-4)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01295827)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170311620
MEDLINE PMID
  27998967 (http://www.ncbi.nlm.nih.gov/pubmed/27998967)
PUI
  L615803866
DOI
  10.1093/annonc/mdw640
FULL TEXT LINK
  http://dx.doi.org/10.1093/annonc/mdw640
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 96
TITLE
  Immune-checkpoint-inhibitors: Immune-related adverse events
ORIGINAL (NON-ENGLISH) TITLE
  Immuncheckpoint-Inhibitoren: Immunvermittelte Nebenwirkungen
AUTHOR NAMES
  Behling J.
  Schach A.
  Loquai C.
  Grabbe S.
AUTHOR ADDRESSES
  (Behling J.; Schach A.; Loquai C.; Grabbe S., 
Stephan.grabbe@unimedizin-mainz.de) Hautklinik der Universitätsmedizin, 
Langenbeckstraße. 1, Mainz, Germany.
SOURCE
  Arzneimitteltherapie (2017) 35:6 (190-198). Date of Publication: 2017
ISSN
  0723-6913
BOOK PUBLISHER
  Wissenschaftliche Verlagsgesellschaft mbH, 
amt@wissenschaftliche-verlagsgesellschaft.de
ABSTRACT
  In oncology immune-checkpoint-inhibitors are rapidly gaining in importance. 
The aim is to increase anti-tumoral T-cell responses by blocking a negative 
regulator of T-cell activation on T-cells or their ligand (on tumor cells) 
and antigen-presenting cells. Stimulating the immune system can induce 
immune-related adverse events (irAEs) which can affect any tissue or organ 
system. Mostly affected are the skin (exanthema), intestine (colitis), 
endocrine organs (thyreoiditis, hypophysitis), liver (hepatitis), muscles 
(myositis, myocarditis) and lung (pneumonitis). Due to the diversity of 
possible autoimmune induced adverse events it is important that the therapy 
with immune-checkpoint-inhibitors is supervised by an experienced physician. 
A rapid identification of side effects and immediate initiation of systemic 
immunosuppression can be necessary.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction)
  immune checkpoint inhibitor (adverse drug reaction)
  immunostimulating agent (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction
  cancer immunotherapy
EMTREE MEDICAL INDEX TERMS
  colitis (side effect)
  hepatitis (side effect)
  human
  hypophysitis (side effect)
  immunosuppressive treatment
  myocarditis (side effect)
  myositis (side effect)
  pneumonia (side effect)
  rash (side effect)
  review
  T lymphocyte
  thyroiditis (side effect)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  German
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  20170480062
PUI
  L617174138
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 97
TITLE
  Effectiveness of nivolumab in large-cell neuroendocrine carcinoma of the 
lung - A report of two cases
AUTHOR NAMES
  Daido W.
  Yamasaki M.
  Saito N.
  Ishiyama S.
  Deguchi N.
  Taniwaki M.
  Daga H.
  Ohashi N.
AUTHOR ADDRESSES
  (Daido W.; Yamasaki M.; Saito N.; Ishiyama S.; Deguchi N.; Taniwaki M.; 
Ohashi N.) Dept. of Respiratory Disease, Hiroshima Red Cross Hospital, 
Atomic-Bomb Survivors Hospital, Japan.
(Daga H.) Dept. of Medical Oncology, Osaka City General Hospital, Japan.
(Ohashi N.) Ohashi Clinic, Japan.
SOURCE
  Japanese Journal of Cancer and Chemotherapy (2017) 44:1 (59-62). Date of 
Publication: 1 Jan 2017
ISSN
  0385-0684
BOOK PUBLISHER
  Japanese Journal of Cancer and Chemotherapy Publishers Inc., 
ccp@blue.ocn.ne.jp
ABSTRACT
  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. Conclusion: Nivolumab can be a valuable 
treatment option for LCNEC.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (drug therapy)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy)
  progastrin releasing peptide (endogenous compound)
  tumor marker (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  large cell lung carcinoma (drug therapy, diagnosis, drug therapy, surgery)
  large cell neuroendocrine carcinoma (drug therapy, diagnosis, drug therapy, 
surgery)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  brain metastasis
  cancer chemotherapy
  cancer radiotherapy
  cancer staging
  case report
  drug efficacy
  human
  human tissue
  lung adenocarcinoma (diagnosis, drug therapy, radiotherapy)
  lung biopsy
  lung lesion
  male
  mediastinum metastasis
  middle aged
  treatment response
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English, Japanese
EMBASE ACCESSION NUMBER
  20170211702
MEDLINE PMID
  28174381 (http://www.ncbi.nlm.nih.gov/pubmed/28174381)
PUI
  L614941718
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 98
TITLE
  Hyponatremia can be a powerful predictor of the development of isolated ACTH 
deficiency associated with nivolumab treatment
AUTHOR NAMES
  Cho K.Y.
  Miyoshi H.
  Nakamura A.
  Kurita T.
  Atsumi T.
AUTHOR ADDRESSES
  (Cho K.Y., kyuyong-cho@med.hokudai.ac.jp; Miyoshi H.; Nakamura A.; Atsumi 
T.) Division of Rheumatology, Endocrinology and Nephrology, Hokkaido 
University Graduate School of Medicine, Sapporo, Japan.
(Kurita T.) Department of Internal Medicine, Japanese Red Cross Kitami 
Hospital, Kitami, Japan.
CORRESPONDENCE ADDRESS
  K.Y. Cho, Division of Rheumatology, Endocrinology and Nephrology, Hokkaido 
University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo, 
Hokkaido, Japan. Email: kyuyong-cho@med.hokudai.ac.jp
SOURCE
  Endocrine Journal (2017) 64:2 (235-236). Date of Publication: 2017
ISSN
  1348-4540 (electronic)
  0918-8959
BOOK PUBLISHER
  Japan Endocrine Society, endo-soc-japan@ml.infoweb.ne.jp
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  hydrocortisone (drug therapy, endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  corticotropin deficiency (drug therapy, side effect, diagnosis, drug 
therapy, side effect)
  disease course
  hyponatremia (side effect, diagnosis, side effect)
  prediction
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  case report
  corticotropin blood level
  drug safety
  endocrine function test
  fatigue (side effect)
  female
  hormone substitution
  human
  hydrocortisone blood level
  hydrocortisone release
  hypotension
  laboratory test
  letter
  loss of appetite (side effect)
  male
  melanoma (drug therapy)
  middle aged
  nausea (side effect)
  non small cell lung cancer (drug therapy)
  pain (side effect)
  treatment response
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  hydrocortisone (50-23-7)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170156969
PUI
  L614613118
DOI
  10.1507/endocrj.EJ16-0596
FULL TEXT LINK
  http://dx.doi.org/10.1507/endocrj.EJ16-0596
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 99
TITLE
  The molecular underpinnings of prostate cancer: impacts on management and 
pathology practice
AUTHOR NAMES
  Rodrigues D.N.
  Boysen G.
  Sumanasuriya S.
  Seed G.
  Marzo A.M.D.
  de Bono J.
AUTHOR ADDRESSES
  (Rodrigues D.N., Daniel.Navarodrigues@icr.ac.uk; Boysen G.; Sumanasuriya S.; 
Seed G.; de Bono J., Johann.DeBono@icr.ac.uk) The Institute of Cancer 
Research, 15 Cotswold Road, Sutton, Surrey, United Kingdom.
(Rodrigues D.N., Daniel.Navarodrigues@icr.ac.uk; Boysen G.; Sumanasuriya S.; 
de Bono J., Johann.DeBono@icr.ac.uk) Royal Marsden NHS Foundation Trust, 
Downs Road, Sutton, Surrey, United Kingdom.
(Marzo A.M.D.) Department of Pathology, Johns Hopkins University School of 
Medicine, Baltimore, United States.
CORRESPONDENCE ADDRESS
  D.N. Rodrigues, The Institute of Cancer Research, 15 Cotswold Road, Sutton, 
Surrey, United Kingdom. Email: Daniel.Navarodrigues@icr.ac.uk
SOURCE
  Journal of Pathology (2017) 241:2 (173-182). Date of Publication: 1 Jan 2017
ISSN
  1096-9896 (electronic)
  0022-3417
BOOK PUBLISHER
  John Wiley and Sons Ltd, Southern Gate, Chichester, West Sussex, United 
Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  androgen receptor (endogenous compound)
  cyclin dependent kinase 4 (endogenous compound)
  cyclin dependent kinase 6 (endogenous compound)
  messenger RNA (endogenous compound)
  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  prostate cancer (etiology)
EMTREE MEDICAL INDEX TERMS
  advanced cancer
  alternative RNA splicing
  cancer prognosis
  chromatin structure
  DNA repair
  gene deletion
  genomic instability
  germline mutation
  human
  male
  mismatch repair
  phenotype
  priority journal
  review
  signal transduction
  solid malignant neoplasm
  somatic mutation
  transcriptomics
CAS REGISTRY NUMBERS
  cyclin dependent kinase 4 (147014-97-9)
  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (210488-47-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Urology and Nephrology (28)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160926774
MEDLINE PMID
  27753448 (http://www.ncbi.nlm.nih.gov/pubmed/27753448)
PUI
  L613769533
DOI
  10.1002/path.4826
FULL TEXT LINK
  http://dx.doi.org/10.1002/path.4826
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 100
TITLE
  Inflammatory arthritis and sicca syndrome induced by nivolumab and 
ipilimumab
AUTHOR NAMES
  Cappelli L.C.
  Gutierrez A.K.
  Baer A.N.
  Albayda J.
  Manno R.L.
  Haque U.
  Lipson E.J.
  Bleich K.B.
  Shah A.A.
  Naidoo J.
  Brahmer J.R.
  Le D.
  Bingham C.O.
AUTHOR ADDRESSES
  (Cappelli L.C., lcappel1@jhmi.edu; Gutierrez A.K.; Baer A.N.; Albayda J.; 
Manno R.L.; Haque U.; Shah A.A.; Bingham C.O.) Division of Rheumatology, 
Department of Medicine, Johns Hopkins University, 5200 Eastern Avenue, MFL 
Center Tower 4100, Baltimore, United States.
(Lipson E.J.; Naidoo J.; Brahmer J.R.; Le D.) Department of Oncology, Johns 
Hopkins University, Baltimore, United States.
(Bleich K.B.) Department of Radiology, Johns Hopkins University, Baltimore, 
United States.
CORRESPONDENCE ADDRESS
  L.C. Cappelli, Division of Rheumatology, Department of Medicine, Johns 
Hopkins University, 5200 Eastern Avenue, MFL Center Tower 4100, Baltimore, 
United States. Email: lcappel1@jhmi.edu
SOURCE
  Annals of the Rheumatic Diseases (2017) 76:1 (43-50). Date of Publication: 1 
Jan 2017
ISSN
  1468-2060 (electronic)
  0003-4967
BOOK PUBLISHER
  BMJ Publishing Group, subscriptions@bmjgroup.com
ABSTRACT
  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 immunerelated 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. 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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  antinuclear antibody (endogenous compound)
  corticosteroid (drug therapy)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  infliximab
  methotrexate (drug therapy)
  prednisone (drug therapy)
  programmed death 1 receptor (endogenous compound)
  tumor necrosis factor inhibitor (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  rheumatoid arthritis (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
  Sjoegren syndrome (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adult
  adverse outcome
  aged
  article
  cancer chemotherapy
  cell death
  cell survival
  clinical article
  colitis (drug therapy, side effect)
  controlled study
  corticosteroid therapy
  drug megadose
  drug response
  drug safety
  female
  human
  interstitial nephritis (side effect)
  kidney carcinoma (drug therapy)
  male
  melanoma (drug therapy)
  metastatic melanoma (drug therapy)
  middle aged
  monotherapy
  non small cell lung cancer (drug therapy)
  nuclear magnetic resonance imaging
  pneumonia (side effect)
  rheumatology
  salivary gland disease (side effect)
  small cell lung cancer (drug therapy)
  solid malignant neoplasm (drug therapy)
  synovial fluid
  talonavicular joint
  thyroiditis (side effect)
  ultrasound
CAS REGISTRY NUMBERS
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  methotrexate (15475-56-6, 59-05-2, 7413-34-5)
  nivolumab (946414-94-4)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Arthritis and Rheumatism (31)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160513031
MEDLINE PMID
  27307501 (http://www.ncbi.nlm.nih.gov/pubmed/27307501)
PUI
  L611182205
DOI
  10.1136/annrheumdis-2016-209782
FULL TEXT LINK
  http://dx.doi.org/10.1136/annrheumdis-2016-209782
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 101
TITLE
  Ipilimumab-induced hypophysitis and ileocolitis: Serial pituitary MRI 
findings
AUTHOR NAMES
  Singh D.
  Hsu C.C.-T.
  Kwan G.N.C.
  Bhuta S.
AUTHOR ADDRESSES
  (Singh D., dsingh1386@gmail.com) Department of Medical Imaging, School of 
Medicine, University of Queensland, Brisbane, Australia.
(Hsu C.C.-T.; Kwan G.N.C.; Bhuta S.) Department of Medical Imaging, Gold 
Coast University Hospital, Southport, Australia.
CORRESPONDENCE ADDRESS
  D. Singh, Department of Medical Imaging, School of Medicine, University of 
Queensland, Brisbane, Australia. Email: dsingh1386@gmail.com
SOURCE
  Neurology India (2017) 65:1 (165-166). Date of Publication: 1 Jan 2017
ISSN
  1998-4022 (electronic)
  0028-3886
BOOK PUBLISHER
  Medknow Publications, B9, Kanara Business Centre, off Link Road, Ghatkopar 
(E), Mumbai, India.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  dexamethasone (drug combination, drug dose, drug therapy)
  follitropin (endogenous compound)
  hydrocortisone (endogenous compound)
  luteinizing hormone (endogenous compound)
  prednisone (drug combination, drug dose, drug therapy)
  prolactin (endogenous compound)
  testosterone (endogenous compound)
  testosterone undecanoate (intramuscular drug administration)
  thyrotropin (endogenous compound)
  thyroxine (drug therapy, endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  colitis (drug therapy, side effect, diagnosis, drug therapy, side effect)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
  ileum disease (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
  nuclear magnetic resonance imaging
EMTREE MEDICAL INDEX TERMS
  abdominal pain
  adult
  case report
  colon biopsy
  computer assisted tomography
  contrast enhancement
  diarrhea
  disease severity
  drug megadose
  drug withdrawal
  granulomatous inflammation (diagnosis)
  headache
  histopathology
  human
  human cell
  human tissue
  hypothyroidism (diagnosis, drug therapy)
  laboratory test
  letter
  male
  melanoma (drug therapy)
  middle aged
  migraine
  nausea
  neurologic examination
  pain severity
  sigmoidoscopy
  vertigo
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  dexamethasone (50-02-2)
  follitropin (9002-68-0)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  prednisone (53-03-2)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
  testosterone (58-22-0)
  testosterone undecanoate (5949-44-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170063651
PUI
  L614160211
DOI
  10.4103/0028-3886.198182
FULL TEXT LINK
  http://dx.doi.org/10.4103/0028-3886.198182
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 102
TITLE
  Diabetic Ketoacidosis as an Immune-related Adverse Event from Pembrolizumab 
in Non-Small Cell Lung Cancer
AUTHOR NAMES
  Leonardi G.C.
  Oxnard G.R.
  Haas A.
  Lang J.P.
  Williams J.S.
  Awad M.M.
AUTHOR ADDRESSES
  (Leonardi G.C.; Oxnard G.R.; Awad M.M., mark_awad@dfci.harvard.edu) Lowe 
Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline 
Avenue, Boston, United States.
(Haas A.; Williams J.S.) Division of Endocrinology, Diabetes and 
Hypertension, United States.
(Lang J.P.) Department of Medicine, Brigham and Women's Hospital, Boston, 
United States.
CORRESPONDENCE ADDRESS
  M.M. Awad, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 
450 Brookline Avenue, Boston, United States. Email: 
mark_awad@dfci.harvard.edu
SOURCE
  Journal of Immunotherapy (2017) 40:6 (249-251). Date of Publication: 2017
ISSN
  1537-4513 (electronic)
  1524-9557
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  C peptide (endogenous compound)
  glutamate decarboxylase 65 antibody (endogenous compound)
  hemoglobin A1c (endogenous compound)
  insulin (drug therapy)
  insulin aspart (drug therapy)
  insulin glargine (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  diabetic ketoacidosis (drug therapy, side effect, drug therapy, side effect)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  cancer chemotherapy
  case report
  drug response
  evening dosage
  glucose blood level
  glycemic control
  human
  insulin treatment
  male
  priority journal
  x-ray computed tomography
CAS REGISTRY NUMBERS
  C peptide (59112-80-0)
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
  insulin aspart (116094-23-6)
  insulin glargine (160337-95-1)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170391085
MEDLINE PMID
  28557813 (http://www.ncbi.nlm.nih.gov/pubmed/28557813)
PUI
  L616519972
DOI
  10.1097/CJI.0000000000000173
FULL TEXT LINK
  http://dx.doi.org/10.1097/CJI.0000000000000173
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 103
TITLE
  Ipilimumab-associated cholestatic hepatitis: A case report and literature 
review
AUTHOR NAMES
  Yildirim S.
  Deniz K.
  Doǧan E.
  Başkol M.
  Gürsoy Ş.
  Özkan M.
AUTHOR ADDRESSES
  (Yildirim S.; Başkol M.; Gürsoy Ş.) Departments of A Gastroenterology, 
Turkey.
(Deniz K., drkdeniz@yahoo.com) Departments of Pathology, Faculty of 
Medicine, Erciyes University, Kayseri, Turkey.
(Doǧan E.; Özkan M.) Departments of Oncology, Erciyes University, Kayseri, 
Turkey.
CORRESPONDENCE ADDRESS
  K. Deniz, Departments of Pathology, Faculty of Medicine, Erciyes University, 
Kayseri, Turkey. Email: drkdeniz@yahoo.com
SOURCE
  Melanoma Research (2017) 27:4 (380-382). Date of Publication: 2017
ISSN
  1473-5636 (electronic)
  0960-8931
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  alkaline phosphatase (endogenous compound)
  amylase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  bilirubin (endogenous compound)
  bilirubin glucuronide (endogenous compound)
  gamma glutamyltransferase (endogenous compound)
  prednisolone (drug therapy)
  temozolomide (drug therapy)
  triacylglycerol lipase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cholestatic hepatitis (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  alanine aminotransferase blood level
  alkaline phosphatase blood level
  amylase blood level
  apoptosis
  aspartate aminotransferase blood level
  bile duct injury
  bilirubin blood level
  case report
  cholestasis
  drug dose increase
  human
  human tissue
  inflammation
  jaundice
  leg edema
  liver biopsy
  liver necrosis
  lymphocytic infiltration
  maintenance therapy
  male
  metastatic melanoma (drug therapy)
  middle aged
  multiple cycle treatment
  priority journal
  review
  treatment response
  triacylglycerol lipase blood level
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  alkaline phosphatase (9001-78-9)
  amylase (9000-90-2, 9000-92-4, 9001-19-8)
  aspartate aminotransferase (9000-97-9)
  bilirubin (18422-02-1, 635-65-4)
  bilirubin glucuronide (27071-67-6)
  gamma glutamyltransferase (85876-02-4)
  ipilimumab (477202-00-9)
  prednisolone (50-24-8)
  temozolomide (85622-93-1)
  triacylglycerol lipase (9001-62-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170482813
PUI
  L617186302
DOI
  10.1097/CMR.0000000000000366
FULL TEXT LINK
  http://dx.doi.org/10.1097/CMR.0000000000000366
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 104
TITLE
  Endocrine toxicity of immune checkpoint inhibitors: Essential crosstalk 
between endocrinologists and oncologists
AUTHOR NAMES
  Illouz F.
  Briet C.
  Cloix L.
  Le Corre Y.
  Baize N.
  Urban T.
  Martin L.
  Rodien P.
AUTHOR ADDRESSES
  (Illouz F., frillouz@chu-angers.fr; Briet C.; Rodien P.) Department of 
Endocrinology, Diabetes and Nutrition Reference Centre of Rare Thyroid 
Disease Hospital of Angers Angers Cedex 09 F-49933 France
(Briet C.; Rodien P.) MITOVASC Institute INSERM U1083 University of Angers 
Angers Cedex 09 F-49933 France
(Cloix L.) Department of Endocrinology Hospital of Orléans Orléans F-45000 
France
(Le Corre Y.; Martin L.) Department of Dermatology Hospital of Angers 
University of Angers Angers Cedex 09 F-49933 France
(Baize N.) UTTIOM Unit for Innovate Therapy in Medical Oncology Hospital of 
Angers Angers Cedex 09 F-49933 France
(Urban T.) Department of Pulmonology and Thoracic Oncology Hospital of 
Angers Angers Cedex 09 F-49933 France
(Urban T.) INSERM UMRS 1066 University of Angers Angers Cedex 09 F-49933 
France
CORRESPONDENCE ADDRESS
  F. Illouz, Département d'Endocrinologie Diabétologie Nutrition, Centre de 
référence des maladies rares de la thyroïde, CHU d'Angers, Angers Cedex 09 
F-49933, France Email: frillouz@chu-angers.fr
SOURCE
  Cancer Medicine (2017). Date of Publication: 2017
ISSN
  2045-7634 (electronic)
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
  Two types of immune checkpoint inhibitors, both antibodies that target 
cytotoxic T-lymphocyte antigen-4 and those that target programmed cell 
death-protein 1, have been approved for use in melanoma, non-small-cell lung 
cancer, and renal cell carcinoma as first-line or second-line therapy. Their 
adverse events are primarily regarded as immune-related adverse events. We 
felt it was important to pinpoint and discuss certain preconceptions or 
misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes 
induced by immune checkpoint inhibitors. We have identified areas of 
uncertainty and unmet requirements, including essential interaction between 
endocrinologists and oncologists. Five issues have been identified for 
discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity 
severity, (3) treatment of toxicity, (4) withdrawal or continuation of 
immunotherapy, (5) preventive action.
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine system
  endocrinologist
  immunotherapy
  oncologist
  thyroid disease
  toxicity
EMTREE MEDICAL INDEX TERMS
  diagnosis
  human
  uncertainty
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170522153
PUI
  L617422894
DOI
  10.1002/cam4.1145
FULL TEXT LINK
  http://dx.doi.org/10.1002/cam4.1145
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 105
TITLE
  Comprehensive screening for PD-L1 expression in thyroid cancer
AUTHOR NAMES
  Ahn S.
  Kim T.H.
  Kim S.W.
  Ki C.S.
  Jang H.W.
  Kim J.S.
  Kim J.H.
  Choe J.-H.
  Shin J.H.
  Hahn S.Y.
  Oh Y.L.
  Chung J.H.
AUTHOR ADDRESSES
  (Ahn S.) Department of Pathology, Ewha Womans University, School of 
Medicine, Seoul, South Korea.
(Kim T.H.; Kim S.W.; Chung J.H., thyroid@skku.edu) Division of Endocrinology 
and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical 
Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
(Ki C.S.) Department of Laboratory Medicine and Genetics, Samsung Medical 
Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
(Jang H.W.) Department of Medical Education, Sungkyunkwan University School 
of Medicine, Seoul, South Korea.
(Kim J.S.; Kim J.H.; Choe J.-H.) Division of Breast and Endocrine Surgery, 
Department of Surgery, Samsung Medical Center, Sungkyunkwan University 
School of Medicine, Seoul, South Korea.
(Shin J.H.; Hahn S.Y.) Department of Radiology, Center for Imaging Science, 
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 
South Korea.
(Oh Y.L., bijou@skku.edu) Department of Pathology and Translational 
Genomics, Sungkyunkwan University School of Medicine, Seoul, South Korea.
CORRESPONDENCE ADDRESS
  Y.L. Oh, Department of Pathology and Translational Genomics, Sungkyunkwan 
University School of Medicine, Seoul, South Korea. Email: bijou@skku.edu
SOURCE
  Endocrine-Related Cancer (2017) 24:2 (97-106). Date of Publication: 2017
ISSN
  1479-6821 (electronic)
  1351-0088
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
  genomic DNA (endogenous compound)
  telomerase reverse transcriptase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer prognosis
  cancer screening
  thyroid cancer (surgery)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer growth
  cancer patient
  cancer recurrence
  cancer size
  cancer specific survival
  cancer staging
  cancer surgery
  cellular distribution
  controlled study
  female
  follow up
  Hashimoto disease
  histology
  human
  human tissue
  immunohistochemistry
  major clinical study
  male
  metastasis
  middle aged
  poorly differentiated thyroid cancer (surgery)
  primary tumor
  promoter region
  protein expression
  thyroid carcinoma (surgery)
  thyroid follicular carcinoma (surgery)
  thyroid papillary carcinoma (surgery)
  tissue microarray
  tumor associated leukocyte
CAS REGISTRY NUMBERS
  telomerase reverse transcriptase (120178-12-3)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170139403
MEDLINE PMID
  28093480 (http://www.ncbi.nlm.nih.gov/pubmed/28093480)
PUI
  L614522904
DOI
  10.1530/ERC-16-0421
FULL TEXT LINK
  http://dx.doi.org/10.1530/ERC-16-0421
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 106
TITLE
  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
AUTHOR NAMES
  Ishikawa K.
  Shono-Saito T.
  Yamate T.
  Kai Y.
  Sakai T.
  Shimizu F.
  Yamada Y.
  Mori H.
  Noso S.
  Ikegami H.
  Kojima H.
  Tanaka H.
  Fujiwara S.
  Hatano Y.
AUTHOR ADDRESSES
  (Ishikawa K.; Shono-Saito T.; Yamate T.; Kai Y.; Sakai T.; Fujiwara S.; 
Hatano Y., hatano@oita-u.ac.jp) Department of Dermatology, Faculty of 
Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu, Japan.
(Shimizu F.) Department of Plastic Surgery, Faculty of Medicine, Oita 
University, 1-1 Idaigaoka, Hasama-machi, Yufu, Japan.
(Yamada Y.; Mori H.) Department of Radiology, Faculty of Medicine, Oita 
University, 1-1 Idaigaoka, Hasama-machi, Yufu, Japan.
(Noso S.; Ikegami H.) Department of Endocrinology Metabolism and Diabetes, 
Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, 
Osaka, Japan.
(Kojima H.; Tanaka H.) HLA Foundation Laboratory, Kyoto, Japan.
CORRESPONDENCE ADDRESS
  Y. Hatano, Department of Dermatology, Faculty of Medicine, Oita University, 
1-1 Idaigaoka, Hasama-machi, Yufu, Japan. Email: hatano@oita-u.ac.jp
SOURCE
  European Journal of Dermatology (2017) 27:2 (184-185). Date of Publication: 
2017
ISSN
  1952-4013 (electronic)
  1167-1122
BOOK PUBLISHER
  John Libbey Eurotext, 127, avenue de la Republique, Montrouge, France. 
contact@jle.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  HLA antigen (endogenous compound)
  nivolumab (drug therapy)
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
  cysteinyldopa
  hemoglobin A1c (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  fulminant insulin dependent diabetes mellitus (diagnosis)
  insulin dependent diabetes mellitus (diagnosis)
  melanoma (drug therapy, diagnosis, drug therapy)
  organ size
  pancreatic volume
EMTREE MEDICAL INDEX TERMS
  adipose tissue
  adult
  blood sampling
  breslow thickness
  cancer chemotherapy
  case report
  computer assisted tomography
  cytotoxic T lymphocyte antigen 4 gene
  female
  gene
  genotype
  HLA antigen gene
  human
  hyperglycemia
  insulin treatment
  letter
  lymph node metastasis
  middle aged
  oncological parameters
  polydipsia
  single nucleotide polymorphism
CAS REGISTRY NUMBERS
  cysteinyldopa (19641-92-0)
  hemoglobin A1c (62572-11-6)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Drug Literature Index (37)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170284969
PUI
  L615491345
DOI
  10.1684/ejd.2016.2923
FULL TEXT LINK
  http://dx.doi.org/10.1684/ejd.2016.2923
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 107
TITLE
  Combination avelumab and utomilumab immunotherapy can induce diabetic 
ketoacidosis
AUTHOR NAMES
  Atkins P.W.
  Thompson D.M.
AUTHOR ADDRESSES
  (Atkins P.W.; Thompson D.M., David.Thompson@vch.ca) Division of 
Endocrinology, Department of Medicine, University of British Columbia, 
Vancouver, British Columbia, Canada
CORRESPONDENCE ADDRESS
  D.M. Thompson, Gordon and Leslie Diamond Center, 2775, Laurel Street, 4th, 
Floor Vancouver, BC, V5Z 1M9 Canada Email: David.Thompson@vch.ca
SOURCE
  Diabetes and Metabolism (2017). Date of Publication: 2017
ISSN
  1878-1780 (electronic)
  1262-3636
BOOK PUBLISHER
  Elsevier Masson SAS, 62 rue Camille Desmoulins, Issy les Moulineaux Cedex, 
France.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  avelumab
  utomilumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  diabetic ketoacidosis
  immunotherapy
EMTREE MEDICAL INDEX TERMS
  drug therapy
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170446510
PUI
  L616895733
DOI
  10.1016/j.diabet.2017.05.005
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.diabet.2017.05.005
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 108
TITLE
  Late-onset nivolumab-mediated pneumonitis in a patient with melanoma and 
multiple immune-related adverse events
AUTHOR NAMES
  DIamantopoulos P.T.
  Gaggadi M.
  Kassi E.
  Benopoulou O.
  Anastasopoulou A.
  Gogas H.
AUTHOR ADDRESSES
  (DIamantopoulos P.T., pandiamantopoulos@gmail.com; Kassi E.; Benopoulou O.; 
Anastasopoulou A.; Gogas H.) First Department of Internal Medicine, National 
and Kapodistrian, University of Athens, Athens, Greece.
(Gaggadi M.) Department of Pneumology, Laikon General Hospital, Athens, 
Greece.
CORRESPONDENCE ADDRESS
  P.T. DIamantopoulos, First Department of Internal Medicine, National and 
Kapodistrian, University of Athens, Athens, Greece. Email: 
pandiamantopoulos@gmail.com
SOURCE
  Melanoma Research (2017) 27:4 (391-395). Date of Publication: 2017
ISSN
  1473-5636 (electronic)
  0960-8931
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
ABSTRACT
  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 
Fcγ receptor polymorphisms are possible targets of the relevant research.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug dose, drug therapy)
EMTREE DRUG INDEX TERMS
  acetylsalicylic acid
  alkaline phosphatase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  atorvastatin
  B Raf kinase (endogenous compound)
  bilirubin (endogenous compound)
  carvedilol
  Fc receptor (endogenous compound)
  gamma glutamyltransferase (endogenous compound)
  HLA antigen (endogenous compound)
  lactate dehydrogenase (endogenous compound)
  moxifloxacin
  prednisone
  spironolactone
  thiamazole (drug dose)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  pneumonia (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  acute hepatitis (side effect)
  adult
  alkaline phosphatase blood level
  article
  aspartate aminotransferase blood level
  bilirubin blood level
  brain radiography
  brain surgery
  bronchoscopy
  cancer staging
  case report
  clinical examination
  computer assisted tomography
  coronary artery disease
  coughing
  drug dose titration
  dyspnea
  female
  follow up
  gamma glutamyl transferase blood level
  haplotype
  hospital patient
  hospitalization
  human
  hyperthyroidism (side effect)
  hypothyroidism (side effect)
  hypoxia
  in-transit metastasis
  jaundice
  laboratory test
  lactate dehydrogenase blood level
  lung lavage
  malaise
  medical history
  medical information
  middle aged
  nausea
  oxygen therapy
  priority journal
  thorax radiography
  thyrotropin blood level
  tonic clonic seizure
  treatment duration
  ulcer
CAS REGISTRY NUMBERS
  acetylsalicylic acid (493-53-8, 50-78-2, 53663-74-4, 53664-49-6, 63781-77-1)
  alkaline phosphatase (9001-78-9)
  aspartate aminotransferase (9000-97-9)
  atorvastatin (134523-00-5, 134523-03-8)
  bilirubin (18422-02-1, 635-65-4)
  carvedilol (72956-09-3)
  gamma glutamyltransferase (85876-02-4)
  lactate dehydrogenase (9001-60-9)
  moxifloxacin (151096-09-2)
  nivolumab (946414-94-4)
  prednisone (53-03-2)
  spironolactone (52-01-7)
  thiamazole (60-56-0)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Radiology (14)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170283738
PUI
  L615487681
DOI
  10.1097/CMR.0000000000000355
FULL TEXT LINK
  http://dx.doi.org/10.1097/CMR.0000000000000355
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 109
TITLE
  PD-L1 expression in human placentas and gestational trophoblastic diseases
AUTHOR NAMES
  Veras E.
  Kurman R.J.
  Wang T.-L.
  Shih I.-M.
AUTHOR ADDRESSES
  (Veras E.; Kurman R.J.; Wang T.-L.; Shih I.-M., ishih@jhmi.edu) Departments 
of Pathology, Gynecology and Obstetrics, Johns Hopkins Medical Institutions, 
Johns Hopkins University School of Medicine, Baltimore, United States.
(Veras E.; Kurman R.J.; Wang T.-L.; Shih I.-M., ishih@jhmi.edu) Departments 
of Oncology, Johns Hopkins Medical Institutions, Baltimore, United States.
CORRESPONDENCE ADDRESS
  I.-M. Shih, Departments of Pathology, Gynecology and Obstetrics, Johns 
Hopkins Medical Institutions, Johns Hopkins University School of Medicine, 
Baltimore, United States. Email: ishih@jhmi.edu
SOURCE
  International Journal of Gynecological Pathology (2017) 36:2 (146-153). Date 
of Publication: 2017
ISSN
  1538-7151 (electronic)
  0277-1691
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  One of the major immune checkpoints responsible for immune evasion in cancer 
cells is the interaction between programmed cell death-1 (PD-1) and its 
ligand (PD-L1). As human trophoblastic cells display many of the features of 
malignant cells such as the ability to invade normal tissue including blood 
vessels and are apparently not eradicated by the host immune system, we 
undertook the present study to determine whether PD-L1 was upregulated in 
different types of trophoblastic cells during normal pregnancy and in 
gestational trophoblastic diseases. Immunohistochemistry using an 
anti-PD-L1-specific antibody demonstrated that in early and term normal 
placentas, PD-L1 was highly expressed in syncytiotrophoblast and to a much 
lower extent in intermediate trophoblastic cells located in the chorion 
laeve and implantation site. PDL1 immunoreactivity was undetectable in 
cytotrophoblastic cells. This staining pattern in normal placenta was 
recapitulated in various types of gestational trophoblastic disease. PD-L1 
was highly expressed by syncytiotrophoblast in complete moles and 
choriocarcinomas. The intermediate trophoblastic neoplasms, placental site 
trophoblastic tumors, and epithelioid trophoblastic tumors showed variable 
PD-L1 immunoreactivity but at a lower intensity than in the neoplastic 
syncytiotrophoblast in choriocarcinoma. In addition, we observed 
PD-1-positive lymphocytes located within the implantation site and in 
trophoblastic tumors. In summary, this study describes a novel mechanism for 
trophoblastic cells to create a tolerogenic feto-maternal interface by 
upregulating PD-L1 in syncytiotrophoblast and in intermediate trophoblast. 
Trophoblastic tumors may also use PD-L1 expression to evade the host immune 
response thereby promoting their survival.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  placenta
  trophoblastic tumor
EMTREE MEDICAL INDEX TERMS
  abortion
  article
  brain
  breast
  choriocarcinoma
  chorion
  chorion villus
  controlled study
  cytotrophoblast
  female
  gallbladder
  human
  human tissue
  hydatidiform mole
  immune evasion
  immune response
  immunohistochemistry
  immunological tolerance
  immunoreactivity
  immunosurveillance
  kidney
  large intestine
  lung
  lymph node
  lymphocyte
  pancreas
  priority journal
  protein expression
  regulatory T lymphocyte
  salivary gland
  small intestine
  stomach
  syncytiotrophoblast
  tonsil
  trophoblast
  tumor microenvironment
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160492127
MEDLINE PMID
  27362903 (http://www.ncbi.nlm.nih.gov/pubmed/27362903)
PUI
  L611065411
DOI
  10.1097/PGP.0000000000000305
FULL TEXT LINK
  http://dx.doi.org/10.1097/PGP.0000000000000305
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 110
TITLE
  Small cell lung cancer transformation during immunotherapy with nivolumab: A 
case report
AUTHOR NAMES
  Imakita T.
  Fujita K.
  Kanai O.
  Terashima T.
  Mio T.
AUTHOR ADDRESSES
  (Imakita T.; Fujita K., kfujita-oka@umin.ac.jp; Kanai O.; Mio T.) Division 
of Respiratory Medicine, National Hospital Organization Kyoto Medical 
Center, Kyoto, Japan.
(Imakita T.) Department of Respiratory Medicine, Hyogo Prefectural Amagasaki 
General Medical Center, Japan.
(Terashima T.) Division of Clinical Pathology, National Hospital 
Organization Kyoto Medical Center, Kyoto, Japan.
CORRESPONDENCE ADDRESS
  K. Fujita, Division of Respiratory Medicine, National Hospital Organization 
Kyoto Medical Center, 1-1, Fukakusa-Mukaihata-Cho, Fushimi-Ku, Kyoto, Japan. 
Email: kfujita-oka@umin.ac.jp
SOURCE
  Respiratory Medicine Case Reports (2017) 21 (52-55). Date of Publication: 
2017
ISSN
  2213-0071 (electronic)
BOOK PUBLISHER
  W.B. Saunders Ltd
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (drug therapy)
EMTREE DRUG INDEX TERMS
  anaplastic lymphoma kinase (endogenous compound)
  bevacizumab (adverse drug reaction, drug therapy)
  carcinoembryonic antigen (endogenous compound)
  docetaxel (adverse drug reaction, drug therapy)
  epidermal growth factor receptor (endogenous compound)
  homeobox protein Nkx 2.1 (endogenous compound)
  synaptophysin (endogenous compound)
  tumor marker (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  malignant transformation
  small cell lung cancer
EMTREE MEDICAL INDEX TERMS
  aged
  article
  bronchoscopy
  cancer staging
  case report
  digestive system perforation (side effect)
  epidermal growth factor receptor gene
  human
  human tissue
  immunopathology
  male
  multiple cycle treatment
  non small cell lung cancer (diagnosis, drug therapy)
  nuclear magnetic resonance imaging
  pleura effusion (diagnosis)
  positron emission tomography-computed tomography
  transbronchial biopsy
  tumor volume
CAS REGISTRY NUMBERS
  anaplastic lymphoma kinase (166433-56-3)
  bevacizumab (216974-75-3)
  docetaxel (114977-28-5)
  epidermal growth factor receptor (79079-06-4)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Radiology (14)
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170237595
PUI
  L615037398
DOI
  10.1016/j.rmcr.2017.03.019
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.rmcr.2017.03.019
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 111
TITLE
  Advances in understanding hypopituitarism
AUTHOR NAMES
  Kopczak A.
  Stieg M.R.
  Renner U.
  Stalla G.K.
AUTHOR ADDRESSES
  (Kopczak A., anna_kopczak@psych.mpg.de; Stieg M.R.; Renner U.; Stalla G.K.) 
Max Planck Institute of Psychiatry, Clinical Neuroendocrinology, 
Kraepelinstr. 2-10, Munich, Germany.
CORRESPONDENCE ADDRESS
  A. Kopczak, Max Planck Institute of Psychiatry, Clinical Neuroendocrinology, 
Kraepelinstr. 2-10, Munich, Germany. Email: anna_kopczak@psych.mpg.de
SOURCE
  F1000Research (2017) 6 Article Number: 178. Date of Publication: 2017
ISSN
  1759-796X (electronic)
  2046-1402
BOOK PUBLISHER
  Faculty of 1000 Ltd, info@f1000.com
ABSTRACT
  The understanding of hypopituitarism has increased over the last three 
years. This review provides an overview of the most important recent 
findings. Most of the recent research in hypopituitarism has focused on 
genetics. New diagnostic techniques like next-generation sequencing have led 
to the description of different genetic mutations causative for congenital 
dysfunction of the pituitary gland while new molecular mechanisms underlying 
pituitary ontogenesis have also been described. Furthermore, hypopituitarism 
may occur because of an impairment of the distinctive vascularization of the 
pituitary gland, especially by disruption of the long vessel connection 
between the hypothalamus and the pituitary. Controversial findings have been 
published on post-traumatic hypopituitarism. Moreover, autoimmunity has been 
discussed in recent years as a possible reason for hypopituitarism. With the 
use of new drugs such as ipilimumab, hypopituitarism as a side effect of 
pharmaceuticals has come into focus. Besides new findings on the 
pathomechanism of hypopituitarism, there are new diagnostic tools in 
development, such as new growth hormone stimulants that are currently being 
tested in clinical trials. Moreover, cortisol measurement in scalp hair is a 
promising tool for monitoring cortisol levels over time.
EMTREE DRUG INDEX TERMS
  corticotropin releasing factor (endogenous compound)
  hypothalamus hormone (endogenous compound)
  ipilimumab (adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypopituitarism (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  autoimmune hypophysitis
  autoimmunity
  clinical feature
  congenital disorder
  congenital hypopituitarism
  gene mutation
  genetic association
  growth hormone deficiency
  human
  hydrocortisone blood level
  hypophyseal blood supply
  hypophysis
  hypothalamus
  next generation sequencing
  nonhuman
  ontogeny
  post traumatic hypopituitarism
  review
  traumatic brain injury
  vascularization
CAS REGISTRY NUMBERS
  corticotropin releasing factor (9015-71-8, 178359-01-8, 79804-71-0, 
86297-72-5, 86784-80-7)
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170198347
PUI
  L614766588
DOI
  10.12688/f1000research.9436.1
FULL TEXT LINK
  http://dx.doi.org/10.12688/f1000research.9436.1
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 112
TITLE
  Clinical practice and mechanism of endocrinological adverse events 
associated with immune checkpoint inhibitors
AUTHOR NAMES
  Iwama S.
  Arima H.
AUTHOR ADDRESSES
  (Iwama S.) Research Center of Health, Physical Fitness and Sports, Nagoya 
University, Japan.
(Iwama S.; Arima H.) Department of Endocrinology and Diabetes, Nagoya 
University Graduate School of Medicine, Japan.
SOURCE
  Japanese Journal of Clinical Immunology (2017) 40:2 (90-94). Date of 
Publication: 2017
ISSN
  1349-7413 (electronic)
  0911-4300
BOOK PUBLISHER
  Japan Society for Clinical Immunology, jsci@nifty.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  checkpoint kinase inhibitor (adverse drug reaction, drug therapy)
  immune checkpoint inhibitor (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cell cycle checkpoint
  clinical practice
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  antineoplastic activity
  article
  cancer immunotherapy
  endocrine system
  gastrointestinal tract
  human
  kidney carcinoma
  liver
  melanoma
  non small cell lung cancer
  skin
  T lymphocyte activation
  unspecified side effect (side effect)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English, Japanese
EMBASE ACCESSION NUMBER
  20170427399
MEDLINE PMID
  28603206 (http://www.ncbi.nlm.nih.gov/pubmed/28603206)
PUI
  L616788153
DOI
  10.2177/jsci.40.90
FULL TEXT LINK
  http://dx.doi.org/10.2177/jsci.40.90
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 113
TITLE
  Varied immuno-related adverse events induced by immune-check point 
inhibitors — Nivolumab-associated psoriasiform dermatitis related with 
increased serum level of interleukin-6 —
AUTHOR NAMES
  Okiyama N.
  Tanaka R.
AUTHOR ADDRESSES
  (Okiyama N.; Tanaka R.) Department of Dermatology, Faculty of Medicine, 
University of Tsukuba, Japan.
SOURCE
  Japanese Journal of Clinical Immunology (2017) 40:2 (95-101). Date of 
Publication: 2017
ISSN
  1349-7413 (electronic)
  0911-4300
BOOK PUBLISHER
  Japan Society for Clinical Immunology, jsci@nifty.com
ABSTRACT
  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-β 
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-α levels after nivolumab treatment compared to 
progressive MM patients.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  checkpoint kinase inhibitor (adverse drug reaction, drug therapy)
  interleukin 6 (endogenous compound)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  beta interferon (adverse drug reaction)
  immunoglobulin (drug therapy, intravenous drug administration)
  prednisolone (drug therapy, oral drug administration)
  tumor necrosis factor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease
  melanoma (drug therapy, drug therapy)
  psoriasis (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  aged
  anamnesis
  article
  case report
  controlled study
  female
  human
  hyperthyroidism
  hypothyroidism
  male
  muscle weakness
  polyradiculoneuropathy (drug therapy, side effect)
  side effect (side effect)
  somatosensory disorder
  thyroiditis (side effect)
  very elderly
CAS REGISTRY NUMBERS
  immunoglobulin (9007-83-4)
  nivolumab (946414-94-4)
  prednisolone (50-24-8)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English, Japanese
EMBASE ACCESSION NUMBER
  20170427400
MEDLINE PMID
  28603207 (http://www.ncbi.nlm.nih.gov/pubmed/28603207)
PUI
  L616788156
DOI
  10.2177/jsci.40.95
FULL TEXT LINK
  http://dx.doi.org/10.2177/jsci.40.95
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 114
TITLE
  Immunotherapy in ovarian cancer
AUTHOR NAMES
  Krishnan V.
  Berek J.S.
  Dorigo O.
AUTHOR ADDRESSES
  (Krishnan V.) Department of Obstetrics and Gynecology, Stanford University 
School of Medicine, Stanford, United States.
(Berek J.S.; Dorigo O., odorigo@stanford.edu) Department of Obstetrics and 
Gynecology, Stanford Womens Cancer Center, Stanford University School of 
Medicine, Stanford, United States.
CORRESPONDENCE ADDRESS
  O. Dorigo, Department of Obstetrics and Gynecology, Stanford Womens Cancer 
Center, Stanford University School of Medicine, Stanford, United States. 
Email: odorigo@stanford.edu
SOURCE
  Current Problems in Cancer (2017) 41:1 (48-63). Date of Publication: 1 Jan 
2017
ISSN
  1535-6345 (electronic)
  0147-0272
BOOK PUBLISHER
  Mosby Inc., customerservice@mosby.com
ABSTRACT
  Immunotherapy aims to develop combination approaches that simultaneously 
augment immunity while preventing local immune suppression. Despite advances 
in combinatorial chemotherapy regimens and the advent of intraperitoneal 
chemotherapy administration, current therapeutic options for patients with 
ovarian cancer are inadequate. Advances in immunotherapy offer a promising 
frontier for treating ovarian tumors. Multiple immunotherapeutic modalities 
are currently developed and tested in clinical trials. Antibody-based 
therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen 
receptor–modified T cells have demonstrated preclinical success and entered 
clinical testing. In this review, we discuss these promising 
immunotherapeutic approaches and emphasize the importance of combinatorial 
treatment strategies and biomarker discovery.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immunologic agent (drug therapy)
EMTREE DRUG INDEX TERMS
  bevacizumab
  biological marker (endogenous compound)
  cancer antibody
  catumaxomab
  cetuximab
  cytotoxic T lymphocyte antigen 4
  dendritic cell vaccine
  immune checkpoint inhibitor
  leukocyte antibody
  panitumumab
  peptide vaccine
  programmed death 1 ligand 1
  programmed death 1 receptor
  recombinant vaccine
  unclassified drug
  virus vaccine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adoptive transfer
  article
  cell therapy
  ex vivo study
  human
  in vivo study
  nonhuman
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  randomized controlled trial (topic)
  tumor associated leukocyte
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  catumaxomab (509077-98-9)
  cetuximab (205923-56-4)
  panitumumab (339177-26-3)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170095743
MEDLINE PMID
  28169004 (http://www.ncbi.nlm.nih.gov/pubmed/28169004)
PUI
  L614311200
DOI
  10.1016/j.currproblcancer.2016.11.003
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.currproblcancer.2016.11.003
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 115
TITLE
  Combination therapy of cytotoxic t-lymphocyte-associated antigen 4 (ctla-4) 
and programmed death 1 (pd1) blocker, check point inhibitors for treatment 
of patients with advanced and recurrent epithelial ovarian cancer
AUTHOR NAMES
  Farghaly S.A.
AUTHOR ADDRESSES
  (Farghaly S.A., samirfarghaly@yahoo.com) Joan and Sanford I. Weill Medical 
College, New York Presbyterian Hospital, Weill Cornell Medical Center, 
Cornell University, New York, United States.
CORRESPONDENCE ADDRESS
  S.A. Farghaly, Joan and Sanford I. Weill Medical College, New York 
Presbyterian Hospital, Weill Cornell Medical Center, Cornell University, New 
York, United States. Email: samirfarghaly@yahoo.com
SOURCE
  European Journal of Gynaecological Oncology (2017) 38:1 (7-9). Date of 
Publication: 2017
ISSN
  0392-2936
BOOK PUBLISHER
  S.O.G. CANADA Inc.
ABSTRACT
  The standard of care for patients with recurrent ovarian cancer is 
platinum-based combination chemotherapy for those who relapse more than six 
months after completing adjuvant therapy. The use of biological agents such 
as bevacizumab has increased progression-free survival (PFS), but has not 
shown a significant increase in overall survival (OS). Immunotherapy 
treatment modality is being actively pursued for patients with ovarian 
cancer. The goal of immunotherapy is to generate a tumor specific, T cell 
response that decrease residual disease, and protects against future 
recurrence. Combination therapy of anti-PD-1 antibodies, and anti-CTLA-4 
antibodies reverses the TIL dysfunction and induces tumor regression in 
solid tumors, including ovarian cancer. When GM-CSF vaccine is added, it 
results in increased tumor rejection.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  bevacizumab (clinical trial, drug combination, drug therapy)
  cytotoxic T lymphocyte antigen 4 antibody (clinical trial, drug combination, 
drug therapy)
EMTREE DRUG INDEX TERMS
  biological marker (endogenous compound)
  granulocyte macrophage colony stimulating factor vaccine (drug combination, 
drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer combination chemotherapy
  cancer immunotherapy
  cancer recurrence
  ovary carcinoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  cancer patient
  cancer survival
  clinical outcome
  drug cytotoxicity
  female
  human
  monotherapy
  overall survival
  phase 1 clinical trial (topic)
  progression free survival
  review
  T lymphocyte activation
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170189733
PUI
  L614781052
DOI
  10.12892/ejgo3880.2017
FULL TEXT LINK
  http://dx.doi.org/10.12892/ejgo3880.2017
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 116
TITLE
  Immune-mediated Disease in Ipilimumab Immunotherapy of Melanoma with FDG 
PET-CT
AUTHOR NAMES
  Wachsmann J.W.
  Ganti R.
  Peng F.
AUTHOR ADDRESSES
  (Wachsmann J.W., Jason.Wachsmann@UTSouthwestern.edu; Ganti R.; Peng F.) 
Department of Radiology, University of Texas Southwestern Medical Center, 
5323 Harry Hines Blvd., Dallas, United States.
(Peng F.) Advanced Imaging Research Center, University of Texas Southwestern 
Medical Center, Dallas, United States.
CORRESPONDENCE ADDRESS
  J.W. Wachsmann, Department of Radiology, University of Texas Southwestern 
Medical Center, 5323 Harry Hines Blvd., Dallas, United States. Email: 
Jason.Wachsmann@UTSouthwestern.edu
SOURCE
  Academic Radiology (2017) 24:1 (111-115). Date of Publication: 1 Jan 2017
ISSN
  1878-4046 (electronic)
  1076-6332
BOOK PUBLISHER
  Elsevier USA
ABSTRACT
  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. 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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  fluorodeoxyglucose f 18 (intravenous drug administration)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  hydrocortisone (drug therapy)
  levothyroxine (drug therapy)
  thyroglobulin antibody (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  computer assisted emission tomography
  immune mediated injury (side effect, side effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  antibody blood level
  cancer chemotherapy
  cancer patient
  case report
  case study
  colitis (side effect)
  female
  follow up
  human
  hypophysitis (drug therapy, side effect)
  male
  middle aged
  pancreatitis (side effect)
  PET-CT scanner
  priority journal
  retrospective study
  review
  substitution therapy
  therapy effect
  thyroiditis (side effect)
  treatment response
  whole body CT
  whole body PET
DEVICE TRADE NAMES
  Biograph PET-CT scanner  , United StatesSiemens

DEVICE MANUFACTURERS
   (United States)Siemens
CAS REGISTRY NUMBERS
  fluorodeoxyglucose f 18 (63503-12-8)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160885850
MEDLINE PMID
  27818005 (http://www.ncbi.nlm.nih.gov/pubmed/27818005)
PUI
  L613536320
DOI
  10.1016/j.acra.2016.08.005
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.acra.2016.08.005
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 117
TITLE
  Transient thyrotoxicosis during nivolumab treatment
AUTHOR NAMES
  van Kooten M.J.
  van den Berg G.
  Glaudemans A.W.J.M.
  Hiltermann T.J.N.
  Groen H.J.M.
  Rutgers A.
  Links T.P.
AUTHOR ADDRESSES
  (van Kooten M.J.; van den Berg G., g.van.den.berg@umcg.nl; Links T.P.) 
Department of Endocrinology, University of Groningen, University Medical 
Center Groningen, Groningen, Netherlands.
(Glaudemans A.W.J.M.) Department of Nuclear Medicine and Molecular Imaging, 
University of Groningen, University Medical Center Groningen, Groningen, 
Netherlands.
(Hiltermann T.J.N.; Groen H.J.M.) Department of Pulmonology, University of 
Groningen, University Medical Center Groningen, Groningen, Netherlands.
(Rutgers A.) Department of Rheumatology and Clinical Immunology, University 
of Groningen, University Medical Center Groningen, Groningen, Netherlands.
CORRESPONDENCE ADDRESS
  G. van den Berg, Department of Endocrinology, University of Groningen, 
University Medical Center Groningen, Groningen, Netherlands. Email: 
g.van.den.berg@umcg.nl
SOURCE
  Netherlands Journal of Medicine (2017) 75:5 (204-207). Date of Publication: 
2017
ISSN
  0300-2977
BOOK PUBLISHER
  Van Zuiden Communications BV, zuiden@zuidencomm.nl
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  atenolol (drug therapy)
  beta adrenergic receptor blocking agent
  levothyroxine
  thiamazole (drug therapy)
  thyroid peroxidase antibody (endogenous compound)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thyrotoxicosis (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  body weight loss
  cancer staging
  case report
  drug withdrawal
  fatigue (side effect)
  female
  free liothyronine index
  free thyroxine index
  goiter (side effect)
  Graves disease (drug therapy)
  heart palpitation (side effect)
  human
  hyperhidrosis (side effect)
  hypothyroidism (side effect)
  immunotherapy
  middle aged
  non small cell lung cancer
  positron emission tomography-computed tomography
  Sjoegren syndrome
  tachycardia (side effect)
CAS REGISTRY NUMBERS
  atenolol (29122-68-7, 93379-54-5)
  levothyroxine (51-48-9)
  nivolumab (946414-94-4)
  thiamazole (60-56-0)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170454042
PUI
  L616963431
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 118
TITLE
  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
AUTHOR NAMES
  Hellmann M.D.
  Rizvi N.A.
  Goldman J.W.
  Gettinger S.N.
  Borghaei H.
  Brahmer J.R.
  Ready N.E.
  Gerber D.E.
  Chow L.Q.
  Juergens R.A.
  Shepherd F.A.
  Laurie S.A.
  Geese W.J.
  Agrawal S.
  Young T.C.
  Li X.
  Antonia S.J.
AUTHOR ADDRESSES
  (Hellmann M.D., hellmanm@mskcc.org; Rizvi N.A.) Memorial Sloan Kettering 
Cancer Center, New York, United States.
(Goldman J.W.) UCLA, Jonsson Comprehensive Cancer Center, Los Angeles, 
United States.
(Gettinger S.N.) Yale Comprehensive Cancer Center, New Haven, United States.
(Borghaei H.) Fox Chase Cancer Center, Philadelphia, United States.
(Brahmer J.R.) Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 
Baltimore, United States.
(Ready N.E.) Duke University Medical Center, Durham, United States.
(Gerber D.E.) UT Southwestern Medical Center, Dallas, United States.
(Chow L.Q.) University of Washington, Seattle, United States.
(Juergens R.A.) Juravinski Cancer Centre, McMaster University, Hamilton, 
Canada.
(Shepherd F.A.) Princess Margaret Cancer Centre, University of Toronto, 
Toronto, Canada.
(Laurie S.A.) Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, 
Canada.
(Geese W.J.; Agrawal S.; Young T.C.; Li X.) Bristol-Myers Squibb, Princeton, 
United States.
(Antonia S.J.) H Lee Moffitt Cancer Center & Research Institute, Tampa, 
United States.
CORRESPONDENCE ADDRESS
  M.D. Hellmann, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New 
York, United States. Email: hellmanm@mskcc.org
SOURCE
  The Lancet Oncology (2017) 18:1 (31-41). Date of Publication: 1 Jan 2017
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  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. 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. 
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. 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. Funding Bristol-Myers Squibb.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy)
  nivolumab (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  amylase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  creatinine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure (side effect)
  adrenal insufficiency (side effect)
  adult
  advanced cancer (drug therapy)
  aged
  alanine aminotransferase blood level
  anemia (side effect)
  arthralgia (side effect)
  article
  aspartate aminotransferase blood level
  brain disease (side effect)
  cancer staging
  cataract (side effect)
  cohort analysis
  colitis (side effect)
  controlled study
  creatinine blood level
  decreased appetite (side effect)
  dehydration (side effect)
  diabetes mellitus (side effect)
  diarrhea (side effect)
  dosage schedule comparison
  drug dose comparison
  drug efficacy
  drug fatality (side effect)
  drug safety
  drug tolerability
  drug withdrawal
  dyspnea (side effect)
  endocrine disease (side effect)
  esophagitis (side effect)
  facial nerve disease (side effect)
  fatigue (side effect)
  female
  fever (side effect)
  follow up
  gastrointestinal symptom (side effect)
  human
  human tissue
  hyperthyroidism (side effect)
  hypertransaminasemia (side effect)
  hypokalemia (side effect)
  hyponatremia (side effect)
  increased appetite (side effect)
  infusion related reaction (side effect)
  liver disease (side effect)
  lung disease (side effect)
  lung embolism (side effect)
  lymphocyte count
  maculopapular rash (side effect)
  major clinical study
  male
  multicenter study
  nausea (side effect)
  nephrotoxicity (side effect)
  open study
  outcome assessment
  overall survival
  pancreatitis (side effect)
  phase 1 clinical trial
  pneumonia (side effect)
  priority journal
  progression free survival
  pruritus (side effect)
  radiation necrosis (side effect)
  randomized controlled trial
  rash (side effect)
  respiratory distress (side effect)
  side effect (side effect)
  skin disease (side effect)
  skin toxicity (side effect)
  survival time
  treatment duration
  treatment response
  triacylglycerol lipase blood level
  United States
  vomiting (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  amylase (9000-90-2, 9000-92-4, 9001-19-8)
  aspartate aminotransferase (9000-97-9)
  creatinine (19230-81-0, 60-27-5)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Public Health, Social Medicine and Epidemiology (17)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01454102, NCT02367781, NCT02453282, NCT02477826, NCT02578680)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170006359
MEDLINE PMID
  27932067 (http://www.ncbi.nlm.nih.gov/pubmed/27932067)
PUI
  L613934515
DOI
  10.1016/S1470-2045(16)30624-6
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(16)30624-6
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 119
TITLE
  Case of hypophysitis caused by nivolumab
AUTHOR NAMES
  Ishikawa M.
  Oashi K.
AUTHOR ADDRESSES
  (Ishikawa M., m-ishikawa@cancer-c.pref.saitama.jp; Oashi K.) Department of 
Dermatology, Saitama Cancer Center, Saitama, Japan.
CORRESPONDENCE ADDRESS
  M. Ishikawa, Department of Dermatology, Saitama Cancer Center, Saitama, 
Japan. Email: m-ishikawa@cancer-c.pref.saitama.jp
SOURCE
  Journal of Dermatology (2017) 44:1 (109-110). Date of Publication: 1 Jan 
2017
ISSN
  1346-8138 (electronic)
  0385-2407
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  dacarbazine (drug therapy)
  hydrocortisone (drug therapy, endogenous compound, oral drug administration)
  hydrocortisone sodium succinate (drug combination, drug therapy)
  oxygen (drug combination, drug therapy, inhalational drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (drug therapy)
  adrenal metastasis
  adult
  anorexia
  body weight loss
  case report
  depressed blood pressure
  drug dose increase
  drug withdrawal
  human
  hypothyroidism (side effect)
  infusion related reaction (drug therapy, side effect)
  interstitial pneumonia (side effect)
  letter
  malaise
  male
  melanoma (drug therapy)
  middle aged
  multiple cycle treatment
  myalgia
  nausea
  nuclear magnetic resonance imaging
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  dacarbazine (4342-03-4)
  hydrocortisone (50-23-7)
  hydrocortisone sodium succinate (125-04-2, 2203-97-6)
  nivolumab (946414-94-4)
  oxygen (7782-44-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20160405458
MEDLINE PMID
  27178147 (http://www.ncbi.nlm.nih.gov/pubmed/27178147)
PUI
  L610556665
DOI
  10.1111/1346-8138.13437
FULL TEXT LINK
  http://dx.doi.org/10.1111/1346-8138.13437
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 120
TITLE
  Fulminant type 1 diabetes caused by dual immune checkpoint blockade in 
metastatic renal cell carcinoma
AUTHOR NAMES
  Teló G.H.
  Carvalhal G.F.
  Cauduro C.G.S.
  Webber V.S.
  Barrios C.H.
  Fay A.P.
AUTHOR ADDRESSES
  (Teló G.H.) Endocrinology Department, Federal University of Rio Grande do 
Sul (UFRGS), Porto Alegre, Brazil.
(Carvalhal G.F.; Cauduro C.G.S.; Barrios C.H.; Fay A.P., andre.fay@pucrs.br) 
School of Medicine, PUCRS, Porto Alegre, Brazil.
(Webber V.S.; Barrios C.H.; Fay A.P., andre.fay@pucrs.br) Clinical Research 
Center, PUCRS, Porto Alegre, Brazil.
(Barrios C.H.; Fay A.P., andre.fay@pucrs.br) Medical Oncology, Hospital do 
CâncerMãe de Deus, Porto Alegre, Brazil.
(Barrios C.H.; Fay A.P., andre.fay@pucrs.br) Latin American Cooperative 
Oncology Group (LACOG), Porto Alegre, Brazil.
CORRESPONDENCE ADDRESS
  A.P. Fay, School of Medicine, PUCRS, Porto Alegre, Brazil. Email: 
andre.fay@pucrs.br
SOURCE
  Annals of Oncology (2017) 28:1 (191-192). Date of Publication: 1 Jan 2017
ISSN
  1569-8041 (electronic)
  0923-7534
BOOK PUBLISHER
  Oxford University Press, jnl.info@oup.co.uk
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  triacylglycerol lipase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  fulminant insulin dependent diabetes mellitus (side effect, diagnosis, side 
effect)
  insulin dependent diabetes mellitus (side effect, diagnosis, side effect)
  kidney carcinoma (drug therapy, drug therapy)
  metastasis (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  case report
  computer assisted tomography
  confusion
  diabetic ketoacidosis
  drug response
  fatigue
  fever
  flu like syndrome
  glycemic control
  human
  hyperglycemia
  ketoacidosis
  letter
  male
  middle aged
  pancreatitis (diagnosis)
  pneumonia
  polydipsia
  polyuria
  triacylglycerol lipase blood level
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  triacylglycerol lipase (9001-62-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170214180
PUI
  L614949602
DOI
  10.1093/annonc/mdw447
FULL TEXT LINK
  http://dx.doi.org/10.1093/annonc/mdw447
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 121
TITLE
  Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes 
mellitus secondary to combination ipilimumab and nivolumab immunotherapy
AUTHOR NAMES
  Lowe J.R.
  Perry D.J.
  Salama A.K.S.
  Mathews C.E.
  Moss L.G.
  Hanks B.A.
AUTHOR ADDRESSES
  (Lowe J.R., jared.lowe@duke.edu) Duke University Medical Center, Department 
of Medicine, Durham, United States.
(Perry D.J., perryd@pathology.ufl.edu; Mathews C.E., 
clayton.mathews@pathology.ufl.edu) University of Florida College of 
Medicine, Department of Pathology, Immunology, and Laboratory Medicine, 
Gainesville, United States.
(Salama A.K.S., april.salama@duke.edu; Hanks B.A., hanks004@mc.duke.edu) 
Duke University Medical Center, Department of Medicine, Division of Medical 
Oncology, Melanoma Program, Duke Cancer Institute, Durham, United States.
(Moss L.G., larry.moss@duke.edu) Duke University Medical Center, Duke 
Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism 
Center, Department of Medicine, Division of Endocrinology, Metabolism, and 
Nutrition, Durham, United States.
CORRESPONDENCE ADDRESS
  B.A. Hanks, Duke University Medical Center, Department of Medicine, Division 
of Medical Oncology, Melanoma Program, Duke Cancer Institute, Durham, United 
States. Email: hanks004@mc.duke.edu
SOURCE
  Journal for ImmunoTherapy of Cancer (2016) 4:1 Article Number: 89. Date of 
Publication: 20 Dec 2016
ISSN
  2051-1426 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (clinical trial, drug combination, drug therapy)
  nivolumab (clinical trial, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  glutamate decarboxylase (endogenous compound)
  levothyroxine
  liothyronine (endogenous compound)
  loperamide
  methylprednisolone
  metoprolol (drug therapy)
  microsome antibody (endogenous compound)
  prednisone (drug therapy)
  thyrotropin (endogenous compound)
  thyrotropin receptor antibody (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  genetic risk
  insulin dependent diabetes mellitus (diagnosis)
  risk assessment
EMTREE MEDICAL INDEX TERMS
  adult
  article
  autoimmune thyroiditis (drug therapy)
  case report
  colitis
  diabetic ketoacidosis
  diarrhea
  drug dose reduction
  drug substitution
  drug withdrawal
  fine needle aspiration biopsy
  genetic predisposition
  hot flush
  human
  human tissue
  hypertransaminasemia
  hypothyroidism
  liver toxicity
  lymph node dissection
  male
  melanoma (drug therapy)
  middle aged
  multiple cycle treatment
  myalgia
  nausea and vomiting
  positron emission tomography
  priority journal
  randomized controlled trial (topic)
  rash
  single nucleotide polymorphism
  tachycardia
  weakness
CAS REGISTRY NUMBERS
  glutamate decarboxylase (9024-58-2)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  liothyronine (6138-47-2, 6893-02-3)
  loperamide (34552-83-5, 53179-11-6)
  methylprednisolone (6923-42-8, 83-43-2)
  metoprolol (37350-58-6)
  nivolumab (946414-94-4)
  prednisone (53-03-2)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Drug Literature Index (37)
  Internal Medicine (6)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01927419)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160938608
PUI
  L613765193
DOI
  10.1186/s40425-016-0196-z
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40425-016-0196-z
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 122
TITLE
  Immune-related endocrine disorders in novel immune checkpoint inhibition 
therapy
AUTHOR NAMES
  Min L.
AUTHOR ADDRESSES
  (Min L., lmin@bwh.harvard.edu) Division of Endocrinology, Diabetes and 
Hypertension, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, 
United States.
SOURCE
  Genes and Diseases (2016) 3:4 (252-256). Date of Publication: 1 Dec 2016
ISSN
  2352-3042 (electronic)
BOOK PUBLISHER
  Chongqing yi ke da xue, di 2 lin chuang xue yuan Bing du xing gan yan yan 
jiu suo
ABSTRACT
  Immune checkpoint inhibition against advance malignancies was named 
breakthrough discovery by the science magazine in 2013. In numerous clinical 
studies, monoclonal antibodies against the immune checkpoints, CTLA4, PD1 
and PD1 ligand PDL1 have shown promising tumor response in different type of 
metastatic malignancies. The adverse events are autoimmune-related. The 
endocrine disorders, hypophysitis and thyroiditis are among the most common 
side effects associated with immune checkpoint inhibition treatment. 
Hypophysitis, a very rare endocrine disorder occurs in about one tenth of 
the patients receiving anti-CTLA4 treatment. Thyroiditis, on the other hand, 
is more commonly seen in patients receiving anti-PD1 treatment. In addition, 
both thyroiditis and hypophysitis are common in patients receiving 
combination treatment with anti-CTLA4 and anti-PD1 treatment. The time to 
onset of hypophysitis and thyroiditis is short. Most of the endocrine 
disorders occur within 12 weeks after initiation of the immune checkpoint 
inhibition therapy. Hypophysitis can manifest as total anterior pituitary 
hormone deficiency or isolated pituitary hormone deficiency. Diabetes 
insipidus is rare. TSH and gonadotropin deficiencies may be reversible but 
ACTH deficiency appears permanent. Thyroiditis can present as hypothyroidism 
or thyrotoxicosis followed by hypothyroidism. Hypothyroidism appears 
irreversible. Early identifying the onset of hypophysitis and thyroiditis 
and proper management of these endocrine disorders will improve the quality 
of the life and the outcome of this novel immunotherapy.
EMTREE DRUG INDEX TERMS
  adenohypophysis hormone (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease
  immunopathology
EMTREE MEDICAL INDEX TERMS
  corticotropin deficiency
  diabetes insipidus
  gonadotropin deficiency
  human
  hypophysitis
  hypothyroidism
  rare disease
  review
  thyroiditis
  thyrotoxicosis
CAS REGISTRY NUMBERS
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Public Health, Social Medicine and Epidemiology (17)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160880072
PUI
  L613503451
DOI
  10.1016/j.gendis.2016.10.002
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.gendis.2016.10.002
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 123
TITLE
  Hypophysitis Secondary to Cytotoxic T-Lymphocyte–Associated Protein 4 
Blockade: Insights into Pathogenesis from an Autopsy Series
AUTHOR NAMES
  Caturegli P.
  Di Dalmazi G.
  Lombardi M.
  Grosso F.
  Larman H.B.
  Larman T.
  Taverna G.
  Cosottini M.
  Lupi I.
AUTHOR ADDRESSES
  (Caturegli P., pcat@jhmi.edu; Di Dalmazi G.; Larman H.B.; Larman T.) 
Division of Immunology, Department of Pathology, The Johns Hopkins School of 
Medicine, Baltimore, United States.
(Di Dalmazi G.) Department of Medicine, G. D'Annunzio University of Chieti, 
Chieti, Italy.
(Lombardi M.) Endocrinology Unit, Saints Anthony and Biagio, and Cesare 
Arrigo Hospital, Alessandria, Italy.
(Lombardi M.; Grosso F.) Oncology Center, Saints Anthony and Biagio, and 
Cesare Arrigo Hospital, Alessandria, Italy.
(Taverna G.) Department of Radiology, Mesothelioma Unit, Saint Spirit 
Hospital, Casale Monferrato, Italy.
(Cosottini M.) Department of Translational Research and New Technologies in 
Medicine and Surgery, University of Pisa, Pisa, Italy.
(Lupi I.) Department of Endocrinology, University of Pisa, Pisa, Italy.
CORRESPONDENCE ADDRESS
  P. Caturegli, Johns Hopkins Pathology, Room 656, Ross Bldg, 720 Rutland Ave, 
Baltimore, United States. Email: pcat@jhmi.edu
SOURCE
  American Journal of Pathology (2016) 186:12 (3225-3235). Date of 
Publication: 1 Dec 2016
ISSN
  1525-2191 (electronic)
  0002-9440
BOOK PUBLISHER
  Elsevier Inc., usjcs@elsevier.com
ABSTRACT
  Hypophysitis that develops in cancer patients treated with monoclonal 
antibodies blocking cytotoxic T-lymphocyte–associated protein 4 (CTLA-4; an 
inhibitory molecule classically expressed on T cells) is now reported at an 
incidence of approximately 10%. Its pathogenesis is unknown, in part because 
no pathologic examination of the pituitary gland has been reported to date. 
We analyzed at autopsy the pituitary glands of six cancer patients treated 
with CTLA-4 blockade, one with clinical and pathologic evidence of 
hypophysitis, one with mild lymphocytic infiltration in the pituitary gland 
but no clinical signs of hypophysitis, and four with normal pituitary 
structure and function. CTLA-4 antigen was expressed by pituitary endocrine 
cells in all patients but at different levels. The highest levels were found 
in the patient who had clinical and pathologic evidence of severe 
hypophysitis. This high pituitary CTLA-4 expression was associated with 
T-cell infiltration and IgG-dependent complement fixation and phagocytosis, 
immune reactions that induced an extensive destruction of the 
adenohypophyseal architecture. Pituitary CTLA-4 expression was confirmed in 
a validation group of 37 surgical pituitary adenomas and 11 normal pituitary 
glands. The study suggests that administration of CTLA-4 blocking antibodies 
to patients who express high levels of CTLA-4 antigen in the pituitary can 
cause an aggressive (necrotizing) form of hypophysitis through type IV 
(T-cell dependent) and type II (IgG dependent) immune mechanisms.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  blocking antibody
  cytotoxic T lymphocyte antigen 4
EMTREE DRUG INDEX TERMS
  immunoglobulin G (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (etiology)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  antigen expression
  article
  autopsy
  cancer patient
  cell infiltration
  clinical article
  cytotoxic T lymphocyte
  endocrine cell
  female
  human
  human cell
  human tissue
  hypersensitivity
  hypophysis
  hypophysis adenoma
  hypophysis function
  immunity
  lymphocytic infiltration
  male
  middle aged
  pathogenesis
  priority journal
CAS REGISTRY NUMBERS
  immunoglobulin G (97794-27-9)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160853536
MEDLINE PMID
  27750046 (http://www.ncbi.nlm.nih.gov/pubmed/27750046)
PUI
  L613343715
DOI
  10.1016/j.ajpath.2016.08.020
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ajpath.2016.08.020
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 124
TITLE
  Evaluation of efficacy and safety of different pembrolizumab dose/schedules 
in treatment of non-small-cell lung cancer and melanoma: A systematic review
AUTHOR NAMES
  Abdel-Rahman O.
AUTHOR ADDRESSES
  (Abdel-Rahman O., omar.abdelrhman@med.asu.edu.eg) Clinical Oncology 
Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
CORRESPONDENCE ADDRESS
  O. Abdel-Rahman, Clinical Oncology Department, Faculty of Medicine, Ain 
Shams University, Cairo, Egypt. Email: omar.abdelrhman@med.asu.edu.eg
SOURCE
  Immunotherapy (2016) 8:12 (1383-1391). Date of Publication: 1 Dec 2016
ISSN
  1750-7448 (electronic)
  1750-743X
BOOK PUBLISHER
  Future Medicine Ltd., info@futuremedicine.com
ABSTRACT
  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). 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. Selection criteria: Prospective clinical trials 
reporting the outcomes of more than one dose schedule of pembrolizumab in 
the treatment of advanced NSCLC and melanoma. Data collection & analysis: 
The review author extracted information on the outcomes of the study for 
this review, and presented the results. 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).
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug dose, drug 
therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  cancer immunotherapy
  diarrhea (side effect)
  dosage schedule comparison
  dose response
  drug dose comparison
  drug efficacy
  drug safety
  hepatitis (side effect)
  human
  hypertransaminasemia (side effect)
  hypothyroidism (side effect)
  nephritis (side effect)
  outcome assessment
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pneumonia (side effect)
  priority journal
  prospective study
  randomized controlled trial (topic)
  rash (side effect)
  review
  systematic review
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01295827, NCT01704287, NCT01866319, NCT01905657)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160945527
MEDLINE PMID
  27892744 (http://www.ncbi.nlm.nih.gov/pubmed/27892744)
PUI
  L613868676
DOI
  10.2217/imt-2016-0075
FULL TEXT LINK
  http://dx.doi.org/10.2217/imt-2016-0075
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 125
TITLE
  Sunitinib in the treatment of metastatic renal cell carcinoma
AUTHOR NAMES
  Schmid T.A.
  Gore M.E.
AUTHOR ADDRESSES
  (Schmid T.A., Thomas.Schmid@rmh.nhs.uk) Royal Marsden NHS Foundation Trust, 
Fulham Road, London, United Kingdom.
(Gore M.E.) Royal Marsden NHS Foundation Trust, London, United Kingdom.
CORRESPONDENCE ADDRESS
  T.A. Schmid, Royal Marsden NHS Foundation Trust, Fulham Road, London, United 
Kingdom. Email: Thomas.Schmid@rmh.nhs.uk
SOURCE
  Therapeutic Advances in Urology (2016) 8:6 (348-371). Date of Publication: 1 
Dec 2016
ISSN
  1756-2880 (electronic)
  1756-2872
BOOK PUBLISHER
  SAGE Publications Inc., claims@sagepub.com
ABSTRACT
  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-α). 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  sunitinib (adverse drug reaction, clinical trial, drug therapy, oral drug 
administration)
EMTREE DRUG INDEX TERMS
  alpha interferon (adverse drug reaction)
  bevacizumab (adverse drug reaction, drug combination, intravenous drug 
administration)
  everolimus (drug combination, oral drug administration)
  mammalian target of rapamycin inhibitor
  nivolumab (adverse drug reaction, drug combination)
  pazopanib
  protein tyrosine kinase inhibitor
  rocapuldencel T (drug combination)
  sorafenib
  temsirolimus (drug combination, intravenous drug administration)
  trebananib (drug combination, intravenous drug administration)
  vasculotropin receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  kidney metastasis (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  asthenia
  clinical trial (topic)
  constipation (side effect)
  diarrhea (side effect)
  drug dose escalation
  drug efficacy
  drug tolerability
  dysgeusia (side effect)
  dyspepsia (side effect)
  epistaxis (side effect)
  fatigue (side effect)
  hand foot syndrome (side effect)
  headache (side effect)
  hemolytic anemia (side effect)
  human
  hypertension (side effect)
  hyponatremia (side effect)
  hypothyroidism (side effect)
  nausea (side effect)
  peripheral edema (side effect)
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  proteinuria (side effect)
  rash (side effect)
  review
  stomatitis (side effect)
  thrombocytopenia (side effect)
  thrombotic thrombocytopenic purpura (side effect)
  toxicity (side effect)
  tumor regression
DRUG TRADE NAMES
  sutent  Pfizer

DRUG MANUFACTURERS
  Pfizer
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  everolimus (159351-69-6)
  nivolumab (946414-94-4)
  pazopanib (444731-52-6, 635702-64-6)
  sorafenib (284461-73-0)
  sunitinib (341031-54-7, 557795-19-4)
  temsirolimus (162635-04-3, 343261-52-9)
  trebananib (894356-79-7)
  vasculotropin receptor (301253-48-5)
EMBASE CLASSIFICATIONS
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01472081, NCT01582672)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160859968
PUI
  L613375206
DOI
  10.1177/1756287216663979
FULL TEXT LINK
  http://dx.doi.org/10.1177/1756287216663979
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 126
TITLE
  Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis, and 
autophagy in ovarian cancer and melanoma
AUTHOR NAMES
  Clark C.A.
  Gupta H.B.
  Sareddy G.
  Pandeswara S.
  Lao S.
  Yuan B.
  Drerup J.M.
  Padron A.
  Conejo-Garcia J.
  Murthy K.
  Liu Y.
  Turk M.J.
  Thedieck K.
  Hurez V.
  Li R.
  Vadlamudi R.
  Curiel T.J.
AUTHOR ADDRESSES
  (Clark C.A.; Drerup J.M.; Murthy K.; Li R.; Vadlamudi R.; Curiel T.J., 
curielt@uthscsa.edu) Graduate School of Biomedical Sciences, University of 
Texas Health Science Center, San Antonio, United States.
(Clark C.A.; Gupta H.B.; Pandeswara S.; Lao S.; Yuan B.; Drerup J.M.; Padron 
A.; Murthy K.; Liu Y.; Hurez V.; Curiel T.J., curielt@uthscsa.edu) 
Department of Medicine, University of Texas Health Science Center, San 
Antonio, United States.
(Sareddy G.; Li R.; Vadlamudi R.; Curiel T.J., curielt@uthscsa.edu) Cancer 
Therapy and Research Center, University of Texas Health Science Center, San 
Antonio, United States.
(Sareddy G.; Vadlamudi R.) Department of Obstetrics and Gynecology, 
University of Texas Health Science Center, San Antonio, United States.
(Yuan B.; Li R.) Department of Molecular Medicine, University of Texas 
Health Science Center, San Antonio, United States.
(Conejo-Garcia J.) Tumor Microenvironment and Metastasis Program, Wistar 
Institute, Philadelphia, United States.
(Liu Y.) Xiangya School of Medicine, Central South University, Changsha, 
China.
(Turk M.J.) Department of Microbiology and Immunology, Geisel School of 
Medicine at Dartmouth, Hanover, United States.
(Thedieck K.) Department of Pediatrics, Center for Liver, Digestive and 
Metabolic Diseases, University of Groningen, University Medical Center 
Groningen, Groningen, Netherlands.
(Thedieck K.) Department for Neuroscience, School of Medicine and Health 
Sciences, University Oldenburg, Oldenburg, Germany.
CORRESPONDENCE ADDRESS
  T.J. Curiel, Department of Medicine, University of Texas Health Science 
Center at San Antonio, STRF MC 8252, 8403 Floyd Curl Drive, San Antonio, 
United States. Email: curielt@uthscsa.edu
SOURCE
  Cancer Research (2016) 76:23 (6964-6974). Date of Publication: 1 Dec 2016
ISSN
  1538-7445 (electronic)
  0008-5472
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  PD-L1 antibodies produce efficacious clinical responses in diverse human 
cancers, but the basis for their effects remains unclear, leaving a gap in 
the understanding of how to rationally leverage therapeutic activity. PD-L1 
is widely expressed in tumor cells, but its contributions to tumor 
pathogenicity are incompletely understood. In this study, we evaluated the 
hypothesis that PD-L1 exerts tumor cell-intrinsic signals that are critical 
for pathogenesis. Using RNAi methodology, we attenuated PD-L1 in the murine 
ovarian cell line ID8agg and the melanoma cell line B16 (termed PD-L1(lo) 
cells), which express basal PD-L1. We observed that PD-L1(lo) cells 
proliferated more weakly than control cells in vitro. As expected, PD-L1(lo) 
cells formed tumors in immunocompetent mice relatively more slowly, but 
unexpectedly, they also formed tumors more slowly in immunodeficient NSG 
mice. RNA sequencing analysis identified a number of genes involved in 
autophagy and mTOR signaling that were affected by PD-L1 expression. In 
support of a functional role, PD-L1 attenuation augmented autophagy and 
blunted the ability of autophagy inhibitors to limit proliferation in vitro 
and in vivo in NSG mice. PD-L1 attenuation also reduced mTORC1 activity and 
augmented the antiproliferative effects of the mTORC1 inhibitor rapamycin. 
PD-L1(lo) cells were also relatively deficient in metastasis to the lung, 
and we found that anti-PD-L1 administration could block tumor cell growth 
and metastasis in NSG mice. This therapeutic effect was observed with B16 
cells but not ID8agg cells, illustrating tumor- or compartmental-specific 
effects in the therapeutic setting. Overall, our findings extend 
understanding of PD-L1 functions, illustrate nonimmune effects of anti-PD-L1 
immunotherapy, and suggest broader uses for PD-L1 as a biomarker for 
assessing cancer therapeutic responses.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  mammalian target of rapamycin (endogenous compound)
  mammalian target of rapamycin complex 1 (endogenous compound)
  rapamycin
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (etiology)
  ovary cancer (etiology)
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  animal model
  article
  autophagy
  carcinogenesis
  cell proliferation
  controlled study
  female
  human
  human cell
  in vitro study
  lung metastasis
  male
  melanoma cell line
  mouse
  NOD SCID gamma mouse
  nonhuman
  ovarian cancer cell line
  priority journal
  protein expression
  RNA sequence
  signal transduction
  tumor growth
CAS REGISTRY NUMBERS
  rapamycin (53123-88-9)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160904491
MEDLINE PMID
  27671674 (http://www.ncbi.nlm.nih.gov/pubmed/27671674)
PUI
  L613599534
DOI
  10.1158/0008-5472.CAN-16-0258
FULL TEXT LINK
  http://dx.doi.org/10.1158/0008-5472.CAN-16-0258
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 127
TITLE
  Immunotherapy for breast cancer: past, present, and future
AUTHOR NAMES
  Spellman A.
  Tang S.-C.
AUTHOR ADDRESSES
  (Spellman A.; Tang S.-C., stang@gru.edu) Georgia Regents University Cancer 
Center, 1411 Laney Walker Boulevard, Augusta, United States.
(Tang S.-C., stang@gru.edu) Tianjin Medical University Cancer Institute and 
Hospital, Huanhuxi Road, Hexi District, Tianjin, China.
CORRESPONDENCE ADDRESS
  S.-C. Tang, Georgia Regents University Cancer Center, 1411 Laney Walker 
Boulevard, Augusta, United States. Email: stang@gru.edu
SOURCE
  Cancer and Metastasis Reviews (2016) 35:4 (525-546). Date of Publication: 1 
Dec 2016
ISSN
  1573-7233 (electronic)
  0167-7659
BOOK PUBLISHER
  Springer New York LLC, barbara.b.bertram@gsk.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (clinical trial, drug therapy)
  bispecific antibody (clinical trial, drug therapy)
  cancer vaccine (drug therapy)
  monoclonal antibody (clinical trial, drug therapy)
  tumor marker (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  breast cancer (drug therapy, drug therapy)
  cancer immunotherapy
EMTREE MEDICAL INDEX TERMS
  antibody dependent cellular cytotoxicity
  article
  clinical trial
  human
  immunocompetent cell
  molecularly targeted therapy
  priority journal
  tumor microenvironment
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00083278)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160892848
MEDLINE PMID
  27913998 (http://www.ncbi.nlm.nih.gov/pubmed/27913998)
PUI
  L613562713
DOI
  10.1007/s10555-016-9654-9
FULL TEXT LINK
  http://dx.doi.org/10.1007/s10555-016-9654-9
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 128
TITLE
  Nivolumab-Induced Pericardial Tamponade: A Case Report and Discussion
AUTHOR NAMES
  Kushnir I.
  Wolf I.
AUTHOR ADDRESSES
  (Kushnir I., igalku@tlvmc.gov.il; Wolf I.) Oncology Division, Tel Aviv 
Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, 6 
Weizmann Street, Tel Aviv, Israel.
SOURCE
  Cardiology (Switzerland) (2016) 136:1 (49-51). Date of Publication: 1 Dec 
2016
ISSN
  1421-9751 (electronic)
  0008-6312
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  carboplatin (drug combination, drug therapy)
  paclitaxel (drug combination, drug therapy)
  prednisone
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  heart tamponade (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  artificial ventilation
  cancer staging
  case report
  computer assisted tomography
  cytology
  dyspnea (side effect)
  human
  male
  multiple cycle treatment
  pericardial effusion
  pericardiocentesis
  priority journal
  radiation dose
  respiratory failure (side effect)
  squamous cell lung carcinoma (drug therapy, radiotherapy)
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Cardiovascular Diseases and Cardiovascular Surgery (18)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160627923
PUI
  L611901167
DOI
  10.1159/000447053
FULL TEXT LINK
  http://dx.doi.org/10.1159/000447053
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 129
TITLE
  BRAF V600 mutation-negative metastatic or inoperable melanoma: Survival 
advantage
AUTHOR ADDRESSES
  SOURCE
  Prescrire International (2016) 25:177 (289-291). Date of Publication: 1 Dec 
2016
ISSN
  1167-7422
BOOK PUBLISHER
  Association Mieux Prescrire, international@prescrire.org
ABSTRACT
  • Existing drugs are poorly effective in patients with inoperable or 
metastatic melanoma without a mutation in the BRAF gene at position V600. 
The first-line treatment of choice for patients with BRAF V600-positive 
melanoma is a combination of dabrafenib (a BRAF inhibitor) and trametinib. • 
Nivolumab is a human monoclonal antibody designed to block receptors for 
PD-1 (programmed cell death-1) and thus to enhance T lymphocyte activity, 
especially against tumour cells. Nivolumab has been authorised in Europe as 
monotherapy for patients with inoperable or metastatic melanoma, regardless 
of BRAF V600 status. • Nivolumab has not been compared with the dabrafenib + 
trametinib combination in patients with BRAF V600-positive melanoma. • A 
randomised double-blind trial versus dacarbazine involved 418 patients with 
inoperable or metastatic BRAF V600-negative melanoma who had not yet 
received medication for this stage of the disease. The trial was halted 
prematurely when an unscheduled analysis showed an improvement in one-year 
survival with nivolumab compared to dacarbazine (73% versus 42%, p<0.0001). 
• A double-blind trial compared firstline treatment with nivolumab, 
ipilimumab or a combination of the two drugs. The mortality results are not 
yet available in mid-2016. The median time to melanoma aggravation or death 
was 6.9 months in the nivolumab group, 2.9 months in the ipilimumab group, 
and 11.5 months with the combination (p<0.001). • A comparative, randomised, 
unblinded trial included 405 patients with metastatic or inoperable melanoma 
in whom at least one drug had failed. An interim analysis conducted after 
about two years showed no statistically significant difference in median 
survival between patients who received nivolumab and those who received 
cytotoxic drugs. • As expected, given its protein structure and mechanism, 
the adverse effects of nivolumab are mainly due to immunological mechanisms. 
They are numerous and affect many organs: skin rash and toxic epidermal 
necrolysis, thyroid dysfunction, hepatitis, pneumonia, colitis and 
encephalitis. Adverse effects were serious in 9% of patients, and a few 
cases were fatal. • In practice, first-line nivolumab monotherapy was 
significantly more effective than dacarbazine in a trial in patients with 
BRAF V600-negative inoperable or metastatic melanoma. Although its 
evaluation must continue, nivolumab already seems to be a better option than 
dacarbazine and ipilimumab for treatment-naive patients, provided they 
receive detailed and balanced information on the uncertainties, efficacy and 
adverse effects of this new drug. For other patients, there is no evidence 
that nivolumab monotherapy represents an advantage over other available 
treatments.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison - placebo, drug comparison, drug therapy)
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
  carboplatin (clinical trial, drug combination, drug therapy)
  creatinine (endogenous compound)
  dacarbazine (clinical trial, drug comparison - placebo, drug comparison, 
drug therapy)
  ipilimumab (clinical trial, drug combination, drug comparison, drug therapy)
  liver enzyme (endogenous compound)
  paclitaxel (clinical trial, drug combination, drug therapy)
  placebo
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  BRAF gene
  cancer survival
  gene mutation
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  allergic reaction (side effect)
  autoimmune hepatitis (side effect)
  cancer growth
  cancer mortality
  colitis (side effect)
  creatinine blood level
  demyelination (side effect)
  diabetes mellitus (side effect)
  diarrhea (side effect)
  drug contraindication
  drug efficacy
  drug indication
  drug safety
  drug treatment failure
  encephalitis (side effect)
  enzyme blood level
  fatigue (side effect)
  Guillain Barre syndrome (side effect)
  hepatitis (side effect)
  human
  hypersensitivity (side effect)
  hyperthyroidism (side effect)
  hypopituitarism (side effect)
  hypothyroidism (side effect)
  kidney failure (side effect)
  liver injury (side effect)
  monotherapy
  motor dysfunction (side effect)
  multiple cycle treatment
  nausea (side effect)
  neuropathy (side effect)
  oncogene
  pancreatitis (side effect)
  paralysis (side effect)
  pneumonia (side effect)
  protein targeting
  pruritus (side effect)
  randomized controlled trial (topic)
  rash (side effect)
  review
  side effect (side effect)
  thyroid disease (side effect)
  toxic epidermal necrolysis (side effect)
  treatment duration
  vitiligo (side effect)
DRUG TRADE NAMES
  opdivo
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  creatinine (19230-81-0, 60-27-5)
  dacarbazine (4342-03-4)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160925887
PUI
  L613765884
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 130
TITLE
  Nivolumab-associated acute glomerulonephritis: a case report and literature 
review
AUTHOR NAMES
  Jung K.
  Zeng X.
  Bilusic M.
AUTHOR ADDRESSES
  (Jung K., Kyungsuk.Jung@fccc.edu) Department of Medicine, Fox Chase Cancer 
Center, 333 Cottman Ave, Philadelphia, United States.
(Zeng X., Xu.Zeng@tuhs.temple.edu) Department of Pathology and Laboratory 
Medicine, Lewis Katz School of Medicine, Temple University, 3500N Broad St., 
Philadelphia, United States.
(Bilusic M., mbilusic@gmail.com) Department of Medical Oncology, Fox Chase 
Cancer Center, 333 Cottman Ave, Philadelphia, United States.
CORRESPONDENCE ADDRESS
  K. Jung, Department of Medicine, Fox Chase Cancer Center, 333 Cottman Ave, 
Philadelphia, United States. Email: Kyungsuk.Jung@fccc.edu
SOURCE
  BMC Nephrology (2016) 17:1 (1-6). Date of Publication: 22 Nov 2016
ISSN
  1471-2369 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 
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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  creatinine (endogenous compound)
  methylprednisolone (drug therapy, intravenous drug administration)
  pazopanib (drug therapy)
  potassium (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  acute glomerulonephritis (drug therapy, side effect, diagnosis, drug 
therapy, side effect, therapy)
  immune complex nephritis (drug therapy, side effect, diagnosis, drug 
therapy, side effect, therapy)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure (side effect)
  aged
  ankle edema
  antineoplastic activity
  article
  body weight gain
  cancer growth
  case report
  creatinine blood level
  drug dose increase
  drug megadose
  drug response
  drug withdrawal
  electron microscopy
  fatigue
  follow up
  hemodialysis
  human
  human tissue
  immunosuppressive treatment
  kidney biopsy
  kidney carcinoma (drug therapy)
  kidney function
  loss of appetite
  male
  outcome assessment
  physical examination
  potassium blood level
  symptom
  systemic therapy
  urea nitrogen blood level
  weakness
CAS REGISTRY NUMBERS
  creatinine (19230-81-0, 60-27-5)
  methylprednisolone (6923-42-8, 83-43-2)
  nivolumab (946414-94-4)
  pazopanib (444731-52-6, 635702-64-6)
  potassium (7440-09-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160867778
MEDLINE PMID
  27876011 (http://www.ncbi.nlm.nih.gov/pubmed/27876011)
PUI
  L613329664
DOI
  10.1186/s12882-016-0408-2
FULL TEXT LINK
  http://dx.doi.org/10.1186/s12882-016-0408-2
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 131
TITLE
  Metastatic Merkel cell carcinoma response to nivolumab
AUTHOR NAMES
  Walocko F.M.
  Scheier B.Y.
  Harms P.W.
  Fecher L.A.
  Lao C.D.
AUTHOR ADDRESSES
  (Walocko F.M., fwalocko@med.umich.edu) University of Michigan Medical 
School, Ann Arbor, United States.
(Scheier B.Y., bscheier@med.umich.edu; Fecher L.A., lfecher@med.umich.edu; 
Lao C.D., clao@med.umich.edu) University of Michigan, Division of 
Hematology/Oncology, Department of Internal Medicine, C451 Med Inn, 1500 
East Medical Center Drive, Ann Arbor, United States.
(Harms P.W., paulharm@med.umich.edu) University of Michigan, Department of 
Pathology, Ann Arbor, United States.
(Harms P.W., paulharm@med.umich.edu) University of Michigan, Department of 
Dermatology, Ann Arbor, United States.
CORRESPONDENCE ADDRESS
  C.D. Lao, University of Michigan, Division of Hematology/Oncology, 
Department of Internal Medicine, C451 Med Inn, 1500 East Medical Center 
Drive, Ann Arbor, United States. Email: clao@med.umich.edu
SOURCE
  Journal for ImmunoTherapy of Cancer (2016) 4:1 Article Number: 79. Date of 
Publication: 15 Nov 2016
ISSN
  2051-1426 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (drug therapy, intravenous drug administration)
EMTREE DRUG INDEX TERMS
  CD56 antigen (endogenous compound)
  cytokeratin 20 (endogenous compound)
  fluorodeoxyglucose
  neuron specific enolase (endogenous compound)
  prednisone
  steroid (drug therapy, intravenous drug administration)
  virus large T antigen
  virus small T antigen
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  merkel cell carcinoma (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  autoimmune hepatitis (complication, drug therapy)
  case report
  computer assisted emission tomography
  human
  human tissue
  immunohistochemistry
  lung biopsy
  lymphadenopathy
  male
  Merkel cell polyomavirus
  metabolism
  multiple cycle treatment
  pneumonia (drug therapy)
  polymerase chain reaction
  priority journal
  very elderly
CAS REGISTRY NUMBERS
  fluorodeoxyglucose (29702-43-0)
  nivolumab (946414-94-4)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02155647, NCT02267603)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160874986
PUI
  L613401868
DOI
  10.1186/s40425-016-0186-1
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40425-016-0186-1
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 132
TITLE
  Neurologic complications of immune checkpoint inhibitors
AUTHOR NAMES
  Hottinger A.F.
AUTHOR ADDRESSES
  (Hottinger A.F., Andreas.hottinger@chuv.ch) Department of Clinical 
Neurosciences, Department of Oncology, Centre Hospitalier Universitaire 
Vaudois, Lausanne University, Rue du Bugnon 46, Lausanne, Switzerland.
CORRESPONDENCE ADDRESS
  A.F. Hottinger, Department of Clinical Neurosciences, Department of 
Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University, Rue 
du Bugnon 46, Lausanne, Switzerland. Email: Andreas.hottinger@chuv.ch
SOURCE
  Current Opinion in Neurology (2016) 29:6 (806-812). Date of Publication: 13 
Nov 2016
ISSN
  1473-6551 (electronic)
  1350-7540
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
ABSTRACT
  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 lymphocyteassociated 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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immune checkpoint inhibitor (adverse drug reaction)
  monoclonal antibody (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  ipilimumab
  nivolumab
  pembrolizumab
  programmed death 1 receptor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  neurological complication (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  chronic immune demyelinating polyneuropathy
  encephalitis
  enteric neuropathy
  Guillain Barre syndrome
  human
  hypophysitis
  meningo radiculo neuritis
  myasthenia gravis
  neuropathy
  peripheral neuropathy
  polyneuropathy
  polyradiculitis
  review
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160688762
MEDLINE PMID
  27653290 (http://www.ncbi.nlm.nih.gov/pubmed/27653290)
PUI
  L612333629
DOI
  10.1097/WCO.0000000000000391
FULL TEXT LINK
  http://dx.doi.org/10.1097/WCO.0000000000000391
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 133
TITLE
  Management of adverse events related to new cancer immunotherapy (immune 
checkpoint inhibitors)
AUTHOR NAMES
  Bourke J.M.
  O'Sullivan M.
  Khattak M.A.
AUTHOR ADDRESSES
  (Bourke J.M., Jack.Bourke@health.wa.gov.au; O'Sullivan M.; Khattak M.A.) 
Fiona Stanley Hospital, Perth, WA
SOURCE
  The Medical journal of Australia (2016) 205:9 (418-424). Date of 
Publication: 7 Nov 2016
ISSN
  1326-5377 (electronic)
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  immunosuppressive agent (drug administration, adverse drug reaction)
  ipilimumab
  monoclonal antibody (drug administration, adverse drug reaction, drug 
administration, adverse drug reaction)
  nivolumab
  pembrolizumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cell cycle checkpoint
EMTREE MEDICAL INDEX TERMS
  drug eruption (etiology)
  human
  hypophysis disease (etiology)
  lung tumor (drug therapy)
  melanoma (drug therapy)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  27809739 (http://www.ncbi.nlm.nih.gov/pubmed/27809739)
PUI
  L615393623
COPYRIGHT
  Copyright 2017 Medline is the source for the citation and abstract of this 
record.

RECORD 134
TITLE
  Incidence of thyroid-related adverse events in melanoma patients treated 
with pembrolizumab
AUTHOR NAMES
  De Filette J.
  Jansen Y.
  Schreuer M.
  Everaert H.
  Velkeniers B.
  Neyns B.
  Bravenboer B.
AUTHOR ADDRESSES
  (De Filette J., jdefilet@vub.ac.be; Velkeniers B.; Bravenboer B.) Department 
of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit 
Brussel, Campus Jette, Laarbeeklaan 101, Brussels, Belgium.
(Jansen Y.; Schreuer M.; Neyns B.) Department of Medical Oncology, 
Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, 
Belgium.
(Everaert H.) Nuclear Medicine Universitair, Ziekenhuis Brussel, Vrije 
Universiteit Brussel, Brussels, Belgium.
CORRESPONDENCE ADDRESS
  J. De Filette, Department of Endocrinology, Universitair Ziekenhuis Brussel, 
Vrije Universiteit Brussel, Campus Jette, Laarbeeklaan 101, Brussels, 
Belgium. Email: jdefilet@vub.ac.be
SOURCE
  Journal of Clinical Endocrinology and Metabolism (2016) 101:11 (4431-4439). 
Date of Publication: 1 Nov 2016
ISSN
  1945-7197 (electronic)
  0021-972X
BOOK PUBLISHER
  Endocrine Society, mzendell@endo-society.org
ABSTRACT
  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. Objective: To assess the incidence and 
characteristics of pembrolizumab-associated thyroid dysfunction. 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. Patients: Ninety-nine patients 
with advancedmelanoma(age, 26.3-93.6 years;63.6%females)who received at 
least one administration of pembrolizumab. Main Outcome Measures: Patient 
characteristics, thyroid function (TSH, free T4), thyroid autoantibodies, 
and 18FDG-PET/CT. 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. 
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. (J Clin Endocrinol Metab 
101: 4431-4439, 2016).
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  amiodarone (adverse drug reaction)
  fluorodeoxyglucose f 18 (intravenous drug administration)
  ipilimumab (drug concentration, drug therapy, pharmacokinetics)
  levothyroxine (drug therapy)
  propranolol (drug therapy)
  technetium 99m
  thionamide (drug therapy)
  thyroid antibody (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  incidence
  melanoma (drug therapy, drug therapy)
  thyroid disease (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer (drug therapy)
  aged
  article
  cancer center
  cancer patient
  computer assisted emission tomography
  controlled study
  disease course
  drug blood level
  drug half life
  drug uptake
  female
  functional assessment
  health care access
  health program
  human
  hypothyroidism (drug therapy, side effect)
  major clinical study
  male
  patient monitoring
  PET-CT scanner
  priority journal
  prospective study
  thyroid function
  thyroiditis (diagnosis)
  thyrotoxicosis (side effect)
DRUG TRADE NAMES
  keytruda  Merck Sharp and Dohme

DRUG MANUFACTURERS
  Merck Sharp and Dohme
DEVICE TRADE NAMES
  Gemini TF64  Philips

DEVICE MANUFACTURERS
  Philips
CAS REGISTRY NUMBERS
  amiodarone (1951-25-3, 19774-82-4, 62067-87-2)
  fluorodeoxyglucose f 18 (63503-12-8)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  pembrolizumab (1374853-91-4)
  propranolol (13013-17-7, 318-98-9, 3506-09-0, 4199-09-1, 525-66-6)
  technetium 99m (14133-76-7)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Nuclear Medicine (23)
  Biophysics, Bioengineering and Medical Instrumentation (27)
  Endocrinology (3)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160829575
MEDLINE PMID
  27571185 (http://www.ncbi.nlm.nih.gov/pubmed/27571185)
PUI
  L613230710
DOI
  10.1210/jc.2016-2300
FULL TEXT LINK
  http://dx.doi.org/10.1210/jc.2016-2300
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 135
TITLE
  Pembrolizumab-triggered Uveitis: An Additional Surrogate Marker for 
Responders in Melanoma Immunotherapy?
AUTHOR NAMES
  Diem S.
  Keller F.
  Rüesch R.
  Maillard S.A.
  Speiser D.E.
  Dummer R.
  Siano M.
  Urner-Bloch U.
  Goldinger S.M.
  Flatz L.
AUTHOR ADDRESSES
  (Diem S.; Siano M.) Department of Oncology, Kantonal Hospital St Gallen, St 
Gallen, Switzerland.
(Diem S.) Department of Oncology, Hospital Grabs, Grabs, Switzerland.
(Keller F.; Rüesch R.) Department of Ophthalmology, Kantonal Hospital St 
Gallen, St Gallen, Switzerland.
(Maillard S.A.; Speiser D.E.) Ludwig Cancer Research Center, University of 
Lausanne, Lausanne, Switzerland.
(Dummer R.; Goldinger S.M.; Flatz L., lukas.flatz@gmail.com) Department of 
Dermatology, University Hospital of Zurich, Zurich, Switzerland.
(Urner-Bloch U.) Private Ophthalmic Practice in Cooperation with the Skin 
Cancer Unit, University Hospital of Zurich, Zurich, Switzerland.
(Flatz L., lukas.flatz@gmail.com) Department of Dermatology/Allergology, 
Kantonal Hospital St Gallen, St Gallen, Switzerland.
(Flatz L., lukas.flatz@gmail.com) Institute of Immunobiology, Kantonal 
Hospital St Gallen, St Gallen, Switzerland.
CORRESPONDENCE ADDRESS
  L. Flatz, Departments of Dermatology/Allergology and Immunobiology, Cantonal 
Hospital of St. Gallen, Rorschacherstrasse 95, St Gallen, Switzerland. 
Email: lukas.flatz@gmail.com
SOURCE
  Journal of Immunotherapy (2016) 39:9 (379-382). Date of Publication: 1 Nov 
2016
ISSN
  1537-4513 (electronic)
  1524-9557
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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 pembrolizumabinduced 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  antibiotic agent (topical drug administration)
  B Raf kinase (endogenous compound)
  dorzolamide plus timolol (drug therapy)
  ipilimumab
  mydriatic agent (topical drug administration)
  nepafenac (topical drug administration)
  nonsteroid antiinflammatory agent (topical drug administration)
  prednisolone acetate (topical drug administration)
  scopolamine (topical drug administration)
  steroid (oral drug administration, topical drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  metastatic melanoma (drug therapy, diagnosis, drug therapy)
  pembrolizumab induced uveitis (diagnosis)
  uveitis (side effect, side effect)
  wild type metastatic melanoma (diagnosis)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  anterior eye chamber
  article
  case report
  cataract extraction
  cell infiltration
  computer assisted tomography
  disease marker
  drug substitution
  drug withdrawal
  endophthalmitis (diagnosis)
  human
  human tissue
  intraocular pressure abnormality (drug therapy)
  liver metastasis
  lymph node metastasis
  macular edema
  male
  middle aged
  multiple cycle treatment
  optical coherence tomography
  priority journal
  rash (side effect)
  retina macula cystoid edema
  skin biopsy
  tumor regression
  visual disorder
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nepafenac (78281-72-8)
  pembrolizumab (1374853-91-4)
  prednisolone acetate (52-21-1, 52628-64-5)
  scopolamine (138-12-5, 51-34-3, 55-16-3)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01543698)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160689812
MEDLINE PMID
  27662340 (http://www.ncbi.nlm.nih.gov/pubmed/27662340)
PUI
  L612344355
DOI
  10.1097/CJI.0000000000000143
FULL TEXT LINK
  http://dx.doi.org/10.1097/CJI.0000000000000143
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 136
TITLE
  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
AUTHOR NAMES
  Hodi F.S.
  Chesney J.
  Pavlick A.C.
  Robert C.
  Grossmann K.F.
  McDermott D.F.
  Linette G.P.
  Meyer N.
  Giguere J.K.
  Agarwala S.S.
  Shaheen M.
  Ernstoff M.S.
  Minor D.R.
  Salama A.K.
  Taylor M.H.
  Ott P.A.
  Horak C.
  Gagnier P.
  Jiang J.
  Wolchok J.D.
  Postow M.A.
AUTHOR ADDRESSES
  (Hodi F.S., stephen_hodi@dfci.harvard.edu; Ott P.A.) Dana-Farber Cancer 
Institute, Boston, United States.
(Chesney J.) University of Louisville, Louisville, United States.
(Pavlick A.C.) New York University, New York, United States.
(Robert C.) Gustave Roussy, INSERM U981, Paris, France.
(Grossmann K.F.) Huntsman Cancer Institute, Salt Lake City, United States.
(McDermott D.F.) Beth Israel Deaconess Medical Center, Boston, United 
States.
(Linette G.P.) Washington University School of Medicine, St Louis, United 
States.
(Meyer N.) Institut Universitaire du Cancer, Toulouse, France.
(Giguere J.K.) Greenville Health System Cancer Institute, Greenville, United 
States.
(Agarwala S.S.) St Luke's Cancer Center and Temple University, Bethlehem, 
United States.
(Shaheen M.) University of New Mexico, Albuquerque, United States.
(Ernstoff M.S.) Dartmouth-Hitchcock Medical Center, Lebanon, United States.
(Minor D.R.) California Pacific Center for Melanoma Research, San Francisco, 
United States.
(Salama A.K.) Duke University Medical Center, Durham, United States.
(Taylor M.H.) Oregon Health & Science University, Portland, United States.
(Horak C.; Gagnier P.; Jiang J.) Bristol-Myers Squibb, Princeton, United 
States.
(Wolchok J.D.; Postow M.A.) Memorial Sloan Kettering Cancer Center and Weill 
Cornell Medical College, New York, United States.
CORRESPONDENCE ADDRESS
  F.S. Hodi, Dana-Farber Cancer Institute, Boston, United States. Email: 
stephen_hodi@dfci.harvard.edu
SOURCE
  The Lancet Oncology (2016) 17:11 (1558-1568). Date of Publication: 1 Nov 
2016
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  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. 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. 
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. 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. Funding Bristol-Myers Squibb.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison - placebo, drug comparison, drug therapy, intravenous drug 
administration)
  nivolumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison - placebo, drug comparison, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  amylase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  placebo
  triacylglycerol lipase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  cancer survival
  melanoma (drug therapy, drug therapy)
  overall survival
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adrenal insufficiency (side effect)
  adult
  alanine aminotransferase blood level
  amylase blood level
  aphthous stomatitis (side effect)
  article
  ascites (side effect)
  aspartate aminotransferase blood level
  atrial fibrillation (side effect)
  autoimmune disease (side effect)
  BRAF gene
  cancer registry
  chill (side effect)
  colitis (side effect)
  constipation (side effect)
  controlled study
  coughing (side effect)
  decreased appetite (side effect)
  dehydration (side effect)
  diabetic ketoacidosis (side effect)
  diarrhea (side effect)
  disease severity
  dizziness (side effect)
  double blind procedure
  drug efficacy
  drug safety
  dyspnea (side effect)
  enterocolitis (side effect)
  eye pain (side effect)
  fatigue (side effect)
  febrile neutropenia (side effect)
  fever (side effect)
  France
  gene mutation
  Guillain Barre syndrome (side effect)
  headache (side effect)
  heart infarction (side effect)
  heart ventricle arrhythmia (side effect)
  heart ventricle tachycardia (side effect)
  hepatitis (side effect)
  human
  hypoalbuminemia (side effect)
  hyponatremia (side effect)
  hypophysitis (side effect)
  hypothermia (side effect)
  hypothyroidism (side effect)
  institutional review
  leukocytosis (side effect)
  maculopapular rash (side effect)
  major clinical study
  malabsorption (side effect)
  multicenter study
  mutational analysis
  myalgia (side effect)
  nausea (side effect)
  neutropenia (side effect)
  oncogene
  pain (side effect)
  pancreatitis (side effect)
  paresthesia (side effect)
  phase 2 clinical trial
  pneumonia (side effect)
  priority journal
  pruritus (side effect)
  randomized controlled trial
  rash (side effect)
  respiratory failure (side effect)
  side effect (side effect)
  triacylglycerol lipase blood level
  United States
  vomiting (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  amylase (9000-90-2, 9000-92-4, 9001-19-8)
  aspartate aminotransferase (9000-97-9)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  triacylglycerol lipase (9001-62-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01927419)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160835458
MEDLINE PMID
  27622997 (http://www.ncbi.nlm.nih.gov/pubmed/27622997)
PUI
  L613251510
DOI
  10.1016/S1470-2045(16)30366-7
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(16)30366-7
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 137
TITLE
  Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy
AUTHOR NAMES
  Okamoto M.
  Okamoto M.
  Gotoh K.
  Masaki T.
  Ozeki Y.
  Ando H.
  Anai M.
  Sato A.
  Yoshida Y.
  Ueda S.
  Kakuma T.
  Shibata H.
AUTHOR ADDRESSES
  (Okamoto M.; Okamoto M.; Gotoh K.; Masaki T.; Ozeki Y.; Ando H.; Anai M.; 
Sato A.; Yoshida Y.; Ueda S.; Kakuma T.; Shibata H., 
hiro-405@cb3.so-net.ne.jp) Department of Endocrinology, Metabolism, 
Rheumatology and Nephrology, Faculty of Medicine, Oita University, Oita, 
Japan.
CORRESPONDENCE ADDRESS
  H. Shibata, Department of Endocrinology, Metabolism, Rheumatology and 
Nephrology, Faculty of Medicine, Oita University, Oita, Japan. Email: 
hiro-405@cb3.so-net.ne.jp
SOURCE
  Journal of Diabetes Investigation (2016) 7:6 (915-918). Date of Publication: 
1 Nov 2016
ISSN
  2040-1124 (electronic)
  2040-1116
BOOK PUBLISHER
  Blackwell Publishing, info@asia.blackpublishing.com.au
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  autoantibody (endogenous compound)
  C peptide (endogenous compound)
  glucose (endogenous compound)
  hemoglobin A1c (endogenous compound)
  HLA antigen (endogenous compound)
  insulin (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  insulin dependent diabetes mellitus (drug therapy, side effect, drug 
therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  alcohol consumption
  article
  case report
  chronic pancreatitis
  computer assisted tomography
  endoscopic ultrasonography
  female
  glucose blood level
  glucose tolerance test
  haplotype
  human
  hyperglycemia
  insulin release
  Japanese (people)
  ketonuria
  limit of detection
  melanoma (drug therapy)
  middle aged
  priority journal
  protein blood level
  T lymphocyte activation
CAS REGISTRY NUMBERS
  C peptide (59112-80-0)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160430212
MEDLINE PMID
  27181090 (http://www.ncbi.nlm.nih.gov/pubmed/27181090)
PUI
  L610664472
DOI
  10.1111/jdi.12531
FULL TEXT LINK
  http://dx.doi.org/10.1111/jdi.12531
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 138
TITLE
  Multiplatform-based molecular subtypes of non-small-cell lung cancer
AUTHOR NAMES
  Chen F.
  Zhang Y.
  Parra E.
  Rodriguez J.
  Behrens C.
  Akbani R.
  Lu Y.
  Kurie J.M.
  Gibbons D.L.
  Mills G.B.
  Wistuba I.I.
  Creighton C.J.
AUTHOR ADDRESSES
  (Chen F.) Dan L. Duncan Comprehensive Cancer Center, Division of 
Biostatistics, Baylor College of Medicine, Houston, TX, USA
(Zhang Y.; Parra E.; Rodriguez J.; Behrens C.; Akbani R.; Lu Y.; Kurie J.M.; 
Gibbons D.L.; Mills G.B.; Wistuba I.I.; Creighton C.J.)
CORRESPONDENCE ADDRESS
  F. Chen, Dan L. Duncan Comprehensive Cancer Center, Division of 
Biostatistics, Baylor College of Medicine, Houston, TX, USA
SOURCE
  Oncogene (2016). Date of Publication: 24 Oct 2016
ISSN
  1476-5594 (electronic)
  0950-9232
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  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.Oncogene 
advance online publication, 24 October 2016; doi:10.1038/onc.2016.303.
EMTREE DRUG INDEX TERMS
  cancer testis antigen
  CD3 antigen
  CD8 antigen
  endogenous compound
  mammalian target of rapamycin
  programmed death 1 ligand 1
  programmed death 1 ligand 2
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  non small cell lung cancer
EMTREE MEDICAL INDEX TERMS
  adenocarcinoma
  cell infiltration
  controlled study
  CpG island
  data base
  differentiation
  DNA methylation
  DNA transcription
  gene activation
  human
  human tissue
  immunocompetent cell
  immunohistochemistry
  major clinical study
  neuroendocrine tumor
  oncogene
  phenotype
  prognosis
  protein expression
  publication
  squamous cell carcinoma
  thorax
  tumor resistance
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160773066
PUI
  L612933499
DOI
  10.1038/onc.2016.303
FULL TEXT LINK
  http://dx.doi.org/10.1038/onc.2016.303
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 139
TITLE
  Acute visual loss after ipilimumab treatment for metastatic melanoma
AUTHOR NAMES
  Wilson M.A.
  Guld K.
  Galetta S.
  Walsh R.D.
  Kharlip J.
  Tamhankar M.
  McGettigan S.
  Schuchter L.M.
  Fecher L.A.
AUTHOR ADDRESSES
  (Wilson M.A., Melissa.Wilson@nyumc.org; McGettigan S., 
Suzanne.McGettigan@uphs.upenn.edu; Schuchter L.M., 
Lynn.Schuchter@uphs.upenn.edu; Fecher L.A., LFecher@med.umich.edu) 
University of Pennsylvania, Division of Hematology/Oncology, Department of 
Medicine, Philadelphia, United States.
(Guld K., Kelly.Guld@ucsf.edu) University of Pennsylvania, Department of 
Medicine, Philadelphia, United States.
(Galetta S., Steven.Galetta@nyumc.org) NYU Langone Medical Center, 
Department of Neurology, New York, United States.
(Walsh R.D., rdwalsh@mcw.edu) Medical College of Wisconsin, Departments of 
Ophthalmology and Neurology, Milwaukee, United States.
(Kharlip J., Julia.Kharlip@uphs.upenn.edu) University of Pennsylvania, 
Division of Endocrinology, Department of Medicine, Philadelphia, United 
States.
(Tamhankar M., Madhura.Tamhankar@uphs.upenn.edu) University of Pennsylvania 
Health System, Department of Ophthalmology, Scheie Eye Institute, 
Philadelphia, United States.
(Wilson M.A., Melissa.Wilson@nyumc.org) NYU Langone Medical Center, Present 
address: Division of Hematology and Medical Oncology, Laura and Isaac 
Perlmutter Cancer Center, New York, United States.
(Fecher L.A., LFecher@med.umich.edu) University of Michigan, Present 
address: Division of Hematology/Oncology, Department of Internal Medicine, 
C366 MIB 1500 E. Medical Center Drive, SPC5848, Ann Arbor, United States.
(Guld K., Kelly.Guld@ucsf.edu) UCSF Medical Center, Present address: 
Department of Cardiology, San Francisco, United States.
CORRESPONDENCE ADDRESS
  L.A. Fecher, University of Michigan, Present address: Division of 
Hematology/Oncology, Department of Internal Medicine, C366 MIB 1500 E. 
Medical Center Drive, SPC5848, Ann Arbor, United States. Email: 
LFecher@med.umich.edu
SOURCE
  Journal for ImmunoTherapy of Cancer (2016) 4:1 Article Number: 66. Date of 
Publication: 18 Oct 2016
ISSN
  2051-1426 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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). 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. Conclusions: 
This case highlights the need for recognition of atypical immune mediated 
processes associated with newer checkpoint inhibitor therapies including 
ipilimumab.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  carboplatin
  enoxaparin
  follitropin (endogenous compound)
  hydrocortisone
  luteinizing hormone (endogenous compound)
  methylprednisolone (adverse drug reaction, intravenous drug administration)
  mycophenolate mofetil
  paclitaxel
  prednisone
  sorafenib
  temozolomide
  testosterone (endogenous compound)
  thyrotropin (endogenous compound)
  tumor necrosis factor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (diagnosis)
  visual impairment (side effect, complication, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  afferent pupillary defect
  article
  aseptic meningitis
  cancer recurrence
  case report
  cerebrospinal fluid analysis
  color vision defect
  computer assisted tomography
  diarrhea (side effect)
  disease course
  dizziness (side effect)
  drug dose increase
  drug dose reduction
  drug substitution
  drug withdrawal
  dyspnea (side effect)
  fatigue (side effect)
  headache (side effect)
  human
  hypophysitis (side effect)
  inguinal lymph node
  lumbar puncture
  lung embolism
  male
  middle aged
  multiple cycle treatment
  nuclear magnetic resonance imaging
  optic neuritis (side effect)
  peripheral neuropathy
  plasmapheresis
  priority journal
  rash (side effect)
  sentinel lymph node biopsy
  visual acuity
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  enoxaparin (679809-58-6)
  follitropin (9002-68-0)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  methylprednisolone (6923-42-8, 83-43-2)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
  paclitaxel (33069-62-4)
  prednisone (53-03-2)
  sorafenib (284461-73-0)
  temozolomide (85622-93-1)
  testosterone (58-22-0)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160874999
MEDLINE PMID
  27777775 (http://www.ncbi.nlm.nih.gov/pubmed/27777775)
PUI
  L613401854
DOI
  10.1186/s40425-016-0170-9
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40425-016-0170-9
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 140
TITLE
  Antitumor activity of nivolumab on hemodialysis after renal allograft 
rejection
AUTHOR NAMES
  Ong M.
  Ibrahim A.M.
  Bourassa-Blanchette S.
  Canil C.
  Fairhead T.
  Knoll G.
AUTHOR ADDRESSES
  (Ong M., mong@toh.ca; Bourassa-Blanchette S., sbourassa@toh.ca; Canil C., 
ccanil@toh.ca; Fairhead T., tfairhead@toh.ca; Knoll G., gknoll@toh.ca) The 
Ottawa Hospital, Department of Medicine, 501 Smyth Road, Ottawa, Canada.
(Ong M., mong@toh.ca; Ibrahim A.M., andibrahim@toh.ca) The Ottawa Hospital 
Research Institute, 501 Smyth Road, Ottawa, Canada.
CORRESPONDENCE ADDRESS
  M. Ong, The Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, 
Canada. Email: mong@toh.ca
SOURCE
  Journal for ImmunoTherapy of Cancer (2016) 4:1 Article Number: 64. Date of 
Publication: 18 Oct 2016
ISSN
  2051-1426 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  Background: Nivolumab (Opdivo™) 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. 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. 
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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, intravenous drug administration)
EMTREE DRUG INDEX TERMS
  basiliximab
  creatinine
  methylprednisolone (adverse drug reaction, intravenous drug administration)
  mycophenolate mofetil
  piperacillin plus tazobactam
  prednisone
  tacrolimus
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antineoplastic activity
  hemodialysis
  kidney allograft rejection
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adult
  anorexia (side effect)
  article
  case report
  computer assisted tomography
  diabetic ketoacidosis (side effect)
  drug dose reduction
  endobronchial ultrasonography
  fatigue (side effect)
  female
  glomerulus filtration rate
  human
  hyperpigmentation
  lethargy (side effect)
  loose feces (side effect)
  lung nodule
  lymphoscintigraphy
  malaise (side effect)
  metastatic melanoma
  middle aged
  nausea (side effect)
  positron emission tomography
  priority journal
  single drug dose
  steroid therapy
  vomiting (side effect)
DRUG TRADE NAMES
  opdivo
CAS REGISTRY NUMBERS
  creatinine (19230-81-0, 60-27-5)
  methylprednisolone (6923-42-8, 83-43-2)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
  nivolumab (946414-94-4)
  prednisone (53-03-2)
  tacrolimus (104987-11-3)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160874997
MEDLINE PMID
  27777773 (http://www.ncbi.nlm.nih.gov/pubmed/27777773)
PUI
  L613401855
DOI
  10.1186/s40425-016-0171-8
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40425-016-0171-8
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 141
TITLE
  Management of adverse events following treatment with anti-programmed 
death-1 agents
AUTHOR NAMES
  Weber J.S.
  Postow M.
  Lao C.D.
  Schadendorf D.
AUTHOR ADDRESSES
  (Weber J.S., jeffrey.weber2@nyumc.org) Laura and Isaac Perlmutter Cancer 
Center, New York University Langone Medical Center, New York, United States.
(Postow M.) Memorial Sloan Kettering Cancer Center, New York, United States.
(Postow M.) Weill Cornell Medical College, New York, United States.
(Lao C.D.) Department of Internal Medicine, University of Michigan, Ann 
Arbor, United States.
(Schadendorf D.) University Hospital Essen, Essen, Germany.
CORRESPONDENCE ADDRESS
  J.S. Weber, Laura and Isaac Perlmutter Cancer Center, 522 1st Avenue, Room 
1310, New York, United States. Email: jeffrey.weber2@nyumc.org
SOURCE
  Oncologist (2016) 21:10 (1230-1240). Date of Publication: 1 Oct 2016
ISSN
  1549-490X (electronic)
  1083-7159
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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. Were view 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
  pembrolizumab (adverse drug reaction, drug combination, drug therapy)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  acid lipase (endogenous compound)
  alanine aminotransferase (endogenous compound)
  amylase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  autoantibody (endogenous compound)
  bilirubin (endogenous compound)
  C reactive protein (endogenous compound)
  corticosteroid
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  gamma glutamyltransferase (endogenous compound)
  infliximab (drug therapy)
  lactate dehydrogenase (endogenous compound)
  mesalazine (drug therapy)
  methylprednisolone (drug therapy, intravenous drug administration)
  mycophenolate mofetil (adverse drug reaction, drug therapy, oral drug 
administration)
  vemurafenib (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  alanine aminotransferase blood level
  amenorrhea
  article
  aspartate aminotransferase blood level
  backache
  biopsy
  bloating (side effect)
  bronchoscopy
  cell cycle checkpoint
  colitis (drug therapy, side effect)
  colonoscopy
  computer assisted emission tomography
  depression (side effect)
  diarrhea (drug therapy, side effect)
  disease ontology
  enteritis (drug therapy)
  eosinophilia
  erectile dysfunction
  esophagitis (drug therapy)
  fatigue (side effect)
  follow up
  human
  hypoglycemia
  hypophysitis (side effect)
  hypothyroidism (side effect)
  immunosuppressive treatment
  inflammation
  liver toxicity (side effect)
  lung nodule
  lymph node dissection
  lymph node metastasis
  monotherapy
  mydriasis
  pancreatitis
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pneumonia (side effect)
  priority journal
  pruritus (side effect)
  pulse oximetry
  randomized controlled trial (topic)
  rash (side effect)
  ultrasound
  visual system examination
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  amylase (9000-90-2, 9000-92-4, 9001-19-8)
  aspartate aminotransferase (9000-97-9)
  bilirubin (18422-02-1, 635-65-4)
  C reactive protein (9007-41-4)
  gamma glutamyltransferase (85876-02-4)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  lactate dehydrogenase (9001-60-9)
  mesalazine (89-57-6)
  methylprednisolone (6923-42-8, 83-43-2)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Health Policy, Economics and Management (36)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160756467
MEDLINE PMID
  27401894 (http://www.ncbi.nlm.nih.gov/pubmed/27401894)
PUI
  L612705910
DOI
  10.1634/theoncologist.2016-0055
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2016-0055
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 142
TITLE
  Treatment of the Immune-Related Adverse Effects of Immune Checkpoint 
Inhibitors: A Review
AUTHOR NAMES
  Friedman C.F.
  Proverbs-Singh T.A.
  Postow M.A.
AUTHOR ADDRESSES
  (Friedman C.F.) Department of Medicine, Memorial Sloan Kettering Cancer 
Center, New York, New York2Weill Cornell Medical College, New York, New York
(Proverbs-Singh T.A.) Department of Medicine, Memorial Sloan Kettering 
Cancer Center, New York, New York2Weill Cornell Medical College, New York, 
New York
(Postow M.A.) Department of Medicine, Memorial Sloan Kettering Cancer 
Center, New York, New York2Weill Cornell Medical College, New York, New York
SOURCE
  JAMA oncology (2016) 2:10 (1346-1353). Date of Publication: 1 Oct 2016
ISSN
  2374-2445 (electronic)
ABSTRACT
  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).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.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.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (adverse drug reaction)
  corticosteroid (drug therapy)
  immunosuppressive agent (drug therapy)
  ipilimumab
  monoclonal antibody (adverse drug reaction, adverse drug reaction)
  pembrolizumab
EMTREE MEDICAL INDEX TERMS
  chemically induced
  colitis (drug therapy)
  human
  pneumonia (drug therapy)
  rash (drug therapy)
  toxic hepatitis (etiology)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  pembrolizumab (1374853-91-4)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  27367787 (http://www.ncbi.nlm.nih.gov/pubmed/27367787)
PUI
  L614589351
DOI
  10.1001/jamaoncol.2016.1051
FULL TEXT LINK
  http://dx.doi.org/10.1001/jamaoncol.2016.1051
COPYRIGHT
  Copyright 2017 Medline is the source for the citation and abstract of this 
record.

RECORD 143
TITLE
  Programmed cell death-1 pathway inhibitors in genitourinary malignancies: 
Specific side-effects and their management
AUTHOR NAMES
  Tripathi A.
  Kaymakcalan M.D.
  LeBoeuf N.R.
  Harshman L.C.
AUTHOR ADDRESSES
  (Tripathi A.; Kaymakcalan M.D.; Harshman L.C., 
LaurenC_Harshman@dfci.harvard.edu) Lank Center for Genitourinary Oncology, 
Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, United States.
(LeBoeuf N.R.) Center for Cutaneous Oncology, Department of Dermatology, 
Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical 
School, Boston, United States.
CORRESPONDENCE ADDRESS
  L.C. Harshman, Lank Center for Genitourinary Oncology, Dana-Farber Cancer 
Institute, 450 Brookline Avenue, Boston, United States. Email: 
LaurenC_Harshman@dfci.harvard.edu
SOURCE
  Current Opinion in Urology (2016) 26:6 (548-555). Date of Publication: 1 Oct 
2016
ISSN
  1473-6586 (electronic)
  0963-0643
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
ABSTRACT
  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. 
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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction, drug therapy)
  immunosuppressive agent (adverse drug reaction, drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  antihistaminic agent (drug therapy)
  aspartate aminotransferase (endogenous compound)
  atezolizumab (adverse drug reaction)
  bilirubin (endogenous compound)
  corticotropin (endogenous compound)
  creatinine (endogenous compound)
  follitropin (endogenous compound)
  infliximab (drug therapy)
  ipilimumab (adverse drug reaction)
  luteinizing hormone (endogenous compound)
  mycophenolate mofetil (drug therapy)
  nivolumab (adverse drug reaction)
  pembrolizumab
  prednisolone (drug therapy)
  prednisone (adverse drug reaction, drug therapy)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction (drug therapy, drug therapy)
  cancer immunotherapy
  urogenital tract cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  acute febrile neutrophilic dermatosis (side effect)
  adrenal insufficiency (drug therapy, side effect)
  alanine aminotransferase blood level
  alopecia (side effect)
  aspartate aminotransferase blood level
  bilirubin blood level
  blood pressure
  bullous pemphigoid (side effect)
  chill (side effect)
  colitis (drug therapy, side effect)
  corticosteroid therapy
  corticotropin blood level
  creatinine blood level
  Cytomegalovirus
  diarrhea (drug therapy, side effect)
  drug eruption (side effect)
  drug fever (side effect)
  dyspnea (side effect)
  eczema (side effect)
  esophagus candidiasis (side effect)
  fatigue (side effect)
  flushing
  follitropin blood level
  gingivitis (side effect)
  Guillain Barre syndrome (drug therapy, side effect)
  Herpes simplex virus
  human
  hydration
  hyperthyroidism (side effect)
  hypophysitis (drug therapy, side effect)
  hypopigmentation (side effect)
  hypothyroidism (side effect)
  immunosuppressive treatment
  incidence
  insulin dependent diabetes mellitus (side effect)
  interstitial nephritis (side effect)
  invasive aspergillosis (side effect)
  kidney carcinoma
  lichenoid eruption (side effect)
  liver toxicity (drug therapy, side effect)
  luteinizing hormone blood level
  maculopapular rash (side effect)
  myelitis (side effect)
  oral mucositis (side effect)
  paraneoplastic neuropathy (side effect)
  Pneumocystis pneumonia (side effect)
  pneumonia (drug therapy, side effect)
  posterior reversible encephalopathy syndrome (side effect)
  premedication
  priority journal
  pruritus (side effect)
  psoriasis (side effect)
  pustule (side effect)
  review
  Sjoegren syndrome (side effect)
  skin exfoliation (drug therapy, side effect)
  strongyloidiasis (side effect)
  thyrotropin blood level
  transitional cell carcinoma
  urticaria (side effect)
  Varicella zoster virus
  virus reactivation
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  atezolizumab (1380723-44-3)
  bilirubin (18422-02-1, 635-65-4)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  creatinine (19230-81-0, 60-27-5)
  follitropin (9002-68-0)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  prednisolone (50-24-8)
  prednisone (53-03-2)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160598879
PUI
  L611686891
DOI
  10.1097/MOU.0000000000000332
FULL TEXT LINK
  http://dx.doi.org/10.1097/MOU.0000000000000332
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 144
TITLE
  Perspectives for immunotherapy in endocrine cancer
AUTHOR NAMES
  Latteyer S.
  Tiedje V.
  Schilling B.
  Führer D.
AUTHOR ADDRESSES
  (Latteyer S.; Tiedje V.; Führer D., Dagmar.fuehrer@uk-essen.de) Department 
of Endocrinology and Metabolism, University Hospital Essen, University of 
Duisburg-Essen, Essen, Germany.
(Latteyer S.; Tiedje V.; Führer D., Dagmar.fuehrer@uk-essen.de) Endocrine 
Tumour Center at West German Cancer Center (WTZ), Essen, Germany.
(Schilling B.) Department of Dermatology, Venereology and Allergology, 
University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
(Schilling B.) German Cancer Consortium (DKTK), Heidelberg, Germany.
CORRESPONDENCE ADDRESS
  D. Führer, Department of Endocrinology and Metabolism, University Hospital 
Essen, University of Duisburg-Essen, Essen, Germany. Email: 
Dagmar.fuehrer@uk-essen.de
SOURCE
  Endocrine-Related Cancer (2016) 23:10 (R469-R484). Date of Publication: 1 
Oct 2016
ISSN
  1479-6821 (electronic)
  1351-0088
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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 
antitumor 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug therapy)
  immune checkpoint inhibitor (drug therapy)
  immunomodulating agent (drug therapy)
EMTREE DRUG INDEX TERMS
  cancer antibody
  cell antibody
  immune checkpoint receptor (endogenous compound)
  receptor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  endocrine tumor (drug therapy, drug therapy, therapy)
EMTREE MEDICAL INDEX TERMS
  cancer cell
  cancer patient
  cell therapy
  gastrointestinal neuroendocrine tumor
  human
  imaging
  immune response
  nonhuman
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pheochromocytoma
  randomized controlled trial (topic)
  review
  thyroid cancer
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00257205)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160793750
MEDLINE PMID
  27485460 (http://www.ncbi.nlm.nih.gov/pubmed/27485460)
PUI
  L613013529
DOI
  10.1530/ERC-16-0169
FULL TEXT LINK
  http://dx.doi.org/10.1530/ERC-16-0169
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 145
TITLE
  Prognostic value of programmed death ligand 1 and programmed death 1 
expression in thymic carcinoma
AUTHOR NAMES
  Yokoyama S.
  Miyoshi H.
  Nakashima K.
  Shimono J.
  Hashiguchi T.
  Mitsuoka M.
  Takamori S.
  Akagi Y.
  Ohshima K.
AUTHOR ADDRESSES
  (Yokoyama S.; Hashiguchi T.; Mitsuoka M.; Takamori S.; Akagi Y.) Department 
of Surgery, Kurume University School of Medicine, Kurume, Japan.
(Miyoshi H., miyoshi_hiroaki@med.kurume-u.ac.jp; Nakashima K.; Shimono J.; 
Hashiguchi T.; Ohshima K.) Department of Pathology, Kurume University School 
of Medicine, 67 Asahi-machi, Kurume, Japan.
CORRESPONDENCE ADDRESS
  H. Miyoshi, Department of Pathology, Kurume University School of Medicine, 
67 Asahi-machi, Kurume, Japan. Email: miyoshi_hiroaki@med.kurume-u.ac.jp
SOURCE
  Clinical Cancer Research (2016) 22:18 (4727-4734). Date of Publication: 15 
Sep 2016
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  Purpose: The immune checkpoint of the programmed death 1/programmed death 
ligand 1 (PD-1/PD-L1) pathway is believed to play an important role in 
evasion of host antitumor immune surveillance in various malignancies; 
however, little is known about its role in thymic carcinoma. This study 
investigated PD-1/PD-L1 expression and its association with 
clinicopathologic features, the expression of immune-related proteins in 
tumorinfiltrating lymphocytes (TIL), and patient prognosis. Experimental 
Design: PD-L1 and PD-1 expression was evaluated by IHC in 25 thymic 
carcinoma tissue specimens. Copy number alterations of the PD-L1 gene in 11 
cases were assessed in formalin-fixed, paraffin-embedded material using 
qRT-PCR. Results: Compared with normal subjects, 3 thymic carcinoma patients 
showed an increase in PD-L1 copy number, whereas 8 did not. PD-L1 was 
significantly overexpressed in cases with copy number gain as compared with 
normal cases. High PD-L1 expression was associated with higher disease-free 
and overall survival rates as compared to cases with low expression. 
Prognostic analysis revealed low PD-L1 expression and high number of PD-1+ 
TILs as significant predictors of poor survival, together with Masaoka-Koga 
stage IVa/IVb disease and incomplete resection. In the quantitative analysis 
of TILs, PD-L1 expression correlated proportionally with the number of 
infiltrating CTLs. Conclusions: Here, for the first time, we report that 
PD-L1 and PD-1 expression might be useful prognostic predictors in thymic 
carcinoma. Further studies are expected to substantiate the prognostic value 
of PD-L1 and PD-1 expression, and the potential efficacy of targeting the 
PD-1/PD-L1 pathway in thymic carcinoma via immunotherapy. Clin Cancer Res; 
22(18); 4727-34.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer prognosis
  protein expression
  thymus cancer
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer immunotherapy
  cancer patient
  cancer staging
  cancer tissue
  clinical article
  clinical feature
  controlled study
  copy number variation
  disease free survival
  female
  histopathology
  human
  human tissue
  immunohistochemistry
  male
  overall survival
  PD L1 gene
  priority journal
  protein analysis
  protein targeting
  quantitative analysis
  reverse transcription polymerase chain reaction
  tissue microarray
  tumor associated leukocyte
EMBASE CLASSIFICATIONS
  Cancer (16)
  Hematology (25)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160735272
MEDLINE PMID
  27166394 (http://www.ncbi.nlm.nih.gov/pubmed/27166394)
PUI
  L612507709
DOI
  10.1158/1078-0432.CCR-16-0434
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-16-0434
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 146
TITLE
  Debilitating skin toxicity associated with pembrolizumab therapy in an 
81-year-old female with malignant melanoma
AUTHOR NAMES
  Khokhar M.O.
  Kettle J.
  Palla A.R.
AUTHOR ADDRESSES
  (Khokhar M.O., khokharm@health.missouri.edu; Palla A.R.) Division of 
Hematology and Oncology, Department of Medicine, Ellis Fischel Cancer 
Center, University of Missouri Columbia, Fellow Hematology Oncology, 1, 
Hospital Drive, Columbia, United States.
(Kettle J.) Division of Hematology and Oncology, Department of Pharmacy, 
Ellis Fischel Cancer Center, University of Missouri Columbia, Columbia, 
United States.
CORRESPONDENCE ADDRESS
  M.O. Khokhar, Division of Hematology and Oncology, Department of Medicine, 
Ellis Fischel Cancer Center, University of Missouri Columbia, Fellow 
Hematology Oncology, 1, Hospital Drive, Columbia, United States. Email: 
khokharm@health.missouri.edu
SOURCE
  Case Reports in Oncology (2016) 9:3 (833-839). Date of Publication: 13 Sep 
2016
ISSN
  1662-6575 (electronic)
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
  dexamethasone (drug therapy, topical drug administration)
  everolimus
  ipilimumab
  moxifloxacin (drug therapy, topical drug administration)
  nivolumab
  paclitaxel
  prednisone (parenteral drug administration)
  sorafenib
  temozolamide
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  skin toxicity
EMTREE MEDICAL INDEX TERMS
  aged
  article
  blepharoconjuncitivits (drug therapy, side effect)
  blepharoconjuncitivits (drug therapy, side effect)
  cancer growth
  case report
  computer assisted tomography
  drug dose reduction
  edema (side effect)
  eye inflammation (drug therapy, side effect)
  eye redness (drug therapy, side effect)
  female
  finger malformation (side effect)
  fluid therapy
  human
  human tissue
  lip disease (side effect)
  multiple cycle treatment
  nail disease (side effect)
  positron emission tomography
  priority journal
  psoriasis (side effect)
  skin exfoliation (side effect)
  very elderly
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  everolimus (159351-69-6)
  ipilimumab (477202-00-9)
  moxifloxacin (151096-09-2)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  pembrolizumab (1374853-91-4)
  prednisone (53-03-2)
  sorafenib (284461-73-0)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Gerontology and Geriatrics (20)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170053998
PUI
  L614114475
DOI
  10.1159/000452944
FULL TEXT LINK
  http://dx.doi.org/10.1159/000452944
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 147
TITLE
  A case of poorly differentiated large-cell neuroendocrine carcinoma of the 
cecum: A rare malignancy, with review of the literature
AUTHOR NAMES
  Mertz A.T.
  Ojemuyiwa M.A.
AUTHOR ADDRESSES
  (Mertz A.T.) Uniformed Services University of the Health Sciences, Bethesda, 
United States.
(Ojemuyiwa M.A., michelle.a.ojemuyiwa.mil@mail.mil) Murtha Cancer Center, 
Walter Reed National Military Medical Center, 4954 North Palmer Road, 
America Bldg 19, Bethesda, United States.
CORRESPONDENCE ADDRESS
  M.A. Ojemuyiwa, Murtha Cancer Center, Walter Reed National Military Medical 
Center, 4954 North Palmer Road, America Bldg 19, Bethesda, United States. 
Email: michelle.a.ojemuyiwa.mil@mail.mil
SOURCE
  Case Reports in Oncology (2016) 9:3 (847-853). Date of Publication: 13 Sep 
2016
ISSN
  1662-6575 (electronic)
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  cisplatin (drug therapy)
  etoposide (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cecum cancer (drug therapy, diagnosis, drug therapy)
  large cell neuroendocrine carcinoma (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adenocarcinoma
  adult
  anastomosis
  article
  cancer prognosis
  case report
  colonoscopy
  female
  hemicolectomy
  human
  human tissue
  middle aged
  multiple cycle treatment
  positron emission tomography
  priority journal
  protein expression
  small cell lung cancer
  x-ray computed tomography
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  etoposide (33419-42-0)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160923570
PUI
  L613758292
DOI
  10.1159/000452655
FULL TEXT LINK
  http://dx.doi.org/10.1159/000452655
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 148
TITLE
  Hypophysitis: Evaluation and Management
AUTHOR NAMES
  Faje A.
AUTHOR ADDRESSES
  (Faje A., afaje@partners.org) Massachusetts General Hospital and Harvard 
Medical School, Neuroendocrine Unit, 55 Fruit Street, Boston, United States.
CORRESPONDENCE ADDRESS
  A. Faje, Massachusetts General Hospital and Harvard Medical School, 
Neuroendocrine Unit, 55 Fruit Street, Boston, United States. Email: 
afaje@partners.org
SOURCE
  Clinical Diabetes and Endocrinology (2016) 2:1 Article Number: 15. Date of 
Publication: 6 Sep 2016
ISSN
  2055-8260 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  azathioprine (drug therapy)
  cyclosporine (drug therapy)
  glucocorticoid (drug therapy)
  infliximab (drug therapy)
  methotrexate (drug therapy)
  mycophenolate mofetil (drug therapy)
  rituximab (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, diagnosis, drug therapy, epidemiology, etiology, 
radiotherapy, surgery)
EMTREE MEDICAL INDEX TERMS
  article
  clinical evaluation
  clinical feature
  differential diagnosis
  endocrine surgery
  histopathology
  human
  immunopathogenesis
  incidence
  priority journal
  radiodiagnosis
  stereotactic radiosurgery
CAS REGISTRY NUMBERS
  azathioprine (446-86-6)
  cyclosporin (79217-60-0)
  infliximab (170277-31-3)
  methotrexate (15475-56-6, 59-05-2, 7413-34-5)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
  rituximab (174722-31-7)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160652374
PUI
  L611989307
DOI
  10.1186/s40842-016-0034-8
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40842-016-0034-8
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 149
TITLE
  Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: 
clinical review
AUTHOR NAMES
  Joshi M.N.
  Whitelaw B.C.
  Palomar M.T.P.
  Wu Y.
  Carroll P.V.
AUTHOR ADDRESSES
  (Joshi M.N., mamta.joshi@gstt.nhs.uk; Carroll P.V.) Departments of 
Endocrinology, Guy's & St Thomas NHS Foundation Trust, London, United 
Kingdom.
(Whitelaw B.C.) Department of Endocrinology, Kings College London NHS 
Foundation Trust, London, United Kingdom.
(Palomar M.T.P.; Wu Y.) Medical Oncology, Guy's & St Thomas NHS Foundation 
Trust, London, United Kingdom.
CORRESPONDENCE ADDRESS
  M.N. Joshi, Departments of Endocrinology, Guy's & St Thomas NHS Foundation 
Trust, London, United Kingdom. Email: mamta.joshi@gstt.nhs.uk
SOURCE
  Clinical Endocrinology (2016) 85:3 (331-339). Date of Publication: 1 Sep 
2016
ISSN
  1365-2265 (electronic)
  0300-0664
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immune checkpoint inhibitor (adverse drug reaction)
  monoclonal antibody (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  hypophysis hormone
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease
  hypophysitis (side effect, side effect)
  immunotherapy
EMTREE MEDICAL INDEX TERMS
  adrenal disease
  biochemical analysis
  classification
  clinical assessment
  clinical feature
  diagnostic procedure
  drug mechanism
  follow up
  hormone substitution
  human
  hypophysis disease
  incidence
  information retrieval
  pathophysiology
  priority journal
  publication
  radiodiagnosis
  review
  thyroid disease (side effect)
CAS REGISTRY NUMBERS
  hypophysis hormone (85883-81-4)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160602882
MEDLINE PMID
  26998595 (http://www.ncbi.nlm.nih.gov/pubmed/26998595)
PUI
  L611711151
DOI
  10.1111/cen.13063
FULL TEXT LINK
  http://dx.doi.org/10.1111/cen.13063
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 150
TITLE
  Immune checkpoint inhibitors for advanced melanoma-evidences and future 
perspectives
AUTHOR NAMES
  Nakamura Y.
  Teramoto Y.
  Asami Y.
  Matsuya T.
  Yamamoto A.
AUTHOR ADDRESSES
  (Nakamura Y.; Teramoto Y.; Asami Y.; Matsuya T.; Yamamoto A.) Dept. of Skin 
Oncology/Dermatology, Saitama Medical University, International Medical 
Center, 1397-1 Yamane, Hidaka, Saitama, Japan.
CORRESPONDENCE ADDRESS
  Y. Nakamura, Dept. of Skin Oncology/Dermatology, Saitama Medical University, 
International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan.
SOURCE
  Japanese Journal of Cancer and Chemotherapy (2016) 43:9 (1036-1040). Date of 
Publication: 1 Sep 2016
ISSN
  0385-0684
BOOK PUBLISHER
  Japanese Journal of Cancer and Chemotherapy Publishers Inc., 
ccp@blue.ocn.ne.jp
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  monoclonal antibody (adverse drug reaction, drug combination, drug therapy)
  programmed death 1 receptor antibody (adverse drug reaction, drug 
combination, drug therapy)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 antibody (drug combination, drug therapy)
  mitogen activated protein kinase (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  cancer immunotherapy
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adverse drug reaction
  article
  cancer chemotherapy
  cancer incidence
  clinical effectiveness
  colitis (side effect)
  comparative study
  cytotoxicity
  drug determination
  drug withdrawal
  endocrine disease (side effect)
  human
  incidence
  overall survival
  pneumonia (side effect)
  progression free survival
  treatment duration
  treatment response
CAS REGISTRY NUMBERS
  mitogen activated protein kinase (142243-02-5)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English, Japanese
EMBASE ACCESSION NUMBER
  20170037538
MEDLINE PMID
  27628544 (http://www.ncbi.nlm.nih.gov/pubmed/27628544)
PUI
  L614043869
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 151
TITLE
  Drug-induced myocarditis after nivolumab treatment in a patient with PDL1- 
negative squamous cell carcinoma of the lung
AUTHOR NAMES
  Semper H.
  Muehlberg F.
  Schulz-Menger J.
  Allewelt M.
  Grohé C.
AUTHOR ADDRESSES
  (Semper H.; Allewelt M.; Grohé C., Christian.grohe@pgdiakonie.de) ELK Thorax 
Center, Lindenberger Weg 27, Berlin, Germany.
(Muehlberg F.; Schulz-Menger J.) Working Group on Cardiovascular Magnetic 
Resonance, Experimental and Clinical Research Center, A Joint Cooperation 
Between the Charité Medical Faculty and the Max-delbrück Center for 
Molecular Medicine and HELIOS Hospital Berlin Buch, Department of Cardiology 
and Nephrology, Schwanebecker Chaussee 50, Berlin, Germany.
CORRESPONDENCE ADDRESS
  C. Grohé, ELK Thorax Center, Lindenberger Weg 27, Berlin, Germany. Email: 
Christian.grohe@pgdiakonie.de
SOURCE
  Lung Cancer (2016) 99 (117-119). Date of Publication: 1 Sep 2016
ISSN
  1872-8332 (electronic)
  0169-5002
BOOK PUBLISHER
  Elsevier Ireland Ltd
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  beta adrenergic receptor blocking agent (drug therapy)
  biological marker (endogenous compound)
  C reactive protein (endogenous compound)
  cisplatin (drug combination, drug therapy)
  D dimer (endogenous compound)
  dipeptidyl carboxypeptidase inhibitor (drug therapy)
  diuretic agent (drug therapy)
  gadolinium
  prednisolone (drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
  troponin T (endogenous compound)
  vinorelbine tartrate (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  drug induced disease (side effect, diagnosis, side effect)
  myocarditis (side effect, diagnosis, side effect)
  squamous cell lung carcinoma (drug therapy, drug therapy, radiotherapy)
EMTREE MEDICAL INDEX TERMS
  aged
  aortic regurgitation
  article
  brain metastasis (radiotherapy)
  cancer combination chemotherapy
  cancer control
  cancer fatigue
  cancer patient
  cancer radiotherapy
  cancer regression
  cardiovascular magnetic resonance
  case report
  computer assisted tomography
  contrast enhancement
  corticosteroid therapy
  dyspnea
  electrocardiogram
  heart function
  heart left ventricle failure (drug therapy)
  heart right bundle branch block
  hospice care
  hospital admission
  human
  hypokinesia
  immunohistochemistry
  laboratory diagnosis
  liver metastasis
  lung angiography
  lung embolism
  male
  multiple cycle treatment
  pericardial effusion
  poor general condition
  priority journal
  radiotherapy dosage
  sinus tachycardia
  ST segment depression
  thorax pain
  transthoracic echocardiography
  treatment response
CAS REGISTRY NUMBERS
  C reactive protein (9007-41-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  gadolinium (7440-54-2)
  nivolumab (946414-94-4)
  prednisolone (50-24-8)
  troponin T (60304-72-5)
EMBASE CLASSIFICATIONS
  Radiology (14)
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Cardiovascular Diseases and Cardiovascular Surgery (18)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160527077
MEDLINE PMID
  27565924 (http://www.ncbi.nlm.nih.gov/pubmed/27565924)
PUI
  L611219250
DOI
  10.1016/j.lungcan.2016.06.025
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.lungcan.2016.06.025
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 152
TITLE
  Antiangiogenic therapies in ovarian cancer
AUTHOR NAMES
  Reinthaller A.
AUTHOR ADDRESSES
  (Reinthaller A., alexander.reinthaller@meduniwien.ac.at) Gynecologic Cancer 
Unit, Comprehensive Cancer Center Vienna, Department of Gynecology & 
Gynecologic Oncology, Medical University Vienna, Vienna, Austria.
CORRESPONDENCE ADDRESS
  A. Reinthaller, Gynecologic Cancer Unit, Comprehensive Cancer Center Vienna, 
Department of Gynecology & Gynecologic Oncology, Medical University Vienna, 
Vienna, Austria. Email: alexander.reinthaller@meduniwien.ac.at
SOURCE
  Memo - Magazine of European Medical Oncology (2016) 9:3 (139-143). Date of 
Publication: 1 Sep 2016
ISSN
  1865-5076 (electronic)
  1865-5041
BOOK PUBLISHER
  Springer-Verlag Wien, michaela.bolli@springer.at
ABSTRACT
  Angiogenesis plays a pivotal role in normal ovarian physiology as well as in 
the formation and progression of ovarian cancer. Several well-designed 
phase II and III trials studied the efficacy of antiangiogenic agents in 
advanced ovarian cancer. The results of these trials demonstrated 
significantly prolonged progression-free survival when antiangiogenic agents 
were used as a maintenance therapy. To date, no effect on overall survival 
could be ascertained. The most widely studied antiangiogenic agent, 
bevacizumab – a monoclonal humanized antibody against vascular endothelial 
growth factor – was effective in all phases of the disease (first-line 
therapy, platinum-sensitive and platinum-resistant recurrence). These 
results led to regulatory approval in many countries including the European 
Union. Other anti-VEGF agents such as tyrosine kinase inhibitors have not 
shown increased activity but increased toxicity relative to bevacizumab. 
Agents targeting angiopoietin-1 and -2 are in development and new 
combinations with PARP inhibitors and immune checkpoint inhibitors are 
studied. This review summarizes the current data and knowledge on the 
clinical use of antiangiogenic agents in advanced ovarian cancer.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  angiogenesis inhibitor (clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  bevacizumab (clinical trial, drug combination, drug comparison, drug 
therapy)
  carboplatin (clinical trial, drug combination, drug comparison, drug 
therapy)
  doxorubicin (clinical trial, drug therapy)
  gemcitabine (clinical trial, drug combination, drug comparison, drug 
therapy)
  nintedanib (clinical trial, drug combination, drug therapy)
  paclitaxel (clinical trial, drug combination, drug therapy)
  pazopanib (clinical trial, drug therapy)
  topotecan (clinical trial, drug therapy)
  trebananib (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antiangiogenic therapy
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  cancer adjuvant therapy
  cancer combination chemotherapy
  cancer resistance
  cancer staging
  cancer survival
  clinical effectiveness
  disease association
  drug efficacy
  drug safety
  human
  priority journal
  progression free survival
  recurrent disease
  review
  treatment duration
  treatment planning
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  carboplatin (41575-94-4)
  doxorubicin (23214-92-8, 25316-40-9)
  gemcitabine (103882-84-4)
  nintedanib (928326-83-4, 656247-17-5, 656247-18-6)
  paclitaxel (33069-62-4)
  pazopanib (444731-52-6, 635702-64-6)
  topotecan (119413-54-6, 123948-87-8)
  trebananib (894356-79-7)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160679000
PUI
  L612271620
DOI
  10.1007/s12254-016-0282-4
FULL TEXT LINK
  http://dx.doi.org/10.1007/s12254-016-0282-4
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 153
TITLE
  Immune checkpoint therapy and type 1 diabetes
AUTHOR NAMES
  Ikegami H.
  Kawabata Y.
  Noso S.
AUTHOR ADDRESSES
  (Ikegami H., ikegami@med.kindai.ac.jp; Kawabata Y.; Noso S.) Department of 
Endocrinology, Metabolism and Diabetes, Kindai University Faculty of 
Medicine, 377-2 Ohno-higashi, Osaka-sayama, Japan.
CORRESPONDENCE ADDRESS
  H. Ikegami, Department of Endocrinology, Metabolism and Diabetes, Kindai 
University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Japan. 
Email: ikegami@med.kindai.ac.jp
SOURCE
  Diabetology International (2016) 7:3 (221-227). Date of Publication: 1 Sep 
2016
ISSN
  2190-1686 (electronic)
  2190-1678
BOOK PUBLISHER
  Springer-Verlag Tokyo, orders@springer.jp
ABSTRACT
  Type 1 diabetes is caused by destruction of insulin-producing beta cells of 
the pancreas. The etiology of type 1 diabetes is immune-mediated by either 
an organ-specific autoimmune mechanism in autoimmune type 1 diabetes or a 
still unknown but probably immune-mediated mechanism in fulminant type 1 
diabetes. Immunomodulation is therefore expected to accelerate or inhibit 
type 1 diabetes. Recent progress in anti-cancer therapy by immune-checkpoint 
blockade, such as anti-PD-1 and anti-CTLA4 monoclonal antibodies, has 
markedly improved the prognosis of patients with advanced cancers. These 
drugs activate anti-tumor immunity by blocking inhibitory signals of T 
lymphocytes. Activation of immunological pathways, however, is expected to 
accelerate immune-mediated diseases. In fact, the development of 
autoimmune-thyroid diseases and type 1 diabetes, including fulminant type 1 
diabetes, has been reported in patients treated with immune checkpoint 
blockers. The development of fulminant type 1 diabetes is a major concern 
because of its abrupt onset and very rapid progression, leading to death 
unless proper treatment is initiated immediately after diagnosis. In this 
review, the development of type 1 diabetes with immune-checkpoint therapy 
and its etiological background are discussed.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immune checkpoint therapy
  immunomodulation
  insulin dependent diabetes mellitus (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  antigen presenting cell
  autoimmune thyroiditis (side effect)
  cancer therapy
  drug effect
  ethnic group
  human
  immunity
  malignant neoplasm (drug therapy)
  priority journal
  review
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160626603
PUI
  L611827101
DOI
  10.1007/s13340-016-0276-9
FULL TEXT LINK
  http://dx.doi.org/10.1007/s13340-016-0276-9
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 154
TITLE
  Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic 
epithelial tumors: Impact on treatment efficacy and alteration in expression 
after chemotherapy
AUTHOR NAMES
  Katsuya Y.
  Horinouchi H.
  Asao T.
  Kitahara S.
  Goto Y.
  Kanda S.
  Fujiwara Y.
  Nokihara H.
  Yamamoto N.
  Watanabe S.-I.
  Tsuta K.
  Ohe Y.
AUTHOR ADDRESSES
  (Katsuya Y.; Horinouchi H., hhorinou@ncc.go.jp; Asao T.; Kitahara S.; Goto 
Y.; Kanda S.; Fujiwara Y.; Nokihara H.; Yamamoto N.; Ohe Y.) Department of 
Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
(Katsuya Y.; Tsuta K.) Division of Pathology and Clinical Laboratory, 
National Cancer Center Hospital, Tokyo, Japan.
(Fujiwara Y.; Yamamoto N.) Department of Experimental Therapeutics, 
Exploratory Oncology Research & Clinical Trial Center, National Cancer 
Center Hospital, Tokyo, Japan.
(Watanabe S.-I.) Division of Thoracic Surgery, National Cancer Center 
Hospital, Tokyo, Japan.
(Tsuta K.) Department of Pathology and Laboratory Medicine Kansai Medical 
University, Japan.
CORRESPONDENCE ADDRESS
  H. Horinouchi, Department of Thoracic Oncology, National Cancer Center 
Hospital, Tokyo, Japan. Email: hhorinou@ncc.go.jp
SOURCE
  Lung Cancer (2016) 99 (4-10). Date of Publication: 1 Sep 2016
ISSN
  1872-8332 (electronic)
  0169-5002
BOOK PUBLISHER
  Elsevier Ireland Ltd
ABSTRACT
  Backgrounds To understand the clinical impact of PD-1/L1 expression in 
thymoma (TM) and thymic carcinoma (TC), we evaluated the frequency of 
PD-1/L1 expression in pre/post chemotherapy specimens and the correlation 
with the treatment efficacy. Methods The expression of PD-1/L1 was evaluated 
using immunohistochemistry in patients with TM or TC treated with 
chemotherapy between 2000 and 2014. Using formalin-fixed, paraffin-embedded 
tissue samples and a PD-L1 antibody, the expression of PD-L1 in the TM and 
TC specimens was reported in terms of the H-score (0–300), with a score ≥1 
being defined as positive. The PD-1 expression in the tumor-infiltrating 
immune cells was evaluated based on the intensity (0–3) of staining using a 
PD-1 antibody. The objective response rate, progression-free survival, and 
the difference in PD-1/L1 expression between the pre/post chemotherapy were 
evaluated. Results Thirty patients (TM/TC 12/18) were evaluated. PD-L1 
positivity were TM/TC 67%/41%. Within the PD-L1 positive/negative 
populations, the objective response rates were 50%/0% for TM and 14%/20% for 
TC. No significant differences in progression-free survival were seen 
according to the PD-L1 expression status. Increases in both the PD-L1 and 
PD-1 scores were observed after chemotherapy in six serial pre/post 
chemotherapy TM specimens, with a mean PD-L1 score and a median PD-1 
intensity of 42/93, and 0/2.5, respectively. Conclusions The substantially 
high expression of PD-L1 and the increase in PD-L1 and PD-1 expression after 
chemotherapy supports anti-PD-1/L1 drugs therapy for TM and TC as well as 
the development of a strategy for its sequential use after chemotherapy.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  carboplatin (drug combination, drug therapy)
  cisplatin (drug combination, drug therapy)
  doxorubicin (drug combination, drug therapy)
  etoposide (drug combination, drug therapy)
  gemcitabine (drug combination, drug therapy)
  paclitaxel (drug combination, drug therapy)
  vincristine (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer combination chemotherapy
  epithelium tumor (drug therapy, drug therapy)
  thymic epithelial tumor (drug therapy, drug therapy)
  thymoma (drug therapy, drug therapy)
  thymus cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer control
  cancer survival
  clinical article
  comparative study
  controlled study
  drug efficacy
  drug response
  evaluation study
  female
  human
  human tissue
  immunocompetent cell
  immunohistochemistry
  male
  priority journal
  progression free survival
  protein expression
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  doxorubicin (23214-92-8, 25316-40-9)
  etoposide (33419-42-0, 433304-61-1)
  gemcitabine (103882-84-4)
  paclitaxel (33069-62-4)
  vincristine (57-22-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Hematology (25)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160476536
MEDLINE PMID
  27565906 (http://www.ncbi.nlm.nih.gov/pubmed/27565906)
PUI
  L610895826
DOI
  10.1016/j.lungcan.2016.05.007
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.lungcan.2016.05.007
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 155
TITLE
  Cytotoxic and targeted therapy for hereditary cancers
AUTHOR NAMES
  Iyevleva A.G.
  Imyanitov E.N.
AUTHOR ADDRESSES
  (Iyevleva A.G., aglayai@inbox.ru; Imyanitov E.N., evgeny@imyanitov.spb.ru) 
N.N. Petrov Institute of Oncology, Pesochny-2, St. Petersburg, Russian 
Federation.
(Iyevleva A.G., aglayai@inbox.ru; Imyanitov E.N., evgeny@imyanitov.spb.ru) 
St. Petersburg Pediatric Medical University, St. Petersburg, Russian 
Federation.
(Imyanitov E.N., evgeny@imyanitov.spb.ru) I.I. Mechnikov North-Western 
Medical University, St. Petersburg, Russian Federation.
(Imyanitov E.N., evgeny@imyanitov.spb.ru) St. Petersburg State University, 
St. Petersburg, Russian Federation.
CORRESPONDENCE ADDRESS
  E.N. Imyanitov, N.N. Petrov Institute of Oncology, Pesochny-2, St. 
Petersburg, Russian Federation. Email: evgeny@imyanitov.spb.ru
SOURCE
  Hereditary Cancer in Clinical Practice (2016) 14:1 Article Number: 17. Date 
of Publication: 23 Aug 2016
ISSN
  1897-4287 (electronic)
  1731-2302
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic agent (drug therapy)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy)
  mammalian target of rapamycin inhibitor
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
inhibitor
  pembrolizumab (drug therapy)
  platinum (drug therapy)
  RET inhibitor (drug therapy)
  SMO inhibitor (drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hereditary tumor syndrome (drug therapy, drug therapy)
  molecularly targeted therapy
EMTREE MEDICAL INDEX TERMS
  antigenicity
  article
  basal cell nevus syndrome (drug therapy)
  breast cancer (drug therapy)
  cancer chemotherapy
  cancer patient
  germline mutation
  haploinsufficiency
  hereditary nonpolyposis colorectal cancer (drug therapy)
  human
  microsatellite instability
  oncogene
  therapeutic index
  thyroid medullary carcinoma (drug therapy)
  treatment response
  tuberous sclerosis
  tumor suppressor gene
CAS REGISTRY NUMBERS
  pembrolizumab (1374853-91-4)
  platinum (7440-06-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160613229
PUI
  L611742325
DOI
  10.1186/s13053-016-0057-2
FULL TEXT LINK
  http://dx.doi.org/10.1186/s13053-016-0057-2
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 156
TITLE
  Pembrolizumab-associated minimal change disease in a patient with malignant 
pleural mesothelioma
AUTHOR NAMES
  Bickel A.
  Koneth I.
  Enzler-Tschudy A.
  Neuweiler J.
  Flatz L.
  Früh M.
AUTHOR ADDRESSES
  (Bickel A., angelika.bickel@kssg.ch; Früh M., martin.frueh@kssg.ch) Cantonal 
Hospital St. Gallen, Department of Oncology and Haematology, 
Rorschacherstrasse 95, St. Gallen, Switzerland.
(Koneth I., irene.koneth@kssg.ch) Cantonal Hospital St.Gallen, Division of 
Nephrology and Transplantation Medicine, St. Gallen, Switzerland.
(Enzler-Tschudy A., annette.enzler-tschudy@kssg.ch; Neuweiler J., 
joerg.neuweiler@kssg.ch) Institute of Pathology, Cantonal Hospital St. 
Gallen, St. Gallen, Switzerland.
(Flatz L., lukas.flatz@kssg.ch) Cantonal Hospital St. Gallen, Department of 
Dermatology, St. Gallen, Switzerland.
CORRESPONDENCE ADDRESS
  A. Bickel, Cantonal Hospital St. Gallen, Department of Oncology and 
Haematology, Rorschacherstrasse 95, St. Gallen, Switzerland. Email: 
angelika.bickel@kssg.ch
SOURCE
  BMC Cancer (2016) 16:1 Article Number: 656. Date of Publication: 19 Aug 2016
ISSN
  1471-2407 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  angiotensin 2 receptor antagonist
  carboplatin (drug therapy)
  creatinine (endogenous compound)
  diuretic agent
  pemetrexed (drug therapy)
  prednisone
  vinorelbine tartrate (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  kidney disease (side effect, diagnosis, side effect)
  mesothelioma (drug therapy, diagnosis, drug therapy)
  minimal change disease (side effect, diagnosis, side effect)
  pleura mesothelioma (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure
  adult
  article
  cancer growth
  case report
  creatinine blood level
  drug withdrawal
  electron microscopy
  eyelid edema (side effect)
  generalized edema (side effect)
  glomerulus filtration rate
  human
  hypercholesterolemia
  hypoalbuminemia
  immunofluorescence microscopy
  kidney biopsy
  leg edema (side effect)
  middle aged
  multiple cycle treatment
  nephrotic syndrome
  nephrotoxicity (side effect)
  proteinuria
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  creatinine (19230-81-0, 60-27-5)
  navelbine (125317-39-7, 71486-22-1)
  pembrolizumab (1374853-91-4)
  pemetrexed (137281-23-3, 150399-23-8)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160609313
MEDLINE PMID
  27543082 (http://www.ncbi.nlm.nih.gov/pubmed/27543082)
PUI
  L611712328
DOI
  10.1186/s12885-016-2718-y
FULL TEXT LINK
  http://dx.doi.org/10.1186/s12885-016-2718-y
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 157
TITLE
  Immune checkpoint blockade reveals the stimulatory capacity of 
tumor-associated CD103(+) dendritic cells in late-stage ovarian cancer
AUTHOR NAMES
  Flies D.B.
  Higuchi T.
  Harris J.C.
  Jha V.
  Gimotty P.A.
  Adams S.F.
AUTHOR ADDRESSES
  (Flies D.B.; Higuchi T.; Harris J.C.; Adams S.F., Sadams@salud.unm.edu) 
Division of Gynecologic Oncology, University of New Mexico Comprehensive 
Cancer Center, Albuquerque, United States.
(Jha V.; Adams S.F., Sadams@salud.unm.edu) Ovarian Cancer Research Center, 
The University of Pennsylvania, Philadelphia, United States.
(Gimotty P.A.) Department of Biostatistics, The University of Pennsylvania, 
Philadelphia, United States.
(Jha V.) Department of Biology, Arapahoe Community College, Littleton, 
United States.
CORRESPONDENCE ADDRESS
  S.F. Adams, University of New Mexico Health Sciences Center, 1201 Camino de 
Salud, MSC07-4025, Albuquerque, United States. Email: Sadams@salud.unm.edu
SOURCE
  OncoImmunology (2016) 5:8 Article Number: e1185583. Date of Publication: 2 
Aug 2016
ISSN
  2162-402X (electronic)
  2162-4011
BOOK PUBLISHER
  Taylor and Francis Inc., 325 Chestnut St, Suite 800, Philadelphia, United 
States.
ABSTRACT
  Although immune infiltrates in ovarian cancer are associated with improved 
survival, the ovarian tumor environment has been characterized as 
immunosuppressive, due in part to functional shifts among dendritic cells 
with disease progression. We hypothesized that flux in dendritic cell 
subpopulations with cancer progression were responsible for observed 
differences in antitumor immune responses in early and late-stage disease. 
Here we identify three dendritic cell subsets with disparate functions in 
the ovarian tumor environment. CD11c+CD11b(−)CD103(+) dendritic cells are 
absent in the peritoneal cavity of healthy mice but comprise up to 40% of 
dendritic cells in tumor-bearing mice and retain T cell stimulatory capacity 
in advanced disease. Among CD11c+CD11b+ cells, Lair-1 expression 
distinguishes stimulatory and immunoregulatory DC subsets, which are also 
enriched in the tumor environment. Notably, PD-L1 is expressed by Lair-1(hi) 
immunoregulatory dendritic cells, and may contribute to local tumor 
antigen-specific T cell dysfunction. Using an adoptive transfer model, we 
find that PD-1 blockade enables tumor-associated CD103(+) dendritic cells to 
promote disease clearance. These data demonstrate that antitumor immune 
capacity is maintained among local dendritic cell subpopulations in the 
tumor environment with cancer progression. Similar dendritic cell subsets 
are present in malignant ascites from women with ovarian cancer, supporting 
the translational relevance of these results.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  CD103 antigen (endogenous compound)
EMTREE DRUG INDEX TERMS
  CD11 antigen (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  dendritic cell
  immune response
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  animal model
  article
  ascites
  cell survival
  clinical article
  female
  human
  mouse
  nonhuman
  tumor microenvironment
CAS REGISTRY NUMBERS
  CD103 antigen (269047-90-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160573569
PUI
  L611533341
DOI
  10.1080/2162402X.2016.1185583
FULL TEXT LINK
  http://dx.doi.org/10.1080/2162402X.2016.1185583
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 158
TITLE
  New immunotherapy strategies in breast cancer
AUTHOR NAMES
  Yu L.-Y.
  Li M.-P.
  Kuang D.-B.
  Zhang C.-M.
  Chen X.-P.
AUTHOR ADDRESSES
  (Yu L.-Y., yulinhuil9910530@163.com; Li M.-P.; Kuang D.-B.; Zhang C.-M.; 
Chen X.-P., chenxp74@holmail.com) Dept of Clinical Pharmacology', Central 
South University, Xiangya Hospital, Chungsha, China.
(Yu L.-Y., yulinhuil9910530@163.com; Li M.-P.; Kuang D.-B.; Zhang C.-M.; 
Chen X.-P., chenxp74@holmail.com) Institute of Clinical Pharmacology, 
Central South University, Hunan Key laboratory of Pharmacogenetics, 
Changsha, China.
SOURCE
  Chinese Pharmacological Bulletin (2016) 32:8 (1037-1040). Date of 
Publication: 1 Aug 2016
ISSN
  1001-1978
BOOK PUBLISHER
  Institute of Clinical Pharmacology
ABSTRACT
  Breast cancer is the principal cause of death in malignancy women, usually 
treated with the combination of surgery, chemotherapy, radiotherapy and 
endocrinotherapy. With the de-velopment of cell biology, molecular biology, 
immunology, immunotherapy becomes a new field of breast cancer treatment. In 
this review, we discuss new findings in breast cancer immunotherapy, 
including recent successes with bispecific antibodies and immune checkpoint 
blockade. We also discuss therapeulie cancer vaccines and highlight several 
additional immunotherapy modalities in early stages of development.
EMTREE DRUG INDEX TERMS
  cancer vaccine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  breast cancer
  cancer immunotherapy
EMTREE MEDICAL INDEX TERMS
  antibody specificity
  article
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
LANGUAGE OF ARTICLE
  Chinese
LANGUAGE OF SUMMARY
  English, Chinese
EMBASE ACCESSION NUMBER
  20160682827
PUI
  L612297931
DOI
  10.3969/j.issn.1001-1978.2016.08.001
FULL TEXT LINK
  http://dx.doi.org/10.3969/j.issn.1001-1978.2016.08.001
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 159
TITLE
  Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for 
IFNγ-Induced Indoleamine 2, 3-Dioxygenase
AUTHOR NAMES
  Sharma R.
  Di Dalmazi G.
  Caturegli P.
AUTHOR ADDRESSES
  (Sharma R.; Di Dalmazi G.; Caturegli P., pcat@jhmi.edu) Department of 
Pathology, Johns Hopkins University School of Medicine, Baltimore, United 
States.
(Di Dalmazi G.) Department of Medicine, G. d'Annunzio University of Chieti, 
Cheti, Italy.
(Caturegli P., pcat@jhmi.edu) Harry Feinstone Department of Molecular 
Microbiology and Immunology, Bloomberg School of Public Health, Johns 
Hopkins University, Baltimore, United States.
CORRESPONDENCE ADDRESS
  P. Caturegli, Department of Pathology, Johns Hopkins University School of 
Medicine, Baltimore, United States. Email: pcat@jhmi.edu
SOURCE
  Thyroid (2016) 26:8 (1117-1124). Date of Publication: 1 Aug 2016
ISSN
  1557-9077 (electronic)
  1050-7256
BOOK PUBLISHER
  Mary Ann Liebert Inc., info@liebertpub.com
ABSTRACT
  Background: Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a 
negative regulator of immune responses that suppresses the activity of 
effector T cells and contributes to the maintenance of self tolerance. When 
blocked therapeutically, CTLA-4 leads to an overall activation of T cells 
that has been exploited for cancer control, a control associated however 
with a variety of immune-related side effects such as autoimmune 
thyroiditis. To investigate the mechanism(s) underlying this form of 
thyroiditis, we used the NOD-H2(h4) mouse, a model that develops thyroiditis 
at very high incidence after addition of iodine to the drinking water. 
Methods: NOD-H2(h4) mice were started on drinking water supplemented with 
0.05% sodium iodide when 8 weeks old and then injected with a hamster 
monoclonal antibody against mouse CTLA-4, polyclonal hamster 
immunoglobulins, or phosphate buffered saline when 11 weeks old. One month 
later (15 weeks of age), mice were sacrificed to assess thyroiditis, general 
immune responses in blood and spleen, and expression of indoleamine 2, 
3-dioxygenase (IDO) in the thyroid and in isolated antigen-presenting cells 
after stimulation with interferon gamma. The study also analyzed IDO 
expression in four autopsy cases of metastatic melanoma who had received 
treatment with a CTLA-4 blocking antibody, and six surgical pathology 
Hashimoto thyroiditis controls. Results: CTLA-4 blockade worsened autoimmune 
thyroiditis, as assessed by a greater incidence, a more aggressive 
mononuclear cell infiltration in thyroids, and higher thyroglobulin antibody 
levels when compared to the control groups. CTLA-4 blockade also expanded 
the proportion of splenic CD4+ effector T cells, as well as the production 
of interleukin (IL)-2, interferon gamma, IL-10, and IL-13 cytokines. 
Interestingly, CTLA-4 blockade induced a strong expression of IDO in mouse 
and human thyroid glands, an expression that could represent a 
counter-regulatory mechanism to protect against the inflammatory 
environment. Conclusions: This study shows that CTLA-4 blockade exacerbates 
the iodine-accelerated form of thyroiditis typical of the NOD-H2(h4) mouse. 
The study could also have implications for cancer patients who develop 
thyroiditis as an immune-related adverse event after CTLA-4 blockade.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  gamma interferon (endogenous compound)
  indoleamine 2,3 dioxygenase (endogenous compound)
EMTREE DRUG INDEX TERMS
  drinking water
  interleukin 10 (endogenous compound)
  interleukin 13 (endogenous compound)
  interleukin 2 (endogenous compound)
  iodine
  ipilimumab (drug therapy)
  phosphate buffered saline
  thyroglobulin antibody
  ticilimumab (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune thyroiditis
  disease exacerbation
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  animal cell
  animal experiment
  animal model
  antigen presenting cell
  article
  autopsy
  blood
  cell infiltration
  cell isolation
  controlled study
  cytokine production
  dendritic cell
  disease severity
  female
  Hashimoto disease
  human
  human tissue
  immune response
  incidence
  male
  metastatic melanoma (drug therapy)
  middle aged
  mononuclear cell
  morbidity
  mouse
  natural killer cell
  nonhuman
  peritoneum macrophage
  priority journal
  protein expression
  regulatory mechanism
  spleen
  T lymphocyte
  thyroid gland
DRUG MANUFACTURERS
  Astra Zeneca
  Bristol
  Meyer
  Squibb
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
  indoleamine 2,3 dioxygenase ()
  interleukin 13 (148157-34-0)
  interleukin 2 (85898-30-2)
  iodine (7553-56-2)
  ipilimumab (477202-00-9)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160588644
MEDLINE PMID
  27296629 (http://www.ncbi.nlm.nih.gov/pubmed/27296629)
PUI
  L611613487
DOI
  10.1089/thy.2016.0092
FULL TEXT LINK
  http://dx.doi.org/10.1089/thy.2016.0092
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 160
TITLE
  Pituitary Dysfunction: A Case Series of Immune Checkpoint Inhibitor–Related 
Hypophysitis in an Emergency Department
AUTHOR NAMES
  Miller A.H.
  Brock P.
  Jim Yeung S.-C.
AUTHOR ADDRESSES
  (Miller A.H.; Brock P.; Jim Yeung S.-C.) Department of Emergency Medicine, 
University of Texas MD Anderson Cancer Center, Houston, United States.
SOURCE
  Annals of Emergency Medicine (2016) 68:2 (249-250). Date of Publication: 1 
Aug 2016
ISSN
  1097-6760 (electronic)
  0196-0644
BOOK PUBLISHER
  Mosby Inc., customerservice@mosby.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug therapy)
  immune checkpoint inhibitor (drug therapy)
  immunomodulating agent (drug therapy)
EMTREE DRUG INDEX TERMS
  glucocorticoid (drug therapy)
  hydrocortisone sodium succinate (drug therapy, intravenous drug 
administration)
  ipilimumab (adverse drug reaction)
  prolactin (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency
  blood pressure regulation
  cancer chemotherapy
  drug megadose
  emergency physician
  emergency ward
  human
  hyponatremia
  hypopituitarism
  hypothyroidism
  letter
  nuclear magnetic resonance imaging
  priority journal
  prolactin blood level
CAS REGISTRY NUMBERS
  hydrocortisone sodium succinate (125-04-2, 2203-97-6)
  ipilimumab (477202-00-9)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20160874514
MEDLINE PMID
  27451306 (http://www.ncbi.nlm.nih.gov/pubmed/27451306)
PUI
  L613479098
DOI
  10.1016/j.annemergmed.2016.03.048
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.annemergmed.2016.03.048
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 161
TITLE
  Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate 
cancer
AUTHOR NAMES
  Graff J.N.
  Alumkal J.J.
  Drake C.G.
  Thomas G.V.
  Redmond W.L.
  Farhad M.
  Cetnar J.P.
  Ey F.S.
  Bergan R.C.
  Slottke R.
  Beer T.M.
AUTHOR ADDRESSES
  (Graff J.N., graffj@ohsu.edu; Alumkal J.J.; Cetnar J.P.; Ey F.S.; Bergan 
R.C.; Slottke R.; Beer T.M.) Division of Hematology/Oncology, Knight Cancer 
Institute, Oregon Health and Science University, Portland, United States.
(Graff J.N., graffj@ohsu.edu) VA Portland Health Care System, Portland, 
United States.
(Drake C.G.) Sidney Kimmel Comprehensive Cancer Center and the Brady 
Urological Institute, Johns Hopkins University School of Medicine, 
Baltimore, United States.
(Thomas G.V.) Pathology and Laboratory Medicine, Oregon Health and Science 
University, Portland, United States.
(Redmond W.L.; Farhad M.) Robert W. Franz Cancer Research Center, Earle A. 
Chiles Research Institute, Providence Portland Medical Center, Portland, 
United States.
(Farhad M.) Cell, Developmental, Cancer Biology Department, Oregon Health 
and Science University, Portland, United States.
CORRESPONDENCE ADDRESS
  J.N. Graff, Division of Hematology/Oncology, Knight Cancer Institute, Oregon 
Health and Science University, Portland, United States. Email: 
graffj@ohsu.edu
SOURCE
  Oncotarget (2016) 7:33 (52810-52817). Date of Publication: 1 Aug 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  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 
immunerelated 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy, intravenous drug administration)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  CD163 antigen (endogenous compound)
  CD3 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  creatine kinase (endogenous compound)
  enzalutamide (drug combination, drug therapy, oral drug administration)
  programmed death 1 ligand 1 (endogenous compound)
  prostate specific antigen (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  castration resistant prostate cancer (drug therapy, drug resistance, drug 
therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  accidental injury (side effect)
  aged
  anorexia (side effect)
  arthralgia (side effect)
  article
  body weight loss
  bone pain (side effect)
  cell infiltration
  cheilitis (side effect)
  clinical article
  confusion (side effect)
  constipation (side effect)
  diarrhea (side effect)
  drug efficacy
  drug response
  drug safety
  drug withdrawal
  dysphagia (side effect)
  dyspnea (side effect)
  fatigue (side effect)
  fracture (side effect)
  genetic analysis
  genital edema (side effect)
  hot flush (side effect)
  human
  human tissue
  hypothyroidism (side effect)
  immunohistochemistry
  insomnia (side effect)
  maculopapular rash (side effect)
  male
  microsatellite instability
  mucosa inflammation (side effect)
  multiple cycle treatment
  muscle weakness (side effect)
  myalgia (side effect)
  myelitis (side effect)
  myositis (side effect)
  nausea (side effect)
  pain (side effect)
  phase 2 clinical trial
  protein expression
  sensory neuropathy (side effect)
  side effect (side effect)
  tachycardia (side effect)
  treatment outcome
  tumor biopsy
  urinary tract infection (side effect)
  vertigo (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  creatine kinase (9001-15-4)
  enzalutamide (915087-33-1)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02312557)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160610667
MEDLINE PMID
  27429197 (http://www.ncbi.nlm.nih.gov/pubmed/27429197)
PUI
  L611764059
DOI
  10.18632/oncotarget.10547
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.10547
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 162
TITLE
  Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in 
combination
AUTHOR NAMES
  Boutros C.
  Tarhini A.
  Routier E.
  Lambotte O.
  Ladurie F.L.
  Carbonnel F.
  Izzeddine H.
  Marabelle A.
  Champiat S.
  Berdelou A.
  Lanoy E.
  Texier M.
  Libenciuc C.
  Eggermont A.M.M.
  Soria J.-C.
  Mateus C.
  Robert C.
AUTHOR ADDRESSES
  (Boutros C.; Routier E.; Libenciuc C.; Eggermont A.M.M.; Mateus C.; Robert 
C., caroline.robert@gustaveroussy.fr) Dermatology Service, Department of 
Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif, France.
(Tarhini A.) University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, United 
States.
(Lambotte O.) AP-HP, Internal Medicine Department, University Hospital of 
Bictre, 78 Rue du General Leclerc, Le Kremlin-Bicetre, France.
(Lambotte O.; Carbonnel F.; Eggermont A.M.M.; Soria J.-C.; Robert C., 
caroline.robert@gustaveroussy.fr) Paris Sud University, 63 Rue Gabriel Peri, 
Le Kremlin Bictre, France.
(Lambotte O.) INSERM Unit U1184, 63 Rue Gabriel Peri, Le Kremlin Bictre, 
France.
(Ladurie F.L.) Thoracic and Vascular Surgery Service, Centre Chirurgical 
Marie Lannelongue, 133 Avenue de la Resistance, Le Plessis-Robinson, France.
(Carbonnel F.) Department of Gastroenterology, University Hospital of 
Bictre, Paris Sud University, 78 Rue du General Leclerc, Le Kremlin-Bicetre, 
France.
(Izzeddine H.) Department of Nephrology, Pitié-Salptrire Hospital, 4783 
Boulevard de l'hopital, Paris, France.
(Marabelle A.; Soria J.-C.) Drug Development Department (DITEP), Gustave 
Roussy, 114 Rue Edouard Vaillant, Villejuif, France.
(Champiat S.; Soria J.-C.; Robert C., caroline.robert@gustaveroussy.fr) 
INSERM Unit U981, 114 Rue Edouard Vaillant, Villejuif, France.
(Berdelou A.) Department of Nuclear Medicine and Endocrine Oncology, Gustave 
Roussy, 114 Rue Edouard Vaillant, Villejuif, France.
(Lanoy E.; Texier M.) Biostatistic and Epidemiology Unit, Gustave Roussy, 
114 Rue Edouard Vaillant, Villejuif, France.
CORRESPONDENCE ADDRESS
  C. Robert, Dermatology Service, Department of Medicine, Gustave Roussy, 114 
Rue Edouard Vaillant, Villejuif, France. Email: 
caroline.robert@gustaveroussy.fr
SOURCE
  Nature Reviews Clinical Oncology (2016) 13:8 (473-486). Date of Publication: 
1 Aug 2016
ISSN
  1759-4782 (electronic)
  1759-4774
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction, drug 
combination, pharmacology)
  monoclonal antibody (adverse drug reaction, drug combination, pharmacology)
  programmed cell death 1 antibody (adverse drug reaction, drug combination, 
pharmacology)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  ipilimumab (adverse drug reaction, pharmacology)
  nivolumab (adverse drug reaction, pharmacology)
  pembrolizumab (adverse drug reaction, pharmacology)
  programmed death 1 receptor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug safety
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult respiratory distress syndrome (side effect)
  aseptic meningitis (side effect)
  autoimmune disease (side effect)
  autoimmune hepatitis (side effect)
  cancer combination chemotherapy
  central nervous system disease (side effect)
  colitis (side effect)
  cytopenia (side effect)
  diarrhea (side effect)
  digestive system perforation (side effect)
  drug eruption (side effect)
  drug fatality (side effect)
  drug mechanism
  endocrine disease (side effect)
  enterocolitis (side effect)
  eosinophilia (side effect)
  eye toxicity (side effect)
  fatigue (side effect)
  fever (side effect)
  gastritis (side effect)
  gastrointestinal disease
  gastrointestinal toxicity (side effect)
  Guillain Barre syndrome (side effect)
  hemophilia A (side effect)
  human
  hyperthyroidism (side effect)
  hyponatremia (side effect)
  hypophysitis (side effect)
  hypopituitarism (side effect)
  hypothyroidism (side effect)
  infusion related reaction (side effect)
  kidney failure (side effect)
  liver toxicity (side effect)
  lung alveolitis (side effect)
  lung granulomatosis (side effect)
  lung toxicity (side effect)
  maculopapular rash (side effect)
  molecularly targeted therapy
  monotherapy
  musculoskeletal disease (side effect)
  myalgia (side effect)
  nausea (side effect)
  neuritis (side effect)
  nonhuman
  pancreatitis (side effect)
  pneumonia (side effect)
  polymyositis (side effect)
  practice guideline
  priority journal
  pruritus (side effect)
  rash (side effect)
  review
  risk benefit analysis
  sarcoidosis (side effect)
  side effect (side effect)
  skin disease (side effect)
  skin toxicity (side effect)
  skin ulcer (side effect)
  thyroiditis (side effect)
  thyrotoxicosis (side effect)
  toxic hepatitis (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160353407
MEDLINE PMID
  27141885 (http://www.ncbi.nlm.nih.gov/pubmed/27141885)
PUI
  L610260014
DOI
  10.1038/nrclinonc.2016.58
FULL TEXT LINK
  http://dx.doi.org/10.1038/nrclinonc.2016.58
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 163
TITLE
  Targeting suppressive myeloid cells potentiates checkpoint inhibitors to 
control spontaneous neuroblastoma
AUTHOR NAMES
  Mao Y.
  Eissler N.
  Blanc K.L.
  Johnsen J.I.
  Kogner P.
  Kiessling R.
AUTHOR ADDRESSES
  (Mao Y., Yumeng.Mao@ki.se; Kiessling R., Rolf.Kiessling@ki.se) Department of 
Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, CCK 
R8:01, KS Ringen, R8:01, Stockholm, Sweden.
(Eissler N.; Johnsen J.I.; Kogner P.) Childhood Cancer Research Unit, 
Department of Women's and Children's Health, Karolinska Institutet, Astrid 
Lindgren Children's Hospital, Stockholm, Sweden.
(Blanc K.L.) Department of Medicine, Karolinska Institutet, Hematology 
Centre, Karolinska University Hospital, Stockholm, Sweden.
CORRESPONDENCE ADDRESS
  R. Kiessling, Department of Oncology-Pathology, Cancer Center Karolinska, 
Karolinska Institutet, CCK R8:01, KS Ringen, R8:01, Stockholm, Sweden. 
Email: Rolf.Kiessling@ki.se
SOURCE
  Clinical Cancer Research (2016) 22:15 (3849-3859). Date of Publication: 1 
Aug 2016
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  Purpose: Neuroblastoma is the most common extracranial solid cancer type in 
childhood, and high-risk patients have poor prognosis despite aggressive 
multimodal treatment. Neuroblastoma-driven inflammation contributes to the 
induction of suppressive myeloid cells that hamper efficient antitumor 
immune responses. Therefore, we sought to enhance antitumor immunity by 
removing immunosuppression mediated by myeloid cells. Experimental Design: 
The prognostic values of myeloid cells are demonstrated by analyzing genomic 
datasets of neuroblastoma patients. The impact of tumor-derived factors on 
myelopoiesis and local induction of suppressive myeloid cells is dissected 
by in vitro culture models using freshly isolated human CD34(+) 
hematopoietic stem cells, primary human monocytes, and murine bone marrow 
cells. To test the therapeutic efficacy of BLZ945 as a monotherapy or in 
combination with checkpoint inhibitors, we used a transgenic murine model 
(TH-MYCN) that develops aggressive spontaneous neuroblastoma. Results: We 
report that infiltrating CSF-1R(+) myeloid cells predict poor clinical 
outcome in patients with neuroblastoma. In vitro, neuroblastoma-derived 
factors interfere with early development of myeloid cells and enable 
suppressive functions on human monocytes through M-CSF/CSF-1R interaction. 
In a transgenic mouse model (TH-MYCN) resembling high-risk human 
neuroblastoma, antagonizing CSF-1R with a selective inhibitor (BLZ945) 
modulates the induction of human and murine suppressive myeloid cells and 
efficiently limit tumor progression. While checkpoint inhibitors are 
insufficient in controlling tumor growth, combining BLZ945 with PD-1/PD-L1 
blocking antibodies results in superior tumor control. Conclusions: Our 
results demonstrate the essential role of CSF-1R signaling during the 
induction of suppressive myeloid cells and emphasize its clinical potential 
as an immunotherapy for human cancers.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  blz 945 (drug combination, drug therapy, oral drug administration, 
pharmacology)
  checkpoint inhibitor (drug combination, drug therapy)
  programmed death 1 ligand 1 antibody (drug combination, drug therapy, 
intraperitoneal drug administration)
  programmed death 1 receptor antibody (drug combination, drug therapy, 
intraperitoneal drug administration)
  protein antibody (drug combination, drug therapy)
  protein tyrosine kinase inhibitor (drug combination, drug therapy, 
pharmacology)
EMTREE DRUG INDEX TERMS
  colony stimulating factor 1 (endogenous compound)
  cytokine (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  bone marrow cell
  neuroblastoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal tissue
  antineoplastic activity
  article
  cancer control
  cancer growth
  cell differentiation
  cell isolation
  controlled study
  drug efficacy
  flow cytometry
  hematopoietic stem cell
  human
  human cell
  in vitro study
  monocyte
  monotherapy
  mouse
  myelopoiesis
  neuroblastoma cell line
  nonhuman
  priority journal
  prognosis
  protein interaction
  T lymphocyte
  transgenic mouse
DRUG TRADE NAMES
  blz 945  Novartis

DRUG MANUFACTURERS
  BioXCell
  Novartis
CAS REGISTRY NUMBERS
  colony stimulating factor 1 (81627-83-0)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160574257
MEDLINE PMID
  26957560 (http://www.ncbi.nlm.nih.gov/pubmed/26957560)
PUI
  L611502999
DOI
  10.1158/1078-0432.CCR-15-1912
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-15-1912
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 164
TITLE
  Immune checkpoint inhibitors: A new opportunity in the treatment of ovarian 
cancer?
AUTHOR NAMES
  Mittica G.
  Genta S.
  Aglietta M.
  Valabrega G.
AUTHOR ADDRESSES
  (Mittica G., gloria.mittica@ircc.it; Genta S., sofia.genta@ircc.it; Aglietta 
M., massimo.aglietta@ircc.it; Valabrega G., giorgio.valabrega@ircc.it) 
Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin, Italy.
(Mittica G., gloria.mittica@ircc.it; Genta S., sofia.genta@ircc.it; Aglietta 
M., massimo.aglietta@ircc.it; Valabrega G., giorgio.valabrega@ircc.it) 
Department of Oncology, University of Torino, Turin, Italy.
CORRESPONDENCE ADDRESS
  G. Valabrega, Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin, Italy. 
Email: giorgio.valabrega@ircc.it
SOURCE
  International Journal of Molecular Sciences (2016) 17:7 Article Number: 
1169. Date of Publication: 20 Jul 2016
ISSN
  1422-0067 (electronic)
  1661-6596
BOOK PUBLISHER
  MDPI AG, Postfach, Basel, Switzerland.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immune checkpoint inhibitor (endogenous compound)
  peptides and proteins (endogenous compound)
EMTREE DRUG INDEX TERMS
  avelumab (adverse drug reaction, drug therapy)
  bms 936559 (adverse drug reaction)
  gamma interferon (endogenous compound)
  granulocyte macrophage colony stimulating factor
  ipilimumab (adverse drug reaction)
  nivolumab (adverse drug reaction)
  pembrolizumab (adverse drug reaction)
  programmed death 1 ligand 1 antibody (endogenous compound)
  programmed death 1 ligand 2 antibody (endogenous compound)
  programmed death 1 receptor antibody
  T lymphocyte associated protein 4 (endogenous compound)
  T lymphocyte receptor (endogenous compound)
  ticilimumab (adverse drug reaction)
  tumor antigen (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  anemia (side effect)
  arthralgia (side effect)
  cancer cell
  cancer chemotherapy
  cancer prognosis
  cancer recurrence
  cancer survival
  decreased appetite (side effect)
  diarrhea (side effect)
  fatigue
  fever (side effect)
  headache (side effect)
  heart arrhythmia (side effect)
  human
  hypertransaminasemia (side effect)
  hypothyroidism (side effect)
  immune system
  infusion related reaction (side effect)
  lymphocytopenia (side effect)
  nausea (side effect)
  ovary carcinoma
  overall survival
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  protein expression
  rash (side effect)
  review
  tumor microenvironment
CAS REGISTRY NUMBERS
  avelumab (1537032-82-8)
  gamma interferon (82115-62-6)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160548250
MEDLINE PMID
  27447625 (http://www.ncbi.nlm.nih.gov/pubmed/27447625)
PUI
  L611290680
DOI
  10.3390/ijms17071169
FULL TEXT LINK
  http://dx.doi.org/10.3390/ijms17071169
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 165
TITLE
  Meta-analysis of immune-related adverse events of ipilimumab for advanced 
malignant tumors
AUTHOR NAMES
  Xia T.-Y.
  Chen C.
  Ren Q.-L.
AUTHOR ADDRESSES
  (Xia T.-Y., 442992416@qq.com) Department of Oncology, The People's Hospital 
of Dazu District, Chongqing, China.
(Chen C.; Ren Q.-L., renqlwu@yahoo.com.cn) Department of Oncology, The First 
Affiliated Hospital of Chongqing Medical University, Chongqing, China.
CORRESPONDENCE ADDRESS
  Q.-L. Ren, Department of Oncology, The First Affiliated Hospital of 
Chongqing Medical University, Chongqing, China. Email: renqlwu@yahoo.com.cn
SOURCE
  Chinese Journal of New Drugs (2016) 25:13 (1555-1560). Date of Publication: 
15 Jul 2016
ISSN
  1003-3734
BOOK PUBLISHER
  Chinese Journal of New Drugs Co. Ltd.
ABSTRACT
  Objective: To evaluate the immune-related adverse events of ipilimumab for 
advanced malignant tumors by meta-analysis. Methods: Databases including 
Pubmed, Cochrane Library, EMBase, ClinicalTrials.gov databases, Wanfang, 
CNKI, and VIP were searched. Randomized controlled trials (RCTs) focusing on 
ipilimumab for advanced malignant tumors were collected. All the literatures 
retrieved were screened according to the inclusion and exclusion criteria. 
The software RevMan 5.3 was used for meta-analysis. Results:Four RCTs with 2 
different types of malignancies and 2 875 patients were included in this 
meta-analysis. The results of meta-analysis suggested that the 
immune-related cutaneous and gastrointestinal side-effects showed 
significant differences between the 2 groups in pruritus (RR=3.57, 95% 
CI:2.40~5.33, P<0.000 01), rash (RR=3.63, 95% CI:2.90~4.55, P<0.000 01), 
diarrhea (RR=2.45, 95% CI:2.12~2.84, P<0.000 01), colitis (RR=11.42, 95% 
CI:6.13~21.28, P<0.000 01). However, there were no significant differences 
in increase of aminopherase and endocrine-related adverse events [alanine 
aminotransferase (RR=2.22, 95% CI:0.59~8.34, P=0.24), aspartate 
aminotransferase (RR=2.37, 95% CI:0.58~9.66, P=0.23), hypothyroidism 
(RR=4.70, 95% CI:0.98~22.39, P=0.05), hypophysitis (RR=13.32, 95% CI: 
0.76~233.37, P=0.08), hypoadrenocorticism (RR=2.98, 95% CI:0.73~12.11, 
P=0.13)]. Conclusion:Ipilimumab is associated with a significantly increased 
risk of immune-related cutaneous and gastrointestinal side-effects in 
malignant tumor sufferers, without raising risk of elevation of aminopherase 
and incidence of endocrine-related adverse events.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  malignant neoplasm (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal disease (side effect)
  article
  colitis (side effect)
  data base
  diarrhea (side effect)
  human
  hypoadrenocorticism (side effect)
  hypoadrenocorticism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  meta analysis
  pruritus (side effect)
  randomized controlled trial (topic)
  rash (side effect)
  side effect (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Chinese
LANGUAGE OF SUMMARY
  English, Chinese
EMBASE ACCESSION NUMBER
  20160554982
PUI
  L611387499
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 166
TITLE
  Endocrinological side-effects of immune checkpoint inhibitors
AUTHOR NAMES
  Torino F.
  Corsello S.M.
  Salvatori R.
AUTHOR ADDRESSES
  (Torino F.) Department of Systems Medicine, Chr. of Medical Oncology, Tor 
Vergata University of Rome, Italy.
(Corsello S.M.) Endocrinology Unit, Catholic University of Sacred Heart, 
Rome, Italy.
(Salvatori R., salvator@jhmi.edu) Division of Endocrinology and Metabolism 
and Pituitary Center, Johns Hopkins University, 1830 East Monument Street, 
#333, Baltimore, United States.
CORRESPONDENCE ADDRESS
  R. Salvatori, Division of Endocrinology and Metabolism and Pituitary Center, 
Johns Hopkins University, 1830 East Monument Street, #333, Baltimore, United 
States. Email: salvator@jhmi.edu
SOURCE
  Current Opinion in Oncology (2016) 28:4 (278-287). Date of Publication: 1 
Jul 2016
ISSN
  1531-703X (electronic)
  1040-8746
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction)
  immune checkpoint inhibitor (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  hormones and agents acting on the endocrine system (drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease (drug therapy, side effect, drug therapy, etiology, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adrenal disease (drug therapy, side effect)
  clinical trial (topic)
  diabetic ketoacidosis (side effect)
  human
  hypophysitis (drug therapy, side effect)
  incidence
  insulin dependent diabetes mellitus (side effect)
  nonhuman
  pathophysiology
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  practice guideline
  priority journal
  review
  thyroid disease (drug therapy, side effect)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160343436
MEDLINE PMID
  27136136 (http://www.ncbi.nlm.nih.gov/pubmed/27136136)
PUI
  L610202292
DOI
  10.1097/CCO.0000000000000293
FULL TEXT LINK
  http://dx.doi.org/10.1097/CCO.0000000000000293
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 167
TITLE
  Management of side effects of immune checkpoint blockade by anti-CTLA-4 and 
anti-PD-1 antibodies in metastatic melanoma
AUTHOR NAMES
  Kähler K.C.
  Hassel J.C.
  Heinzerling L.
  Loquai C.
  Mössner R.
  Ugurel S.
  Zimmer L.
  Gutzmer R.
AUTHOR ADDRESSES
  (Kähler K.C., kkaehler@dermatology.uni-kiel.de) Department of Dermatology, 
Venereology, and Allergology, University Hospital Schleswig-Holstein, Campus 
Kiel, Kiel, Germany.
(Hassel J.C.) Department of Dermatology, and National Cancer Center, 
University Hospital Heidelberg, Heidelberg, Germany.
(Heinzerling L.) Department of Dermatology, University Hospital Erlangen, 
Erlangen, Germany.
(Loquai C.) Department of Dermatology, Medical Faculty, University of Mainz, 
Mainz, Germany.
(Mössner R.) Department of Dermatology, Venereology, and Allergology, 
University Medicine Göttingen, Göttingen, Germany.
(Ugurel S.; Zimmer L.) Department of Dermatology, Venereology and 
Allergology, University Hospital Essen, Essen, Germany.
(Gutzmer R.) Hanover Skin Cancer Center, Department of Dermatology, 
Venereology, and Allergology, Hanover Medical College, Hanover, Germany.
CORRESPONDENCE ADDRESS
  K.C. Kähler, Department of Dermatology, Venereology, and Allergology, 
University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Email: 
kkaehler@dermatology.uni-kiel.de
SOURCE
  JDDG - Journal of the German Society of Dermatology (2016) 14:7 (662-681). 
Date of Publication: 1 Jul 2016
ISSN
  1610-0387 (electronic)
  1610-0379
BOOK PUBLISHER
  Wiley-VCH Verlag, info@wiley-vch.de
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
  nivolumab (adverse drug reaction, drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  bilirubin (endogenous compound)
  C reactive protein (endogenous compound)
  calcium (endogenous compound)
  calgranulin (endogenous compound)
  creatinine (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody (endogenous compound)
  gamma glutamyltransferase (endogenous compound)
  hydrocortisone (endogenous compound)
  lactate dehydrogenase (endogenous compound)
  potassium (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  sodium (endogenous compound)
  thyrotropin (endogenous compound)
  urea (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction
  managed care
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  arthralgia (side effect)
  article
  blood analysis
  blood cell count
  cancer immunotherapy
  cardiomyopathy (side effect)
  checklist
  clinical practice
  clinical trial (topic)
  colitis (side effect)
  cytokine release syndrome (side effect)
  dermatomyositis (side effect)
  diabetic ketoacidosis (side effect)
  diarrhea (side effect)
  drug dose regimen
  drug effect
  drug eruption (side effect)
  drug mechanism
  endocrine ophthalmopathy (side effect)
  episcleritis (side effect)
  fatigue (side effect)
  giant cell arteritis (side effect)
  hematologic disease (side effect)
  hepatitis (side effect)
  human
  hypophysitis (side effect)
  hypothyroidism (side effect)
  immune response
  insulin dependent diabetes mellitus (side effect)
  kidney disease (side effect)
  liver toxicity (side effect)
  lung disease (side effect)
  maculopapular rash (side effect)
  medical history
  meta analysis (topic)
  mucosa
  neurologic disease (side effect)
  pancreas disease (side effect)
  pneumonia (side effect)
  pruritus (side effect)
  rash (side effect)
  rheumatic polymyalgia (side effect)
  side effect (side effect)
  subretinal neovascularization (side effect)
  T lymphocyte
  treatment duration
  uveitis (side effect)
  vasculitis (side effect)
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  bilirubin (18422-02-1, 635-65-4)
  C reactive protein (9007-41-4)
  calcium (7440-70-2, 14092-94-5)
  creatinine (19230-81-0, 60-27-5)
  gamma glutamyltransferase (85876-02-4)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  lactate dehydrogenase (9001-60-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  potassium (7440-09-7)
  sodium (7440-23-5)
  thyrotropin (9002-71-5)
  urea (57-13-6)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160519174
MEDLINE PMID
  27373241 (http://www.ncbi.nlm.nih.gov/pubmed/27373241)
PUI
  L611205798
DOI
  10.1111/ddg.13047
FULL TEXT LINK
  http://dx.doi.org/10.1111/ddg.13047
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 168
TITLE
  Immune checkpoint inhibition in ovarian cancer
AUTHOR NAMES
  Hamanishi J.
  Mandai M.
  Konishi I.
AUTHOR ADDRESSES
  (Hamanishi J., jnkhmns@kuhp.kyoto-u.ac.jp; Konishi I.) Department of 
Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 
Shogoinkawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan.
(Mandai M.) Department of Obstetrics and Gynecology, Kinki University, 
Higashiosaka, Osaka, Japan.
CORRESPONDENCE ADDRESS
  J. Hamanishi, Department of Gynecology and Obstetrics, Kyoto University 
Graduate School of Medicine, 54 Shogoinkawahara-cho, Shogoin, Sakyo-ku, 
Kyoto, Japan. Email: jnkhmns@kuhp.kyoto-u.ac.jp
SOURCE
  International Immunology (2016) 28:7 (339-348). Date of Publication: 1 Jul 
2016
ISSN
  1460-2377 (electronic)
  0953-8178
BOOK PUBLISHER
  Oxford University Press, jnl.info@oup.co.uk
ABSTRACT
  Recent studies have shown that tumor cells acquire escape mechanisms to 
evade host immunity in the tumor microenvironment. Two key immune checkpoint 
pathways mediated by immunosuppressive co-signaling, the first via 
programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-1/PD-L1) and the second 
via CTLA-4 and B7 (CTLA-4/B7), have been previously described. Several 
clinical trials have revealed an outstanding anti-tumor efficacy of immune 
checkpoint inhibitors (anti-CTLA-4 antibody, anti-PD-1 antibody and/or 
anti-PD-L1 antibody) in patients with various types of solid malignancies, 
including non-small cell lung cancer, melanoma, renal cell cancer and 
ovarian cancer. In this review, we examine pre-clinical studies that 
described the local immune status and immune checkpoint signals in ovarian 
cancer, highlight recent clinical trials that evaluated immune checkpoint 
inhibitors against ovarian cancer and discuss the clinical issues regarding 
immune checkpoint inhibitors.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug therapy, pharmacology)
  immune checkpoint inhibitor (drug therapy, pharmacology)
EMTREE DRUG INDEX TERMS
  avelumab
  bms 936559
  cancer vaccine
  CD3 antigen
  cytotoxic T lymphocyte antigen 4 antibody
  granulocyte macrophage colony stimulating factor
  ipilimumab
  pembrolizumab
  programmed death 1 ligand 1
  ticilimumab
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  immune status
  ovary cancer (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  cancer chemotherapy
  disease course
  drug efficacy
  drug tolerability
  female
  human
  immune response
  nonhuman
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  protein expression
  response evaluation criteria in solid tumors
  signal transduction
  survival rate
  T lymphocyte
  T lymphocyte activation
  treatment response
  tumor associated leukocyte
  upregulation
DRUG TRADE NAMES
  bms 936558
  bms 936559
  mdx 1106
  msb 0010718c
CAS REGISTRY NUMBERS
  avelumab (1537032-82-8)
  ipilimumab (477202-00-9)
  pembrolizumab (1374853-91-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00729664)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160501539
MEDLINE PMID
  27055470 (http://www.ncbi.nlm.nih.gov/pubmed/27055470)
PUI
  L611124254
DOI
  10.1093/intimm/dxw020
FULL TEXT LINK
  http://dx.doi.org/10.1093/intimm/dxw020
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 169
TITLE
  Immune checkpoint inhibitors: Review and management of endocrine adverse 
events
AUTHOR NAMES
  González-Rodríguez E.
  Rodríguez-Abreu D.
AUTHOR ADDRESSES
  (González-Rodríguez E., elisaglezrguez@gmail.com) Section of Endocrinology 
and Nutrition, Hospital Universitario de Gran Canaria Doctor Negrín, Las 
Palmas de Gran Canaria, Spain.
(Rodríguez-Abreu D.) Section of Medical Oncology, Hospital Universitario 
Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain.
()
CORRESPONDENCE ADDRESS
  E. González-Rodríguez, Section of Endocrinology and Nutrition, Hospital 
Universitario de Gran Canaria Doctor Negrín, Barranco de La Ballena S/N, Las 
Palmas de Gran Canaria, Spain. Email: elisaglezrguez@gmail.com
SOURCE
  Oncologist (2016) 21:7 (804-816). Date of Publication: 1 Jul 2016
ISSN
  1549-490X (electronic)
  1083-7159
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  checkpoint kinase inhibitor
EMTREE DRUG INDEX TERMS
  atezolizumab (adverse drug reaction)
  avelumab (adverse drug reaction)
  corticotropin (endogenous compound)
  cytotoxic T lymphocyte antigen 4
  durvalumab (adverse drug reaction)
  estradiol (endogenous compound)
  follitropin (endogenous compound)
  hydrocortisone (endogenous compound)
  intermedin (endogenous compound)
  ipilimumab (adverse drug reaction)
  luteinizing hormone (endogenous compound)
  nivolumab (adverse drug reaction)
  pembrolizumab (adverse drug reaction)
  pidilizumab (adverse drug reaction)
  programmed death 1 receptor (endogenous compound)
  prolactin (endogenous compound)
  proopiomelanocortin (endogenous compound)
  testosterone (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
  ticilimumab (adverse drug reaction)
  tyrosinase related protein 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug induced disease
  endocrine disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  cancer survival
  cell activation
  cell proliferation
  circadian rhythm
  clinical trial (topic)
  diabetes mellitus
  eye disease
  free liothyronine index
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  immune response
  immunotherapy
  metastatic melanoma
  priority journal
  protein expression
  review
  thyroid disease
  thyroiditis (side effect)
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  avelumab (1537032-82-8)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  durvalumab (1428935-60-7)
  estradiol (50-28-2)
  follitropin (9002-68-0)
  hydrocortisone (50-23-7)
  intermedin (9002-79-3, 9046-72-4)
  ipilimumab (477202-00-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  pidilizumab (1036730-42-3)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
  proopiomelanocortin (66796-54-1)
  testosterone (58-22-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160535545
MEDLINE PMID
  27306911 (http://www.ncbi.nlm.nih.gov/pubmed/27306911)
PUI
  L611220417
DOI
  10.1634/theoncologist.2015-0509
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2015-0509
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 170
TITLE
  Late-onset panhypopituitarism in a 72-year-old male patient treated with 
ipilimumab for metastatic melanoma: a case report
AUTHOR NAMES
  Vancieri G.
  Bellia A.
  Lauro D.
AUTHOR ADDRESSES
  (Vancieri G.; Bellia A.; Lauro D., d.lauro@med.uniroma2.it) Division of 
Endocrinology and Diabetology, Department of Systems Medicine, University of 
Rome “Tor Vergata”, Rome, Italy.
CORRESPONDENCE ADDRESS
  D. Lauro, Division of Endocrinology and Diabetology, Department of Systems 
Medicine, University of Rome “Tor Vergata”, Rome, Italy. Email: 
d.lauro@med.uniroma2.it
SOURCE
  Journal of Endocrinological Investigation (2016) 39:7 (805-806). Date of 
Publication: 1 Jul 2016
ISSN
  1720-8386 (electronic)
  0391-4097
BOOK PUBLISHER
  Springer International Publishing
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  cortisone acetate (drug therapy)
  dipeptidyl carboxypeptidase inhibitor
  hydrochlorothiazide
  hydrocortisone (endogenous compound)
  levothyroxine (drug therapy)
  luteinizing hormone (endogenous compound)
  prolactin (endogenous compound)
  somatomedin C (endogenous compound)
  testosterone (endogenous compound)
  testosterone enantate (drug therapy)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune hypophysitis (side effect, side effect)
  hypopituitarism (drug therapy, side effect, drug therapy, side effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  antihypertensive therapy
  cancer immunotherapy
  case report
  computer assisted tomography
  corticotropin blood level
  electrocardiogram
  emergency ward
  fatigue
  hormone substitution
  human
  hydrocortisone blood level
  Italian (citizen)
  letter
  luteinizing hormone blood level
  male
  new-onset atrial fibrillation
  nuclear magnetic resonance imaging
  presyncope
  prolactin blood level
  testosterone blood level
  thyrotropin blood level
  thyroxine blood level
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  cortisone acetate (50-04-4)
  hydrochlorothiazide (58-93-5)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
  somatomedin C (67763-96-6)
  testosterone (58-22-0)
  testosterone enantate (315-37-7)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20160478209
MEDLINE PMID
  26883763 (http://www.ncbi.nlm.nih.gov/pubmed/26883763)
PUI
  L610967362
DOI
  10.1007/s40618-016-0439-3
FULL TEXT LINK
  http://dx.doi.org/10.1007/s40618-016-0439-3
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 171
TITLE
  Merkel Cell Carcinoma Therapeutic Update
AUTHOR NAMES
  Cassler N.M.
  Merrill D.
  Bichakjian C.K.
  Brownell I.
AUTHOR ADDRESSES
  (Cassler N.M.) Department of Dermatology, Walter Reed National Military 
Medical Center, Bethesda, United States.
(Merrill D.) University of Missouri-Kansas City School of Medicine, Kansas 
City, United States.
(Bichakjian C.K.) Department of Dermatology, University of Michigan Medical 
School, Ann Arbor, United States.
(Brownell I., Isaac.brownell@nih.gov) Dermatology Branch, National Cancer 
Institute, National Institutes of Health, 10 Center Drive, Bethesda, United 
States.
CORRESPONDENCE ADDRESS
  I. Brownell, Dermatology Branch, National Cancer Institute, National 
Institutes of Health, 10 Center Drive, Bethesda, United States. Email: 
Isaac.brownell@nih.gov
SOURCE
  Current Treatment Options in Oncology (2016) 17:7 Article Number: 36. Date 
of Publication: 1 Jul 2016
ISSN
  1534-6277 (electronic)
  1527-2729
BOOK PUBLISHER
  Springer New York LLC, barbara.b.bertram@gsk.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  angiopeptin (clinical trial, drug therapy)
  antineoplastic agent (adverse drug reaction, drug therapy)
  avelumab (clinical trial, drug therapy)
  cabozantinib (clinical trial, drug therapy, pharmacology)
  carboplatin (adverse drug reaction, drug combination, drug therapy)
  chromogranin A (endogenous compound)
  cisplatin (drug combination, drug therapy)
  cyclophosphamide (adverse drug reaction, drug combination, drug therapy)
  doxorubicin (adverse drug reaction, drug combination, drug therapy)
  durvalumab (clinical trial, drug combination, drug therapy)
  etoposide (adverse drug reaction, drug combination, drug therapy)
  idelalisib (drug therapy)
  imatinib (clinical trial, drug therapy)
  interleukin 12 (clinical trial, drug therapy, intratumoral drug 
administration)
  ipilimumab (clinical trial, drug therapy, pharmacology)
  mammalian target of rapamycin inhibitor
  octreotide (clinical trial, drug therapy)
  pasireotide (clinical trial, drug therapy)
  pazopanib (drug therapy)
  pembrolizumab (clinical trial, drug therapy)
  phosphatidylinositol 3 kinase (endogenous compound)
  platinum complex (drug combination, drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  protein kinase B (endogenous compound)
  protein tyrosine kinase inhibitor (pharmacology)
  sapanisertib (clinical trial, drug therapy)
  ticilimumab (clinical trial, drug combination, drug therapy)
  unindexed drug
  vincristine (adverse drug reaction, drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  merkel cell carcinoma (drug therapy, diagnosis, drug therapy, radiotherapy, 
surgery, therapy)
EMTREE MEDICAL INDEX TERMS
  adoptive transfer
  brachytherapy
  cancer immunotherapy
  cancer palliative therapy
  cancer radiotherapy
  cancer staging
  cancer surgery
  computer assisted tomography
  drug effect
  drug fatality (side effect)
  drug response
  drug targeting
  enzyme inhibition
  gene mutation
  histopathology
  human
  intensity modulated radiation therapy
  Merkel cell polyomavirus
  molecularly targeted therapy
  nonhuman
  personalized medicine
  positron emission tomography
  review
  sentinel lymph node biopsy
  skin surgery
  unspecified side effect (side effect)
DRUG TRADE NAMES
  mln 0128
CAS REGISTRY NUMBERS
  angiopeptin (113294-82-9)
  avelumab (1537032-82-8)
  cabozantinib (942407-59-2, 1140909-48-3, 849217-68-1)
  carboplatin (41575-94-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  cyclophosphamide (50-18-0)
  doxorubicin (23214-92-8, 25316-40-9)
  durvalumab (1428935-60-7)
  etoposide (33419-42-0)
  idelalisib (1146702-54-6, 870281-82-6)
  imatinib (152459-95-5, 220127-57-1)
  interleukin 12 (138415-13-1)
  ipilimumab (477202-00-9)
  octreotide (83150-76-9, 1607842-55-6)
  pasireotide (396091-73-9)
  pazopanib (444731-52-6, 635702-64-6)
  pembrolizumab (1374853-91-4)
  phosphatidylinositol 3 kinase (115926-52-8)
  protein kinase B (148640-14-6)
  sapanisertib (1224844-38-5)
  ticilimumab (745013-59-6)
  vincristine (57-22-7)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Human Genetics (22)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160478039
MEDLINE PMID
  27262710 (http://www.ncbi.nlm.nih.gov/pubmed/27262710)
PUI
  L610904699
DOI
  10.1007/s11864-016-0409-1
FULL TEXT LINK
  http://dx.doi.org/10.1007/s11864-016-0409-1
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 172
TITLE
  Erratum: Correction to Lancet Oncol 2016; 17: 888, 890, 892 (The Lancet 
Oncology (2016) 17(7) (883–895) (S1470204516300985) 
(10.1016/S1470-2045(16)30098-5))
AUTHOR ADDRESSES
  SOURCE
  The Lancet Oncology (2016) 17:7 (e270). Date of Publication: 1 Jul 2016
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab 
plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a 
multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016; 17: 883–95—In 
this Article, the first line in the third paragraph of the Results, “blinded 
independent central review” should have been “investigator-assessed RECIST”. 
In the seventh paragraph of the Results, the number of patients in the 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort who had diarrhoea as a 
serious adverse event should have been two (4%), not four (7%). In the 
seventh paragraph of the Results, “one patient with hypothyroidism, 
hyperglycaemia and increased alanine aminotransferase” should have been “one 
patient with hypothyroidism and hyperglycaemia”. These corrections have been 
made to the online version as of June 28, 2016, and the printed version is 
correct.
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  error
EMTREE MEDICAL INDEX TERMS
  erratum
  priority journal
EMBASE CLASSIFICATIONS
  Cancer (16)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160737355
PUI
  L612717767
DOI
  10.1016/S1470-2045(16)30221-2
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(16)30221-2
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 173
TITLE
  Immune-mediated respiratory adverse events of checkpoint inhibitors
AUTHOR NAMES
  Tabchi S.
  Messier C.
  Blais N.
AUTHOR ADDRESSES
  (Tabchi S.; Blais N., normand.blais.chum@ssss.gouv.qc.ca) Department of 
Hematology-Oncology, Centre Hospitalier de l'Université de Montré Al, 
Montreal, Canada.
(Messier C.) Department of Pharmacy, Centre Hospitalier de l'Université de 
Montreál, Montreal, Canada.
CORRESPONDENCE ADDRESS
  N. Blais, Department of Hematology-Oncology, Centre Hospitalier de 
l'Université de Montré Al, Montreal, Canada. Email: 
normand.blais.chum@ssss.gouv.qc.ca
SOURCE
  Current Opinion in Oncology (2016) 28:4 (269-277). Date of Publication: 1 
Jul 2016
ISSN
  1531-703X (electronic)
  1040-8746
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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. 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. 
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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction)
  immune checkpoint inhibitor (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  respiratory tract agent (drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunopathology (side effect, side effect)
  respiratory tract disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  cancer immunotherapy
  cancer patient
  clinical trial (topic)
  drug safety
  human
  incidence
  pathophysiology
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pneumonia (diagnosis, drug therapy, etiology, side effect)
  priority journal
  respiratory system
  review
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160352978
MEDLINE PMID
  27138570 (http://www.ncbi.nlm.nih.gov/pubmed/27138570)
PUI
  L610258882
DOI
  10.1097/CCO.0000000000000291
FULL TEXT LINK
  http://dx.doi.org/10.1097/CCO.0000000000000291
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 174
TITLE
  Japanese Society of Medical Oncology 2016 Annual Meeting
AUTHOR ADDRESSES
  SOURCE
  Annals of Oncology (2016) 27 Supplement 7. Date of Publication: 1 Jul 2016
CONFERENCE NAME
  14th Annual Meeting of the Japanese Society of Medical Oncology
CONFERENCE LOCATION
  Kobe, Japan
CONFERENCE DATE
  2016-07-28 to 2016-07-30
ISSN
  1569-8041
BOOK PUBLISHER
  Oxford University Press
ABSTRACT
  The proceedings contain 265 papers. The topics discussed include: 
personalized medicine in HER2-positive breast cancer; current status of 
lenvatinib for thyroid cancer; phase Ia/Ib study of taselisib in Japanese 
patients with solid tumors or hormone receptor positive breast cancer; HBOC 
management in PARP inhibitor development: Japanese perspective; ramucirumab 
for gastric cancer; phase II trial of sorafenib for advanced or metastatic 
medullary thyroid carcinoma and anaplastic thyroid carcinoma; development of 
a nationwide genomic screening network and clinical trial for lung cancer 
with rare driver oncogenes; vandetanib for thyroid cancer; overcoming 
endocrine therapy resistance in breast cancer, a cat and mouse game?; PD-1 
signal inhibitors for ovarian cancer: perspectives and issues; the clinical 
outcome of pazopanib treatment for soft tissue sarcomas: a japanese 
musculoskeletal oncology group study; molecular-targeted therapies and 
genomic characterization in gynecologic cancers; new treatment options in 
gynecologic malignancy the PI3K/AKT/mTOR inhibitor in gynecologic 
malignancy; antiangiogenic therapy in gynecologic malignancy; current status 
and future perspective in metastatic colorectal cancer: SCRUM-Japan 
GI-SCREEN project in japan; early specialized palliative care in Japan: a 
feasibility study; subgroup analysis in RAISE: a phase III study of FOLFIRI 
1 ramucirumab or placebo in patients with advanced mCRC; and final survival 
results of a multicenter phase i/ii study of tas-102 with bevacizumab for 
mCRC (C-TASK FORCE).
EMTREE DRUG INDEX TERMS
  bevacizumab
  endogenous compound
  epidermal growth factor receptor 2
  hormone receptor
  lenvatinib
  mammalian target of rapamycin inhibitor
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
inhibitor
  pazopanib
  phosphatidylinositol 3 kinase
  placebo
  programmed death 1 receptor
  protein kinase B
  ramucirumab
  sorafenib
  taselisib
  tipiracil plus trifluridine
  unclassified drug
  vandetanib
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  oncology
EMTREE MEDICAL INDEX TERMS
  animal model
  antiangiogenic therapy
  breast cancer
  cancer epidemiology
  cat
  clinical outcome
  clinical study
  clinical trial
  controlled clinical trial
  controlled study
  driver
  drug resistance
  drug therapy
  feasibility study
  female
  hormonal therapy
  human
  human versus animal comparison
  Japan
  Japanese (citizen)
  lung cancer
  metastatic colorectal cancer
  molecularly targeted therapy
  nonhuman
  oncogene
  ovary cancer
  palliative therapy
  personalized medicine
  phase 1 clinical trial
  phase 2 clinical trial
  screening
  soft tissue sarcoma
  stomach cancer
  survival
  thyroid medullary carcinoma
  tumor resistance
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  epidermal growth factor receptor 2 (137632-09-8)
  lenvatinib (417716-92-8, 857890-39-2)
  pazopanib (444731-52-6, 635702-64-6)
  phosphatidylinositol 3 kinase (115926-52-8)
  protein kinase B (148640-14-6)
  ramucirumab (947687-13-0)
  sorafenib (284461-73-0)
  taselisib (1282512-48-4)
  vandetanib (338992-00-0, 338992-48-6, 443913-73-3)
LANGUAGE OF ARTICLE
  English
PUI
  L615048790
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 175
TITLE
  Recent insights and advances in the management of merkel cell carcinoma
AUTHOR NAMES
  Banks P.D.
  Sandhu S.
  Gyorki D.E.
  Johnston M.L.
  Rischin D.
AUTHOR ADDRESSES
  (Banks P.D.; Sandhu S.; Gyorki D.E.; Johnston M.L.; Rischin D., 
danny.rischin@petermac.org) Department of Medical Oncology, Peter MacCallum 
Cancer Centre, Melbourne, Australia.
CORRESPONDENCE ADDRESS
  D. Rischin, Department of Medical Oncology, Peter MacCallum Cancer Centre, 
Melbourne, Australia. Email: danny.rischin@petermac.org
SOURCE
  Journal of Oncology Practice (2016) 12:7 (637-646). Date of Publication: 1 
Jul 2016
ISSN
  1935-469X (electronic)
  1554-7477
BOOK PUBLISHER
  American Society of Clinical Oncology, jcoservice@asco.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (clinical trial, drug therapy)
  monoclonal antibody (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  merkel cell carcinoma (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  cancer immunotherapy
  cancer staging
  clinical feature
  distant metastasis
  follow up
  histology
  histopathology
  human
  immunobiology
  Merkel cell polyomavirus
  molecularly targeted therapy
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  review
  sentinel lymph node biopsy
  tumor biopsy
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00655655)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160544518
MEDLINE PMID
  27407160 (http://www.ncbi.nlm.nih.gov/pubmed/27407160)
PUI
  L611333751
DOI
  10.1200/JOP.2016.013367
FULL TEXT LINK
  http://dx.doi.org/10.1200/JOP.2016.013367
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 176
TITLE
  Ocular and orbital side-effects of checkpoint inhibitors: A review article
AUTHOR NAMES
  Antoun J.
  Titah C.
  Cochereau I.
AUTHOR ADDRESSES
  (Antoun J., joelle.antoun@hotmail.com) Saint Joseph University, Faculty of 
Medicine, Beirut, Lebanon.
(Antoun J., joelle.antoun@hotmail.com; Titah C.; Cochereau I.) Fondation 
Ophtalmologique Adolphe de Rothschild, Paris, France.
(Cochereau I.) Hôpital Bichat Claude Bernard, Faculté de Médecine Diderot, 
Paris, France.
CORRESPONDENCE ADDRESS
  I. Cochereau, Fondation Ophtalmologique Adolphe de Rothschild, Paris, 
France. Email: joelle.antoun@hotmail.com
SOURCE
  Current Opinion in Oncology (2016) 28:4 (288-294). Date of Publication: 1 
Jul 2016
ISSN
  1531-703X (electronic)
  1040-8746
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction, drug therapy)
  checkpoint inhibitor (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticosteroid (drug therapy)
  steroid (drug therapy, topical drug administration)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer chemotherapy
  eye disease (side effect, side effect)
  orbit disease (side effect, side effect)
  side effect (side effect)
EMTREE MEDICAL INDEX TERMS
  adverse drug reaction (drug therapy, side effect)
  cancer patient
  corticosteroid therapy
  drug withdrawal
  endocrine ophthalmopathy (side effect)
  eye inflammation (drug therapy)
  giant cell arteritis (side effect)
  human
  idiopathic disease (side effect)
  immune related adverse event (drug therapy, side effect)
  immune related adverse event (drug therapy, side effect)
  immunopathology (drug therapy, side effect)
  keratitis (side effect)
  melanoma (drug therapy)
  oncologist
  ophthalmologist
  orbit inflammation (drug therapy, side effect)
  patient care
  prevalence
  priority journal
  retinopathy (side effect)
  review
  rheumatic polymyalgia (side effect)
  steroid therapy
  subretinal neovascularization (side effect)
  systematic review
  systemic therapy
  uveitis (side effect)
  Vogt Koyanagi syndrome (side effect)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160343357
MEDLINE PMID
  27136135 (http://www.ncbi.nlm.nih.gov/pubmed/27136135)
PUI
  L610202191
DOI
  10.1097/CCO.0000000000000296
FULL TEXT LINK
  http://dx.doi.org/10.1097/CCO.0000000000000296
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 177
TITLE
  Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced 
Differentiated and Anaplastic Thyroid Cancer
AUTHOR NAMES
  Bastman J.J.
  Serracino H.S.
  Zhu Y.
  Koenig M.R.
  Mateescu V.
  Sams S.B.
  Davies K.D.
  Raeburn C.D.
  McIntyre R.C.
  Haugen B.R.
  French J.D.
AUTHOR ADDRESSES
  (Bastman J.J.; Serracino H.S.; Zhu Y.; Koenig M.R.; Mateescu V.; Sams S.B.; 
Davies K.D.; Raeburn C.D.; McIntyre R.C.; Haugen B.R.; French J.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
SOURCE
  The Journal of clinical endocrinology and metabolism (2016) 101:7 
(2863-2873). Date of Publication: 1 Jul 2016
ISSN
  1945-7197 (electronic)
ABSTRACT
  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.OBJECTIVE: We hypothesized that a T-cell response is generated in 
advanced thyroid cancer and may be a viable therapeutic target.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.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.SETTING: 
The study was conducted at the University of Colorado Hospital.PATIENTS: 
Thyroid cancer patients undergoing thyroidectomy or completion surgery for 
advanced disease between 2002 and 2013 participated in the 
study.INTERVENTION: There were no interventions.MAIN OUTCOME MEASURE: Immune 
markers were analyzed for association with disease severity.CONCLUSIONS: 
PD-1 checkpoint blockades may have therapeutic efficacy in patients with 
aggressive forms of thyroid cancer.
EMTREE DRUG INDEX TERMS
  PDCD1 protein, human
  programmed death 1 receptor
  tumor marker
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  CD8+ T lymphocyte
  cell cycle checkpoint
  female
  gene expression regulation
  genetics
  human
  immunology
  male
  middle aged
  pathology
  physiology
  prognosis
  signal transduction
  thyroid carcinoma (diagnosis)
  thyroid tumor (diagnosis)
  tumor associated leukocyte
  tumor invasion
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  27045886 (http://www.ncbi.nlm.nih.gov/pubmed/27045886)
PUI
  L617204330
DOI
  10.1210/jc.2015-4227
FULL TEXT LINK
  http://dx.doi.org/10.1210/jc.2015-4227
COPYRIGHT
  Copyright 2017 Medline is the source for the citation and abstract of this 
record.

RECORD 178
TITLE
  FGFR inhibitors: Effects on cancer cells, tumor microenvironment and 
whole-body homeostasis (Review)
AUTHOR NAMES
  Katoh M.
AUTHOR ADDRESSES
  (Katoh M., mkatoh-kkr@umin.ac.jp) Department of Omics Network, National 
Cancer Center, 5-1-1 Tsukiji, Chuo-ward Tokyo, Japan.
CORRESPONDENCE ADDRESS
  M. Katoh, Department of Omics Network, National Cancer Center, 5-1-1 
Tsukiji, Chuo-ward Tokyo, Japan. Email: mkatoh-kkr@umin.ac.jp
SOURCE
  International Journal of Molecular Medicine (2016) 38:1 (3-15). Date of 
Publication: 1 Jul 2016
ISSN
  1791-244X (electronic)
  1107-3756
BOOK PUBLISHER
  Spandidos Publications, 10 Vriaxidos Street, Athens, Greece.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  fibroblast growth factor receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  afatinib (drug therapy)
  axitinib (drug therapy)
  azd 4547 (drug therapy)
  cabozantinib (drug therapy)
  ceritinib (drug therapy)
  colony stimulating factor 1 (endogenous compound)
  crizotinib (drug therapy)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  dovitinib (drug therapy)
  erdafitinib (drug therapy)
  erlotinib (drug therapy)
  fibroblast growth factor receptor 19 (endogenous compound)
  fibroblast growth factor receptor 2 (endogenous compound)
  fibroblast growth factor receptor 20 (endogenous compound)
  fibroblast growth factor receptor 21 (endogenous compound)
  fibroblast growth factor receptor 23 (endogenous compound)
  fibroblast growth factor receptor 4 (endogenous compound)
  fibroblast growth factor receptor 7 (endogenous compound)
  gefitinib (drug therapy)
  heparan sulfate
  infigratinib (drug therapy)
  lapatinib (drug therapy)
  lenvatinib (drug therapy)
  monoclonal antibody (endogenous compound)
  ponatinib (drug therapy)
  protein tyrosine kinase inhibitor
  proteoglycan (endogenous compound)
  unclassified drug
  unindexed drug
  vasculotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer cell
  tumor microenvironment
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  breast cancer (drug therapy)
  cancer incidence
  cancer patient
  carboxy terminal sequence
  controlled study
  cost benefit analysis
  disease free survival
  endothelium cell
  FGFR1 gene
  gene
  gene sequence
  health care system
  homeostasis
  human
  human cell
  immune evasion
  immunocompetent cell
  liver toxicity
  lung cancer (drug therapy)
  missense mutation
  paracrine signaling
  priority journal
  promoter region
  regulatory T lymphocyte
  review
  stomach cancer (drug therapy)
  stroma cell
DRUG TRADE NAMES
  azd4547
  bgj398
  jnj 42756493
  ly2874455
  ponatinib
CAS REGISTRY NUMBERS
  afatinib (439081-18-2, 850140-72-6, 850140-73-7)
  axitinib (319460-85-0)
  cabozantinib (942407-59-2, 1140909-48-3, 849217-68-1)
  ceritinib (1032900-25-6)
  colony stimulating factor 1 (81627-83-0)
  crizotinib (877399-52-5)
  dovitinib (804551-71-1, 915769-50-5)
  erdafitinib (1346242-81-6)
  erlotinib (183319-69-9, 183321-74-6)
  fibroblast growth factor receptor (153424-51-2)
  fibroblast growth factor receptor 4 (147573-63-5)
  gefitinib (184475-35-2, 184475-55-6, 184475-56-7)
  heparan sulfate (9050-30-0)
  infigratinib (872511-34-7)
  lapatinib (231277-92-2, 388082-78-8, 437755-78-7)
  lenvatinib (417716-92-8, 857890-39-2)
  ponatinib (943319-70-8, 1114544-31-8)
  vasculotropin (127464-60-2)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Gastroenterology (48)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160544608
MEDLINE PMID
  27245147 (http://www.ncbi.nlm.nih.gov/pubmed/27245147)
PUI
  L611333490
DOI
  10.3892/ijmm.2016.2620
FULL TEXT LINK
  http://dx.doi.org/10.3892/ijmm.2016.2620
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 179
TITLE
  Neoadjuvant chemotherapy modulates the immune microenvironment in metastases 
of tubo-ovarian high-grade serous carcinoma
AUTHOR NAMES
  Böhm S.
  Montfort A.
  Pearce O.M.T.
  Topping J.
  Chakravarty P.
  Everitt G.L.A.
  Clear A.
  McDermott J.R.
  Ennis D.
  Dowe T.
  Fitzpatrick A.
  Brockbank E.C.
  Lawrence A.C.
  Jeyarajah A.
  Faruqi A.Z.
  McNeish I.A.
  Singh N.
  Lockley M.
  Balkwill F.R.
AUTHOR ADDRESSES
  (Böhm S.; Montfort A.; Pearce O.M.T.; Topping J.; Everitt G.L.A.; Clear A.; 
McDermott J.R.; Ennis D.; Dowe T.; McNeish I.A.; Lockley M.; Balkwill F.R., 
f.balkwill@qmul.ac.uk) Barts Cancer Institute, Centre for Cancer and 
Inflammation, Queen Mary University of London, Charterhouse Square, London, 
United Kingdom.
(Böhm S.; Fitzpatrick A.; Lockley M.) Medical Oncology, Barts Health NHS 
Trust, London, United Kingdom.
(Chakravarty P.) Bioinformatics Core, Francis Crick Institute, London, 
United Kingdom.
(McDermott J.R.; Faruqi A.Z.; Singh N.) Department of Pathology, Barts 
Health NHS Trust, London, United Kingdom.
(Ennis D.; McNeish I.A.) Wolfson Wohl Cancer Research Centre, Institute of 
Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
(Brockbank E.C.; Lawrence A.C.; Jeyarajah A.) Gynaecological Oncology, Barts 
Health NHS Trust, London, United Kingdom.
CORRESPONDENCE ADDRESS
  F.R. Balkwill, Barts Cancer Institute, Centre for Cancer and Inflammation, 
Queen Mary University of London, Charterhouse Square, London, United 
Kingdom. Email: f.balkwill@qmul.ac.uk
SOURCE
  Clinical Cancer Research (2016) 22:12 (3025-3036). Date of Publication: 15 
Jun 2016
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  Purpose: The purpose of this study was to assess the effect of neoadjuvant 
chemotherapy (NACT) on immune activation in stage IIIC/IV tubo-ovarian 
high-grade serous carcinoma (HGSC), and its relationship to treatment 
response. Experimental Design: We obtained pre- and posttreatment omental 
biopsies and blood samples from a total of 54 patients undergoing 
platinum-based NACT and 6 patients undergoing primary debulking surgery. We 
measured T-cell density and phenotype, immune activation, and markers of 
cancer-related inflammation using IHC, flow cytometry, 
electrochemiluminescence assays, and RNA sequencing and related our findings 
to the histopathologic treatment response. Results: There was evidence of 
T-cell activation in omental biopsies after NACT: CD4(+) T cells showed 
enhanced IFNγ production and antitumor Th1 gene signatures were increased. 
T-cell activation was more pronounced with good response to NACT. The CD8(+) 
T-cell and CD45RO(+) memory cell density in the tumor microenvironment was 
unchanged after NACT but biopsies showing a good therapeutic response had 
significantly fewer FoxP3(+) T regulatory (Treg) cells. This finding was 
supported by a reduction in a Treg cell gene signature in post-versus 
pre-NACT samples that was more pronounced in good responders. Plasma levels 
of proinflammatory cytokines decreased in all patients after NACT. However, 
a high proportion of T cells in biopsies expressed immune checkpoint 
molecules PD-1 and CTLA4, and PD-L1 levels were significantly increased 
after NACT. Conclusions: NACT may enhance host immune response but this 
effect is tempered by high/increased levels of PD-1, CTLA4, and PD-L1. 
Sequential chemoimmunotherapy may improve disease control in advanced HGSC.
EMTREE DRUG INDEX TERMS
  platinum complex (drug therapy)
  transcription factor FOXP3 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer adjuvant therapy
  immunomodulation
  ovary carcinoma (drug therapy, diagnosis, drug therapy, surgery)
  tubo ovarian high grade serous carcinoma (drug therapy, diagnosis, drug 
therapy, surgery)
  tumor microenvironment
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer staging
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  controlled study
  cytokine production
  electrochemistry
  female
  flow cytometry
  histopathology
  human
  human tissue
  immunohistochemistry
  institutional review
  laparoscopy
  lymphocyte activation
  major clinical study
  outcome assessment
  overall survival
  priority journal
  progression free survival
  regulatory T lymphocyte
  RNA isolation
  RNA sequence
  transcriptomics
  treatment response
  tumor biopsy
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160459461
MEDLINE PMID
  27306793 (http://www.ncbi.nlm.nih.gov/pubmed/27306793)
PUI
  L610811505
DOI
  10.1158/1078-0432.CCR-15-2657
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-15-2657
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 180
TITLE
  Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of 
anti-PD-1 therapy
AUTHOR NAMES
  Hofmann L.
  Forschner A.
  Loquai C.
  Goldinger S.M.
  Zimmer L.
  Ugurel S.
  Schmidgen M.I.
  Gutzmer R.
  Utikal J.S.
  Göppner D.
  Hassel J.C.
  Meier F.
  Tietze J.K.
  Thomas I.
  Weishaupt C.
  Leverkus M.
  Wahl R.
  Dietrich U.
  Garbe C.
  Kirchberger M.C.
  Eigentler T.
  Berking C.
  Gesierich A.
  Krackhardt A.M.
  Schadendorf D.
  Schuler G.
  Dummer R.
  Heinzerling L.M.
AUTHOR ADDRESSES
  (Hofmann L.; Kirchberger M.C.; Schuler G.; Heinzerling L.M., 
Lucie.Heinzerling@uk-erlangen.de) Department of Dermatology, University 
Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 
Erlangen, Germany.
(Forschner A.; Thomas I.; Garbe C.; Eigentler T.) Department of Dermatology, 
University Hospital Tübingen, Germany.
(Loquai C.; Schmidgen M.I.) Department of Dermatology, University Hospital 
Mainz, Germany.
(Goldinger S.M.; Dummer R.) Department of Dermatology, University Hospital 
Zurich, Switzerland.
(Zimmer L.; Ugurel S.; Schadendorf D.) Department of Dermatology, University 
Hospital, University Duisburg-Essen, Germany.
(Gutzmer R.) Department of Dermatology and Allergy, Skin Cancer Center 
Hannover, Hannover Medical School, Germany.
(Utikal J.S.) Skin Cancer Unit, German Cancer Research Center (DKFZ), 
Heidelberg, Germany.
(Utikal J.S.) Department of Dermatology, Venereology and Allergology, 
University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 
Mannheim, Germany.
(Göppner D.) Department of Dermatology, University Hospital Magdeburg, 
Germany.
(Hassel J.C.) Department of Dermatology, University Hospital Heidelberg, 
Germany.
(Meier F.; Dietrich U.) Department of Dermatology, University Hospital 
Dresden, Germany.
(Tietze J.K.; Berking C.) Department of Dermatology and Allergology, 
Ludwig-Maximilian-University (LMU) Munich, Germany.
(Weishaupt C.) Department of Dermatology, University Hospital Münster, 
Münster, Germany.
(Leverkus M.; Wahl R.) Department of Dermatology, University Hospital RWTH 
Aachen, Germany.
(Gesierich A.) Department of Dermatology, University Hospital Würzburg, 
Germany.
(Krackhardt A.M.) III. Medical Department, Technische Universität München 
(TUM), Munich, Germany.
CORRESPONDENCE ADDRESS
  L.M. Heinzerling, Department of Dermatology, University Hospital Erlangen, 
Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany. 
Email: Lucie.Heinzerling@uk-erlangen.de
SOURCE
  European Journal of Cancer (2016) 60 (190-199). Date of Publication: 1 Jun 
2016
ISSN
  1879-0852 (electronic)
  0959-8049
BOOK PUBLISHER
  Elsevier Ltd
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
  pembrolizumab (adverse drug reaction, drug combination, drug therapy, 
intravenous drug administration)
EMTREE DRUG INDEX TERMS
  analgesic agent
  antiinfective agent
  carboplatin (drug combination, drug therapy)
  corticosteroid derivative (drug combination, drug therapy)
  dapagliflozin
  dexamethasone (drug therapy, intraocular drug administration)
  enalapril
  glimepiride
  glucose (endogenous compound)
  hydrocortisone (drug therapy)
  indapamide
  infliximab (drug therapy, intravenous drug administration)
  insulin (drug therapy)
  levocetirizine (drug therapy)
  metformin (drug therapy)
  methylprednisolone (drug combination, drug therapy, intravenous drug 
administration, oral drug administration)
  metronidazole (drug therapy)
  mycophenolate mofetil (drug therapy, oral drug administration)
  mydriatic agent (drug therapy)
  paclitaxel (drug combination, drug therapy)
  prednisolone (drug therapy, intravenous drug administration, oral drug 
administration)
  salicylic acid (drug therapy)
  triamcinolone acetonide (drug combination, drug therapy, oral drug 
administration)
  urea (drug therapy)
  vemurafenib (drug therapy)
  vitamin D derivative (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease
  gastrointestinal disease
  kidney disease
  liver disease
  skin disease
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adrenal insufficiency (side effect)
  adult
  aged
  alopecia (side effect)
  anorexia (side effect)
  appetite disorder (side effect)
  article
  autoimmune hepatitis (side effect)
  balanitis (drug therapy, side effect)
  body weight loss
  cancer center
  cancer combination chemotherapy
  cancer radiotherapy
  colitis (side effect)
  contact allergy (side effect)
  corticosteroid therapy
  dermatitis (drug therapy)
  diarrhea (drug therapy, side effect)
  esophagitis (side effect)
  face erythema (side effect)
  fatigue (side effect)
  feces impaction (side effect)
  female
  fever (side effect)
  Germany
  glucose blood level
  hair loss (side effect)
  Hashimoto disease (side effect)
  hepatitis (side effect)
  hepatomegaly (side effect)
  human
  human tissue
  hyperthyroidism (side effect)
  hypertransaminasemia (drug therapy, side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  insulin dependent diabetes mellitus (side effect)
  iritis (drug therapy, side effect)
  ketoacidosis (side effect)
  kidney failure (side effect)
  lichen planus (drug therapy, side effect)
  liver biopsy
  lymphadenopathy (side effect)
  major clinical study
  male
  metastatic melanoma (drug therapy, radiotherapy)
  middle aged
  multimodality cancer therapy
  multiple cycle treatment
  nausea (side effect)
  nephritis (side effect)
  non insulin dependent diabetes mellitus (drug therapy, side effect)
  oral pruritus (side effect)
  pancreatic insufficiency (drug therapy, side effect)
  pancreatitis (drug therapy, side effect)
  papule (side effect)
  photophobia (side effect)
  pneumonia (side effect)
  polydipsia (side effect)
  priority journal
  psoriasis vulgaris (side effect)
  retrospective study
  rosacea (drug therapy)
  shivering (side effect)
  skin defect (drug therapy)
  Switzerland
  systemic therapy
  very elderly
  vitiligo (side effect)
  vomiting (side effect)
  weakness (side effect)
  xerostomia (side effect)
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  dapagliflozin (461432-26-8)
  dexamethasone (50-02-2)
  enalapril (75847-73-3)
  glimepiride (93479-97-1)
  glucose (50-99-7, 84778-64-3)
  hydrocortisone (50-23-7)
  indapamide (26807-65-8)
  infliximab (170277-31-3)
  insulin (9004-10-8)
  ipilimumab (477202-00-9)
  levocetirizine (130018-77-8)
  metformin (1115-70-4, 657-24-9)
  methylprednisolone (6923-42-8, 83-43-2)
  metronidazole (39322-38-8, 443-48-1)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  pembrolizumab (1374853-91-4)
  prednisolone (50-24-8)
  salicylic acid (63-36-5, 69-72-7)
  triamcinolone acetonide (76-25-5)
  urea (57-13-6)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160324290
MEDLINE PMID
  27085692 (http://www.ncbi.nlm.nih.gov/pubmed/27085692)
PUI
  L610072839
DOI
  10.1016/j.ejca.2016.02.025
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ejca.2016.02.025
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 181
TITLE
  Economic burden of toxicities associated with treating metastatic melanoma 
in the United States
AUTHOR NAMES
  Bilir S.P.
  Ma Q.
  Zhao Z.
  Wehler E.
  Munakata J.
  Barber B.
AUTHOR ADDRESSES
  (Bilir S.P.; Wehler E.) Health Economics and Outcomes Research, IMS Health, 
San Francisco, United States.
(Ma Q.; Zhao Z.; Barber B.) Amgen, Thousand Oaks, United States.
(Munakata J.) Medical and Scientific Services, Health Economics and Outcomes 
Research, IMS Health, San Francisco, United States.
SOURCE
  American Health and Drug Benefits (2016) 9:4 (203-212). Date of Publication: 
1 Jun 2016
ISSN
  1942-2970 (electronic)
  1942-2962
BOOK PUBLISHER
  Engage Healthcare Communications, Inc., nick@engagehc.com
ABSTRACT
  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. 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. 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. 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. 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.
EMTREE DRUG INDEX TERMS
  B Raf kinase inhibitor (drug therapy)
  dabrafenib (adverse drug reaction, drug therapy)
  dacarbazine (drug therapy)
  interleukin 2 (drug therapy)
  ipilimumab (adverse drug reaction, drug therapy)
  mitogen activated protein kinase kinase inhibitor (drug therapy)
  talimogene laherparepvec (adverse drug reaction, drug therapy)
  temozolomide (drug therapy)
  trametinib (adverse drug reaction, drug therapy)
  vemurafenib (adverse drug reaction, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  economic evaluation
  metastatic melanoma (drug therapy, disease management, drug therapy)
EMTREE MEDICAL INDEX TERMS
  acute heart infarction
  adult
  aged
  anemia (side effect)
  anuria
  article
  cellulitis (side effect)
  colitis (side effect)
  coma
  cost effectiveness analysis
  diarrhea (side effect)
  drug labeling
  dyspnea
  female
  fever (side effect)
  follow up
  headache
  human
  hypertension (side effect)
  hypertransaminasemia (side effect)
  hyponatremia
  hypophysitis (side effect)
  keratoacanthoma (side effect)
  major clinical study
  male
  neutropenia
  oliguria
  peripheral neuropathy
  phase 2 clinical trial
  phase 3 clinical trial
  rash (side effect)
  sepsis
  skin carcinoma (side effect)
  squamous cell carcinoma (side effect)
  thrombocytopenia
  vomiting (side effect)
CAS REGISTRY NUMBERS
  dabrafenib (1195765-45-7, 1195768-06-9)
  dacarbazine (4342-03-4)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  talimogene laherparepvec (1187560-31-1)
  temozolomide (85622-93-1)
  trametinib (1187431-43-1, 871700-17-3)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Health Policy, Economics and Management (36)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160484020
PUI
  L611011154
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 182
TITLE
  Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects 
of anti-PD-1 therapy
AUTHOR NAMES
  Zimmer L.
  Goldinger S.M.
  Hofmann L.
  Loquai C.
  Ugurel S.
  Thomas I.
  Schmidgen M.I.
  Gutzmer R.
  Utikal J.S.
  Göppner D.
  Hassel J.C.
  Meier F.
  Tietze J.K.
  Forschner A.
  Weishaupt C.
  Leverkus M.
  Wahl R.
  Dietrich U.
  Garbe C.
  Kirchberger M.C.
  Eigentler T.
  Berking C.
  Gesierich A.
  Krackhardt A.M.
  Schadendorf D.
  Schuler G.
  Dummer R.
  Heinzerling L.M.
AUTHOR ADDRESSES
  (Zimmer L.; Ugurel S.; Schadendorf D.) Department of Dermatology, University 
Hospital, University Duisburg-Essen, Germany.
(Goldinger S.M.; Dummer R.) Department of Dermatology, University Hospital 
Zurich, Switzerland.
(Hofmann L.; Kirchberger M.C.; Schuler G.; Heinzerling L.M., 
Lucie.Heinzerling@uk-erlangen.de) Department of Dermatology, University 
Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 
Erlangen, Germany.
(Loquai C.; Schmidgen M.I.) Department of Dermatology, University Hospital 
Mainz, Germany.
(Thomas I.; Forschner A.; Garbe C.; Eigentler T.) Department of Dermatology, 
University Hospital Tübingen, Germany.
(Gutzmer R.) Department of Dermatology and Allergy, Skin Cancer Center 
Hannover, Hannover Medical School, Germany.
(Utikal J.S.) Skin Cancer Unit, German Cancer Research Center (DKFZ), 
Heidelberg, Germany.
(Utikal J.S.) Department of Dermatology, Venereology and Allergology, 
University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 
Mannheim, Germany.
(Göppner D.) Department of Dermatology, University Hospital Magdeburg, 
Germany.
(Hassel J.C.) Department of Dermatology, University Hospital Heidelberg, 
Germany.
(Meier F.; Dietrich U.) Department of Dermatology, University Hospital 
Dresden, Germany.
(Tietze J.K.; Berking C.) Department of Dermatology and Allergology, 
University Hospital Munich (LMU), Germany.
(Weishaupt C.) Department of Dermatology, University Hospital Münster, 
Germany.
(Leverkus M.; Wahl R.) Department of Dermatology, University Hospital RWTH 
Aachen, Germany.
(Gesierich A.) Department of Dermatology, University Hospital Würzburg, 
Germany.
(Krackhardt A.M.) III. Medical Department, Technische Universität München 
(TUM) Munich, Germany.
CORRESPONDENCE ADDRESS
  L.M. Heinzerling, Department of Dermatology, University Hospital Erlangen, 
Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany. 
Email: Lucie.Heinzerling@uk-erlangen.de
SOURCE
  European Journal of Cancer (2016) 60 (210-225). Date of Publication: 1 Jun 
2016
ISSN
  1879-0852 (electronic)
  0959-8049
BOOK PUBLISHER
  Elsevier Ltd
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
  pembrolizumab (adverse drug reaction, drug combination, drug therapy, 
intravenous drug administration)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  alpha interferon (clinical trial, drug dose, drug therapy)
  antinuclear antibody (endogenous compound)
  C reactive protein (endogenous compound)
  carboplatin (drug combination, drug therapy)
  corticosteroid (drug dose, drug therapy, intravenous drug administration, 
oral drug administration)
  creatine kinase (endogenous compound)
  dabrafenib (adverse drug reaction, drug combination, drug therapy, oral drug 
administration)
  dacarbazine (drug combination, drug therapy)
  dexamethasone (drug therapy, oral drug administration)
  hydroxymethylglutaryl coenzyme A reductase inhibitor (adverse drug reaction)
  immunoglobulin (drug therapy, intravenous drug administration)
  infliximab (drug therapy)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  La antibody (endogenous compound)
  levetiracetam (drug therapy, oral drug administration)
  lorazepam (drug therapy)
  magnesium (drug therapy)
  methylprednisolone (drug dose, drug therapy, intravenous drug 
administration, oral drug administration)
  paclitaxel (drug combination, drug therapy)
  piperacillin plus tazobactam (drug therapy)
  prednisolone (drug dose, drug therapy, intravenous drug administration, oral 
drug administration)
  pregabalin (drug therapy, oral drug administration)
  pyridostigmine (drug dose, drug therapy, oral drug administration)
  Ro antibody (endogenous compound)
  smooth muscle antibody (endogenous compound)
  sultamicillin (drug therapy, intravenous drug administration)
  unindexed drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction (side effect, side effect)
  cardiovascular disease (side effect, side effect)
  eye disease (side effect, side effect)
  musculoskeletal disease (side effect, side effect)
  neurologic disease (side effect, side effect)
  respiratory tract disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adjuvant therapy
  adult
  aged
  anemia (side effect)
  angina pectoris (side effect)
  antibiotic therapy
  aphasia (drug therapy)
  arthralgia (side effect)
  article
  autoimmune disease (side effect)
  autoimmune thyroiditis (side effect)
  blurred vision (side effect)
  bradykinesia (drug therapy)
  brain metastasis (radiotherapy)
  bronchitis (side effect)
  conjunctivitis (side effect)
  coronary angiography
  corticosteroid therapy
  coughing (side effect)
  coxitis (drug therapy, side effect)
  cystitis (side effect)
  demyelination (side effect)
  diarrhea (side effect)
  disease exacerbation (drug therapy, side effect)
  drug dose reduction
  drug induced disease (side effect)
  drug megadose
  drug substitution
  drug withdrawal
  dry eye (side effect)
  dyspnea (side effect)
  eye movement disorder (side effect)
  fatigue (side effect)
  female
  gastritis (side effect)
  Germany
  gingivitis (side effect)
  Guillain Barre syndrome (drug therapy, side effect)
  heart arrest (side effect)
  heart arrhythmia (side effect)
  heart atrium flutter (drug therapy, side effect)
  heart ventricle arrhythmia (side effect)
  hemoptysis (side effect)
  hip pain (side effect)
  human
  hypertension (side effect)
  hypothyroidism (side effect)
  immunosuppressive treatment
  iritis (side effect)
  larynx edema (side effect)
  left ventricular systolic dysfunction (drug therapy, side effect)
  leukocyte count
  leukopenia (side effect)
  lung fibrosis (drug therapy, side effect)
  lung metastasis (drug therapy, radiotherapy)
  lung sarcoidosis (side effect)
  lymph node metastasis (drug therapy)
  major clinical study
  male
  metastatic melanoma (drug therapy, radiotherapy, surgery)
  middle aged
  multicenter study
  muscle spasm (side effect)
  muscle weakness (side effect)
  myalgia (drug therapy, side effect)
  myasthenia gravis (drug therapy, side effect, therapy)
  myositis (drug therapy, side effect)
  neutropenia (side effect)
  otitis (side effect)
  oxygen saturation
  paralysis (drug therapy)
  paresis (drug therapy, side effect)
  paresthesia (drug therapy)
  parkinsonism (drug therapy)
  pharyngitis (side effect)
  plasmapheresis
  pneumonia (drug therapy, side effect)
  polyneuropathy (drug therapy)
  polyradiculitis (drug therapy, side effect)
  priority journal
  psoriatic arthritis (side effect)
  radiculitis (drug therapy, side effect)
  retrospective study
  rheumatic polymyalgia (side effect)
  seizure (drug therapy)
  shoulder arthritis (drug therapy, side effect)
  side effect (side effect)
  sinus tachycardia (side effect)
  sinusitis (side effect)
  soft tissue metastasis (drug therapy)
  Switzerland
  synovitis (side effect)
  systemic inflammatory response syndrome (side effect)
  systemic therapy
  takotsubo cardiomyopathy (drug therapy)
  uveitis (side effect)
  voice change
CAS REGISTRY NUMBERS
  C reactive protein (9007-41-4)
  carboplatin (41575-94-4)
  creatine kinase (9001-15-4)
  dabrafenib (1195765-45-7, 1195768-06-9)
  dacarbazine (4342-03-4)
  dexamethasone (50-02-2)
  immunoglobulin (9007-83-4)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  levetiracetam (102767-28-2)
  lorazepam (846-49-1)
  magnesium (7439-95-4)
  methylprednisolone (6923-42-8, 83-43-2)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  pembrolizumab (1374853-91-4)
  prednisolone (50-24-8)
  pregabalin (148553-50-8)
  pyridostigmine (101-26-8, 155-97-5)
  sultamicillin (58694-35-2, 76497-13-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Cardiovascular Diseases and Cardiovascular Surgery (18)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160324316
MEDLINE PMID
  27084345 (http://www.ncbi.nlm.nih.gov/pubmed/27084345)
PUI
  L610072878
DOI
  10.1016/j.ejca.2016.02.024
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ejca.2016.02.024
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 183
TITLE
  A case report of insulin-dependent diabetes as immune-related toxicity of 
pembrolizumab: presentation, management and outcome
AUTHOR NAMES
  Hansen E.
  Sahasrabudhe D.
  Sievert L.
AUTHOR ADDRESSES
  (Hansen E., Elizabeth_hansen@urmc.rochester.edu; Sahasrabudhe D.; Sievert 
L.) University of Rochester Medical Center, 601 Elmwood Avenue, Box 617, 
Rochester, United States.
CORRESPONDENCE ADDRESS
  E. Hansen, University of Rochester Medical Center, 601 Elmwood Avenue, Box 
617, Rochester, United States. Email: Elizabeth_hansen@urmc.rochester.edu
SOURCE
  Cancer Immunology, Immunotherapy (2016) 65:6 (765-767). Date of Publication: 
1 Jun 2016
ISSN
  1432-0851 (electronic)
  0340-7004
BOOK PUBLISHER
  Springer Science and Business Media Deutschland GmbH, info@springer-sbm.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  alpha2b interferon (drug therapy)
  B Raf kinase (endogenous compound)
  C peptide (endogenous compound)
  dabrafenib (drug combination, drug therapy)
  glucose (endogenous compound)
  glutamate decarboxylase antibody (endogenous compound)
  hemoglobin A1c (endogenous compound)
  interleukin 2 (drug combination, drug therapy)
  ipilimumab (drug combination, drug therapy)
  long acting insulin (drug therapy)
  short acting insulin (drug therapy)
  trametinib (drug combination, drug therapy)
  vemurafenib (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunotoxicity (side effect, side effect)
  insulin dependent diabetes mellitus (drug therapy, side effect, diagnosis, 
drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  axillary lymph node
  body weight disorder (side effect)
  body weight gain
  body weight loss
  cancer adjuvant therapy
  cancer combination chemotherapy
  cancer staging
  cancer surgery
  case report
  compassionate use
  cutaneous melanoma (drug therapy, surgery)
  drug megadose
  drug withdrawal
  fatigue (side effect)
  gastroesophageal reflux (side effect)
  gene mutation
  glucose blood level
  hair discoloration (side effect)
  human
  hypothyroidism (side effect)
  letter
  liver tumor (drug therapy)
  lung biopsy
  lymph node dissection
  lymphadenopathy
  male
  metastatic melanoma (drug therapy)
  middle aged
  polydipsia
  polyuria
  priority journal
  rash
  tumor biopsy
  wide excision
CAS REGISTRY NUMBERS
  alpha2b interferon (99210-65-8)
  C peptide (59112-80-0)
  dabrafenib (1195765-45-7, 1195768-06-9)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  pembrolizumab (1374853-91-4)
  trametinib (1187431-43-1, 871700-17-3)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20160294004
MEDLINE PMID
  27067877 (http://www.ncbi.nlm.nih.gov/pubmed/27067877)
PUI
  L609833201
DOI
  10.1007/s00262-016-1835-4
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00262-016-1835-4
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 184
TITLE
  Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 
1 diabetes
AUTHOR NAMES
  Miyoshi Y.
  Ogawa O.
  Oyama Y.
AUTHOR ADDRESSES
  (Miyoshi Y., miyoshi.yuka@kameda.jp; Ogawa O.) Department of Diabetes and 
Endocrinology, Kameda Medical Center, Kamogawa, Japan.
(Oyama Y.) Department of Oncology, Kameda Medical Center, Kamogawa, Japan.
CORRESPONDENCE ADDRESS
  Y. Miyoshi, Department of Diabetes and Endocrinology, Kameda Medical Center, 
929 Higashi-cho, Kamogawa, Japan. Email: miyoshi.yuka@kameda.jp
SOURCE
  Tohoku Journal of Experimental Medicine (2016) 239:2 (155-158). Date of 
Publication: 1 Jun 2016
ISSN
  1349-3329 (electronic)
  0040-8727
BOOK PUBLISHER
  Tohoku University Medical Press, ed.office@ehs.med.tohoku.ac.jp
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  hemoglobin A1c (endogenous compound)
  insulin (drug combination, drug therapy, endogenous compound)
  sodium chloride (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  fulminant type 1 diabetes (drug therapy, side effect, diagnosis, drug 
therapy, side effect)
  insulin dependent diabetes mellitus (drug therapy, side effect, diagnosis, 
drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  aged
  anorexia (complication)
  article
  body weight loss
  case report
  continuous infusion
  diabetic ketoacidosis (complication, diagnosis, drug therapy)
  diarrhea
  female
  function test
  glucagon stimulation test
  hospital admission
  human
  hyperglycemia (diagnosis)
  insulin release
  insulin treatment
  ketonuria (diagnosis)
  laboratory test
  local excision
  melanoma (diagnosis, drug therapy, surgery)
  metabolic acidosis (diagnosis)
  nausea
  treatment duration
  vagina bleeding
  vaginal melanoma (diagnosis, drug therapy, surgery)
  vaginal melanoma (drug therapy)
  vomiting
CAS REGISTRY NUMBERS
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
  nivolumab (946414-94-4)
  sodium chloride (7647-14-5)
EMBASE CLASSIFICATIONS
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160457619
MEDLINE PMID
  27297738 (http://www.ncbi.nlm.nih.gov/pubmed/27297738)
PUI
  L610786711
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 185
TITLE
  Nivolumab-induced thyroid dysfunction
AUTHOR NAMES
  Tanaka R.
  Fujisawa Y.
  Maruyama H.
  Nakamura Y.
  Yoshino K.
  Ohtsuka M.
  Fujimoto M.
AUTHOR ADDRESSES
  (Tanaka R., ryota621@hotmail.co.jp; Fujisawa Y.; Maruyama H.; Fujimoto M.) 
Department of Dermatology, Faculty of Medicine, University of Tsukuba, 
Ibaraki, Japan.
(Nakamura Y.) Department of Skin Oncology Dermatology, Saitama Medical 
University International Medical Center, Saitama, Japan.
(Yoshino K.) Department of Dermatology, Tokyo Metropolitan Komagome 
Hospital, Tokyo, Japan.
(Ohtsuka M.) Department of Dermatology, Fukushima Medical University School 
of Medicine, Fukushima, Japan.
CORRESPONDENCE ADDRESS
  R. Tanaka, Department of Dermatology, Faculty of Medicine, University of 
Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki, Japan. Email: 
ryota621@hotmail.co.jp
SOURCE
  Japanese Journal of Clinical Oncology (2016) 46:6 (575-579) Article Number: 
hyw036. Date of Publication: 1 Jun 2016
ISSN
  1465-3621 (electronic)
  0368-2811
BOOK PUBLISHER
  Oxford University Press, jnl.info@oup.co.uk
ABSTRACT
  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 >39.5°C 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  dacarbazine (drug therapy)
  liothyronine (endogenous compound)
  prednisolone (drug therapy, oral drug administration)
  thyroglobulin antibody (endogenous compound)
  thyroid peroxidase antibody (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thyroid disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  autoimmune disease (drug therapy)
  autoimmune myositis (drug therapy)
  autoimmune myositis (drug therapy)
  case report
  color Doppler flowmetry
  drug withdrawal
  echography
  fatigue (side effect)
  female
  fever (side effect)
  Hashimoto disease
  hormone substitution
  human
  hyperthyroidism (side effect)
  hypothyroidism (side effect)
  male
  melanoma (drug therapy)
  middle aged
  mucosal melanoma (drug therapy)
  myalgia (side effect)
  myositis (drug therapy)
  response evaluation criteria in solid tumors
  subclinical hypothyroidism
  thyroiditis (side effect)
  vagina tumor (drug therapy)
  vaginal melanoma (drug therapy)
  vaginal melanoma (drug therapy)
  very elderly
CAS REGISTRY NUMBERS
  dacarbazine (4342-03-4)
  liothyronine (6138-47-2, 6893-02-3)
  nivolumab (946414-94-4)
  prednisolone (50-24-8)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160761310
MEDLINE PMID
  27012985 (http://www.ncbi.nlm.nih.gov/pubmed/27012985)
PUI
  L612875602
DOI
  10.1093/jjco/hyw036
FULL TEXT LINK
  http://dx.doi.org/10.1093/jjco/hyw036
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 186
TITLE
  ESMO ECCO 2015: The highlights of immunotherapy and targeted therapies
ORIGINAL (NON-ENGLISH) TITLE
  ESMO ECCO 2015: les temps forts de l'immunothérapie et des thérapies ciblées
AUTHOR NAMES
  Bonnet C.
  Beinse G.
  Cabel L.
  Cochereau D.
  Lavaud P.
  Rochefort P.
  Tabouret E.
  Turpin A.
  Verlingue L.
  Vicier C.
  Massard C.
AUTHOR ADDRESSES
  (Bonnet C.; Beinse G.; Cabel L.; Cochereau D.; Lavaud P.; Rochefort P.; 
Tabouret E.; Turpin A.; Verlingue L.; Vicier C.; Massard C., 
christophe.massard@gustaveroussy.fr) AERIO, 149, avenue du Maine, Paris, 
France.
(Massard C., christophe.massard@gustaveroussy.fr) DITEP, Gustave-Roussy, 
Villejuif, France.
CORRESPONDENCE ADDRESS
  C. Massard, DITEP, Gustave-Roussy, Villejuif, France. Email: 
christophe.massard@gustaveroussy.fr
SOURCE
  Bulletin du Cancer (2016) 103:6 (594-603). Date of Publication: 1 Jun 2016
ISSN
  1769-6917 (electronic)
  0007-4551
BOOK PUBLISHER
  John Libbey Eurotext, 127, avenue de la Republique, Montrouge, France.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  atezolizumab (clinical trial, drug therapy)
  cabozantinib (drug therapy)
  everolimus (drug therapy)
  nivolumab (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  cancer immunotherapy
  kidney cancer (drug therapy, drug therapy)
  lung cancer (drug therapy, drug therapy)
  molecularly targeted therapy
  neuroendocrine tumor (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  blood sampling
  human
  personalized medicine
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  urinalysis
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  cabozantinib (942407-59-2, 1140909-48-3, 849217-68-1)
  everolimus (159351-69-6)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  French
LANGUAGE OF SUMMARY
  English, French
EMBASE ACCESSION NUMBER
  20160462408
MEDLINE PMID
  27229364 (http://www.ncbi.nlm.nih.gov/pubmed/27229364)
PUI
  L610885519
DOI
  10.1016/j.bulcan.2016.04.001
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.bulcan.2016.04.001
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 187
TITLE
  Immune checkpoint therapy for non-small-cell lung cancer
AUTHOR NAMES
  Miyauchi E.
  Inoue A.
AUTHOR ADDRESSES
  (Miyauchi E.) Department of Respiratory Medicine, Tohoku University 
Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan.
(Inoue A.) Dept. of Palliative Medicine, Tohoku University, School of 
Medicine, Japan.
CORRESPONDENCE ADDRESS
  E. Miyauchi, Department of Respiratory Medicine, Tohoku University Hospital, 
1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan.
SOURCE
  Japanese Journal of Cancer and Chemotherapy (2016) 43:6 (666-671). Date of 
Publication: 1 Jun 2016
ISSN
  0385-0684
BOOK PUBLISHER
  Japanese Journal of Cancer and Chemotherapy Publishers Inc., 
ccp@blue.ocn.ne.jp
ABSTRACT
  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 IE 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  cytotoxic agent
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  immune checkpoint therapy
  non small cell lung cancer
EMTREE MEDICAL INDEX TERMS
  apoptosis
  article
  cancer survival
  cell infiltration
  cytotoxic T lymphocyte
  endocrine disease (side effect)
  enterocolitis (side effect)
  human
  immune response
  lymphocyte proliferation
  neuropathy (side effect)
  regulatory T lymphocyte
  signal transduction
  tumor microenvironment
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English, Japanese
EMBASE ACCESSION NUMBER
  20160650292
MEDLINE PMID
  27306803 (http://www.ncbi.nlm.nih.gov/pubmed/27306803)
PUI
  L612048049
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 188
TITLE
  Pembrolizumab for patients with PD-L1-positive advanced gastric cancer 
(KEYNOTE-012): a multicentre, open-label, phase 1b trial
AUTHOR NAMES
  Muro K.
  Chung H.C.
  Shankaran V.
  Geva R.
  Catenacci D.
  Gupta S.
  Eder J.P.
  Golan T.
  Le D.T.
  Burtness B.
  McRee A.J.
  Lin C.-C.
  Pathiraja K.
  Lunceford J.
  Emancipator K.
  Juco J.
  Koshiji M.
  Bang Y.-J.
AUTHOR ADDRESSES
  (Muro K., kmuro@aichi-cc.jp) Aichi Cancer Center Hospital, Nagoya, Japan.
(Chung H.C.) Yonsei Cancer Center, Yonsei University College of Medicine, 
Seoul, South Korea.
(Shankaran V.) University of Washington, Seattle, United States.
(Geva R.) Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
(Catenacci D.) University of Chicago, Chicago, United States.
(Gupta S.) University of Minnesota, Minneapolis, United States.
(Eder J.P.) Yale University, New Haven, United States.
(Golan T.) Sheba Medical Center, Ramat Gan, Israel.
(Le D.T.) Kimmel Cancer Center, Johns Hopkins University, Baltimore, United 
States.
(Burtness B.) Fox Chase Cancer Center, Philadelphia, United States.
(McRee A.J.) University of North Carolina Lineberger Comprehensive Cancer 
Center, Chapel Hill, United States.
(Lin C.-C.) National Taiwan University Hospital, Taipei, Taiwan.
(Pathiraja K.; Lunceford J.; Emancipator K.; Juco J.; Koshiji M.) Merck & 
Co, Kenilworth, United States.
(Bang Y.-J.) Seoul National University College of Medicine, Seoul, South 
Korea.
CORRESPONDENCE ADDRESS
  K. Muro, Correspondence to: Dr Kei Muro, Aichi Cancer Center Hospital, 
Nagoya, Japan. Email: kmuro@aichi-cc.jp
SOURCE
  The Lancet Oncology (2016) 17:6 (717-726). Date of Publication: 1 Jun 2016
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  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. 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. 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. 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. Funding Merck & Co.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  stomach cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  antineoplastic activity
  arthralgia (side effect)
  article
  cancer fatigue (side effect)
  cancer recurrence
  clinical article
  clinical feature
  controlled study
  decreased appetite (side effect)
  disease course
  drug efficacy
  drug fatality (side effect)
  drug mechanism
  drug response
  drug safety
  drug tolerability
  drug withdrawal
  female
  gastroesophageal reflux (side effect)
  human
  hypothyroidism (side effect)
  interstitial lung disease (side effect)
  larynx disorder (side effect)
  male
  metastasis (drug therapy)
  metastasis potential
  multicenter study
  pemphigoid (side effect)
  peripheral sensory neuropathy (side effect)
  peripheral sensory neuropathy (side effect)
  phase 1 clinical trial
  pneumonia (side effect)
  priority journal
  protein determination
  protein function
  pruritus (side effect)
  sensory neuropathy (side effect)
  stomach adenocarcinoma (drug therapy)
  treatment duration
CAS REGISTRY NUMBERS
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01848834)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160348678
MEDLINE PMID
  27157491 (http://www.ncbi.nlm.nih.gov/pubmed/27157491)
PUI
  L610229594
DOI
  10.1016/S1470-2045(16)00175-3
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(16)00175-3
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 189
TITLE
  Determining predictive factors for immune checkpoint inhibitor toxicity: 
Response to Letter to the Editors “A case report of insulin-dependent 
diabetes as immune-related toxicity of pembrolizumab: presentation, 
management and outcome”
AUTHOR NAMES
  Spain L.
  Larkin J.
  Martin-Liberal J.
AUTHOR ADDRESSES
  (Spain L.; Larkin J.) Melanoma Unit, Royal Marsden NHS Foundation Trust, 
Fulham Road, London, United Kingdom.
(Martin-Liberal J., jmartinliberal@gmail.com) Department of Medical 
Oncology, Vall d’Hebron University Hospital, Vall d’Hebron Institute of 
Oncology (VHIO), Pg Vall d’Hebron, 119-129, Barcelona, Spain.
CORRESPONDENCE ADDRESS
  J. Martin-Liberal, Department of Medical Oncology, Vall d’Hebron University 
Hospital, Vall d’Hebron Institute of Oncology (VHIO), Pg Vall d’Hebron, 
119-129, Barcelona, Spain. Email: jmartinliberal@gmail.com
SOURCE
  Cancer Immunology, Immunotherapy (2016) 65:6 (769-770). Date of Publication: 
1 Jun 2016
ISSN
  1432-0851 (electronic)
  0340-7004
BOOK PUBLISHER
  Springer Science and Business Media Deutschland GmbH, info@springer-sbm.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunotoxicity (side effect, side effect)
  insulin dependent diabetes mellitus (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  colitis
  disease association
  disease course
  genotype
  HLA typing
  human
  insulin dependence
  letter
  outcome assessment
  predictive value
  priority journal
CAS REGISTRY NUMBERS
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20160390796
MEDLINE PMID
  27194054 (http://www.ncbi.nlm.nih.gov/pubmed/27194054)
PUI
  L610481095
DOI
  10.1007/s00262-016-1845-2
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00262-016-1845-2
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 190
TITLE
  Anti-PD-L1/PD-1 immune therapies in ovarian cancer: basic mechanism and 
future clinical application
AUTHOR NAMES
  Mandai M.
  Hamanishi J.
  Abiko K.
  Matsumura N.
  Baba T.
  Konishi I.
AUTHOR ADDRESSES
  (Mandai M., mandai@med.kindai.ac.jp) Department of Obstetrics and 
Gynecology, Faculty of Medicine, Kinki University, Osaka-Sayama, Japan.
(Hamanishi J.; Abiko K.; Matsumura N.; Baba T.; Konishi I.) Department of 
Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 
Kyoto, Japan.
CORRESPONDENCE ADDRESS
  M. Mandai, Department of Obstetrics and Gynecology, Faculty of Medicine, 
Kinki University, Osaka-Sayama, Japan. Email: mandai@med.kindai.ac.jp
SOURCE
  International Journal of Clinical Oncology (2016) 21:3 (456-461). Date of 
Publication: 1 Jun 2016
ISSN
  1437-7772 (electronic)
  1341-9625
BOOK PUBLISHER
  Springer Tokyo, orders@springer.jp
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cell antibody (drug therapy, pharmacology)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 ligand 1 antibody (drug combination, drug therapy, 
pharmacology)
  programmed death 1 receptor (endogenous compound)
  programmed death 1 receptor antibody (drug combination, drug therapy, 
pharmacology)
EMTREE DRUG INDEX TERMS
  cisplatin
  cytotoxic T lymphocyte antigen 4 antibody
  trabectedin
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  cancer combination chemotherapy
  cancer prognosis
  cell infiltration
  cell proliferation
  cytotoxic T lymphocyte
  human
  molecularly targeted therapy
  nonhuman
  ovarian cancer cell line
  overall survival
  priority journal
  progression free survival
  protein expression
  regulatory T lymphocyte
  review
  tumor associated leukocyte
  tumor immunity
  tumor microenvironment
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  trabectedin (114899-77-3)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160211212
MEDLINE PMID
  26968587 (http://www.ncbi.nlm.nih.gov/pubmed/26968587)
PUI
  L608976026
DOI
  10.1007/s10147-016-0968-y
FULL TEXT LINK
  http://dx.doi.org/10.1007/s10147-016-0968-y
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 191
TITLE
  Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in 
Japanese patients with advanced solid tumors
AUTHOR NAMES
  Shimizu T.
  Seto T.
  Hirai F.
  Takenoyama M.
  Nosaki K.
  Tsurutani J.
  Kaneda H.
  Iwasa T.
  Kawakami H.
  Noguchi K.
  Shimamoto T.
  Nakagawa K.
AUTHOR ADDRESSES
  (Shimizu T., jcog9511@hotmail.co.jp; Tsurutani J.; Kaneda H.; Iwasa T.; 
Kawakami H.; Nakagawa K.) Department of Medical Oncology, Kindai University 
Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, Japan.
(Seto T.; Hirai F.; Takenoyama M.; Nosaki K.) Department of Thoracic 
Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 
Japan.
(Noguchi K.; Shimamoto T.) MSD K.K., Kitanomaru square, 1-13-12 Kudan-kita, 
Chiyoda-ku, Tokyo, Japan.
CORRESPONDENCE ADDRESS
  T. Shimizu, Department of Medical Oncology, Kindai University Faculty of 
Medicine, 377-2 Ohno-higashi, Osaka-sayama, Japan. Email: 
jcog9511@hotmail.co.jp
SOURCE
  Investigational New Drugs (2016) 34:3 (347-354). Date of Publication: 1 Jun 
2016
ISSN
  1573-0646 (electronic)
  0167-6997
BOOK PUBLISHER
  Springer New York LLC, barbara.b.bertram@gsk.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug concentration, 
drug dose, drug therapy, intravenous drug administration, pharmacokinetics, 
pharmacology)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  cholesterol (endogenous compound)
  glycyrrhetinic acid (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer
  aged
  alanine aminotransferase blood level
  anemia (side effect)
  antineoplastic activity
  article
  aspartate aminotransferase blood level
  body weight loss
  brain infarction (side effect)
  Caucasian
  cholesterol blood level
  clinical article
  cohort analysis
  controlled study
  dehydration (side effect)
  drug blood level
  drug clearance
  drug distribution
  drug dose escalation
  drug efficacy
  drug eruption (side effect)
  drug half life
  drug safety
  drug tolerability
  dyspnea (side effect)
  female
  fever (side effect)
  human
  hyperglycemia (side effect)
  hyperkalemia (side effect)
  hypertriglyceridemia (side effect)
  hypokalemia (side effect)
  hyponatremia (side effect)
  infection (side effect)
  Japanese (people)
  limit of quantitation
  malaise (side effect)
  male
  multiple cycle treatment
  nausea (side effect)
  neutropenia (side effect)
  open study
  phase 1 clinical trial
  pneumonia (side effect)
  priority journal
  protein expression
  rash (side effect)
  side effect (side effect)
  thrombocytopenia (side effect)
  tumor growth
  urticaria (side effect)
DRUG TRADE NAMES
  mk 3475
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  cholesterol (57-88-5)
  glycyrrhetinic acid (471-53-4)
  pembrolizumab (1374853-91-4)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01840579)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160245144
MEDLINE PMID
  27000274 (http://www.ncbi.nlm.nih.gov/pubmed/27000274)
PUI
  L609239328
DOI
  10.1007/s10637-016-0347-6
FULL TEXT LINK
  http://dx.doi.org/10.1007/s10637-016-0347-6
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 192
TITLE
  Immune checkpoint blockade in ovarian cancer
ORIGINAL (NON-ENGLISH) TITLE
  Immun-Checkpoint-Inhibitor bei Eierstockkrebs
AUTHOR NAMES
  Weiss L.
  Huemer F.
  Mlineritsch B.
  Greil R.
AUTHOR ADDRESSES
  (Weiss L., lu.weiss@salk.at; Huemer F.; Mlineritsch B.; Greil R.) 3rd 
Medical Department of Hematology, Medical Oncology, Hemostaseology, 
Rheumatology and Infectious Disease, Salzburg Cancer Research Institute 
(SCRI), Muellner Hauptstraße 48, Salzburg, Austria.
CORRESPONDENCE ADDRESS
  L. Weiss, 3rd Medical Department of Hematology, Medical Oncology, 
Hemostaseology, Rheumatology and Infectious Disease, Salzburg Cancer 
Research Institute (SCRI), Muellner Hauptstraße 48, Salzburg, Austria. 
Email: lu.weiss@salk.at
SOURCE
  Memo - Magazine of European Medical Oncology (2016) 9:2 (82-84). Date of 
Publication: 1 Jun 2016
ISSN
  1865-5076 (electronic)
  1865-5041
BOOK PUBLISHER
  Springer-Verlag Wien, michaela.bolli@springer.at
ABSTRACT
  Increased numbers of tumour infiltrating T‑cells have long been associated 
with a better prognosis in ovarian cancer, which has led to the general 
assumption of a relevant impact of T‑cellular anti-tumour immunity in this 
disease. As a consequence of this knowledge, a multitude of immunologic 
therapies has emerged over the past years. Although some reports could 
evidence a successful induction of anti-tumour T‑cells, in general, these 
attempts did not translate into clinically significant activity. As has 
already been shown in other tumour entities, immune checkpoint blockade – 
mainly antibodies directed against PD-1 and PD-L1 – could possibly become 
a real “game changer” in ovarian cancer in the future.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy)
  avelumab (adverse drug reaction, drug therapy)
  bms 93655 (drug therapy)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  ipilimumab
  monoclonal antibody (drug therapy)
  nivolumab (drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  cancer prognosis
  corticosteroid therapy
  disease control
  drug efficacy
  drug mechanism
  human
  lymphocyte function
  overall survival
  phase 1 clinical trial (topic)
  priority journal
  protein expression
  response evaluation criteria in solid tumors
  review
  T lymphocyte
  treatment outcome
  tumor associated leukocyte
  tumor immunity
  unspecified side effect (side effect)
CAS REGISTRY NUMBERS
  avelumab (1537032-82-8)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160498326
PUI
  L611007262
DOI
  10.1007/s12254-016-0267-3
FULL TEXT LINK
  http://dx.doi.org/10.1007/s12254-016-0267-3
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 193
TITLE
  Programmed death-ligand 1 overexpression is a prognostic marker for 
aggressive papillary thyroid cancer and its variants
AUTHOR NAMES
  Chowdhury S.
  Veyhl J.
  Jessa F.
  Polyakova O.
  Alenzi A.
  MacMillan C.
  Ralhan R.
  Walfish P.G.
AUTHOR ADDRESSES
  (Chowdhury S.; Veyhl J.; Jessa F.; Polyakova O.; Alenzi A.; Ralhan R., 
rralhan@mtsinai.on.ca; Walfish P.G., pwalfish@mtsinai.on.ca) Alex and Simona 
Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, 
Toronto, Canada.
(Ralhan R., rralhan@mtsinai.on.ca; Walfish P.G., pwalfish@mtsinai.on.ca) 
Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, 
Department of Otolaryngology-Head and Neck Surgery Program, Mount Sinai 
Hospital, Toronto, Canada.
(MacMillan C.; Ralhan R., rralhan@mtsinai.on.ca; Walfish P.G., 
pwalfish@mtsinai.on.ca) Department of Pathology and Laboratory Medicine, 
Mount Sinai Hospital, Toronto, Canada.
(MacMillan C.; Ralhan R., rralhan@mtsinai.on.ca; Walfish P.G., 
pwalfish@mtsinai.on.ca) Laboratory Medicine and Pathobiology, University of 
Toronto, Toronto, Canada.
(Ralhan R., rralhan@mtsinai.on.ca) Department of Otolaryngology-Head and 
Neck Surgery, Mount Sinai Hospital, Toronto, Canada.
(Ralhan R., rralhan@mtsinai.on.ca) Department of Otolaryngology-Head and 
Neck Surgery, University of Toronto, Toronto, Canada.
(Polyakova O.; Alenzi A.; Walfish P.G., pwalfish@mtsinai.on.ca) Department 
of Medicine, Endocrine Division, Mount Sinai Hospital and University of 
Toronto Medical School, Toronto, Canada.
CORRESPONDENCE ADDRESS
  P.G. Walfish, Alex and Simona Shnaider Research Laboratory in Molecular 
Oncology, Mount Sinai Hospital, Toronto, Canada. Email: 
pwalfish@mtsinai.on.ca
SOURCE
  Oncotarget (2016) 7:22 (32318-32328). Date of Publication: 31 May 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  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.
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thyroid papillary carcinoma
EMTREE MEDICAL INDEX TERMS
  adolescent
  aged
  article
  cancer prognosis
  cancer staging
  clinical protocol
  controlled study
  disease free survival
  female
  gene overexpression
  genetic variability
  human
  human cell
  immunohistochemistry
  limit of detection
  major clinical study
  male
  predictive value
  protein expression
  protein localization
  tumor classification
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160439965
MEDLINE PMID
  27086918 (http://www.ncbi.nlm.nih.gov/pubmed/27086918)
PUI
  L610767487
DOI
  10.18632/oncotarget.8698
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.8698
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 194
TITLE
  Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated 
patients with uveal melanoma
AUTHOR NAMES
  Karydis I.
  Chan P.Y.
  Wheater M.
  Arriola E.
  Szlosarek P.W.
  Ottensmeier C.H.
AUTHOR ADDRESSES
  (Karydis I., i.karydis@southampton.ac.uk; Ottensmeier C.H.) Cancer Sciences 
Academic Unit, University of Southampton, Southampton, United Kingdom.
(Chan P.Y.; Szlosarek P.W.) Department of Medical Oncology, St Bartholomew’s 
Hospital, London, United Kingdom.
(Wheater M.; Arriola E.) Medical Oncology, University Hospital Southampton, 
Southampton, United Kingdom.
(Szlosarek P.W.) Barts Cancer Institute, Queen Mary University of London, 
United Kingdom.
CORRESPONDENCE ADDRESS
  I. Karydis, Cancer Sciences Academic Unit, University of Southampton, 
Southampton, United Kingdom. Email: i.karydis@southampton.ac.uk
SOURCE
  OncoImmunology (2016) 5:5 Article Number: e1143997. Date of Publication: 3 
May 2016
ISSN
  2162-402X (electronic)
  2162-4011
BOOK PUBLISHER
  Taylor and Francis Inc., 325 Chestnut St, Suite 800, Philadelphia, United 
States.
ABSTRACT
  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. 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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  lactate dehydrogenase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  uvea melanoma (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  chemoembolization
  clinical article
  compassionate use
  cutaneous melanoma
  diarrhea (side effect)
  fatigue (side effect)
  female
  human
  hypertransaminasemia (side effect)
  hypophysitis (side effect)
  immune response
  male
  multiple cycle treatment
  muscle weakness (side effect)
  oral mucositis (side effect)
  outcome assessment
  pancreatic insufficiency (side effect)
  pruritus (side effect)
  radiofrequency ablation
  rash (side effect)
  retrospective study
  Sjoegren syndrome (side effect)
  tumor associated leukocyte
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  ipilimumab (477202-00-9)
  lactate dehydrogenase (9001-60-9)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160477696
PUI
  L610965468
DOI
  10.1080/2162402X.2016.1143997
FULL TEXT LINK
  http://dx.doi.org/10.1080/2162402X.2016.1143997
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 195
TITLE
  HLA ligandomics identifies histone deacetylase 1 as target for ovarian 
cancer immunotherapy
AUTHOR NAMES
  Peper J.K.
  Bösmüller H.-C.
  Schuster H.
  Gückel B.
  Hörzer H.
  Roehle K.
  Schäfer R.
  Wagner P.
  Rammensee H.-G.
  Stevanović S.
  Fend F.
  Staebler A.
AUTHOR ADDRESSES
  (Peper J.K.; Schuster H.; Roehle K.; Rammensee H.-G.; Stevanović S.) 
Department of Immunology, Institute of Cell Biology, University of Tübingen, 
Tübingen, Germany.
(Bösmüller H.-C.; Fend F.; Staebler A.) Institute of Pathology, University 
Hospital of Tübingen, Tübingen, Germany.
(Gückel B.; Hörzer H.; Wagner P., p.wagner@med.uni-tuebingen.de) Department 
of Obstetrics and Gynecology, University Hospital of Tübingen, Tübingen, 
Germany.
(Schäfer R.) Department of Clinical and Experimental Transfusion Medicine, 
University Hospital of Tübingen, Tübingen, Germany.
(Rammensee H.-G.; Stevanović S.; Fend F.) German Cancer Consortium (DKTK), 
DKFZ partner site Tübingen, Tübingen, Germany.
(Gückel B.) Department of Radiology, University Hospital of Tübingen, 
Tübingen, Germany.
CORRESPONDENCE ADDRESS
  P. Wagner, Department of Obstetrics and Gynecology, University Hospital of 
Tübingen, Tübingen, Germany. Email: p.wagner@med.uni-tuebingen.de
SOURCE
  OncoImmunology (2016) 5:5 Article Number: e1065369. Date of Publication: 3 
May 2016
ISSN
  2162-402X (electronic)
  2162-4011
BOOK PUBLISHER
  Taylor and Francis Inc., 325 Chestnut St, Suite 800, Philadelphia, United 
States.
ABSTRACT
  The recent approval of clincially effective immune checkpoint inhibitors 
illustrates the potential of cancer immunotherapy. A challenging task 
remains the identification of specific targets guiding immunotherapy. 
Facilitated by technical advances, the direct identification of 
physiologically relevant targets is enabled by analyzing the HLA ligandome 
of cancer cells. Since recent publications demonstrate the immunogenicity of 
ovarian cancer (OvCa), immunotherapies, including peptide-based cancer 
vaccines, represent a promising treatment approach. To identify vaccine 
peptides, we employed a combined strategy of HLA ligandomics in high-grade 
serous OvCa samples and immunogenicity analysis. Only few proteins were 
naturally presented as HLA ligands on all samples analyzed, including 
histone deacetylase (HDAC) 1 and 2. In vitro priming of CD8(+) T cells 
demonstrated that two HDAC1/2-derived HLA ligands can induce T-cell 
responses, capable of killing HLA-matched tumor cells. High HDAC1 expression 
shown by immunohistochemistry in 136 high-grade serous OvCa patients 
associated with significantly reduced overall survival (OS), whereas 
patients with high numbers of CD3(+) tumor-infiltrating lymphocytes (TILs) 
in the tumor epithelium and CD8(+) TILs in the tumor stroma showed improved 
OS. However, correlating HDAC1 expression with TILs, high levels of TILs 
abrogated the impact of HDAC1 on OS. This study strengthens the role of 
HDAC1/2 as an important tumor antigen in OvCa, demonstrating its impact on 
OS in a large cohort of OvCa patients. We further identified two immunogenic 
HDAC1-derived peptides, which frequently induce multi-functional T-cell 
responses in many donors, suitable for future multi-peptide vaccine trials 
in OvCa patients.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  histone deacetylase 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  HLA A antigen (endogenous compound)
  HLA B antigen (endogenous compound)
  HLA C antigen (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  HLA typing
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  article
  cancer prognosis
  controlled study
  cytotoxicity
  enzyme linked immunospot assay
  epithelium cell
  female
  human
  human cell
  human tissue
  immune response
  immunogenicity
  immunohistochemistry
  liquid chromatography
  major clinical study
  mass spectrometry
  normal human
  protein expression
  stroma cell
  tumor associated leukocyte
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160322835
PUI
  L610067558
DOI
  10.1080/2162402X.2015.1065369
FULL TEXT LINK
  http://dx.doi.org/10.1080/2162402X.2015.1065369
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 196
TITLE
  Therapy monitoring and management of adverse events in PD-1/PD-L1 immune 
checkpoint inhibition
ORIGINAL (NON-ENGLISH) TITLE
  Therapiemonitoring und Nebenwirkungsmanagement bei 
PD-1/PD-L1-Immuncheckpoint-Inhibition
AUTHOR NAMES
  Oppel-Heuchel H.
  Grimm M.-O.
AUTHOR ADDRESSES
  (Oppel-Heuchel H., Harriet.Oppel@med.uni-jena.de; Grimm M.-O.) Urologische 
Klinik und Poliklinik, Universitätsklinikum Jena, Lessingsstraße 1, Jena, 
Germany.
CORRESPONDENCE ADDRESS
  H. Oppel-Heuchel, Urologische Klinik und Poliklinik, Universitätsklinikum 
Jena, Lessingsstraße 1, Jena, Germany. Email: Harriet.Oppel@med.uni-jena.de
SOURCE
  Urologe (2016) 55:5 (677-690). Date of Publication: 1 May 2016
ISSN
  1433-0563 (electronic)
  0340-2592
BOOK PUBLISHER
  Springer Verlag, service@springer.de
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction)
  programmed death 1 ligand 1
EMTREE DRUG INDEX TERMS
  corticosteroid
  immunosuppressive agent
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction (side effect, side effect)
  cancer immunotherapy
  drug monitoring
EMTREE MEDICAL INDEX TERMS
  article
  colitis (side effect)
  diarrhea (side effect)
  hepatitis (side effect)
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  immunosuppressive treatment
  nephritis (side effect)
  pneumonia (side effect)
  skin disease (side effect)
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  German
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  20160353783
MEDLINE PMID
  27146870 (http://www.ncbi.nlm.nih.gov/pubmed/27146870)
PUI
  L610261047
DOI
  10.1007/s00120-016-0109-2
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00120-016-0109-2
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 197
TITLE
  Immune response in breast cancer brain metastases and their 
microenvironment: The role of the PD-1/PD-L axis
AUTHOR NAMES
  Duchnowska R.
  Peksa R.
  Radecka B.
  Mandat T.
  Trojanowski T.
  Jarosz B.
  Czartoryska-Arłukowicz B.
  Olszewski W.P.
  Och W.
  Kalinka-Warzocha E.
  Kozłowski W.
  Kowalczyk A.
  Loi S.
  Biernat W.
  Jassem J.
AUTHOR ADDRESSES
  (Duchnowska R., rdtt@wp.pl) Department of Oncology, Military Institute of 
Medicine, Szaserów St 128, Warsaw, Poland.
(Peksa R., rafalpeksa@gumed.edu.pl; Biernat W., biernat@gumed.edu.pl) 
Medical University of Gdańsk, Department of Pathology, 7 Debinki St, Gdańsk, 
Poland.
(Radecka B., brad@onkologia.opole.pl) Department of Oncology, Regional 
Oncology Center, 66a Katowicka St, Opole, Poland.
(Mandat T., tomaszmandat@yahoo.com) Department of Neurosurgery, Oncology 
Center-Institute, 5 Roentgena St, Warsaw, Poland.
(Trojanowski T., t.trojanowski@am.lublin.pl; Jarosz B., 
bozenajarosz@poczta.onet.pl) Medical University of Lublin, Department of 
Neurosurgery, 1 Al. Racławickie, Lublin, Poland.
(Czartoryska-Arłukowicz B., barlukowicz@poczta.onet.pl) Department of 
Oncology, Regional Oncology Center, 12 Ogrodowa St, Białystok, Poland.
(Olszewski W.P., wppo@o2.pl) Department of Pathology, Oncology 
Center-Institute, 5 Roentgena St, Warsaw, Poland.
(Och W., waldekoch@o2.pl) Regional Hospital, Department of Neurosurgery, 18 
Zołnierska St, Olsztyn, Poland.
(Kalinka-Warzocha E., ewakalinka@wp.pl) Department of Oncology, Regional 
Oncology Center, 62 Pabianicka St, Łódź, Poland.
(Kozłowski W., wojciechkozlowski@interia.pl) Department of Pathology, 
Military Institute of Medicine, Szaserów St 128, Warsaw, Poland.
(Kowalczyk A., akow@gumed.edu.pl; Jassem J., jjassem@gumed.edu.pl) Medical 
University of Gdańsk, Department of Oncology and Radiotherapy, 7 Debinki St, 
Gdańsk, Poland.
(Loi S., Sherene.Loi@petermac.org) Division of Cancer Medicine and Research, 
Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, East 
Melbourne, Australia.
CORRESPONDENCE ADDRESS
  R. Duchnowska, Department of Oncology, Military Institute of Medicine, 
Szaserów St 128, Warsaw, Poland. Email: rdtt@wp.pl
SOURCE
  Breast Cancer Research (2016) 18:1 Article Number: 43. Date of Publication: 
27 Apr 2016
ISSN
  1465-542X (electronic)
  1465-5411
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  Background: A better understanding of immune response in breast cancer brain 
metastases (BCBM) may prompt new preventive and therapeutic strategies. 
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. 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). 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 ligand 2 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy)
  CD4 antigen (endogenous compound)
  CD68 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  epidermal growth factor receptor 2 (endogenous compound)
  glial fibrillary acidic protein (endogenous compound)
  lapatinib (drug therapy)
  trastuzumab (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  brain metastasis (drug therapy, drug therapy, radiotherapy, surgery)
  breast cancer (drug therapy, drug therapy, surgery)
  immune response
  tumor microenvironment
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  brain radiation
  breast surgery
  cancer hormone therapy
  cancer prognosis
  cancer surgery
  cancer survival
  controlled study
  human
  human tissue
  lymphocytic infiltration
  macrophage
  major clinical study
  microglia
  phenotype
  protein expression
  tumor associated leukocyte
CAS REGISTRY NUMBERS
  epidermal growth factor receptor 2 (137632-09-8)
  lapatinib (231277-92-2, 388082-78-8, 437755-78-7)
  trastuzumab (180288-69-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160356552
MEDLINE PMID
  27117582 (http://www.ncbi.nlm.nih.gov/pubmed/27117582)
PUI
  L610209003
DOI
  10.1186/s13058-016-0702-8
FULL TEXT LINK
  http://dx.doi.org/10.1186/s13058-016-0702-8
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 198
TITLE
  Phase II study of autologous monocyte-derived mRNA electroporated dendritic 
cells (TriMixDC-MEL) plus ipilimumab in patientswith pretreated advanced 
melanoma
AUTHOR NAMES
  Wilgenhof S.
  Corthals J.
  Heirman C.
  Van Baren N.
  Lucas S.
  Kvistborg P.
  Thielemans K.
  Neyns B.
AUTHOR ADDRESSES
  (Wilgenhof S.; Thielemans K.; Neyns B., Bart.Neyns@uzbrussel.be) 
Universitair Ziekenhuis Brussel, Laarbeeklaan 101, Brussels, Belgium.
(Wilgenhof S.; Corthals J.; Heirman C.; Thielemans K.) Vrije Universiteit 
Brussel, Belgium.
(Van Baren N.) Ludwig Institute for Cancer Research, Belgium.
(Lucas S.) De Duve Institute, Universite Catholique de Louvain, Brussels, 
Belgium.
(Kvistborg P.) Netherlands Cancer Institute, Amsterdam, Netherlands.
CORRESPONDENCE ADDRESS
  B. Neyns, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, Brussels, 
Belgium. Email: Bart.Neyns@uzbrussel.be
SOURCE
  Journal of Clinical Oncology (2016) 34:12 (1330-1338). Date of Publication: 
20 Apr 2016
ISSN
  1527-7755 (electronic)
  0732-183X
BOOK PUBLISHER
  American Society of Clinical Oncology, jcoservice@asco.org
ABSTRACT
  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. Patients and Methods Thirty-nine patients were treated 
with TriMixDC-MEL (4 3 106 cells administered intradermally and 20 3 106 
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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  alpha2b interferon
  B Raf kinase inhibitor
  C reactive protein (endogenous compound)
  corticosteroid (drug therapy)
  lactate dehydrogenase (endogenous compound)
  messenger RNA (endogenous compound)
  mitogen activated protein kinase kinase inhibitor
  mycophenolate mofetil (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy, therapy)
  advanced melanoma (drug therapy, drug therapy, therapy)
  autologous monocyte derived mRNA electroporated dendritic cell
  cell therapy
  dendritic cell
  melanoma (drug therapy, drug therapy, therapy)
  multimodality cancer therapy
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer control
  cancer staging
  chill (complication, drug therapy)
  clinical article
  colitis (side effect)
  controlled study
  dermatitis (side effect)
  diarrhea (side effect)
  disease course
  disease duration
  drug safety
  erythrocyte sedimentation rate
  female
  flu like syndrome (complication, drug therapy)
  follow up
  hepatitis (complication, side effect)
  hepatitis C (drug therapy)
  human
  hypophysitis (side effect)
  hypopituitarism (side effect)
  injection site reaction (complication, drug therapy)
  lactate dehydrogenase blood level
  lymphadenopathy (side effect)
  lymphocyte count
  maintenance therapy
  male
  myalgia (side effect)
  Ogilvie syndrome (side effect)
  peripheral blood mononuclear cell
  phase 2 clinical trial
  pneumonia (side effect)
  polymerase chain reaction
  priority journal
  progression free survival
  treatment duration
CAS REGISTRY NUMBERS
  alpha2b interferon (99210-65-8)
  C reactive protein (9007-41-4)
  ipilimumab (477202-00-9)
  lactate dehydrogenase (9001-60-9)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160305553
MEDLINE PMID
  26926680 (http://www.ncbi.nlm.nih.gov/pubmed/26926680)
PUI
  L609745686
DOI
  10.1200/JCO.2015.63.4121
FULL TEXT LINK
  http://dx.doi.org/10.1200/JCO.2015.63.4121
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 199
TITLE
  A Phase I study of indoximod in patients with advanced malignancies
AUTHOR NAMES
  Soliman H.H.
  Minton S.E.
  Han H.S.
  Ismail-Khan R.
  Neuger A.
  Khambati F.
  Noyes D.
  Lush R.
  Chiappori A.A.
  Roberts J.D.
  Link C.
  Vahanian N.N.
  Mautino M.
  Streicher H.
  Sullivan D.M.
  Antonia S.J.
AUTHOR ADDRESSES
  (Soliman H.H., hatem.soliman@moffitt.org; Minton S.E.; Han H.S.; Ismail-Khan 
R.; Neuger A.; Khambati F.; Noyes D.; Lush R.; Chiappori A.A.; Sullivan 
D.M.; Antonia S.J.) H. Lee Moffitt Cancer Center and Research Institute, 
Tampa, United States.
(Roberts J.D.) Massey Cancer Center, Virginia Commonwealth University, 
Richmond, United States.
(Link C.; Vahanian N.N.; Mautino M.) NewLink Genetics Inc., Ames, United 
States.
(Streicher H.) Cancer Therapeutics Evaluation Program, National Cancer 
Institute, Bethesda, United States.
CORRESPONDENCE ADDRESS
  H.H. Soliman, H. Lee Moffitt Cancer Center and Research Institute, Tampa, 
United States. Email: hatem.soliman@moffitt.org
SOURCE
  Oncotarget (2016) 7:16 (22928-22938). Date of Publication: 19 Apr 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  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. 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. 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 μM 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  indoximod (adverse drug reaction, clinical trial, drug therapy, 
pharmacokinetics)
EMTREE DRUG INDEX TERMS
  alkaline phosphatase (endogenous compound)
  C reactive protein (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  solid malignant neoplasm (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adult
  aged
  anemia (side effect)
  anorexia (side effect)
  area under the curve
  article
  backache (side effect)
  blurred vision (side effect)
  body weight loss
  brain ischemia (side effect)
  cancer fatigue (side effect)
  clinical effectiveness
  confusion (side effect)
  constipation (side effect)
  controlled study
  coughing (side effect)
  dehydration (side effect)
  diarrhea (side effect)
  dizziness (side effect)
  drug efficacy
  drug fatality (side effect)
  drug half life
  drug safety
  drug tolerability
  dyspnea (side effect)
  encephalomyelitis (side effect)
  fatigue (side effect)
  female
  fever (side effect)
  fracture (side effect)
  headache (side effect)
  hip pain (side effect)
  human
  hyperglycemia (side effect)
  hyperkalemia (side effect)
  hypocalcemia (side effect)
  hypokalemia (side effect)
  hyponatremia (side effect)
  hypophysitis (side effect)
  ileus (side effect)
  insomnia (side effect)
  intestine obstruction (side effect)
  knee pain (side effect)
  leg pain (side effect)
  leukocytosis (side effect)
  lymphocytopenia (side effect)
  major clinical study
  male
  maximum plasma concentration
  molecular dynamics
  multiple cycle treatment
  nausea (side effect)
  neutropenia (side effect)
  pain (side effect)
  peripheral edema (side effect)
  phase 1 clinical trial
  pleura effusion (side effect)
  protein determination
  proteinuria (side effect)
  prothrombin time
  rash (side effect)
  sensory neuropathy (side effect)
  shoulder pain (side effect)
  thrombocytopenia (side effect)
  urea nitrogen blood level
  urinary tract infection (side effect)
  vomiting (side effect)
  weakness (side effect)
  young adult
CAS REGISTRY NUMBERS
  alkaline phosphatase (9001-78-9)
  C reactive protein (9007-41-4)
  indoximod (110117-83-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00567931)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160357077
MEDLINE PMID
  27008709 (http://www.ncbi.nlm.nih.gov/pubmed/27008709)
PUI
  L610277152
DOI
  10.18632/oncotarget.8216
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.8216
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 200
TITLE
  A rare case of thyroid storm
AUTHOR NAMES
  McMillen B.
  Dhillon M.S.
  Yong-Yow S.
AUTHOR ADDRESSES
  (McMillen B., bmcmille@IUHealth.org; Dhillon M.S.; Yong-Yow S.) Department 
of Family Medicine, Indiana University School of Medicine, Indianapolis, 
United States.
CORRESPONDENCE ADDRESS
  B. McMillen, Department of Family Medicine, Indiana University School of 
Medicine, Indianapolis, United States. Email: bmcmille@IUHealth.org
SOURCE
  BMJ Case Reports (2016) 2016 Article Number: 582. Date of Publication: 18 
Apr 2016
ISSN
  1757-790X (electronic)
BOOK PUBLISHER
  BMJ Publishing Group, subscriptions@bmjgroup.com
ABSTRACT
  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 
β-blockers, antithyroid medications and systemic steroids resulting in an 
improvement in thyroid function testing and symptoms.
EMTREE DRUG INDEX TERMS
  colestyramine (drug therapy)
  hydrocortisone (drug therapy)
  interferon (drug therapy)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  meropenem (drug therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
  prednisone (drug therapy, oral drug administration)
  propranolol (drug therapy)
  thiamazole (adverse drug reaction, drug therapy)
  vancomycin (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thyroid crisis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adult
  agitation
  agranulocytosis (side effect)
  anxiety
  article
  cancer immunotherapy
  cancer surgery
  case report
  computer assisted tomography
  diaphoresis
  differential diagnosis
  drug megadose
  drug withdrawal
  echography
  female
  fever (drug therapy)
  human
  lung metastasis (surgery)
  metastatic melanoma (drug therapy, surgery)
  nausea
  priority journal
  tachycardia
  thyroid function test
  video assisted thoracoscopic surgery
  vomiting
  wedge resection
  young adult
CAS REGISTRY NUMBERS
  colestyramine (11041-12-6, 58391-37-0)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  meropenem (96036-03-2)
  nivolumab (946414-94-4)
  prednisone (53-03-2)
  propranolol (13013-17-7, 318-98-9, 3506-09-0, 4199-09-1, 525-66-6)
  thiamazole (60-56-0)
  vancomycin (1404-90-6, 1404-93-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160348228
MEDLINE PMID
  27090545 (http://www.ncbi.nlm.nih.gov/pubmed/27090545)
PUI
  L610092959
DOI
  10.1136/bcr-2016-214603
FULL TEXT LINK
  http://dx.doi.org/10.1136/bcr-2016-214603
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 201
TITLE
  Importance and methods of searching for E-publications ahead of print in 
systematic reviews
AUTHOR NAMES
  Thompson J.C.
  Quigley J.M.
  Halfpenny N.J.A.
  Scott D.A.
  Hawkins N.S.
AUTHOR ADDRESSES
  (Thompson J.C., Juliette.thompson@iconplc.com; Quigley J.M.; Halfpenny 
N.J.A.; Scott D.A.) ICON Health Economics and Epidemiology, 100 Park Drive, 
Milton Park, Abingdon, Oxford, Oxon, United Kingdom.
(Hawkins N.S.) London School of Hygiene and Tropical Medicine, London, 
United Kingdom.
CORRESPONDENCE ADDRESS
  J.C. Thompson, ICON Health Economics and Epidemiology, 100 Park Drive, 
Milton Park, Abingdon, Oxford, Oxon, United Kingdom. Email: 
Juliette.thompson@iconplc.com
SOURCE
  Evidence-Based Medicine (2016) 21:2 (55-59). Date of Publication: 1 Apr 2016
ISSN
  1473-6810 (electronic)
  1356-5524
BOOK PUBLISHER
  BMJ Publishing Group, subscriptions@bmjgroup.com
ABSTRACT
  In an attempt to keep pace with the increasing number of trials being 
conducted each year, journals make articles available as E-publications 
ahead of print. E-publications are not available to search through the 
conventional databases (MEDLINE, EMBASE, CENTRAL) used in systematic 
reviews, but are searchable using PubMed. We used a search syntax designed 
to exclusively identify E-publications in PubMed to assess the importance of 
searching for E-publications in systematic reviews. Two case studies were 
conducted: updating de novo systematic reviews in particularly active areas 
of current research, type 2 diabetes mellitus and advanced melanoma. A 
search for E-publications was conducted concurrently to the conventional 
systematic reviews. Network diagrams were constructed with and without the 
results of the E-publications search to demonstrate the potential impact 
E-publications could have on any evidence synthesis. The advanced melanoma 
systematic review conducted in conventional databases identified nine 
studies. The E-publication search identified three additional studies 
reporting information for three new interventions and additional information 
for five interventions. Critically, if an evidence synthesis were to be 
conducted the identification of one of the pivotal nivolumab trials, 
CheckMate 067, (ipilimumab, nivolumab and ipilimumab+nivolumab) allows the 
connection of an otherwise disconnected evidence network. The diabetes 
systematic review conducted in conventional databases identified 28 studies. 
The E-publication search identified one additional study including an extra 
intervention; if evidence synthesis were feasible, the E-publication would 
add a loop to the evidence network which could influence analysis results. 
Failure to search for E-publications ahead of print may mean that evidence 
syntheses do not take into account all the data publicly available at the 
time of review.
EMTREE DRUG INDEX TERMS
  ipilimumab
  nivolumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  e publication
  melanoma
  non insulin dependent diabetes mellitus
  publication
EMTREE MEDICAL INDEX TERMS
  data base
  human
  medical literature
  neuroscience
  review
  systematic review
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Public Health, Social Medicine and Epidemiology (17)
  Endocrinology (3)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160197363
PUI
  L608885316
DOI
  10.1136/ebmed-2015-110374
FULL TEXT LINK
  http://dx.doi.org/10.1136/ebmed-2015-110374
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 202
TITLE
  Targeting the programmed cell death-1 pathway in breast and ovarian cancer
AUTHOR NAMES
  Emens L.A.
  Kok M.
  Ojalvo L.S.
AUTHOR ADDRESSES
  (Emens L.A., emensle@jhmi.edu) Department of Oncology, Sidney Kimmel 
Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University 
School of Medicine, Research Building 1, 1650 Orleans Street, Baltimore, 
United States.
(Kok M.) Netherlands Cancer Institute, Amsterdam, Netherlands.
(Ojalvo L.S.) Kelly Gynecologic Oncology Service, Department of Obstetrics 
and Gynecology, Johns Hopkins University School of Medicine, Baltimore, 
United States.
CORRESPONDENCE ADDRESS
  L.A. Emens, Department of Oncology, Sidney Kimmel Comprehensive Cancer 
Center at Johns Hopkins, Johns Hopkins University School of Medicine, 
Research Building 1, 1650 Orleans Street, Baltimore, United States. Email: 
emensle@jhmi.edu
SOURCE
  Current Opinion in Obstetrics and Gynecology (2016) 28:2 (142-147). Date of 
Publication: 1 Apr 2016
ISSN
  1473-656X (electronic)
  1040-872X
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  atezolizumab
  avelumab
  biological marker
  bms 936559
  cytotoxic T lymphocyte antigen 4
  gamma interferon
  pembrolizumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  breast cancer
  ovary cancer
  protein targeting
EMTREE MEDICAL INDEX TERMS
  cancer immunotherapy
  drug activity
  drug tolerability
  human
  immune response
  priority journal
  protein expression
  review
  signal transduction
  tissue microarray
  treatment response
  tumor microenvironment
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  avelumab (1537032-82-8)
  gamma interferon (82115-62-6)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Human Genetics (22)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160143304
MEDLINE PMID
  26881392 (http://www.ncbi.nlm.nih.gov/pubmed/26881392)
PUI
  L608481196
DOI
  10.1097/GCO.0000000000000257
FULL TEXT LINK
  http://dx.doi.org/10.1097/GCO.0000000000000257
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 203
TITLE
  Diagnosis, monitoring and management of immune-related adverse drug 
reactions of anti-PD-1 antibody therapy
AUTHOR NAMES
  Eigentler T.K.
  Hassel J.C.
  Berking C.
  Aberle J.
  Bachmann O.
  Grünwald V.
  Kähler K.C.
  Loquai C.
  Reinmuth N.
  Steins M.
  Zimmer L.
  Sendl A.
  Gutzmer R.
AUTHOR ADDRESSES
  (Eigentler T.K., thomas.eigentler@med.uni-tuebingen.de) Department of 
Dermatology, Center for Dermatooncology, University Medical Center Tübingen, 
Germany.
(Hassel J.C., jessica.hassel@med.uni-heidelberg.de) Department of 
Dermatology, University Hospital Heidelberg, Germany.
(Berking C., carola.berking@med.uni-muenchen.de) Department of Dermatology 
and Allergy, University Hospital Munich, Munich, Germany.
(Aberle J., aberle@uke.de) Department of Internal Medicine III, University 
Hospital Hamburg Eppendorf, Germany.
(Bachmann O., bachmann.oliver@mh-hannover.de) Department of 
Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 
Germany.
(Grünwald V., Gruenwald.Victor@mh-hannover.de) Department of Hematology, 
Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 
Germany.
(Kähler K.C., kckaehler@dermatology.uni-kiel.de) Department of Dermatology, 
University Hospital Schleswig-Holstein, Campus Kiel, Germany.
(Loquai C., Carmen.Loquai@unimedizin-mainz.de) Department of Dermatology, 
University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
(Reinmuth N., n.reinmuth@lungenclinic.de) Department of Thoracic Oncology, 
LungenClinic Grosshansdorf, Germany.
(Steins M., martin.steins@med.uni-heidelberg.de) Department of Thoracic 
Oncology, Thoraxklinik, University of Heidelberg, Germany.
(Zimmer L., lisa.zimmer@uk-essen.de) Department of Dermatology, University 
Hospital, University Essen-Duisburg, Germany.
(Sendl A., anna.sendl@bms.com) Bristol-Myers Squibb GmbH andKGaA, Munich, 
Germany.
(Gutzmer R., gutzmer.ralf@mh-hannover.de) Department of Dermatology and 
Allergy, Skin Cancer Center Hannover, Hannover Medical School, Germany.
CORRESPONDENCE ADDRESS
  R. Gutzmer, Department of Dermatology and Allergy, Skin Cancer Center 
Hannover, Hannover Medical School, Germany. Email: 
gutzmer.ralf@mh-hannover.de
SOURCE
  Cancer Treatment Reviews (2016) 45 (7-18). Date of Publication: 1 Apr 2016
ISSN
  1532-1967 (electronic)
  0305-7372
BOOK PUBLISHER
  W.B. Saunders Ltd
ABSTRACT
  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 6 months - 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug concentration, drug 
therapy, pharmacokinetics, pharmacology)
  pembrolizumab (adverse drug reaction, clinical trial, drug concentration, 
drug therapy, pharmacokinetics, pharmacology)
EMTREE DRUG INDEX TERMS
  antidiarrheal agent (drug therapy)
  antihistaminic agent (drug therapy)
  antipruritic agent (drug therapy)
  glucocorticoid (drug therapy)
  ipilimumab
  levothyroxine (drug therapy)
  methylprednisolone (drug therapy)
  programmed death 1 receptor (endogenous compound)
  thiamazole (drug therapy)
  urea (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction (diagnosis, disease management)
  drug surveillance program
  immune related adverse drug reaction (diagnosis, disease management)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure (side effect)
  adrenal insufficiency (side effect)
  advanced cancer (drug therapy)
  article
  autoimmune hepatitis (diagnosis, side effect)
  autoimmune thyroiditis (diagnosis, drug therapy, side effect)
  blood cell count
  clinical chemistry
  clinical examination
  clinical trial (topic)
  colitis (drug therapy, side effect, therapy)
  diabetes mellitus (side effect)
  diabetic ketoacidosis (side effect)
  diarrhea (drug therapy, side effect, therapy)
  disease severity
  drug blood level
  drug clearance
  drug contraindication
  drug half life
  drug hypersensitivity (side effect)
  drug withdrawal
  early diagnosis
  electrolyte intake
  hormone substitution
  human
  hydration
  hyperthyroidism (side effect)
  hypertransaminasemia (side effect)
  hypophysitis (drug therapy, side effect)
  hypothyroidism (drug therapy, side effect)
  infusion related reaction (drug therapy, side effect)
  interstitial nephritis (side effect)
  kidney failure (drug therapy, side effect)
  laboratory test
  liver dysfunction (side effect)
  maculopapular rash (side effect)
  melanoma (drug therapy)
  non small cell lung cancer (drug therapy)
  nonhuman
  patient monitoring
  pharmacodynamics
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pneumonia (diagnosis, drug therapy, side effect)
  pruritus (side effect)
  rash (drug therapy, side effect)
  risk benefit analysis
  serology
  squamous cell carcinoma (drug therapy)
  steady state
  symptomatology
  toxic hepatitis (drug therapy, side effect)
  treatment withdrawal
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  methylprednisolone (6923-42-8, 83-43-2)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  thiamazole (60-56-0)
  urea (57-13-6)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160172574
MEDLINE PMID
  26922661 (http://www.ncbi.nlm.nih.gov/pubmed/26922661)
PUI
  L608593436
DOI
  10.1016/j.ctrv.2016.02.003
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ctrv.2016.02.003
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 204
TITLE
  Clinicopathologic and Prognostic Implications of Programmed Death Ligand 1 
Expression in Thymoma Presented at the Sixteenth World Conference on Lung 
Cancer, Denver, CO, September 6-9, 2015.
AUTHOR NAMES
  Yokoyama S.
  Miyoshi H.
  Nishi T.
  Hashiguchi T.
  Mitsuoka M.
  Takamori S.
  Akagi Y.
  Kakuma T.
  Ohshima K.
AUTHOR ADDRESSES
  (Yokoyama S.; Nishi T.; Hashiguchi T.; Mitsuoka M.; Takamori S.; Akagi Y.) 
Department of Surgery, Kurume University, School of Medicine, Kurume, Japan.
(Miyoshi H., miyoshi_hiroaki@med.kurume-u.ac.jp; Ohshima K.) Department of 
Pathology, Kurume University, School of Medicine, 67 Asahi-machi, Kurume, 
Japan.
(Kakuma T.) Biostatistics Center, Kurume University, Kurume, Japan.
CORRESPONDENCE ADDRESS
  H. Miyoshi, Department of Pathology, Kurume University, School of Medicine, 
67 Asahi-machi, Kurume, Japan. Email: miyoshi_hiroaki@med.kurume-u.ac.jp
SOURCE
  Annals of Thoracic Surgery (2016) 101:4 (1361-1369). Date of Publication: 1 
Apr 2016
ISSN
  1552-6259 (electronic)
  0003-4975
BOOK PUBLISHER
  Elsevier USA
ABSTRACT
  Background Programmed death ligand 1 (PD-L1) has been reported to be 
expressed in various malignancies and is considered to be a prognostic 
factor and an immunotherapeutic target. The aim of this study was to 
characterize PD-L1 expression in thymoma and determine statistical 
associations between this expression and clinical features. Methods We 
reviewed formalin-fixed, paraffin-embedded tissue specimens from 82 thymoma 
cases accumulated at Kurume University, the majority of which achieved 
surgical complete resection. Expression of PD-L1 was evaluated by 
immunohistochemistry. Statistical associations between PD-L1 expression and 
clinicopathologic features were evaluated by using χ(2) test and Fisher's 
exact test. Disease-free survival and overall survival curves were 
established by the Kaplan-Meier method and compared using a log-rank test. 
Predictive factors for disease-free survival after complete resection were 
analyzed by using a Cox proportional hazards model in univariate and 
multivariate analysis. Results Overall, 44 thymoma cases (54%) revealed high 
PD-L1 expression. High PD-L1 expression was statistically associated with 
Masaoka stage III/IV disease (p = 0.043) and World Health Organization type 
B2 or B3 thymoma (p = 0.044). Disease-free survival after complete resection 
in high PD-L1 expression was significantly worse than that in low PD-L1 
expression (p = 0.021), although there was no significant difference in 
overall survival (p = 0.957). Multivariate analysis also revealed high PD-L1 
expression as an independent risk factor for recurrence (p = 0.008). 
Conclusions Characterization of PD-L1 expression in thymoma should enable 
more effective clinical approaches, including prognostic stratification of 
patients and potential use of anti-PD-L1 antibody immunotherapy.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  prognosis
  thymoma (surgery)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  disease free survival
  female
  human
  human tissue
  immunohistochemistry
  major clinical study
  male
  Masaoka stage
  multivariate analysis
  overall survival
  priority journal
  proportional hazards model
  protein expression
  recurrence risk
  retrospective study
  risk assessment
  staging
  thymectomy
  tumor recurrence
  univariate analysis
  world health organization
EMBASE CLASSIFICATIONS
  Clinical and Experimental Biochemistry (29)
  Surgery (9)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160042717
MEDLINE PMID
  26794891 (http://www.ncbi.nlm.nih.gov/pubmed/26794891)
PUI
  L607756881
DOI
  10.1016/j.athoracsur.2015.10.044
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.athoracsur.2015.10.044
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 205
TITLE
  Anti-angiogenic agents in ovarian cancer: Past, present, and future
AUTHOR NAMES
  Monk B.J.
  Minion L.E.
  Coleman R.L.
AUTHOR ADDRESSES
  (Monk B.J., bradley.monk@chw.edu; Minion L.E.) Division of Gynecologic 
Oncology, The University of Arizona Cancer Center, Creighton University 
School of Medicine at St Joseph's Hospital and Medical Center, Phoenix, 
United States.
(Coleman R.L.) Department of Gynecologic Oncology and Reproductive Medicine, 
The University of Texas MD Anderson Cancer Center, Houston, United States.
CORRESPONDENCE ADDRESS
  B.J. Monk, Division of Gynecologic Oncology, University of Arizona Cancer 
Center, Department of Obstetrics and Gynecology, Creighton University School 
of Medicine at Dignity Health St Joseph's Hospital and Medical Center, 500 
W. Thomas Road, Suite 660, Phoenix, United States. Email: 
bradley.monk@chw.edu
SOURCE
  Annals of Oncology (2016) 27 Supplement 1 (i33-i39) Article Number: mdw091. 
Date of Publication: 1 Apr 2016
ISSN
  1569-8041 (electronic)
  0923-7534
BOOK PUBLISHER
  Oxford University Press, jnl.info@oup.co.uk
ABSTRACT
  Angiogenesis plays a pivotal role in normal ovarian physiology as well as in 
the progression of ovarian cancer through ascitesformation and metastatic 
spread. Bevacizumab (Avastin®, Genentech; South San Francisco, CA, USA), a 
humanized antivascularendothelial growth factor (VEGF) monoclonal antibody, 
is the most widely studied anti-angiogenesis agent bothacross tumor types 
and specifically in epithelial ovarian cancer. In 2005, single-agent 
bevacizumab at 15 mg/kg (IV) every 3weeks was first reported to be active in 
a case of recurrent high-grade serous ovarian cancer after failing 11th line 
cytotoxictreatment. Since then, many case series, phase II and phase III 
trials have confirmed these results leading to regulatoryapproval in most 
countries including the US Food and Drug Administration in 2014. Guidelines 
now give clearrecommendations as to when and how bevacizumab should be 
integrated into the ovarian cancer treatmentparadigm. Other anti-VEGF agents 
such as the VEGF receptor (VEGFR) tyrosine kinase inhibitors have notshown 
increased activity or reduced toxicity relative to bevacizumab. However, 
anti-angiogenics other thananti-VEGF/VEGFR agents such as those targeting 
Angiopoietin-1 and -2 are in development as well as novelcombinations with 
vascular disrupting agents (VDAs), PARP inhibitors and immune checkpoint 
inhibitors. Clearly,the benefits of anti-angiogenic agents such as 
bevacizumab must be carefully weighed against the cost and 
associatedtoxicities. Although almost all patients with ovarian cancer will 
receive an anti-angiogenic compound, curesare not increased. Predictive 
biomarkers are an urgent unmet need.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  bevacizumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
EMTREE DRUG INDEX TERMS
  biological marker (endogenous compound)
  cediranib (clinical trial, drug therapy)
  combretastatin A4 phosphate (clinical trial, drug combination, drug therapy)
  nintedanib (clinical trial, drug therapy)
  olaparib (clinical trial, drug combination, drug therapy)
  pazopanib (clinical trial, drug therapy)
  trebananib (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  arterial thromboembolism (side effect)
  article
  bone marrow suppression (side effect)
  cancer prognosis
  cost effectiveness analysis
  digestive system fistula (side effect)
  digestive system perforation (side effect)
  drug approval
  drug efficacy
  drug safety
  drug tolerability
  food and drug administration
  hoarseness (side effect)
  human
  hypertension (side effect)
  overall survival
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  progression free survival
  proteinuria (side effect)
  randomized controlled trial (topic)
  survival time
  treatment duration
  treatment response
  treatment withdrawal
  venous thromboembolism (side effect)
DRUG TRADE NAMES
  avastin  , United StatesGenentech

DRUG MANUFACTURERS
   (United States)Genentech
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  cediranib (288383-20-0, 857036-77-2)
  combretastatin A4 phosphate (168555-66-6, 222030-63-9, 229027-07-0, 
404886-32-4)
  nintedanib (928326-83-4, 656247-17-5, 656247-18-6)
  olaparib (763113-22-0)
  pazopanib (444731-52-6, 635702-64-6)
  trebananib (894356-79-7)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01462890, NCT01837251, NCT02477644)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160361814
PUI
  L610305538
DOI
  10.1093/annonc/mdw093
FULL TEXT LINK
  http://dx.doi.org/10.1093/annonc/mdw093
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 206
TITLE
  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
AUTHOR NAMES
  Antonilli M.
  Rahimi H.
  Visconti V.
  Napoletano C.
  Ruscito I.
  Zizzari I.G.
  Caponnetto S.
  Barchiesi G.
  Iadarola R.
  Pierelli L.
  Rughetti A.
  Bellati F.
  Panici P.B.
  Nuti M.
AUTHOR ADDRESSES
  (Antonilli M.; Ruscito I.; Iadarola R.; Bellati F.; Panici P.B.) Department 
of Gynecology,Obstetrics and Urology, 'Sapienza' University of Rome, 
Policlinico Umberto I, Rome, Italy.
(Rahimi H.; Visconti V.; Napoletano C.; Zizzari I.G.; Caponnetto S.; 
Barchiesi G.; Pierelli L.; Rughetti A.; Nuti M., marianna.nuti@uniroma1.it) 
Department of Experimental Medicine, 'Sapienza' University of Rome, 
Policlinico Umberto I, Rome, Italy.
CORRESPONDENCE ADDRESS
  M. Nuti, Department of Experimental Medicine, 'Sapienza' University of Rome, 
Policlinico Umberto I, Rome, Italy. Email: marianna.nuti@uniroma1.it
SOURCE
  International Journal of Oncology (2016) 48:4 (1369-1378). Date of 
Publication: 1 Apr 2016
ISSN
  1791-2423 (electronic)
  1019-6439
BOOK PUBLISHER
  Spandidos Publications, 10 Vriaxidos Street, Athens, Greece. 
subscriptions@spandidos-publications.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  peptide vaccine (adverse drug reaction, clinical trial, drug dose, drug 
therapy, subcutaneous drug administration)
EMTREE DRUG INDEX TERMS
  carcinoembryonic antigen
  CD8 antigen (endogenous compound)
  epidermal growth factor receptor 2
  HLA A2 antigen
  montanide ISA 51
  mucin 1
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  breast cancer (drug therapy, drug therapy)
  cancer immunization
  consolidation chemotherapy
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  allergy (side effect)
  alopecia (side effect)
  anemia (side effect)
  article
  cancer patient
  cancer recurrence
  CD8+ T lymphocyte
  clinical article
  diarrhea (side effect)
  drug efficacy
  drug megadose
  drug safety
  drug tolerability
  feasibility study
  female
  fever (side effect)
  human
  human cell
  immune response
  injection site reaction (side effect)
  leukopenia (side effect)
  liver toxicity (side effect)
  low drug dose
  medication compliance
  nausea (side effect)
  paraaortic lymph node
  patient compliance
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phlebitis (side effect)
  priority journal
  side effect (side effect)
  skin toxicity (side effect)
  T lymphocyte activation
  thrombocytopenia (side effect)
  treatment outcome
  vomiting (side effect)
DRUG MANUFACTURERS
   (Switzerland)clinalfa merck biosciences
   (France)Seppic
CAS REGISTRY NUMBERS
  epidermal growth factor receptor 2 (137632-09-8)
  mucin 1 (212255-06-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160157925
MEDLINE PMID
  26892612 (http://www.ncbi.nlm.nih.gov/pubmed/26892612)
PUI
  L608571198
DOI
  10.3892/ijo.2016.3386
FULL TEXT LINK
  http://dx.doi.org/10.3892/ijo.2016.3386
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 207
TITLE
  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
AUTHOR NAMES
  Brauner E.
  Gunda V.
  Borre P.V.
  Zurakowski D.
  Kim Y.S.
  Dennett K.V.
  Amin S.
  Freeman G.J.
  Parangi S.
AUTHOR ADDRESSES
  (Brauner E.; Gunda V.; Borre P.V.; Kim Y.S.; Dennett K.V.; Amin S.; Parangi 
S., sparangi@partners.org) Department of Surgery, Massachusetts General 
Hospital, Harvard Medical School, Boston, United States.
(Zurakowski D.) Department of Surgery, Boston Children's Hospital, Harvard 
Medical School, Boston, United States.
(Zurakowski D.) Department of Anesthesia, Boston Children's Hospital, 
Harvard Medical School, Boston, United States.
(Kim Y.S.) Department of Surgery, Ulsan University Hospital, University of 
Ulsan College of Medicine, Ulsan, South Korea.
(Freeman G.J.) Department of Medical Oncology, Dana-Farber Cancer Institute, 
Harvard Medical School, Boston, United States.
CORRESPONDENCE ADDRESS
  S. Parangi, Department of Surgery, Massachusetts General Hospital, Harvard 
Medical School, Boston, United States. Email: sparangi@partners.org
SOURCE
  Oncotarget (2016) 7:13 (17194-17211). Date of Publication: 29 Mar 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  B Raf kinase (endogenous compound)
  monoclonal antibody (drug combination, drug interaction, drug therapy, 
intraperitoneal drug administration)
  n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 
difluorophenyl]propanesulfonamide (drug combination, drug interaction, drug 
therapy)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 ligand 1 antibody (drug combination, drug interaction, 
drug therapy, intraperitoneal drug administration)
EMTREE DRUG INDEX TERMS
  mitogen activated protein kinase kinase (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  anaplastic thyroid carcinoma (drug therapy, drug therapy)
  tumor immunity
  tumor regression
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  animal experiment
  animal model
  article
  CD8+ T lymphocyte
  clinical article
  controlled study
  cytotoxic T lymphocyte
  cytotoxicity
  drug potentiation
  female
  gene expression
  human
  human tissue
  male
  mouse
  nonhuman
  protein expression
  regulatory T lymphocyte
  tumor volume
  very elderly
DRUG TRADE NAMES
  plx 4720
CAS REGISTRY NUMBERS
  mitogen activated protein kinase kinase (142805-58-1)
  n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 
difluorophenyl]propanesulfonamide (918505-84-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160419753
MEDLINE PMID
  26943572 (http://www.ncbi.nlm.nih.gov/pubmed/26943572)
PUI
  L610625590
DOI
  10.18632/oncotarget.7839
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.7839
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 208
TITLE
  FDA approval summary: Pembrolizumab for the treatment of patients with 
metastatic non-small cell lung cancer whose tumors express programmed 
death-ligand 1
AUTHOR NAMES
  Sul J.
  Blumenthal G.M.
  Jiang X.
  He K.
  Keegan P.
  Pazdur R.
AUTHOR ADDRESSES
  (Sul J., joohee.sul@fda.hhs.gov; Blumenthal G.M.; Jiang X.; He K.; Keegan 
P.; Pazdur R.) Office of Hematology and Oncology Products, Center for Drug 
Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, 
United States.
CORRESPONDENCE ADDRESS
  J. Sul, Office of Hematology and Oncology Products, Center for Drug 
Evaluation and Research, U.S. Food and Drug Administration, 10903 New 
Hampshire Avenue, White Oak 22, Silver Spring, United States. Email: 
joohee.sul@fda.hhs.gov
SOURCE
  Oncologist (2016) 21:5 (643-650). Date of Publication: 29 Mar 2016
ISSN
  1549-490X (electronic)
  1083-7159
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacoeconomics)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  epidermal growth factor receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastasis
  non small cell lung cancer (drug therapy, disease management, drug therapy)
  protein expression
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer staging
  colitis (side effect)
  coughing (side effect)
  decreased appetite (side effect)
  dyspnea (side effect)
  fatigue (side effect)
  female
  follow up
  gene mutation
  human
  human tissue
  hypophysitis (side effect)
  immunohistochemistry
  lung embolism (side effect)
  major clinical study
  male
  patient selection
  phase 1 clinical trial
  pleura effusion (side effect)
  pneumonia (side effect)
  priority journal
  scoring system
CAS REGISTRY NUMBERS
  epidermal growth factor receptor (79079-06-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160360847
MEDLINE PMID
  27026676 (http://www.ncbi.nlm.nih.gov/pubmed/27026676)
PUI
  L610251722
DOI
  10.1634/theoncologist.2015-0498
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2015-0498
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 209
TITLE
  Association and prognostic significance of BRCA1/2-mutation status with 
neoantigen load, number of tumor-infiltrating lymphocytes and expression of 
PD-1/PD-L1 in high grade serous ovarian cancer
AUTHOR NAMES
  Strickland K.C.
  Howitt B.E.
  Shukla S.A.
  Rodig S.
  Ritterhouse L.L.
  Liu J.F.
  Garber J.E.
  Chowdhury D.
  Wu C.J.
  D'Andrea A.D.
  Matulonis U.A.
  Konstantinopoulos P.A.
AUTHOR ADDRESSES
  (Strickland K.C.; Howitt B.E.; Rodig S.; Ritterhouse L.L.) Department of 
Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, 
United States.
(Shukla S.A.; Wu C.J.) The Broad Institute of Harvard, MIT, Cambridge, 
United States.
(Liu J.F.; Matulonis U.A.; Konstantinopoulos P.A., 
panagiotis_konstantinopoulos@dfci.harvard.edu) Department of Nuclear 
Medicine, Chinese PLA General Hospital, Beijing, China.
(Shukla S.A.; Garber J.E.; Wu C.J.) College of Medical Laboratory Science 
and Technology, Harbin Medical University, Daqing, China.
(Chowdhury D.; D'Andrea A.D.) Division of Genomic Stability and DNA Repair, 
Dana Farber Cancer Institute, Harvard Medical School, Boston, United States.
CORRESPONDENCE ADDRESS
  P.A. Konstantinopoulos, Department of Nuclear Medicine, Chinese PLA General 
Hospital, Beijing, China. Email: 
panagiotis_konstantinopoulos@dfci.harvard.edu
SOURCE
  Oncotarget (2016) 7:12 (13587-13598). Date of Publication: 22 Mar 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  Immune checkpoint inhibitors (e.g., anti-PD-1 and anti-PD-L1 antibodies) 
have demonstrated remarkable efficacy against hypermutated cancers such as 
melanomas and lung carcinomas. One explanation for this effect is that 
hypermutated lesions harbor more tumor-specific neoantigens that stimulate 
recruitment of an increased number of tumor-infiltrating lymphocytes (TILs), 
which is counterbalanced by overexpression of immune checkpoints such as 
PD-1 or PD-L1. Given that BRCA1/2-mutated high grade serous ovarian cancers 
(HGSOCs) exhibit a higher mutational load and a unique mutational signature 
with an elevated number of larger indels up to 50 bp, we hypothesized that 
they may also harbor more tumor-specific neoantigens, and, therefore, 
exhibit increased TILs and PD-1/PD-L1 expression. Here, we report 
significantly higher predicted neoantigens in BRCA1/2-mutated tumors 
compared to tumors without alterations in homologous recombination (HR) 
genes (HR-proficient tumors). Tumors with higher neoantigen load were 
associated with improved overall survival and higher expression of immune 
genes associated with tumor cytotoxicity such as genes of the TCR, the 
IFN-gamma and the TNFR pathways. Furthermore, immunohistochemistry studies 
demonstrated that BRCA1/2-mutated tumors exhibited significantly increased 
CD3+ and CD8+ TILs, as well as elevated expression of PD-1 and PD-L1 in 
tumor-associated immune cells compared to HR-proficient tumors. Survival 
analysis showed that both BRCA1/2-mutation status and number of TILs were 
independently associated with outcome. Of note, two distinct groups of 
HGSOCs, one with very poor prognosis (HR proficient with low number of TILs) 
and one with very good prognosis (BRCA1/2-mutated tumors with high number of 
TILs) were defined. These findings support a link between BRCA1/2-mutation 
status, immunogenicity and survival, and suggesting that BRCA1/2-mutated 
HGSOCs may be more sensitive to PD-1/PD-L1 inhibitors compared to 
HR-proficient HGSOCs.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  BRCA1 protein (endogenous compound)
  BRCA2 protein (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  antigen (endogenous compound)
  CD3 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  neoantigen (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer prognosis
  ovary cancer
  tumor associated leukocyte
EMTREE MEDICAL INDEX TERMS
  article
  cell count
  cell survival
  controlled study
  disease association
  homologous recombination
  human
  human tissue
  immunogenicity
  immunohistochemistry
  mutational analysis
  overall survival
  survival rate
  survival time
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160419583
MEDLINE PMID
  26871470 (http://www.ncbi.nlm.nih.gov/pubmed/26871470)
PUI
  L610625442
DOI
  10.18632/oncotarget.7277
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.7277
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 210
TITLE
  Phase i clinical trial of ipilimumab in pediatric patients with advanced 
solid tumors
AUTHOR NAMES
  Merchant M.S.
  Wright M.
  Baird K.
  Wexler L.H.
  Rodriguez-Galindo C.
  Bernstein D.
  Delbrook C.
  Lodish M.
  Bishop R.
  Wolchok J.D.
  Streicher H.
  Mackall C.L.
AUTHOR ADDRESSES
  (Merchant M.S.; Wright M.; Baird K.; Bernstein D.; Delbrook C.; Mackall 
C.L., mackallc@mail.nih.gov) Pediatric Oncology Branch, National Cancer 
Institute, National Institutes of Health, Building 10 CRC, 10 Center Drive, 
Bethesda, United States.
(Wexler L.H.) Department of Pediatrics, Memorial Sloan Kettering Cancer 
Center, New York, United States.
(Wexler L.H.; Wolchok J.D.) Weill-Cornell Medical College, New York, United 
States.
(Rodriguez-Galindo C.) Pediatric Oncology, Dana Farber Cancer Institute, 
Boston, United States.
(Lodish M.) National Institute of Child Health and Human Development, NIH, 
Bethesda, United States.
(Bishop R.) National Eye Institute, NIH, Bethesda, United States.
(Wolchok J.D.) Department of Medicine, Memorial Sloan Kettering Cancer 
Center, New York, United States.
(Streicher H.) Investigational Drug Branch, National Cancer Institute, NIH, 
Bethesda, United States.
CORRESPONDENCE ADDRESS
  C.L. Mackall, Pediatric Oncology Branch, National Cancer Institute, National 
Institutes of Health, Building 10 CRC, 10 Center Drive, Bethesda, United 
States. Email: mackallc@mail.nih.gov
SOURCE
  Clinical Cancer Research (2016) 22:6 (1364-1370). Date of Publication: 15 
Mar 2016
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  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. 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/m2 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. 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). 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. Clin Cancer Res; 22(6); 1364-70.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug concentration, drug 
dose, drug therapy, intravenous drug administration, pharmacokinetics)
EMTREE DRUG INDEX TERMS
  CD19 antigen (endogenous compound)
  CD20 antigen (endogenous compound)
  HLA DR antigen (endogenous compound)
  Ki 67 antigen (endogenous compound)
  transcription factor FOXP3 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  pediatrics
  solid malignant neoplasm (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adolescent
  adult
  area under the curve
  article
  bladder carcinoma (drug therapy)
  cancer growth
  cancer recurrence
  cancer survival
  CD3+ T lymphocyte
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  cell population
  child
  clear cell sarcoma (drug therapy)
  clinical article
  cohort analysis
  colitis (side effect)
  correlational study
  dose response
  drug blood level
  drug clearance
  drug dose escalation
  drug half life
  drug safety
  drug tolerability
  endocrine disease (side effect)
  female
  human
  hypertransaminasemia (side effect)
  hypophysitis (side effect)
  immunocompetent cell
  immunogenicity
  kidney carcinoma (drug therapy)
  male
  maximum plasma concentration
  melanoma (drug therapy)
  minimum plasma concentration
  multiple cycle treatment
  myalgia (side effect)
  neuroblastoma (drug therapy)
  osteosarcoma (drug therapy)
  overall survival
  pancreatitis (side effect)
  phase 1 clinical trial
  pleomorphic sarcoma (drug therapy)
  pleomorphic sarcoma (drug therapy)
  pleura effusion (side effect)
  pneumonia (side effect)
  priority journal
  rash (side effect)
  rhabdomyosarcoma (drug therapy)
  sarcoma (drug therapy)
  synovial sarcoma (drug therapy)
  thyroiditis (side effect)
  time to maximum plasma concentration
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Pediatrics and Pediatric Surgery (7)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01445379)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160257401
MEDLINE PMID
  26534966 (http://www.ncbi.nlm.nih.gov/pubmed/26534966)
PUI
  L609210065
DOI
  10.1158/1078-0432.CCR-15-0491
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-15-0491
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 211
TITLE
  Endocrinopathies induced by immune-checkpoint inhibitors in advanced 
non-small cell lung cancer
AUTHOR NAMES
  Rossi E.
  Sgambato A.
  De Chiara G.
  Casaluce F.
  Losanno T.
  Sacco P.C.
  Santabarbara G.
  Gridelli C.
AUTHOR ADDRESSES
  (Rossi E.; Sacco P.C.; Santabarbara G.; Gridelli C., cgridelli@libero.it) 
Division of Medical Oncology, S. G. Moscati Hospital, Avellino, Italy.
(Sgambato A.; Casaluce F.) Department of Clinical and Experimental Medicine, 
Second University of Naples, Naples, Italy.
(De Chiara G.) Division of Pathologic Anatomy, S. G. Moscati Hospital, 
Avellino, Italy.
(Losanno T.) Department of Experimental Medicine, Sapienza University, Rome, 
Italy.
CORRESPONDENCE ADDRESS
  C. Gridelli, Division of Medical Oncology, S. G. Moscati Hospital, Avellino, 
Italy. Email: cgridelli@libero.it
SOURCE
  Expert Review of Clinical Pharmacology (2016) 9:3 (419-428). Date of 
Publication: 3 Mar 2016
ISSN
  1751-2441 (electronic)
  1751-2433
BOOK PUBLISHER
  Taylor and Francis Ltd, info@expert-reviews.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  atezolizumab (adverse drug reaction, drug therapy)
  cytotoxic T lymphocyte antigen 4
  durvalumab (adverse drug reaction, drug therapy)
  ipilimumab (drug therapy)
  monoclonal antibody (adverse drug reaction, drug therapy)
  nivolumab (adverse drug reaction, drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
  ticilimumab (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  endocrine disease (side effect, side effect)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency
  cancer immunotherapy
  human
  hyperthyroidism
  hypophysitis
  hypothyroidism
  practice guideline
  review
DRUG TRADE NAMES
  medi 4736
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  durvalumab (1428935-60-7)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160147595
MEDLINE PMID
  26681547 (http://www.ncbi.nlm.nih.gov/pubmed/26681547)
PUI
  L608511599
DOI
  10.1586/17512433.2016.1133289
FULL TEXT LINK
  http://dx.doi.org/10.1586/17512433.2016.1133289
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 212
TITLE
  Ipilimumab-induced Ocular and Orbital Inflammation - A Case Series and 
Review of the Literature
AUTHOR NAMES
  Papavasileiou E.
  Prasad S.
  Freitag S.K.
  Sobrin L.
  Lobo A.-M.
AUTHOR ADDRESSES
  (Papavasileiou E.; Freitag S.K.; Sobrin L.; Lobo A.-M., 
Ann-Marie_Lobo@meei.harvard.edu) Department of Ophthalmology, Harvard 
Medical School, Massachusetts Eye and Ear Infirmary, 243 Charles Street, 
Boston, United States.
(Prasad S.) Department of Neurology, Harvard Medical School, Brigham and 
Womens Hospital, Boston, United States.
CORRESPONDENCE ADDRESS
  A.-M. Lobo, Department of Ophthalmology, Harvard Medical School, 
Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, United 
States. Email: Ann-Marie_Lobo@meei.harvard.edu
SOURCE
  Ocular Immunology and Inflammation (2016) 24:2 (140-146). Date of 
Publication: 3 Mar 2016
ISSN
  1744-5078 (electronic)
  0927-3948
BOOK PUBLISHER
  Taylor and Francis Ltd, healthcare.enquiries@informa.com
ABSTRACT
  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.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.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.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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  aciclovir (drug therapy, oral drug administration)
  bevacizumab (drug therapy)
  corticosteroid (drug therapy, oral drug administration, topical drug 
administration)
  erythromycin (drug therapy, topical drug administration)
  hydrocortisone (drug therapy)
  methylprednisolone (intravenous drug administration)
  prednisolone acetate (drug therapy, topical drug administration)
  prednisone (oral drug administration)
  steroid (drug therapy, intravenous drug administration, oral drug 
administration, topical drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  eye inflammation (drug therapy, side effect, drug therapy, side effect)
  orbit inflammation (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  autoimmune hepatitis (side effect)
  autoimmune pancreatitis (side effect)
  cancer chemotherapy
  cancer growth
  chemosis (drug therapy, side effect)
  clinical article
  clinical feature
  colitis (side effect)
  corticosteroid therapy
  diplopia (drug therapy, side effect)
  drug withdrawal
  exophthalmos (drug therapy, side effect)
  eye pain (side effect)
  eyelid edema (side effect)
  female
  human
  hypophysitis (drug therapy, side effect)
  keratitis (drug therapy)
  male
  metastatic melanoma (drug therapy)
  middle aged
  neuroimaging
  nuclear magnetic resonance imaging
  ophthalmoplegia (drug therapy)
  retrospective study
  systemic therapy
  thyroiditis (drug therapy, side effect)
  topical treatment
  uveitis (drug therapy)
CAS REGISTRY NUMBERS
  aciclovir (59277-89-3)
  bevacizumab (216974-75-3)
  erythromycin (114-07-8, 70536-18-4)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisolone acetate (52-21-1, 52628-64-5)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Dermatology and Venereology (13)
  Radiology (14)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015326933
MEDLINE PMID
  25760920 (http://www.ncbi.nlm.nih.gov/pubmed/25760920)
PUI
  L605775448
DOI
  10.3109/09273948.2014.1001858
FULL TEXT LINK
  http://dx.doi.org/10.3109/09273948.2014.1001858
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 213
TITLE
  Management of toxicities of immune checkpoint inhibitors
AUTHOR NAMES
  Spain L.
  Diem S.
  Larkin J.
AUTHOR ADDRESSES
  (Spain L.; Diem S.; Larkin J., james.larkin@rmh.nhs.uk) Melanoma Unit, Royal 
Marsden Foundation Trust, Fulham Road, London, United Kingdom.
CORRESPONDENCE ADDRESS
  J. Larkin, Melanoma Unit, Royal Marsden Foundation Trust, Fulham Road, 
London, United Kingdom. Email: james.larkin@rmh.nhs.uk
SOURCE
  Cancer Treatment Reviews (2016) 44 (51-60). Date of Publication: 1 Mar 2016
ISSN
  1532-1967 (electronic)
  0305-7372
BOOK PUBLISHER
  W.B. Saunders Ltd
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction, drug therapy)
  immune checkpoint inhibitor (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  immunosuppressive agent (drug therapy)
  ipilimumab (adverse drug reaction, drug therapy)
  nivolumab (adverse drug reaction, drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
  prednisolone (drug therapy)
  steroid (drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug safety
  patient care
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  anemia (side effect)
  antineoplastic activity
  arthralgia (side effect)
  cancer chemotherapy
  cancer grading
  cancer immunotherapy
  cancer survival
  cardiotoxicity (side effect)
  clinical trial (topic)
  colitis (side effect)
  conjunctivitis (side effect)
  diabetes mellitus (drug therapy, side effect)
  diarrhea (side effect)
  disease severity
  drug efficacy
  endocrine disease (side effect)
  endocrine ophthalmopathy (side effect)
  enterocolitis (side effect)
  eye toxicity (side effect)
  fatigue (side effect)
  gastritis (drug therapy, side effect)
  gastrointestinal symptom (side effect)
  hepatitis (side effect)
  human
  hypertension (drug therapy, side effect)
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  immune response
  insomnia (drug therapy, side effect)
  iritis (side effect)
  kidney cancer (drug therapy)
  kidney injury (side effect)
  lung cancer (drug therapy)
  lymphoma (drug therapy)
  melanoma (drug therapy)
  mesothelioma (drug therapy)
  mood disorder (drug therapy, side effect)
  myalgia (side effect)
  myositis (side effect)
  nephritis (side effect)
  neurologic disease (side effect)
  neutropenia (side effect)
  opportunistic infection (drug therapy, side effect)
  osteoporosis (drug therapy)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  Pneumocystis pneumonia (drug therapy, side effect)
  pneumonia (side effect)
  pruritus (side effect)
  rash (side effect)
  review
  rheumatic disease (side effect)
  rheumatoid arthritis (side effect)
  risk benefit analysis
  skin toxicity (side effect)
  thrombocytopenia (side effect)
  thyroid disease (side effect)
  treatment indication
  uveitis (side effect)
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  prednisolone (50-24-8)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02041533, NCT02279862)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160169679
MEDLINE PMID
  26874776 (http://www.ncbi.nlm.nih.gov/pubmed/26874776)
PUI
  L608605639
DOI
  10.1016/j.ctrv.2016.02.001
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ctrv.2016.02.001
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 214
TITLE
  Targeted therapy and immunotherapy in ovarian cancer
AUTHOR NAMES
  Kim J.-W.
AUTHOR ADDRESSES
  (Kim J.-W., kjwksh@snu.ac.kr) Department of Obstetrics and Gynecology, Seoul 
National University, College of Medicine, Seoul, South Korea.
CORRESPONDENCE ADDRESS
  J.-W. Kim, Department of Obstetrics and Gynecology, Seoul National 
University, College of Medicine, Seoul, South Korea. Email: kjwksh@snu.ac.kr
SOURCE
  Journal of the Korean Medical Association (2016) 59:3 (180-188). Date of 
Publication: 1 Mar 2016
ISSN
  1975-8456
BOOK PUBLISHER
  Korean Medical Association, intl@kma.org
ABSTRACT
  Epithelial ovarian cancer is one of the last treatment areas to be 
influenced by the 'personalized medicine' bandwagon. Some anti-angiogenic 
agents, poly (ADP-ribose) polymerase (PARP), and immune checkpoint 
inhibitors have shown efficacy in early stages of development for the 
treatment of epithelial ovarian cancer. As a result of vigorous clinical 
trials, bevacizumab, cediranib, pazopanib, olaparib, and rucaparib, either 
used alone or in adjunct to conventional cytotoxic agents, have all been 
shown to improve progression-free survival in first-line/maintenance, 
platinumresistant or sensitive recurrent settings. A biomarker for 
bevacizumab is currently elusive. Olaparib is the first drug approved for 
the treatment of high-grade serous tumors and requires routine testing for 
BRCA mutation. Trial results of PARP inhibitors in the homologous 
recombination-deficient (non BRCA mutation) population are awaited and the 
introduction of these agents into the clinic will require robust methods of 
detecting homologous recombinationdeficiency. Second-generation studies 
combining anti-angiogenic agents with PARP inhibitors are in progress and 
early results in the recurrent setting are encouraging. Trials with immune 
checkpoint inhibitors such as nivolumab produced prolonged responses in a 
small set of ovarian cancer cases and need further exploration, for example 
in combination with anti-angiogenic agents. The application of targeted 
agents and immunologics, alone or in combination, to induce a survival 
advantage in patients with epithelial ovarian cancer should be continued.
EMTREE DRUG INDEX TERMS
  bevacizumab (clinical trial, drug therapy)
  cediranib (clinical trial, drug therapy)
  cytotoxic agent (clinical trial, drug therapy)
  nivolumab (clinical trial, drug therapy)
  olaparib (clinical trial, drug therapy)
  pazopanib (clinical trial, drug therapy)
  rucaparib (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  molecularly targeted therapy
  ovary cancer (drug therapy, drug therapy, therapy)
EMTREE MEDICAL INDEX TERMS
  article
  clinical trial (topic)
  gene mutation
  homologous recombination
  human
  progression free survival
  treatment response
  tumor suppressor gene
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  cediranib (288383-20-0, 857036-77-2)
  nivolumab (946414-94-4)
  olaparib (763113-22-0)
  pazopanib (444731-52-6, 635702-64-6)
  rucaparib (283173-50-2, 459868-92-9)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  Korean
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160256725
PUI
  L609354581
DOI
  10.5124/jkma.2016.59.3.180
FULL TEXT LINK
  http://dx.doi.org/10.5124/jkma.2016.59.3.180
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 215
TITLE
  Medical treatment involving investigational drugs and genetic profile of 
thymic carcinoma
AUTHOR NAMES
  Asao T.
  Fujiwara Y.
  Sunami K.
  Kitahara S.
  Goto Y.
  Kanda S.
  Horinouchi H.
  Nokihara H.
  Yamamoto N.
  Ichikawa H.
  Kohno T.
  Tsuta K.
  Watanabe S.-I.
  Takahashi K.
  Ohe Y.
AUTHOR ADDRESSES
  (Asao T.; Fujiwara Y., yutakafu@ncc.go.jp; Sunami K.; Kitahara S.; Goto Y.; 
Kanda S.; Horinouchi H.; Nokihara H.; Yamamoto N.; Ohe Y.) Department of 
Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
(Asao T.; Takahashi K.) Department of Respiratory Medicine, Juntendo 
University Graduate School of Medicine, Tokyo, Japan.
(Ichikawa H.) Division of Genomics, National Cancer Center Research 
Institute, Tokyo, Japan.
(Kohno T.) Division of Genome Biology, National Cancer Center Research 
Institute, Tokyo, Japan.
(Tsuta K.) Department of Pathology, National Cancer Center Hospital, Tokyo, 
Japan.
(Tsuta K.) Department of Clinical Sciences and Laboratory Medicine, Kansai 
Medical University, Moriguchi, Japan.
(Watanabe S.-I.) Department of Thoracic Surgery, National Cancer Center 
Hospital, Tokyo, Japan.
CORRESPONDENCE ADDRESS
  Y. Fujiwara, Corresponding author at: Department of Thoracic Oncology, 
National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, Japan. 
Email: yutakafu@ncc.go.jp
SOURCE
  Lung Cancer (2016) 93 (77-81). Date of Publication: 1 Mar 2016
ISSN
  1872-8332 (electronic)
  0169-5002
BOOK PUBLISHER
  Elsevier Ireland Ltd
ABSTRACT
  Background: Thymic carcinoma is a rare neoplasm of the thymus, and 
information regarding its genetic profile and optimal medical treatment is 
limited. We sought to characterize the genetic profile of thymic carcinoma 
and to evaluate the efficacy of various medical treatments, including 
treatment with tyrosine kinase inhibitors (TKIs), cytotoxic agents, and 
immune checkpoint inhibitors. Methods: We retrospectively reviewed medical 
records of 64 consecutive patients with thymic carcinoma at the National 
Cancer Center Hospital between April 1973 and March 2014. We analyzed 
treatment course of patients who underwent medical treatment involving 
investigational drugs. For patients with available tissue samples, targeted 
sequencing of 50 cancer-related genes using next-generation sequencing was 
performed. Results: Thirty-six patients had received chemotherapy. Median 
progression-free survival in patients receiving first-line chemotherapy was 
7.07 months (95% confidence interval, 5.67-8.93). Median survival time was 
32.6 months (95% confidence interval, 23.2-43.4). As second- or later-line 
chemotherapy, a total of 13 patients were treated with 24 investigational 
drugs, including 8 multi-targeted TKIs, 5 cytotoxic agents, and 2 immune 
checkpoint inhibitors. Six (24%) of the patients treated with 
investigational drugs maintained disease control for at least 6 months. 
Tissue samples of 52 patients (81.3%) were available for targeted 
sequencing, consisting of 52 formalin-fixed, paraffin-embedded (FFPE) and 16 
fresh frozen tissue samples. The genetic alterations of TP53, KRAS, FBXW7, 
and NRAS were detected in 7 patients (13.5%), and no KIT mutations were 
noted. Conclusions: Multi-targeted TKIs exhibited potential clinical 
efficacy for previously-treated thymic carcinoma. The frequency of genetic 
alterations in this study was low, with no apparent relationship with the 
efficacy of chemotherapy.
EMTREE DRUG INDEX TERMS
  anthracycline (drug therapy)
  carboplatin (drug therapy)
  cytotoxic agent (drug therapy)
  docetaxel (drug therapy)
  gemcitabine (drug therapy)
  K ras protein (endogenous compound)
  paclitaxel (drug therapy)
  protein p53 (endogenous compound)
  protein tyrosine kinase inhibitor (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thymus cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer chemotherapy
  cancer control
  cancer survival
  drug efficacy
  FBXW7 gene
  female
  gene mutation
  human
  human tissue
  major clinical study
  male
  median survival time
  medical record review
  next generation sequencing
  oncogene
  oncogene N ras
  priority journal
  progression free survival
  retrospective study
  treatment response
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  docetaxel (114977-28-5)
  gemcitabine (103882-84-4)
  paclitaxel (33069-62-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160183617
MEDLINE PMID
  26898618 (http://www.ncbi.nlm.nih.gov/pubmed/26898618)
PUI
  L608724570
DOI
  10.1016/j.lungcan.2016.01.004
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.lungcan.2016.01.004
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 216
TITLE
  New Approaches for Immune Directed Treatment for Ovarian Cancer
AUTHOR NAMES
  Hardwick N.
  Frankel P.H.
  Cristea M.
AUTHOR ADDRESSES
  (Hardwick N.) Department of Experimental Therapeutics, Beckman Research 
Institute of City of Hope, 1500 East Duarte Road, Duarte, United States.
(Frankel P.H.) Division of Biostatistics, Beckman Research Institute of City 
of Hope, 1500 East Duarte Road, Duarte, United States.
(Cristea M., mcristea@coh.org) Department of Medical Oncology, City of Hope, 
1500 East Duarte Road, Duarte, United States.
CORRESPONDENCE ADDRESS
  M. Cristea, Department of Medical Oncology, City of Hope, 1500 East Duarte 
Road, Duarte, United States. Email: mcristea@coh.org
SOURCE
  Current Treatment Options in Oncology (2016) 17:3 Article Number: 14. Date 
of Publication: 1 Mar 2016
ISSN
  1534-6277 (electronic)
  1527-2729
BOOK PUBLISHER
  Springer New York LLC, barbara.b.bertram@gsk.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  abagovomab (drug therapy)
  avelumab (drug therapy)
  cancer vaccine (drug therapy)
  farletuzumab (drug therapy)
  nivolumab (drug therapy)
  peptide vaccine (drug therapy)
  virus vaccine (drug therapy)
  volociximab (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer (drug therapy, drug therapy, prevention, therapy)
EMTREE MEDICAL INDEX TERMS
  adoptive cell therapy
  cancer immunization
  cell therapy
  dendritic cell therapy
  genetic engineering
  human
  multicenter study (topic)
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  randomized controlled trial (topic)
  review
  T lymphocyte
  tumor associated leukocyte
DRUG TRADE NAMES
  ACA 125
CAS REGISTRY NUMBERS
  abagovomab (792921-10-9)
  avelumab (1537032-82-8)
  farletuzumab (896723-44-7)
  nivolumab (946414-94-4)
  volociximab (558480-40-3)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00703105, NCT01132014, NCT01246440, NCT01489371, NCT01556841, NCT02111941, NCT02132988, NCT02166905, NCT02275039, NCT02346747, NCT02470559, NCT02482090, NCT02484404)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160193592
MEDLINE PMID
  26942589 (http://www.ncbi.nlm.nih.gov/pubmed/26942589)
PUI
  L608767509
DOI
  10.1007/s11864-016-0389-1
FULL TEXT LINK
  http://dx.doi.org/10.1007/s11864-016-0389-1
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 217
TITLE
  Nivolumab in resected and unresectable metastatic melanoma: Characteristics 
of immune-related adverse events and association with outcomes
AUTHOR NAMES
  Freeman-Keller M.
  Kim Y.
  Cronin H.
  Richards A.
  Gibney G.
  Weber J.S.
AUTHOR ADDRESSES
  (Freeman-Keller M., morganna.freemankeller@moffitt.org) Department of 
Graduate Medical Education, University of South Florida, Moffitt Cancer 
Center, MCC-GME, 12902 USF Magnolia Drive, Tampa, United States.
(Kim Y.) Department of Biostatistics and Bioinformatics, Moffitt Cancer 
Center, Tampa, United States.
(Cronin H.; Richards A.) Clinical Trials Office, Moffitt Cancer Center, 
Tampa, United States.
(Gibney G.) Department of Cutaneous Oncology, Lombardi Comprehensive Cancer 
Center, Washington, United States.
(Weber J.S.) Donald A. Adam Comprehensive Melanoma Research Center, Moffitt 
Cancer Center, Tampa, United States.
CORRESPONDENCE ADDRESS
  M. Freeman-Keller, Department of Graduate Medical Education, University of 
South Florida, Moffitt Cancer Center, MCC-GME, 12902 USF Magnolia Drive, 
Tampa, United States. Email: morganna.freemankeller@moffitt.org
SOURCE
  Clinical Cancer Research (2016) 22:4 (886-894). Date of Publication: 15 Feb 
2016
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  Purpose: Retrospective analysis of irAEs in melanoma patients treated with 
nivolumab. 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. 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). Conclusions: 
Cutaneous irAEs are associated with improved survival in melanoma patients 
treated with nivolumab, and clinical benefit should be validated in larger 
prospective analyses.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
EMTREE DRUG INDEX TERMS
  amylase (endogenous compound)
  peptide vaccine (drug combination, drug therapy)
  triacylglycerol lipase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy, surgery)
EMTREE MEDICAL INDEX TERMS
  article
  cancer surgery
  colitis (side effect)
  cytotoxic T lymphocyte
  diarrhea (side effect)
  endocrine disease (side effect)
  enteritis (side effect)
  fatigue (side effect)
  gastrointestinal symptom (side effect)
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  major clinical study
  mucosa inflammation (side effect)
  myalgia (side effect)
  overall survival
  phase 1 clinical trial
  pneumonia (side effect)
  priority journal
  prospective study
  pruritus (side effect)
  rash (side effect)
  remission
  retrospective study
  survival
  treatment outcome
  tumor regression
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  amylase (9000-90-2, 9000-92-4, 9001-19-8)
  nivolumab (946414-94-4)
  triacylglycerol lipase (9001-62-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01176461, NCT01176474)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160327352
MEDLINE PMID
  26446948 (http://www.ncbi.nlm.nih.gov/pubmed/26446948)
PUI
  L609943386
DOI
  10.1158/1078-0432.CCR-15-1136
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-15-1136
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 218
TITLE
  Risk of endocrine complications in cancer patients treated with immune check 
point inhibitors: A meta-analysis
AUTHOR NAMES
  Abdel-Rahman O.
  Elhalawani H.
  Fouad M.
AUTHOR ADDRESSES
  (Abdel-Rahman O., omar.abdelrhman@med.asu.edu.eg; Elhalawani H.) Clinical 
Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, 
Egypt.
(Fouad M.) Medical Microbiology and Immunology Department, Faculty of 
Medicine, Ain Shams University, Cairo, Egypt.
CORRESPONDENCE ADDRESS
  O. Abdel-Rahman, Clinical Oncology Department, Faculty of Medicine, Ain 
Shams University, Cairo, Egypt. Email: omar.abdelrhman@med.asu.edu.eg
SOURCE
  Future Oncology (2016) 12:3 (413-425). Date of Publication: 1 Feb 2016
ISSN
  1744-8301 (electronic)
  1479-6694
BOOK PUBLISHER
  Future Medicine Ltd., info@futuremedicine.com
ABSTRACT
  Background: We performed a meta-analysis of the risk of endocrine adverse 
events associated with immune check point inhibitors. Methods: Eligible 
studies included randomized trials of cancer patients on immune checkpoint 
inhibitors; describing events of hypothyroidism, hyperthyroidism, 
hypophysitis and adrenal insufficiency. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction)
  nivolumab (adverse drug reaction)
  pembrolizumab (adverse drug reaction)
  pidilizumab (adverse drug reaction)
  ticilimumab (adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  cancer patient
  dose response
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  incidence
  meta analysis
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  randomized controlled trial (topic)
  review
  risk factor
  systematic review
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  pidilizumab (1036730-42-3)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160088671
MEDLINE PMID
  26775673 (http://www.ncbi.nlm.nih.gov/pubmed/26775673)
PUI
  L608016883
DOI
  10.2217/fon.15.222
FULL TEXT LINK
  http://dx.doi.org/10.2217/fon.15.222
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 219
TITLE
  2016 Gastrointestinal Cancers Symposium
AUTHOR ADDRESSES
  SOURCE
  Journal of Clinical Oncology (2016) 34:4 SUPPL. 1. Date of Publication: 1 
Feb 2016
CONFERENCE NAME
  2016 Gastrointestinal Cancers Symposium
CONFERENCE LOCATION
  San Francisco, CA, United States
CONFERENCE DATE
  2016-01-21 to 2016-01-23
ISSN
  0732-183X
BOOK PUBLISHER
  American Society of Clinical Oncology
ABSTRACT
  The proceedings contain 767 papers. The topics discussed include: resected 
pancreatic cancer (PC): impact of adjuvant therapy (Rx) at a highvolume 
center (HVC) on overall survival (OS); phase III randomized study of 
sorafenib plus doxorubicin versus sorafenib in patients with advanced 
hepatocellular carcinoma (HCC): CALGB 80802 (Alliance); evofosfamide 
(TH-302) in combination with gemcitabine in previously untreated patients 
with metastatic or locally advanced unresectable pancreatic ductal 
adenocarcinoma: primary analysis of the randomized, double-blind phase III 
MAESTRO study; NETTER-1 phase III: progression-free survival, radiographic 
response, and preliminary overall survival results in patients with midgut 
neuroendocrine tumors treated with 177-LuDotatate; and PD-1 blockade in 
mismatch repair deficient non-colorectal gastrointestinal cancers.
EMTREE DRUG INDEX TERMS
  doxorubicin
  evofosfamide
  gemcitabine
  sorafenib
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  digestive system cancer
EMTREE MEDICAL INDEX TERMS
  adjuvant therapy
  human
  liver cell carcinoma
  midgut
  mismatch repair
  neuroendocrine tumor
  overall survival
  pancreas adenocarcinoma
  pancreas cancer
  patient
  progression free survival
LANGUAGE OF ARTICLE
  English
PUI
  L72225346
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 220
TITLE
  CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells
AUTHOR NAMES
  Katsuta E.
  Tanaka S.
  Mogushi K.
  Shimada S.
  Akiyama Y.
  Aihara A.
  Matsumura S.
  Mitsunori Y.
  Ban D.
  Ochiai T.
  Kudo A.
  Fukamachi H.
  Tanaka H.
  Nakayama K.
  Arii S.
  Tanabe M.
AUTHOR ADDRESSES
  (Katsuta E.; Tanaka S., tanaka.monc@tmd.ac.jp; Shimada S.; Akiyama Y.; 
Fukamachi H.) Departments of Molecular Oncology, Graduate School of 
Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo, Japan.
(Katsuta E.; Tanaka S., tanaka.monc@tmd.ac.jp; Aihara A.; Matsumura S.; 
Mitsunori Y.; Ban D.; Ochiai T.; Kudo A.; Arii S.; Tanabe M.) Departments of 
Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo, 
Japan.
(Mogushi K.; Tanaka H.) Departments of Bioinformatics, Medical Research 
Institute, Tokyo, Japan.
(Nakayama K.) Oxygen Biology Unit, Frontier Research Laboratory, Medical 
Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
CORRESPONDENCE ADDRESS
  S. Tanaka, Departments of Molecular Oncology, Graduate School of Medicine, 
Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo, Japan. Email: 
tanaka.monc@tmd.ac.jp
SOURCE
  International Journal of Oncology (2016) 48:2 (657-669). Date of 
Publication: 1 Feb 2016
ISSN
  1791-2423 (electronic)
  1019-6439
BOOK PUBLISHER
  Spandidos Publications, 10 Vriaxidos Street, Athens, Greece.
ABSTRACT
  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 c 
ells, b ut n ot c ontrol 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  5' nucleotidase (endogenous compound)
EMTREE DRUG INDEX TERMS
  aldehyde dehydrogenase (endogenous compound)
  Ki 67 antigen (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer stem cell
  pancreas islet cell tumor
EMTREE MEDICAL INDEX TERMS
  adult
  animal cell
  animal experiment
  animal model
  animal tissue
  article
  carcinogenesis
  cell invasion
  cell motility
  cell population
  cell proliferation
  clinical article
  controlled study
  DNA microarray
  drug targeting
  enzyme activity
  female
  gene expression
  gene overexpression
  human
  immunocytochemistry
  immunohistochemistry
  in vitro study
  in vivo study
  liver metastasis
  lymph node metastasis
  male
  mesenchymal stem cell
  mouse
  nonhuman
  peritoneum metastasis
  priority journal
  protein expression
  tumor growth
CAS REGISTRY NUMBERS
  5' nucleotidase (9027-73-0)
  aldehyde dehydrogenase (37353-37-0, 9028-86-8)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160104035
MEDLINE PMID
  26691441 (http://www.ncbi.nlm.nih.gov/pubmed/26691441)
PUI
  L608134942
DOI
  10.3892/ijo.2015.3299
FULL TEXT LINK
  http://dx.doi.org/10.3892/ijo.2015.3299
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 221
TITLE
  Immune-related adverse events with immune checkpoint blockade: A 
comprehensive review
AUTHOR NAMES
  Michot J.M.
  Bigenwald C.
  Champiat S.
  Collins M.
  Carbonnel F.
  Postel-Vinay S.
  Berdelou A.
  Varga A.
  Bahleda R.
  Hollebecque A.
  Massard C.
  Fuerea A.
  Ribrag V.
  Gazzah A.
  Armand J.P.
  Amellal N.
  Angevin E.
  Noel N.
  Boutros C.
  Mateus C.
  Robert C.
  Soria J.C.
  Marabelle A.
  Lambotte O.
AUTHOR ADDRESSES
  (Michot J.M., jean-marie.michot@gustaveroussy.fr; Bigenwald C.; Berdelou A.; 
Fuerea A.; Ribrag V.; Boutros C.; Mateus C.; Robert C.) Department of 
Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, Villejuif, 
France.
(Michot J.M., jean-marie.michot@gustaveroussy.fr; Champiat S.; Postel-Vinay 
S.; Varga A.; Bahleda R.; Hollebecque A.; Massard C.; Fuerea A.; Ribrag V.; 
Gazzah A.; Armand J.P.; Amellal N.; Angevin E.; Boutros C.; Mateus C.; 
Robert C.; Soria J.C.; Marabelle A.) Drug Development Department, Gustave 
Roussy Comprehensive Cancer Center, Villejuif, France.
(Michot J.M., jean-marie.michot@gustaveroussy.fr; Noel N.; Boutros C.; 
Mateus C.; Robert C.; Lambotte O.) Internal Medicine and Clinical Immunology 
Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire 
Bicêtre, Le Kremlin Bicêtre, France.
(Collins M.; Carbonnel F.) Gastroenterology Department, Assistance 
Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, Le Kremlin 
Bicêtre, France.
(Collins M.; Carbonnel F.; Noel N.; Lambotte O.) Université Paris Sud 11, Le 
Kremlin-Bicêtre, France.
(Noel N.; Lambotte O.) CEA, DSV, iMETI, Division of Immunovirology, IDMIT, 
Fontenay-aux-Roses, France.
(Noel N.; Lambotte O.) INSERM, U1184, Center for Immunology of Viral 
Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France.
CORRESPONDENCE ADDRESS
  J.M. Michot, Drug Development Department, Gustave Roussy Comprehensive 
Cancer Center, Villejuif, France. Email: jean-marie.michot@gustaveroussy.fr
SOURCE
  European Journal of Cancer (2016) 54 (139-148). Date of Publication: 1 Feb 
2016
ISSN
  1879-0852 (electronic)
  0959-8049
BOOK PUBLISHER
  Elsevier Ltd
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immune checkpoint blocker (adverse drug reaction)
  immunomodulating agent (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  biological marker (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  steroid (drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  immune related adverse event (drug therapy, side effect, drug therapy, side 
effect)
  immunopathology (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  blood toxicity (side effect)
  cancer patient
  drug efficacy
  drug exposure
  eye toxicity (side effect)
  gastrointestinal disease (side effect)
  human
  hypophysitis (side effect)
  immune response
  immunocompetent cell
  liver toxicity (side effect)
  lung toxicity (side effect)
  nephrotoxicity (side effect)
  neurotoxicity (side effect)
  oncologist
  pancreas disease (side effect)
  polyarthritis (side effect)
  practice guideline
  priority journal
  review
  skin toxicity (side effect)
  target cell
  thyroid disease (side effect)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160023347
MEDLINE PMID
  26765102 (http://www.ncbi.nlm.nih.gov/pubmed/26765102)
PUI
  L607488744
DOI
  10.1016/j.ejca.2015.11.016
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ejca.2015.11.016
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 222
TITLE
  Real-world efficacy, toxicity and clinical management of ipilimumab 
treatment in metastatic melanoma
AUTHOR NAMES
  Khoja L.
  Atenafu E.G.
  Ye Q.
  Gedye C.
  Chappell M.
  Hogg D.
  Butler M.O.
  Joshua A.M.
AUTHOR ADDRESSES
  (Khoja L., leila.khoja@uhn.ca; Atenafu E.G.; Ye Q.; Gedye C.; Chappell M.; 
Hogg D.; Butler M.O.; Joshua A.M., anthony.joshua@uhn.ca) Department of 
Medical Oncology, Princess Margaret Cancer Centre, Toronto, Canada.
CORRESPONDENCE ADDRESS
  L. Khoja, Department of Medical Oncology, Princess Margaret Cancer Centre, 
610 University Avenue, Toronto, Canada. Email: leila.khoja@uhn.ca
SOURCE
  Oncology Letters (2016) 11:2 (1581-1585). Date of Publication: 1 Feb 2016
ISSN
  1792-1082 (electronic)
  1792-1074
BOOK PUBLISHER
  Spandidos Publications, 10 Vriaxidos Street, Athens, Greece.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  infliximab (drug therapy)
  prednisone (drug therapy)
  thyroxine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  arthritis (drug therapy, side effect)
  article
  bone metastasis (side effect)
  clinical feature
  colitis (side effect)
  diarrhea (drug therapy, side effect)
  drug efficacy
  female
  follow up
  hepatitis (drug therapy, side effect)
  human
  hypophysitis (drug therapy, side effect)
  major clinical study
  male
  middle aged
  multiple cycle treatment
  myositis (drug therapy, side effect)
  overall survival
  pneumonia (drug therapy, side effect)
  progression free survival
  rash (drug therapy, side effect)
  retrospective study
  thyroid disease (side effect)
  treatment outcome
  very elderly
CAS REGISTRY NUMBERS
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160049741
PUI
  L607786469
DOI
  10.3892/ol.2015.4069
FULL TEXT LINK
  http://dx.doi.org/10.3892/ol.2015.4069
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 223
TITLE
  Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting 
Autoimmune Disorders
AUTHOR NAMES
  Johnson D.B.
  Sullivan R.J.
  Ott P.A.
  Carlino M.S.
  Khushalani N.I.
  Ye F.
  Guminski A.
  Puzanov I.
  Lawrence D.P.
  Buchbinder E.I.
  Mudigonda T.
  Spencer K.
  Bender C.
  Lee J.
  Kaufman H.L.
  Menzies A.M.
  Hassel J.C.
  Mehnert J.M.
  Sosman J.A.
  Long G.V.
  Clark J.I.
AUTHOR ADDRESSES
  (Johnson D.B.) Department of Medicine, Vanderbilt University Medical Center, 
Nashville, Tennessee
(Sullivan R.J.) Department of Medicine, Massachusetts General Hospital, 
Boston, Massachusetts
(Ott P.A.) Department of Medicine, Dana-Farber Cancer Institute, Boston, 
Massachusetts
(Carlino M.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
(Khushalani N.I.) Department of Medicine, Roswell Park Cancer Institute, 
Buffalo, New York
(Ye F.) Department of Biostatistics, Vanderbilt University Medical Center, 
Nashville, Tennessee
(Guminski A.) Department of Medicine, University of Sydney, Sydney, New 
South Wales, Australia8Department of Medicine, Melanoma Institute Australia, 
Sydney, New South Wales, Australia
(Puzanov I.) Department of Medicine, Vanderbilt University Medical Center, 
Nashville, Tennessee
(Lawrence D.P.) Department of Medicine, Massachusetts General Hospital, 
Boston, Massachusetts
(Buchbinder E.I.) Department of Medicine, Dana-Farber Cancer Institute, 
Boston, Massachusetts
(Mudigonda T.) medical student at School of Medicine, Vanderbilt University 
Medical Center, Nashville, Tennessee
(Spencer K.) Department of Medicine, Rutgers Cancer Institute of New Jersey, 
New Brunswick
(Bender C.) Department of Medicine, Heidelberg University Hospital, 
Heidelberg, Germany
(Lee J.) 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
(Kaufman H.L.) Department of Surgery, Rutgers Cancer Institute of New 
Jersey, New Brunswick
(Menzies A.M.) Department of Medicine, University of Sydney, Sydney, New 
South Wales, Australia8Department of Medicine, Melanoma Institute Australia, 
Sydney, New South Wales, Australia
(Hassel J.C.) Department of Medicine, Heidelberg University Hospital, 
Heidelberg, Germany
(Mehnert J.M.) Department of Medicine, Rutgers Cancer Institute of New 
Jersey, New Brunswick
(Sosman J.A.) Department of Medicine, Vanderbilt University Medical Center, 
Nashville, Tennessee
(Long G.V.) Department of Medicine, University of Sydney, Sydney, New South 
Wales, Australia8Department of Medicine, Melanoma Institute Australia, 
Sydney, New South Wales, Australia
(Clark J.I.) Department of Medicine, Loyola University Medical Center, 
Maywood, Illinois
SOURCE
  JAMA oncology (2016) 2:2 (234-240). Date of Publication: 1 Feb 2016
ISSN
  2374-2445 (electronic)
ABSTRACT
  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.EXPOSURE: Ipilimumab therapy.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.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.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.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.OBJECTIVE: To determine the safety and efficacy of ipilimumab therapy 
in patients with advanced melanoma with preexisting autoimmune disorders.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (adverse drug reaction, drug therapy)
  ipilimumab
  monoclonal antibody (adverse drug reaction, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmunity
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  autoimmune disease (diagnosis)
  clinical trial
  complication
  female
  human
  immunology
  male
  melanoma (drug therapy)
  middle aged
  multicenter study
  pathology
  patient selection
  retrospective study
  risk assessment
  risk factor
  skin tumor (drug therapy)
  tertiary care center
  time factor
  treatment outcome
  very elderly
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  26633184 (http://www.ncbi.nlm.nih.gov/pubmed/26633184)
PUI
  L613637858
DOI
  10.1001/jamaoncol.2015.4368
FULL TEXT LINK
  http://dx.doi.org/10.1001/jamaoncol.2015.4368
COPYRIGHT
  Copyright 2016 Medline is the source for the citation and abstract of this 
record.

RECORD 224
TITLE
  Immunotherapy and hypophysitis: clinical presentation, treatment, and 
biologic insights
AUTHOR NAMES
  Faje A.
AUTHOR ADDRESSES
  (Faje A., afaje@partners.org) BUL 457, Neuroendocrine Unit, Massachusetts 
General Hospital and Harvard Medical School, 55 Fruit Street, Boston, United 
States.
CORRESPONDENCE ADDRESS
  A. Faje, BUL 457, Neuroendocrine Unit, Massachusetts General Hospital and 
Harvard Medical School, 55 Fruit Street, Boston, United States. Email: 
afaje@partners.org
SOURCE
  Pituitary (2016) 19:1 (82-92). Date of Publication: 1 Feb 2016
ISSN
  1573-7403 (electronic)
  1386-341X
BOOK PUBLISHER
  Springer New York LLC, barbara.b.bertram@gsk.com
ABSTRACT
  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. 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). 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  dexamethasone (drug therapy)
  glucocorticoid (drug therapy)
  prednisone (drug therapy)
  thyroid hormone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, 
epidemiology, side effect)
  immunotherapy
EMTREE MEDICAL INDEX TERMS
  clinical feature
  disease association
  disease surveillance
  drug effect
  drug safety
  hormone substitution
  human
  immunoregulation
  longitudinal study
  melanoma (drug therapy)
  nonhuman
  nuclear magnetic resonance imaging
  outcome assessment
  priority journal
  review
  risk factor
  treatment planning
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Public Health, Social Medicine and Epidemiology (17)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015201920
MEDLINE PMID
  26186958 (http://www.ncbi.nlm.nih.gov/pubmed/26186958)
PUI
  L605227425
DOI
  10.1007/s11102-015-0671-4
FULL TEXT LINK
  http://dx.doi.org/10.1007/s11102-015-0671-4
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 225
TITLE
  Serological aggravation of autoimmune thyroid disease in two cases receiving 
nivolumab
AUTHOR NAMES
  Narita T.
  Oiso N.
  Taketomo Y.
  Okahashi K.
  Yamauchi K.
  Sato M.
  Uchida S.
  Matsuda H.
  Kawada A.
AUTHOR ADDRESSES
  (Narita T., narita@med.kindai.ac.jp; Oiso N.; Okahashi K.; Yamauchi K.; Sato 
M.; Uchida S.; Matsuda H.; Kawada A.) Department of Dermatology, Kinki 
University, Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 
Japan.
(Taketomo Y.) Department of Endocrinology, Metabolism and Diabetes, Kinki 
University, Faculty of Medicine, Osaka-Sayama, Japan.
CORRESPONDENCE ADDRESS
  T. Narita, Department of Dermatology, Kinki University, Faculty of Medicine, 
377-2 Ohno-Higashi, Osaka-Sayama, Osaka, Japan. Email: 
narita@med.kindai.ac.jp
SOURCE
  Journal of Dermatology (2016) 43:2 (210-214). Date of Publication: 1 Feb 
2016
ISSN
  1346-8138 (electronic)
  0385-2407
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  beta interferon (drug therapy)
  cisplatin (drug therapy)
  dacarbazine (drug therapy)
  levothyroxine sodium (drug therapy)
  nimustine (drug therapy)
  potassium iodide (drug therapy)
  tamoxifen (drug therapy)
  thyroid extract (drug therapy)
  vincristine (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  Hashimoto disease (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  brain metastasis (radiotherapy, surgery)
  cancer palliative therapy
  cancer radiotherapy
  cancer surgery
  case report
  echography
  female
  human
  lymph node dissection
  lymph node metastasis (surgery)
  male
  melanoma (drug therapy, surgery)
  metastatic melanoma (drug therapy)
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  dacarbazine (4342-03-4)
  levothyroxine sodium (55-03-8)
  nimustine (42471-28-3, 55661-38-6)
  nivolumab (946414-94-4)
  potassium iodide (7681-11-0)
  tamoxifen (10540-29-1)
  vincristine (57-22-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015215532
MEDLINE PMID
  26198822 (http://www.ncbi.nlm.nih.gov/pubmed/26198822)
PUI
  L605298005
DOI
  10.1111/1346-8138.13028
FULL TEXT LINK
  http://dx.doi.org/10.1111/1346-8138.13028
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 226
TITLE
  PD-1 blunts the function of ovarian tumor-infiltrating dendritic cells by 
inactivating NF-κB
AUTHOR NAMES
  Karyampudi L.
  Lamichhane P.
  Krempski J.
  Kalli K.R.
  Behrens M.D.
  Vargas D.M.
  Hartmann L.C.
  Janco J.M.T.
  Dong H.
  Hedin K.E.
  Dietz A.B.
  Goode E.L.
  Knutson K.L.
AUTHOR ADDRESSES
  (Karyampudi L.; Lamichhane P.; Knutson K.L., knutson.keith@mayo.edu) Vaccine 
and Gene Therapy Institute, Port St. Lucie, United States.
(Lamichhane P.; Krempski J.; Behrens M.D.; Vargas D.M.; Dong H.; Hedin K.E.; 
Knutson K.L., knutson.keith@mayo.edu) Department of Immunology, Mayo Clinic, 
Rochester, United States.
(Kalli K.R.; Hartmann L.C.) Department of Oncology, Mayo Clinic, Rochester, 
United States.
(Janco J.M.T.) Department of Gynecologic Surgery Mayo Clinic, Mayo Clinic, 
Rochester, United States.
(Dietz A.B.) HumanCell Therapy Lab, Mayo Clinic, Rochester, United States.
(Goode E.L.) Department of Health Sciences Research, Mayo Clinic, Rochester, 
United States.
(Knutson K.L., knutson.keith@mayo.edu) Department of Immunology, Mayo 
Clinic, 4500 San Pablo Road, Jacksonville, United States.
CORRESPONDENCE ADDRESS
  K.L. Knutson, Department of Immunology, Mayo Clinic, 4500 San Pablo Road, 
Jacksonville, United States. Email: knutson.keith@mayo.edu
SOURCE
  Cancer Research (2016) 76:2 (239-250). Date of Publication: 15 Jan 2016
ISSN
  1538-7445 (electronic)
  0008-5472
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  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-κB; however, in 
contrast to its role in lymphocytes, we found that expression of PD-1 in 
TIDC tonically paralyzed NF-κB activation. Further mechanistic 
investigations showed that PD-1 blocked NF-κB- dependent cytokine release in 
a SHP-2-dependent manner. Conversely, inhibition of NF-κB-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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immunoglobulin enhancer binding protein (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  B7 antigen (endogenous compound)
  CD40 antigen (endogenous compound)
  CD86 antigen (endogenous compound)
  granulocyte colony stimulating factor (endogenous compound)
  interleukin 10 (endogenous compound)
  interleukin 12 (endogenous compound)
  interleukin 6 (endogenous compound)
  major histocompatibility antigen class 1 (endogenous compound)
  protein tyrosine phosphatase SHP 2 (endogenous compound)
  transcription factor RelA (endogenous compound)
  tumor necrosis factor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer infiltration
  cell function
  dendritic cell
  enzyme inactivation
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  adaptive immunity
  animal cell
  animal experiment
  animal model
  animal tissue
  antigen presentation
  article
  cancer immunotherapy
  controlled study
  cytokine release
  enzyme linked immunosorbent assay
  female
  human
  human cell
  human tissue
  immunocompetent cell
  immunoprecipitation
  lymphocyte
  mouse
  myeloid dendritic cell
  nonhuman
  priority journal
  protein expression
  protein function
  protein phosphorylation
  regulatory mechanism
  signal transduction
  Western blotting
CAS REGISTRY NUMBERS
  interleukin 12 (138415-13-1)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160159728
MEDLINE PMID
  26567141 (http://www.ncbi.nlm.nih.gov/pubmed/26567141)
PUI
  L608440079
DOI
  10.1158/0008-5472.CAN-15-0748
FULL TEXT LINK
  http://dx.doi.org/10.1158/0008-5472.CAN-15-0748
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 227
TITLE
  Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of 
the lung
AUTHOR NAMES
  Verma I.
  Modi A.
  Tripathi H.
  Agrawal A.
AUTHOR ADDRESSES
  (Verma I.; Agrawal A.) Department of Medicine, Monmouth Medical Center, Long 
Branch, United States.
(Modi A., modi-anar@cooperhealth.edu) Division of Endocrinology, Diabetes 
and Metabolism, Cooper University Hospital, Camden, United States.
(Tripathi H.) Mower Central Research Lab, Sinai Hospital of Baltimore, 
Baltimore, United States.
CORRESPONDENCE ADDRESS
  A. Modi, Division of Endocrinology, Diabetes and Metabolism, Cooper 
University Hospital, Camden, United States. Email: 
modi-anar@cooperhealth.edu
SOURCE
  BMJ Case Reports (2016) 2016 Article Number: 213692. Date of Publication: 5 
Jan 2016
ISSN
  1757-790X (electronic)
BOOK PUBLISHER
  BMJ Publishing Group, subscriptions@bmjgroup.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  carboplatin (drug therapy)
  D dimer (endogenous compound)
  furosemide (drug therapy)
  liothyronine (endogenous compound)
  metoprolol (drug therapy)
  pemetrexed (drug therapy)
  thyroglobulin antibody (endogenous compound)
  thyroid stimulating immunoglobulin (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  lung adenocarcinoma (drug therapy, drug therapy)
  painless thyroiditis (drug therapy, diagnosis, drug therapy, etiology)
  thyroiditis (side effect, diagnosis, etiology, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  awareness
  brain metastasis (complication, diagnosis, radiotherapy)
  cancer radiotherapy
  cardiomegaly (diagnosis)
  case report
  clinical effectiveness
  clinical feature
  diastolic dysfunction (diagnosis)
  disease activity
  disease association
  diuresis
  drug efficacy
  drug response
  drug safety
  drug tolerability
  drug withdrawal
  echocardiography
  female
  follow up
  human
  hypervolemia (drug therapy)
  lung congestion (diagnosis)
  medical history
  middle aged
  molecular pathology
  multiple cycle treatment
  outcome assessment
  patient assessment
  physical examination
  priority journal
  spine metastasis (complication, diagnosis)
  tachycardia (drug therapy)
  thorax radiography
  thyrotoxicosis (complication, diagnosis)
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  furosemide (54-31-9)
  liothyronine (6138-47-2, 6893-02-3)
  metoprolol (37350-58-6)
  nivolumab (946414-94-4)
  pemetrexed (137281-23-3, 150399-23-8)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160095199
MEDLINE PMID
  26733436 (http://www.ncbi.nlm.nih.gov/pubmed/26733436)
PUI
  L608007089
DOI
  10.1136/bcr-2015-213692
FULL TEXT LINK
  http://dx.doi.org/10.1136/bcr-2015-213692
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 228
TITLE
  Safety of immune checkpoint inhibitors in Chinese patients with melanoma
AUTHOR NAMES
  Wen X.
  Wang Y.
  Ding Y.
  Li D.
  Li J.
  Guo Y.
  Peng R.
  Zhao J.
  Zhang X.
  Zhang X.-S.
AUTHOR ADDRESSES
  (Wen X.; Wang Y.; Ding Y.; Li D.; Li J.; Guo Y.; Peng R.; Zhao J.; Zhang X.; 
Zhang X.-S., zhangxsh@sysucc.org.cn) State Key Laboratory of Oncology in 
South China, Biotherapy Center, Sun Yat-sen University Cancer Center, 
Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 
China.
CORRESPONDENCE ADDRESS
  X.-S. Zhang, State Key Laboratory of Oncology in South China, Biotherapy 
Center, Sun Yat-sen University Cancer Center, Collaborative Innovation 
Center for Cancer Medicine, Guangzhou, Guangdong, China. Email: 
zhangxsh@sysucc.org.cn
SOURCE
  Melanoma Research (2016) 26:3 (284-289). Date of Publication: 2016
ISSN
  1473-5636 (electronic)
  0960-8931
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  pembrolizumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  B Raf kinase (endogenous compound)
  lactate dehydrogenase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  Chinese
  drug tolerability
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult
  aged
  alanine aminotransferase blood level
  arthralgia (side effect)
  article
  aspartate aminotransferase blood level
  clinical article
  diabetes mellitus (side effect)
  diarrhea
  distant metastasis
  drug safety
  endocrine disease (side effect)
  fatigue (side effect)
  female
  gastrointestinal disease (side effect)
  gene mutation
  hepatitis B
  human
  hypokalemia (side effect)
  hypophysis disease (side effect)
  hypophysitis (side effect)
  insomnia (side effect)
  lactate dehydrogenase blood level
  liver disease (side effect)
  liver toxicity
  male
  myalgia (side effect)
  pain (side effect)
  priority journal
  pruritus
  rash
  retrospective study
  skin disease (side effect)
  systemic therapy
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  ipilimumab (477202-00-9)
  lactate dehydrogenase (9001-60-9)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01024231)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160365232
PUI
  L610324285
DOI
  10.1097/CMR.0000000000000256
FULL TEXT LINK
  http://dx.doi.org/10.1097/CMR.0000000000000256
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 229
TITLE
  Merkel cell carcinoma – Current state and the future
AUTHOR NAMES
  Tai P.
  Vu K.
  Torri V.
  Suderman D.
  Dubey A.
AUTHOR ADDRESSES
  (Tai P., patricia.tai@saskcancer.ca; Suderman D.) Allan Blair Cancer Center, 
Regina, Canada.
(Vu K.) Maisonneuve- Rosemont Hospital, 5689 Boul. Rosemont, Montreal, 
Canada.
(Torri V.; Dubey A.) Cancer Care Manitoba, Winnipeg, Canada.
CORRESPONDENCE ADDRESS
  P. Tai, Allan Blair Cancer Center, Regina, Canada. Email: 
patricia.tai@saskcancer.ca
SOURCE
  Current Cancer Therapy Reviews (2016) 12:2 (79-86). Date of Publication: 
2016
ISSN
  1875-6301 (electronic)
  1573-3947
BOOK PUBLISHER
  Bentham Science Publishers B.V., P.O. Box 294, Bussum, Netherlands.
ABSTRACT
  Merkel cell carcinoma (MCC) is a rare type of skin cancer. It is the first 
human cancer known to be associated with a polyomavirus. The vast majority 
of publications are case reports. Our goal is to discuss practical 
suggestions for the treatment, based on our clinical experience and a review 
of the literature. Surgery is the initial treatment of choice. Radiotherapy 
is used as primary or adjuvant treatment. The chemotherapeutic approach 
follows that of neuroendocrine neoplasms, using cisplatin and etoposide. 
Researchers are looking into other active drugs which have been used for 
melanoma including temozolomide, and PD-1 inhibitors. Scientists are 
studying mutations in MCC to identify potential targets for more effective 
systemic treatments. We hope this review will be useful for clinicians to 
apply current principles and provide food for thought to improve treatment 
outcomes.
EMTREE DRUG INDEX TERMS
  chromogranin (endogenous compound)
  cisplatin (drug therapy)
  etoposide (drug therapy)
  programmed death 1 receptor (endogenous compound)
  synaptophysin (endogenous compound)
  temozolomide (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  merkel cell carcinoma (drug therapy, diagnosis, drug therapy, radiotherapy, 
surgery)
EMTREE MEDICAL INDEX TERMS
  adjuvant chemotherapy
  adult
  aged
  biopsy
  case report
  computer assisted tomography
  disease course
  elbow injury
  endocrine tumor
  female
  human
  immunohistochemistry
  lipoma (diagnosis)
  male
  microscopy
  middle aged
  Polyomavirus
  priority journal
  prostate cancer
  review
  skin cyst
  skin transplantation
  very elderly
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  etoposide (33419-42-0)
  temozolomide (85622-93-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170088266
PUI
  L614273581
DOI
  10.2174/1573394712666160921153207
FULL TEXT LINK
  http://dx.doi.org/10.2174/1573394712666160921153207
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 230
TITLE
  CD103+ intraepithelial T cells in high-grade serous ovarian cancer are 
phenotypically diverse TCRαβ+ CD8αβ+ T cells that can be targeted for cancer 
immunotherapy
AUTHOR NAMES
  Komdeur F.L.
  Wouters M.C.A.
  Workel H.H.
  Tijans A.M.
  Terwindt A.L.J.
  Brunekreeft K.L.
  Plat A.
  Klip H.G.
  Eggink F.A.
  Leffers N.
  Helfrich W.
  Samplonius D.F.
  Bremer E.
  Wisman G.B.A.
  Daemen T.
  Duiker E.W.
  Hollema H.
  Nijman H.W.
  de Bruyn M.
AUTHOR ADDRESSES
  (Komdeur F.L.; Wouters M.C.A.; Workel H.H.; Tijans A.M.; Terwindt A.L.J.; 
Brunekreeft K.L.; Plat A.; Klip H.G.; Eggink F.A.; Leffers N.; Wisman 
G.B.A.; Nijman H.W., h.w.nijman@umcg.nl; de Bruyn M.) University of 
Groningen, University Medical Center Groningen, Department of Obstetrics and 
Gynecology, Netherlands.
(Wouters M.C.A.; Daemen T.) University of Groningen, University Medical 
Center Groningen, Department of Medical Microbiology, Netherlands.
(Helfrich W.; Samplonius D.F.; Bremer E.) University of Groningen, 
University Medical Center Groningen, Department of Surgery, Netherlands.
(Duiker E.W.; Hollema H.) University of Groningen, University Medical Center 
Groningen, Department of Pathology, Netherlands.
CORRESPONDENCE ADDRESS
  H.W. Nijman, University of Groningen, University Medical Center Groningen, 
Department of Obstetrics and Gynecology, Netherlands. Email: 
h.w.nijman@umcg.nl
SOURCE
  Oncotarget (2016) 7:46 (75130-75144). Date of Publication: 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  CD103+ tumor-infiltrating lymphocytes (TIL) have been linked to specific 
epithelial infiltration and a prolonged survival in high-grade serous 
epithelial ovarian cancer (HGSC). However, whether these cells are induced 
as part of an ongoing anti- HGSC immune response or represent 
non-specifically expanded resident or mucosal lymphocytes remains largely 
unknown. In this study, we first confirmed that CD103+ TIL from HGSC were 
predominantly localized in the cancer epithelium and were strongly 
correlated with an improved prognosis. We further demonstrate that CD103+ 
TIL were almost exclusively CD3+ TCRαβ+ CD8αβ+ CD4-T cells, but 
heterogeneously expressed T cell memory and differentiation markers. 
Activation of peripheral T cells in the presence of HGSC was sufficient to 
trigger induction of CD103 in over 90% of all CD8+ cells in a T cell 
receptor (TCR)- and TGFβR1-dependent manner. Finally, CD103+ TIL isolated 
from primary HGSC showed signs of recent activation and dominantly 
co-expressed key immunotherapeutic targets PD-1 and CD27. Taken together, 
our data indicate CD103+ TIL in HGSC are formed as the result of an adaptive 
anti-tumor immune response that might be reactivated by (dual) checkpoint 
inhibition.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  CD103 antigen (endogenous compound)
  T lymphocyte receptor alpha chain (endogenous compound)
  T lymphocyte receptor beta chain (endogenous compound)
EMTREE DRUG INDEX TERMS
  CD27 antigen (endogenous compound)
  CD3 antigen (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  transforming growth factor beta receptor 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  high grade serous ovary cancer
  ovary cancer
  tumor associated leukocyte
EMTREE MEDICAL INDEX TERMS
  adaptive immunity
  antigen expression
  article
  cancer epithelium
  cancer prognosis
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  cellular distribution
  controlled study
  epithelium
  female
  genetic association
  human
  human cell
  human tissue
  lymphocyte differentiation
  major clinical study
  memory T lymphocyte
  phenotype
  protein analysis
  protein induction
  protein localization
  protein targeting
  signal transduction
  T lymphocyte activation
CAS REGISTRY NUMBERS
  CD103 antigen (269047-90-7)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160863394
MEDLINE PMID
  27650547 (http://www.ncbi.nlm.nih.gov/pubmed/27650547)
PUI
  L613412620
DOI
  10.18632/oncotarget.12077
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.12077
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 231
TITLE
  The role of PD-1 - A programmed cell death receptor 1 - And its ligands in 
ovarian cancer immunotherapy
ORIGINAL (NON-ENGLISH) TITLE
  Znaczenie PD-1 - Receptora programowanej śmierci-1 - I jego ligandów w 
immunoterapii raka jajnika
AUTHOR NAMES
  Markowska A.
  Sajdak S.
  Lubin J.
  Markowska J.
AUTHOR ADDRESSES
  (Markowska A.) Department of Perinatology and Women's Diseases, Poznan 
University of Medical Sciences, Polna 33, Poznan, Poland.
(Sajdak S.) Department of Gynecological Surgery, Poznan University of 
Medical Sciences, Poznan, Poland.
(Lubin J.) Wielkopolska Centre of Pulmonology and Thoracic Surgery, Poznan, 
Poland.
(Markowska J.) Department of Oncology, Division of Gynecological Oncology, 
Poznan University of Medical Sciences, Poznan, Poland.
CORRESPONDENCE ADDRESS
  A. Markowska, Department of Perinatology and Women's Diseases, Poznan 
University of Medical Sciences, Polna 33, Poznan, Poland.
SOURCE
  Current Gynecologic Oncology (2016) 14:2 (117-120). Date of Publication: 
2016
ISSN
  2081-1632
BOOK PUBLISHER
  Medical Communications, info@medical.pl
ABSTRACT
  The immune system plays an important role in both cancer development and 
destruction. Tumor cells have developed mechanisms to evade an effective 
immune response. One of these involves the use of immune checkpoint 
pathways, which modulate the intensity and duration of such responses. There 
are two immune checkpoint receptors that have been most thoroughly studied: 
CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and PD-1 (programmed 
cell death protein 1 pathway), involved in regulatory T cell responses. The 
anti-CTLA-4 antibody is used in the treatment of many malignancies, 
including non-small-cell lung cancer, prostate cancer and melanoma. PD-1 and 
its ligands, PD-L1 and PD-L2, represent an immune axis protecting cancer 
cells against regulatory T cells (cytotoxic CD8(+) cells and CD4(+) helper 
cells). Nivolumab, a monoclonal antibody, blocks PD-1 and, as a result, its 
binding to its ligands. Consequently, T cell antitumor activity is restored, 
which appears promising in clinical trials involving patients with 
malignancies in multiple locations, including non-small-cell lung cancer, 
melanoma and ovarian cancer, clear cell ovarian carcinoma in particular. 
Nivolumab therapy is not devoid of adverse effects, which affect about 40% 
of patients with ovarian cancer. These include e.g. arrhythmia, fever, 
anemia and decreased lymphocyte count. It is believed that combining a 
therapy that blocks the key immune checkpoints with other anticancer agents, 
including chemotherapy, radiation therapy or other targeted therapies, will 
improve treatment efficacy in malignancies, including ovarian cancer.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  nivolumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  article
  immune response
  melanoma
  non small cell lung cancer
  prostate cancer
  regulatory T lymphocyte
  tumor localization
CAS REGISTRY NUMBERS
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English, Polish
LANGUAGE OF SUMMARY
  English, Polish
EMBASE ACCESSION NUMBER
  20170190384
PUI
  L614727802
DOI
  10.15557/CGO.2016.0014
FULL TEXT LINK
  http://dx.doi.org/10.15557/CGO.2016.0014
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 232
TITLE
  NETs: Organ-related epigenetic derangements and potential clinical 
applications
AUTHOR NAMES
  Cives M.
  Simone V.
  Rizzo F.M.
  Silvestris F.
AUTHOR ADDRESSES
  (Cives M.; Simone V.; Rizzo F.M.; Silvestris F., 
francesco.silvestris@uniba.it) Department of Biomedical Sciences and Human 
Oncology, Section of Internal Medicine and Clinical Oncology, University of 
Bari 'Aldo Moro', Bari, Italy.
CORRESPONDENCE ADDRESS
  F. Silvestris, Department of Biomedical Sciences and Human Oncology, Section 
of Internal Medicine and Clinical Oncology, University of Bari 'Aldo Moro', 
Bari, Italy. Email: francesco.silvestris@uniba.it
SOURCE
  Oncotarget (2016) 7:35 (57414-57429). Date of Publication: 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  azacitidine (drug therapy, pharmacology)
  belinostat (drug therapy)
  butyric acid (pharmacology)
  decitabine (drug therapy, pharmacology)
  entinostat (pharmacology)
  lithium (pharmacology)
  panobinostat (clinical trial, drug therapy)
  romidepsin (drug therapy)
  trichostatin A (pharmacology)
  tumor marker (endogenous compound)
  valproic acid (clinical trial, drug therapy, pharmacology)
  vorinostat (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  epigenetics
  neuroendocrine tumor (drug therapy, drug therapy, etiology)
EMTREE MEDICAL INDEX TERMS
  antiproliferative activity
  article
  cancer prognosis
  chromatin assembly and disassembly
  DNA methylation
  drug mechanism
  gene expression profiling
  gene expression regulation
  human
  immunostimulation
  lung tumor (etiology)
  pancreas islet cell tumor (etiology)
  small intestine tumor (etiology)
CAS REGISTRY NUMBERS
  azacitidine (320-67-2, 52934-49-3)
  belinostat (414864-00-9)
  butyric acid (107-92-6, 156-54-7, 461-55-2)
  decitabine (2353-33-5)
  entinostat (209783-80-2)
  lithium (7439-93-2)
  panobinostat (404950-80-7)
  romidepsin (128517-07-7)
  trichostatin A (58880-19-6)
  valproic acid (1069-66-5, 99-66-1)
  vorinostat (149647-78-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Endocrinology (3)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160644264
MEDLINE PMID
  27418145 (http://www.ncbi.nlm.nih.gov/pubmed/27418145)
PUI
  L612006955
DOI
  10.18632/oncotarget.10598
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.10598
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 233
TITLE
  Hyponatraemia secondary to nivolumab-induced primary adrenal failure
AUTHOR NAMES
  Trainer H.
  Hulse P.
  Higham C.E.
  Trainer P.
  Lorigan P.
AUTHOR ADDRESSES
  (Hulse P.) Department of Radiology, The Christie NHS Foundation Trust, 
University of Manchester, Manchester Academic Health Science Centre, 
Manchester, United Kingdom.
(Trainer H.; Higham C.E.; Trainer P.) Department of Endocrinology, The 
Christie NHS Foundation Trust, University of Manchester, Manchester Academic 
Health Science Centre, Manchester, United Kingdom.
(Lorigan P., Paul.Lorigan@manchester.ac.uk) Department of Medical Oncology, 
The Christie NHS Foundation Trust, University of Manchester, Manchester 
Academic Health Science Centre, Manchester, United Kingdom.
CORRESPONDENCE ADDRESS
  P. Lorigan, Department of Medical Oncology, The Christie NHS Foundation 
Trust, University of Manchester, Manchester Academic Health Science Centre, 
Manchester, United Kingdom. Email: Paul.Lorigan@manchester.ac.uk
SOURCE
  Endocrinology, Diabetes and Metabolism Case Reports (2016) 2016 Article 
Number: 16-0108. Date of Publication: 2016
ISSN
  2052-0573 (electronic)
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  fludrocortisone (drug therapy)
  hydrocortisone (drug therapy, oral drug administration)
  renin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adrenal insufficiency (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
  hyponatremia
EMTREE MEDICAL INDEX TERMS
  adult
  anorexia
  article
  bleeding
  body weight loss
  case report
  drug dose reduction
  fatigue
  histology
  human
  human tissue
  hydrocortisone blood level
  male
  melanoma (diagnosis)
  multiple cycle treatment
  positron emission tomography
  priority journal
  retroperitoneal cancer (diagnosis, drug therapy)
  sodium blood level
  x-ray computed tomography
CAS REGISTRY NUMBERS
  fludrocortisone (127-31-1)
  hydrocortisone (50-23-7)
  nivolumab (946414-94-4)
  renin (61506-93-2, 9015-94-5)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170082994
PUI
  L614190606
DOI
  10.1530/EDM-16-0108
FULL TEXT LINK
  http://dx.doi.org/10.1530/EDM-16-0108
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 234
TITLE
  Mutational landscape of MCPyV-positive and MCPyV-negative merkel cell 
carcinomas with implications for immunotherapy
AUTHOR NAMES
  Goh G.
  Walradt T.
  Markarov V.
  Blom A.
  Riaz N.
  Doumani R.
  Stafstrom K.
  Moshiri A.
  Yelistratova L.
  Levinsohn J.
  Chan T.A.
  Nghiem P.
  Lifton R.P.
  Choi J.
AUTHOR ADDRESSES
  (Goh G.; Lifton R.P., richard.lifton@yale.edu) Department of Genetics, Yale 
School of Medicine, New Haven, United States.
(Goh G.; Lifton R.P., richard.lifton@yale.edu) Howard Hughes Medical 
Institute, Yale School of Medicine, New Haven, United States.
(Walradt T.; Levinsohn J.; Choi J., Jaehyuk.choi@northwestern.edu) 
Department of Dermatology, Yale School of Medicine, New Haven, United 
States.
(Markarov V.; Chan T.A.) Human Oncology and Pathogenesis Program, Memorial 
Sloan Kettering Cancer Center, New York, United States.
(Blom A.; Doumani R.; Stafstrom K.; Moshiri A.; Yelistratova L.; Nghiem P.) 
Department of Dermatology, University of Washington, Seattle, United States.
(Riaz N.; Chan T.A.) Department of Radiation Oncology, Memorial Sloan 
Kettering Cancer Center, New York, United States.
(Riaz N.; Nghiem P.) Department of Pathology, University of Washington, 
Seattle, United States.
(Nghiem P.) Fred Hutchinson Cancer Center, Seattle, United States.
(Choi J., Jaehyuk.choi@northwestern.edu) Department of Dermatology, Veterans 
Affairs Healthcare, West Haven, United States.
(Choi J., Jaehyuk.choi@northwestern.edu) Department of Dermatology, Feinberg 
School of Medicine, Northwestern University, Chicago, United States.
CORRESPONDENCE ADDRESS
  J. Choi, Department of Dermatology, Yale School of Medicine, New Haven, 
United States. Email: Jaehyuk.choi@northwestern.edu
SOURCE
  Oncotarget (2016) 7:3 (3403-3415). Date of Publication: 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  ATM protein (endogenous compound)
  BRCA1 protein (endogenous compound)
  DNA mismatch repair protein MSH2 (endogenous compound)
  K ras protein (endogenous compound)
  Notch1 receptor (endogenous compound)
  Notch2 receptor (endogenous compound)
  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (endogenous compound)
  protein p53 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gene mutation
  merkel cell carcinoma (etiology)
  Merkel cell polyomavirus
EMTREE MEDICAL INDEX TERMS
  article
  ASXL1 gene
  ATM gene
  cancer immunotherapy
  cancer survival
  controlled study
  disease activity
  exome
  gain of function mutation
  genome analysis
  human
  MAP3K1 gene
  MLL2 gene
  MLL3 gene
  molecular dynamics
  molecular pathology
  MSH2 gene
  Notch1 gene
  Notch2 gene
  oncogene
  oncogene H ras
  oncogene K ras
  PIK3CA gene
  PTEN gene
  RB1 gene
  sequence analysis
  somatic mutation
  survival rate
  survival time
  TRAF7 gene
  TSC1 gene
  tumor suppressor gene
CAS REGISTRY NUMBERS
  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (210488-47-4)
  protein MSH2 (153700-72-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Microbiology: Bacteriology, Mycology, Parasitology and Virology (4)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160257190
MEDLINE PMID
  26655088 (http://www.ncbi.nlm.nih.gov/pubmed/26655088)
PUI
  L609355762
DOI
  10.18632/oncotarget.6494
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.6494
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 235
TITLE
  No hair loss, but colitis or pneumonitis: Unique side effects of immune 
checkpoint inhibitors for cancer
ORIGINAL (NON-ENGLISH) TITLE
  Klinische les: Geen haaruitval, maar wel colitis of pneumonitis: Unieke 
bijwerkingen van immuun-checkpoint-remmers voor kanker
AUTHOR NAMES
  Steenbruggen T.G.
  Van Den Heuvel M.M.
  Blank C.U.
  Van Dieren J.M.
  Haanen J.B.A.G.
  Kok M.
AUTHOR ADDRESSES
  (Steenbruggen T.G.; Van Den Heuvel M.M., m.kok@nki.nl; Blank C.U.; Van 
Dieren J.M.; Haanen J.B.A.G.; Kok M.) Nederlands Kanker Instituut, Antoni 
van Leeuwenhoek, Amsterdam, Netherlands.
CORRESPONDENCE ADDRESS
  M.M. Van Den Heuvel, Nederlands Kanker Instituut, Antoni van Leeuwenhoek, 
Amsterdam, Netherlands. Email: m.kok@nki.nl
SOURCE
  Nederlands Tijdschrift voor Geneeskunde (2016) 160:34 Article Number: a9873. 
Date of Publication: 2016
ISSN
  0028-2162
BOOK PUBLISHER
  Bohn Stafleu van Loghum, e.smid@ntvg.nl
ABSTRACT
  Immunotherapy with checkpoint inhibitors is an effective strategy for 
several cancers. In some patients longterm remissions are seen. However, 
enhancement of the immune response can be accompanied by immunerelated 
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 lifethreatening 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 ipilimumabinduced colitis and a lung 
cancer patient with pneumonitis after antiPD1. We then summarise the most 
common toxicities of checkpoint inhibitors, emphasising the need to 
familiarise the practitioner with irAEs of approved and emerging 
immunotherapies.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  immunomodulating agent
  infliximab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  colitis (side effect, side effect)
  pneumonia (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  article
  case report
  endocrine disease
  hepatitis
  human
  lung cancer (drug therapy)
  melanoma (drug therapy)
CAS REGISTRY NUMBERS
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English, Dutch
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160737817
MEDLINE PMID
  27438388 (http://www.ncbi.nlm.nih.gov/pubmed/27438388)
PUI
  L612718447
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 236
TITLE
  A multidisciplinary approach to toxicity management of modern immune 
checkpoint inhibitors in cancer therapy
AUTHOR NAMES
  Kottschade L.
  Brys A.
  Peikert T.
  Ryder M.
  Raffals L.
  Brewer J.
  Mosca P.
  Markovic S.
AUTHOR ADDRESSES
  (Kottschade L., kottschade.lisa@mayo.edu; Markovic S.) Division of Medical 
Oncology, Mayo Clinic, 200 First Street SW, Rochester, United States.
(Peikert T.) Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 
Rochester, United States.
(Ryder M.) Division of Endocrinology, Mayo Clinic, Rochester, United States.
(Raffals L.) Division of Gastroenterology and Hepatology, Mayo Clinic, 
Rochester, United States.
(Brewer J.) Division of Dermatology, Mayo Clinic, Rochester, United States.
(Markovic S.) Division of Hematology, Mayo Clinic, Rochester, United States.
(Brys A.) Duke University, School of Medicine, Durham, United States.
(Mosca P.) Division of Advance Oncologic and GI Surgery, Duke University, 
Durham, United States.
CORRESPONDENCE ADDRESS
  L. Kottschade, Division of Medical Oncology, Mayo Clinic, 200 First Street 
SW, Rochester, United States. Email: kottschade.lisa@mayo.edu
SOURCE
  Melanoma Research (2016) 26:5 (469-480). Date of Publication: 2016
ISSN
  1473-5636 (electronic)
  0960-8931
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immunomodulating agent (adverse drug reaction, clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  drug induced disease (side effect, side effect)
  immune related adverse event (side effect, side effect)
  malignant neoplasm (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  clinical feature
  clinical trial (topic)
  endocrine disease (side effect)
  eye toxicity (side effect)
  gastrointestinal toxicity (side effect)
  human
  hypophysitis (side effect)
  liver toxicity (side effect)
  lung toxicity (side effect)
  nephrotoxicity (side effect)
  neurotoxicity (side effect)
  pancreas disease (side effect)
  priority journal
  skin toxicity (side effect)
  thyroid disease (side effect)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160456611
MEDLINE PMID
  27306502 (http://www.ncbi.nlm.nih.gov/pubmed/27306502)
PUI
  L610851186
DOI
  10.1097/CMR.0000000000000273
FULL TEXT LINK
  http://dx.doi.org/10.1097/CMR.0000000000000273
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 237
TITLE
  Glucocorticoids did not reverse type 1 diabetes mellitus secondary to 
pembrolizumab in a patient with metastatic melanoma
AUTHOR NAMES
  Aleksova J.
  Lau P.K.H.
  Soldatos G.
  McArthur G.
AUTHOR ADDRESSES
  (Aleksova J., jasnaaleksova@hotmail.com) Monash Health, Clayton, Australia.
(Lau P.K.H.; Soldatos G.) Peter MacCallum Cancer Institute, Cancer Medicine, 
East Melbourne, Australia.
(Soldatos G.) Monash Centre for Health Research and Implementation, 
Melbourne, Australia.
(McArthur G.) Department of Medical Oncology, Peter MacCallum Cancer Centre, 
East Melbourne, Australia.
(McArthur G.) Sir Peter MacCallum Department of Oncology, University of 
Melbourne, Parkville, Australia.
CORRESPONDENCE ADDRESS
  J. Aleksova, Monash Health, Clayton, Australia. Email: 
jasnaaleksova@hotmail.com
SOURCE
  BMJ Case Reports (2016) 2016 Article Number: 217454. Date of Publication: 
2016
ISSN
  1757-790X (electronic)
BOOK PUBLISHER
  BMJ Publishing Group, subscriptions@bmjgroup.com
ABSTRACT
  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 β 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  glucocorticoid (drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
  prednisolone (drug therapy, oral drug administration)
EMTREE DRUG INDEX TERMS
  C peptide (endogenous compound)
  glucose (endogenous compound)
  hemoglobin A1c (endogenous compound)
  insulin (drug therapy, subcutaneous drug administration)
  ipilimumab (drug therapy, intravenous drug administration)
  liothyronine (endogenous compound)
  protein S 100 (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
  transcription factor Sox10 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  insulin dependent diabetes mellitus (drug therapy, side effect, drug 
therapy, side effect)
  metastatic melanoma (drug therapy, diagnosis, drug therapy, radiotherapy, 
surgery)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  case report
  computer assisted tomography
  coughing
  diabetic ketoacidosis (drug therapy, side effect)
  differential diagnosis
  drug dose escalation
  drug withdrawal
  dyspnea
  hemicolectomy
  histopathology
  human
  hyperglycemia
  insulin deficiency
  insulin resistance
  intestine obstruction
  intussusception
  male
  middle aged
  multimodality cancer therapy
  multiple cycle treatment
  nuclear magnetic resonance imaging
  polydipsia (side effect)
  polyuria (side effect)
  positron emission tomography
  priority journal
  thorax radiography
  thyroid disease
CAS REGISTRY NUMBERS
  C peptide (59112-80-0)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  insulin (9004-10-8)
  ipilimumab (477202-00-9)
  liothyronine (6138-47-2, 6893-02-3)
  pembrolizumab (1374853-91-4)
  prednisolone (50-24-8)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160880932
MEDLINE PMID
  27881588 (http://www.ncbi.nlm.nih.gov/pubmed/27881588)
PUI
  L613434786
DOI
  10.1136/bcr-2016-217454
FULL TEXT LINK
  http://dx.doi.org/10.1136/bcr-2016-217454
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 238
TITLE
  Abstracts for Acta Clinica Belgica “26th Meeting of the Belgian Endocrine 
Society”
AUTHOR ADDRESSES
  SOURCE
  Acta Clinica Belgica: International Journal of Clinical and Laboratory 
Medicine (2016) 71 Supplement 3. Date of Publication: 2016
CONFERENCE NAME
  26th Meeting of the Belgian Endocrine Society
CONFERENCE LOCATION
  Brussels, Belgium
CONFERENCE DATE
  2016-10-14 to 2016-10-15
ISSN
  2295-3337
BOOK PUBLISHER
  Taylor and Francis Ltd.
ABSTRACT
  The proceedings contain 31 papers. The topics discussed include: an intact 
dopamine sensitivity in the brain; a necessity to recover hyperprolactinemia 
and galactorrhea in a female hemodialysis patient?; unveiling mechanisms of 
pancreatic β-cell demise in TRMT10A diabetes and identification of β-cell 
protective approaches; long-term effects of metformin as adjunct therapy in 
patients with type 1 diabetes; Zinner's syndrome in a patient with X-linked 
Kallmann syndrome: case report; dilemmas in the clinical work-up of a 
primary hypertriglyceridemia; prolactin modulates insulin capacity and thus 
insulin secretion in obese male adults; therapy-induced neuritis: a rare but 
severe complication of diabetes; somatic mosaicism is implicated in the 
etiology of XLAG syndrome; pituitary stalk metastases from renal cell 
carcinoma; should we start hormone substitution despite palliative care? a 
case report; glucose intolerance after a recent history of gestational 
diabetes based on the IADPSG criteria; catecholamine-secreting tumor during 
pregnancy: a rare but potentially life-threatening condition - case report; 
predicting type 2 diabetes mellitus: a comparison between the FINDRISC score 
and the metabolic syndrome; cortical bone size deficit in adult patients 
with type 1 diabetes mellitus; a new clinical presentation of a non-so-rare 
disease, the DiGeorge syndrome; and incidence of thyroid immune-related 
adverse events in melanoma patients treated with pembrolizumab in an 
expanded access programme.
EMTREE DRUG INDEX TERMS
  dopamine
  endogenous compound
  insulin
  metformin
  pembrolizumab
  prolactin
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  pancreas islet beta cell
EMTREE MEDICAL INDEX TERMS
  adult
  adverse drug reaction
  cancer size
  cancer susceptibility
  case report
  clinical trial
  compassionate use
  controlled study
  cortical bone
  diabetic complication
  DiGeorge syndrome
  drug therapy
  female
  galactorrhea
  glucose intolerance
  hemodialysis patient
  hormone substitution
  human
  hyperprolactinemia
  hypertriglyceridemia
  insulin release
  Kallmann syndrome
  kidney carcinoma
  melanoma
  metabolic syndrome X
  metastasis
  mosaicism
  neuritis
  non insulin dependent diabetes mellitus
  palliative therapy
  pituitary stalk
  pregnancy diabetes mellitus
  rare disease
  side effect
CAS REGISTRY NUMBERS
  dopamine (51-61-6, 62-31-7)
  insulin (9004-10-8)
  metformin (1115-70-4, 657-24-9)
  pembrolizumab (1374853-91-4)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
LANGUAGE OF ARTICLE
  English
PUI
  L616191794
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 239
TITLE
  Anti-PD-1/PD-L1 antibody therapy for pretreated advanced nonsmall-cell lung 
cancer A meta-analysis of randomized clinical trials
AUTHOR NAMES
  Zhou G.-W.
  Xiong Y.
  Chen S.
  Xia F.
  Li Q.
  Hu J.
AUTHOR ADDRESSES
  (Zhou G.-W.; Xiong Y.; Chen S.; Li Q.) Department of Respiratory and 
Critical Care Medicine, Changhai Hospital, Second Military Medical 
University, China.
(Xia F.) Department of Pulmonary Medicine, Hospital of People's Liberation 
Army, Shanghai, China.
(Hu J., pondlily@163.com) Department of Oncology, First Affiliated Hospital 
to PLA General Hospital, 51 Fucheng Road, Beijing, China.
CORRESPONDENCE ADDRESS
  J. Hu, Department of Oncology, First Affiliated Hospital to PLA General 
Hospital, 51 Fucheng Road, Beijing, China. Email: pondlily@163.com
SOURCE
  Medicine (United States) (2016) 95:35 Article Number: e4611. Date of 
Publication: 2016
ISSN
  1536-5964 (electronic)
  0025-7974
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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. 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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antibody (adverse drug reaction, clinical trial, drug therapy)
  antineoplastic agent (adverse drug reaction, clinical trial, drug therapy)
  programmed death 1 antibody (adverse drug reaction, clinical trial, drug 
therapy)
  programmed death 1 ligand 1 antibody (adverse drug reaction, clinical trial, 
drug therapy)
EMTREE DRUG INDEX TERMS
  atezolizumab
  docetaxel
  nivolumab
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  cancer survival
  drug efficacy
  drug safety
  human
  hypothyroidism
  meta analysis
  overall survival
  pneumonia
  priority journal
  progression free survival
  randomized controlled trial (topic)
  review
  systematic review
  unspecified side effect (side effect)
DRUG TRADE NAMES
  mpdl 3280a
CAS REGISTRY NUMBERS
  atezolizumab (1380723-44-3)
  docetaxel (114977-28-5)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160668494
MEDLINE PMID
  27583876 (http://www.ncbi.nlm.nih.gov/pubmed/27583876)
PUI
  L612209541
DOI
  10.1097/MD.0000000000004611
FULL TEXT LINK
  http://dx.doi.org/10.1097/MD.0000000000004611
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 240
TITLE
  Clinical update in aspects of the management of autoimmune thyroid diseases
AUTHOR NAMES
  Topliss D.J.
AUTHOR ADDRESSES
  (Topliss D.J., duncan.topliss@monash.edu) Department of Endocrinology and 
Diabetes, The Alfred, Melbourne, Australia.
(Topliss D.J., duncan.topliss@monash.edu) Department of Medicine, Monash 
University, Melbourne, Australia.
CORRESPONDENCE ADDRESS
  D.J. Topliss, Department of Endocrinology and Diabetes, The Alfred, 55 
Commercial Rd, Melbourne, Australia. Email: duncan.topliss@monash.edu
SOURCE
  Endocrinology and Metabolism (2016) 31:4 (493-499). Date of Publication: 
2016
ISSN
  2093-5978 (electronic)
  2093-596X
BOOK PUBLISHER
  Korean Endocrine Society, endo@endocrinololgy.or.kr
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  alemtuzumab
  CD52 antigen
  cell surface receptor
  cytotoxic T lymphocyte antigen 4
  immunoglobulin G4
  interferon
  iodine
  ipilimumab
  nivolumab
  pembrolizumab
  programmed death 1 receptor
  thyrotropin receptor
  thyroxine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune thyroiditis
EMTREE MEDICAL INDEX TERMS
  atrial fibrillation
  Graves disease
  Hashimoto disease
  human
  hypothyroidism
  immune response
  immunoglobulin G4 related disease
  review
  subclinical hypothyroidism
  thyroid carcinoma
CAS REGISTRY NUMBERS
  alemtuzumab (216503-57-0)
  iodine (7553-56-2)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170006173
PUI
  L613932201
DOI
  10.3803/EnM.2016.31.4.493
FULL TEXT LINK
  http://dx.doi.org/10.3803/EnM.2016.31.4.493
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 241
TITLE
  PD-L1 expression in metastatic neuroblastoma as an additional mechanism for 
limiting immune surveillance
AUTHOR NAMES
  Dondero A.
  Pastorino F.
  Chiesa M.D.
  Corrias M.V.
  Morandi F.
  Pistoia V.
  Olive D.
  Bellora F.
  Locatelli F.
  Castellano A.
  Moretta L.
  Moretta A.
  Bottino C.
  Castriconi R.
AUTHOR ADDRESSES
  (Dondero A.; Chiesa M.D.; Bellora F.; Moretta A., alemoret@unige.it; Bottino 
C.; Castriconi R.) Dipartimento di Medicina Sperimentale, Università degli 
Studi di Genova, Italy.
(Pastorino F.; Corrias M.V.; Morandi F.; Pistoia V.; Moretta L.; Bottino C.) 
Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy.
(Olive D.) CRCM, Team Immunity and Cancer, Inserm, Institut Paoli-Calmettes, 
Aix-Marseille Université, CNRS, UM 105, U1068, UMR7258, Marseille, France.
(Locatelli F.; Castellano A.) Università di Pavia and Dipartimento di 
Onco-Ematologia Pediatrica, Ospedale Bambino Gesù, Roma, Italy.
(Moretta A., alemoret@unige.it; Castriconi R.) Centro di Eccellenza per le 
Ricerche Biomediche, Università degli Studi di Genova, Viale Benedetto XV, 
Genova, Italy.
CORRESPONDENCE ADDRESS
  A. Moretta, Dipartimento di Medicina Sperimentale, Università degli Studi di 
Genova, Italy. Email: alemoret@unige.it
SOURCE
  OncoImmunology (2016) 5:1. Date of Publication: 2016
ISSN
  2162-402X (electronic)
  2162-4011
BOOK PUBLISHER
  Taylor and Francis Inc., 325 Chestnut St, Suite 800, Philadelphia, United 
States.
ABSTRACT
  The prognosis of high-risk neuroblastoma (NB) remains poor, although 
immunotherapies with anti-GD2 antibodies have been reported to provide some 
benefit. Immunotherapies can be associated with an IFNγ storm that induces 
in tumor cells the “adaptive immune resistance” characterized by the de-novo 
expression of Programmed Death Ligands (PD-Ls). Tumor cells can also 
constitutively express PD-Ls in response to oncogenic signaling. Here, we 
analyze the constitutive and the inducible surface expression of PD-Ls in NB 
cells. We show that virtually all HLA class I(pos) NB cell lines 
constitutively express PD-L1, whereas PD-L2 is rarely detected. IFNγ 
upregulates or induces PD-L1 both in NB cell lines in vitro and in NB 
engrafted nude/nude mice. Importantly, after IFNγ stimulation PD-L1 can be 
acquired by NB cell lines, as well as by metastatic neuroblasts isolated 
from bone marrow aspirates of high-risk NB patients, characterized by 
different MYCN amplification status. Interestingly, in one patient NB cells 
were poorly responsive to IFNγ stimulation, pointing out that responsiveness 
to IFNγ might represent a further element of heterogeneity in metastatic 
neuroblasts. Finally, we document the presence of lymphocytes expressing the 
PD-1 receptor in NB-infiltrated bone marrow of patients. PD-1(pos) cells are 
mainly represented by αβ T cells, but also include small populations of γδ T 
cells and NK cells. Moreover, PD-1(pos) T cells have a higher expression of 
activation markers. Overall, our data show that a PD-L1-mediated immune 
resistance mechanism occurs in metastatic neuroblasts and provide a 
biological rationale for blocking the PD-1/PD-Ls axis in future combined 
immunotherapeutic approaches.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  gamma interferon
  ganglioside GD2 (endogenous compound)
  HLA antigen class 1 (endogenous compound)
  monoclonal antibody
  programmed death 1 ligand 2 (endogenous compound)
  tumor necrosis factor
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunosurveillance
  neuroblastoma
EMTREE MEDICAL INDEX TERMS
  animal experiment
  animal model
  article
  bone marrow biopsy
  controlled study
  cytofluorometry
  cytokine release
  female
  gamma delta T lymphocyte
  gene expression regulation
  high risk patient
  human
  human cell
  immunostimulation
  metastasis
  mouse
  natural killer T cell
  neuroblastoma cell line
  nonhuman
  protein expression
  T lymphocyte activation
  tumor xenograft
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
  ganglioside GD2 (65988-71-8)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160052655
PUI
  L607799459
DOI
  10.1080/2162402X.2015.1064578
FULL TEXT LINK
  http://dx.doi.org/10.1080/2162402X.2015.1064578
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 242
TITLE
  Response to Pembrolizumab in a Patient with Relapsing Thymoma
AUTHOR NAMES
  Zander T.
  Aebi S.
  Rast A.C.
  Zander A.
  Winterhalder R.
  Brand C.
  Diebold J.
  Gautschi O.
AUTHOR ADDRESSES
  (Zander T., thilo.zander@luks.ch; Aebi S.; Winterhalder R.; Gautschi O.) 
Department of Medical Oncology, Cantonal Hospital Lucerne, Medical Oncology, 
Spitalstrasse Lucerne, Lucerne, Switzerland.
(Rast A.C.; Brand C.) Department of Dermatology, Cantonal Hospital Lucerne, 
Lucerne, Switzerland.
(Zander A.) Department of Radiology, Cantonal Hospital Lucerne, Lucerne, 
Switzerland.
(Diebold J.) Department of Pathology, Cantonal Hospital Lucerne, Lucerne, 
Switzerland.
CORRESPONDENCE ADDRESS
  T. Zander, Department of Medical Oncology, Cantonal Hospital Lucerne, 
Medical Oncology, Spitalstrasse Lucerne, Lucerne, Switzerland. Email: 
thilo.zander@luks.ch
SOURCE
  Journal of Thoracic Oncology (2016) 11:12 (e147-e149). Date of Publication: 
2016
ISSN
  1556-1380 (electronic)
  1556-0864
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  carboplatin (drug therapy)
  cisplatin (drug therapy)
  cyclophosphamide (drug therapy)
  doxorubicin (drug therapy)
  glucocorticoid (topical drug administration)
  immunoglobulin (intravenous drug administration)
  infliximab
  paclitaxel (drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thymoma (drug therapy, drug therapy, radiotherapy, surgery)
  treatment response
  tumor recurrence
EMTREE MEDICAL INDEX TERMS
  adjuvant radiotherapy
  adult
  article
  cancer staging
  cancer surgery
  case report
  chemoradiotherapy
  computer assisted tomography
  drug safety
  drug withdrawal
  epithelium cell
  hospitalization
  human
  human tissue
  induction chemotherapy
  male
  middle aged
  multiple cycle treatment
  next generation sequencing
  pericardium
  plasmapheresis
  protein expression
  skin toxicity (side effect)
  thoracotomy
  treatment withdrawal
  tumor regression
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  cyclophosphamide (50-18-0)
  doxorubicin (23214-92-8, 25316-40-9)
  immunoglobulin (9007-83-4)
  infliximab (170277-31-3)
  paclitaxel (33069-62-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20170078603
MEDLINE PMID
  27498287 (http://www.ncbi.nlm.nih.gov/pubmed/27498287)
PUI
  L614181643
DOI
  10.1016/j.jtho.2016.07.018
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.jtho.2016.07.018
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 243
TITLE
  The impact of PD-L1 expression in patients with metastatic GEP-NETs
AUTHOR NAMES
  Kim S.T.
  Ha S.Y.
  Lee S.
  Ahn S.
  Lee J.
  Park S.H.
  Park J.O.
  Lim H.Y.
  Kang W.K.
  Kim K.-M.
  Park Y.S.
AUTHOR ADDRESSES
  (Kim S.T.; Lee S.; Lee J.; Park S.H.; Park J.O.; Lim H.Y.; Kang W.K.; Park 
Y.S., pys27hmo@skku.edu) Division of Hematology-Oncology, Department of 
Medicine, Samsung Medical Center, Sungkyunkwan University School of 
Medicine, Seoul, South Korea.
(Ha S.Y.; Ahn S.; Kim K.-M., kkmkys@skku.edu) Department of Pathology and 
Translational Genomics, Samsung Medical Center, Sungkyunkwan University 
School of Medicine, Seoul, South Korea.
CORRESPONDENCE ADDRESS
  Y.S. Park, Division of Hematology/Oncology, Department of Medicine, Samsung 
Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, 
Gangnam-gu, Seoul, South Korea. Email: pys27hmo@skku.edu
SOURCE
  Journal of Cancer (2016) 7:5 (484-489). Date of Publication: 2016
ISSN
  1837-9664 (electronic)
BOOK PUBLISHER
  Ivyspring International Publisher, info@ivyspring.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gastroenteropancreatic neuroendocrine tumor (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  biliary tract cancer (drug therapy)
  cancer classification
  cancer grading
  cancer immunotherapy
  cancer patient
  cancer tissue
  clinical article
  duodenum cancer (drug therapy)
  female
  foregut
  human
  human tissue
  male
  overall survival
  pancreas cancer (drug therapy)
  primary tumor (drug therapy)
  progression free survival
  protein expression
  stomach cancer (drug therapy)
  survival
  systemic therapy
  treatment response
  world health organization
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160417329
PUI
  L610559058
DOI
  10.7150/jca.13711
FULL TEXT LINK
  http://dx.doi.org/10.7150/jca.13711
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 244
TITLE
  Increased expression of programmed death ligand 1 (PD-L1) in human pituitary 
tumors
AUTHOR NAMES
  Mei Y.
  Bi W.L.
  Greenwald N.F.
  Du Z.
  Agar N.Y.R.
  Kaiser U.B.
  Woodmansee W.W.
  Reardon D.A.
  Freeman G.J.
  Fecci P.E.
  Laws E.R.
  Santagata S.
  Dunn G.P.
  Dunn I.F.
AUTHOR ADDRESSES
  (Mei Y.; Bi W.L.; Greenwald N.F.; Agar N.Y.R.; Laws E.R.; Dunn I.F., 
idunn@partners.org) Department of Neurosurgery, Brigham and Women's 
Hospital, Harvard Medical School, Boston, United States.
(Bi W.L.; Greenwald N.F.; Agar N.Y.R.; Santagata S.) Department of Cancer 
Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
United States.
(Du Z.; Santagata S.) Department of Pathology, Brigham and Women's Hospital, 
Harvard Medical School, Boston, United States.
(Kaiser U.B.; Woodmansee W.W.) Division of Endocrinology, Brigham and 
Women's Hospital, Harvard Medical School, Boston, United States.
(Reardon D.A.; Freeman G.J.) Department of Medical Oncology, Dana-Farber 
Cancer Institute, Harvard Medical School, Boston, United States.
(Fecci P.E.) Department of Neurosurgery, Duke University School of Medicine, 
Durham, United States.
(Fecci P.E.) Preston Robert Tisch Brain Tumor Center, Duke University 
Medical Center, Durham, United States.
(Dunn G.P., gpdunn@wustl.edu) Department of Neurological Surgery, Washington 
University School of Medicine, St. Louis, United States.
(Dunn G.P., gpdunn@wustl.edu) Center for Human Immunology and Immunotherapy 
Programs, Washington University School of Medicine, St. Louis, United 
States.
CORRESPONDENCE ADDRESS
  G.P. Dunn, Department of Neurological Surgery, Washington University School 
of Medicine, St. Louis, United States. Email: gpdunn@wustl.edu
SOURCE
  Oncotarget (2016) 7:47 (76565-76576). Date of Publication: 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  Purpose: Subsets of pituitary tumors exhibit an aggressive clinical courses 
and recur despite surgery, radiation, and chemotherapy. Because modulation 
of the immune response through inhibition of T-cell checkpoints has led to 
durable clinical responses in multiple malignancies, we explored whether 
pituitary adenomas express immune-related biomarkers that could suggest 
suitability for immunotherapy. Specifically, programmed death ligand 1 
(PD-L1) has emerged as a potential biomarker whose expression may portend 
more favorable responses to immune checkpoint blockade therapies. We thus 
investigated the expression of PD-L1 in pituitary adenomas. Methods: PD-L1 
RNA and protein expression were evaluated in 48 pituitary tumors, including 
functioning and non-functioning adenomas as well as atypical and recurrent 
tumors. Tumor infiltrating lymphocyte populations were also assessed by 
immunohistochemistry. Results: Pituitary tumors express variable levels of 
PD-L1 transcript and protein. PD-L1 RNA and protein expression were 
significantly increased in functioning (growth hormone and 
prolactin-expressing) pituitary adenomas compared to non-functioning (null 
cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas 
harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor 
infiltrating lymphocytes were observed in all pituitary tumors and were 
positively correlated with increased PD-L1 expression, particularly in the 
functional subtypes. Conclusions: Human pituitary adenomas harbor PD-L1 
across subtypes, with significantly higher expression in functioning 
adenomas compared to non-functioning adenomas. This expression is 
accompanied by the presence of tumor infiltrating lymphocytes. These 
findings suggest the existence of an immune response to pituitary tumors and 
raise the possibility of considering checkpoint blockade immunotherapy in 
cases refractory to conventional management.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  CD3 antigen (endogenous compound)
  CD4 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  growth hormone (endogenous compound)
  prolactin (endogenous compound)
  receptor type tyrosine protein phosphatase C (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysis adenoma
  protein expression
EMTREE MEDICAL INDEX TERMS
  animal cell
  article
  cancer immunotherapy
  controlled study
  human
  human cell
  human tissue
  immune response
  immunocompetent cell
  immunohistochemistry
  lymphocyte subpopulation
  lymphocytic infiltration
  mouse
  nonhuman
  protein analysis
  protein function
  protein protein interaction
CAS REGISTRY NUMBERS
  growth hormone (36992-73-1, 37267-05-3, 66419-50-9, 9002-72-6)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160876836
MEDLINE PMID
  27655724 (http://www.ncbi.nlm.nih.gov/pubmed/27655724)
PUI
  L613490669
DOI
  10.18632/oncotarget.12088
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.12088
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 245
TITLE
  Treatment of ipilimumab induced graves' disease in a patient with metastatic 
melanoma
AUTHOR NAMES
  Azmat U.
  Liebner D.
  Joehlin-Price A.
  Agrawal A.
  Nabhan F.
AUTHOR ADDRESSES
  (Azmat U.; Nabhan F., fadi.nabhan@osumc.edu) Division of Endocrinology, 
Diabetes, and Metabolism, Ohio State University, Columbus, United States.
(Liebner D.) Division of Medical Oncology, Department of Biomedical 
Informatics, Ohio State University, Columbus, United States.
(Joehlin-Price A.) Department of Pathology, Ohio State University, Columbus, 
United States.
(Agrawal A.) Department of Otolaryngology, Head and Neck Surgery, Ohio State 
University, Columbus, United States.
CORRESPONDENCE ADDRESS
  F. Nabhan, Division of Endocrinology, Diabetes, and Metabolism, Ohio State 
University, Columbus, United States. Email: fadi.nabhan@osumc.edu
SOURCE
  Case Reports in Endocrinology (2016) 2016 Article Number: 2087525. Date of 
Publication: 2016
ISSN
  2090-651X (electronic)
  2090-6501
BOOK PUBLISHER
  Hindawi Publishing Corporation, 410 Park Avenue, 15th Floor, 287 pmb, New 
York, United States.
ABSTRACT
  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 residualmelanoma. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  immunoglobulin (endogenous compound)
  iodine 123
  levothyroxine
  liothyronine (endogenous compound)
  thiamazole
  thyroid stimulating immunoglobulin (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  Graves disease (side effect, side effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  case report
  cervical lymph node
  cervical lymphadenopathy
  drug megadose
  drug substitution
  drug withdrawal
  free liothyronine index
  free thyroxine index
  human
  hyperthyroidism (surgery)
  immune response
  immunoglobulin blood level
  lung nodule
  male
  multiple cycle treatment
  neck dissection
  thyroid function test
  thyroidectomy
  treatment response
  x-ray computed tomography
CAS REGISTRY NUMBERS
  immunoglobulin (9007-83-4)
  iodine 123 (15715-08-9)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  liothyronine (6138-47-2, 6893-02-3)
  thiamazole (60-56-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20170046344
PUI
  L614039795
DOI
  10.1155/2016/2087525
FULL TEXT LINK
  http://dx.doi.org/10.1155/2016/2087525
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 246
TITLE
  A rare thyroid metastasis from uveal melanoma and response to immunotherapy 
agents
AUTHOR NAMES
  Collins D.C.
  Yela R.
  Horgan N.
  Power D.G.
AUTHOR ADDRESSES
  (Collins D.C., collinsdearbhaile1@gmail.com; Power D.G., 
derek.power1@hse.ie) Department of Medical Oncology, Cork University 
Hospital, Wilton, Co. Cork, Ireland.
(Yela R., ruben.yela@hse.ie) Department of Histopathology, Cork University 
Hospital, Wilton, Co. Cork, Ireland.
(Horgan N., noel.horgan@rveeh.ie) Department of Ophthalmology, Royal 
Victoria Eye and Ear Hospital, Dublin 2, Ireland.
CORRESPONDENCE ADDRESS
  D.C. Collins, Department of Medical Oncology, Cork University Hospital, 
Wilton, Co. Cork, Ireland. Email: collinsdearbhaile1@gmail.com
SOURCE
  Case Reports in Oncological Medicine (2016) 2016 Article Number: 6564094. 
Date of Publication: 2016
ISSN
  2090-6714 (electronic)
  2090-6706
BOOK PUBLISHER
  Hindawi Publishing Corporation, 410 Park Avenue, 15th Floor, 287 pmb, New 
York, United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  thyroid metastasis (side effect, complication, side effect)
  uvea melanoma (drug therapy, diagnosis, drug therapy, surgery)
EMTREE MEDICAL INDEX TERMS
  adrenal disease
  adult
  article
  case report
  chromosome 3
  chromosome 8
  computer assisted tomography
  enucleation
  fluorescence in situ hybridization
  gene mutation
  histopathology
  human
  immunocytochemistry
  lung metastasis (diagnosis)
  lung nodule (complication, diagnosis)
  male
  metastatic melanoma (complication, diagnosis)
  middle aged
  monosomy (diagnosis)
  photon emission tomography
  priority journal
  thyroid follicle
  wild type
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160344655
PUI
  L609991580
DOI
  10.1155/2016/6564094
FULL TEXT LINK
  http://dx.doi.org/10.1155/2016/6564094
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 247
TITLE
  Actions of L-thyroxine and Nano-diamino-tetrac (Nanotetrac) on PD-L1 in 
cancer cells
AUTHOR NAMES
  Lin H.-Y.
  Chin Y.-T.
  Nana A.W.
  Shih Y.-J.
  Lai H.-Y.
  Tang H.-Y.
  Leinung M.
  Mousa S.A.
  Davis P.J.
AUTHOR ADDRESSES
  (Lin H.-Y.; Nana A.W.) PhD Program for Cancer Biology and Drug Discovery, 
College of Medical Science and Technology, Taipei Medical University, 
Taipei, Taiwan.
(Lin H.-Y.; Chin Y.-T.; Shih Y.-J.; Lai H.-Y.) Taipei Cancer Center, Taipei 
Medical University, Taipei, Taiwan.
(Chin Y.-T.) Department of Dentistry, Wan-Fang Medical Center, Taipei 
Medical University, Taipei, Taiwan.
(Tang H.-Y.; Mousa S.A.; Davis P.J., pdavis.ordwayst@gmail.com) 
Pharmaceutical Research Institute, Albany College of Pharmacy and Health 
Sciences, Albany, United States.
(Tang H.-Y.; Mousa S.A.; Davis P.J., pdavis.ordwayst@gmail.com) 
NanoPharmaceuticals LLC, Rensselaer, United States.
(Leinung M.; Davis P.J., pdavis.ordwayst@gmail.com) Department of Medicine, 
Albany Medical College, Albany, United States.
CORRESPONDENCE ADDRESS
  P.J. Davis, Pharmaceutical Research Institute, Albany College of Pharmacy 
and Health Sciences, 1 Discovery Drive, Rensselaer, United States. Email: 
pdavis.ordwayst@gmail.com
SOURCE
  Steroids (2016) 114 (59-67). Date of Publication: 2016
ISSN
  1878-5867 (electronic)
  0039-128X
BOOK PUBLISHER
  Elsevier Inc., usjcs@elsevier.com
ABSTRACT
  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 αvβ3. 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, T(4)) 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 T(4)(10(−7) M total; 10(−10) M 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(−7) M) reduced PD-L1 in T(4)-exposed cells 
by 21% (mRNA) and 39% (protein) (p < 0.05, all changes). In HCT116 cells, 
T(4)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 
T(4)-treated cells lowered mRNA by 33% and protein by 66%. In HT-29 cells, 
T(4)increased PD-L1 mRNA by 62% and protein by 27%. NDAT lowered basal and 
T(4)-stimulated responses in PD-L1 mRNA and protein by 35–40% (p < 0.05). 
Activation of ERK1/2 was involved in T(4)-induced PD-L1 accumulation. We 
propose that, by a nongenomic mechanism, endogenous T(4)may clinically 
support activity of the defensive PD-1/PD-L1 checkpoint in tumor cells. NDAT 
non-immunologically suppresses basal and T(4)-induced PD-L1 gene expression 
and protein accumulation in cancer cells.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug development, pharmacology)
  levothyroxine (endogenous compound)
  nanodiaminotetrac (drug development, pharmacology)
  nanotetrac (drug development, pharmacology)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  messenger RNA (endogenous compound)
  mitogen activated protein kinase 1 (endogenous compound)
  mitogen activated protein kinase 3 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer cell
EMTREE MEDICAL INDEX TERMS
  article
  breast cancer cell line
  colon carcinoma
  concentration response
  controlled study
  drug effect
  drug mechanism
  enzyme activation
  gene expression
  HCT 116 cell line
  HT-29 cell line
  human
  human cell
  in vitro study
  protein expression
  quantitative analysis
  real time polymerase chain reaction
CAS REGISTRY NUMBERS
  levothyroxine (51-48-9)
  mitogen activated protein kinase 1 (137632-08-7)
  mitogen activated protein kinase 3 (137632-07-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160464106
MEDLINE PMID
  27221508 (http://www.ncbi.nlm.nih.gov/pubmed/27221508)
PUI
  L610890345
DOI
  10.1016/j.steroids.2016.05.006
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.steroids.2016.05.006
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 248
TITLE
  Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: 
Clinical review
AUTHOR NAMES
  Joshi M.N.
  Whitelaw B.C.
  Palomar M.T.P.
  Wu Y.
  Carroll P.V.
AUTHOR ADDRESSES
  (Joshi M.N., mamta.joshi@gstt.nhs.uk; Carroll P.V.) Departments of 
Endocrinology Guy's and St Thomas NHS Foundation Trust London UK
(Whitelaw B.C.) Department of Endocrinology Kings College London NHS 
Foundation Trust London UK
(Palomar M.T.P.; Wu Y.) Medical Oncology Guy's and St Thomas NHS Foundation 
Trust London UK
CORRESPONDENCE ADDRESS
  M.N. Joshi, 3rd Floor Lambeth Wing, St Thomas Hospital, London SE1 7EH, UK 
Email: mamta.joshi@gstt.nhs.uk
SOURCE
  Clinical Endocrinology (2016). Date of Publication: 2016
ISSN
  1365-2265 (electronic)
  0300-0664
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  glucocorticoid
  hormone
  hypophysis hormone
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease
  hypophysitis
EMTREE MEDICAL INDEX TERMS
  clinical study
  drug dosage form
  hormone deficiency
  human
  hypopituitarism
  immunotherapy
  screening
  side effect
  thyroid disease
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160301975
PUI
  L609901328
DOI
  10.1111/cen.13063
FULL TEXT LINK
  http://dx.doi.org/10.1111/cen.13063
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 249
TITLE
  Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) 
expression in cancer cells and tumorinfiltrating lymphocytes in ovarian high 
grade serous carcinoma
AUTHOR NAMES
  Darb-Esfahani S.
  Kunze C.A.
  Kulbe H.
  Sehouli J.
  Wienert S.
  Lindner J.
  Budczies J.
  Bockmayr M.
  Dietel M.
  Denkert C.
  Braicu I.
  Jöhrens K.
AUTHOR ADDRESSES
  (Darb-Esfahani S., silvia.darb-esfahani@charite.de; Kunze C.A.; Wienert S.; 
Lindner J.; Budczies J.; Bockmayr M.; Dietel M.; Denkert C.; Jöhrens K.) 
Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.
(Darb-Esfahani S., silvia.darb-esfahani@charite.de; Kulbe H.; Sehouli J.; 
Denkert C.; Braicu I.) Tumorbank Ovarian Cancer Network, Department of 
Gynecology, Charité Universitätsmedizin Berlin, Berlin, Germany.
(Kulbe H.; Sehouli J.; Braicu I.) Department of Gynecology, Charité 
Universitätsmedizin Berlin, Berlin, Germany.
(Wienert S.) VM Scope GmbH, Berlin, Germany.
CORRESPONDENCE ADDRESS
  S. Darb-Esfahani, Institute of Pathology, Charité Universitätsmedizin 
Berlin, Berlin, Germany. Email: silvia.darb-esfahani@charite.de
SOURCE
  Oncotarget (2016) 7:2 (1486-1499). Date of Publication: 2016
ISSN
  1949-2553 (electronic)
BOOK PUBLISHER
  Impact Journals LLC, editors@impactaging.com
ABSTRACT
  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. 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. 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). 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  CD3 antigen (endogenous compound)
  CD4 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  messenger RNA (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer prognosis
  ovarian cancer cell line
  ovary carcinoma
  protein expression
  tumor associated leukocyte
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer grading
  cancer survival
  computer model
  controlled study
  female
  gene
  gene expression
  human
  human tissue
  immunohistochemistry
  immunomodulation
  major clinical study
  middle aged
  overall survival
  PD 1 gene
  PD L1 gene
  predictive value
  progression free survival
  protein function
  protein protein interaction
  reverse transcription polymerase chain reaction
  survival prediction
  tissue microarray
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Human Genetics (22)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160119785
MEDLINE PMID
  26625204 (http://www.ncbi.nlm.nih.gov/pubmed/26625204)
PUI
  L608271537
DOI
  10.18632/oncotarget.6429
FULL TEXT LINK
  http://dx.doi.org/10.18632/oncotarget.6429
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 250
TITLE
  Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma
AUTHOR NAMES
  Okano Y.
  Satoh T.
  Horiguchi K.
  Toyoda M.
  Osaki A.
  Matsumoto S.
  Tomaru T.
  Nakajima Y.
  Ishii S.
  Ozawa A.
  Shibusawa N.
  Shimada T.
  Higuchi T.
  Chikamatsu K.
  Yamada M.
AUTHOR ADDRESSES
  (Okano Y.; Satoh T., tsato@gunma-u.ac.jp; Horiguchi K.; Osaki A.; Matsumoto 
S.; Tomaru T.; Nakajima Y.; Ishii S.; Ozawa A.; Shibusawa N.; Yamada M.) 
Department of Medicine and Molecular Science, Gunma University Graduate 
School of Medicine, Maebashi, Japan.
(Toyoda M.; Chikamatsu K.) Department of Otolaryngology-Head and Neck 
Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan.
(Shimada T.; Higuchi T.) Department of Diagnostic, Interventional Radiology 
and Nuclear Medicine, Gunma University Graduate School of Medicine, 
Maebashi, Japan.
CORRESPONDENCE ADDRESS
  T. Satoh, Department of Medicine and Molecular Science, Gunma University 
Graduate School of Medicine, Maebashi, Japan. Email: tsato@gunma-u.ac.jp
SOURCE
  Endocrine Journal (2016) 63:10 (905-912). Date of Publication: 2016
ISSN
  1348-4540 (electronic)
  0918-8959
BOOK PUBLISHER
  Japan Endocrine Society, endo-soc-japan@ml.infoweb.ne.jp
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  antibody (endogenous compound)
  corticotropin (endogenous compound)
  corticotropin releasing factor (endogenous compound)
  creatinine (endogenous compound)
  fluorodeoxyglucose f 18
  hydrocortisone (adverse drug reaction, endogenous compound, intravenous drug 
administration, oral drug administration)
  liothyronine (endogenous compound)
  nitrogen (endogenous compound)
  pituitary cell antibody 1 (endogenous compound)
  pralmorelin (endogenous compound)
  prasterone sulfate (endogenous compound)
  prolactin (endogenous compound)
  somatomedin C (endogenous compound)
  testosterone (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
  unclassified drug
  urea (endogenous compound)
  vasopressin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (side effect, diagnosis, side effect)
  melanoma (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  alcohol consumption
  antibody detection
  article
  case report
  computer assisted emission tomography
  corticotropin blood level
  corticotropin release
  creatinine blood level
  drug efficacy
  drug monitoring
  endoscopy
  eosinophilia
  essential hypertension
  fatigue
  histopathology
  hospital discharge
  human
  hydrocortisone blood level
  hyponatremia
  laboratory test
  liothyronine blood level
  loss of appetite
  male
  malnutrition
  medical history
  middle aged
  nuclear magnetic resonance imaging
  oropharynx tumor
  pituitary function test
  plasma osmolarity
  polydipsia (side effect)
  polyuria (side effect)
  primary tumor
  prolactin blood level
  prolactin release
  smoking
  testosterone blood level
  thyrotropin blood level
  thyroxine blood level
  treatment response
  tumor biopsy
  urea nitrogen blood level
  vasopressin blood level
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  corticotropin releasing factor (9015-71-8, 178359-01-8, 79804-71-0, 
86297-72-5, 86784-80-7)
  creatinine (19230-81-0, 60-27-5)
  fluorodeoxyglucose f 18 (63503-12-8)
  hydrocortisone (50-23-7)
  liothyronine (6138-47-2, 6893-02-3)
  nitrogen (7727-37-9)
  nivolumab (946414-94-4)
  pralmorelin (158827-34-0, 158861-67-7)
  prasterone sulfate (651-48-9)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
  somatomedin C (67763-96-6)
  testosterone (58-22-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
  urea (57-13-6)
  vasopressin (11000-17-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160791596
MEDLINE PMID
  27440480 (http://www.ncbi.nlm.nih.gov/pubmed/27440480)
PUI
  L613006211
DOI
  10.1507/endocrj.EJ16-0161
FULL TEXT LINK
  http://dx.doi.org/10.1507/endocrj.EJ16-0161
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 251
TITLE
  Severe acute interstitial nephritis after combination immune-checkpoint 
inhibitor therapy for metastatic melanoma
AUTHOR NAMES
  Murakami N.
  Borges T.J.
  Yamashita M.
  Riella L.V.
AUTHOR ADDRESSES
  (Murakami N.; Borges T.J.; Riella L.V., lriella@bwh.harvard.edu) Renal 
Division, Brigham and Women's Hospital, Harvard Medical School, Boston, 
United States.
(Yamashita M.) Department of Pathology, Brigham and Women's Hospital, 
Harvard Medical School, Boston, United States.
(Riella L.V., lriella@bwh.harvard.edu) Transplantation Research Center, 
Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
CORRESPONDENCE ADDRESS
  L.V. Riella, Renal Division, Brigham and Women's Hospital, Harvard Medical 
School, Boston, United States. Email: lriella@bwh.harvard.edu
SOURCE
  Clinical Kidney Journal (2016) 9:3 (411-417). Date of Publication: 2016
ISSN
  2048-8513 (electronic)
  2048-8505
BOOK PUBLISHER
  Oxford University Press, jnl.info@oup.co.uk
ABSTRACT
  Immune-checkpoint inhibitors are emerging as revolutionary drugs for 
certainmalignancies. 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-oldmanwithmetastaticmalignantmelanoma 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination)
  nivolumab (adverse drug reaction, drug combination)
EMTREE DRUG INDEX TERMS
  albumin (endogenous compound)
  CD4 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  ciprofloxacin
  creatinine (endogenous compound)
  gamma interferon inducible protein 10 (endogenous compound)
  granzyme B (endogenous compound)
  interleukin 1 receptor accessory protein (endogenous compound)
  methylprednisolone sodium succinate (drug therapy, intravenous drug 
administration)
  mycophenolate mofetil (drug therapy, intravenous drug administration)
  perforin (endogenous compound)
  prednisone (drug therapy)
  sulfanilamide
  tumor necrosis factor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  interstitial nephritis (drug therapy, side effect, diagnosis, drug therapy, 
etiology, side effect)
  metastatic melanoma (diagnosis)
EMTREE MEDICAL INDEX TERMS
  abdomen
  acute kidney failure
  aged
  albumin blood level
  article
  back
  body weight loss
  cancer diagnosis
  cancer recurrence
  cancer staging
  case report
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  computer assisted emission tomography
  creatinine blood level
  cutaneous melanoma
  dermatitis
  drug dose increase
  essential hypertension
  human
  human tissue
  immunohistochemistry
  kidney biopsy
  leg edema
  local excision
  lymph node metastasis (diagnosis)
  male
  measles like rash (side effect)
  nasolabial fold
  pancytopenia
  physical examination
  priority journal
  skin biopsy
  steroid therapy
  submandibular lymph node
  thorax
  urinalysis
CAS REGISTRY NUMBERS
  ciprofloxacin (85721-33-1)
  creatinine (19230-81-0, 60-27-5)
  gamma interferon inducible protein 10 (97741-20-3)
  granzyme B ()
  ipilimumab (477202-00-9)
  methylprednisolone sodium succinate (2375-03-3, 2921-57-5)
  mycophenolate mofetil (116680-01-4, 128794-94-5)
  nivolumab (946414-94-4)
  perforin (119332-27-3)
  prednisone (53-03-2)
  sulfanilamide (34612-79-8, 6101-31-1, 63-74-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160548871
PUI
  L611358407
DOI
  10.1093/ckj/sfw024
FULL TEXT LINK
  http://dx.doi.org/10.1093/ckj/sfw024
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 252
TITLE
  Humanized affinity-matured monoclonal antibody 8H9 has potent antitumor 
activity and binds to FG loop of tumor antigen B7-H3
AUTHOR NAMES
  Ahmed M.
  Cheng M.
  Zhao Q.
  Goldgur Y.
  Cheal S.M.
  Guo H.-F.
  Larson S.M.
  Cheung N.-K.V.
AUTHOR ADDRESSES
  (Ahmed M.; Cheng M.; Zhao Q.; Guo H.-F.; Cheung N.-K.V., cheungn@mskcc.org) 
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York 
Ave., New York, United States.
(Cheal S.M.; Larson S.M.) Department of Radiology, Memorial Sloan Kettering 
Cancer Center, New York, United States.
(Goldgur Y.) Structural Biology Program, Memorial Sloan Kettering Cancer 
Center, New York, United States.
(Larson S.M.) Program in Molecular Pharmacology, Memorial Sloan Kettering 
Cancer Center, New York, United States.
CORRESPONDENCE ADDRESS
  N.-K.V. Cheung, Department of Pediatrics, Memorial Sloan Kettering Cancer 
Center, 1275 York Ave., New York, United States. Email: cheungn@mskcc.org
SOURCE
  Journal of Biological Chemistry (2015) 290:50 (30018-30029). Date of 
Publication: 11 Dec 2015
ISSN
  1083-351X (electronic)
  0021-9258
BOOK PUBLISHER
  American Society for Biochemistry and Molecular Biology Inc., 9650 Rockville 
Pike, Bethesda, United States.
ABSTRACT
  Background: B7-H3 is an immune inhibitory ligand and an antigen on many 
solid tumors. Results: Antibody 8H9 was humanized and affinity-matured, and 
its epitope was mapped to the FG loop of B7-H3. Conclusion: hu8H9 antibodies 
had potent antitumor activity and may modulate immune inhibitory properties 
of B7-H3. Significance: Antibodies were developed to target solid tumors and 
affect immune checkpoint blockade.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug analysis, drug therapy, intravenous drug 
administration, pharmacology)
  B7 H3 antigen
  monoclonal antibody (drug analysis, drug therapy, intravenous drug 
administration, pharmacology)
  monoclonal antibody 8H9 (drug analysis, drug therapy, intravenous drug 
administration, pharmacology)
  tumor antigen
EMTREE DRUG INDEX TERMS
  immunoglobulin G (endogenous compound)
  single chain fragment variable antibody (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antineoplastic activity
  drug binding
  neuroblastoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  animal model
  animal tissue
  antibody combining site
  article
  binding affinity
  cell mediated cytotoxicity
  controlled study
  drug distribution
  drug potency
  drug structure
  drug targeting
  EC50
  female
  human
  human cell
  immunoreactivity
  in vitro study
  mouse
  nonhuman
  priority journal
  protein expression
CAS REGISTRY NUMBERS
  immunoglobulin G (97794-27-9)
  single chain fragment variable antibody (334577-34-3, 334577-38-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Neurology and Neurosurgery (8)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00089245, NCT01099644, NCT01502917)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20151028894
PUI
  L607206544
DOI
  10.1074/jbc.M115.679852
FULL TEXT LINK
  http://dx.doi.org/10.1074/jbc.M115.679852
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 253
TITLE
  Safety and antitumor activity of Anti-PD-1 antibody, nivolumab, in patients 
with platinum-resistant ovarian cancer
AUTHOR NAMES
  Hamanishi J.
  Mandai M.
  Ikeda T.
  Minami M.
  Kawaguchi A.
  Murayama T.
  Kanai M.
  Mori Y.
  Matsumoto S.
  Chikuma S.
  Matsumura N.
  Abiko K.
  Baba T.
  Yamaguchi K.
  Ueda A.
  Hosoe Y.
  Morita S.
  Yokode M.
  Shimizu A.
  Honjo T.
  Konishi I.
AUTHOR ADDRESSES
  (Hamanishi J., jnkhmns@kuhp.kyoto-u.ac.jp; Kanai M.; Mori Y.; Matsumoto S.; 
Chikuma S.; Matsumura N.; Abiko K.; Baba T.; Yamaguchi K.; Ueda A.; Hosoe 
Y.; Honjo T.; Konishi I.) Kyoto University Graduate School of Medicine, 
Department of Gynecology and Obstetrics, 54 Kawahara-cho, Shogoin, Sakyo-ku, 
Kyoto, Japan.
(Mandai M.) Kinki University Faculty of Medicine, Osaka, Japan.
(Ikeda T.; Minami M.; Kawaguchi A.; Murayama T.; Morita S.; Yokode M.; 
Shimizu A.) Kyoto University Hospital, Kyoto, Japan.
CORRESPONDENCE ADDRESS
  J. Hamanishi, Kyoto University Graduate School of Medicine, Department of 
Gynecology and Obstetrics, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan. 
Email: jnkhmns@kuhp.kyoto-u.ac.jp
SOURCE
  Journal of Clinical Oncology (2015) 33:34 (4015-4022). Date of Publication: 
1 Dec 2015
ISSN
  1527-7755 (electronic)
  0732-183X
BOOK PUBLISHER
  American Society of Clinical Oncology, jcoservice@asco.org
ABSTRACT
  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. 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. 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. 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 platinumresistant 
ovarian cancer indicate the merit of additional large-scale investigations 
(UMIN Clinical Trials Registry UMIN000005714).
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, intravenous drug administration)
  platinum
EMTREE DRUG INDEX TERMS
  albumin (endogenous compound)
  aspartate aminotransferase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antineoplastic activity
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  anemia (side effect)
  arthralgia (side effect)
  article
  cancer control
  cancer survival
  clinical article
  cohort analysis
  controlled study
  drug efficacy
  drug safety
  fatigue (side effect)
  female
  human
  hypothyroidism (side effect)
  lymphocytopenia (side effect)
  maculopapular rash (side effect)
  middle aged
  multiple cycle treatment
  open study
  phase 2 clinical trial
  priority journal
  progression free survival
  survival time
  tachycardia (side effect)
  thyroiditis (side effect)
  treatment outcome
DRUG MANUFACTURERS
   (Japan)Ono
CAS REGISTRY NUMBERS
  aspartate aminotransferase (9000-97-9)
  nivolumab (946414-94-4)
  platinum (7440-06-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20151060730
MEDLINE PMID
  26351349 (http://www.ncbi.nlm.nih.gov/pubmed/26351349)
PUI
  L607356084
DOI
  10.1200/JCO.2015.62.3397
FULL TEXT LINK
  http://dx.doi.org/10.1200/JCO.2015.62.3397
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 254
TITLE
  The Mechanism by Which MYCN Amplification Confers an Enhanced Sensitivity to 
a PCNA-Derived Cell Permeable Peptide in Neuroblastoma Cells
AUTHOR NAMES
  Gu L.
  Chu P.
  Lingeman R.
  McDaniel H.
  Kechichian S.
  Hickey R.J.
  Liu Z.
  Yuan Y.-C.
  Sandoval J.A.
  Fields G.B.
  Malkas L.H.
AUTHOR ADDRESSES
  (Gu L., lgu@coh.org; Lingeman R.; Kechichian S.; Malkas L.H.) Department of 
Molecular and Cellular Biology, Beckman Research Institute, City of Hope, 
Duarte, United States.
(Chu P.) Department of Pathology, Beckman Research Institute, City of Hope, 
Duarte, United States.
(McDaniel H.) Department of Pediatrics, Vanderbilt University School of 
Medicine, Nashville, United States.
(Hickey R.J.) Department of Molecular Medicine, Beckman Research Institute, 
City of Hope, Duarte, United States.
(Liu Z.; Yuan Y.-C.) Bioinformatic Core, Beckman Research Institute, City of 
Hope, Duarte, United States.
(Sandoval J.A.) Department of Surgery, St. Jude Children's Research 
Hospital, Memphis, United States.
(Fields G.B.) Florida Atlantic University and The Scripps Research 
Institute/Scripps Florida, Jupiter, United States.
CORRESPONDENCE ADDRESS
  L. Gu, Department of Molecular and Cellular Biology, Beckman Research 
Institute, City of Hope, Duarte, United States. Email: lgu@coh.org
SOURCE
  EBioMedicine (2015) 2:12 (1923-1931). Date of Publication: 1 Dec 2015
ISSN
  2352-3964 (electronic)
BOOK PUBLISHER
  Elsevier
ABSTRACT
  Dysregulated expression of MYC family genes is a hallmark of many 
malignancies. Unfortunately, these proteins are not amenable to blockade by 
small molecules or protein-based therapeutic agents. Therefore, we must find 
alternative approaches to target MYC-driven cancers. Amplification of MYCN, 
a MYC family member, predicts high-risk neuroblastoma (NB) disease. We have 
shown that R9-caPep blocks the interaction of PCNA with its binding partners 
and selectively kills human NB cells, especially those with MYCN 
amplification, and we now show the mechanism. We found elevated levels of 
DNA replication stress in MYCN-amplified NB cells. R9-caPep exacerbated DNA 
replication stress in MYCN-amplified NB cells and NB cells with an augmented 
level of MYC by interfering with DNA replication fork extension, leading to 
Chk1 dependence and susceptibility to Chk1 inhibition. We describe how these 
effects may be exploited for treating NB.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cycline (endogenous compound)
  Myc protein (endogenous compound)
EMTREE DRUG INDEX TERMS
  checkpoint kinase 1 (endogenous compound)
  checkpoint kinase inhibitor
  histone H2A (endogenous compound)
  R9 caPep peptide
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gene amplification
  neuroblastoma
EMTREE MEDICAL INDEX TERMS
  amino acid sequence
  article
  bone marrow derived mesenchymal stem cell
  cell growth
  chemoluminescence
  chemosensitivity
  controlled study
  DNA damage
  DNA replication
  gene expression
  genetic transfection
  growth inhibition
  human
  human cell
  immunohistochemistry
  nucleotide sequence
  peptide analysis
  phosphorylation
  priority journal
  sensitivity analysis
  Western blotting
MOLECULAR SEQUENCE NUMBERS
  GENBANK (GSE66586)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015528000
MEDLINE PMID
  26844271 (http://www.ncbi.nlm.nih.gov/pubmed/26844271)
PUI
  L606999372
DOI
  10.1016/j.ebiom.2015.11.016
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ebiom.2015.11.016
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 255
TITLE
  Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer 
immunotherapy
AUTHOR NAMES
  Lu J.
  Lee-Gabel L.
  Nadeau M.C.
  Ferencz T.M.
  Soefje S.A.
AUTHOR ADDRESSES
  (Lu J., jing.lu@ynhh.org; Lee-Gabel L.; Nadeau M.C.; Ferencz T.M.) 
Department of Pharmacy, Smilow Cancer Hospital at Yale-New Haven, 35 Park 
Street, New Haven, United States.
(Soefje S.A.) Department of Pharmacy, University Medical Center 
Brackenridge, Seton Healthcare Family, Austin, United States.
CORRESPONDENCE ADDRESS
  J. Lu, Department of Pharmacy, Smilow Cancer Hospital at Yale-New Haven, 35 
Park Street, New Haven, United States. Email: jing.lu@ynhh.org
SOURCE
  Journal of Oncology Pharmacy Practice (2015) 21:6 (451-467). Date of 
Publication: 1 Dec 2015
ISSN
  1477-092X (electronic)
  1078-1552
BOOK PUBLISHER
  SAGE Publications Ltd, info@sagepub.co.uk
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction)
  immunomodulating agent (adverse drug reaction)
  programmed death 1 ligand 1 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  analgesic agent (drug therapy)
  antihistaminic agent (drug therapy)
  antipyretic agent (drug therapy)
  atezolizumab (adverse drug reaction, pharmacokinetics, pharmacology)
  avelumab (pharmacokinetics, pharmacology)
  bms 936559 (adverse drug reaction, pharmacokinetics, pharmacology)
  corticosteroid (drug therapy)
  dexamethasone (drug therapy)
  diphenoxylate (drug therapy)
  durvalumab (adverse drug reaction, pharmacology)
  hydrocortisone (drug therapy)
  immunoglobulin (drug therapy)
  infliximab (drug therapy)
  ipilimumab (drug combination)
  levothyroxine (drug therapy)
  loperamide (drug therapy)
  methylprednisolone (drug therapy)
  mineralocorticoid (drug therapy)
  nivolumab (adverse drug reaction, drug combination, pharmacokinetics, 
pharmacology)
  pembrolizumab (adverse drug reaction, pharmacokinetics, pharmacology)
  pidilizumab (adverse drug reaction, pharmacokinetics, pharmacology)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  clinical evaluation
EMTREE MEDICAL INDEX TERMS
  anemia (side effect)
  area under the curve
  arthralgia (side effect)
  asthenia (side effect)
  chill (side effect)
  colitis (side effect)
  constipation (side effect)
  corticosteroid therapy
  coughing (side effect)
  cytokine storm (side effect)
  decreased appetite (side effect)
  diarrhea (side effect)
  drug blood level
  drug distribution
  drug efficacy
  drug eruption (drug therapy, side effect)
  drug half life
  drug mechanism
  drug response
  drug safety
  dyspnea (side effect)
  endocrine disease (drug therapy, side effect)
  eye disease (drug therapy, side effect)
  fatigue (side effect)
  fever (side effect)
  food and drug administration
  gastrointestinal symptom (drug therapy, side effect)
  half life time
  headache (side effect)
  hepatitis (side effect)
  hormone substitution
  human
  hyperglycemia (side effect)
  hypophosphatemia (side effect)
  hypothyroidism (side effect)
  infusion related reaction (drug therapy, side effect)
  insomnia (side effect)
  liver disease (drug therapy, side effect)
  lymphocytopenia (side effect)
  maximum plasma concentration
  monotherapy
  multicenter study (topic)
  musculoskeletal pain (side effect)
  myalgia (side effect)
  nausea (side effect)
  neurologic disease (drug therapy, side effect)
  neutropenia (side effect)
  occupational hazard
  opportunistic infection (side effect)
  pharmacodynamics
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  phase 4 clinical trial (topic)
  pneumonia (side effect)
  practice guideline
  priority journal
  pruritus (side effect)
  randomized controlled trial (topic)
  rash (side effect)
  review
  side effect (side effect)
  signal transduction
  tumor lysis syndrome (side effect)
  vitiligo (side effect)
  volume of distribution
  vomiting (side effect)
DRUG TRADE NAMES
  bms 936558  Bristol Myers Squibb

  bms 936559  Bristol Myers Squibb

  ct 011  CureTech

  mdx 1105  Bristol Myers Squibb

  mdx 1106  Bristol Myers Squibb

  medi 4736  Medimmune

  mk 3475  Merck

  mpdl 3280a  Genentech Roche

  msb 0010718c  EMD Serono

DRUG MANUFACTURERS
  Bristol Myers Squibb
  CureTech
  EMD Serono
  Genentech Roche
  Medimmune
  Merck
CAS REGISTRY NUMBERS
  avelumab (1537032-82-8)
  dexamethasone (50-02-2)
  diphenoxylate (3810-80-8, 915-30-0)
  durvalumab (1428935-60-7)
  hydrocortisone (50-23-7)
  immunoglobulin (9007-83-4)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  loperamide (34552-83-5, 53179-11-6)
  methylprednisolone (6923-42-8, 83-43-2)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  pidilizumab (1036730-42-3)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Public Health, Social Medicine and Epidemiology (17)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015474284
MEDLINE PMID
  24917416 (http://www.ncbi.nlm.nih.gov/pubmed/24917416)
PUI
  L606628513
DOI
  10.1177/1078155214538087
FULL TEXT LINK
  http://dx.doi.org/10.1177/1078155214538087
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 256
TITLE
  Corrigendum to Ipilimumab-induced hypophysitis in melanoma patients: An 
Australian case series. [Intern Med J (2015), 45, 1066-1073]. DOI: 
10.1111/imj.12819
AUTHOR ADDRESSES
  SOURCE
  Internal Medicine Journal (2015) 45:12 (1318). Date of Publication: 1 Dec 
2015
ISSN
  1445-5994 (electronic)
  1444-0903
BOOK PUBLISHER
  Blackwell Publishing, info@asia.blackpublishing.com.au
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  case study
  hypophysitis
  melanoma
EMTREE MEDICAL INDEX TERMS
  clinical study
  human
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  20151016283
PUI
  L607207831
DOI
  10.1111/imj.12943
FULL TEXT LINK
  http://dx.doi.org/10.1111/imj.12943
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 257
TITLE
  A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, 
Providing Enhanced Ovarian Cancer Immuno-Chemotherapy
AUTHOR NAMES
  Awuah S.G.
  Zheng Y.-R.
  Bruno P.M.
  Hemann M.T.
  Lippard S.J.
AUTHOR ADDRESSES
  (Awuah S.G.; Zheng Y.-R.; Lippard S.J., lippard@mit.edu) Department of 
Chemistry, Massachusetts Institute of Technology, Cambridge, United States.
(Bruno P.M.; Hemann M.T.; Lippard S.J., lippard@mit.edu) Koch Institute for 
Integrative Cancer Research, Massachusetts Institute of Technology, 
Cambridge, United States.
CORRESPONDENCE ADDRESS
  S.J. Lippard, Department of Chemistry, Massachusetts Institute of 
Technology, Cambridge, United States.
SOURCE
  Journal of the American Chemical Society (2015) 137:47 (14854-14857). Date 
of Publication: 12 Nov 2015
ISSN
  1520-5126 (electronic)
  0002-7863
BOOK PUBLISHER
  American Chemical Society, service@acs.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug development, pharmacology)
  indoleamine 2,3 dioxygenase inhibitor (drug development, pharmacology)
  platinum derivative (drug development, pharmacology)
EMTREE DRUG INDEX TERMS
  cisplatin
  kynurenine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer chemotherapy
  cancer immunotherapy
  ovary cancer (drug resistance)
EMTREE MEDICAL INDEX TERMS
  article
  autocrine effect
  cancer resistance
  cell proliferation
  controlled study
  cross linking
  female
  human
  human cell
  immunomodulation
  mouse
  nonhuman
  ovarian cancer cell line
  T lymphocyte
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  kynurenine (16055-80-4, 343-65-7)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015553243
MEDLINE PMID
  26561720 (http://www.ncbi.nlm.nih.gov/pubmed/26561720)
PUI
  L607106989
DOI
  10.1021/jacs.5b10182
FULL TEXT LINK
  http://dx.doi.org/10.1021/jacs.5b10182
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 258
TITLE
  Immunotherapy in lung cancer treatment: The checkpoint inhibitors
ORIGINAL (NON-ENGLISH) TITLE
  Immunothérapie dans le cancer bronchique : Les inhibiteurs de Checkpoints
AUTHOR NAMES
  Mennecier B.
AUTHOR ADDRESSES
  (Mennecier B., bertrand.mennecier@chru-strasbourg.fr) Pôle de pathologie 
thoracique, Nouvel hôpital civil, 1, place de l'Hôpital, Strasbourg, France.
CORRESPONDENCE ADDRESS
  B. Mennecier, Pôle de pathologie thoracique, Nouvel hôpital civil, 1, place 
de l'Hôpital, Strasbourg, France. Email: 
bertrand.mennecier@chru-strasbourg.fr
SOURCE
  Revue des Maladies Respiratoires Actualites (2015) 7:4 (353-360). Date of 
Publication: 1 Nov 2015
ISSN
  1877-122X (electronic)
  1877-1203
BOOK PUBLISHER
  Elsevier Masson SAS, 62 rue Camille Desmoulins, Issy les Moulineaux Cedex, 
France.
ABSTRACT
  Immunotherapy in lung cancer has usually been extremely disappointing. 
Highlighting the role of checkpoint inhibitors totally relaunched this 
therapeutic track. Two checkpoints are the targets of these inhibitors : 
CTLA4 and the PD1/PDL1 axis. Drugs blocking the latter are particularly 
developed in lung cancer and will be more widely the subject of this review. 
This year was very rich in data regarding efficacy, with for the first time 
some results of phase III trials, in pre-treated patients, and the results 
of large phase II studies on substantial numbers of patients. Toxicity data 
of these new drugs appear to be broadly similar between drugs and usually 
acceptable, but with toxicity profiles poorly known by thoracic oncologists 
(thyroiditis, rashes, colitis, etc.). A predictive biomarker identification 
for effectiveness of these drugs is needed but remains to be validated. 
Despite the significant heterogeneity between studies concerning thresholds 
and the cells tested for immunohistochemistry, it seems to draw a trend that 
should bring to validate PDL1 as a biomarker, at least in non-squamous cell 
carcinoma. It's a very promising therapeutic, the approvals are coming, 
currently in the second line only, but the development of these drugs 
continues particularly in first line, as a single agent or in combination 
with chemotherapy or tyrosine kinase inhibitors.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  protein tyrosine kinase inhibitor (drug dose)
  synapsin I (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  lung cancer
EMTREE MEDICAL INDEX TERMS
  article
  cancer combination chemotherapy
  death
  drug approval
  human
  immunohistochemistry
  phase 3 clinical trial (topic)
  single drug dose
  squamous cell carcinoma
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Pharmacy (39)
LANGUAGE OF ARTICLE
  French
LANGUAGE OF SUMMARY
  English, French
EMBASE ACCESSION NUMBER
  20160026981
PUI
  L607648654
DOI
  10.1016/S1877-1203(16)30017-9
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1877-1203(16)30017-9
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 259
TITLE
  Ipilimumab-induced autoimmune hypophysitis: Diagnostic and management 
challenges illustrated by a clinical case
ORIGINAL (NON-ENGLISH) TITLE
  Hipofisite induzida por ipilimumab: Desafios diagnósticos e terapêuticos
AUTHOR NAMES
  Marques P.
  Grossman A.
AUTHOR ADDRESSES
  (Marques P., pedro.miguel.sousa.marques@gmail.com) Serviço de 
Endocrinologia, Instituto Português de Oncologia de Lisboa, Lisboa, 
Portugal.
(Grossman A.) Department Endocrinology and Metabolism, Oxford Centre for 
Diabetes, Oxford, United Kingdom.
CORRESPONDENCE ADDRESS
  P. Marques, Serviço de Endocrinologia, Instituto Português de Oncologia de 
Lisboa, Lisboa, Portugal. Email: pedro.miguel.sousa.marques@gmail.com
SOURCE
  Acta Medica Portuguesa (2015) 28:6 (775-779). Date of Publication: 1 Nov 
2015
ISSN
  1646-0758 (electronic)
  0870-399X
BOOK PUBLISHER
  CELOM
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  gonadotropin (endogenous compound)
  hydrocortisone (drug therapy, oral drug administration)
  levothyroxine
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune hypophysitis (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  case report
  fatigue
  female
  headache
  human
  hydrocortisone blood level
  nausea
  nuclear magnetic resonance imaging
CAS REGISTRY NUMBERS
  gonadotropin (63231-54-9)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English, Portuguese
EMBASE ACCESSION NUMBER
  20160008412
MEDLINE PMID
  27265913 (http://www.ncbi.nlm.nih.gov/pubmed/27265913)
PUI
  L607487157
COPYRIGHT
  Copyright 2018 Elsevier B.V., All rights reserved.

RECORD 260
TITLE
  Phase II study of ipilimumab monotherapy in Japanese patients with advanced 
melanoma
AUTHOR NAMES
  Yamazaki N.
  Kiyohara Y.
  Uhara H.
  Fukushima S.
  Uchi H.
  Shibagaki N.
  Tsutsumida A.
  Yoshikawa S.
  Okuyama R.
  Ito Y.
  Tokudome T.
AUTHOR ADDRESSES
  (Yamazaki N.; Tsutsumida A.) Department of Dermatologic Oncology, National 
Cancer Center Hospital, Tokyo, Japan.
(Kiyohara Y.; Yoshikawa S.) Dermatology Division, Shizuoka Cancer Center, 
Shizuoka, Japan.
(Uhara H.; Okuyama R.) Department of Dermatology, Shinshu University, School 
of Medicine, Matsumoto, Japan.
(Fukushima S.) Department of Dermatology and Plastic Surgery, Faculty of 
Life Sciences, Kumamoto University, Kumamoto, Japan.
(Uchi H.) Department of Dermatology, Graduate School of Medical Sciences, 
Kyushu University, Fukuoka, Japan.
(Shibagaki N.) Department of Dermatology, University of Yamanashi Hospital, 
Yamanashi, Japan.
(Ito Y.; Tokudome T., takuto0806@gmail.com) Research and Development, 
Bristol-Myers K.K., 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, Japan.
CORRESPONDENCE ADDRESS
  T. Tokudome, Research and Development, Bristol-Myers K.K., 6-5-1, 
Nishishinjuku, Shinjuku-ku, Tokyo, Japan.
SOURCE
  Cancer Chemotherapy and Pharmacology (2015) 76:5 (997-1004). Date of 
Publication: 1 Nov 2015
ISSN
  1432-0843 (electronic)
  0344-5704
BOOK PUBLISHER
  Springer Verlag, service@springer.de
ABSTRACT
  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. 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). 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. 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.gov identifier: NCT01990859.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  C reactive protein (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  alopecia (side effect)
  article
  cancer control
  cancer patient
  cancer survival
  clinical article
  clinical trial
  decreased appetite (side effect)
  diabetes mellitus (side effect)
  diarrhea (side effect)
  drug efficacy
  drug eruption (side effect)
  drug hypersensitivity (side effect)
  drug safety
  drug withdrawal
  female
  fever (side effect)
  follow up
  gastrointestinal disease (side effect)
  human
  immunopathology (side effect)
  Japanese (people)
  long term survival
  male
  metabolic disorder (side effect)
  monotherapy
  nutritional disorder (side effect)
  priority journal
  pruritus (side effect)
  side effect (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  C reactive protein (9007-41-4)
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT1990859)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015466201
MEDLINE PMID
  26410424 (http://www.ncbi.nlm.nih.gov/pubmed/26410424)
PUI
  L606486940
DOI
  10.1007/s00280-015-2873-x
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00280-015-2873-x
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 261
TITLE
  Ipilimumab-Induced Adrenalitis: A Possible Pitfall in 18F-FDG-PET/CT
AUTHOR NAMES
  Bacanovic S.
  Burger I.A.
  Stolzmann P.
  Hafner J.
  Huellner M.W.
AUTHOR ADDRESSES
  (Bacanovic S.; Burger I.A.; Stolzmann P.; Hafner J.; Huellner M.W.) 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
SOURCE
  Clinical nuclear medicine (2015) 40:11 (e518-e519). Date of Publication: 1 
Nov 2015
ISSN
  1536-0229 (electronic)
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (adverse drug reaction)
  fluorodeoxyglucose f 18
  ipilimumab
  monoclonal antibody (adverse drug reaction)
  radiopharmaceutical agent
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  computer assisted tomography
  positron emission tomography
  scintiscanning
EMTREE MEDICAL INDEX TERMS
  adrenal cortex hyperfunction
  aged
  case report
  chemically induced
  human
  laboratory diagnosis
  male
  melanoma (drug therapy)
  metastasis
  multimodal imaging
  pathology
CAS REGISTRY NUMBERS
  fluorodeoxyglucose f 18 (63503-12-8)
  ipilimumab (477202-00-9)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  26164177 (http://www.ncbi.nlm.nih.gov/pubmed/26164177)
PUI
  L610827973
DOI
  10.1097/RLU.0000000000000887
FULL TEXT LINK
  http://dx.doi.org/10.1097/RLU.0000000000000887
COPYRIGHT
  Copyright 2016 Medline is the source for the citation and abstract of this 
record.

RECORD 262
TITLE
  Immune-mediated adverse events of anticytotoxic T lymphocyte-associated 
antigen 4 antibody therapy in metastatic melanoma
AUTHOR NAMES
  Quirk S.K.
  Shure A.K.
  Agrawal D.K.
AUTHOR ADDRESSES
  (Quirk S.K.; Shure A.K.; Agrawal D.K., dkagr@creighton.edu) Center for 
Clinical and Translational Science, Creighton University, School of 
Medicine, 2500 California Plaza, Omaha, United States.
CORRESPONDENCE ADDRESS
  D.K. Agrawal, Center for Clinical and Translational Science, Creighton 
University, School of Medicine, 2500 California Plaza, Omaha, United States. 
Email: dkagr@creighton.edu
SOURCE
  Translational Research (2015) 166:5 (412-424). Date of Publication: 1 Nov 
2015
ISSN
  1878-1810 (electronic)
  1931-5244
BOOK PUBLISHER
  Mosby Inc., customerservice@mosby.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 antibody
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
EMTREE DRUG INDEX TERMS
  APC protein
  cytotoxic T lymphocyte antigen 4
  granulocyte macrophage colony stimulating factor (drug combination)
  interleukin 2 (drug combination)
  nivolumab (drug combination)
  programmed death 1 ligand 1
  programmed death 1 receptor
  T lymphocyte receptor
  talimogene laherparepvec (drug combination)
  ticilimumab (clinical trial)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction
  cancer immunotherapy
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  cancer combination chemotherapy
  cellular immunity
  colitis (side effect)
  cytokine release
  cytotoxic T lymphocyte
  diarrhea (side effect)
  drug safety
  effector cell
  endocrine disease (side effect)
  eye disease (side effect)
  gastrointestinal symptom (side effect)
  hematologic disease (side effect)
  human
  kidney disease (side effect)
  neurological complication (side effect)
  opportunistic infection (side effect)
  overall survival
  phase 3 clinical trial (topic)
  priority journal
  regulatory T lymphocyte
  review
  toxic hepatitis (side effect)
CAS REGISTRY NUMBERS
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  talimogene laherparepvec (1187560-31-1)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015181117
MEDLINE PMID
  26118951 (http://www.ncbi.nlm.nih.gov/pubmed/26118951)
PUI
  L605123474
DOI
  10.1016/j.trsl.2015.06.005
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.trsl.2015.06.005
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 263
TITLE
  Pembrolizumab in the management of metastatic melanoma
AUTHOR NAMES
  Spain L.
  Younger E.
  Hatipoglu E.
  Larkin J.
AUTHOR ADDRESSES
  (Spain L.; Younger E.; Hatipoglu E.; Larkin J., james.larkin@rmh.nhs.uk) 
Royal Marsden Hospital, Fulham Road, London, United Kingdom.
CORRESPONDENCE ADDRESS
  J. Larkin, Royal Marsden Hospital, Fulham Road, London, United Kingdom. 
Email: james.larkin@rmh.nhs.uk
SOURCE
  Melanoma Management (2015) 2:4 (315-325). Date of Publication: 1 Nov 2015
ISSN
  2045-0893 (electronic)
  2045-0885
BOOK PUBLISHER
  Future Medicine Ltd., info@futuremedicine.com
ABSTRACT
  Pembrolizumab is a humanized IgG4 anti-PD-1 antibody that plays a major role 
in the treatment of advanced melanoma. Through blockade of PD-1, it leads to 
an increase in effector T-cell activity in the tumor microenvironment. 
Clinical trial outcomes for pembrolizumab in addition to pharmacokinetics, 
pharmacodynamics and safety of the compound are discussed in this article. 
Phase I trials have demonstrated safety and efficacy of pembrolizumab in 
advanced, pretreated melanoma patients. When compared with chemotherapy in a 
Phase II trial of ipilimumab-refractory patients, those treated with 
pembrolizumab showed superior progression-free survival. In addition, in the 
pivotal Phase III trial pembrolizumab improved overall survival compared 
with ipilimumab in patients naive to immune checkpoint inhibition. 
Pembrolizumab is well tolerated and has a favorable safety profile. Common 
adverse events are fatigue, rash, itching and diarrhea. Less frequent 
immune-related adverse events include hypothyroidism, colitis, hepatitis and 
pneumonitis.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug comparison, pharmacokinetics, 
pharmacology)
EMTREE DRUG INDEX TERMS
  aminotransferase (endogenous compound)
  ipilimumab (adverse drug reaction, drug combination, drug comparison, drug 
therapy)
  nivolumab (adverse drug reaction, drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  advanced cancer
  aminotransferase blood level
  article
  cancer combination chemotherapy
  colitis (side effect)
  diarrhea (side effect)
  drug absorption
  drug efficacy
  drug excretion
  drug metabolism
  drug safety
  drug tolerability
  fatigue (side effect)
  hepatitis (side effect)
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  overall survival
  pharmacodynamics
  pneumonia (side effect)
  postmarketing surveillance
  priority journal
  progression free survival
  pruritus (side effect)
  rash (side effect)
  side effect (side effect)
  survival rate
  uveitis (side effect)
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  aminotransferase (9031-66-7)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20151004487
PUI
  L607153713
DOI
  10.2217/mmt.15.33
FULL TEXT LINK
  http://dx.doi.org/10.2217/mmt.15.33
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 264
TITLE
  CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in 
BRCA1-Deficient Ovarian Cancer
AUTHOR NAMES
  Higuchi T.
  Flies D.B.
  Marjon N.A.
  Mantia-Smaldone G.
  Ronner L.
  Gimotty P.A.
  Adams S.F.
AUTHOR ADDRESSES
  (Higuchi T.; Flies D.B.; Marjon N.A.; Adams S.F., SAdams@salud.unm.edu) 
University of New Mexico Cancer Center, Division of Gynecologic Oncology, 1 
University of New Mexico, MSC07-4025, 1201 Camino de Salud NE, Albuquerque, 
United States.
(Mantia-Smaldone G.) Fox Chase Cancer Center, Philadelphia, United States.
(Ronner L.) Carnegie Mellon University, Pittsburgh, United States.
(Gimotty P.A.) University of Pennsylvania, Philadelphia, United States.
CORRESPONDENCE ADDRESS
  S.F. Adams, University of New Mexico Cancer Center, Division of Gynecologic 
Oncology, 1 University of New Mexico, MSC07-4025, 1201 Camino de Salud NE, 
Albuquerque, United States. Email: SAdams@salud.unm.edu
SOURCE
  Cancer Immunology Research (2015) 3:11 (1257-1268). Date of Publication: 1 
Nov 2015
ISSN
  2326-6074 (electronic)
  2326-6066
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  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 
IFNγ 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 IFNγ 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  BRCA1 protein (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody (drug interaction, pharmacology)
  veliparib (drug interaction, oral drug administration, pharmacology)
EMTREE DRUG INDEX TERMS
  gamma interferon (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  animal model
  article
  cancer cell
  cancer survival
  controlled study
  cytotoxicity
  female
  human
  human cell
  immunity
  immunological memory
  in vitro study
  long term survival
  mouse
  nonhuman
  peritoneum tumor
DRUG TRADE NAMES
  abt 888  Active Biochem

DRUG MANUFACTURERS
  Active Biochem
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
  veliparib (912444-00-9)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160116819
MEDLINE PMID
  26138335 (http://www.ncbi.nlm.nih.gov/pubmed/26138335)
PUI
  L608073637
DOI
  10.1158/2326-6066.CIR-15-0044
FULL TEXT LINK
  http://dx.doi.org/10.1158/2326-6066.CIR-15-0044
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 265
TITLE
  Phase Ia Study of FoxP3(+) CD4 Treg Depletion by Infusion of a Humanized 
Anti-CCR4 Antibody, KW-0761, in Cancer Patients
AUTHOR NAMES
  Kurose K.
  Ohue Y.
  Wada H.
  Iida S.
  Ishida T.
  Kojima T.
  Doi T.
  Suzuki S.
  Isobe M.
  Funakoshi T.
  Kakimi K.
  Nishikawa H.
  Udono H.
  Oka M.
  Ueda R.
  Nakayama E.
AUTHOR ADDRESSES
  (Kurose K.; Ohue Y.; Isobe M.; Oka M.) Department of Respiratory Medicine, 
Kawasaki Medical School, Kurashiki, Okayama, Japan.
(Wada H.) Department of Clinical Research in Tumor Immunology, Osaka 
University Graduate School of Medicine, Suita, Osaka, Japan.
(Iida S.; Ishida T.) Department of Hematology and Oncology, Nagoya City 
University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
(Kojima T.; Doi T.) Exploratory Oncology Research and Clinical Trial Center, 
Kashiwa, Chiba, Japan.
(Suzuki S.; Ueda R., uedaryu@aichi-med-u.ac.jp) Department of Tumor 
Immunology, Aichi Medical University, 1-1 Yazako-karimata, Nagakute, Aichi, 
Japan.
(Funakoshi T.) Department of Dermatology, Keio University School of 
Medicine, Shinjuku-ku, Tokyo, Japan.
(Kakimi K.) Department of Immunotherapeutics, University of Tokyo Hospital, 
Bunkyo-Ku, Tokyo, Japan.
(Nishikawa H.) Experimental Immunology, Immunology Frontier Research Center, 
Osaka University, Suita, Osaka, Japan.
(Udono H.) Department of Immunology, Okayama University, Graduate School of 
Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.
(Nakayama E., nakayama@mw.kawasaki-m.ac.jp) Faculty of Health and Welfare, 
Kawasaki University of Medical Welfare, 288 Matsushima, Kurashiki, Okayama, 
Japan.
CORRESPONDENCE ADDRESS
  E. Nakayama, Faculty of Health and Welfare, Kawasaki University of Medical 
Welfare, 288 Matsushima, Kurashiki, Okayama, Japan.
SOURCE
  Clinical Cancer Research (2015) 21:19 (4327-4336). Date of Publication: 1 
Oct 2015
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  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. 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, 
includingTregs,andinductionofimmune responseswereanalyzed. Results: The 
results showed that KW-0761 infusion in a dose range between0.1mg/kg and 
1.0mg/kgwas safe andwell tolerated. Nodose-limiting toxicitywas 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  mogamulizumab (adverse drug reaction, clinical trial, drug dose, drug 
therapy, intravenous drug administration, pharmacokinetics)
  transcription factor FOXP3 (endogenous compound)
EMTREE DRUG INDEX TERMS
  chemokine receptor CCR4 (endogenous compound)
  gamma glutamyltransferase (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  CD4+ T lymphocyte
  esophagus cancer (drug therapy, drug therapy)
  lung cancer (drug therapy, drug therapy)
  regulatory T lymphocyte
  T cell depletion
EMTREE MEDICAL INDEX TERMS
  antibody response
  article
  cancer immunotherapy
  CD8+ T lymphocyte
  clinical article
  controlled clinical trial
  controlled study
  dose response
  drug dose escalation
  drug efficacy
  drug half life
  drug safety
  drug tolerability
  gamma glutamyl transferase blood level
  human
  leukopenia (side effect)
  lymphocyte subpopulation
  lymphocytopenia (side effect)
  maximum plasma concentration
  neutropenia (side effect)
  outcome assessment
  overall survival
  peripheral blood mononuclear cell
  phase 1 clinical trial
  priority journal
  progression free survival
  protein expression
  rash (side effect)
  side effect (side effect)
  skin biopsy
  Th17 cell
  Th2 cell
DRUG TRADE NAMES
  kw 0761
CAS REGISTRY NUMBERS
  chemokine receptor CCR4 (169936-75-8)
  gamma glutamyltransferase (85876-02-4)
  mogamulizumab (1159266-37-1)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01929486)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015486168
MEDLINE PMID
  26429981 (http://www.ncbi.nlm.nih.gov/pubmed/26429981)
PUI
  L606602401
DOI
  10.1158/1078-0432.CCR-15-0357
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-15-0357
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 266
TITLE
  Radiographic profiling of immune-related adverse events in advanced melanoma 
patients treated with ipilimumab
AUTHOR NAMES
  Tirumani S.H.
  Ramaiya N.H.
  Keraliya A.
  Bailey N.D.
  Ott P.A.
  Stephen Hodi F.
  Nishino M.
AUTHOR ADDRESSES
  (Tirumani S.H.; Ramaiya N.H.; Keraliya A.; Nishino M., 
Mizuki_Nishino@dfci.harvard.edu) Department of Radiology, Dana-Farber Cancer 
Institute and Brigham and Women's Hospital, 450 Brookline Avenue, Boston, 
United States.
(Bailey N.D.; Ott P.A.; Stephen Hodi F.) Department of Medical Oncology and 
Melanoma Center, Dana-Farber Cancer Institute and Brigham and Women's 
Hospital, Boston, United States.
CORRESPONDENCE ADDRESS
  M. Nishino, Department of Radiology, Dana-Farber Cancer Institute and 
Brigham and Women's Hospital, 450 Brookline Avenue, Boston, United States. 
Email: Mizuki_Nishino@dfci.harvard.edu
SOURCE
  Cancer Immunology Research (2015) 3:10 (1185-1192). Date of Publication: 1 
Oct 2015
ISSN
  2326-6074 (electronic)
  2326-6066
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  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, 0.2-9.1months). 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  fluorodeoxyglucose f 18
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  whole body imaging
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer (drug therapy)
  article
  colitis (side effect)
  computer assisted tomography
  contrast enhancement
  drug effect
  female
  hepatitis (side effect)
  human
  image analysis
  lymphadenopathy (side effect)
  major clinical study
  male
  middle aged
  pancreatitis (side effect)
  picture archiving and communication system
  pneumonia (side effect)
  positron emission tomography
  thyroiditis (side effect)
DEVICE TRADE NAMES
  Centricity  GE Healthcare

DEVICE MANUFACTURERS
  GE Healthcare
CAS REGISTRY NUMBERS
  fluorodeoxyglucose f 18 (63503-12-8)
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Biophysics, Bioengineering and Medical Instrumentation (27)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160278158
MEDLINE PMID
  26100356 (http://www.ncbi.nlm.nih.gov/pubmed/26100356)
PUI
  L609295908
DOI
  10.1158/2326-6066.CIR-15-0102
FULL TEXT LINK
  http://dx.doi.org/10.1158/2326-6066.CIR-15-0102
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 267
TITLE
  Ipilimumab-induced hypophysitis in melanoma patients: An Australian case 
series
AUTHOR NAMES
  Lam T.
  Chan M.M.K.
  Sweeting A.N.
  De Sousa S.M.C.
  Clements A.
  Carlino M.S.
  Long G.V.
  Tonks K.
  Chua E.
  Kefford R.F.
  Chipps D.R.
AUTHOR ADDRESSES
  (Lam T., Tess0508@gmail.com; Chipps D.R.) Department of Diabetes and 
Endocrinology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, 
Australia.
(Chan M.M.K.; Clements A.; Carlino M.S.; Kefford R.F.) Department of Medical 
Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, 
Australia.
(Chan M.M.K.; Sweeting A.N.; Clements A.; Carlino M.S.; Long G.V.; Chua E.; 
Kefford R.F.; Chipps D.R.) Sydney Medical School, University of Sydney, 
Sydney, Australia.
(Chan M.M.K.) Department of Endocrinology, Royal Prince Alfred Hospital, 
Sydney, Australia.
(Sweeting A.N.; Chua E.) Department of Endocrinology, St Vincent's Hospital, 
Sydney, Australia.
(De Sousa S.M.C.; Tonks K.) Hormones and Cancer Group, Garvan Institute of 
Medical Research, Sydney, Australia.
(De Sousa S.M.C.) Diabetes and Metabolism Division, Garvan Institute of 
Medical Research, Sydney, Australia.
(Carlino M.S.; Long G.V.; Kefford R.F.) Melanoma Institute of Australia, 
Sydney, Australia.
(Tonks K.) Australian School of Advanced Medicine, Macquarie University, 
Sydney, Australia.
(Kefford R.F.) Central Coast Cancer Centre, Gosford Hospital, Sydney, 
Australia.
CORRESPONDENCE ADDRESS
  T. Lam, Department of Diabetes and Endocrinology, Westmead Hospital, Corner 
of Darcy and Hawkesbury Road, Westmead, Sydney, Australia. Email: 
Tess0508@gmail.com
SOURCE
  Internal Medicine Journal (2015) 45:10 (1066-1073). Date of Publication: 1 
Oct 2015
ISSN
  1445-5994 (electronic)
  1444-0903
BOOK PUBLISHER
  Blackwell Publishing, info@asia.blackpublishing.com.au
ABSTRACT
  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. 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. 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. 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. 
Conclusions: There is significant morbidity associated with development of 
IH. We suggest guidelines to assist with early recognition and therapeutic 
intervention.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  antibody (drug therapy)
  dacarbazine (drug therapy)
  glucocorticoid (drug dose, drug therapy)
  hydrocortisone (drug therapy, endogenous compound, intravenous drug 
administration)
  levothyroxine (drug therapy)
  NY ESO 1 antigen (drug therapy)
  pembrolizumab (drug therapy)
  prednisone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, drug therapy, side effect)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  Australian
  case study
  clinical article
  clinical feature
  drug megadose
  drug withdrawal
  female
  human
  hydrocortisone blood level
  hypophysis adrenal system
  hypophysis thyroid system
  hypothyroidism (drug therapy)
  male
  priority journal
DRUG TRADE NAMES
  yervoy  , United StatesBristol Myers Squibb

DRUG MANUFACTURERS
   (United States)Bristol Myers Squibb
CAS REGISTRY NUMBERS
  dacarbazine (4342-03-4)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  pembrolizumab (1374853-91-4)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015419600
MEDLINE PMID
  26010858 (http://www.ncbi.nlm.nih.gov/pubmed/26010858)
PUI
  L606257399
DOI
  10.1111/imj.12819
FULL TEXT LINK
  http://dx.doi.org/10.1111/imj.12819
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 268
TITLE
  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
AUTHOR NAMES
  Mony J.T.
  Zhang L.
  Ma T.
  Grabosch S.
  Tirodkar T.S.
  Brozick J.
  Tseng G.
  Elishaev E.
  Edwards R.P.
  Huang X.
  Vlad A.M.
AUTHOR ADDRESSES
  (Mony J.T.; Zhang L.; Grabosch S.; Tirodkar T.S.; Edwards R.P.; Huang X.; 
Vlad A.M., vladam@upmc.edu) Department of Obstetrics, Gynecology and 
Reproductive Sciences, University of Pittsburgh School of Medicine, 204 
Craft Ave, Pittsburgh, United States.
(Mony J.T.; Zhang L.; Grabosch S.; Tirodkar T.S.; Brozick J.; Edwards R.P.; 
Huang X.; Vlad A.M., vladam@upmc.edu) Magee-Womens Research Institute B403, 
204 Craft Ave, Pittsburgh, United States.
(Ma T.; Tseng G.) Department of Biostatistics, University of Pittsburgh 
Graduate School of Public Health, Pittsburgh, United States.
(Elishaev E.) Department of Pathology, Magee-Womens Hospital, University of 
Pittsburgh Medical Center, Pittsburgh, United States.
CORRESPONDENCE ADDRESS
  A.M. Vlad, Department of Obstetrics, Gynecology and Reproductive Sciences, 
University of Pittsburgh School of Medicine, 204 Craft Ave, Pittsburgh, 
United States.
SOURCE
  Cancer Immunology, Immunotherapy (2015) 64:9 (1095-1108). Date of 
Publication: 21 Sep 2015
ISSN
  1432-0851 (electronic)
  0340-7004
BOOK PUBLISHER
  Springer Science and Business Media Deutschland GmbH, info@springer-sbm.com
ABSTRACT
  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 × 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 μg/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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  monoclonal antibody (drug therapy, intraperitoneal drug administration)
  mucin 1 (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer survival
  humoral immunity
  ovary cancer (drug therapy, drug therapy)
  T lymphocyte
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  animal model
  animal tissue
  antibody titer
  article
  cellular immunity
  controlled study
  female
  human
  lymphocytic infiltration
  nonhuman
  priority journal
  spleen cell
  transgenic mouse
  treatment response
CAS REGISTRY NUMBERS
  mucin 1 (212255-06-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015067174
MEDLINE PMID
  25998800 (http://www.ncbi.nlm.nih.gov/pubmed/25998800)
PUI
  L604498759
DOI
  10.1007/s00262-015-1712-6
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00262-015-1712-6
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 269
TITLE
  Differences in B7 and CD28 family gene expression in the peripheral blood 
between newly diagnosed young-onset and adult-onset type 1 diabetes patients
AUTHOR NAMES
  Pruul K.
  Kisand K.
  Alnek K.
  Metsküla K.
  Reimand K.
  Heilman K.
  Peet A.
  Varik K.
  Peetsalu M.
  Einberg Ü.
  Tillmann V.
  Uibo R.
AUTHOR ADDRESSES
  (Pruul K.; Kisand K.; Alnek K.; Metsküla K.; Reimand K.; Uibo R., 
raivo.uibo@ut.ee) Department of Immunology, Institute of Biomedicine and 
Translational Medicine, University of Tartu, Ravila 19, Tartu, Estonia.
(Pruul K.; Kisand K.; Alnek K.; Metsküla K.; Reimand K.; Uibo R., 
raivo.uibo@ut.ee) Centre for Translational Medicine, University of Tartu, 
Ravila 19, Tartu, Estonia.
(Heilman K.; Peet A.; Tillmann V.) Children's Clinic of Tartu University 
Hospital, N. Lunini 6, Tartu, Estonia.
(Heilman K.; Einberg Ü.) Tallinn Children's Hospital, Tervise 28, Tallinn, 
Estonia.
(Peet A.; Tillmann V.) Department of Paediatrics, University of Tartu, N. 
Lunini 6, Tartu, Estonia.
(Varik K.; Peetsalu M.) Surgery Clinic, Tartu University Hospital, L. 
Puusepa 8A, Tartu, Estonia.
(Uibo R., raivo.uibo@ut.ee) Estonian Academy of Sciences, Kohtu 6, Tallinn, 
Estonia.
CORRESPONDENCE ADDRESS
  R. Uibo, Department of Immunology, Institute of Bio- and Translational 
Medicine, University of Tartu, Ravila Street 19, Tartu, Estonia.
SOURCE
  Molecular and Cellular Endocrinology (2015) 412 (265-271). Date of 
Publication: 5 Sep 2015
ISSN
  1872-8057 (electronic)
  0303-7207
BOOK PUBLISHER
  Elsevier Ireland Ltd
ABSTRACT
  Type-1 diabetes (T1D) is a heterogeneous autoimmune disease, and there are 
pathogenetic differences between young- and adult-onset T1D patients. We 
hypothesized that the expressions of genes involved in costimulatory immune 
system pathways in peripheral blood are differently regulated in young- and 
adult-onset T1D.Study group I consisted of 80 children, adolescents, and 
young adults (age range 1.4-21.4 y; 31 controls and 49 T1D patients). Study 
group II consisted of 48 adults (age range 22.0-78.4 y; 30 controls and 18 
T1D patients). The mRNA expression levels of CD86, CD28, CD25, CD226, CD40, 
BTLA, GITR, PDCD1, FoxP3, TGF-β, ICOS, sCTLA4, flCTLA4, and CD80 were 
measured in peripheral blood. Genetic polymorphisms (. HLA haplotypes; 
rs231806, rs231775, and rs3087243 in CTLA4; rs763361 in CD226; and rs706778 
in CD25) and T1D-associated autoantibodies were analyzed.In group I, there 
was significantly lower expression of CD226 in T1D patients than in the 
controls. In group II, there were significantly higher expression levels of 
CD86 and TGF-β in T1D patients than in the controls. In the T1D patients in 
group I, the upregulated CD80 expression correlated with the expression of 
both CTLA4 splice variants (. sCTLA4 and flCTLA4). In contrast, in group II, 
upregulated CD86 correlated with TGF-β and CD25. In group I, the inhibitory 
CD80-CTLA4 pathway was activated, whereas, in group II, the activation 
CD86-CD28 pathway and TGF-β production were activated. These results 
emphasize the differences between young-onset and adult-onset T1D in the 
regulation of costimulatory pathways. These differences should be considered 
when developing novel treatments for T1D.
EMTREE DRUG INDEX TERMS
  B7 antigen (endogenous compound)
  CD22 antigen (endogenous compound)
  CD28 antigen (endogenous compound)
  CD40 antigen (endogenous compound)
  CD86 antigen (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  glucocorticoid induced tumor necrosis factor receptor (endogenous compound)
  glutamate decarboxylase 65 (endogenous compound)
  glutamate decarboxylase antibody (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  protein tyrosine phosphatase (endogenous compound)
  transcription factor FOXP3 (endogenous compound)
  transforming growth factor beta (endogenous compound)
  zinc transporter (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  B7 gene
  CD28 gene
  gene expression
  genetic variability
  insulin dependent diabetes mellitus (etiology)
  onset age
EMTREE MEDICAL INDEX TERMS
  adolescent
  adult
  article
  BTLA gene
  CD226 gene
  CD25 gene
  CD40 gene
  CD80 gene
  CD86 gene
  child
  controlled study
  female
  flCTLA4 gene
  FoxP3 gene
  gene function
  genetic association
  genetic polymorphism
  GITR gene
  human
  ICOS gene
  major clinical study
  male
  pathogenesis
  PDCD1 gene
  priority journal
  protein analysis
  reverse transcription polymerase chain reaction
  sCTLA4 gene
  TGF beta gene
  upregulation
CAS REGISTRY NUMBERS
  protein tyrosine phosphatase (79747-53-8, 97162-86-2)
EMBASE CLASSIFICATIONS
  Human Genetics (22)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015083984
PUI
  L604624207
DOI
  10.1016/j.mce.2015.05.012
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.mce.2015.05.012
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 270
TITLE
  Immune related adverse events associated with anti-CTLA-4 antibodies: 
Systematic review and meta-analysis
AUTHOR NAMES
  Bertrand A.
  Kostine M.
  Barnetche T.
  Truchetet M.-E.
  Schaeverbeke T.
AUTHOR ADDRESSES
  (Bertrand A., anne.bertrand87@gmail.com; Kostine M., 
mariekostine@hotmail.fr; Barnetche T., thomas.barnetche@chu-bordeaux.fr; 
Truchetet M.-E., marie-elise.truchetet@chu-bordeaux.fr; Schaeverbeke T., 
thierry.schaeverbeke@chu-bordeaux.fr) Département de Rhumatologie, Hôpital 
Pellegrin, CHU de Bordeaux, Bordeaux, France.
(Truchetet M.-E., marie-elise.truchetet@chu-bordeaux.fr) Université de 
Bordeaux, Laboratoire d'Immunologie, UMR-CNRS 5164, Bordeaux, France.
(Schaeverbeke T., thierry.schaeverbeke@chu-bordeaux.fr) Université de 
Bordeaux, Unité sous Contrat, Infections à Mycoplasmes et à Chlamydia chez 
l'Homme, Bordeaux, France.
CORRESPONDENCE ADDRESS
  A. Bertrand, Département de Rhumatologie, Hôpital Pellegrin, CHU de 
Bordeaux, Bordeaux, France.
SOURCE
  BMC Medicine (2015) 13:1 Article Number: 211. Date of Publication: 4 Sep 
2015
ISSN
  1741-7015 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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). 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<sup>©</sup>, package meta. 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-Barré 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy)
  ticilimumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  corticosteroid (adverse drug reaction, clinical trial, drug therapy, 
intravenous drug administration, oral drug administration)
  infliximab (clinical trial, drug therapy)
  loperamide (clinical trial, drug therapy)
  mycophenolic acid (clinical trial, drug therapy)
  prednisone (clinical trial, drug therapy)
  steroid (clinical trial, drug therapy)
  tacrolimus (clinical trial, drug therapy)
  thymocyte antibody (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  acute febrile neutrophilic dermatosis (side effect)
  alanine aminotransferase blood level
  alopecia (side effect)
  article
  aseptic meningitis (side effect)
  aspartate aminotransferase blood level
  asthenia (side effect)
  bladder cancer (drug therapy)
  colitis (drug therapy, side effect, therapy)
  colorectal cancer (drug therapy)
  cytopenia (side effect)
  dermatitis (drug therapy)
  diabetes insipidus (side effect)
  diarrhea (side effect)
  dose response
  drug safety
  dyspnea (side effect)
  eczema (side effect)
  endocrine disease (side effect)
  endocrine ophthalmopathy (side effect)
  epidermal spongiosis (drug therapy, side effect)
  epidermal spongiosis (drug therapy, side effect)
  erectile dysfunction (side effect)
  esophagus cancer (drug therapy)
  eye disease (side effect)
  fever (side effect)
  gastrointestinal disease (side effect)
  giant cell arteritis (side effect)
  Guillain Barre syndrome (side effect)
  headache (side effect)
  hematologic disease (side effect)
  hemophilia A (side effect)
  hepatitis (side effect)
  human
  hyperthyroidism (side effect)
  hypophysitis (drug therapy, side effect)
  hypothyroidism (side effect)
  immunity
  immunotoxicity
  incidence
  kidney carcinoma (drug therapy)
  libido disorder (side effect)
  liver disease (side effect)
  liver toxicity (drug therapy)
  lupus erythematosus nephritis (side effect)
  lymphadenopathy (side effect)
  lymphocytic infiltration (drug therapy, side effect)
  melanoma (drug therapy)
  mesothelioma (drug therapy)
  meta analysis (topic)
  multiple cycle treatment
  myasthenia (side effect)
  myelitis (side effect)
  myositis (side effect)
  nausea (side effect)
  neurologic disease (drug therapy, side effect, therapy)
  orbital myositis (side effect)
  organizing pneumonia (side effect)
  pancreas cancer (drug therapy)
  pancreatitis (side effect)
  papule (side effect)
  plasmapheresis
  prostate cancer (drug therapy)
  pruritus (side effect)
  rash (side effect)
  rectum hemorrhage (side effect)
  rehydration
  rheumatic disease (side effect)
  rheumatic polymyalgia (side effect)
  rosacea (side effect)
  sarcoidosis (side effect)
  skin disease (drug therapy, side effect)
  stomach cancer (drug therapy)
  survival rate
  systematic review
  T lymphocyte activation
  thyroiditis (side effect)
  time to treatment
  treatment duration
  treatment withdrawal
  unspecified side effect (side effect)
  uveitis (side effect)
  visual disorder (side effect)
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  loperamide (34552-83-5, 53179-11-6)
  mycophenolic acid (23047-11-2, 24280-93-1)
  prednisone (53-03-2)
  tacrolimus (104987-11-3)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015351368
MEDLINE PMID
  26337719 (http://www.ncbi.nlm.nih.gov/pubmed/26337719)
PUI
  L605893935
DOI
  10.1186/s12916-015-0455-8
FULL TEXT LINK
  http://dx.doi.org/10.1186/s12916-015-0455-8
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 271
TITLE
  T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and 
infection
AUTHOR NAMES
  McKinney E.F.
  Lee J.C.
  Jayne D.R.W.
  Lyons P.A.
  Smith K.G.C.
AUTHOR ADDRESSES
  (McKinney E.F., efm30@cam.ac.uk; Lee J.C.; Jayne D.R.W.; Lyons P.A.; Smith 
K.G.C., kgcs2@cam.ac.uk) Department of Medicine, University of Cambridge 
School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, 
United Kingdom.
(McKinney E.F., efm30@cam.ac.uk; Lee J.C.; Lyons P.A.; Smith K.G.C., 
kgcs2@cam.ac.uk) Cambridge Institute for Medical Research, University of 
Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
CORRESPONDENCE ADDRESS
  E.F. McKinney, Department of Medicine, University of Cambridge School of 
Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, United 
Kingdom.
SOURCE
  Nature (2015) 523:7562 (612-616). Date of Publication: 30 Jul 2015
ISSN
  1476-4687 (electronic)
  0028-0836
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  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 â €helpâ 
€™ 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 â 
€non-exhaustedâ €™ 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.
EMTREE DRUG INDEX TERMS
  CD2 antigen (endogenous compound)
  programmed death 1 receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmunity
  cell stress
  infection
  T lymphocyte
EMTREE MEDICAL INDEX TERMS
  article
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  human
  nonhuman
  priority journal
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Microbiology: Bacteriology, Mycology, Parasitology and Virology (4)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015243533
MEDLINE PMID
  26123020 (http://www.ncbi.nlm.nih.gov/pubmed/26123020)
PUI
  L605408016
DOI
  10.1038/nature14468
FULL TEXT LINK
  http://dx.doi.org/10.1038/nature14468
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 272
TITLE
  Steroid responsive encephalopathy associated with autoimmune thyroiditis 
following ipilimumab therapy: a case report
AUTHOR NAMES
  Carl D.
  Grüllich C.
  Hering S.
  Schabet M.
AUTHOR ADDRESSES
  (Carl D., david.carl@mail.klinikum-darmstadt.de; Schabet M., 
martin.schabet@kliniken-lb.de) Department of Neurology, Klinikum 
Ludwigsburg, Posilipostraße 4, Ludwigsburg, Germany
(Grüllich C., carsten.gruellich@nct-heidelberg.de) National Cent Tumor 
Diseases (NCT), Heidelberg, Germany
(Hering S., steffen.hering@kliniken-lb.de) Department of Internal Medicine, 
Klinikum Bietigheim, Bietigheim-Bissingen, Germany
SOURCE
  BMC research notes (2015) 8 (316). Date of Publication: 26 Jul 2015
ISSN
  1756-0500 (electronic)
ABSTRACT
  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.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.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.
EMTREE DRUG INDEX TERMS
  anti-thyroglobulin
  antineoplastic agent (drug administration, adverse drug reaction)
  autoantibody
  ipilimumab
  methylprednisolone (drug therapy)
  monoclonal antibody (drug administration, adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  chemically induced
EMTREE MEDICAL INDEX TERMS
  autoimmune thyroiditis (drug therapy)
  biosynthesis
  brain disease (drug therapy)
  case report
  human
  male
  middle aged
  pathology
  prostate tumor (drug therapy)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  26209970 (http://www.ncbi.nlm.nih.gov/pubmed/26209970)
PUI
  L615162645
DOI
  10.1186/s13104-015-1283-9
FULL TEXT LINK
  http://dx.doi.org/10.1186/s13104-015-1283-9
COPYRIGHT
  Copyright 2017 Medline is the source for the citation and abstract of this 
record.

RECORD 273
TITLE
  Anaplastic Thyroid Cancer: Outcome and the Mutation/Expression Profiles of 
Potential Targets
AUTHOR NAMES
  Wu H.
  Sun Y.
  Ye H.
  Yang S.
  Lee S.L.
  de las Morenas A.
AUTHOR ADDRESSES
  (Wu H., hao.wu@bcm.edu) Department of Pathology, Texas Children’s Hospital, 
Baylor College of Medicine, AB190.11, 6621 Fannin Street, Houston, United 
States.
(Wu H., hao.wu@bcm.edu; Sun Y.; Yang S.; de las Morenas A.) Department of 
Pathology and Laboratory Medicine, Boston University Medical Center, Boston, 
United States.
(Ye H.) Department of Pathology and Laboratory Medicine, Beth Israel 
Deaconess Medical Center, Harvard Medical School, Boston, United States.
(Lee S.L.) Section of Endocrinology, Diabetes and Nutrition, Department of 
Medicine, Boston University Medical Center, Boston, United States.
CORRESPONDENCE ADDRESS
  H. Wu, Department of Pathology and Laboratory Medicine, Boston University 
Medical Center, Boston, United States.
SOURCE
  Pathology and Oncology Research (2015) 21:3 (695-701). Date of Publication: 
5 Jul 2015
ISSN
  1532-2807 (electronic)
  1219-4956
BOOK PUBLISHER
  Kluwer Academic Publishers
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
  epidermal growth factor receptor (endogenous compound)
  K ras protein (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  stem cell factor receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  anaplastic thyroid carcinoma (etiology)
  gene expression profiling
  gene mutation
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  BRAF gene
  cancer survival
  codon
  controlled study
  EGFR gene
  exon
  female
  gene sequence
  human
  human tissue
  immunohistochemistry
  major clinical study
  male
  middle aged
  oncogene K ras
  overall survival
  polymerase chain reaction
  protein expression
  survival rate
  survival time
  wild type
CAS REGISTRY NUMBERS
  epidermal growth factor receptor (79079-06-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015684412
MEDLINE PMID
  25588542 (http://www.ncbi.nlm.nih.gov/pubmed/25588542)
PUI
  L601588972
DOI
  10.1007/s12253-014-9876-5
FULL TEXT LINK
  http://dx.doi.org/10.1007/s12253-014-9876-5
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 274
TITLE
  Checkpoint immunotherapy for cancer: Superior survival, unaccustomed 
toxicities
AUTHOR NAMES
  Gedye C.
  van der Westhuizen A.
  John T.
AUTHOR ADDRESSES
  (Gedye C., craig.gedye@newcastle.edu.au) School of Biomedical Sciences and 
Pharmacy, Hunter Medical Research Institute, University of Newcastle, 
Newcastle, Australia.
(Gedye C., craig.gedye@newcastle.edu.au; van der Westhuizen A.) Department 
of Medical Oncology, Calvary Mater Newcastle, Newcastle, Australia.
(John T.) Department of Medical Oncology, Olivia Newton John Cancer and 
Wellness Centre, Austin Hospital, Melbourne, Australia.
CORRESPONDENCE ADDRESS
  C. Gedye, School of Biomedical Sciences and Pharmacy, Hunter Medical 
Research Institute, University of Newcastle, 1 Kookaburra Crescent, New 
Lambton Heights, Newcastle, Australia. Email: craig.gedye@newcastle.edu.au
SOURCE
  Internal Medicine Journal (2015) 45:7 (696-701). Date of Publication: 1 Jul 
2015
ISSN
  1445-5994 (electronic)
  1444-0903
BOOK PUBLISHER
  Blackwell Publishing, info@asia.blackpublishing.com.au
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction)
  nivolumab
  pembrolizumab
EMTREE DRUG INDEX TERMS
  cancer antibody
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  immunosuppressive agent
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  cancer survival
EMTREE MEDICAL INDEX TERMS
  abdominal discomfort (side effect)
  autoimmune disease
  bloating (side effect)
  cancer chemotherapy
  cancer therapy
  clinical assessment
  clinical trial (topic)
  colitis (side effect)
  diarrhea (side effect)
  drug efficacy
  drug eruption (side effect)
  drug mechanism
  enzyme inhibition
  human
  immune system
  immunostimulation
  intestine perforation (side effect)
  managed care
  mesothelioma
  metastatic melanoma
  non small cell lung cancer
  overall survival
  peritonitis (side effect)
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  randomized controlled trial (topic)
  rectum hemorrhage (side effect)
  review
  small cell lung cancer
DRUG TRADE NAMES
  bms 936558
  keytruda  , United StatesMerck Sharp and Dohme

  mk 3475  , United StatesMerck Sharp and Dohme

  yervoy  , United StatesBristol

DRUG MANUFACTURERS
   (United States)Bristol
   (United States)Merck Sharp and Dohme
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015169365
MEDLINE PMID
  25444021 (http://www.ncbi.nlm.nih.gov/pubmed/25444021)
PUI
  L605059631
DOI
  10.1111/imj.12653
FULL TEXT LINK
  http://dx.doi.org/10.1111/imj.12653
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 275
TITLE
  Combination of Id2 knockdown whole tumor cells and checkpoint blockade: A 
potent vaccine strategy in a mouse neuroblastoma model
AUTHOR NAMES
  Chakrabarti L.
  Morgan C.
  Sandler A.D.
AUTHOR ADDRESSES
  (Chakrabarti L.; Morgan C.; Sandler A.D., asandler@childrensnational.org) 
Joseph E. Robert Jr. Center for Surgical Care, Sheikh Zayed Institute for 
Pediatric Surgical Innovation, Children's National Medical Center, George 
Washington University, Washington, United States.
SOURCE
  PLoS ONE (2015) 10:6 Article Number: e0129237. Date of Publication: 16 Jun 
2015
ISSN
  1932-6203 (electronic)
BOOK PUBLISHER
  Public Library of Science, plos@plos.org
ABSTRACT
  Tumor vaccines have held much promise, but to date have demonstrated little 
clinical success. This lack of success is conceivably due to poor tumor 
antigen presentation combined with immuno-suppressive mechanisms exploited 
by the tumor itself. Knock down of Inhibitor of differentiation protein 2 
(Id2-kd) in mouse neuroblastoma whole tumor cells rendered these cells 
immunogenic. Id2-kd neuroblastoma (Neuro2a) cells (Id2-kd N2a) failed to 
grow in most immune competent mice and these mice subsequently developed 
immunity against further wild-type Neuro2a tumor cell challenge. Id2-kd N2a 
cells grew aggressively in immune-compromised hosts, thereby establishing 
the immunogenicity of these cells. Therapeutic vaccination with Id2-kd N2a 
cells alone suppressed tumor growth even in established neuroblastoma tumors 
and when used in combination with immune checkpoint blockade eradicated 
large established tumors. Mechanistically, immune cell depletion studies 
demonstrated that while CD8+ T cells are critical for antitumor immunity, 
CD4+ T cells are also required to induce a sustained long-lasting helper 
effect. An increase in number of CD8+ T-cells and enhanced production of 
interferon gamma (IFNγ) was observed in tumor antigen stimulated splenocytes 
of vaccinated mice. More importantly, a massive influx of cytotoxic CD8+ 
T-cells infiltrated the shrinking tumor following combined immunotherapy. 
These findings show that down regulation of Id2 induced tumor cell immunity 
and in combination with checkpoint blockade produced a novel, potent, T-cell 
mediated tumor vaccine strategy.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  inhibitor of differentiation 2 (endogenous compound)
  tumor cell vaccine (drug therapy, pharmacology)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 antibody (drug therapy, intraperitoneal 
drug administration, pharmacology)
  gamma interferon (endogenous compound)
  lentivirus vector
  tumor antigen
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cell cycle checkpoint
  gene silencing
  neuroblastoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  animal model
  animal tissue
  antigen presentation
  article
  cancer immunization
  cancer immunotherapy
  cancer inhibition
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  cell growth
  controlled study
  cytokine production
  down regulation
  female
  human
  human cell
  human tissue
  immune deficiency
  immunocompetence
  immunocompromised patient
  immunogenicity
  lymphocytic infiltration
  mouse
  mouse model
  neuroblastoma cell
  nonhuman
  spleen cell
  tumor cell
  tumor immunity
  whole cell
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015225777
MEDLINE PMID
  26079374 (http://www.ncbi.nlm.nih.gov/pubmed/26079374)
PUI
  L605265705
DOI
  10.1371/journal.pone.0129237
FULL TEXT LINK
  http://dx.doi.org/10.1371/journal.pone.0129237
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 276
TITLE
  Swinging for the fences: Long-term survival with ipilimumab in metastatic 
melanoma
AUTHOR NAMES
  Gibney G.T.
  Atkins M.B.
AUTHOR ADDRESSES
  (Gibney G.T.) Moffitt Cancer Center, University of South Florida, Tampa, 
United States.
(Atkins M.B.) Georgetown-Lombardi Comprehensive Cancer Center, 
Medstar-Georgetown University Hospital, Washington, United States.
SOURCE
  Journal of Clinical Oncology (2015) 33:17 (1873-1877). Date of Publication: 
10 Jun 2015
ISSN
  1527-7755 (electronic)
  0732-183X
BOOK PUBLISHER
  American Society of Clinical Oncology, jcoservice@asco.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  alpha interferon
  B Raf kinase (endogenous compound)
  corticosteroid
  dabrafenib (drug combination, drug therapy)
  interleukin 2 (endogenous compound)
  lactate dehydrogenase (endogenous compound)
  nivolumab (drug combination, drug therapy)
  pembrolizumab (drug therapy)
  trametinib (drug combination, drug therapy)
  vemurafenib (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer survival
  long term survival
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency
  article
  central nervous system metastasis
  computer assisted tomography
  craniotomy
  hormone substitution
  immunotherapy
  lactate dehydrogenase blood level
  long term care
  lung nodule
  lymph node dissection
  nuclear magnetic resonance imaging
  priority journal
  stereotactic radiosurgery
  wild type
CAS REGISTRY NUMBERS
  dabrafenib (1195765-45-7, 1195768-06-9)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  lactate dehydrogenase (9001-60-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  trametinib (1187431-43-1, 871700-17-3)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015202413
MEDLINE PMID
  25964248 (http://www.ncbi.nlm.nih.gov/pubmed/25964248)
PUI
  L605202620
DOI
  10.1200/JCO.2014.60.1807
FULL TEXT LINK
  http://dx.doi.org/10.1200/JCO.2014.60.1807
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 277
TITLE
  Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case 
report
AUTHOR NAMES
  Martin-Liberal J.
  Furness A.J.S.
  Joshi K.
  Peggs K.S.
  Quezada S.A.
  Larkin J.
AUTHOR ADDRESSES
  (Martin-Liberal J.; Furness A.J.S.; Joshi K.; Larkin J., 
james.larkin@rmh.nhs.uk) Renal and Melanoma Unit, The Royal Marsden 
Hospital, Fulham Road, London, United Kingdom.
(Furness A.J.S.; Joshi K.; Peggs K.S.; Quezada S.A.) Cancer Immunology Unit, 
University College London Cancer Institute, 72 Huntley St, London, United 
Kingdom.
CORRESPONDENCE ADDRESS
  J. Larkin, Renal and Melanoma Unit, The Royal Marsden Hospital, Fulham Road, 
London, United Kingdom.
SOURCE
  Cancer Immunology, Immunotherapy (2015) 64:6 (765-767). Date of Publication: 
6 Jun 2015
ISSN
  1432-0851 (electronic)
  0340-7004
BOOK PUBLISHER
  Springer Science and Business Media Deutschland GmbH, info@springer-sbm.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pembrolizumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  glucose (endogenous compound)
  glutamate decarboxylase antibody (endogenous compound)
  HLA antigen (endogenous compound)
  infusion fluid (drug therapy, intravenous drug administration)
  insulin (drug therapy, subcutaneous drug administration)
  ipilimumab (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune diabetes (drug therapy, side effect, drug therapy, etiology, side 
effect)
  autoimmune disease (drug therapy, side effect, drug therapy, etiology, side 
effect)
  insulin dependent diabetes mellitus (drug therapy, side effect, drug 
therapy, etiology, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  antibody titer
  article
  case report
  compassionate use
  cutaneous melanoma (drug therapy, surgery)
  diabetic ketoacidosis (drug therapy)
  drug tolerability
  female
  glucose blood level
  human
  insulin treatment
  lethargy (side effect)
  middle aged
  polydipsia (side effect)
  polyuria (side effect)
  priority journal
  treatment outcome
  vomiting (side effect)
CAS REGISTRY NUMBERS
  glucose (50-99-7, 84778-64-3)
  insulin (9004-10-8)
  ipilimumab (477202-00-9)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015883518
MEDLINE PMID
  25828465 (http://www.ncbi.nlm.nih.gov/pubmed/25828465)
PUI
  L603529007
DOI
  10.1007/s00262-015-1689-1
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00262-015-1689-1
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 278
TITLE
  Early recognition of ipilimumab-related autoimmune hypophysitis in patients 
with metastatic melanoma: Case studies and recommendations for management
AUTHOR NAMES
  Tiu C.
  Pezaro C.
  Davis I.D.
  Grossmann M.
  Parente P.
AUTHOR ADDRESSES
  (Tiu C.; Pezaro C.; Davis I.D.; Parente P., phillip.parente@monash.edu) 
Department of Medical Oncology, Eastern Health, Box Hill, Australia.
(Pezaro C.; Davis I.D.; Parente P., phillip.parente@monash.edu) Department 
of Endocrinology, Eastern Health, Box Hill, Australia.
(Grossmann M.) Eastern Health Clinical School, Monash University, Box Hill, 
Australia.
CORRESPONDENCE ADDRESS
  P. Parente, Oncology Unit, Box Hill Hospital, Nelson Road, Box Hill, 
Australia. Email: phillip.parente@monash.edu
SOURCE
  Asia-Pacific Journal of Clinical Oncology (2015) 11:2 (190-194). Date of 
Publication: 1 Jun 2015
ISSN
  1743-7563 (electronic)
  1743-7555
BOOK PUBLISHER
  Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  B Raf kinase
  corticotropin
  cortisone
  dacarbazine
  dexamethasone (drug therapy)
  testosterone
  thyroxine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease (side effect, side effect)
  drug induced disease (drug therapy, side effect, drug therapy, side effect)
  hypophysitis (drug therapy, side effect, drug therapy, side effect)
  metastatic melanoma (drug therapy, drug therapy, radiotherapy, surgery)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency
  adult
  article
  autoimmune hepatitis (drug therapy)
  brain metastasis (diagnosis, surgery)
  brain scintiscanning
  cancer chemotherapy
  cancer radiotherapy
  cancer staging
  case report
  computer assisted tomography
  craniotomy
  drug megadose
  hormone substitution
  human
  hypogonadism
  hypopituitarism
  inguinal lymph node
  liver biopsy
  liver function test
  liver metastasis
  lung metastasis
  lymph node dissection
  male
  middle aged
  nuclear magnetic resonance imaging
  positron emission tomography
  priority journal
  skin metastasis
  spleen metastasis
  subcutaneous nodule
  wide excision
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  cortisone (53-06-5)
  dacarbazine (4342-03-4)
  dexamethasone (50-02-2)
  ipilimumab (477202-00-9)
  testosterone (58-22-0)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015921660
MEDLINE PMID
  25855890 (http://www.ncbi.nlm.nih.gov/pubmed/25855890)
PUI
  L603766660
DOI
  10.1111/ajco.12348
FULL TEXT LINK
  http://dx.doi.org/10.1111/ajco.12348
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 279
TITLE
  New targets in breast cancer
AUTHOR NAMES
  Jhaveri A.
  Pusztai L.
AUTHOR ADDRESSES
  (Jhaveri A., ami.jhaveri@yale.edu; Pusztai L., lajos.pusztai@yale.edu) Yale 
Cancer Center, Yale School of Medicine, 333 Cedar St, PO Box 208032, New 
Haven, United States.
CORRESPONDENCE ADDRESS
  A. Jhaveri, Yale Cancer Center, Yale School of Medicine, 333 Cedar St, PO 
Box 208032, New Haven, United States.
SOURCE
  Memo - Magazine of European Medical Oncology (2015) 8:2 (86-91). Date of 
Publication: 1 Jun 2015
ISSN
  1865-5076 (electronic)
  1865-5041
BOOK PUBLISHER
  Springer-Verlag Wien, michaela.bolli@springer.at
ABSTRACT
  In the past few years, the therapeutic strategies for breast cancer have 
broadened substantially beyond endocrine therapy, chemotherapy, and human 
epidermal growth factor receptor 2-targeted agents to include several new 
drugs with unique mechanism of actions including antibody–drug conjugates, 
inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of 
rapamycin pathway, cyclin-dependent kinases 4/6, histone deacetylases and 
the poly ADP ribose polymerase as well as immune checkpoint modulators. 
Novel clinical trial designs are also being implemented in the clinic to 
assess the therapeutic potential of targeting rare molecular abnormalities 
observed in breast cancers (fibroblast growth factor receptor amplification, 
inactivating mutations in BRCA, activating mutations in HER2, epidermal 
growth factor receptor, c-Kit, Akt, etc.).
EMTREE DRUG INDEX TERMS
  8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 
f][1,6]naphthyridin 3(2h) one (clinical trial, drug therapy)
  abiraterone (clinical trial, drug therapy)
  alpelisib (clinical trial, drug therapy)
  androgen receptor (endogenous compound)
  apitolisib (clinical trial, drug therapy)
  bicalutamide (clinical trial, drug therapy)
  buparlisib (clinical trial, drug combination, drug therapy)
  cyclin dependent kinase 4 (endogenous compound)
  cyclin dependent kinase 6 (endogenous compound)
  enobosarm (clinical trial, drug therapy)
  enzalutamide (clinical trial, drug combination, drug therapy)
  epidermal growth factor receptor 2 (endogenous compound)
  everolimus (clinical trial, drug combination, drug therapy)
  fibroblast growth factor receptor (endogenous compound)
  glembatumumab vedotin (clinical trial, drug therapy)
  histone deacetylase (endogenous compound)
  mammalian target of rapamycin (endogenous compound)
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
(endogenous compound)
  olaparib (clinical trial, drug therapy)
  phosphatidylinositol 3 kinase (endogenous compound)
  pictilisib (clinical trial, drug therapy)
  protein kinase B (endogenous compound)
  rucaparib (clinical trial, drug therapy)
  stem cell factor (endogenous compound)
  talazoparib (clinical trial, drug therapy)
  taselisib (clinical trial, drug therapy)
  trastuzumab (clinical trial, drug combination, drug therapy)
  trastuzumab emtansine (clinical trial, drug therapy)
  unindexed drug
  veliparib (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  breast cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  cancer patient
  drug design
  drug efficacy
  drug targeting
  human
  molecular mechanics
  overall survival
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  progression free survival
  review
  signal transduction
  treatment outcome
  treatment response
DRUG TRADE NAMES
  abt 888
  ag014699
  azd 2281
  bmn 673
  byl719
  CDX 011
  gdc 0032
  gdc 0941
  gdc 0980
  mk2206
  t dm1
CAS REGISTRY NUMBERS
  8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 
f][1,6]naphthyridin 3(2h) one (1032349-93-1, 1032350-13-2)
  abiraterone (154229-19-3)
  alpelisib (1217486-61-7)
  apitolisib (1032754-93-0)
  bicalutamide (90357-06-5)
  buparlisib (1202777-78-3, 944396-07-0, 1312445-63-8)
  cyclin dependent kinase 4 (147014-97-9)
  enobosarm (841205-47-8)
  enzalutamide (915087-33-1)
  epidermal growth factor receptor 2 (137632-09-8)
  everolimus (159351-69-6)
  fibroblast growth factor receptor (153424-51-2)
  glembatumumab vedotin (1182215-65-1)
  histone deacetylase (9076-57-7)
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
(58319-92-9)
  olaparib (763113-22-0)
  phosphatidylinositol 3 kinase (115926-52-8)
  pictilisib (957054-30-7)
  protein kinase B (148640-14-6)
  rucaparib (283173-50-2, 459868-92-9)
  talazoparib (1207456-01-6, 1373431-65-2)
  taselisib (1282512-48-4)
  trastuzumab (180288-69-1)
  trastuzumab emtansine (1018448-65-1)
  veliparib (912444-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015728129
PUI
  L602139863
DOI
  10.1007/s12254-015-0197-5
FULL TEXT LINK
  http://dx.doi.org/10.1007/s12254-015-0197-5
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 280
TITLE
  Molecular pathways in renal cell carcinoma: Recent advances in genetics and 
molecular biology
AUTHOR NAMES
  Su D.
  Singer E.A.
  Srinivasan R.
AUTHOR ADDRESSES
  (Su D.; Srinivasan R., ramasrin@mail.nih.gov) Urologic Oncology Branch, 
Center for Cancer Research, National Cancer Institute, 10 Center Drive, 
Bethesda, United States.
(Singer E.A.) Section of Urologic Oncology, Rutgers Cancer Institute of New 
Jersey, Robert Wood Johnson Medical School, New Brunswick, United States.
CORRESPONDENCE ADDRESS
  R. Srinivasan, Urologic Oncology Branch, Center for Cancer Research, 
National Cancer Institute, 10 Center Drive, Bethesda, United States. Email: 
ramasrin@mail.nih.gov
SOURCE
  Current Opinion in Oncology (2015) 27:3 (217-223). Date of Publication: 27 
May 2015
ISSN
  1531-703X (electronic)
  1040-8746
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS
  cullin (endogenous compound)
  cullin 3 (endogenous compound)
  erythroid derived 2 like 2 (endogenous compound)
  fumarate hydratase (endogenous compound)
  hypoxia inducible factor (endogenous compound)
  kelch like ECH associated protein 1 (endogenous compound)
  mammalian target of rapamycin (endogenous compound)
  nuclear factor (endogenous compound)
  phosphatidylinositol 3 kinase (endogenous compound)
  protein kinase B (endogenous compound)
  scatter factor (endogenous compound)
  scatter factor receptor (endogenous compound)
  unclassified drug
  vasculotropin (endogenous compound)
  vasculotropin receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer genetics
  kidney carcinoma (etiology)
  molecular biology
EMTREE MEDICAL INDEX TERMS
  advanced cancer
  BAP1 gene
  cancer prognosis
  cancer survival
  chromatin assembly and disassembly
  citric acid cycle
  gene sequence
  genomics
  hereditary tumor syndrome (etiology)
  human
  nonhuman
  oncogene
  oxidative stress
  PBRM1 gene
  priority journal
  review
  SETD2 gene
  systemic therapy
CAS REGISTRY NUMBERS
  fumarate hydratase (9032-88-6)
  phosphatidylinositol 3 kinase (115926-52-8)
  protein kinase B (148640-14-6)
  scatter factor (67256-21-7, 72980-71-3)
  vasculotropin (127464-60-2)
  vasculotropin receptor (301253-48-5)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Urology and Nephrology (28)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015977903
MEDLINE PMID
  25811348 (http://www.ncbi.nlm.nih.gov/pubmed/25811348)
PUI
  L604037759
DOI
  10.1097/CCO.0000000000000186
FULL TEXT LINK
  http://dx.doi.org/10.1097/CCO.0000000000000186
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 281
TITLE
  Survivorship in immune therapy: Assessing chronic immune toxicities, health 
outcomes, and functional status among long-term ipilimumab survivors at a 
single referral center
AUTHOR NAMES
  Johnson D.B.
  Friedman D.L.
  Berry E.
  Decker I.
  Ye F.
  Zhao S.
  Morgans A.K.
  Puzanov I.
  Sosman J.A.
  Lovly C.M.
AUTHOR ADDRESSES
  (Johnson D.B., douglas.b.johnson@vanderbilt.edu; Berry E.; Decker I.; 
Morgans A.K.; Puzanov I.; Sosman J.A.; Lovly C.M.) Department of Medicine, 
Vanderbilt University Medical Center, 777 Preston Research Building, 
Nashville, United States.
(Friedman D.L.) Department of Pediatrics, Vanderbilt University Medical 
Center, Nashville, United States.
(Ye F.; Zhao S.) Department of Quantitative Sciences, Vanderbilt University 
Medical Center, Nashville, United States.
(Lovly C.M.) Department of Cancer Biology, Vanderbilt University Medical 
Center, Nashville, United States.
CORRESPONDENCE ADDRESS
  D.B. Johnson, Department of Medicine, Vanderbilt University Medical Center, 
777 Preston Research Building, Nashville, United States. Email: 
douglas.b.johnson@vanderbilt.edu
SOURCE
  Cancer Immunology Research (2015) 3:5 (464-469). Date of Publication: 1 May 
2015
ISSN
  2326-6074 (electronic)
  2326-6066
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  antibiotic agent (drug therapy, topical drug administration)
  antibody (adverse drug reaction)
  antihistaminic agent (drug combination, drug therapy, oral drug 
administration)
  bevacizumab
  corticosteroid (drug therapy, topical drug administration)
  dexamethasone
  hydrocortisone (drug combination, drug therapy, topical drug administration)
  interleukin 2 (drug therapy)
  methylprednisolone (drug therapy)
  narcotic agent (drug therapy)
  prednisone
  programmed death 1 receptor antibody (adverse drug reaction)
  testosterone
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  cancer survivor
  functional status
  immunotoxicity (side effect, side effect)
  metastatic melanoma (drug therapy, drug therapy, radiotherapy, surgery)
EMTREE MEDICAL INDEX TERMS
  acute appendicitis (side effect)
  adrenal insufficiency (side effect)
  adult
  aged
  amnesia (complication)
  androgen therapy
  aphasia (side effect)
  arm injury (drug therapy, side effect)
  article
  brain metastasis (complication, radiotherapy)
  cancer adjuvant therapy
  cancer chemotherapy
  cancer prognosis
  cancer radiotherapy
  cerebrovascular accident (complication)
  clinical assessment
  cohort analysis
  colitis (side effect)
  diarrhea (drug therapy, side effect)
  drug efficacy
  drug megadose
  dry skin (side effect)
  eczema (side effect)
  endocrine disease (complication)
  episcleritis (side effect)
  female
  follow up
  gastrointestinal toxicity (side effect)
  health status
  hematologic disease (side effect)
  hormone substitution
  human
  hypophysitis (drug therapy, side effect)
  hypopituitarism (side effect)
  lacunar stroke (side effect)
  limb weakness (side effect)
  liver injury (side effect)
  major clinical study
  male
  medical record review
  morbidity
  mortality
  muscle denervation (drug therapy, side effect)
  neurological complication (complication)
  neuropathic pain (drug therapy, side effect)
  overall survival
  paresthesia (side effect)
  pericardial effusion (side effect)
  peripheral neuropathy (side effect)
  progression free survival
  pruritus (drug therapy, side effect)
  radiation necrosis (complication)
  rash (drug therapy, side effect)
  retrospective study
  rib fracture (side effect)
  seizure (complication)
  side effect (side effect)
  skin disease (side effect)
  skin graft ulcer (side effect)
  skin graft ulcer (side effect)
  spine fracture (side effect)
  thyroid gland
  treatment outcome
  treatment response
  university hospital
  uveitis (side effect)
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  dexamethasone (50-02-2)
  hydrocortisone (50-23-7)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
  testosterone (58-22-0)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00094653)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160258004
MEDLINE PMID
  25649350 (http://www.ncbi.nlm.nih.gov/pubmed/25649350)
PUI
  L609230157
DOI
  10.1158/2326-6066.CIR-14-0217
FULL TEXT LINK
  http://dx.doi.org/10.1158/2326-6066.CIR-14-0217
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 282
TITLE
  Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma
AUTHOR NAMES
  Katsuya Y.
  Fujita Y.
  Horinouchi H.
  Ohe Y.
  Watanabe S.-I.
  Tsuta K.
AUTHOR ADDRESSES
  (Katsuya Y.; Tsuta K., ktsuta@ncc.go.jp) Division of Pathology and Clinical 
Laboratory, National Cancer Center Hospital, Tokyo, Japan.
(Katsuya Y.; Horinouchi H.; Ohe Y.) Department of Thoracic Oncology, 
National Cancer Center Hospital, Tokyo, Japan.
(Fujita Y.) Division of Molecular and Cellular Medicine, National Cancer 
Center Research Institute, Tokyo, Japan.
(Watanabe S.-I.) Division of Thoracic Surgery, National Cancer Center 
Hospital, Tokyo, Japan.
CORRESPONDENCE ADDRESS
  K. Tsuta, Division of Pathology and Clinical Laboratory, National Cancer 
Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo, Japan.
SOURCE
  Lung Cancer (2015) 88:2 (154-159). Date of Publication: 1 May 2015
ISSN
  1872-8332 (electronic)
  0169-5002
BOOK PUBLISHER
  Elsevier Ireland Ltd
ABSTRACT
  Purpose: The immune checkpoint ligand programmed cell death 1 ligand 1 
(PD-L1) is expressed in various tumors and is associated with the response 
to anti programmed cell death 1 (PD-1)/PD-L1 drugs. We evaluated PD-L1 
expression in thymomas and thymic carcinomas to determine whether PD-L1 
represents a therapeutic target in unresectable thymomas or thymic 
carcinomas that could be amenable to antibody-based immunotherapy. Method: A 
tissue microarray (TMA) comprised of 101 thymomas and 38 thymic carcinomas 
samples was evaluated. After validation of the rabbit monoclonal PD-L1 
antibody (clone E1L3N), the TMA was stained and the tumor PD-L1 expression 
score was calculated using a semiquantitive method (by multiplying the 
intensity [0-3] by the staining area [0-100%]). Results: Seventy percent of 
thymic carcinoma (type C) and 23% of thymoma (types A, AB, and B) samples 
stained positive for PD-L1 (. P<. .001). A WHO classification (type C vs 
types A, AB, and B) was significantly associated with positive PD-L1 
expression (. P=. 0.006), though multivariate analysis did not show PD-L1 
positive was a significant negative factor of overall survival (hazard 
ratio. =. 0.99, 95% confidence interval. =. 0.35-2.73; P=. 0.987). 
Conclusions: To the best of our knowledge, this is the largest-scale study 
to evaluate PD-L1 expression in thymomas and thymic carcinomas. The data 
suggest that the anti PD-1/PD-L1 drug could be of potential use in 
immunotherapy for unresectable or relapsed thymomas and thymic carcinomas.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunohistochemistry
  thymus cancer (drug therapy, diagnosis, drug therapy, surgery)
EMTREE MEDICAL INDEX TERMS
  A-549 cell line
  adult
  aged
  article
  cancer chemotherapy
  cancer diagnosis
  cancer recurrence
  cancer staging
  cancer surgery
  cancer survival
  controlled study
  disease classification
  female
  human
  human cell
  major clinical study
  male
  multivariate analysis
  overall survival
  priority journal
  protein expression
  tissue microarray
  world health organization
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Public Health, Social Medicine and Epidemiology (17)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015840362
MEDLINE PMID
  25799277 (http://www.ncbi.nlm.nih.gov/pubmed/25799277)
PUI
  L603106783
DOI
  10.1016/j.lungcan.2015.03.003
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.lungcan.2015.03.003
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 283
TITLE
  IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of 
ovarian cancer
AUTHOR NAMES
  Abiko K.
  Matsumura N.
  Hamanishi J.
  Horikawa N.
  Murakami R.
  Yamaguchi K.
  Yoshioka Y.
  Baba T.
  Konishi I.
  Mandai M.
AUTHOR ADDRESSES
  (Abiko K.; Matsumura N., noriomi@kuhp.kyoto-u.ac.jp; Hamanishi J.; Horikawa 
N.; Murakami R.; Yamaguchi K.; Yoshioka Y.; Baba T.; Konishi I.) Department 
of Gynecology and Obstetrics, Kyoto University, Graduate School of Medicine, 
54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
(Mandai M.) Department of Obstetrics and Gynecology, Faculty of Medicine, 
Kinki University, 377-2 Onohigashi, Osakasayama, Osaka, Japan.
CORRESPONDENCE ADDRESS
  N. Matsumura, Department of Gynecology and Obstetrics, Kyoto University, 
Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 
Japan.
SOURCE
  British Journal of Cancer (2015) 112:9 (1501-1509). Date of Publication: 28 
Apr 2015
ISSN
  1532-1827 (electronic)
  0007-0920
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  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.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-γ signals was assessed.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-γ 
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-γ into subcutaneous tumours induced PD-L1 
expression and promoted tumour growth, and PD-L1 depletion completely 
abrogated tumour growth caused by IFN-γ injection 
(P=0.01).Conclusions:Interferon-γ secreted by CD8-positive lymphocytes 
upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The 
lymphocyte infiltration and the IFN-γ status may be the key to effective 
anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  gamma interferon (drug toxicity)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  gamma interferon receptor 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer
  protein expression
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  animal model
  article
  cancer survival
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  clinical article
  controlled study
  disease course
  female
  human
  human tissue
  lymphocytic infiltration
  mouse
  nonhuman
  ovarian cancer cell line
  peritoneum tumor
  priority journal
  protein depletion
  stroma
  tumor associated leukocyte
  tumor growth
  tumor microenvironment
  upregulation
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015887946
MEDLINE PMID
  25867264 (http://www.ncbi.nlm.nih.gov/pubmed/25867264)
PUI
  L603557267
DOI
  10.1038/bjc.2015.101
FULL TEXT LINK
  http://dx.doi.org/10.1038/bjc.2015.101
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 284
TITLE
  Ipilimumab-induced toxicities and the gastroenterologist
AUTHOR NAMES
  Cheng R.
  Cooper A.
  Kench J.
  Watson G.
  Bye W.
  Mcneil C.
  Shackel N.
AUTHOR ADDRESSES
  (Cheng R., r.cheng@centenary.org.au; Bye W.; Shackel N.) A.W. Morrow 
Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, 
Australia.
(Kench J.; Watson G.) Department of Tissue Pathology and Diagnostic 
Oncology, Royal Prince Alfred Hospital, Camperdown, Australia.
(Cooper A.; Mcneil C.) Royal Prince Alfred Hospital, Camperdown, Australia.
(Cooper A.; Mcneil C.) Chris O'Brien Lifehouse, Camperdown, Australia.
(Mcneil C.) Melanoma Institute of Australia, North Sydney, Australia.
CORRESPONDENCE ADDRESS
  R. Cheng, Liver Injury and Cancer Laboratory, Centenary Institute, Royal 
Prince Alfred Hospital, Building 93, Missenden Road, Camperdown, Australia.
SOURCE
  Journal of Gastroenterology and Hepatology (Australia) (2015) 30:4 
(657-666). Date of Publication: 1 Apr 2015
ISSN
  1440-1746 (electronic)
  0815-9319
BOOK PUBLISHER
  Blackwell Publishing, info@asia.blackpublishing.com.au
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, drug toxicity)
EMTREE DRUG INDEX TERMS
  alanine aminotransferase (endogenous compound)
  codeine (drug therapy)
  corticotropin (endogenous compound)
  enoxaparin (drug therapy)
  growth hormone (endogenous compound)
  infliximab (drug dose, drug therapy, intravenous drug administration)
  loperamide (drug therapy)
  methylprednisolone (drug dose, drug therapy, intravenous drug 
administration)
  mycophenolate mofetil (drug therapy)
  prednisone (clinical trial, drug dose, drug therapy, oral drug 
administration)
  testosterone (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  colitis (drug therapy, drug therapy)
  drug induced disease (drug therapy, drug therapy)
  gastroenterologist
  toxic hepatitis (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  alanine aminotransferase blood level
  article
  autoimmune hepatitis (drug therapy)
  bone metastasis
  bradycardia
  brain metastasis
  case report
  colon biopsy
  colonoscopy
  corticotropin blood level
  cytomegalovirus infection
  diarrhea (drug therapy, side effect)
  disease course
  drug dose escalation
  drug dose reduction
  drug megadose
  drug pulse therapy
  drug withdrawal
  erythrocyte transfusion
  growth hormone blood level
  hospital readmission
  human
  hypopituitarism (drug therapy)
  immune complex nephritis (side effect)
  immunosuppressive treatment
  inflammatory infiltrate
  inguinal lymph node
  interstitial nephritis (drug therapy)
  kidney biopsy
  kidney dysfunction (side effect)
  kidney function
  limit of detection
  liver biopsy
  liver function test
  liver metastasis
  lung metastasis
  lymph node metastasis
  male
  metastatic melanoma (drug therapy)
  middle aged
  peritoneum tumor
  pneumonia (side effect)
  portal vein thrombosis (drug therapy)
  priority journal
  randomized controlled trial (topic)
  rectum hemorrhage (therapy)
  rehydration
  side effect (side effect)
  sigmoidoscopy
  single drug dose
  steroid therapy
  systemic therapy
  testosterone blood level
  thorax pain (side effect)
  thyrotropin blood level
  treatment duration
  very elderly
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  codeine (76-57-3)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  enoxaparin (679809-58-6)
  growth hormone (36992-73-1, 37267-05-3, 66419-50-9, 9002-72-6)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  loperamide (34552-83-5, 53179-11-6)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
  testosterone (58-22-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015832049
MEDLINE PMID
  25641691 (http://www.ncbi.nlm.nih.gov/pubmed/25641691)
PUI
  L603020844
DOI
  10.1111/jgh.12888
FULL TEXT LINK
  http://dx.doi.org/10.1111/jgh.12888
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 285
TITLE
  A new form of hypophisitis following ipilimumab therapy
ORIGINAL (NON-ENGLISH) TITLE
  Une nouvelle forme d'hypophysite secondaire à l'ipilimumab
AUTHOR NAMES
  Schmutz J.-L.
AUTHOR ADDRESSES
  (Schmutz J.-L., jl.schmutz@chu-nancy.fr) Département de Dermatologie et 
Allergologie, Bâtiment des Spécialités Médicales, 6, rue du Morvan, 
Vandœuvre-lès-Nancy, France.
CORRESPONDENCE ADDRESS
  J.-L. Schmutz, Département de Dermatologie et Allergologie, Bâtiment des 
Spécialités Médicales, 6, rue du Morvan, Vandœuvre-lès-Nancy, France. Email: 
jl.schmutz@chu-nancy.fr
SOURCE
  Annales de Dermatologie et de Venereologie (2015) 142:4 (307-308). Date of 
Publication: 1 Apr 2015
ISSN
  0151-9638
BOOK PUBLISHER
  Elsevier Masson SAS, 62 rue Camille Desmoulins, Issy les Moulineaux Cedex, 
France.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  human
  short survey
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  French
EMBASE ACCESSION NUMBER
  2015823325
MEDLINE PMID
  25770731 (http://www.ncbi.nlm.nih.gov/pubmed/25770731)
PUI
  L602941058
DOI
  10.1016/j.annder.2015.02.001
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.annder.2015.02.001
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 286
TITLE
  Immunotherapeutic approaches to ovarian cancer treatment
AUTHOR NAMES
  Chester C.
  Dorigo O.
  Berek J.S.
  Kohrt H.
AUTHOR ADDRESSES
  (Chester C., cchester@stanford.edu; Kohrt H., kohrt@stanford.edu) Department 
of Medicine, Division of Oncology, Stanford University School of Medicine, 
Stanford, United States.
(Dorigo O., odorigo@stanford.edu; Berek J.S., jberek@stanford.edu) Stanford 
Women's Cancer Center, Division of Gynecologic Oncology, Department of 
Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, 
United States.
CORRESPONDENCE ADDRESS
  H. Kohrt, Department of Medicine, Division of Oncology, Stanford University 
School of Medicine, Stanford, United States.
SOURCE
  Journal for ImmunoTherapy of Cancer (2015) 3:1 Article Number: 7. Date of 
Publication: 24 Mar 2015
ISSN
  2051-1426 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  Despite advances in combinatorial chemotherapy regimens and the advent of 
intraperitoneal chemotherapy administration, current therapeutic options for 
ovarian cancer patients are inadequate. Immunotherapy offers a novel and 
promising therapeutic strategy for treating ovarian tumors. Following the 
demonstration of the immunogenicity of ovarian tumors, multiple 
immunotherapeutic modalities have been developed. Antibody-based therapies, 
immune checkpoint blockade, cancer vaccines, and chimeric antigen 
receptor-modified T cells have demonstrated preclinical success and entered 
clinical testing. In this review, we discuss these promising 
immunotherapeutic approaches and emphasize the importance of combinatorial 
treatment strategies and biomarker discovery.
EMTREE DRUG INDEX TERMS
  4 amino n (3 chloro 4 fluorophenyl) n' hydroxy 1,2,5 oxadiazole 3 
carboximidamide (clinical trial, drug therapy)
  bevacizumab (clinical trial, drug therapy)
  catumaxomab (clinical trial, drug therapy)
  cetuximab (clinical trial, drug therapy)
  cyclophosphamide (clinical trial, drug therapy)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  dendritic cell vaccine (clinical trial, drug therapy)
  indoleamine 2,3 dioxygenase (endogenous compound)
  indoximod (clinical trial, drug therapy)
  interleukin 2 (clinical trial, drug therapy)
  ipilupimab (clinical trial, drug therapy)
  macrophage derived chemokine (endogenous compound)
  monoclonal antibody (clinical trial, drug therapy)
  montanide ISA 51 (clinical trial, drug therapy)
  nivolumab (clinical trial, drug therapy)
  NY ESO 1 antigen (clinical trial, drug therapy)
  panitumumab (clinical trial, drug therapy)
  pembrolizumab (clinical trial, drug therapy)
  peptide vaccine (clinical trial, drug therapy)
  programmed death 1 receptor (endogenous compound)
  protein p53 (clinical trial, drug therapy)
  recombinant granulocyte macrophage colony stimulating factor (clinical 
trial, drug therapy)
  unclassified drug
  V set domain containing T cell activation inhibitor 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adoptive immunotherapy
  antibody dependent cellular cytotoxicity
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  cytokine production
  dendritic cell
  disease free survival
  gene expression
  human
  immune response
  natural killer cell
  nonhuman
  overall survival
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  progression free survival
  review
  Th2 cell
  tumor associated leukocyte
DRUG TRADE NAMES
  avastin  Hoffmann La Roche

  cvac  Prima

  erbitux  Bms

  incb 024360  Incyte

  keytruda  Merck

  removab  Fresenius

  vectibix  Amgen

DRUG MANUFACTURERS
  Amgen
  Bms
  Fresenius
  Hoffmann La Roche
  Incyte
  Merck
  Prima
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  catumaxomab (509077-98-9)
  cetuximab (205923-56-4)
  cyclophosphamide (50-18-0)
  indoleamine 2,3 dioxygenase ()
  indoximod (110117-83-4)
  interleukin 2 (85898-30-2)
  nivolumab (946414-94-4)
  panitumumab (339177-26-3)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00088413, NCT00603460, NCT01132014, NCT01312376, NCT01494688, NCT01611558, NCT02048709, NCT02327078)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015944749
PUI
  L603834366
DOI
  10.1186/s40425-015-0051-7
FULL TEXT LINK
  http://dx.doi.org/10.1186/s40425-015-0051-7
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 287
TITLE
  Febrile neutropenia in a metastatic melanoma patient treated with ipilimumab 
- Case report
AUTHOR NAMES
  Woźniak S.
  Mackiewicz-Wysocka M.
  Krokowicz L.
  Kwinta L.
  Mackiewicz J.
AUTHOR ADDRESSES
  (Woźniak S.; Kwinta L.) Department of Chemotherapy, Greater Poland Cancer 
Centre, Poznan, Poland.
(Mackiewicz-Wysocka M.) Department of Dermatology, Poznan University of 
Medical Sciences, Poznan, Poland.
(Krokowicz L.) Department of General, Endocrinological and 
Gastroenterological Oncology Surgery, University of Medical Sciences, 
Poznan, Poland.
(Mackiewicz J., jmackiewicz@biocontract.com) Medical Biotechnology, 
University of Medical Sciences, 36 Zambrowska Street, Poznan, Poland.
(Mackiewicz J., jmackiewicz@biocontract.com) Department of Diagnostics and 
Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland.
(Mackiewicz J., jmackiewicz@biocontract.com) Department of Medical Oncology, 
Małgorzata Medical Center, rem, Poland.
SOURCE
  Oncology Research and Treatment (2015) 38:3 (105-108). Date of Publication: 
24 Mar 2015
ISSN
  2296-5270
BOOK PUBLISHER
  S. Karger AG
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  amoxicillin plus clavulanic acid
  dacarbazine (drug therapy)
  filgrastim (drug therapy, subcutaneous drug administration)
  fluconazole (drug therapy, intravenous drug administration)
  granulocyte antibody (endogenous compound)
  meropenem (drug therapy, intravenous drug administration)
  methylprednisolone (drug therapy, intravenous drug administration, oral drug 
administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  febrile neutropenia (drug therapy, side effect, drug therapy, side effect)
  metastatic melanoma (drug therapy, drug therapy, surgery)
EMTREE MEDICAL INDEX TERMS
  adult
  agranulocytosis (side effect)
  article
  bone marrow biopsy
  brain metastasis (complication, drug therapy)
  case report
  coughing (side effect)
  fatality
  human
  leukocyte count
  lymph node dissection
  lymph node metastasis (complication, surgery)
  male
  multiple cycle treatment
  platelet count
  rash (side effect)
  treatment outcome
DRUG TRADE NAMES
  yervoy  , GermanyBristol

DRUG MANUFACTURERS
   (Germany)Bristol
CAS REGISTRY NUMBERS
  amoxicillin plus clavulanic acid (74469-00-4, 79198-29-1)
  dacarbazine (4342-03-4)
  filgrastim (121181-53-1)
  fluconazole (86386-73-4)
  ipilimumab (477202-00-9)
  meropenem (96036-03-2)
  methylprednisolone (6923-42-8, 83-43-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015853923
MEDLINE PMID
  25792081 (http://www.ncbi.nlm.nih.gov/pubmed/25792081)
PUI
  L603250975
DOI
  10.1159/000377650
FULL TEXT LINK
  http://dx.doi.org/10.1159/000377650
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 288
TITLE
  Ipilimumab and immune-mediated adverse events: A case report of anti-CTLA4 
induced ileitis
AUTHOR NAMES
  Venditti O.
  De Lisi D.
  Caricato M.
  Caputo D.
  Capolupo G.T.
  Taffon C.
  Pagliara E.
  Battisi S.
  Frezza A.M.
  Onetti Muda A.
  Tonini G.
  Santini D.
AUTHOR ADDRESSES
  (Venditti O., o.venditti@unicampus.it; De Lisi D., d.delisi@unicampus.it; 
Frezza A.M., a.frezza@unicampus.it; Tonini G., g.tonini@unicampus.it; 
Santini D., d.santini@unicampus.it) Università Campus Bio-Medico di Roma, 
Department of Medical Oncology, via Alvaro del Portillo 200, Rome, Italy.
(Caricato M., m.caricato@unicampus.it; Caputo D., d.caputo@unicampus.it; 
Capolupo G.T., g.capolupo@unicampus.it) Università Campus Bio-Medico di 
Roma, Department of General Surgery, Via Álvaro del Portillo, 200, Rome, 
Italy.
(Taffon C., c.taffon@unicampus.it; Onetti Muda A., a.onetti@unicampus.it) 
Università Campus Bio-Medico di Roma, Department of Pathology Università, 
Via Álvaro del Portillo, 200, Rome, Italy.
(Pagliara E., e.pagliara@unicampus.it; Battisi S., s.battisti@unicampus.it) 
Campus Bio-Medico di Roma, Department of Radiology Università, Via Álvaro 
del Portillo, 200, Rome, Italy.
CORRESPONDENCE ADDRESS
  O. Venditti, Università Campus Bio-Medico di Roma, Department of Medical 
Oncology, via Alvaro del Portillo 200, Rome, Italy. Email: 
o.venditti@unicampus.it
SOURCE
  BMC Cancer (2015) 15:1 Article Number: 87. Date of Publication: 1 Mar 2015
ISSN
  1471-2407 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody
  dabrafenib (drug therapy, oral drug administration)
  fluorodeoxyglucose f 18
  hemoglobin (endogenous compound)
  methylprednisolone (intravenous drug administration)
  prednisone (oral drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ileitis (side effect, side effect)
  immune mediated ileitis
  immunopathology (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  anemia (side effect)
  antibody titer
  article
  asthenia (side effect)
  blood clotting disorder (side effect)
  BRAF gene
  cancer chemotherapy
  cancer palliative therapy
  cancer staging
  carcinomatosis (complication, surgery)
  carcinomatous peritonitis (complication, surgery)
  case report
  colon resection
  colonoscopy
  computer assisted tomography
  diarrhea (side effect)
  disease severity
  epigenetics
  erythrocyte transfusion
  exon
  female
  fever (side effect)
  follow up
  gastrointestinal hemorrhage (side effect, surgery)
  histopathology
  human
  human cell
  human tissue
  immune mediated ilietis (side effect)
  immune mediated ilietis (side effect)
  inflammatory infiltrate
  intestine biopsy
  lung metastasis (complication, diagnosis, drug therapy)
  lymph node dissection
  lymph node metastasis (complication, surgery)
  lymphocyte proliferation
  metastatic melanoma (drug therapy)
  middle aged
  multiple cycle treatment
  mutational analysis
  nausea (side effect)
  physical examination
  positron emission tomography
  T lymphocyte activation
  terminal ileum
  thrombocyte transfusion
  thrombocytopenia (side effect, therapy)
  tumor localization
  tumor volume
CAS REGISTRY NUMBERS
  dabrafenib (1195765-45-7, 1195768-06-9)
  fluorodeoxyglucose f 18 (63503-12-8)
  hemoglobin (9008-02-0)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Hematology (25)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015002434
MEDLINE PMID
  25885696 (http://www.ncbi.nlm.nih.gov/pubmed/25885696)
PUI
  L604195994
DOI
  10.1186/s12885-015-1074-7
FULL TEXT LINK
  http://dx.doi.org/10.1186/s12885-015-1074-7
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 289
TITLE
  Systemic high-dose corticosteroid treatment does not improve the outcome of 
ipilimumab-related hypophysitis: A retrospective cohort study
AUTHOR NAMES
  Min L.
  Hodi F.S.
  Giobbie-Hurder A.
  Ott P.A.
  Luke J.J.
  Donahue H.
  Davis M.
  Carroll R.S.
  Kaiser U.B.
AUTHOR ADDRESSES
  (Min L., lmin1@partners.org; Carroll R.S.; Kaiser U.B.) Division of 
Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, 221 
Longwood Avenue, Boston, United States.
(Hodi F.S.; Giobbie-Hurder A.; Ott P.A.; Luke J.J.; Donahue H.; Davis M.) 
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United 
States.
(Luke J.J.) Melanoma and Developmental Therapeutics Clinics, University of 
Chicago, Chicago, United States.
CORRESPONDENCE ADDRESS
  L. Min, Division of Endocrinology, Diabetes and Hypertension, Brigham and 
Women's Hospital, 221 Longwood Avenue, Boston, United States. Email: 
lmin1@partners.org
SOURCE
  Clinical Cancer Research (2015) 21:4 (749-755). Date of Publication: 15 Feb 
2015
ISSN
  1557-3265 (electronic)
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., helen.atkins@aacr.org
ABSTRACT
  To examine the onset and outcome of ipilimumabrelated hypophysitis and the 
response to treatment with systemic high-dose corticosteroids (HDS). 
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. 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. Conclusion: Systemic HDS therapy in patients with 
ipilimu-mab-related hypophysitis may not be indicated. Instead, supportive 
treatment of hypophysitis-related hormone deficiencies with the 
corresponding hormone replacement should be given. Clin Cancer Res; 21(4); 
749-55. -2014 AACR.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  corticosteroid (drug therapy)
  dexamethasone (adverse drug reaction, drug therapy)
  hydrocortisone (drug therapy)
  ipilimumab (adverse drug reaction, drug therapy)
  prednisone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (drug therapy, side effect)
  article
  brain metastasis (side effect)
  cancer survival
  drug efficacy
  drug megadose
  drug response
  drug withdrawal
  female
  human
  hyperprolactinemia
  hypogonadism (drug therapy, side effect)
  hyponatremia (drug therapy, side effect)
  hypophysis disease (drug therapy, side effect)
  hypopituitarism
  hypothyroidism (drug therapy, side effect)
  incidence
  major clinical study
  male
  metastatic melanoma (drug therapy)
  overall survival
  pituitary enlargement (drug therapy, side effect)
  pituitary enlargement (drug therapy, side effect)
  retrospective study
  sex difference
  survival rate
  treatment duration
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015765615
MEDLINE PMID
  25538262 (http://www.ncbi.nlm.nih.gov/pubmed/25538262)
PUI
  L602249147
DOI
  10.1158/1078-0432.CCR-14-2353
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-14-2353
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 290
TITLE
  Immune checkpoint inhibitor therapy associated hypophysitis
AUTHOR NAMES
  Mahzari M.
  Liu D.
  Arnaout A.
  Lochnan H.
AUTHOR ADDRESSES
  (Mahzari M.; Liu D.; Arnaout A.; Lochnan H., hlochnan@toh.on.ca) Division of 
Endocrinology and Metabolism, Department of Medicine, University of Ottawa 
and the Ottawa Hospital, Ottawa, Canada.
CORRESPONDENCE ADDRESS
  H. Lochnan, Division of Endocrinology and Metabolism, Department of 
Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, Canada.
SOURCE
  Clinical Medicine Insights: Endocrinology and Diabetes (2015) 8 (21-28). 
Date of Publication: 28 Jan 2015
ISSN
  1179-5514 (electronic)
  1179-5514
BOOK PUBLISHER
  Libertas Academica Ltd., PO Box 300-874, Albany 0751, Mairangi Bay, 
Auckland, New Zealand.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, pharmacology)
EMTREE DRUG INDEX TERMS
  prednisone (drug therapy)
  prolactin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, etiology, 
side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency
  adult
  aged
  cancer immunotherapy
  clinical article
  clinical feature
  drug mechanism
  drug megadose
  drug withdrawal
  female
  headache
  hormone determination
  human
  hypogonadism
  hypophysis adrenal system
  hypothyroidism
  male
  metastatic melanoma (drug therapy)
  middle aged
  nuclear magnetic resonance imaging
  pathogenesis
  review
  sex difference
  substitution therapy
  very elderly
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015873316
PUI
  L603285466
DOI
  10.4137/CMED.S22469
FULL TEXT LINK
  http://dx.doi.org/10.4137/CMED.S22469
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 291
TITLE
  Induction of painless thyroiditis in patients receiving programmed death 1 
receptor immunotherapy for metastatic malignancies
AUTHOR NAMES
  Orlov S.
  Salari F.
  Kashat L.
  Walfish P.G.
AUTHOR ADDRESSES
  (Orlov S.; Salari F.; Kashat L.; Walfish P.G., pwalfish@mtsinai.on.ca) 
Department of Medicine, Mt. Sinai Hospital, Toronto, Canada.
(Walfish P.G., pwalfish@mtsinai.on.ca) Endocrine Division, 
Otolaryngology-Head and Neck Surgery Program, Mt. Sinai Hospital, Toronto, 
Canada.
(Walfish P.G., pwalfish@mtsinai.on.ca) University of Toronto School of 
Medicine, Toronto, Canada.
CORRESPONDENCE ADDRESS
  P.G. Walfish, Department of Thyroid Oncology, Mount Sinai Hospital, 413-7, 
600 University Ave., Toronto, Canada.
SOURCE
  Journal of Clinical Endocrinology and Metabolism (2015) 100:5 (1738-1741). 
Date of Publication: 1 May 2015
ISSN
  1945-7197 (electronic)
  0021-972X
BOOK PUBLISHER
  Endocrine Society, mzendell@endo-society.org
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction, drug therapy)
  programmed death 1 receptor monoclonal antibody (adverse drug reaction, drug 
therapy, intravenous drug administration)
EMTREE DRUG INDEX TERMS
  beta adrenergic receptor blocking agent (drug therapy)
  immunoglobulin (endogenous compound)
  liothyronine (endogenous compound)
  thyroid antibody (endogenous compound)
  thyroid hormone (drug therapy)
  thyrotropin (endogenous compound)
  thyrotropin binding inhibitory immunoglobulin (endogenous compound)
  thyroxine (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  metastasis (drug therapy, drug therapy)
  painless thyroiditis syndrome (drug therapy, side effect, drug therapy, side 
effect)
  thyroiditis (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer (drug therapy)
  aged
  article
  clinical article
  drug exposure
  female
  free liothyronine index
  free thyroxine index
  hormone substitution
  human
  hypothyroidism (diagnosis, drug therapy)
  male
  middle aged
  priority journal
  thyrotoxicosis (diagnosis, drug therapy, side effect)
  treatment duration
  very elderly
CAS REGISTRY NUMBERS
  immunoglobulin (9007-83-4)
  liothyronine (6138-47-2, 6893-02-3)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015046697
MEDLINE PMID
  25751110 (http://www.ncbi.nlm.nih.gov/pubmed/25751110)
PUI
  L604399305
DOI
  10.1210/jc.2014-4560
FULL TEXT LINK
  http://dx.doi.org/10.1210/jc.2014-4560
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 292
TITLE
  Development of thyroglobulin antibodies after GVAX immunotherapy is 
associated with prolonged survival
AUTHOR NAMES
  De Remigis A.
  De Gruijl T.D.
  Uram J.N.
  Tzou S.-C.
  Iwama S.
  Talor M.V.
  Armstrong T.D.
  Santegoets S.J.A.M.
  Slovin S.F.
  Zheng L.
  Laheru D.A.
  Jaffee E.M.
  Gerritsen W.R.
  Van Den Eertwegh A.J.M.
  Le D.T.
  Caturegli P.
AUTHOR ADDRESSES
  (De Remigis A.; Tzou S.-C.; Iwama S.; Talor M.V.; Caturegli P., 
pcat@jhmi.edu) Department of Pathology, Johns Hopkins University, Johns 
Hopkins Pathology, Ross Building, 720 Rutland Avenue, Baltimore, United 
States.
(De Gruijl T.D.; Santegoets S.J.A.M.; Gerritsen W.R.; Van Den Eertwegh 
A.J.M.) Department of Medical Oncology, VU University Medical Centre, 
Amsterdam, Netherlands.
(Uram J.N.; Armstrong T.D.; Zheng L.; Laheru D.A.; Jaffee E.M.; Le D.T.) 
Sidney Kimmel Cancer Center, Skip Viragh Center for Pancreatic Cancer 
Research and Clinical Care, Sol Goldman Pancreatic Cancer Center at Johns 
Hopkins, Baltimore, United States.
(Slovin S.F.) Department of Medicine, Memorial Sloan-Kettering Cancer 
Center, New York, United States.
(Slovin S.F.) Department of Medicine, Weill-Cornell Medical College, New 
York, United States.
(Caturegli P., pcat@jhmi.edu) Feinstone Department of Molecular Microbiology 
and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, 
United States.
CORRESPONDENCE ADDRESS
  P. Caturegli, Department of Pathology, Johns Hopkins University, Johns 
Hopkins Pathology, Ross Building, 720 Rutland Avenue, Baltimore, United 
States.
SOURCE
  International Journal of Cancer (2015) 136:1 (127-137). Date of Publication: 
1 Jan 2015
ISSN
  1097-0215 (electronic)
  0020-7136
BOOK PUBLISHER
  Wiley-Liss Inc., info@wiley.com
ABSTRACT
  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. What's new? Auto-inflammatory responses against the thyroid gland 
can develop in association with cancer immunotherapy, but little is known 
about the mechanism or significance of immunotherapy-related autoimmune 
thyroiditis. Here, the production of thyroglobulin antibodies (TgAbs) in 
response to treatment with the vaccine GVAX, administered either alone or in 
association with the immunotherapeutic antibody ipilimumab, was explored in 
pancreatic, prostate, and colon cancer patients. TgAbs were produced 
specifically following GVAX immunotherapy and were found to recognize unique 
antigenic epitopes. TgAbs production also was associated with improved 
overall survival, suggesting that it may be a useful predictive tool in the 
clinical setting.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  granulocyte macrophage colony stimulating factor vaccine (clinical trial, 
drug combination, drug therapy)
  thyroglobulin antibody (endogenous compound)
EMTREE DRUG INDEX TERMS
  actin antibody (endogenous compound)
  antibody (endogenous compound)
  epitope (endogenous compound)
  insulin antibody (endogenous compound)
  ipilimumab (clinical trial, drug combination, drug therapy)
  myeloperoxidase antibody (endogenous compound)
  proteinase 3 antibody (endogenous compound)
  thyroid peroxidase antibody (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunization
  long term survival
EMTREE MEDICAL INDEX TERMS
  antibody titer
  article
  cancer combination chemotherapy
  cancer survival
  colon cancer (drug therapy, prevention)
  controlled study
  enzyme linked immunosorbent assay
  Hashimoto disease
  human
  major clinical study
  male
  monotherapy
  pancreas cancer (drug therapy, prevention)
  priority journal
  prostate cancer (drug therapy)
  randomized controlled trial (topic)
  seroconversion
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00323882, NCT00389610, NCT00656123, NCT00836407, NCT01510288)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014729208
MEDLINE PMID
  24832153 (http://www.ncbi.nlm.nih.gov/pubmed/24832153)
PUI
  L53150111
DOI
  10.1002/ijc.28973
FULL TEXT LINK
  http://dx.doi.org/10.1002/ijc.28973
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 293
TITLE
  Ipilimumab may increase the severity of cutenaous toxicity related to 
radiotherapy
AUTHOR NAMES
  Eryllmaz M.K.
  Mutlu H.
  Salim D.K.
  Musri F.Y.
  Tural D.
  Başsorgun I.
  Coşkun H.Ş.
AUTHOR ADDRESSES
  (Eryllmaz M.K., drangelkarakurt@hotmail.com; Mutlu H.; Salim D.K.; Musri 
F.Y.; Tural D.; Coşkun H.Ş.) Department of Medical Oncology, Akdeniz 
University, School of Medicine, Antalya, Turkey.
(Başsorgun I.) Department of Pathology, Akdeniz University, School of 
Medicine, Antalya, Turkey.
CORRESPONDENCE ADDRESS
  M.K. Eryllmaz, Email: drangelkarakurt@hotmail.com
SOURCE
  Journal of Oncology Pharmacy Practice (2015) 22:3 (533-536). Date of 
Publication: 2015
ISSN
  1477-092X (electronic)
  1078-1552
BOOK PUBLISHER
  SAGE Publications Ltd, info@sagepub.co.uk
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  alpha interferon (drug dose, drug therapy, intravenous drug administration, 
subcutaneous drug administration)
  methylprednisolone (drug therapy, oral drug administration)
  vemurafenib (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer radiotherapy
  skin toxicity (side effect, complication, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer patient
  case report
  corticosteroid therapy
  disease severity
  drug megadose
  drug withdrawal
  female
  human
  human tissue
  hyperemia (complication)
  intensity modulated radiation therapy
  maculopapular rash (drug therapy, side effect)
  metastatic melanoma (drug therapy, radiotherapy)
  middle aged
  multiple cycle treatment
  palliative therapy
  priority journal
  rash (complication)
  skin biopsy
  treatment response
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Radiology (14)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160327491
MEDLINE PMID
  25694346 (http://www.ncbi.nlm.nih.gov/pubmed/25694346)
PUI
  L610085101
DOI
  10.1177/1078155215572930
FULL TEXT LINK
  http://dx.doi.org/10.1177/1078155215572930
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 294
TITLE
  Ipilimumab-induced hypophysitis: Review of the literature
AUTHOR NAMES
  Araujo P.B.
  Coelho M.C.A.
  Arruda M.
  Gadelha M.R.
  Neto L.V.
AUTHOR ADDRESSES
  (Araujo P.B., paulabruna@gmail.com; Coelho M.C.A., 
carolinealvescoelho@yahoo.com.br; Arruda M., mariana.arruda.silva@gmail.com; 
Gadelha M.R., mgadelha@hucff.ufrj.br; Neto L.V., netolv@gmail.com) 
Department of Internal Medicine and Endocrine Unit, Med. Sch. and Hospital 
Universitario Clementino Fraga Filho, Universidade Federal Do Rio de 
Janeiro, Rua Professor Rodolpho Paulo Rocco 255 9 andar, 21941-913 Rio de 
Janeiro, RJ, Brazil.
(Coelho M.C.A., carolinealvescoelho@yahoo.com.br) Endocrinology Unit, 
Hospital Universitário Pedro Ernesto, Universidade Estadual Do Rio de 
Janeiro, Rio de Janeiro, RJ, Brazil.
(Coelho M.C.A., carolinealvescoelho@yahoo.com.br) Instituto Estadual de 
Diabetes e Endocrinologia, Rio de Janeiro, RJ, Brazil.
(Neto L.V., netolv@gmail.com) Endocrinology Unit, Hospital Federal da Lagoa, 
Rio-De-Janeiro-RJ, Brazil.
CORRESPONDENCE ADDRESS
  L.V. Neto, Department of Internal Medicine and Endocrine Unit, Med. Sch. and 
Hospital Universitario Clementino Fraga Filho, Universidade Federal Do Rio 
de Janeiro, Rua Professor Rodolpho Paulo Rocco 255 9 andar, 21941-913 Rio de 
Janeiro, RJ, Brazil.
SOURCE
  Journal of Endocrinological Investigation (2015) 38:11 (1159-1166). Date of 
Publication: 1 Nov 2015
ISSN
  1720-8386 (electronic)
  0391-4097
BOOK PUBLISHER
  Springer International Publishing
ABSTRACT
  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). 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. 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). 
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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  glucocorticoid (endogenous compound)
  hydrocortisone (endogenous compound)
  prednisone
  prolactin (endogenous compound)
  thyroid hormone
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug induced disease (side effect, diagnosis, side effect)
  hypophysitis (side effect, diagnosis, side effect)
  ipilimumab induced hypophysitis (side effect, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency
  adult
  adverse outcome
  amnesia (side effect)
  antineoplastic activity
  arthritis (side effect)
  cancer fatigue (side effect)
  cancer immunotherapy
  case report
  clinical assessment
  clinical evaluation
  clinical feature
  constipation (side effect)
  dizziness
  headache (side effect)
  hormone substitution
  human
  hydrocortisone blood level
  hypogonadism (side effect)
  hypophysis
  hypophysis function
  hypopituitarism
  hypothyroidism (side effect)
  laboratory test
  libido disorder (side effect)
  lung metastasis (drug therapy)
  male
  medical history
  medical information
  Medline
  middle aged
  multiple cycle treatment
  nuclear magnetic resonance imaging
  review
  systematic review
  T lymphocyte activation
  treatment response
CAS REGISTRY NUMBERS
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015441030
PUI
  L606417537
DOI
  10.1007/s40618-015-0301-z
FULL TEXT LINK
  http://dx.doi.org/10.1007/s40618-015-0301-z
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 295
TITLE
  Checkpoint kinase 1 inhibitors as targeted molecular agents for clear cell 
carcinoma of the ovary (Review)
AUTHOR NAMES
  Kobayashi H.
  Shigetomi H.
  Yoshimoto C.
AUTHOR ADDRESSES
  (Kobayashi H., hirokoba@naramed-u.ac.jp; Shigetomi H.; Yoshimoto C.) 
Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, 
Japan.
CORRESPONDENCE ADDRESS
  H. Kobayashi, Department of Obstetrics and Gynecology, Nara Medical 
University, 840 Shijo-cho, Kashihara, Japan.
SOURCE
  Oncology Letters (2015) 10:2 (571-576). Date of Publication: 2015
ISSN
  1792-1082 (electronic)
  1792-1074
BOOK PUBLISHER
  Spandidos Publications, 10 Vriaxidos Street, Athens, Greece.
ABSTRACT
  In clear cell carcinoma of the ovary, chemoresistance frequently results in 
treatment failure. The present study aimed to review the potential 
association of transcription factor hepatocyte nuclear factor (HNF)-1β with 
cell cycle checkpoint machinery, as a mechanism for chemoresistance. The 
English-language literature on the subject was reviewed to identify genomic 
alterations and aberrant molecular pathways interacting with chemoresistance 
in clear cell carcinoma. Oxidative stress induced by repeated hemorrhage 
induces greater susceptibility of endometriotic cells to DNA damage, and 
subsequent malignant transformation results in endometriosis-associated 
ovarian cancer. Molecular changes, including those in HNF-1β and checkpoint 
kinase 1 (Chk1), may be a manifestation of essential alterations in cell 
cycle regulation, detoxification and chemoresistance in clear cell 
carcinoma. Chk1 is a critical signal transducer in the cell cycle checkpoint 
machinery. DNA damage, in turn, increases persistent phosphorylation of Chk1 
and induction of G2/M phase cell cycle arrest in cells overexpressing 
HNF-1β. HNF-1β deletion induces apoptosis, suggesting that enhanced levels 
of HNF-1β may be associated with chemoresistance. Targeted therapy with Chk1 
inhibitors may be explored as a potential treatment modality for patients 
with clear cell carcinoma. This provides a novel direction for combination 
therapy, including targeting of Chk1, which may overcome drug resistance and 
improve treatment efficacy.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  checkpoint kinase 1 inhibitor (clinical trial, drug therapy)
  protein kinase inhibitor (clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide 
(clinical trial, drug therapy)
  7 hydroxystaurosporine (clinical trial, drug therapy)
  alpha amino n [5,6 dihydro 2 (1 methyl 1h pyrazol 4 yl) 6 oxo 1h 
pyrrolo[4,3,2 ef][2,3]benzodiazepin 8 yl]cyclohexaneacetamide (clinical 
trial, drug therapy)
  ATM protein (endogenous compound)
  ATR protein (endogenous compound)
  checkpoint kinase 1 (endogenous compound)
  checkpoint kinase 2 (endogenous compound)
  hemoglobin (endogenous compound)
  hepatocyte nuclear factor 1beta (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  clear cell carcinoma (drug therapy, drug therapy)
  molecularly targeted therapy
  ovary carcinoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  apoptosis
  cell cycle arrest
  cell cycle checkpoint
  cell death
  chemosensitivity
  chromosomal instability
  detoxification
  DNA damage
  DNA repair
  endometriosis
  glycogen synthesis
  human
  oxidation
  oxidative stress
  pathogenesis
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  protein phosphorylation
  review
  signal transduction
DRUG TRADE NAMES
  azd 7762
  pf 477736
  ucn 01
CAS REGISTRY NUMBERS
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide 
(1019773-80-8, 860352-01-8)
  7 hydroxystaurosporine (112953-11-4)
  alpha amino n [5,6 dihydro 2 (1 methyl 1h pyrazol 4 yl) 6 oxo 1h 
pyrrolo[4,3,2 ef][2,3]benzodiazepin 8 yl]cyclohexaneacetamide (952021-60-2)
  checkpoint kinase 2 (244634-79-5)
  hemoglobin (9008-02-0)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015141052
PUI
  L604920234
DOI
  10.3892/ol.2015.3268
FULL TEXT LINK
  http://dx.doi.org/10.3892/ol.2015.3268
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 296
TITLE
  Irish Section Meeting - Nutrition at Key Life Stages: New Findings, New 
Approaches
AUTHOR ADDRESSES
  SOURCE
  Proceedings of the Nutrition Society (2015) 74:OCE4. Date of Publication: 1 
Jan 2015
CONFERENCE NAME
  Irish Section Meeting - Nutrition at Key Life Stages: New Findings, New 
Approaches
CONFERENCE LOCATION
  Cork, Ireland
CONFERENCE DATE
  2015-06-17 to 2015-06-19
ISSN
  1475-2719
BOOK PUBLISHER
  Cambridge University Press
ABSTRACT
  The proceedings contain 73 papers. The topics discussed include: dietary 
determinants of vitamin D intake in Irish pre-school children aged 1-4 
years; dietary patterns in Europe: the Food4Me proof of principle study; 
bioavailability of transglutaminase cross-linked sodium casein hydrolysates; 
cord leptin is inversely associated with changes in weight and adiposity in 
infancy; vitamin e status has an impact on plasma n-3 fatty acid proportion 
in a healthy adult Irish population; longitudinal changes in body 
composition during ipilimumab treatment for metastatic melanoma; effect of 
brewers' spent grain (BSG) phenolic extracts on cell viability and 
protective effect against oxidant-induced DNA single strand breaks in U937 
cells; vitamin D status and muscular side-effects in statin users: 
preliminary findings from a seasonal observation study; nutritional and 
social correlates of gestational diabetes; are leptin responses influenced 
by bright light treatment in healthy young individuals; diet quality and 
nutritional adequacy of young children in the UK according to their 
consumption of young child formula and commercial infant food; the 
development of an innovative web based dietary assessment tool for an Irish 
adult population: the diet Ireland tool; and knowledge and awareness of 
iodine nutrition among women of child-bearing age.
EMTREE DRUG INDEX TERMS
  alpha tocopherol
  casein
  endogenous compound
  hydroxymethylglutaryl coenzyme A reductase inhibitor
  ipilimumab
  leptin
  omega 3 fatty acid
  oxidizing agent
  protein glutamine gamma glutamyltransferase
  sodium
  vitamin D
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  bioavailability
EMTREE MEDICAL INDEX TERMS
  adult
  adverse drug reaction
  awareness
  baby food
  body composition
  cell viability
  child
  clinical study
  clinical trial
  controlled study
  cross linking
  DNA strand breakage
  extract
  female
  grain
  human
  hydrolysis
  infancy
  infant
  Ireland
  Irish (citizen)
  metastatic melanoma
  muscle
  nutritional assessment
  obesity
  observational study
  plasma
  pregnancy diabetes mellitus
  side effect
CAS REGISTRY NUMBERS
  alpha tocopherol (1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9)
  casein (9000-71-9)
  ipilimumab (477202-00-9)
  protein glutamine gamma glutamyltransferase (80146-85-6)
  sodium (7440-23-5)
LANGUAGE OF ARTICLE
  English
PUI
  L613577297
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 297
TITLE
  Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse 
event of the anti-CTLA-4 antibody in melanoma
AUTHOR NAMES
  Albarel F.
  Gaudy C.
  Castinetti F.
  Carré T.
  Morange I.
  Conte-Devolx B.
  Grob J.-J.
  Brue T.
AUTHOR ADDRESSES
  (Albarel F.; Castinetti F.; Morange I.; Conte-Devolx B.; Brue T., 
thierry.brue@univ-amu.fr) Assistance Publique-Hôpitaux de Marseille (AP-HM), 
Hôpital Timone, Service d'Endocrinologie, Marseille Cedex 15, Marseille, 
France.
(Albarel F.; Castinetti F.; Morange I.; Conte-Devolx B.; Brue T., 
thierry.brue@univ-amu.fr) Aix-Marseille Université, CNRS, CRN2M-UMR7286, 
Marseille Cedex 15, Marseille, France.
(Gaudy C.; Carré T.; Grob J.-J.) Aix-Marseille Université, Assistance 
Publique-Hôpitaux de Marseille (AP-HM), Service de Dermatologie, Marseille 
Cedex 15, Marseille, France.
CORRESPONDENCE ADDRESS
  T. Brue, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital Timone, 
Service d'Endocrinologie, Marseille Cedex 15, Marseille, France.
SOURCE
  European Journal of Endocrinology (2015) 172:2 (195-204). Date of 
Publication: 1 Feb 2015
ISSN
  1479-683X (electronic)
  0804-4643
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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. 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. Methods: 
Symptoms, pituitary function, and pituitary imaging at diagnosis of 
hypophysitis and during the follow-up were recorded. Results: Of 131 
patients treated with ipilimumab or a placebo, 15 patients (10 mg/kg in 
11/15) presented with hypophysitis (R11.5%) at 9.5G5.9 weeks (meanGS.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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug comparison - placebo, drug therapy)
EMTREE DRUG INDEX TERMS
  glucocorticoid (drug therapy)
  placebo
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse outcome
  hypophysitis (side effect, side effect)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  asthenia
  clinical evaluation
  clinical feature
  controlled study
  corticotroph deficiency (drug therapy)
  corticotroph deficiency (drug therapy)
  diarrhea (side effect)
  disease severity
  drug withdrawal
  enterocolitis (side effect)
  female
  follow up
  gonadotroph deficiency
  headache
  hepatitis (side effect)
  hormone deficiency (drug therapy)
  human
  hyperprolactinemia
  image analysis
  kidney failure (side effect)
  libido disorder
  major clinical study
  male
  outcome assessment
  rash (side effect)
  symptom
  thyrotroph deficiency
  weakness
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015737095
MEDLINE PMID
  25416723 (http://www.ncbi.nlm.nih.gov/pubmed/25416723)
PUI
  L602185034
DOI
  10.1530/EJE-14-0845
FULL TEXT LINK
  http://dx.doi.org/10.1530/EJE-14-0845
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 298
TITLE
  Immunotherapy for metastatic melanoma
ORIGINAL (NON-ENGLISH) TITLE
  Imunoterapie metastazujícího melanomu
AUTHOR NAMES
  Krajsová I.
AUTHOR ADDRESSES
  (Krajsová I., Ivana.Krajsova@vfn.cz) Dermatovenerologická klinika VFN, 
Praze, Czech Republic.
CORRESPONDENCE ADDRESS
  I. Krajsová, Dermatovenerologická klinika VFN v Praze, U Nemocnice 499/2, 
Praha, Czech Republic. Email: Ivana.Krajsova@vfn.cz
SOURCE
  Onkologie (Czech Republic) (2015) 9:4 (183-189). Date of Publication: 2015
ISSN
  1803-5345 (electronic)
  1802-4475
BOOK PUBLISHER
  SOLEN s.r.o., Lazecka 297/51, Olomouc, Czech Republic.
ABSTRACT
  Activation of the immune system is very important step in the treatment 
strategy of metastatic melanoma and greater understanding of function of the 
immune checkpoints led to the development of several immune checkpoint 
inhibitors. Ipilimumab, an anti-CTLA-4 monoclonal antibody, was the first 
agent to demonstrate a survival benefit in patients with metastatic 
cutaneous melanoma. The median OS rate for patients treated with ipilimumab 
was, compared with patients receiving a gp100 vaccine longer (10.9 versus 
6.4 months), and also patients treated with ipilimumab and DTIC compared 
with those treated with DTIC alone had improved OS (median OS 11.2 versus 
9.1 months.) The majority of ipilimumab-related adverse events are immune 
related, and the most common are gastrointenstinal and skin toxicity, 
endocrinopathy and hepatotoxicity. New monoclonal antibody against other 
important immunity checkpoint PD-1 receptor, pembrolizumab and nivolumab, 
got FDA approval at the end of 2014. We are approaching the new era of the 
treatment of melanoma but we cannot say, that we resolved the problem. 
Further research of biomarkers, combination therapies and also optimal 
dosing, and duration of treatment is needed.
EMTREE DRUG INDEX TERMS
  dacarbazine (drug combination, drug comparison, drug therapy)
  glycoprotein gp 100 (drug comparison, drug therapy)
  ipilimumab (adverse drug reaction, drug combination, drug comparison, drug 
therapy)
  nivolumab
  pembrolizumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  cutaneous melanoma (drug therapy)
  drug approval
  endocrine disease (side effect)
  gastrointestinal toxicity (side effect)
  human
  liver toxicity (side effect)
  overall survival
  skin toxicity (side effect)
  survival rate
  treatment duration
CAS REGISTRY NUMBERS
  dacarbazine (4342-03-4)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Czech
LANGUAGE OF SUMMARY
  English, Czech
EMBASE ACCESSION NUMBER
  20160027278
PUI
  L607649852
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 299
TITLE
  Possible pitfalls of lpilimumab therapy in malignant melanoma-a case report
ORIGINAL (NON-ENGLISH) TITLE
  Možná úskalí léčby ipilimumabem u maligního melanomu-kazuistika
AUTHOR NAMES
  Kopecký J.
  Kubeček O.
  Gabalec F.
  Hoffmann P.
  Svilias I.
AUTHOR ADDRESSES
  (Kopecký J., kopecjin@fnhk.cz; Kubeček O.) Klinika Onkologie A Radioterapie, 
LF UK A FN Hradec Králové, Sokolská 581, Hradec Králové, Czech Republic.
(Gabalec F.; Svilias I.) Endokrinologie, IV. Interní Hematologická Klinika, 
LF UK A FN Hradec Králové, Czech Republic.
(Hoffmann P.) Radiologická Klinika, LF UK A FN Hradec Králové, Czech 
Republic.
CORRESPONDENCE ADDRESS
  J. Kopecký, Klinika Onkologie A Radioterapie, LF UK A FN Hradec Králové, 
Sokolská 581, Hradec Králové, Czech Republic. Email: kopecjin@fnhk.cz
SOURCE
  Klinicka Onkologie (2015) 28:6 (444-449). Date of Publication: 2015
ISSN
  1802-5307 (electronic)
  0862-495X
BOOK PUBLISHER
  Czech Medical Association J.E. Purkyne, cls@cls.cz
ABSTRACT
  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, lpilimumab is one of the 
first so-called modern drugs in melanoma treatment. The therapy is often 
complicated by adverse effects which are referred as immune-related adverse 
events due to its mechanism of action. 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 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer chemotherapy
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  case report
  endocrine disease (side effect)
  female
  human
  skin disease (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Czech
LANGUAGE OF SUMMARY
  English, Czech
EMBASE ACCESSION NUMBER
  20160095736
MEDLINE PMID
  26673995 (http://www.ncbi.nlm.nih.gov/pubmed/26673995)
PUI
  L608059235
DOI
  10.14735/amko2015444
FULL TEXT LINK
  http://dx.doi.org/10.14735/amko2015444
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 300
TITLE
  Anticytotoxic T-lymphocyte antigen-4 induced autoimmune hypophysitis: A case 
report and literature review
AUTHOR NAMES
  Majchel D.
  Korytkowski M.T.
AUTHOR ADDRESSES
  (Majchel D., majchelkossd@upmc.edu; Korytkowski M.T.) Division of 
Endocrinology and Metabolism, Department of Medicine, University of 
Pittsburgh, Medical Center, 3601 Fifth Avenue, Pittsburgh, United States.
CORRESPONDENCE ADDRESS
  D. Majchel, Division of Endocrinology and Metabolism, Department of 
Medicine, University of Pittsburgh, Medical Center, 3601 Fifth Avenue, 
Pittsburgh, United States. Email: majchelkossd@upmc.edu
SOURCE
  Case Reports in Endocrinology (2015) 2015 Article Number: 570293. Date of 
Publication: 2015
ISSN
  2090-651X (electronic)
  2090-6501
BOOK PUBLISHER
  Hindawi Publishing Corporation, 410 Park Avenue, 15th Floor, 287 pmb, New 
York, United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  levonorgestrel
  methylprednisolone (drug therapy, intravenous drug administration)
  nonsteroid antiinflammatory agent (drug therapy)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune hypophysitis (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  body weight gain
  cancer cell
  cancer staging
  case report
  disease association
  disease severity
  drug megadose
  female
  gastrointestinal disease (side effect)
  headache (drug therapy)
  heart palpitation
  hepatitis (side effect)
  human
  human cell
  immunosuppressive treatment
  intrauterine contraceptive device
  leukocytosis
  lymph node dissection
  melanoma (drug therapy, surgery)
  nuclear magnetic resonance imaging
  open study
  pain intensity
  postoperative period
  pruritus (side effect)
  rare disease
  review
  skin disease (side effect)
  sore throat
DRUG TRADE NAMES
  mirena
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  levonorgestrel (797-63-7)
  methylprednisolone (6923-42-8, 83-43-2)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160721705
PUI
  L612447558
DOI
  10.1155/2015/570293
FULL TEXT LINK
  http://dx.doi.org/10.1155/2015/570293
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 301
TITLE
  PD-L1 expression in small cell neuroendocrine carcinomas
AUTHOR NAMES
  Schultheis A.M.
  Scheel A.H.
  Ozretić L.
  George J.
  Thomas R.K.
  Hagemann T.
  Zander T.
  Wolf J.
  Buettner R.
AUTHOR ADDRESSES
  (Schultheis A.M., anne.schultheis@uk-koeln.de; Scheel A.H.; Ozretić L.; 
Buettner R.) Institute of Pathology, University Hospital Cologne, Kerpener 
Strasse 62, Cologne, Germany.
(George J.; Thomas R.K.) Department of Translational Genomics, University of 
Cologne, Cologne, Germany.
(Zander T.; Wolf J.) Department i of Internal Medicine, University Hospital 
Cologne, Cologne, Germany.
(Hagemann T.) Centre for Cancer and Inflammation, Barts Cancer Institute, 
Queen Mary University of London, London, United Kingdom.
(Zander T.; Wolf J.; Buettner R.) Center for Integrated Oncology (CIO) 
Cologne/Bonn, Germany.
(Schultheis A.M., anne.schultheis@uk-koeln.de) Memorial Sloan Kettering 
Cancer Center, Department of Pathology, 1275 York Avenue, New York, United 
States.
CORRESPONDENCE ADDRESS
  A.M. Schultheis, Institute of Pathology, University Hospital Cologne, 
Kerpener Strasse 62, Cologne, Germany.
SOURCE
  European Journal of Cancer (2015) 51:3 (421-426). Date of Publication: 
February 2015
ISSN
  1879-0852 (electronic)
  0959-8049
BOOK PUBLISHER
  Elsevier Ltd
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  pd l1 protein (endogenous compound)
  programmed death 1 receptor (endogenous compound)
  protein (endogenous compound)
EMTREE DRUG INDEX TERMS
  monoclonal antibody (endogenous compound)
  monoclonal antibody 5H1 (endogenous compound)
  monoclonal antibody E1L3N (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  neuroendocrine tumor
  small cell carcinoma
  small cell neuroendocrine carcinoma
EMTREE MEDICAL INDEX TERMS
  article
  cancer diagnosis
  clinical evaluation
  comparative study
  controlled study
  gene expression
  gene expression profiling
  human
  immunohistochemistry
  immunosuppressive treatment
  lung carcinoma
  lymphocyte
  macrophage
  major clinical study
  priority journal
  protein expression
  RNA sequence
  stroma
  T lymphocyte
  tumor associated leukocyte
  tumor microenvironment
CAS REGISTRY NUMBERS
  protein (67254-75-5)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015737987
MEDLINE PMID
  25582496 (http://www.ncbi.nlm.nih.gov/pubmed/25582496)
PUI
  L602169050
DOI
  10.1016/j.ejca.2014.12.006
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ejca.2014.12.006
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 302
TITLE
  Durable complete responses off all treatment in patients with metastatic 
malignant melanoma after sequential immunotherapy followed by a finite 
course of BRAF inhibitor therapy
AUTHOR NAMES
  Wyluda E.J.
  Cheng J.
  Schell T.D.
  Haley J.S.
  Mallon C.
  Neves R.I.
  Robertson G.
  Sivik J.
  Mackley H.
  Talamo G.
  Drabick J.J.
AUTHOR ADDRESSES
  (Wyluda E.J.; Cheng J.; Mallon C.; Talamo G.; Drabick J.J., 
jdrabick@hmc.psu.edu) Division of Hematology Oncology, Penn State Milton S 
Hershey Medical Center, Hershey, United States.
(Schell T.D.; Haley J.S.) Department of Microbiology and Immunology, Penn 
State Milton S Hershey Medical Center, Hershey, United States.
(Neves R.I.) Department of Surgery, Penn State Milton S Hershey Medical 
Center, Hershey, United States.
(Robertson G.; Sivik J.) Melanoma Program, Penn State Milton S Hershey 
Medical Center, Hershey, United States.
(Mackley H.) Department of Pharmacology, Penn State Milton S Hershey Medical 
Center, Hershey, United States.
(Mackley H.) Division of Radiation Oncology, Penn State Milton S Hershey 
Medical Center, Hershey, United States.
CORRESPONDENCE ADDRESS
  J.J. Drabick, Division of Hematology Oncology, Penn State Milton S Hershey 
Medical Center, Hershey, United States.
SOURCE
  Cancer Biology and Therapy (2015) 16:5 (662-670). Date of Publication: 1 Jan 
2015
ISSN
  1555-8576 (electronic)
  1538-4047
BOOK PUBLISHER
  Taylor and Francis Inc., 325 Chestnut St, Suite 800, Philadelphia, United 
States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  antinuclear antibody
  B Raf kinase (endogenous compound)
  celecoxib (drug therapy)
  hydrocortisone (drug therapy)
  interleukin 2 (drug therapy)
  ipilimumab (adverse drug reaction, drug therapy)
  lactate dehydrogenase (endogenous compound)
  levothyroxine (drug therapy)
  steroid (drug therapy)
  temozolomide (drug therapy)
  trametinib (drug therapy)
  vemurafenib (adverse drug reaction, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  metastatic melanoma (drug therapy, drug therapy, radiotherapy, surgery)
  treatment response
EMTREE MEDICAL INDEX TERMS
  adrenal metastasis
  adult
  arthritis (drug therapy)
  article
  axillary lymph node
  bone metastasis
  cancer adjuvant therapy
  cancer growth
  cancer radiotherapy
  cancer regression
  cancer surgery
  case report
  cerebrovascular accident
  chill
  computer assisted emission tomography
  disease exacerbation
  disease severity
  drug dose reduction
  drug eruption (drug therapy, side effect)
  drug intermittent therapy
  drug megadose
  drug withdrawal
  female
  gene mutation
  human
  human tissue
  hypophysitis (drug therapy, side effect)
  in-transit metastasis (surgery)
  inguinal lymph node
  inguinal region
  lactate dehydrogenase blood level
  low drug dose
  lymph node biopsy
  lymph node dissection
  lymph node metastasis (surgery)
  lymphocyte count
  male
  middle aged
  multiple cycle treatment
  neck dissection
  paresis
  polyarthritis (side effect)
  spleen metastasis
  steroid therapy
  substitution therapy
  synovitis (side effect)
  T lymphocyte
  treatment withdrawal
  vitiligo (side effect)
  wide excision
CAS REGISTRY NUMBERS
  celecoxib (169590-42-5)
  hydrocortisone (50-23-7)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  lactate dehydrogenase (9001-60-9)
  levothyroxine (51-48-9)
  temozolomide (85622-93-1)
  trametinib (1187431-43-1, 871700-17-3)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Hematology (25)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015439375
PUI
  L606402327
DOI
  10.1080/15384047.2015.1026507
FULL TEXT LINK
  http://dx.doi.org/10.1080/15384047.2015.1026507
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 303
TITLE
  Managing immune checkpoint-blocking antibody side effects
AUTHOR NAMES
  Postow M.A.
AUTHOR ADDRESSES
  (Postow M.A.) From the Memorial Sloan Kettering Cancer Center, New York, NY; 
Weill Cornell Medical College, New York, NY
SOURCE
  American Society of Clinical Oncology educational book / ASCO. American 
Society of Clinical Oncology. Meeting (2015) (76-83). Date of Publication: 
2015
ISSN
  1548-8756 (electronic)
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (adverse drug reaction)
  cytotoxic T lymphocyte antigen 4
  granulocyte macrophage colony stimulating factor (drug therapy)
  monoclonal antibody (adverse drug reaction)
  programmed death 1 receptor
  recombinant protein (drug therapy)
  sargramostim
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antagonists and inhibitors
EMTREE MEDICAL INDEX TERMS
  chemically induced
  colitis (drug therapy)
  diarrhea (drug therapy)
  human
  immunology
  opportunistic infection (drug therapy, etiology)
  toxic hepatitis (drug therapy, etiology)
CAS REGISTRY NUMBERS
  sargramostim (123774-72-1)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  25993145 (http://www.ncbi.nlm.nih.gov/pubmed/25993145)
PUI
  L612386001
DOI
  10.14694/EdBook_AM.2015.35.76
FULL TEXT LINK
  http://dx.doi.org/10.14694/EdBook_AM.2015.35.76
COPYRIGHT
  Copyright 2016 Medline is the source for the citation and abstract of this 
record.

RECORD 304
TITLE
  β-cell-targeted blockage of PD1 and CTLA4 pathways prevents development of 
autoimmune diabetes and acute allogeneic islets rejection
AUTHOR NAMES
  El Khatib M.M.
  Sakuma T.
  Tonne J.M.
  Mohamed M.S.
  Holditch S.J.
  Lu B.
  Kudva Y.C.
  Ikeda Y.
AUTHOR ADDRESSES
  (El Khatib M.M.; Sakuma T.; Tonne J.M.; Mohamed M.S.; Holditch S.J.; Lu B.; 
Ikeda Y., ikeda.yasuhiro@mayo.edu) Department of Molecular Medicine, Mayo 
Clinic College of Medicine, 200 First Street SW, Rochester, United States.
(Kudva Y.C.) Division of Endocrinology, Mayo Clinic College of Medicine, 
Rochester, United States.
CORRESPONDENCE ADDRESS
  Y. Ikeda, Department of Molecular Medicine, Mayo Clinic College of Medicine, 
200 First Street SW, Rochester, United States.
SOURCE
  Gene Therapy (2015) 22:5 (430-438). Date of Publication: 9 May 2015
ISSN
  1476-5462 (electronic)
  0969-7128
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  Protection of β 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 β-cell-targeted adeno-associated 
virus serotype 8 (AAV8)-based vectors to overexpress an artificial 
PDL1-CTLA4Ig polyprotein or interleukin 10 (IL10). β-Cell-targeted 
expression of PDL1-CTLA4Ig or IL10 preserved β-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 β-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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antidiabetic agent (drug development, drug therapy, pharmacology)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  cytotoxic T lymphocyte antigen 4 immunoglobulin programmed death 1 ligand 1 
(drug development, drug therapy, pharmacology)
  immunosuppressive agent (drug development, drug therapy, pharmacology)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  glucose (endogenous compound)
  interleukin 10 (pharmacology)
  major histocompatibility antigen
  parvovirus vector
  polyprotein
  programmed death 1 ligand 1 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  acute graft rejection (drug therapy, complication, drug therapy, prevention)
  autoimmune disease (drug therapy, drug therapy, prevention, therapy)
  insulin dependent diabetes mellitus (drug therapy, drug therapy, prevention, 
therapy)
  pancreas islet beta cell
EMTREE MEDICAL INDEX TERMS
  Adeno associated virus 8
  allotransplantation
  animal experiment
  animal model
  animal tissue
  antigen presentation
  article
  cell protection
  controlled study
  drug effect
  female
  gene expression
  gene therapy
  glucose blood level
  HEK293 cell line
  human
  human cell
  hyperglycemia
  immune response
  immunohistochemistry
  immunosuppressive treatment
  immunotherapy
  mouse
  nonhuman
  priority journal
  transgene
DRUG MANUFACTURERS
   (United States)GenScript
CAS REGISTRY NUMBERS
  glucose (50-99-7, 84778-64-3)
EMBASE CLASSIFICATIONS
  Human Genetics (22)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015849604
MEDLINE PMID
  25786871 (http://www.ncbi.nlm.nih.gov/pubmed/25786871)
PUI
  L603218655
DOI
  10.1038/gt.2015.18
FULL TEXT LINK
  http://dx.doi.org/10.1038/gt.2015.18
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 305
TITLE
  Late onset ipilimumab-induced pericarditis and pericardial effusion: A rare 
but life threatening complication
AUTHOR NAMES
  Yun S.
  Vincelette N.D.
  Mansour I.
  Hariri D.
  Motamed S.
AUTHOR ADDRESSES
  (Yun S., namaska97@gmail.com; Mansour I., iyadmansour@email.arizona.edu) 
Department of Medicine, University of Arizona, Tucson, United States.
(Vincelette N.D., vincelette.nicole@mayo.edu) Molecular Pharmacology and 
Experimental Therapeutics, Mayo Clinic, Rochester, United States.
(Hariri D., nonahey2@email.arizona.edu) Department of Pathology, University 
of Arizona, Tucson, United States.
(Motamed S., sara_mtd@yahool.com) Midwestern University, Arizona College of 
Osteopathic Medicine, Glendale, United States.
CORRESPONDENCE ADDRESS
  S. Yun, Department of Medicine, University of Arizona, Tucson, United 
States.
SOURCE
  Case Reports in Oncological Medicine (2015) 2015 Article Number: 794842. 
Date of Publication: 2015
ISSN
  2090-6714 (electronic)
  2090-6706
BOOK PUBLISHER
  Hindawi Publishing Corporation, 410 Park Avenue, 15th Floor, 287 pmb, New 
York, United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  budesonide (drug therapy)
  indometacin (drug therapy)
  methylprednisolone (drug therapy, intravenous drug administration)
  prednisone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  pericardial effusion (side effect, diagnosis, etiology, side effect, 
therapy)
  pericarditis (drug therapy, side effect, diagnosis, drug therapy, etiology, 
side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult
  article
  atelectasis
  case report
  clinical feature
  computed tomographic angiography
  computer assisted tomography
  cutaneous melanoma (drug therapy)
  diarrhea (side effect)
  disease severity
  drug megadose
  dyspnea
  electroencephalogram
  fatality
  human
  human tissue
  hypothyroidism (side effect)
  immunopathology
  inflammation
  inflammatory infiltrate
  infusion related reaction (side effect)
  lymphocyte count
  male
  metastasis
  middle aged
  multiple cycle treatment
  pleura effusion (diagnosis, side effect, therapy)
  priority journal
  rare disease
  rash (side effect)
  thoracocentesis
  thorax pain
  thorax radiography
  treatment outcome
CAS REGISTRY NUMBERS
  budesonide (51333-22-3, 51372-29-3)
  indometacin (53-86-1, 74252-25-8, 7681-54-1)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Cardiovascular Diseases and Cardiovascular Surgery (18)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015973326
PUI
  L603834042
DOI
  10.1155/2015/794842
FULL TEXT LINK
  http://dx.doi.org/10.1155/2015/794842
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 306
TITLE
  Immune checkpoint inhibition: Therapeutic implications in epithelial ovarian 
Cancer
AUTHOR NAMES
  Longoria T.C.
  Eskander R.N.
AUTHOR ADDRESSES
  (Longoria T.C.; Eskander R.N., Eskander@uci.edu) Division of Gynecologic 
Oncology, Department of Obstetrics and Gynecology, University of California, 
Irvine-Medical Center, Orange, United States.
CORRESPONDENCE ADDRESS
  R.N. Eskander, 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, United States. Email: 
Eskander@uci.edu
SOURCE
  Recent Patents on Anti-Cancer Drug Discovery (2015) 10:2 (133-144). Date of 
Publication: 2015
ISSN
  2212-3970 (electronic)
  1574-8928
BOOK PUBLISHER
  Bentham Science Publishers B.V., P.O. Box 294, Bussum, Netherlands.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immune checkpoint inhibitor (drug therapy)
  immunomodulating agent (drug therapy)
EMTREE DRUG INDEX TERMS
  adenosine A2a receptor (endogenous compound)
  azacitidine (drug therapy)
  bavituximab (drug therapy)
  bms 936559 (drug therapy)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody (drug therapy)
  dacarbazine (drug therapy)
  entinostat (drug therapy)
  ipilimumab (drug therapy)
  killer cell immunoglobulin like receptor (endogenous compound)
  nivolumab (drug therapy)
  pembrolizumab (drug therapy)
  programmed death 1 receptor (endogenous compound)
  programmed death 1 receptor antibody (drug therapy)
  ticilimumab (drug therapy)
  unclassified drug
  V set domain containing T cell activation inhibitor 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary carcinoma (drug therapy, drug therapy)
  tumor immunity
EMTREE MEDICAL INDEX TERMS
  algorithm
  antineoplastic activity
  article
  cancer cell
  clinical trial (topic)
  drug targeting
  gene
  gene targeting
  human
  immune response
  immunogenicity
  immunosuppressive treatment
  immunosurveillance
  lymphocyte activation gene 3
  meta analysis (topic)
  nonhuman
  patent
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  protein protein interaction
  randomized controlled trial (topic)
  treatment response
  tumor growth
DRUG MANUFACTURERS
  Amplimmune
  Brigham and Womens Hospital
  Bristol Meyers Squibb
  Cellerant Therapeutics
  Innate
  Inserm
  Medarex
  Merck
  Novo Nordisk
  Organon
  Universite De La Mediterranee
CAS REGISTRY NUMBERS
  azacitidine (320-67-2, 52934-49-3)
  bavituximab (648904-28-3)
  dacarbazine (4342-03-4)
  entinostat (209783-80-2)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01295827, NCT01611558, NCT01928576, NCT01975831)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015124942
MEDLINE PMID
  25938471 (http://www.ncbi.nlm.nih.gov/pubmed/25938471)
PUI
  L604847734
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 307
TITLE
  Isolation and validation of anti-B7-H4 scFvs from an ovarian cancer scFv 
yeast-display library
AUTHOR NAMES
  Dangaj D.
  Scholler N.
AUTHOR ADDRESSES
  (Dangaj D.; Scholler N.)
SOURCE
  Methods in Molecular Biology (2015) 1319 (37-49). Date of Publication: 2015
ISSN
  1064-3745
BOOK PUBLISHER
  Humana Press Inc., humana@humanapr.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  V set domain containing T cell activation inhibitor 1
EMTREE DRUG INDEX TERMS
  recombinant antibody
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  antigen binding
  antineoplastic activity
  article
  cancer patient
  cell screening
  controlled study
  drug inhibition
  drug isolation
  human
  human cell
  nonhuman
  priority journal
  validation study
  yeast
DRUG TRADE NAMES
  b 7h 4
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015122739
MEDLINE PMID
  26060068 (http://www.ncbi.nlm.nih.gov/pubmed/26060068)
PUI
  L604778577
DOI
  10.1007/978-1-4939-2748-7_2
FULL TEXT LINK
  http://dx.doi.org/10.1007/978-1-4939-2748-7_2
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 308
TITLE
  Ipilimumab-induced necrotic myelopathy in a patient with metastatic 
melanoma: A case report and review of literature
AUTHOR NAMES
  Abdallah A.-O.
  Herlopian A.
  Ravilla R.
  Bansal M.
  Chandra-Reddy S.
  Mahmoud F.
  Ong S.
  Gokden M.
  Hutchins L.
AUTHOR ADDRESSES
  (Abdallah A.-O.; Bansal M.; Mahmoud F.; Hutchins L., 
HutchinsLauraF@uams.edu) Department of Internal Medicine, Division of 
Hematology and Oncology, University of Arkansas for Medical Sciences (UAMS), 
4301, West Markham St., Little Rock, United States.
(Herlopian A.; Ong S.) Department of Internal Medicine, Division of 
Neurology, University of Arkansas for Medical Sciences (UAMS), Little Rock, 
United States.
(Ravilla R.; Chandra-Reddy S.) Department of Internal Medicine, University 
of Arkansas for Medical Sciences (UAMS), Little Rock, United States.
(Gokden M.) Department of Pathology, University of Arkansas for Medical 
Sciences (UAMS), Little Rock, United States.
CORRESPONDENCE ADDRESS
  L. Hutchins, Department of Internal Medicine, Division of Hematology and 
Oncology, University of Arkansas for Medical Sciences (UAMS), 4301, West 
Markham St., Little Rock, United States. Email: HutchinsLauraF@uams.edu
SOURCE
  Journal of Oncology Pharmacy Practice (2015) 22:3 (537-542). Date of 
Publication: 2015
ISSN
  1477-092X (electronic)
  1078-1552
BOOK PUBLISHER
  SAGE Publications Ltd, info@sagepub.co.uk
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  dexamethasone (drug therapy, intravenous drug administration, oral drug 
administration)
  infliximab (drug therapy, intravenous drug administration)
  prednisone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
  necrotic myelopathy (drug therapy, side effect, drug therapy, side effect)
  spinal cord disease (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aseptic meningitis (side effect)
  cancer patient
  case report
  disease severity
  drug withdrawal
  female
  Guillain Barre syndrome (side effect)
  human
  human tissue
  immunohistochemistry
  meningo radiculo neuritis
  meningo radiculo neuritis (side effect)
  middle aged
  multiple cycle treatment
  myositis (side effect)
  neuritis (side effect)
  posterior reversible encephalopathy syndrome (side effect)
  priority journal
  review
  temporal arteritis (side effect)
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160327470
PUI
  L610084559
DOI
  10.1177/1078155215572932
FULL TEXT LINK
  http://dx.doi.org/10.1177/1078155215572932
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 309
TITLE
  A novel melanoma therapy stirs up a storm: Ipilimumab-induced thyrotoxicosis
AUTHOR NAMES
  Yu C.
  Chopra I.J.
  Ha E.
AUTHOR ADDRESSES
  (Yu C., Christineyu@mednet.ucla.edu; Ha E.) Department of Medicine, 
University of California, 757 Westwood Plaza Blvd, Suite 7501, Los Angeles, 
United States.
(Chopra I.J.) Division of Endocrinology, Department of Medicine, University 
of California, 757 Westwood Plaza Blvd, Suite 7501, Los Angeles, United 
States.
CORRESPONDENCE ADDRESS
  C. Yu, Department of Medicine, University of California, 757 Westwood Plaza 
Blvd, Suite 7501, Los Angeles, United States.
SOURCE
  Endocrinology, Diabetes and Metabolism Case Reports (2015) 2015. Date of 
Publication: 2015
ISSN
  2052-0573 (electronic)
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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 µIU/ml (normal 
0.3–4.7); free tri-iodothyronine (T(3)) was markedly elevated at 1031 pg/dl 
(normal 249–405), as was free thyroxine (T(4)) 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 T(3) 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 T(4)-to-T(3) conversion.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  calcium (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  iopanoic acid (drug therapy)
  liothyronine (endogenous compound)
  monoclonal antibody
  thiamazole (drug therapy)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
  thyrotoxicosis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  aged
  anorexia
  article
  atrial fibrillation
  case report
  computed tomographic angiography
  computer assisted tomography
  diarrhea
  electrocardiography
  emergency ward
  fatigue
  female
  follow up
  functional status
  goiter
  hospital discharge
  human
  hypertension
  leukocyte count
  priority journal
  pulse pressure
  supraventricular tachycardia
  thorax pain
  thyroid function test
  treatment outcome
  very elderly
CAS REGISTRY NUMBERS
  calcium (7440-70-2, 14092-94-5)
  iopanoic acid (96-83-3)
  ipilimumab (477202-00-9)
  liothyronine (6138-47-2, 6893-02-3)
  thiamazole (60-56-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015751626
PUI
  L602239833
DOI
  10.1530/EDM-14-0092
FULL TEXT LINK
  http://dx.doi.org/10.1530/EDM-14-0092
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 310
TITLE
  Recurrent genomic rearrangements in primary testicular lymphoma
AUTHOR NAMES
  Twa D.D.W.
  Mottok A.
  Chan F.C.
  Ben-Neriah S.
  Woolcock B.W.
  Tan K.L.
  Mungall A.J.
  McDonald H.
  Zhao Y.
  Lim R.S.
  Nelson B.H.
  Milne K.
  Shah S.P.
  Morin R.D.
  Marra M.A.
  Scott D.W.
  Gascoyne R.D.
  Steidl C.
AUTHOR ADDRESSES
  (Twa D.D.W.; Mottok A.; Chan F.C.; Ben-Neriah S.; Woolcock B.W.; Tan K.L.; 
Mungall A.J.; Lim R.S.; Shah S.P.; Morin R.D.; Marra M.A.; Scott D.W.; 
Gascoyne R.D.; Steidl C., csteidl@bccancer.bc.ca) Department of Lymphoid 
Cancer Research, BC Cancer Research Centre, BC Cancer Agency, Vancouver, 
Canada.
(Twa D.D.W.; Mottok A.; Gascoyne R.D.; Steidl C., csteidl@bccancer.bc.ca) 
Department of Pathology and Laboratory Medicine, University of British 
Columbia, Vancouver, Canada.
(Chan F.C.) Bioinformatics Training Programme, University of British 
Columbia, Vancouver, Canada.
(McDonald H.; Zhao Y.; Marra M.A.) Canada's Michael Smith Genome Sciences 
Centre, BC Cancer Agency, Vancouver, Canada.
(Nelson B.H.; Milne K.) Deeley Research Centre, BC Cancer Agency, Victoria, 
Canada.
(Nelson B.H.) Department of Medical Genetics, University of British 
Columbia, Vancouver, Canada.
(Morin R.D.) Department of Molecular Biology and Biochemistry, Simon Fraser 
University, Vancouver, Canada.
CORRESPONDENCE ADDRESS
  C. Steidl, Department of Lymphoid Cancer Research, BC Cancer Research 
Centre, BC Cancer Agency, Vancouver, Canada.
SOURCE
  Journal of Pathology (2015) 236:2 (136-141). Date of Publication: 1 Jun 2015
ISSN
  1096-9896 (electronic)
  0022-3417
BOOK PUBLISHER
  John Wiley and Sons Ltd, Southern Gate, Chichester, West Sussex, United 
Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  BRM protein (endogenous compound)
  formaldehyde
  paraffin
  transcription factor (endogenous compound)
  transcription factor FOXP1 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gene rearrangement
  genomics
  large cell lymphoma (etiology)
  primary testicular diffuse large b cell lymphoma (etiology)
  testis cancer (etiology)
EMTREE MEDICAL INDEX TERMS
  article
  B cell lymphoma
  bacterial artificial chromosome
  controlled study
  fluorescence in situ hybridization
  immunohistochemistry
  intron
  priority journal
  protein expression
CAS REGISTRY NUMBERS
  formaldehyde (50-00-0)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Hematology (25)
  Urology and Nephrology (28)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015910990
MEDLINE PMID
  25712539 (http://www.ncbi.nlm.nih.gov/pubmed/25712539)
PUI
  L603686266
DOI
  10.1002/path.4522
FULL TEXT LINK
  http://dx.doi.org/10.1002/path.4522
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 311
TITLE
  Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors
AUTHOR NAMES
  De Felice F.
  Marchetti C.
  Palaia I.
  Musio D.
  Muzii L.
  Tombolini V.
  Panici P.B.
AUTHOR ADDRESSES
  (De Felice F., fradefelice@hotmail.it; Musio D., daniela.musio@libero.it; 
Tombolini V., vincenzo.tombolini@uniroma1.it) Department of Radiotherapy, 
Policlinico Umberto i, Sapienza University of Rome, Viale Regina Elena 326, 
Rome, Italy.
(Marchetti C., clamarchetti@libero.it; Palaia I., 
innocenza.palaia@uniroma1.it; Muzii L., ludovico.muzii@uniroma1.it; Panici 
P.B., pierluigi.benedettipanici@uniroma1.it) Department of Gynecological and 
Obstetrical Sciences and Urological Sciences, Sapienza University of Rome, 
Viale del Policlinico 155, Rome, Italy.
CORRESPONDENCE ADDRESS
  C. Marchetti, Department of Gynecological and Obstetrical Sciences and 
Urological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 
Rome, Italy.
SOURCE
  Journal of Immunology Research (2015) 2015 Article Number: 191832. Date of 
Publication: 2015
ISSN
  2314-7156 (electronic)
  2314-8861
BOOK PUBLISHER
  Hindawi Publishing Corporation, 410 Park Avenue, 15th Floor, 287 pmb, New 
York, United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immunomodulating agent (clinical trial, drug therapy, pharmacology)
EMTREE DRUG INDEX TERMS
  avelumab (adverse drug reaction, clinical trial, drug therapy, pharmacology)
  bms 936559 (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  durvalumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  mpdl 33280a (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  nivolumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  ticilimumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer (drug therapy, drug therapy, surgery)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  anorexia (side effect)
  cancer cell
  clinical practice
  colitis (side effect)
  diarrhea (side effect)
  drug targeting
  effector cell
  endocrine disease (side effect)
  fatigue (side effect)
  female
  hepatitis (side effect)
  human
  hyperglycemia (side effect)
  hypertransaminasemia (side effect)
  hypophysitis (side effect)
  kidney failure (side effect)
  lymphocytopenia (side effect)
  melanoma
  myasthenia gravis (side effect)
  myocarditis (side effect)
  myositis (side effect)
  nausea (side effect)
  pericardial effusion (side effect)
  pneumonia (side effect)
  rash (side effect)
  review
  survival rate
  thyroid disease (side effect)
  vomiting (side effect)
DRUG TRADE NAMES
  bms 936559
  medi 4736
  mpdl 33280a
  msb 0010718c
CAS REGISTRY NUMBERS
  durvalumab (1428935-60-7)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015221182
MEDLINE PMID
  26236750 (http://www.ncbi.nlm.nih.gov/pubmed/26236750)
PUI
  L605263407
DOI
  10.1155/2015/191832
FULL TEXT LINK
  http://dx.doi.org/10.1155/2015/191832
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 312
TITLE
  Parathyroid Hormone-Related Peptide-Linked Hypercalcemia in a Melanoma 
Patient Treated with Ipilimumab: Hormone Source and Clinical and Metabolic 
Correlates
AUTHOR NAMES
  Mills T.A.
  Orloff M.
  Domingo-Vidal M.
  Cotzia P.
  Birbe R.C.
  Draganova-Tacheva R.
  Martinez Cantarin M.P.
  Tuluc M.
  Martinez-Outschoorn U.
AUTHOR ADDRESSES
  (Mills T.A.) Sidney Kimmel College of Medicine, Thomas Jefferson University, 
Philadelphia, United States.
(Orloff M.; Domingo-Vidal M.; Martinez-Outschoorn U., 
ubaldo.martinezoutschoorn@jefferson.edu) Department of Medical Oncology, 
Thomas Jefferson University, 233 S 10th St, Philadelphia, United States.
(Cotzia P.; Birbe R.C.; Draganova-Tacheva R.; Tuluc M.) Department of 
Pathology, Thomas Jefferson University, Philadelphia, United States.
(Martinez Cantarin M.P.) Department of Medicine, Thomas Jefferson 
University, Philadelphia, United States.
CORRESPONDENCE ADDRESS
  U. Martinez-Outschoorn, Department of Medical Oncology, Thomas Jefferson 
University, 233 S 10th St, Philadelphia, United States. Email: 
ubaldo.martinezoutschoorn@jefferson.edu
SOURCE
  Seminars in Oncology (2015) 42:6 (909-914). Date of Publication: 2015
ISSN
  1532-8708 (electronic)
  0093-7754
BOOK PUBLISHER
  W.B. Saunders
ABSTRACT
  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 (β-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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
  parathyroid hormone related protein (endogenous compound)
EMTREE DRUG INDEX TERMS
  beta galactosidase (endogenous compound)
  calcitonin (drug therapy)
  calcium (endogenous compound)
  denosumab (drug therapy)
  ketone body (endogenous compound)
  lactic acid (endogenous compound)
  monocarboxylate transporter 1 (endogenous compound)
  zoledronic acid (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypercalcemia (drug therapy, side effect, drug therapy, etiology, side 
effect)
  metastatic melanoma (drug therapy, drug therapy, radiotherapy)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cachexia
  calcium blood level
  cancer of unknown primary site
  cancer radiotherapy
  case report
  computer assisted tomography
  controlled study
  erythema
  female
  human
  human tissue
  immunohistochemistry
  leg pain
  lymphadenopathy
  melanoma cell
  middle aged
  mitochondrial respiration
  positron emission tomography
  priority journal
  protein expression
  subcutaneous nodule
  swelling
  tumor biopsy
CAS REGISTRY NUMBERS
  beta galactosidase ()
  calcitonin (12321-44-7, 21215-62-3, 9007-12-9)
  calcium (7440-70-2, 14092-94-5)
  denosumab (615258-40-7)
  ipilimumab (477202-00-9)
  lactic acid (113-21-3, 50-21-5)
  zoledronic acid (118072-93-8, 131654-46-1, 165800-06-6, 165800-07-7)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Radiology (14)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  20160255072
MEDLINE PMID
  26615135 (http://www.ncbi.nlm.nih.gov/pubmed/26615135)
PUI
  L609351356
DOI
  10.1053/j.seminoncol.2015.09.006
FULL TEXT LINK
  http://dx.doi.org/10.1053/j.seminoncol.2015.09.006
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 313
TITLE
  Pharmacotherapy for recurrent ovarian cancer: Current status and future 
perspectives
AUTHOR NAMES
  Matsumoto K.
  Onda T.
  Yaegashi N.
AUTHOR ADDRESSES
  (Matsumoto K., kojmatsu@hp.pref.hyogo.jp) Division of Medical Oncology, 
Hyogo Cancer Center, Akashi, Japan.
(Onda T.) Division of Gynecology and Obstetrics, Kitasato University, 
Sagamihara, Japan.
(Yaegashi N.) Division of Gynecology and Obstetrics, Tohoku University, 
Sendai, Japan.
CORRESPONDENCE ADDRESS
  K. Matsumoto, 13-70, Kitaoji-cho, Akashi, Hyogo, Japan.
SOURCE
  Japanese Journal of Clinical Oncology (2015) 45:5 (408-410) Article Number: 
hyv014. Date of Publication: 1 May 2015
ISSN
  1465-3621 (electronic)
  0368-2811
BOOK PUBLISHER
  Oxford University Press, jnl.info@oup.co.uk
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (drug therapy)
EMTREE DRUG INDEX TERMS
  bevacizumab (drug therapy)
  canfosfamide (drug therapy)
  cediranib (drug therapy)
  cytotoxic agent (drug therapy)
  doxorubicin (drug therapy)
  everolimus (drug therapy)
  farletuzumab (drug therapy)
  folic acid antagonist (drug therapy)
  gemcitabine (drug therapy)
  mammalian target of rapamycin inhibitor (drug therapy)
  monoclonal antibody (drug therapy)
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
inhibitor (drug therapy)
  nivolmab (drug therapy)
  nivolumab (drug therapy)
  olaparib (drug therapy)
  paclitaxel (drug therapy)
  pazopanib (drug therapy)
  temsirolimus (drug therapy)
  topotecan (drug therapy)
  trabectedin (drug therapy)
  trebananib (drug therapy)
  treosulfan (drug therapy)
  unclassified drug
  veliparib (drug therapy)
  vintafolide (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer chemotherapy
  cancer recurrence
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  antiangiogenic therapy
  cancer combination chemotherapy
  cancer resistance
  drug efficacy
  human
  monotherapy
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  randomized controlled trial (topic)
  review
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  canfosfamide (158382-37-7, 439943-59-6)
  cediranib (288383-20-0, 857036-77-2)
  doxorubicin (23214-92-8, 25316-40-9)
  everolimus (159351-69-6)
  farletuzumab (896723-44-7)
  gemcitabine (103882-84-4)
  nivolumab (946414-94-4)
  olaparib (763113-22-0)
  paclitaxel (33069-62-4)
  pazopanib (444731-52-6, 635702-64-6)
  temsirolimus (162635-04-3, 343261-52-9)
  topotecan (119413-54-6, 123948-87-8)
  trabectedin (114899-77-3)
  trebananib (894356-79-7)
  treosulfan (21106-06-9, 299-75-2)
  veliparib (912444-00-9)
  vintafolide (742092-03-1, 913082-11-8, 926623-17-8)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01196429)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015017417
MEDLINE PMID
  25765457 (http://www.ncbi.nlm.nih.gov/pubmed/25765457)
PUI
  L604271921
DOI
  10.1093/jjco/hyv014
FULL TEXT LINK
  http://dx.doi.org/10.1093/jjco/hyv014
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 314
TITLE
  A case report of orbital inflammatory syndrome secondary to ipilimumab
AUTHOR NAMES
  Henderson A.D.
  Thomas D.A.
AUTHOR ADDRESSES
  (Henderson A.D., amhenderson@gru.edu; Thomas D.A.) Department of 
Ophthalmology, Georgia Regents University, 1120 15th Street, Augusta, United 
States.
CORRESPONDENCE ADDRESS
  A.D. Henderson, Department of Ophthalmology, Georgia Regents University, 
1120 15th Street, Augusta, United States. Email: amhenderson@gru.edu
SOURCE
  Ophthalmic Plastic and Reconstructive Surgery (2015) 31:3 (e68-e70). Date of 
Publication: 2015
ISSN
  1537-2677 (electronic)
  0740-9303
BOOK PUBLISHER
  Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  levothyroxine (drug therapy)
  phenylephrine
  prednisone (drug therapy, oral drug administration)
  steroid (drug therapy, oral drug administration, topical drug 
administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  orbit inflammation (side effect, diagnosis, etiology, side effect)
  orbital inflammatory syndrome (side effect, diagnosis, etiology, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (complication, drug therapy)
  adult
  article
  axillary lymph node
  blepharitis (side effect)
  cancer adjuvant therapy
  cancer recurrence
  cancer staging
  case report
  chemosis (side effect)
  clinical examination
  clinical trial (topic)
  diplopia (side effect)
  epiphora (side effect)
  episcleritis (drug therapy)
  exophthalmos (side effect)
  extraocular muscle
  eye burning (side effect)
  eye movement disorder (side effect)
  gaze
  headache (drug therapy, side effect)
  human
  hypophysitis (side effect)
  hypothyroidism (drug therapy, side effect)
  lymph node dissection
  lymph node metastasis (surgery)
  male
  metastatic melanoma (drug therapy)
  middle aged
  multiple cycle treatment
  nuclear magnetic resonance imaging
  periorbital edema (side effect)
  photophobia (side effect)
  priority journal
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  phenylephrine (532-38-7, 59-42-7, 61-76-7)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014712957
MEDLINE PMID
  24814274 (http://www.ncbi.nlm.nih.gov/pubmed/24814274)
PUI
  L53130931
DOI
  10.1097/IOP.0000000000000081
FULL TEXT LINK
  http://dx.doi.org/10.1097/IOP.0000000000000081
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 315
TITLE
  Programmed death ligand 1 on Burkholderia pseudomallei-infected human 
polymorphonuclear neutrophils impairs T cell functions
AUTHOR NAMES
  Buddhisa S.
  Rinchai D.
  Ato M.
  Bancroft G.J.
  Lertmemongkolchai G.
AUTHOR ADDRESSES
  (Buddhisa S.; Rinchai D.; Lertmemongkolchai G., ganja_le@kku.ac.th) Centre 
for Research and Development of Medical Diagnostic Laboratories, Faculty of 
Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
(Ato M.) Department of Immunology, National Institute of Infectious 
Diseases, Tokyo, Japan.
(Bancroft G.J.) Department of Immunology and Infection, London School of 
Hygiene and Tropical Medicine, London, United Kingdom.
CORRESPONDENCE ADDRESS
  G. Lertmemongkolchai, Centre for Research and Development of Medical 
Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen 
University, Khon Kaen, Thailand.
SOURCE
  Journal of Immunology (2015) 194:9 (4413-4421). Date of Publication: 1 May 
2015
ISSN
  1550-6606 (electronic)
  0022-1767
BOOK PUBLISHER
  American Association of Immunologists, 9650 Rockville Pike, Bethesda, United 
States.
ABSTRACT
  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<sup>+</sup> T cell proliferation 
and IFN-γ 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<sup>+</sup> T cells and IFN-γ 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  gamma interferon (endogenous compound)
  messenger RNA (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  Burkholderia pseudomallei
  CD4+ T lymphocyte
  host pathogen interaction
  lymphocyte function
  melioidosis (etiology)
  neutrophil
EMTREE MEDICAL INDEX TERMS
  article
  cell interaction
  cellular distribution
  controlled study
  correlational study
  cytokine production
  human
  human cell
  immune deficiency
  non insulin dependent diabetes mellitus
  nonhuman
  pathogenesis
  priority journal
  protein expression
  protein function
  protein localization
  risk assessment
  upregulation
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Microbiology: Bacteriology, Mycology, Parasitology and Virology (4)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015978193
MEDLINE PMID
  25801435 (http://www.ncbi.nlm.nih.gov/pubmed/25801435)
PUI
  L604038248
DOI
  10.4049/jimmunol.1402417
FULL TEXT LINK
  http://dx.doi.org/10.4049/jimmunol.1402417
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 316
TITLE
  Adjuvant ipilimumab versus placebo after complete resection of high-risk 
stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial
AUTHOR NAMES
  Eggermont A.M.M.
  Chiarion-Sileni V.
  Grob J.-J.
  Dummer R.
  Wolchok J.D.
  Schmidt H.
  Hamid O.
  Robert C.
  Ascierto P.A.
  Richards J.M.
  Lebbé C.
  Ferraresi V.
  Smylie M.
  Weber J.S.
  Maio M.
  Konto C.
  Hoos A.
  de Pril V.
  Gurunath R.K.
  de Schaetzen G.
  Suciu S.
  Testori A.
AUTHOR ADDRESSES
  (Eggermont A.M.M., alexander.eggermont@gustaveroussy.fr; Robert C.) Gustave 
Roussy Cancer Campus Grand Paris, Villejuif, France.
(Chiarion-Sileni V.) IOV-IRCCS, Melanoma Oncology Unit, Padova, Italy.
(Grob J.-J.) Aix-Marseille University, Hôpital de La Timone APHM, Marseille, 
France.
(Dummer R.) University of Zürich Hospital, Zürich, Switzerland.
(Wolchok J.D.) Memorial Sloan-Kettering Cancer Center, New York, United 
States.
(Schmidt H.) Aarhus University Hospital, Aarhus, Denmark.
(Hamid O.) The Angeles Clinic and Research Institute, Los Angeles, United 
States.
(Ascierto P.A.) Istituto Nazionale Tumori Fondazione G Pascale, Naples, 
Italy.
(Richards J.M.) Oncology Specialists SC, Park Ridge, United States.
(Lebbé C.) Assistance Publique Hôpitaux de Paris, Dermatology and CIC 
Departments, Hôpital Saint Louis, University Paris 7, INSERM U976, France.
(Ferraresi V.) Istituti Fisioterapici Ospitalieri, Rome, Italy.
(Smylie M.) Cross Cancer Institute, Edmonton, Canada.
(Weber J.S.) H Lee Moffitt Cancer Center, Tampa, United States.
(Maio M.) University Hospital of Siena, Istituto Toscano Tumori, Siena, 
Italy.
(Konto C.; Hoos A.) Bristol-Myers Squibb, Wallingford, United States.
(de Pril V.) Bristol-Myers Squibb, Braine-l'Alleud, Belgium.
(Gurunath R.K.; de Schaetzen G.; Suciu S.) EORTC Headquarters, Brussels, 
Belgium.
(Testori A.) European Institute of Oncology, Milan, Italy.
CORRESPONDENCE ADDRESS
  A.M.M. Eggermont, Gustave Roussy Cancer Campus Grand Paris, University 
Paris-Sud, 114 Rue Edouard Vaillant, Villejuif, France. Email: 
alexander.eggermont@gustaveroussy.fr
SOURCE
  The Lancet Oncology (2015) 16:5 (522-530). Date of Publication: 2015
ISSN
  1474-5488 (electronic)
  1470-2045
BOOK PUBLISHER
  Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
  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. 
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. 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-Barré syndrome. 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. Funding: Bristol-Myers Squibb.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug comparison - 
placebo, drug therapy, intravenous drug administration)
EMTREE DRUG INDEX TERMS
  corticosteroid (drug therapy)
  placebo
  tumor necrosis factor antibody (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cutaneous melanoma (drug therapy, drug therapy, surgery)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adjuvant therapy
  adult
  aged
  article
  body weight gain
  body weight loss
  cancer staging
  controlled study
  coughing (side effect)
  decreased appetite (side effect)
  diarrhea (side effect)
  digestive system perforation (side effect)
  distant metastasis free survival
  double blind procedure
  drug fatality (side effect)
  drug safety
  drug withdrawal
  endocrine disease (side effect)
  fatigue (side effect)
  female
  fever (side effect)
  follow up
  gastrointestinal disease (side effect)
  headache (side effect)
  high risk patient
  human
  hypertransaminasemia (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  immunopathology (side effect)
  intention to treat analysis
  interactive voice response system
  liver disease (side effect)
  lymph node dissection
  lymph node metastasis (complication, prevention, surgery)
  major clinical study
  male
  melanoma (drug therapy)
  multicenter study
  multiple cycle treatment
  multiple organ failure (side effect)
  myocarditis (side effect)
  nausea (side effect)
  neurologic disease (side effect)
  overall survival
  patient compliance
  phase 3 clinical trial
  priority journal
  pruritus (side effect)
  quality of life
  randomized controlled trial
  rash (side effect)
  recurrence free survival
  recurrence risk
  risk benefit analysis
  side effect (side effect)
  skin surgery
  treatment outcome
  ulcerative colitis (side effect)
  vomiting (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  tumor necrosis factor antibody (162774-06-3)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00636168, NCT01274338)
  EudraCT (2007-001974-10)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015877654
MEDLINE PMID
  25840693 (http://www.ncbi.nlm.nih.gov/pubmed/25840693)
PUI
  L603506652
DOI
  10.1016/S1470-2045(15)70122-1
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(15)70122-1
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 317
TITLE
  Biotherapy for neuroendocrine tumours
AUTHOR NAMES
  Alonso-Gordoa T.
  Capdevila J.
  Grande E.
AUTHOR ADDRESSES
  (Alonso-Gordoa T.; Grande E., egrande@oncologiahrc.com) Medical Oncology 
Department, Ramón y Cajal University Hospital, Carretera de Colmenar, 100, 
Madrid, Spain.
(Capdevila J.) Medical Oncology Department, Vall d'Hebrón University 
Hospital, Passeig de la Vall d'Hebrón, 119-129, Barcelona, Spain.
CORRESPONDENCE ADDRESS
  E. Grande, Medical Oncology Department, Ramón y Cajal University Hospital, 
Carretera de Colmenar, 100, Madrid, Spain.
SOURCE
  European Journal of Endocrinology (2015) 172:1 (R31-R46). Date of 
Publication: 1 Jan 2015
ISSN
  1479-683X (electronic)
  0804-4643
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  albinterferon alpha2b (clinical trial, drug comparison, drug therapy)
  alpha interferon (endogenous compound)
  angiogenesis inhibitor
  angiopeptin (clinical trial, drug therapy)
  axitinib (clinical trial, drug combination, drug therapy)
  bevacizumab (clinical trial, drug combination, drug comparison, drug 
therapy)
  cixutumumab (clinical trial, drug combination, drug therapy)
  corticotropin
  dopamine receptor (endogenous compound)
  everolimus (clinical trial, drug combination, drug therapy)
  G protein coupled somatostatin receptor (endogenous compound)
  mammalian target of rapamycin inhibitor
  octreotide (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy, pharmaceutics, pharmacokinetics, pharmacology, 
subcutaneous drug administration)
  pasireotide (clinical trial, drug therapy, pharmacology)
  pertuzumab (clinical trial, drug combination, drug therapy)
  placebo
  somatostatin derivative (drug therapy, pharmacokinetics, pharmacology)
  somatostatin receptor (endogenous compound)
  somatostatin receptor 1 (endogenous compound)
  somatostatin receptor 2 (endogenous compound)
  somatostatin receptor 3 (endogenous compound)
  somatostatin receptor 4 (endogenous compound)
  somatostatin receptor 5 (endogenous compound)
  telotristat etiprate (clinical trial, drug comparison - placebo, drug 
therapy)
  thyrotropin
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  neuroendocrine tumor (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  angiogenesis
  carcinoid (drug therapy)
  carcinoid syndrome (drug therapy)
  cell survival
  cholelithiasis (drug therapy)
  drug approval
  drug binding
  drug dose increase
  drug half life
  drug megadose
  drug protein binding
  drug release
  drug safety
  drug tolerability
  gastrinoma (drug therapy)
  gastroenteropancreatic neuroendocrine tumor (drug therapy)
  gastrointestinal symptom (side effect)
  glucagonoma (drug therapy)
  hormone blood level
  human
  hypophysis adenoma
  immune system
  immunomodulation
  immunotherapy
  injection site pain (side effect)
  insulinoma (drug therapy)
  lung neuroendocrine tumor (drug therapy)
  lung neuroendocrine tumor (drug therapy)
  medulloblastoma
  meningioma
  neuroblastoma
  pancreas islet cell tumor (drug therapy)
  paraganglioma
  patient selection
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  phase 4 clinical trial (topic)
  pheochromocytoma
  review
  somatotrophinoma
  tumor growth
  Verner Morrison syndrome (drug therapy)
DRUG TRADE NAMES
  lx 1606
  som 230
CAS REGISTRY NUMBERS
  albinterferon alpha2b (472960-22-8)
  angiopeptin (113294-82-9)
  axitinib (319460-85-0)
  bevacizumab (216974-75-3)
  cixutumumab (947687-12-9)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  everolimus (159351-69-6)
  octreotide (83150-76-9)
  pasireotide (396091-73-9)
  somatostatin receptor 1 (340766-72-5)
  telotristat etiprate (1137608-69-5)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00569127, NCT00781911, NCT01121939, NCT01204476, NCT01229943, NCT01364415, NCT01374451, NCT01744249)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015651237
MEDLINE PMID
  25430657 (http://www.ncbi.nlm.nih.gov/pubmed/25430657)
PUI
  L601137136
DOI
  10.1530/EJE-14-0354
FULL TEXT LINK
  http://dx.doi.org/10.1530/EJE-14-0354
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 318
TITLE
  Diffuse high intensity PD-L1 staining in thymic epithelial tumors
AUTHOR NAMES
  Padda S.K.
  Riess J.W.
  Schwartz E.J.
  Tian L.
  Kohrt H.E.
  Neal J.W.
  West R.B.
  Wakelee H.A.
AUTHOR ADDRESSES
  (Padda S.K.; Kohrt H.E.; Neal J.W.; Wakelee H.A., hwakelee@stanford.edu) 
Department of Internal Medicine, Stanford Cancer Institute, Stanford 
University, Stanford, United States.
(Riess J.W.) Department of Internal Medicine, University of California 
Davis, Comprehensive Cancer Center, Sacramento, United States.
(Schwartz E.J.; West R.B.) Department of Pathology, Stanford Cancer 
Institute, Stanford University, Stanford, United States.
(Tian L.) Department of Health and Research Policy, Stanford University, 
School of Medicine, Stanford, United States.
CORRESPONDENCE ADDRESS
  H.A. Wakelee, 875 Blake Wilbur Drive, Stanford, United States.
SOURCE
  Journal of Thoracic Oncology (2015) 10:3 (500-508). Date of Publication: 30 
Mar 2015
ISSN
  1556-1380 (electronic)
  1556-0864
BOOK PUBLISHER
  Lippincott Williams and Wilkins, agents@lww.com
ABSTRACT
  Introduction: Blockade of the immune checkpoint programmed death receptor 
ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across 
many tumor types. PD-L1 protein expression by immunohistochemistry is 
emerging as a predictive biomarker of response to these therapies. Here, we 
examine PD-L1 expression in a thymic epithelial tumor (TET) tissue 
microarray (TMA). Methods: The TMA contained 69 TETs and 17 thymic controls, 
with each case represented by triplicate cores. The TMA was stained with 
rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to 
human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = 
none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. 
Those cases with all cores scoring three in the epithelial component were 
categorized as PD-L1<sup>high</sup> and the remaining as 
PD-L1<sup>low</sup>. Results: PD-L1<sup>high</sup> scores were more frequent 
in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and 
histology were significantly correlated, with higher intensity staining in 
World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 
staining of associated lymphocytes. In an adjusted analysis (age/sex), 
PD-L1<sup>high</sup> TETs had a significantly worse overall survival (hazard 
ratio: 5.40, 95% confidence interval: 1.13-25.89; p = 0.035) and a trend for 
worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 
0.94-9.24; p = 0.064). Conclusions: PD-L1 expression was present in all 
cases of TETs within the epithelial component but only in a minority in the 
lymphocytic component. TETs stained more intensely for PD-L1 than in 
controls, and PD-L1<sup>high</sup> TETs were associated with more aggressive 
histology and worse prognosis. This study lends rationale to a clinical 
trial with anti-PD-1/PD-L1 therapy in this rare tumor type.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  epithelium tumor
  thymic epithelial tumor
  thymoma
EMTREE MEDICAL INDEX TERMS
  adolescent
  adult
  aged
  article
  child
  controlled study
  correlational study
  event free survival
  female
  histopathology
  human
  human tissue
  lymphocyte
  major clinical study
  male
  medical examination
  overall survival
  priority journal
  protein expression
  tissue microarray
  trend study
  world health organization
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Endocrinology (3)
  Internal Medicine (6)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014933349
MEDLINE PMID
  25402569 (http://www.ncbi.nlm.nih.gov/pubmed/25402569)
PUI
  L600600029
DOI
  10.1097/JTO.0000000000000429
FULL TEXT LINK
  http://dx.doi.org/10.1097/JTO.0000000000000429
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 319
TITLE
  Nivolumab for treating non-small cell lung cancer
AUTHOR NAMES
  Guibert N.
  Mazières J.
AUTHOR ADDRESSES
  (Guibert N.; Mazières J., mazieres.j@chu-toulouse.fr) Centre Hospitalier 
Universitaire, Thoracic Oncology Unit, Respiratory Disease Department, 
Hôpital Larrey, Université Paul Sabatier, CHU Toulouse, Chemin de 
Pouvourville, Toulouse, Toulouse Cedex, France.
(Mazières J., mazieres.j@chu-toulouse.fr) Hôpital Larrey, Institut 
Universitaire du Cancer, Toulouse, Toulouse Cedex, France.
CORRESPONDENCE ADDRESS
  J. Mazières, Centre Hospitalier Universitaire, Thoracic Oncology Unit, 
Respiratory Disease Department, Hôpital Larrey, Université Paul Sabatier, 
CHU Toulouse, Chemin de Pouvourville, Toulouse, Toulouse Cedex, France. 
Email: mazieres.j@chu-toulouse.fr
SOURCE
  Expert Opinion on Biological Therapy (2015) 15:12 (1789-1797). Date of 
Publication: 1 Jan 2015
ISSN
  1744-7682 (electronic)
  1471-2598
BOOK PUBLISHER
  Taylor and Francis Ltd, healthcare.enquiries@informa.com
ABSTRACT
  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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  nivolumab (adverse drug reaction, drug therapy, pharmacokinetics)
EMTREE DRUG INDEX TERMS
  afatinib
  biological marker
  corticosteroid
  docetaxel
  erlotinib
  programmed death 1 ligand 1 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  cancer chemotherapy
  cancer immunotherapy
  cancer radiotherapy
  cancer survival
  clinical research
  colitis (side effect)
  drug mechanism
  health care quality
  hepatitis (side effect)
  human
  hypophysitis (side effect)
  interstitial pneumonia (side effect)
  mild hepatic impairment (side effect)
  monotherapy
  overall survival
  patient history of chemotherapy
  pneumonia (side effect)
  protein expression
  thyroiditis (side effect)
  translational research
  treatment response
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  afatinib (439081-18-2, 850140-72-6, 850140-73-7)
  docetaxel (114977-28-5)
  erlotinib (183319-69-9, 183321-74-6)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015520551
MEDLINE PMID
  26574148 (http://www.ncbi.nlm.nih.gov/pubmed/26574148)
PUI
  L606954445
DOI
  10.1517/14712598.2015.1114097
FULL TEXT LINK
  http://dx.doi.org/10.1517/14712598.2015.1114097
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 320
TITLE
  Emerging immunotherapies in ovarian cancer
AUTHOR NAMES
  Ojalvo L.S.
  Nichols P.E.
  Jelovac D.
  Emens L.A.
AUTHOR ADDRESSES
  (Ojalvo L.S.) Oncology, Obstetrics and Gynecology, The Kelly Gynecologic 
Oncology Service, Department of Obstetrics and Gynecology, Johns Hopkins 
University School of Medicine, Baltimore, United States.
(Nichols P.E.; Jelovac D.) Oncology, Department of Oncology, Sidney Kimmel 
Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 
Baltimore, United States.
(Emens L.A.) Medical Oncology, Internal Medicine, Immunology, Sidney Kimmel 
Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 
1650 Orleans Street, Baltimore, United States.
CORRESPONDENCE ADDRESS
  L.A. Emens, Department of Oncology and The Sidney Kimmel Comprehensive 
Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 
Bunting-Blaustein Cancer Research Bldg 1, 1650 Orleans St., Baltimore, 
United States.
SOURCE
  Discovery Medicine (2015) 20:109 (97-109). Date of Publication: 2015
ISSN
  1944-7930 (electronic)
  1539-6509
BOOK PUBLISHER
  Solariz, Inc., ops@solariz.info
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  arginase (endogenous compound)
  avelumab (adverse drug reaction, clinical trial, drug therapy)
  bevacizumab
  CA 125 antigen (endogenous compound)
  cancer antibody (endogenous compound)
  CD28 antigen (endogenous compound)
  chemokine (endogenous compound)
  cyclophosphamide
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  endothelin B receptor (endogenous compound)
  folate receptor 1 (endogenous compound)
  indoleamine 2,3 dioxygenase (endogenous compound)
  interleukin 10 (endogenous compound)
  ipilimumab (clinical trial, drug therapy)
  lymphocyte function associated antigen 1 (endogenous compound)
  major histocompatibility antigen class 1 (endogenous compound)
  major histocompatibility antigen class 2 (endogenous compound)
  mesothelin
  nivolumab (clinical trial, drug therapy)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
  protein p53 (endogenous compound)
  T lymphocyte receptor (endogenous compound)
  ticilimumab (clinical trial)
  transcription factor FOXP3 (endogenous compound)
  transforming growth factor beta (endogenous compound)
  tumor antigen (endogenous compound)
  vasculotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy (prevention)
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  arthritis (side effect)
  article
  cancer mortality
  cancer survival
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  cell cycle regulation
  cell death
  cell infiltration
  cell therapy
  clinical trial
  dendritic cell
  human
  hypothyroidism (side effect)
  immune response
  immunocompetent cell
  metastatic melanoma (drug therapy)
  myositis (side effect)
  non small cell lung cancer (drug therapy)
  outcome assessment
  pancreatitis (side effect)
  phase 1 clinical trial
  phase 2 clinical trial
  regulatory T lymphocyte
  suppressor cell
  survival rate
  thyroid disease (side effect)
  tumor microenvironment
CAS REGISTRY NUMBERS
  arginase (9000-96-8)
  avelumab (1537032-82-8)
  bevacizumab (216974-75-3)
  cyclophosphamide (50-18-0)
  indoleamine 2,3 dioxygenase ()
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  ticilimumab (745013-59-6)
  vasculotropin (127464-60-2)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01583686, NCT01611558, NCT02159716, NCT02346747)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015453447
MEDLINE PMID
  26463091 (http://www.ncbi.nlm.nih.gov/pubmed/26463091)
PUI
  L606494084
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 321
TITLE
  Current and Emerging Perspectives on Immunotherapy for Melanoma
AUTHOR NAMES
  Daud A.
AUTHOR ADDRESSES
  (Daud A., Adil.Daud@ucsf.edu) Department of Medicine (Hematology/Oncology), 
University of California San Francisco, MZ Building A, 1600 Divisadero St, 
San Francisco, United States.
(Daud A., Adil.Daud@ucsf.edu) Melanoma Clinical Research, University of 
California San Francisco, Helen Diller Family Comprehensive Cancer Center, 
MZ Building A, 1600 Divisadero St, San Francisco, United States.
CORRESPONDENCE ADDRESS
  A. Daud, Department of Medicine (Hematology/Oncology), University of 
California San Francisco, MZ Building A, 1600 Divisadero St, San Francisco, 
United States. Email: Adil.Daud@ucsf.edu
SOURCE
  Seminars in Oncology (2015) 42 Supplement 3 (S3-S11). Date of Publication: 1 
Dec 2015
ISSN
  1532-8708 (electronic)
  0093-7754
BOOK PUBLISHER
  W.B. Saunders
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction, drug therapy)
  immunomodulating agent (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  ipilimumab (adverse drug reaction, drug therapy)
  nivolumab (drug therapy)
  pembrolizumab (adverse drug reaction, drug therapy)
  programmed death 1 receptor (endogenous compound)
  tumor marker (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  autoimmune disease (side effect)
  cancer immunology
  cancer prognosis
  clinical practice
  clinical trial (topic)
  colitis (side effect)
  diarrhea (side effect)
  drug efficacy
  drug safety
  drug targeting
  hepatitis (side effect)
  human
  hyperthyroidism (side effect)
  hypopituitarism (side effect)
  hypothyroidism (side effect)
  immune system
  nephritis (side effect)
  nonhuman
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  pneumonia (side effect)
  predictive value
  priority journal
  pruritus (side effect)
  randomized controlled trial (topic)
  rash (side effect)
  signal transduction
  thyroid disease (side effect)
  toxic hepatitis (side effect)
  tumor immunity
  uveitis (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT02141542)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015535487
MEDLINE PMID
  26598057 (http://www.ncbi.nlm.nih.gov/pubmed/26598057)
PUI
  L607028242
DOI
  10.1053/j.seminoncol.2015.10.003
FULL TEXT LINK
  http://dx.doi.org/10.1053/j.seminoncol.2015.10.003
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 322
TITLE
  Society for Melanoma Research 2014 Congress
AUTHOR ADDRESSES
  SOURCE
  Pigment Cell and Melanoma Research (2014) 27:6. Date of Publication: 
November 2014
CONFERENCE NAME
  Society for Melanoma Research 2014 Congress
CONFERENCE LOCATION
  Zurich, Switzerland
CONFERENCE DATE
  2014-11-13 to 2014-11-16
ISSN
  1755-1471
BOOK PUBLISHER
  Blackwell Publishing Ltd
ABSTRACT
  The proceedings contain 225 papers. The topics discussed include: tumoral 
growth inhibition by 4-nerolidylcathecol (4-NC) in a melanoma tumor model in 
vivo; global microRNA and target-mRNA expression patterns reflect cellular 
phenotype and inform functional studies in malignant melanoma; 
thrombospondin 1 promotes an in vitro and in vivo invasive phenotype through 
epithelial-to-mesenchymal transition in human melanoma; exome sequencing of 
ABCB5 identifies recurrent mutations that results in increased melanoma cell 
proliferative and invasive capacities; therapeutic options after failure on 
BRAF inhibitors in patients with BRAF-mutated metastatic melanoma; 
UVB-induced Tlr4 dependent neutrophilic inflammation promotes angiotropism 
and metastasis in melanoma; highly sensitive PCR assay for detection of BRAF 
and NRAS mutations in melanoma found in FFPE tissue and plasma derived 
cfDNA; and immunreactivity for CTLA-4 in adenohypophysis and neutrophils 
suggest antibody dependent cytotoxicity to trigger ipilimumab induced 
hypophysitis.
EMTREE DRUG INDEX TERMS
  antibody
  cytotoxic T lymphocyte antigen 4
  ipilimumab
  messenger RNA
  microRNA
  thrombospondin 1
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma
  society
EMTREE MEDICAL INDEX TERMS
  adenohypophysis
  assay
  cytotoxicity
  epithelial mesenchymal transition
  exome
  growth inhibition
  human
  hypophysitis
  in vitro study
  inflammation
  melanoma cell
  metastasis
  metastatic melanoma
  mutation
  neutrophil
  patient
  phenotype
  plasma
  tissues
  tumor model
LANGUAGE OF ARTICLE
  English
PUI
  L71772460
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 323
TITLE
  Ipilimumab treatment associated pituitary hypophysitis: clinical 
presentation and imaging diagnosis
AUTHOR NAMES
  Chodakiewitz Y.
  Brown S.
  Boxerman J.L.
  Brody J.M.
  Rogg J.M.
AUTHOR ADDRESSES
  (Chodakiewitz Y.) Alpert Medical School, Brown University, 222 Richmond St, 
Providence 02903, USA
(Brown S.) Department of Diagnostic Imaging, Rhode Island Hospital, Alpert 
Medical School of Brown University, 593 Eddy Street, Providence 02903, USA
(Boxerman J.L.) Department of Diagnostic Imaging, Rhode Island Hospital, 
Alpert Medical School of Brown University, 593 Eddy Street, Providence 
02903, USA
(Brody J.M.) Department of Diagnostic Imaging, Rhode Island Hospital, Alpert 
Medical School of Brown University, 593 Eddy Street, Providence 02903, USA
(Rogg J.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
SOURCE
  Clinical neurology and neurosurgery (2014) 125 (125-130). Date of 
Publication: 1 Oct 2014
ISSN
  1872-6968 (electronic)
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  ipilimumab
  monoclonal antibody (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  diagnostic imaging
  pathology
EMTREE MEDICAL INDEX TERMS
  human
  hypophysis
  hypopituitarism (diagnosis, drug therapy, diagnosis, drug therapy)
  melanoma (diagnosis, drug therapy, diagnosis, drug therapy)
  nuclear magnetic resonance imaging
  procedures
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  25127260 (http://www.ncbi.nlm.nih.gov/pubmed/25127260)
PUI
  L605702111
DOI
  10.1016/j.clineuro.2014.06.011
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.clineuro.2014.06.011
COPYRIGHT
  Copyright 2016 Medline is the source for the citation and abstract of this 
record.

RECORD 324
TITLE
  The combination of Anti-NKG2D and CTLA-4 Ig therapy prolongs islet allograft 
survival in a murine model
AUTHOR NAMES
  Pawlick R.
  Gala-Lopez B.
  Pepper A.R.
  Mccall M.
  Ziff O.
  Shapiro A.M.J.
AUTHOR ADDRESSES
  (Pawlick R.; Gala-Lopez B.; Pepper A.R.; Mccall M.; Ziff O.; Shapiro A.M.J., 
amjs@islet.ca) Alberta Diabetes InstituteUniversity of AlbertaEdmonton, 
ABCanada
(Shapiro A.M.J., amjs@islet.ca) Clinical Islet Transplant ProgramUniversity 
of AlbertaEdmonton, ABCanada
CORRESPONDENCE ADDRESS
  A.M.J. Shapiro, Alberta Diabetes InstituteUniversity of AlbertaEdmonton, 
ABCanada, . Email: amjs@islet.ca
SOURCE
  American Journal of Transplantation (2014). Date of Publication: 2014
ISSN
  1600-6135
  1600-6143 (electronic)
BOOK PUBLISHER
  Blackwell Publishing Ltd
ABSTRACT
  Islet transplantation is an effective means of treating severe type 1 
diabetes in patients with life-threatening hypoglycemia. Improvements in 
glycemic control with correction of HbA1C enhance quality of life 
irrespective of insulin independence. By antagonizing the Natural Killer 
Group 2, member D (NKG2D) receptor expression on NK and CD8+ T cells, in 
combination with blocking CTLA-4 binding sites, we demonstrate a significant 
delay of graft rejection in islet allotransplant. Anti-NKG2D combined with 
CTLA-4 Ig (n=15) results in prolonged allograft survival, with 84.6±10% of 
the recipients displaying insulin independence compared to controls (n=10, 
p<0.001). The effect of combination therapy on graft survival is superior to 
treatments alone (CTLA-4 Ig vs. combination p=0.024, anti-NKG2D vs. 
combination p<0.001) indicating an interaction between these pathways. In 
addition, combination treatment also improves glucose tolerance when 
compared to controls (n=10, p=0.018). Histologically, NKG2D+ cells were 
significantly decreased within the allograft after 7 days of combination 
treatment (n=6, p=0.029). T cell proliferation was significantly reduced 
with anti-NKG2D therapy and CD8+ T cell daughter fractions were also 
significantly decreased with mAb and combination treatment when measured by 
in vitro mixed lymphocyte reaction (n=5, p=0.015, p=0.005 and p=0.048). 
These results demonstrate that inhibition of NKG2D receptors and 
costimulatory pathways enhance islet allograft survival. © 2014 The American 
Society of Transplantation and the American Society of Transplant Surgeons.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  abatacept
  alloantigen
  cytotoxic T lymphocyte antigen 4
EMTREE DRUG INDEX TERMS
  CD8 antigen
  hemoglobin A1c
  insulin
  nitrogen 15
  receptor
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  graft survival
  laboratory
  modulation
  murine model
  therapy
  transplantation
EMTREE MEDICAL INDEX TERMS
  allograft
  binding site
  cell proliferation
  daughter
  glucose tolerance
  glycemic control
  graft rejection
  human
  hypoglycemia
  in vitro study
  independence
  insulin dependent diabetes mellitus
  mixed lymphocyte reaction
  patient
  quality of life
  recipient
  society
  T lymphocyte
  transplant surgeon
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
PUI
  L53319300
DOI
  10.1111/ajt.12838
FULL TEXT LINK
  http://dx.doi.org/10.1111/ajt.12838
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 325
TITLE
  Abstracts Presented at the 59th Annual Meeting of the Southwest Chapter, 
Society of Nuclear Medicine and Molecular Imaging
AUTHOR ADDRESSES
  SOURCE
  Clinical Nuclear Medicine (2014) 39:9. Date of Publication: September 2014
CONFERENCE NAME
  59th Annual Meeting of the Southwest Chapter, Society of Nuclear Medicine 
and Molecular Imaging
CONFERENCE LOCATION
  New Orleans, LA, United States
CONFERENCE DATE
  2014-03-07 to 2014-03-09
ISSN
  0363-9762
BOOK PUBLISHER
  Lippincott Williams and Wilkins
ABSTRACT
  The proceedings contain 4 papers. The topics discussed include: case report 
of Tc-99m sestamibi thyroid scan in amiodarone-induced thyrotoxicosis 
patient; non malignant causes of elevated FDG accumulation in patients being 
treated with ipilimumab; case review of correlative ultrasound and 
scintigraphic findings of acute cholecystitis; and a case report of 
paraganglioma-pheochromocytoma on FDG-PET/CT and I-123 MIBG.
EMTREE DRUG INDEX TERMS
  amiodarone
  iodine 123
  ipilimumab
  technetium 99m
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  molecular imaging
  nuclear medicine
  society
EMTREE MEDICAL INDEX TERMS
  acute cholecystitis
  case report
  human
  paraganglioma
  patient
  pheochromocytoma
  thyroid gland
  thyrotoxicosis
  ultrasound
LANGUAGE OF ARTICLE
  English
PUI
  L71705146
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 326
TITLE
  Disassembly of mitotic checkpoint complexes by the joint action of the 
AAA-ATPase TRIP13 and p31(comet)
AUTHOR NAMES
  Eytan E.
  Wang K.
  Miniowitz-Shemtov S.
  Sitry-Shevah D.
  Kaisari S.
  Yen T.J.
  Liu S.-T.
  Hershko A.
AUTHOR ADDRESSES
  (Eytan E.; Miniowitz-Shemtov S.; Sitry-Shevah D.; Kaisari S.; Hershko A., 
hershko@tx.technion.ac.il) Unit of Biochemistry, Rappaport Faculty of 
Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
(Wang K.; Liu S.-T.) Department of Biological Sciences, University of 
Toledo, Toledo, OH 43606, United States.
(Yen T.J.) Fox Chase Cancer Center, Philadelphia, PA 19111, United States.
CORRESPONDENCE ADDRESS
  A. Hershko, Unit of Biochemistry, Rappaport Faculty of Medicine, 
Technion-Israel Institute of Technology, Haifa 31096, Israel. Email: 
hershko@tx.technion.ac.il
SOURCE
  Proceedings of the National Academy of Sciences of the United States of 
America (2014) 111:33 (12019-12024). Date of Publication: 19 Aug 2014
ISSN
  1091-6490 (electronic)
  0027-8424
BOOK PUBLISHER
  National Academy of Sciences
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  adenosine triphosphatase (endogenous compound)
  binding protein (endogenous compound)
  protein p31 (endogenous compound)
  thyroid receptor interacting protein 13 (endogenous compound)
EMTREE DRUG INDEX TERMS
  anaphase promoting complex (endogenous compound)
  cell cycle protein 20 (endogenous compound)
  protein Mad2 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  M phase cell cycle checkpoint
  mitotic checkpoint complex disassembly
EMTREE MEDICAL INDEX TERMS
  article
  chromosome inactivation
  controlled study
  female
  HeLa cell line
  human
  human cell
  hydrolysis
  mitosis spindle
  priority journal
  protein analysis
  protein phosphorylation
  protein protein interaction
  protein secretion
CAS REGISTRY NUMBERS
  adenosine triphosphatase (37289-25-1, 9000-83-3)
  anaphase promoting complex (74812-49-0)
EMBASE CLASSIFICATIONS
  Physiology (2)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014556967
MEDLINE PMID
  25092294 (http://www.ncbi.nlm.nih.gov/pubmed/25092294)
PUI
  L373796541
DOI
  10.1073/pnas.1412901111
FULL TEXT LINK
  http://dx.doi.org/10.1073/pnas.1412901111
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 327
TITLE
  Ipilimumab-induced hypophysitis: Early Australian experience
AUTHOR NAMES
  De Sousa S.M.C.
  Long G.V.
  Tonks K.T.
AUTHOR ADDRESSES
  (De Sousa S.M.C.) Department of Endocrinology, St Vincent's Hospital, 
Sydney, NSW, Australia.
(Long G.V.) Melanoma Institute Australia, Sydney, NSW, Australia.
(Tonks K.T.) Diabetes and Metabolism Division, Garvan Institute of Medical 
Research, Sydney, NSW, Australia.
SOURCE
  Medical Journal of Australia (2014) 201:4 (198-199). Date of Publication: 18 
Aug 2014
ISSN
  1326-5377 (electronic)
  0025-729X
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  dexamethasone
  follitropin (endogenous compound)
  hydrocortisone (endogenous compound)
  liothyronine (endogenous compound)
  prednisolone
  testosterone (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (side effect, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  androgen therapy
  anorexia
  asthenia
  case report
  cell proliferation
  dizziness
  drug dose reduction
  drug megadose
  fatigue
  headache
  human
  hypogonadism
  insulin tolerance test
  letter
  lumbar puncture
  male
  metastatic melanoma (drug therapy)
  nuclear magnetic resonance imaging
  T lymphocyte activation
  tumor growth
  vomiting
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  follitropin (9002-68-0)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  liothyronine (6138-47-2, 6893-02-3)
  prednisolone (50-24-8)
  testosterone (58-22-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  2014554713
MEDLINE PMID
  25164840 (http://www.ncbi.nlm.nih.gov/pubmed/25164840)
PUI
  L373790824
DOI
  10.5694/mja14.00803
FULL TEXT LINK
  http://dx.doi.org/10.5694/mja14.00803
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 328
TITLE
  Chk1 Inhibition as a novel therapeutic strategy for treating triple-negative 
breast and ovarian cancers
AUTHOR NAMES
  Bryant C.
  Rawlinson R.
  Massey A.J.
AUTHOR ADDRESSES
  (Bryant C., C.J.Bryant@bath.ac.uk; Rawlinson R., rebecca.rawlinson@bath.edu; 
Massey A.J., a.massey@vernalis.com) Vernalis R and D Ltd, Granta Park, 
Cambridge, United Kingdom.
CORRESPONDENCE ADDRESS
  A.J. Massey, Vernalis R and D Ltd, Granta Park, Cambridge, United Kingdom.
SOURCE
  BMC Cancer (2014) 14:1 Article Number: 570. Date of Publication: 7 Aug 2014
ISSN
  1471-2407 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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.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.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.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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  checkpoint kinase 1 (endogenous compound)
  checkpoint kinase 1 inhibitor (drug combination, drug development, 
pharmacology)
  protein serine threonine kinase inhibitor (drug combination, drug 
development, pharmacology)
  v 158411 (drug combination, drug development, pharmacology)
EMTREE DRUG INDEX TERMS
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide
  alpha amino n [5,6 dihydro 2 (1 methyl 1h pyrazol 4 yl) 6 oxo 1h 
pyrrolo[4,3,2 ef][2,3]benzodiazepin 8 yl]cyclohexaneacetamide
  camptothecin
  carboplatin (drug combination)
  caspase 3 (endogenous compound)
  caspase 7 (endogenous compound)
  cisplatin (drug combination)
  cytarabine
  doxorubicin
  estrogen receptor (endogenous compound)
  etoposide
  gemcitabine (drug combination)
  histone H2AX (endogenous compound)
  mitomycin
  olaparib
  oxaliplatin (drug combination)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer
  triple negative breast cancer
EMTREE MEDICAL INDEX TERMS
  antiproliferative activity
  apoptosis
  article
  breast cancer cell line
  cell cycle arrest
  controlled study
  DNA damage
  DNA fragmentation
  drug cytotoxicity
  drug potentiation
  drug sensitivity
  histone phosphorylation
  human
  human cell
  ovarian cancer cell line
  protein degradation
  Western blotting
DRUG TRADE NAMES
  azd 7762  Axon Medchem

  pf 477736  Selleck

  v 158411
DRUG MANUFACTURERS
  Apin
  Tocris
CAS REGISTRY NUMBERS
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide 
(1019773-80-8, 860352-01-8)
  alpha amino n [5,6 dihydro 2 (1 methyl 1h pyrazol 4 yl) 6 oxo 1h 
pyrrolo[4,3,2 ef][2,3]benzodiazepin 8 yl]cyclohexaneacetamide (952021-60-2)
  camptothecin (7689-03-4)
  carboplatin (41575-94-4)
  caspase 3 (169592-56-7)
  caspase 7 (189258-14-8)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  cytarabine (147-94-4, 69-74-9)
  doxorubicin (23214-92-8, 25316-40-9)
  etoposide (33419-42-0)
  gemcitabine (103882-84-4)
  mitomycin (1404-00-8, 50-07-7, 74349-48-7)
  olaparib (763113-22-0)
  oxaliplatin (61825-94-3)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014893452
MEDLINE PMID
  25104095 (http://www.ncbi.nlm.nih.gov/pubmed/25104095)
PUI
  L600192293
DOI
  10.1186/1471-2407-14-570
FULL TEXT LINK
  http://dx.doi.org/10.1186/1471-2407-14-570
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 329
TITLE
  Ipilimumab-induced hypophysitis and uveitis in a patient with metastatic 
melanoma and a history of ipilimumab-induced skin rash
AUTHOR NAMES
  Nallapaneni N.N.
  Mourya R.
  Bhatt V.R.
  Malhotra S.
  Ganti A.K.
  Tendulkar K.K.
AUTHOR ADDRESSES
  (Nallapaneni N.N.; Tendulkar K.K.) University of Nebraska Medical Center, 
Department of Internal Medicine, Division of Nephrology, United States.
(Mourya R.) Creighton University Medical Center, Department of Internal 
Medicine, United States.
(Bhatt V.R.) University of Nebraska Medical Center, Department of Internal 
Medicine, Division of Hematology and Oncology, United States.
(Malhotra S.) VA Nebraska-Western Iowa Health Care System, Department of 
Internal Medicine, United States.
(Ganti A.K., aganti@unmc.edu) Division of Oncology and Hematology, 
Department of Internal Medicine, University of Nebraska Medical Center, 
Omaha, NE 68198-7680, United States.
CORRESPONDENCE ADDRESS
  A.K. Ganti, Division of Oncology and Hematology, Department of Internal 
Medicine, University of Nebraska Medical Center, Omaha, NE 68198-7680, 
United States. Email: aganti@unmc.edu
SOURCE
  JNCCN Journal of the National Comprehensive Cancer Network (2014) 12:8 
(1077-1081). Date of Publication: 1 Aug 2014
ISSN
  1540-1413 (electronic)
  1540-1405
BOOK PUBLISHER
  Harborside Press, 37 main Street, Cold Spring Harbor, United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  desmopressin (drug therapy)
  hydrocortisone (adverse drug reaction, drug therapy)
  interleukin 2 (drug combination, drug dose, drug therapy)
  levothyroxine (drug therapy)
  meprednisone (drug therapy)
  prednisone (drug therapy, oral drug administration)
  prednisone acetate (drug therapy, topical drug administration)
  vemurafenib (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, drug therapy, side effect)
  metastatic melanoma (drug therapy, drug therapy)
  rash (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adenohypophysis
  adult
  article
  case report
  clinical feature
  colitis (side effect)
  confusion (side effect)
  diabetes insipidus (drug therapy)
  diarrhea (side effect)
  drug megadose
  drug substitution
  drug withdrawal
  hallucination (side effect)
  human
  hypothyroidism (drug therapy)
  male
  medical history
  neurohypophysis
  nuclear magnetic resonance imaging
  pruritus (drug therapy, side effect)
  treatment outcome
  uveitis (drug therapy, side effect)
CAS REGISTRY NUMBERS
  desmopressin (16679-58-6)
  hydrocortisone (50-23-7)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  meprednisone (1247-42-3)
  prednisone (53-03-2)
  prednisone acetate (125-10-0)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014551861
MEDLINE PMID
  25099440 (http://www.ncbi.nlm.nih.gov/pubmed/25099440)
PUI
  L373781815
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 330
TITLE
  Serious haematological toxicity during and after ipilimumab treatment: A 
case series
AUTHOR NAMES
  Simeone E.
  Grimaldi A.M.
  Esposito A.
  Curvietto M.
  Palla M.
  Paone M.
  Mozzillo N.
  Ascierto P.A.
AUTHOR ADDRESSES
  (Simeone E., ester.simeone@gmail.com; Grimaldi A.M., 
dott.a.m.grimaldi@gmail.com; Esposito A., susy.a.esposito@gmail.com; 
Curvietto M., curvietto.ma@gmail.com; Palla M., pallamarco80@gmail.com; 
Paone M., miriam.paone@gmail.com; Ascierto P.A., paolo.ascierto@gmail.com) 
Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto 
Nazionale Tumori Fondazione G. Pascale, Via Mariano Semmola, 80131 Napoli, 
Italy.
(Mozzillo N., nimozzi@tin.it) Department Melanoma and Soft Tissue Cancer, 
Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy.
CORRESPONDENCE ADDRESS
  P.A. Ascierto, Unit of Melanoma, Cancer Immunotherapy and Innovative 
Therapy, Istituto Nazionale Tumori Fondazione G. Pascale, Via Mariano 
Semmola, 80131 Napoli, Italy. Email: paolo.ascierto@gmail.com
SOURCE
  Journal of Medical Case Reports (2014) 8:1 Article Number: 240. Date of 
Publication: 1 Jul 2014
ISSN
  1752-1947 (electronic)
BOOK PUBLISHER
  BioMed Central Ltd., info@biomedcentral.com
ABSTRACT
  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-naïve 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. 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. 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. © 2014 Simeone et al.; licensee BioMed Central 
Ltd.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  antibiotic agent
  fotemustine (adverse drug reaction, drug therapy)
  granulocyte macrophage colony stimulating factor
  methylprednisolone (drug therapy, intravenous drug administration)
  prednisone (oral drug administration)
  temozolomide (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer of unknown primary site (diagnosis)
  eye tumor (drug therapy, diagnosis, drug therapy)
  metastatic melanoma (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  algorithm
  anemia (diagnosis, drug therapy, side effect)
  article
  autoimmunity
  blood cell count
  blood transfusion
  bone marrow biopsy
  brain metastasis (side effect)
  cancer chemotherapy
  cancer recurrence
  cancer staging
  case report
  Caucasian
  disease course
  drug dose increase
  drug efficacy
  drug safety
  dyspnea (side effect)
  erythrocyte
  fatigue (side effect)
  female
  follow up
  functional neuroimaging
  human
  kidney tumor (diagnosis, drug therapy)
  leukopenia (side effect)
  lung metastasis (drug therapy)
  lymphocytic infiltration (diagnosis)
  male
  middle aged
  multiple cycle treatment
  platelet count
  priority journal
  pruritus (side effect)
  treatment outcome
  whole body CT
DEVICE TRADE NAMES
  CyberKnife
CAS REGISTRY NUMBERS
  fotemustine (92118-27-9)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
  temozolomide (85622-93-1)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Cancer (16)
  Hematology (25)
  Biophysics, Bioengineering and Medical Instrumentation (27)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014470240
MEDLINE PMID
  24986059 (http://www.ncbi.nlm.nih.gov/pubmed/24986059)
PUI
  L373517615
DOI
  10.1186/1752-1947-8-240
FULL TEXT LINK
  http://dx.doi.org/10.1186/1752-1947-8-240
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 331
TITLE
  Pituitary expression of CTLA-4 mediates hypophysitis secondary to 
administration of CTLA-4 blocking antibody
AUTHOR NAMES
  Iwama S.
  De Remigis A.
  Callahan M.K.
  Slovin S.F.
  Wolchok J.D.
  Caturegli P.
AUTHOR ADDRESSES
  (Iwama S.; De Remigis A.; Caturegli P., pcat@jhmi.edu) Department of 
Pathology, Johns Hopkins University, Baltimore, MD 21205, United States.
(Iwama S.) Department of Endocrinology and Diabetes, Nagoya University 
Graduate School of Medicine, Nagoya 466-8550, Japan.
(Callahan M.K.; Slovin S.F.; Wolchok J.D.) Department of Medicine, Memorial 
Sloan Kettering Cancer Center, New York, NY 10065, United States.
(Callahan M.K.; Slovin S.F.; Wolchok J.D.) Weill Cornell Medical College, 
New York, NY 10065, United States.
(Wolchok J.D.) Ludwing Institute for Cancer Research, New York, NY 10065, 
United States.
(Caturegli P., pcat@jhmi.edu) Feinstone Department of Molecular Microbiology 
and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, 
MD 21205, United States.
CORRESPONDENCE ADDRESS
  P. Caturegli, Department of Pathology, Johns Hopkins University, Baltimore, 
MD 21205, United States. Email: pcat@jhmi.edu
SOURCE
  Science Translational Medicine (2014) 6:230 Article Number: 230ra45. Date of 
Publication: 2 Apr 2014
ISSN
  1946-6242 (electronic)
  1946-6234
BOOK PUBLISHER
  American Association for the Advancement of Science
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4
EMTREE DRUG INDEX TERMS
  autoantibody (endogenous compound)
  complement component C3d (endogenous compound)
  complement component C4d (endogenous compound)
  corticotropin (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody
  follitropin (endogenous compound)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy)
  pituitary autoantibody (endogenous compound)
  prolactin (endogenous compound)
  thyrotropin (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  ACTH secreting cell
  adult
  advanced cancer (drug therapy)
  aged
  animal experiment
  animal model
  animal tissue
  antibody blood level
  antibody production
  antigen expression
  article
  clinical article
  complement activation
  controlled study
  disease model
  female
  human
  hypersensitivity
  lymphocytic infiltration
  male
  melanoma (drug therapy)
  middle aged
  mouse
  neurotoxicity
  nonhuman
  priority journal
  prostate cancer (drug therapy)
  TSH secreting cell
DRUG TRADE NAMES
  yervoy  Bristol Myers Squibb

DRUG MANUFACTURERS
  Bristol Myers Squibb
CAS REGISTRY NUMBERS
  complement component C3d (80295-45-0)
  complement component C4d (80295-52-9)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  follitropin (9002-68-0)
  ipilimumab (477202-00-9)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00323882, NCT00495066, NCT00623766, NCT00920907)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014282914
MEDLINE PMID
  24695685 (http://www.ncbi.nlm.nih.gov/pubmed/24695685)
PUI
  L372920364
DOI
  10.1126/scitranslmed.3008002
FULL TEXT LINK
  http://dx.doi.org/10.1126/scitranslmed.3008002
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 332
TITLE
  Immune checkpoint blockade in cancer treatment: A double-edged sword 
cross-targeting the host as an "innocent bystander"
AUTHOR NAMES
  Gelao L.
  Criscitiello C.
  Esposito A.
  Goldhirsch A.
  Curigliano G.
AUTHOR ADDRESSES
  (Gelao L., lucia.gelao@ieo.it; Criscitiello C., carmen.criscitiello@ieo.it; 
Esposito A., angela.esposito@ieo.it; Goldhirsch A., aaron.goldhirsch@ieo.it; 
Curigliano G., giuseppe.curigliano@ieo.it) Division of Early Drug 
Development for Innovative Therapies, Istituto Europeo di Oncologia, Via 
Ripamonti 435, Milano 20141, Italy.
CORRESPONDENCE ADDRESS
  G. Curigliano, Division of Early Drug Development for Innovative Therapies, 
Istituto Europeo di Oncologia, Via Ripamonti 435, Milano 20141, Italy. 
Email: giuseppe.curigliano@ieo.it
SOURCE
  Toxins (2014) 6:3 (914-933). Date of Publication: March 2014
ISSN
  2072-6651
BOOK PUBLISHER
  MDPI AG, Postfach, Basel, Switzerland.
ABSTRACT
  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. © 2014 
by the authors; licensee MDPI, Basel, Switzerland.
EMTREE DRUG INDEX TERMS
  alpha2b interferon (drug therapy)
  atezolizumab
  bms 936559
  carboplatin (drug therapy)
  cetuximab (drug therapy)
  cisplatin (drug therapy)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  dabrafenib (drug therapy)
  dacarbazine (drug therapy)
  denileukin diftitox (drug therapy)
  etoposide (drug therapy)
  gemcitabine (drug therapy)
  granulocyte macrophage colony stimulating factor (drug therapy)
  interleukin 2 (endogenous compound)
  interleukin 21 (drug therapy)
  ipilimumab (drug therapy)
  lenalidomide (drug therapy)
  mesylic acid (drug therapy)
  nivolumab (drug therapy)
  paclitaxel (drug therapy)
  pembrolizumab (drug therapy)
  platinum (drug therapy)
  sipuleucel T (drug therapy)
  T lymphocyte receptor (endogenous compound)
  talimogene laherparepvec (drug therapy)
  ticilimumab (drug therapy)
  trametinib (drug therapy)
  tumor antigen (endogenous compound)
  unclassified drug
  unindexed drug
  urelumab
  vemurafenib (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer therapy
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  antigen presenting cell
  antigen recognition
  article
  cell proliferation
  dendritic cell
  head and neck cancer (drug therapy)
  human
  immune response
  immunological tolerance
  immunomodulation
  melanoma (drug therapy)
  non small cell lung cancer
  nonhuman
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  prostate cancer (drug therapy)
  regulatory T lymphocyte
  small cell lung cancer (drug therapy)
  transitional cell carcinoma (drug therapy)
DRUG TRADE NAMES
  bms 663513
  bms 936559
  mpdl3280a
  yervoy
CAS REGISTRY NUMBERS
  alpha2b interferon (99210-65-8)
  carboplatin (41575-94-4)
  cetuximab (205923-56-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  dabrafenib (1195765-45-7, 1195768-06-9)
  dacarbazine (4342-03-4)
  denileukin diftitox (173146-27-5)
  etoposide (33419-42-0)
  gemcitabine (103882-84-4)
  interleukin 2 (85898-30-2)
  interleukin 21 (251100-02-4, 510787-82-3, 542817-56-1)
  ipilimumab (477202-00-9)
  lambrolizumab (1374853-91-4)
  lenalidomide (191732-72-6)
  mesylic acid (2386-57-4, 75-75-2)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  platinum (7440-06-4)
  sipuleucel T (917381-47-6)
  talimogene laherparepvec (1187560-31-1)
  ticilimumab (745013-59-6)
  trametinib (1187431-43-1, 871700-17-3)
  urelumab (934823-49-1)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00636168, NCT00729664, NCT00836407, NCT01024231, NCT01103635, NCT01274338, NCT01285609, NCT01295827, NCT01307618, NCT01331525, NCT01363206, NCT01450761, NCT01454102, NCT01468311, NCT01473940, NCT01489059, NCT01498978, NCT01524991, NCT01565837, NCT01590082, NCT01592370, NCT01604889, NCT01608594, NCT01611558, NCT01629758, NCT01633970, NCT01642004, NCT01643278, NCT01656642, NCT01668784, NCT01673854, NCT01676649, NCT01689974, NCT01711515, NCT01721772, NCT01729806, NCT01738139, NCT01740297, NCT01750580, NCT01750983, NCT01767454, NCT01783938, NCT01810016, NCT01822509, NCT01827111, NCT01832870, NCT01840579, NCT01843374, NCT01844505, NCT01846416, NCT01848834, NCT01853618, NCT01856023, NCT01860430, NCT01866319, NCT01896869, NCT01896999, NCT01903993, NCT01905657, NCT01927419, NCT01928394, NCT01968109, NCT01975831, NCT01988077)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014203936
MEDLINE PMID
  24594636 (http://www.ncbi.nlm.nih.gov/pubmed/24594636)
PUI
  L372662250
DOI
  10.3390/toxins6030914
FULL TEXT LINK
  http://dx.doi.org/10.3390/toxins6030914
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 333
TITLE
  Ipilimumab in the treatment of metastatic melanoma: Management of adverse 
events
AUTHOR NAMES
  Della Vittoria Scarpati G.
  Fusciello C.
  Perri F.
  Sabbatino F.
  Ferrone S.
  Carlomagno C.
  Pepe S.
AUTHOR ADDRESSES
  (Della Vittoria Scarpati G., giuseppina.dellavittoria@alice.it; Pepe S.) 
Department of Medicine, University of Salerno, Salerno, Italy.
(Della Vittoria Scarpati G., giuseppina.dellavittoria@alice.it; Pepe S.) 
Division of Oncology, San Giovanni di Dio e Ruggi d'Aragona Hospital, 
Salerno, Italy.
(Fusciello C.; Carlomagno C.) Department of Clinical Medicine and Surgery, 
University Federico II, Naples, Italy.
(Perri F.) Head and Neck Medical Oncology Unit, National Tumor Institute, 
Naples, Italy.
(Sabbatino F.; Ferrone S.) Department of Surgery, Massachusetts General 
Hospital, Harvard Medical School, Boston, MA, United States.
CORRESPONDENCE ADDRESS
  G. Della Vittoria Scarpati, AOU San Giovanni di Dio e Ruggi d'Aragona, Largo 
Città d'Ippocrate, Salerno, Italy. Email: giuseppina.dellavittoria@alice.it
SOURCE
  OncoTargets and Therapy (2014) 7 (203-209). Date of Publication: 19 Feb 2014
ISSN
  1178-6930
BOOK PUBLISHER
  Dove Medical Press Ltd., PO Box 300-008, Albany, Auckland, New Zealand.
ABSTRACT
  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. © 
2014 Della Vittoria Scarpati et al.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  managed care
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  conservative treatment
  dermatitis (side effect)
  diarrhea (side effect)
  drug safety
  drug tolerability
  early intervention
  endocrine disease (side effect)
  enterocolitis (side effect)
  eye toxicity (side effect)
  gastrointestinal toxicity (side effect)
  hepatitis (side effect)
  human
  hypophysitis (side effect)
  immunopathology (side effect)
  liver toxicity (side effect)
  lung toxicity (side effect)
  neurotoxicity (side effect)
  patient monitoring
  review
  skin toxicity (side effect)
  symptom assessment
  uveitis (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014130935
PUI
  L372427760
DOI
  10.2147/OTT.S57335
FULL TEXT LINK
  http://dx.doi.org/10.2147/OTT.S57335
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 334
TITLE
  Antibody-based immunotherapy for ovarian cancer: Where are we at?
AUTHOR NAMES
  Tse B.W.C.
  Collins A.
  Oehler M.K.
  Zippelius A.
  Heinzelmann-Schwarz V.A.
AUTHOR ADDRESSES
  (Tse B.W.C.; Heinzelmann-Schwarz V.A., viola.heinzelmann@usb.ch) Ovarian 
Cancer Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, 
University of New South Wales, Sydney, Australia.
(Collins A.) School of Biotechnology and Biomolecular Sciences, University 
of New South Wales, Sydney, Australia.
(Oehler M.K.) Department of Gynaecological Oncology, Royal Adelaide 
Hospital, Adelaide, Australia.
(Zippelius A.) Department of Medical Oncology, University Hospital Basel, 
Basel, Switzerland.
(Heinzelmann-Schwarz V.A., viola.heinzelmann@usb.ch) Women's University 
Hospital and Department of Biomedicine, University of Basel, Basel, 
Switzerland.
CORRESPONDENCE ADDRESS
  V.A. Heinzelmann-Schwarz, Department of Biomedicine, University Hospital 
Base, Hebelstrasse 20, Basel CH-4031, Switzerland. Email: 
viola.heinzelmann@usb.ch
SOURCE
  Annals of Oncology (2014) 25:2 (322-331) Article Number: mdt405. Date of 
Publication: February 2014
ISSN
  0923-7534
  1569-8041 (electronic)
BOOK PUBLISHER
  Oxford University Press, Great Clarendon Street, Oxford, United Kingdom.
ABSTRACT
  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-EpCAM × anti-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. © The Author 2013. Published 
by Oxford University Press on behalf of the European Society for Medical 
Oncology. All rights reserved.
EMTREE DRUG INDEX TERMS
  abagovomab (clinical trial, drug therapy, pharmacology, subcutaneous drug 
administration)
  aca 126
  antineoplastic agent (clinical trial, drug therapy, pharmacology)
  CA 125 antigen (endogenous compound)
  catumaxomab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  daclizumab (drug therapy, pharmacology)
  denileukin diftitox (clinical trial, drug therapy)
  ipilimumab (clinical trial, drug therapy, pharmacology)
  mxd 1105 (clinical trial, drug therapy, pharmacology)
  oregovomab (clinical trial, drug therapy, pharmacology)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  cancer survival
  clinical effectiveness
  drug binding
  drug effect
  drug efficacy
  drug indication
  drug mechanism
  drug safety
  drug tolerability
  human
  immunomodulation
  malignant ascites (drug therapy)
  nausea (side effect)
  outcome assessment
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  review
DRUG TRADE NAMES
  aca 126
  mxd 1105
  ontak
  removab
  yervoy
  zenapax
CAS REGISTRY NUMBERS
  abagovomab (792921-10-9)
  catumaxomab (509077-98-9)
  denileukin diftitox (173146-27-5)
  ipilimumab (477202-00-9)
  oregovomab (213327-37-8)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014087098
MEDLINE PMID
  24285017 (http://www.ncbi.nlm.nih.gov/pubmed/24285017)
PUI
  L372254015
DOI
  10.1093/annonc/mdt405
FULL TEXT LINK
  http://dx.doi.org/10.1093/annonc/mdt405
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 335
TITLE
  Endocrine-related adverse events following ipilimumab in patients with 
advanced melanoma: A comprehensive retrospective review from a single 
institution
AUTHOR NAMES
  Ryder M.
  Callahan M.
  Postow M.A.
  Wolchok J.
  Fagin J.A.
AUTHOR ADDRESSES
  (Ryder M., ryder.mabel@mayo.edu; Fagin J.A.) Human Oncology and Pathogenesis 
Program, Memorial Sloan-Kettering Cancer Center, New York, NY, United 
States.
(Ryder M., ryder.mabel@mayo.edu; Postow M.A.; Wolchok J.) Department of 
Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United 
States.
(Wolchok J.) Ludwig Institute for Cancer Research, Memorial Sloan-Kettering 
Cancer Center, New York, NY, United States.
(Callahan M.) Weill Cornell Medical College, New York, NY, United States.
(Fagin J.A.) Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United 
States.
CORRESPONDENCE ADDRESS
  M. Ryder, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering 
Cancer Center, New York, NY, United States. Email: ryder.mabel@mayo.edu
SOURCE
  Endocrine-Related Cancer (2014) 21:2 (371-381). Date of Publication: April 
2014
ISSN
  1479-6821 (electronic)
  1351-0088
BOOK PUBLISHER
  Society for Endocrinology, info@endocrinology.org
ABSTRACT
  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. © 2014 Society for Endocrinology.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  hypophysis hormone (endogenous compound)
  nivolumab (drug combination, drug therapy)
  programmed death 1 receptor (endogenous compound)
  thyroid hormone (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease (side effect, side effect)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal disease (side effect)
  advanced cancer
  article
  cancer incidence
  cancer risk
  disease association
  hormone release
  hormone substitution
  human
  hypophysitis (side effect)
  hypothyroidism (side effect)
  image analysis
  medical history
  nonhuman
  radiography
  retrospective study
  thyroiditis (side effect)
CAS REGISTRY NUMBERS
  hypophysis hormone (85883-81-4)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014310482
MEDLINE PMID
  24610577 (http://www.ncbi.nlm.nih.gov/pubmed/24610577)
PUI
  L373013736
DOI
  10.1530/ERC-13-0499
FULL TEXT LINK
  http://dx.doi.org/10.1530/ERC-13-0499
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 336
TITLE
  Opportunistic autoimmune disorders potentiated by immune-checkpoint 
inhibitors anti-CTLA-(4) and anti-PD-(1)
AUTHOR NAMES
  Kong Y.-C.M.
  Flynn J.C.
AUTHOR ADDRESSES
  (Kong Y.-C.M., ykong@med.wayne.edu) Department of Immunology and 
Microbiology, Wayne State University School of Medicine, Detroit, MI, United 
States.
(Flynn J.C.) Department of Orthopaedic Surgery, Providence Hospital and 
Medical Centers, Southfield, MI, United States.
CORRESPONDENCE ADDRESS
  Y.-C.M. Kong, Department of Immunology and Microbiology, Wayne State 
University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201, 
United States. Email: ykong@med.wayne.edu
SOURCE
  Frontiers in Immunology (2014) 5:MAY Article Number: Article 206. Date of 
Publication: 2014
ISSN
  1664-3224 (electronic)
BOOK PUBLISHER
  Frontiers Research Foundation, info@frontiersin.org
ABSTRACT
  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-CD(52), 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 3-5 years. 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. © 2014 Kong and Flynn.
EMTREE DRUG INDEX TERMS
  alemtuzumab (drug therapy)
  bms 936559
  cytokine (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  ipilimumab (drug therapy)
  nivolumab (drug therapy)
  NY ESO 1 antigen (endogenous compound)
  pembrolizumab (drug therapy)
  programmed death 1 ligand 1 (endogenous compound)
  receptor type tyrosine protein phosphatase C (endogenous compound)
  ticilimumab (drug therapy)
  tumor antigen (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmunity
  tumor immunity
EMTREE MEDICAL INDEX TERMS
  apoptosis
  CD25+ T lymphocyte
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  down regulation
  follow up
  genotype
  human
  immunomodulation
  major histocompatibility complex
  melanoma (drug therapy)
  natural killer cell
  nonhuman
  overall survival
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  regulatory T lymphocyte
  short survey
  signal transduction
  tumor regression
  upregulation
  vaccination
DRUG TRADE NAMES
  bms 936559
CAS REGISTRY NUMBERS
  alemtuzumab (216503-57-0)
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014527057
PUI
  L373705220
DOI
  10.3389/fimmu.2014.00206
FULL TEXT LINK
  http://dx.doi.org/10.3389/fimmu.2014.00206
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 337
TITLE
  Endocrinologic side effects of oncologic treatment with 
anti-CTLA-4-antibodies
ORIGINAL (NON-ENGLISH) TITLE
  Endokrinologische Nebenwirkungen einer onkologischen Therapie mit 
Anti-CTLA-4-Antikörpern
AUTHOR NAMES
  Fischli S.
  Allelein S.
  Zander T.
  Henzen C.
AUTHOR ADDRESSES
  (Fischli S., stefan.fischli@luks.ch; Allelein S.; Henzen C.) Departement 
Medizin, Klinik für Endokrinologie, Luzerner Kantonsspital, CH-6000 Luzern, 
Switzerland.
(Zander T.) Departement Medizin, Klinik für Medizinische Onkologie, Luzerner 
Kantonsspital, Luzern, Switzerland.
CORRESPONDENCE ADDRESS
  S. Fischli, Departement Medizin, Klinik für Endokrinologie, Luzerner 
Kantonsspital, CH-6000 Luzern, Switzerland. Email: stefan.fischli@luks.ch
SOURCE
  Deutsche Medizinische Wochenschrift (2014) 139:19 (966-1000). Date of 
Publication: May 2014
ISSN
  1439-4413 (electronic)
  0012-0472
BOOK PUBLISHER
  Georg Thieme Verlag, kunden.service@thieme.de
ABSTRACT
  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 acitivation and hence 
reduction of the tumor-mediated immuntolerance. 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. © Georg Thieme Verlag KG Stuttgart New York ISSN 
0012-0472.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  anti ctla 4 antibody (adverse drug reaction)
  antineoplastic agent
EMTREE DRUG INDEX TERMS
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer chemotherapy
  endocrine disease (side effect, diagnosis, side effect)
  immunopathology (side effect, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  article
  case report
  hormonal therapy
  human
  immunotherapy
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  German
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  2014299371
MEDLINE PMID
  24782152 (http://www.ncbi.nlm.nih.gov/pubmed/24782152)
PUI
  L372982943
DOI
  10.1055/s-0034-1369961
FULL TEXT LINK
  http://dx.doi.org/10.1055/s-0034-1369961
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 338
TITLE
  Ipilimumab-induced orbital inflammation resembling graves disease with 
subsequent development of systemic hyperthyroidism from CTLA-4 receptor 
suppression
AUTHOR NAMES
  Borodic G.E.
  Hinkle D.
AUTHOR ADDRESSES
  (Borodic G.E., borodic@aol.com; Hinkle D.)
CORRESPONDENCE ADDRESS
  G.E. Borodic, Harvard Medical School, 1261 Furance Brook Parkway, Quincy, 
MA, United States. Email: borodic@aol.com
SOURCE
  Ophthalmic Plastic and Reconstructive Surgery (2014) 30:1 (83). Date of 
Publication: January-February 2014
ISSN
  0740-9303
  1537-2677 (electronic)
BOOK PUBLISHER
  Lippincott Williams and Wilkins, 530 Walnut Street,P O Box 327, 
Philadelphia, United States.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  ipilimumab (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  liothyronine (endogenous compound)
  thyroglobulin antibody (endogenous compound)
  thyroid antibody (endogenous compound)
  thyroid peroxidase antibody (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  Graves disease
  hyperthyroidism
  orbit inflammation (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  anxiety
  body weight loss
  diarrhea (side effect)
  disease course
  heart palpitation (side effect)
  heat intolerance (side effect)
  human
  lethargy (side effect)
  letter
  liothyronine blood level
  priority journal
  unspecified side effect (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  liothyronine (6138-47-2, 6893-02-3)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Ophthalmology (12)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  2014071521
MEDLINE PMID
  24398505 (http://www.ncbi.nlm.nih.gov/pubmed/24398505)
PUI
  L372204569
DOI
  10.1097/IOP.0000000000000033
FULL TEXT LINK
  http://dx.doi.org/10.1097/IOP.0000000000000033
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 339
TITLE
  Ipilimumab treatment associated pituitary hypophysitis: Clinical 
presentation and imaging diagnosis
AUTHOR NAMES
  Chodakiewitz Y.
  Brown S.
  Boxerman J.L.
  Brody J.M.
  Rogg J.M.
AUTHOR ADDRESSES
  (Chodakiewitz Y.) Alpert Medical School, Brown University, 222 Richmond St, 
Providence 02903, United States.
(Brown S.; Boxerman J.L.; Brody J.M.; Rogg J.M., jrogg@lifespan.org) 
Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical 
School of Brown University, 593 Eddy Street, Providence 02903, United 
States.
CORRESPONDENCE ADDRESS
  J.M. Rogg, Department of Diagnostic Imaging, Rhode Island Hospital, Alpert 
Medical School of Brown University, 593 Eddy Street, Providence 02903, 
United States. Email: jrogg@lifespan.org
SOURCE
  Clinical Neurology and Neurosurgery (2014) 125 (125-130). Date of 
Publication: October 2014
ISSN
  1872-6968 (electronic)
  0303-8467
BOOK PUBLISHER
  Elsevier
ABSTRACT
  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. © 2014 Elsevier B.V.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
  dexamethasone
  levothyroxine
  sodium (endogenous compound)
  steroid (drug therapy)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse drug reaction (diagnosis)
  hypophysitis (side effect, diagnosis, side effect)
  nuclear magnetic resonance imaging
  pituitary hypophysitis (side effect, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer chemotherapy
  cancer screening
  cancer staging
  cancer surgery
  case report
  chemosurgery
  comparative study
  contrast enhancement
  diagnostic imaging
  differential diagnosis
  encephalitis (drug therapy)
  endocrine disease
  fatigue
  female
  free liothyronine index
  headache
  human
  human tissue
  hyponatremia
  hypopituitarism
  hypothyroidism
  metastatic melanoma (drug therapy, surgery)
  middle aged
  neuroimaging
  pituitary stalk
  positron emission tomography
  sodium blood level
  steroid therapy
  thorax radiography
  thyrotropin blood level
  treatment response
  visual disorder
  wide excision
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  sodium (7440-23-5)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014562995
PUI
  L373818691
DOI
  10.1016/j.clineuro.2014.06.011
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.clineuro.2014.06.011
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 340
TITLE
  Ipilimumab-induced autoimmune hypophysitis: A differential for sellar mass 
lesions
AUTHOR NAMES
  Rodrigues B.T.
  Otty Z.
  Sangla K.
  Shenoy V.V.
AUTHOR ADDRESSES
  (Rodrigues B.T., beverly.rodrigues@my.jcu.edu.au; Sangla K.; Shenoy V.V.) 
Departments of Diabetes and Endocrinology, The Townsville Hospital, 
Townsville, Australia.
(Otty Z.) Departments of Oncology, The Townsville Hospital, Townsville, 
Australia.
(Rodrigues B.T., beverly.rodrigues@my.jcu.edu.au; Shenoy V.V.) School of 
Medicine and Dentistry, James Cook University, Douglas, Australia.
CORRESPONDENCE ADDRESS
  B.T. Rodrigues, Departments of Diabetes and Endocrinology, The Townsville 
Hospital, Townsville, Australia.
SOURCE
  Endocrinology, Diabetes and Metabolism Case Reports (2014) 2014. Date of 
Publication: 2014
ISSN
  2052-0573 (electronic)
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, drug toxicity)
EMTREE DRUG INDEX TERMS
  hydrocortisone
  methylprednisolone
  prednisolone (drug combination, drug therapy, oral drug administration)
  thyroxine (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis
  metastatic melanoma (drug therapy, drug therapy, radiotherapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  anorexia (side effect)
  article
  body weight gain
  case report
  constipation (side effect)
  drug dose reduction
  fatigue (side effect)
  female
  follow up
  glucose blood level
  headache (side effect)
  human
  hydrocortisone blood level
  hypophysis disease (drug therapy)
  hypothyroidism
  immunomodulation
  male
  mental instability (side effect)
  middle aged
  multiple cycle treatment
  nausea (side effect)
  nuclear magnetic resonance imaging
  optic chiasm
  outcome assessment
  pituitary stalk thickness
  pituitary stalk thickness (drug therapy)
  priority journal
  sella turcica tumor
  sellar mass lesion
  somnolence (side effect)
  spine injury (drug therapy)
  T9 vertebra lesion
  T9 vertebra lesion (drug therapy)
CAS REGISTRY NUMBERS
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisolone (50-24-8)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Radiology (14)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015723017
PUI
  L601975417
DOI
  10.1530/EDM-14-0098
FULL TEXT LINK
  http://dx.doi.org/10.1530/EDM-14-0098
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 341
TITLE
  Kidney injuries related to ipilimumab
AUTHOR NAMES
  Izzedine H.
  Gueutin V.
  Gharbi C.
  Mateus C.
  Robert C.
  Routier E.
  Thomas M.
  Baumelou A.
  Rouvier P.
AUTHOR ADDRESSES
  (Izzedine H., hassan.izzedine@psl.aphp.fr; Gueutin V.; Gharbi C.; Baumelou 
A.) Department of Nephrology, Pitie-Salpetriere, 47-80 Boulevard de 
l'Hôpital, 75013 Paris, France.
(Rouvier P.) Department of Pathology, Pitie Salpetriere Hospital, Paris, 
France.
(Mateus C.; Robert C.; Routier E.; Thomas M.) Department of Dermatology, 
INSERM Unit U 981, Gustave Roussy Institute, Villejuif, Paris-Sud, France.
CORRESPONDENCE ADDRESS
  H. Izzedine, Department of Nephrology, Pitie-Salpetriere, 47-80 Boulevard de 
l'Hôpital, 75013 Paris, France. Email: hassan.izzedine@psl.aphp.fr
SOURCE
  Investigational New Drugs (2014) 32:4 (769-773). Date of Publication: August 
2014
ISSN
  1573-0646 (electronic)
  0167-6997
BOOK PUBLISHER
  Springer New York LLC, journals@springer-sbm.com
ABSTRACT
  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. © 2014 Springer Science+Business Media.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  antihistaminic agent (drug combination, drug therapy)
  creatinine (endogenous compound)
  hydrocortisone (drug combination, drug therapy)
  prednisone (drug therapy, oral drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  interstitial nephritis (drug therapy, side effect, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure
  acute kidney tubule necrosis
  adult
  aged
  anorexia (side effect)
  article
  axillary lymph node
  bone metastasis
  case report
  creatinine blood level
  creatinine clearance
  diarrhea (side effect)
  DRESS syndrome (diagnosis, side effect)
  drug withdrawal
  eosinophilia (drug therapy, side effect)
  fatigue (side effect)
  female
  human
  human tissue
  kidney biopsy
  kidney failure
  leukocyturia
  lung metastasis
  lymph node metastasis (radiotherapy)
  male
  metastatic melanoma (drug therapy)
  middle aged
  multiple cycle treatment
  priority journal
  proteinuria
  pruritus (drug therapy, side effect)
  rash (side effect)
  soft tissue metastasis
  tumor regression
CAS REGISTRY NUMBERS
  creatinine (19230-81-0, 60-27-5)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014483588
MEDLINE PMID
  24687600 (http://www.ncbi.nlm.nih.gov/pubmed/24687600)
PUI
  L53082802
DOI
  10.1007/s10637-014-0092-7
FULL TEXT LINK
  http://dx.doi.org/10.1007/s10637-014-0092-7
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 342
TITLE
  Thyroid-like ophthalmopathy in a euthyroid patient receiving Ipilimumab
AUTHOR NAMES
  McElnea E.
  Ní Mhéalóid Á.
  Moran S.
  Kelly R.
  Fulcher T.
AUTHOR ADDRESSES
  (McElnea E., mcelneaelizabeth@gmail.com; Ní Mhéalóid Á.; Moran S.; Kelly R.; 
Fulcher T.) Department of Ophthalmology, Mater Misericordiae University 
Hospital, Eccles Street, Dublin 7, Ireland.
CORRESPONDENCE ADDRESS
  E. McElnea, Department of Ophthalmology, Mater Misericordiae University 
Hospital, Eccles Street, Dublin 7, Ireland.
SOURCE
  Orbit (2014) 33:6 (424-427). Date of Publication: 1 Dec 2014
ISSN
  1744-5108 (electronic)
  0167-6830
BOOK PUBLISHER
  Informa Healthcare, healthcare.enquiries@informa.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  methylprednisolone (intravenous drug administration)
  prednisolone
  thyroid peroxidase antibody (endogenous compound)
  thyrotropin (endogenous compound)
  thyrotropin receptor antibody (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine ophthalmopathy (side effect, diagnosis, side effect)
  euthyroidism
  thyroid like orbitopathy (side effect, side effect, diagnosis)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  case report
  drug withdrawal
  exophthalmos
  extraocular muscle
  eye movement
  eye redness
  female
  free thyroxine index
  human
  liver metastasis
  lung metastasis
  melanoma (drug therapy)
  nuclear magnetic resonance imaging
  ophthalmoplegia
  physical examination
  thyroid function test
  thyrotropin blood level
  treatment duration
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisolone (50-24-8)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014886495
MEDLINE PMID
  25207976 (http://www.ncbi.nlm.nih.gov/pubmed/25207976)
PUI
  L600378837
DOI
  10.3109/01676830.2014.949792
FULL TEXT LINK
  http://dx.doi.org/10.3109/01676830.2014.949792
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 343
TITLE
  Checkpoint inhibitors in immunotherapy of ovarian cancer
AUTHOR NAMES
  Wang D.-H.
  Guo L.
  Wu X.-H.
AUTHOR ADDRESSES
  (Wang D.-H., czwangdonghui@hotmail.com; Guo L.) First Department of 
Gynecology, Cangzhou Central Hospital, Cangzhou, China.
(Wu X.-H.) Department of Gynecology, Bethune International Peace Hospital, 
Shijiazhuang, China.
CORRESPONDENCE ADDRESS
  D.-H. Wang, First Department of Gynecology, Cangzhou Central Hospital, 
Cangzhou, China.
SOURCE
  Tumor Biology (2014) 36:1 (33-39). Date of Publication: 2014
ISSN
  1423-0380 (electronic)
  1010-4283
BOOK PUBLISHER
  Kluwer Academic Publishers
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 antibody (endogenous compound)
  ipilimumab
  nivolumab
  pembrolizumab
  pidilizumab
  programmed death 1 ligand 1 (endogenous compound)
  ticilimumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  cancer cell
  cancer patient
  female
  human
  immune response
  immune system
  nonhuman
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  review
  tumor immunity
  tumor microenvironment
DRUG TRADE NAMES
  bms 936558
  ct 011
  mdx 1106
  medi 4736
  mk 3475
  mpdl 3280a
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  nivolumab (946414-94-4)
  pembrolizumab (1374853-91-4)
  pidilizumab (1036730-42-3)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01611558)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014942003
MEDLINE PMID
  25409618 (http://www.ncbi.nlm.nih.gov/pubmed/25409618)
PUI
  L600643032
DOI
  10.1007/s13277-014-2848-2
FULL TEXT LINK
  http://dx.doi.org/10.1007/s13277-014-2848-2
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 344
TITLE
  Ipilimumab, not just another anti-cancer therapy: hypophysitis as side 
effect illustrated by four case-reports
AUTHOR NAMES
  Marlier J.
  Cocquyt V.
  Brochez L.
  Van Belle S.
  Kruse V.
AUTHOR ADDRESSES
  (Marlier J., Joke.Marlier@ugent.be; Cocquyt V.; Brochez L.; Van Belle S.; 
Kruse V.) Department of Medical Oncology, University Hospital Ghent, De 
Pintelaan 185, Ghent, Belgium.
CORRESPONDENCE ADDRESS
  J. Marlier, Department of Medical Oncology, University Hospital Ghent, De 
Pintelaan 185, Ghent, Belgium.
SOURCE
  Endocrine (2014) 47:3 (878-883). Date of Publication: 21 Nov 2014
ISSN
  1559-0100 (electronic)
  1355-008X
BOOK PUBLISHER
  Humana Press Inc., humana@humanapr.com
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  cisplatin (drug therapy)
  corticotropin (endogenous compound)
  dacarbazine (drug therapy)
  hydrocortisone (adverse drug reaction, drug therapy)
  levothyroxine (drug therapy)
  methylprednisolone (drug therapy)
  prednisone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult
  adverse outcome
  aged
  article
  brain metastasis (complication, diagnosis, radiotherapy)
  cancer radiotherapy
  cancer staging
  case report
  colitis (side effect)
  disease association
  disease severity
  drug safety
  drug substitution
  drug treatment failure
  drug withdrawal
  fatigue (side effect)
  female
  gastroenteritis (side effect)
  human
  hypokalemia (side effect)
  hypotension (side effect)
  hypothyroidism (side effect)
  lymph node metastasis (complication, diagnosis)
  male
  melanoma (drug therapy)
  middle aged
  multiple cycle treatment
  muscle weakness (side effect)
  outcome assessment
  pain (side effect)
  phonophobia (side effect)
  photophobia (side effect)
  retrospective study
  sarcoidosis (side effect)
  treatment indication
  treatment response
  very elderly
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  dacarbazine (4342-03-4)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014767409
MEDLINE PMID
  24554495 (http://www.ncbi.nlm.nih.gov/pubmed/24554495)
PUI
  L53015915
DOI
  10.1007/s12020-014-0199-9
FULL TEXT LINK
  http://dx.doi.org/10.1007/s12020-014-0199-9
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 345
TITLE
  [Classification and etiology of hyperthyroidism].
ORIGINAL (NON-ENGLISH) TITLE
  Podział i etiopatogeneza nadczynności tarczycy.
AUTHOR NAMES
  Łacka K.
  Fraczek M.M.
AUTHOR ADDRESSES
  (Łacka K.; Fraczek M.M.)
CORRESPONDENCE ADDRESS
  K. Łacka,
SOURCE
  Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego (2014) 
36:213 (206-211). Date of Publication: Mar 2014
ISSN
  1426-9686
ABSTRACT
  The prevalence of hyperthyroidism in women is between 0.5-2% and it is 10 
times less common in men. The most common causes are Graves' disease, toxic 
multinodular goiter, and autonomously functioning thyroid adenoma. Rare 
causes of hyperthyroidisms are as follow: pituitary adenoma, autoimmune 
thyroiditis (Hashitoxicosis), levothyroxine overdose, inadequate iodine 
supplementation (including amiodaron induced hyperthyroidism, iodine-based 
contrast media), hCG excess (pregnancy, gestational trophoblastic disease, 
germ-cell tumors), drug induced hyperthyroidism, differentiated thyroid 
carcinomas and/or their metastases, struma ovarii, and familial 
nonautoimmune hyperthyroidism. This article focuses on the current data of 
etiopathogenesis of hyperthyroidisms. Genetic factors (like HLA-DR3,CD40, 
CTLA-4, PTPN22, FOXP3 CD25) and thyroid specific genes (thyroglobulin, TSHR, 
G(s)alpha) and environmental and endogenous factors (such as age, iodine, 
selenium, emotional stress, smoking, gender, pregnancy, sex hormones, fetal 
microchimerism, fetal growth, bacterial infections, viral infections, 
allergies, drugs (alemtuzumab, interferon alpha, iplimumab/tremelimumab, 
tyrosine kinase inhibitors, denileukindiftitox, thalidomide/lenalidomide, 
exposition to fallout and radiotherapy) have been described.
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hyperthyroidism (epidemiology)
EMTREE MEDICAL INDEX TERMS
  age
  autoimmune thyroiditis (epidemiology)
  classification
  epidemiology
  female
  genetics
  goiter (epidemiology)
  Graves disease (epidemiology)
  human
  hypersensitivity (epidemiology)
  infection (epidemiology)
  male
  mental stress (epidemiology)
  pregnancy
  review
  risk factor
  sex ratio
  smoking (epidemiology)
  thyroid tumor (epidemiology)
LANGUAGE OF ARTICLE
  Polish
MEDLINE PMID
  24779222 (http://www.ncbi.nlm.nih.gov/pubmed/24779222)
PUI
  L373230774
COPYRIGHT
  Copyright 2014 Medline is the source for the citation and abstract of this 
record.

RECORD 346
TITLE
  Checkpoint kinase inhibitor azd7762overcomescisplatin resistance in clear 
cell carcinoma of the ovary
AUTHOR NAMES
  Itamochi H.
  Nishimura M.
  Oumi N.
  Kato M.
  Oishi T.
  Shimada M.
  Sato S.
  Naniwa J.
  Sato S.
  Kudoh A.
  Kigawa J.
  Harada T.
AUTHOR ADDRESSES
  (Itamochi H., itamochi@med.tottori-u.ac.jp; Oishi T.; Shimada M.; Sato S.; 
Naniwa J.; Sato S.; Kudoh A.; Harada T.) Department of Obstetrics and 
Gynecology, Tottori University School of Medicine, Yonago, Japan.
(Nishimura M.; Oumi N.; Kato M.; Kigawa J.) Tottori University Hospital 
Cancer Center, Yonago, Japan.
(Itamochi H., itamochi@med.tottori-u.ac.jp) Department of Obstetrics and 
Gynecology, Tottori University School of Medicine, 36-1 Nishicho, Yonago 
683-8504, Japan.
CORRESPONDENCE ADDRESS
  H. Itamochi, Department of Obstetrics and Gynecology, Tottori University 
School of Medicine, 36-1 Nishicho, Yonago 683-8504, Japan. Email: 
itamochi@med.tottori-u.ac.jp
SOURCE
  International Journal of Gynecological Cancer (2014) 24:1 (61-69). Date of 
Publication: Jannuary 2014
ISSN
  1048-891X
  1525-1438 (electronic)
BOOK PUBLISHER
  Lippincott Williams and Wilkins, 530 Walnut Street,P O Box 327, 
Philadelphia, United States.
ABSTRACT
  Objective: Checkpoint kinase (Chk) inhibitors are thought to increase the 
cytotoxic effects of DNA-damaging agents and are undergoing clinical trials. 
The present study was aimed to assess the potential to use the Chk1 and Chk2 
inhibitor, AZD7762, with other anticancer agents in chemotherapy to treat 
ovarian clear cell carcinoma. Methods: Four ovarian clear cell carcinoma 
cell lines were used in this study. We treated the cells with AZD7762 and 
anticancer agents, then assessed cell viability, cell cycle distribution, 
apoptosis, and the expression of protein in apoptotic pathways and molecules 
downstream of the Chk signaling pathways. We also investigated the effects 
of these drug combinations on tumor growth in a nude mouse xenograft model. 
Results: Synergistic effects from the combination of AZD7762 and cisplatin 
were observed in all 4 cell lines. However, we observed additive effects 
when AZD7762 was combined with paclitaxel on all cell lines tested. AZD7762 
effectively suppressed the Chk signaling pathways activated by cisplatin, 
dramatically enhanced expression of phosphorylated H2A.X, cleaved caspase 9 
and PARP, decreased the proportion of cells in the gap 0/ gap 1 phase and 
the synthesis-phase fraction, and increased apoptotic cells. Combinations of 
small interfering RNA against Chk 1 and small interfering RNA against Chk2 
enhanced the cytotoxic effect of cisplatin in both RMG-I and KK cells. 
Finally, treating mice-bearing RMG-I with AZD7762 and cisplatin 
significantly suppressed growth of tumors in a xenograft model. Conclusions: 
The present study indicates that chemotherapy with AZD7762 and cisplatin 
should be explored as a treatment modality for women with ovarian clear cell 
carcinoma. © 2013 by IGCS and ESGO.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide (drug 
combination, drug interaction, drug therapy, intraperitoneal drug 
administration, pharmacology)
  cisplatin (drug combination, drug interaction, drug therapy, intraperitoneal 
drug administration, pharmacology)
EMTREE DRUG INDEX TERMS
  caspase 9 (endogenous compound)
  checkpoint kinase 1 (endogenous compound)
  checkpoint kinase 2 (endogenous compound)
  firtecan (drug combination)
  histone H2AX (endogenous compound)
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
(endogenous compound)
  paclitaxel (drug combination)
  small interfering RNA (drug interaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer resistance
  clear cell carcinoma (drug therapy, drug resistance, drug therapy)
  ovarian clear cell carcinoma (drug therapy, drug therapy)
  ovary carcinoma (drug therapy, drug resistance, drug therapy)
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  animal model
  animal tissue
  apoptosis
  article
  cancer cell culture
  cancer growth
  cancer inhibition
  cancer size
  cell cycle checkpoint
  cell cycle G0 phase
  cell cycle G1 phase
  cell cycle S phase
  cell viability
  cellular distribution
  controlled study
  cytotoxicity
  dose response
  down regulation
  female
  flow cytometry
  human
  human cell
  IC50
  immunofluorescence
  mouse
  nonhuman
  priority journal
  protein expression
  signal transduction
  Western blotting
DRUG TRADE NAMES
  azd 7762  , NetherlandsAxon Medchem

  sn 38  , JapanYakult Honsha

DRUG MANUFACTURERS
   (Netherlands)Axon Medchem
   (United States)Sigma Aldrich
   (Japan)Yakult Honsha
CAS REGISTRY NUMBERS
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide 
(1019773-80-8, 860352-01-8)
  caspase 9 (180189-96-2)
  checkpoint kinase 2 (244634-79-5)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  firtecan (86639-52-3)
  nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 
(58319-92-9)
  paclitaxel (33069-62-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014103542
MEDLINE PMID
  24362713 (http://www.ncbi.nlm.nih.gov/pubmed/24362713)
PUI
  L372332955
DOI
  10.1097/IGC.0000000000000014
FULL TEXT LINK
  http://dx.doi.org/10.1097/IGC.0000000000000014
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 347
TITLE
  Role of podocyte B7-1 in diabetic nephropathy
AUTHOR NAMES
  Fiorina P.
  Vergani A.
  Bassi R.
  Niewczas M.A.
  Altintas M.M.
  Pezzolesi M.G.
  D'Addio F.
  Chin M.
  Tezza S.
  Nasr M.B.
  Mattinzoli D.
  Ikehata M.
  Corradi D.
  Schumacher V.
  Buvall L.
  Yu C.-C.
  Chang J.-M.
  La Rosa S.
  Finzi G.
  Solini A.
  Vincenti F.
  Rastaldi M.P.
  Reiser J.
  Krolewski A.S.
  Mundel P.H.
  Sayegh M.H.
AUTHOR ADDRESSES
  (Fiorina P., paolo.fiorina@childrens.harvard.edu; Vergani A.; Bassi R.; 
D'Addio F.; Chin M.; Tezza S.; Nasr M.B.; Schumacher V.) Nephrology 
Division, Boston Children's Hospital, Harvard Medical School, Boston, United 
States.
(Fiorina P., paolo.fiorina@childrens.harvard.edu; Vergani A.; Bassi R.; 
D'Addio F.) Department of Medicine, San Raffaele Scientific Institute, 
Milan, Italy.
(Bassi R.) DiSTeBA, Universita' Del Salento, Lecce, Italy.
(Niewczas M.A.; Pezzolesi M.G.; Krolewski A.S.) Section on Genetics and 
Epidemiology, Joslin Diabetes Center, Harvard Medical School, Boston, United 
States.
(Altintas M.M.; Reiser J.) Department of Medicine, Rush University Medical 
Center, Chicago, United States.
(Mattinzoli D.; Ikehata M.; Rastaldi M.P.) Renal Research Laboratory, 
Fondazione IRCCS Ospedale Maggiore Policlinico, Fondazione D'Amico per la 
Ricerca Sulle Malattie Renali, Milan, Italy.
(Corradi D.) Department of Biomedical, Biotechnological and Translational 
Sciences, Unit of Pathology, University of Parma, Parma, Italy.
(Buvall L.; Mundel P.H.) Nephrology Division, Massachusetts General 
Hospital, Boston, United States.
(Yu C.-C.) Graduate Institute of Medicine, College of Medicine, Kaohsiung 
Medical University, Kaohsiung, Taiwan.
(Yu C.-C.; Chang J.-M.) Department of Internal Medicine, Kaohsiung Medical 
University, Kaohsiung, Taiwan.
(La Rosa S.; Finzi G.) Pathology Department, Ospedale di Circolo, Varese, 
Italy.
(Solini A.) Department of Clinical and Experimental Medicine, University of 
Pisa, Pisa, Italy.
(Vincenti F.) Kidney Transplant Service, University of San Francisco, San 
Francisco, United States.
(Sayegh M.H.) Transplantation Research Center, Brigham and Women's Hospital, 
Boston, United States.
(Sayegh M.H.) American University of Beirut, Beirut, Lebanon.
CORRESPONDENCE ADDRESS
  P. Fiorina, Division of Nephrology, Boston Children's Hospital-Harvard 
Medical School, Enders Building, 300 Longwood Avenue, Boston, United States.
SOURCE
  Journal of the American Society of Nephrology (2014) 25:7 (1415-1429). Date 
of Publication: 1 Jul 2014
ISSN
  1533-3450 (electronic)
  1046-6673
BOOK PUBLISHER
  American Society of Nephrology, email@asn-online.org
ABSTRACT
  Podocyte injury and resulting albuminuria are hallmarks of diabetic 
nephropathy, but targeted therapies to halt or prevent these complications 
are currently not available. Here, we show that the immune-related molecule 
B7-1/CD80 is a critical mediator of podocyte injury in type 2 diabetic 
nephropathy. We report the induction of podocyte B7-1 in kidney biopsy 
specimens from patients with type 2 diabetes. Genetic and epidemiologic 
studies revealed the association of two single nucleotide polymorphisms at 
the B7-1 gene with diabetic nephropathy. Furthermore, increased levels of 
the soluble isoform of the B7-1 ligand CD28 correlated with the progression 
to ESRD in individuals with type 2 diabetes. In vitro, high glucose 
conditions prompted the phosphatidylinositol 3 kinase-dependent upregulation 
of B7-1 in podocytes, and the ectopic expression of B7-1 in podocytes 
increased apoptosis and induced disruption of the cytoskeleton that were 
reversed by the B7-1 inhibitor CTLA4-Ig. Podocyte expression of B7-1 was 
also induced in vivo in two murine models of diabetic nephropathy, and 
treatment with CTLA4-Ig prevented increased urinary albumin excretion and 
improved kidney pathology in these animals. Taken together, these results 
identify B7-1 inhibition as a potential therapeutic strategy for the 
prevention or treatment of diabetic nephropathy.
EMTREE DRUG INDEX TERMS
  abatacept
  albumin (endogenous compound)
  B7 antigen (endogenous compound)
  CD28 antigen (endogenous compound)
  creatinine (endogenous compound)
  glucose
  hemoglobin A1c (endogenous compound)
  phosphatidylinositol 3 kinase (endogenous compound)
  synaptopodin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cell function
  diabetic nephropathy
  non insulin dependent diabetes mellitus
  podocyte
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  albuminuria
  animal experiment
  animal model
  apoptosis
  article
  cell disruption
  cell structure
  clinical article
  controlled study
  cytoskeleton
  disease course
  end stage renal disease
  female
  fluorescence activated cell sorting
  follow up
  glucose intake
  human
  human tissue
  in vitro study
  kidney biopsy
  kidney function
  male
  middle aged
  mouse
  nonhuman
  priority journal
  protein degradation
  protein expression
  real time polymerase chain reaction
  risk factor
  single nucleotide polymorphism
  upregulation
  Western blotting
CAS REGISTRY NUMBERS
  abatacept (332348-12-6)
  creatinine (19230-81-0, 60-27-5)
  glucose (50-99-7, 84778-64-3)
  hemoglobin A1c (62572-11-6)
  phosphatidylinositol 3 kinase (115926-52-8)
EMBASE CLASSIFICATIONS
  Urology and Nephrology (28)
  Clinical and Experimental Biochemistry (29)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2015805655
MEDLINE PMID
  24676639 (http://www.ncbi.nlm.nih.gov/pubmed/24676639)
PUI
  L602798852
DOI
  10.1681/ASN.2013050518
FULL TEXT LINK
  http://dx.doi.org/10.1681/ASN.2013050518
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 348
TITLE
  Post ASCO update 2014: head and neck cancer
AUTHOR NAMES
  Pall G.
AUTHOR ADDRESSES
  (Pall G., georg.pall@uki.at) Department of Internal Medicine V, 
Hematology/Oncology, University Hospital Innsbruck, Anichstraße 35, 
Innsbruck, Austria.
CORRESPONDENCE ADDRESS
  G. Pall, Department of Internal Medicine V, Hematology/Oncology, University 
Hospital Innsbruck, Anichstraße 35, Innsbruck, Austria.
SOURCE
  Memo - Magazine of European Medical Oncology (2014) 7:4 (231-236). Date of 
Publication: 2014
ISSN
  1865-5076 (electronic)
  1865-5041
BOOK PUBLISHER
  Springer-Verlag Wien, michaela.bolli@springer.at
ABSTRACT
  The aim of this short review is to summarize some of the most important 
abstracts relating to the field of head and neck cancer presented at the 
ASCO Annual Meeting 2014. An Italian study group presented the first 
randomized phase III trial showing improved survival for patients with 
locally advanced squamous carcinoma of the head and neck using induction 
chemotherapy as an add-on to definitive local chemoradiotherapy or 
radiotherapy plus cetuximab. As these data are in contrast to already 
published trials and many questions around this treatment strategy remain 
unanswered, the definitive place of sequential therapies within the 
treatment algorithms remains to be defined. With the phase Ib data on the 
therapeutic efficacy of the anti-PD-1 antibody pembrolizumab released at the 
ASCO meeting we now for the first time have clinical evidence that modern 
immunotherapeutic strategies are worth studying in head and neck cancer. 
Finally, the phase III SELECT trial establishing lenvatinib as another 
therapeutic option in the treatment of radioiodine-refractory thyroid cancer 
will be discussed. In this study the experimental compound was shown to 
improve response rate and progression free survival with an acceptable 
toxicity profile.
EMTREE DRUG INDEX TERMS
  cetuximab (clinical trial, drug therapy)
  cisplatin (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  docetaxel (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  fluorouracil (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  lenvatinib (adverse drug reaction, clinical trial, drug comparison - 
placebo, drug therapy, oral drug administration)
  pembrolizumab (adverse drug reaction, clinical trial, drug therapy, 
intravenous drug administration)
  placebo
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  head and neck squamous cell carcinoma (drug therapy, drug therapy, 
radiotherapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  cancer prognosis
  cancer survival
  chemoradiotherapy
  decreased appetite (side effect)
  diarrhea (side effect)
  disease severity
  drug dose reduction
  drug efficacy
  drug safety
  drug tolerability
  fatigue (side effect)
  febrile neutropenia (side effect)
  human
  hypertransaminasemia (side effect)
  medication compliance
  multiple cycle treatment
  myalgia (side effect)
  nausea (side effect)
  overall survival
  patient compliance
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  progression free survival
  pruritus (side effect)
  quality of life
  randomized controlled trial (topic)
  rash (side effect)
  review
  risk benefit analysis
  thyroid cancer (drug therapy)
  time to treatment
  treatment response
  treatment withdrawal
  unspecified side effect (side effect)
CAS REGISTRY NUMBERS
  cetuximab (205923-56-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  docetaxel (114977-28-5)
  fluorouracil (51-21-8)
  lenvatinib (417716-92-8, 857890-39-2)
  pembrolizumab (1374853-91-4)
EMBASE CLASSIFICATIONS
  Otorhinolaryngology (11)
  Radiology (14)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014941761
PUI
  L600642220
DOI
  10.1007/s12254-014-0183-3
FULL TEXT LINK
  http://dx.doi.org/10.1007/s12254-014-0183-3
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 349
TITLE
  Anti-PD1 following ipilimumab for mucosal melanoma: durable tumor response 
associated with severe hypothyroidism and rhabdomyolysis
AUTHOR NAMES
  Min L.
  Hodi F.S.
AUTHOR ADDRESSES
  (Min L.; Hodi F.S.) Authors' Affiliations: Department of Medical Oncology, 
Dana-Farber Cancer Institute, Boston, Massachusetts
SOURCE
  Cancer immunology research (2014) 2:1 (15-18). Date of Publication: 1 Jan 
2014
ISSN
  2326-6074 (electronic)
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  antineoplastic agent (pharmacology, drug therapy)
  cytotoxic T lymphocyte antigen 4
  ipilimumab
  monoclonal antibody (pharmacology, drug therapy)
  pembrolizumab
  programmed death 1 receptor
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  pathology
EMTREE MEDICAL INDEX TERMS
  antagonists and inhibitors
  case report
  human
  hypothyroidism (diagnosis, etiology)
  male
  melanoma (drug therapy)
  middle aged
  mucosa
  rhabdomyolysis (diagnosis, etiology)
  treatment outcome
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  pembrolizumab (1374853-91-4)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  24778161 (http://www.ncbi.nlm.nih.gov/pubmed/24778161)
PUI
  L602066018
DOI
  10.1158/2326-6066.CIR-13-0146
FULL TEXT LINK
  http://dx.doi.org/10.1158/2326-6066.CIR-13-0146
COPYRIGHT
  Copyright 2015 Medline is the source for the citation and abstract of this 
record.

RECORD 350
TITLE
  Ipilimumab compassive treatment of metastatic melanoma in Mexico: A case 
series
ORIGINAL (NON-ENGLISH) TITLE
  Tratamiento compasivo con ipilimumab en melanoma metastásico en México: Una 
serie de casos
AUTHOR NAMES
  Álvarez-Avitia M.Á.
  García-Pinzón S.
  González-Trujillo J.L.
  Villalobos-Prieto A.
  Rodríguez-Abraján G.
  Matus-Santos J.
AUTHOR ADDRESSES
  (Álvarez-Avitia M.Á., calis-fue@hotmail.com) Instituto Nacional de 
Cancerología, Secretaría de Salud, México D.F., Mexico.
(García-Pinzón S.) Departamento de Oncología Médica, Hospital Regional de 
Alta Especialidad Dr. Juan Graham Casasús, Villahermosa, Tab., Mexico.
(González-Trujillo J.L.) Fundación Rodolfo Padilla Padilla A.C., León, Gto., 
Mexico.
(Villalobos-Prieto A.) Centro de Cáncer, Hospital ABC, México D.F., Mexico.
(Rodríguez-Abraján G.) Corporativo de Oncología Médica Y Radioterapia del 
Noroeste, Monterrey, N.L., Mexico.
(Matus-Santos J.) Centro Oncológico Diana Laura Riojas de Colosio, Hospital 
Médica Sur, México D.F., Mexico.
CORRESPONDENCE ADDRESS
  M.Á. Álvarez-Avitia, Instituto Nacional de Cancerología, Secretaría de 
Salud, México D.F., Mexico. Email: calis-fue@hotmail.com
SOURCE
  Gaceta Mexicana de Oncologia (2014) 13:2 (112-116). Date of Publication: 
March-April 2014
ISSN
  1665-9201
BOOK PUBLISHER
  Masson-Doyma Mexico, S.A., smeo@prodigy.net.mx
ABSTRACT
  Introduction: Innovations such as ipilimumab, for the treatment of 
immunogenic tumors like metastatic melanoma are available. Objective: 
Describe Progression Free Survival (PFS) in weeks and Overall Survival (OS) 
in weeks with ipilimumab in patients with resistant metastatic melanoma. 
Method: A prospective cohort study was performed. Subjects were recruited 
from 6 oncologic units in Mexico with metastatic melanoma resistant to at 
least 2 treatment interventions. All ethical issues were complied to 
participate. Four cycles of ipilimumab (dose 10 mg/Kg of weight) at weeks 1, 
4, 7 and 10 were administered. Results: Forty one subjects were included. 
Mean age 54.02 ± 17.03 years and female 28 (68.3%). At the end point 24 
(58.5%) died and 17 (41.5%) survived. Median (95% CI) for the PFS in weeks 
was 24.5 (95% CI=15.3-33.7) and for OS in weeks was 50.7 (95% CI=28.4-72.9) 
under ipilimumab treatment. The OS in weeks from the diagnosis date to 
end-point was 128 (95% CI=37.5-218.4). In Cox regression, the only 
statistical predictor was disease stage at diagnosis for PFS in weeks (Beta 
0.677; p=0.03). Reported immune adverse events were hepatic toxicity 2 
(4.8%), pruritus 5 (12.2%), fatigue 8 (19.5%), skin reaction 2 (4.8%), 
endocrine 3 (7.3%), orchitis 1 (2.4%), diarrhea 2 (4.8%), constipation 1 
(2.4%). Discussion: Findings were similar with previous similar series. © 
2014 Gaceta Mexicana de Oncología. Publicado por Masson Doyma México S.A.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  clinical article
  cohort analysis
  constipation (side effect)
  diarrhea (side effect)
  endocrine disease (side effect)
  fatigue (side effect)
  female
  human
  liver toxicity (side effect)
  male
  multiple cycle treatment
  orchitis (side effect)
  overall survival
  progression free survival
  prospective study
  pruritus (side effect)
  skin manifestation (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Spanish
LANGUAGE OF SUMMARY
  English, Spanish
EMBASE ACCESSION NUMBER
  2014532135
PUI
  L373722158
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 351
TITLE
  Ipilimumab-induced hypophysitis: A detailed longitudinal analysis in a large 
cohort of patients with metastatic melanoma
AUTHOR NAMES
  Faje A.T.
  Sullivan R.
  Lawrence D.
  Tritos N.A.
  Fadden R.
  Klibanski A.
  Nachtigall L.
AUTHOR ADDRESSES
  (Faje A.T., afaje@partners.org; Tritos N.A.; Klibanski A.; Nachtigall L.) 
Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical 
School, Massachusetts General Hospital, 55 Fruit Street, Boston, United 
States.
(Sullivan R.; Lawrence D.; Fadden R.) Center for Melanoma, Massachusetts 
General Hospital Cancer Center, Boston, United States.
CORRESPONDENCE ADDRESS
  A.T. Faje, Neuroendocrine Unit, Massachusetts General Hospital and Harvard 
Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, 
United States.
SOURCE
  Journal of Clinical Endocrinology and Metabolism (2014) 99:11 (4078-4085). 
Date of Publication: 1 Nov 2014
ISSN
  1945-7197 (electronic)
  0021-972X
BOOK PUBLISHER
  Endocrine Society, mzendell@endo-society.org
ABSTRACT
  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.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.Design: This was a retrospective review.Setting: The study was 
conducted at a tertiary referral center.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.Intervention(s): The intervention included treatment with Ipi.Main 
Outcome Measure(s): Pituitary magnetic resonance imaging, pituitary hormone 
assessment, and patient survival were measured.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.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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  glucocorticoid (drug therapy)
  hydrocortisone (drug therapy, intravenous drug administration)
  hypophysis hormone (endogenous compound)
  prednisone (drug therapy)
  thyroid hormone
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  age
  aged
  cancer patient
  cancer survival
  clinical article
  cohort analysis
  disease course
  drug approval
  drug dose reduction
  drug megadose
  female
  food and drug administration
  gender
  general hospital
  hormone determination
  human
  hypophysis disease
  hypophysis function
  hypopituitarism (diagnosis)
  hypothyroidism (side effect)
  incidence
  longitudinal study
  male
  nuclear magnetic resonance imaging
  prevalence
  priority journal
  retrospective study
  review
  risk factor
  sensitivity and specificity
  survival prediction
  survival time
  tertiary care center
  thyrotoxicosis (side effect)
  treatment outcome
  United States
  very elderly
CAS REGISTRY NUMBERS
  hydrocortisone (50-23-7)
  hypophysis hormone (85883-81-4)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Endocrinology (3)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014903538
MEDLINE PMID
  25078147 (http://www.ncbi.nlm.nih.gov/pubmed/25078147)
PUI
  L600456830
DOI
  10.1210/jc.2014-2306
FULL TEXT LINK
  http://dx.doi.org/10.1210/jc.2014-2306
COPYRIGHT
  Copyright 2015 Elsevier B.V., All rights reserved.

RECORD 352
TITLE
  Ipilimumab treatment associated pituitary hypophysitis: Clinical 
presentation and imaging diagnosis
AUTHOR NAMES
  Chodakiewitz Y.
  Brown S.
  Boxerman J.L.
  Brody J.M.
  Rogg J.M.
AUTHOR ADDRESSES
  (Chodakiewitz Y.) Alpert Medical School, Brown University, 222 Richmond St, 
Providence, United States.
(Brown S.; Boxerman J.L.; Brody J.M.; Rogg J.M., jrogg@lifespan.org) 
Department of Diagnostic Imaging, Rhode Island Hospital, Alpert Medical 
School of Brown University, 593 Eddy Street, Providence, United States.
CORRESPONDENCE ADDRESS
  J.M. Rogg, Department of Diagnostic Imaging, Rhode Island Hospital, Alpert 
Medical School of Brown University, 593 Eddy Street, Providence, United 
States.
SOURCE
  Clinical Neurology and Neurosurgery (2014) 125 (125-130). Date of 
Publication: October 2014
ISSN
  1872-6968 (electronic)
  0303-8467
BOOK PUBLISHER
  Elsevier
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  dexamethasone
  hydrocortisone (drug combination, drug therapy)
  levothyroxine (drug combination, drug therapy)
  sodium (endogenous compound)
  steroid (drug combination)
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (side effect, diagnosis, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  blood pressure
  brain metastasis (diagnosis, radiotherapy, surgery)
  bronchoscopy
  case report
  clinical feature
  contrast enhancement
  craniotomy
  differential diagnosis
  endocrine disease
  fatigue (side effect)
  female
  follow up
  free thyroxine index
  gamma knife radiosurgery
  headache
  human
  hyponatremia (side effect)
  hypophysis
  hypopituitarism (drug therapy, side effect)
  hypotension (side effect)
  hypothyroidism (drug therapy, side effect)
  metastatic melanoma (drug therapy)
  morphology
  multiple cycle treatment
  nuclear magnetic resonance imaging
  pituitary stalk
  positron emission tomography
  radiodiagnosis
  review
  sodium blood level
  steroid therapy
  visual disorder (side effect)
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  sodium (7440-23-5)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Neurology and Neurosurgery (8)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014803712
PUI
  L600037682
DOI
  10.1016/j.clineuro.2014.06.011
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.clineuro.2014.06.011
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 353
TITLE
  Advantages of Papio anubis for preclinical testing of immunotoxicity of 
candidate therapeutic antagonist antibodies targeting CD28
AUTHOR NAMES
  Poirier N.
  Mary C.
  Le Bas-Bernardet S.
  Daguin V.
  Belarif L.
  Chevalier M.
  Hervouet J.
  Minault D.
  Ville S.
  Charpy V.
  Blancho G.
  Vanhove B.
AUTHOR ADDRESSES
  (Poirier N.; Mary C.; Le Bas-Bernardet S.; Daguin V.; Belarif L.; Chevalier 
M.; Hervouet J.; Minault D.; Ville S.; Charpy V.; Blancho G.; Vanhove B., 
bernard.vanhove@univ-nantes.fr) Institut National de la Sante et de la 
Recherche Medicale Unite Mixte de Recherche, Institut de Transplantation 
Urologie Néphrologie (ITUN), Université de Nantes, Nantes, France.
(Poirier N.; Mary C.; Vanhove B., bernard.vanhove@univ-nantes.fr) Effimune 
SAS, Nantes, France.
(Le Bas-Bernardet S.; Blancho G.) Centre Hospitalier Universitaire, Nantes, 
France.
CORRESPONDENCE ADDRESS
  B. Vanhove, Institut National de la Sante et de la Recherche Medicale Unite 
Mixte de Recherche, Institut de Transplantation Urologie Néphrologie (ITUN), 
Université de Nantes, Nantes, France. Email: bernard.vanhove@univ-nantes.fr
SOURCE
  mAbs (2014) 6:3 (698-707). Date of Publication: May/June 2014
ISSN
  1942-0870 (electronic)
  1942-0862
BOOK PUBLISHER
  Landes Bioscience, kmitchell@landesbioscience.com
ABSTRACT
  Antagonist anti-CD28 antibodies prevent T-cell costimulation and are 
functionally different from CTLA4Ig since they cannot block CTLA-4 and PDL-1 
co-inhibitory signals. They demonstrated preclinical efficacy in suppressing 
effector T cells while enhancing immunoregulatory mechanisms. Because a 
severe cytokine release syndrome was observed during the Phase 1 study with 
the superagonist anti-CD28 TGN1412, development of other anti-CD28 
antibodies requires careful preclinical evaluation to exclude any potential 
immunotoxicity side-effects. The failure to identify immunological toxicity 
of TGN1412 using macaques led us to investigate more relevant preclinical 
models. We report here that contrary to macaques, and like in man, all 
baboon CD4-positive T lymphocytes express CD28 in their effector memory 
cells compartment, a lymphocyte subtype that is the most prone to releasing 
cytokines after reactivation. Baboon lymphocytes are able to release 
pro-inflammatory cytokines in vitro in response to agonist or superagonist 
anti-CD28 antibodies. Furthermore, we compared the reactivity of human and 
baboon lymphocytes after transfer into non obese diabetic/severe combined 
immunodeficiency (NOD/SCID) interleukin-2rγ knockout mice and confirmed that 
both cell types could release inflammatory cytokines in situ after injection 
of agonistic anti-CD28 antibodies. In contrast, FR104, a monovalent 
antagonistic anti-CD28 antibody, did not elicit T cell activation in these 
assays, even in the presence of anti-drug antibodies. Infusion to baboons 
also resulted in an absence of cytokine release. In conclusion, the baboon 
represents a suitable species for preclinical immunotoxicity evaluation of 
anti-CD28 antibodies because their effector memory T cells do express CD28 
and because cytokine release can be assessed in vitro and trans vivo. © 2014 
Landes Bioscience.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  anc 28.1 (drug toxicity)
  fr 104 (drug toxicity)
  immunoglobulin F(ab) fragment (drug toxicity)
  monoclonal antibody CD28 (drug toxicity)
EMTREE DRUG INDEX TERMS
  CD28 antigen (endogenous compound)
  gamma interferon (endogenous compound)
  interleukin 12p70 (endogenous compound)
  interleukin 2 (endogenous compound)
  interleukin 2 receptor gamma (endogenous compound)
  interleukin 4 (endogenous compound)
  interleukin 5 (endogenous compound)
  interleukin 6 (endogenous compound)
  tumor necrosis factor (endogenous compound)
  tumor necrosis factor receptor superfamily member 6 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunotoxicity
  Papio anubis
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  article
  CD4+ T lymphocyte
  cell compartmentalization
  controlled study
  cytokine release
  drug half life
  effector cell
  human
  human cell
  immunogenicity
  in vitro study
  in vivo study
  limit of detection
  lymphocyte proliferation
  maximum plasma concentration
  memory cell
  memory T lymphocyte
  mouse
  nonhuman
  T lymphocyte activation
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
  interleukin 2 (85898-30-2)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Toxicology (52)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2014308214
MEDLINE PMID
  24598534 (http://www.ncbi.nlm.nih.gov/pubmed/24598534)
PUI
  L373007358
DOI
  10.4161/mabs.28375
FULL TEXT LINK
  http://dx.doi.org/10.4161/mabs.28375
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 354
TITLE
  Ipilimumab, a cause of autoimmune hypophysitis
ORIGINAL (NON-ENGLISH) TITLE
  Ipilimumab, una causa de hipofisitis autoinmunitaria
AUTHOR NAMES
  De Hollanda A.
  Aranda G.B.
  Mora M.
  Gaba L.
  Halperin I.
AUTHOR ADDRESSES
  (De Hollanda A., amdehol@clinic.ub.es; Aranda G.B.; Mora M.; Halperin I.) 
Servicio de Endocrinología y Nutrición, Hospital Clínic, Universitat de 
Barcelona, Barcelona, Spain.
(Gaba L.) Servicio de Oncología, Hospital Clínic, Universitat de Barcelona, 
Barcelona, Spain.
CORRESPONDENCE ADDRESS
  A. De Hollanda, Servicio de Endocrinología y Nutrición, Hospital Clínic, 
Universitat de Barcelona, Barcelona, Spain. Email: amdehol@clinic.ub.es
SOURCE
  Endocrinologia y Nutricion (2013) 60:10 (604-606). Date of Publication: 
December 2013
ISSN
  1575-0922
  1579-2021 (electronic)
BOOK PUBLISHER
  Elsevier Doyma, Traversa de Gracia 17-21, Barcelona, Spain.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease (side effect, side effect)
  hypophysitis (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  human
  letter
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Spanish
EMBASE ACCESSION NUMBER
  2013768633
MEDLINE PMID
  23607982 (http://www.ncbi.nlm.nih.gov/pubmed/23607982)
PUI
  L52545819
DOI
  10.1016/j.endonu.2013.01.007
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.endonu.2013.01.007
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 355
TITLE
  MAbs and pituitary dysfunction: Clinical evidence and pathogenic hypotheses
AUTHOR NAMES
  Torino F.
  Barnabei A.
  Paragliola R.M.
  Marchetti P.
  Salvatori R.
  Corsello S.M.
AUTHOR ADDRESSES
  (Torino F.) Department of Systems Medicine, Medical Oncology, Tor Vergata 
University of Rome, Rome, Italy.
(Barnabei A.) Endocrinology Unit, Regina Elena National Cancer Institute, 
Rome, Italy.
(Paragliola R.M.; Corsello S.M., corsello.sm@mclink.it) Endocrinology Unit, 
Università Cattolica, Largo A. Gemelli, 8 - I-00168 Rome, Italy.
(Marchetti P.) Medical Oncology Division, Department of Clinical and 
Molecular Medicine, Sapienza University of Rome, Rome, Italy.
(Salvatori R.) Division of Endocrinology, John Hopkins University School of 
Medicine, Pituitary Center, Baltimore, MD, United States.
CORRESPONDENCE ADDRESS
  S.M. Corsello, Endocrinology Unit, Università Cattolica, Largo A. Gemelli, 8 
- I-00168 Rome, Italy. Email: corsello.sm@mclink.it
SOURCE
  European Journal of Endocrinology (2013) 169:6 (R153-R164). Date of 
Publication: December 2013
ISSN
  0804-4643
  1479-683X (electronic)
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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. 
© 2013 European Society of Endocrinology.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  monoclonal antibody (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  atezolizumab
  bevacizumab (clinical trial, drug combination, drug therapy)
  bms 936559
  carboplatin (clinical trial, drug combination, drug therapy)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy, intravenous drug administration, pharmacology)
  nivolumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  paclitaxel (clinical trial, drug combination, drug therapy)
  pembrolizumab (clinical trial, drug therapy)
  ticilimumab (adverse drug reaction, clinical trial, drug therapy, 
intravenous drug administration, pharmacology)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysis disease (drug therapy, side effect, complication, drug therapy, 
etiology, side effect)
  pituitary dysfunction (drug therapy, side effect, complication, drug 
therapy, etiology, side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  aseptic meningitis (side effect)
  autoimmunity
  brain cancer (radiotherapy)
  brain metastasis (radiotherapy)
  cancer patient
  cancer radiotherapy
  childhood cancer
  clinical feature
  drug dose escalation
  drug dose reduction
  drug efficacy
  drug mechanism
  episcleritis (side effect)
  gastrointestinal symptom (side effect)
  Guillain Barre syndrome (side effect)
  heart disease (side effect)
  hematologic malignancy (drug therapy)
  human
  hyperthyroidism (side effect)
  hypophysis function
  hypophysitis (side effect)
  hypopituitarism (side effect)
  hypothyroidism (side effect)
  kidney disease (side effect)
  liver disease (side effect)
  lung disease (side effect)
  melanoma (drug therapy)
  metastatic melanoma (drug therapy)
  multiple cycle treatment
  myasthenia gravis (side effect)
  non small cell lung cancer (drug therapy)
  optic nerve disease (side effect)
  pancreas disease (side effect)
  pathogenesis
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  pure red cell anemia (side effect)
  review
  skin disease (side effect)
  solid malignant neoplasm (drug therapy)
  thyroid disease (side effect)
  thyroiditis (side effect)
  tumor immunity
  uveitis (side effect)
DRUG TRADE NAMES
  bms 936558
  mdx 1106
  mpdl 3280a
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  carboplatin (41575-94-4)
  ipilimumab (477202-00-9)
  lambrolizumab (1374853-91-4)
  nivolumab (946414-94-4)
  paclitaxel (33069-62-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013744615
MEDLINE PMID
  24001893 (http://www.ncbi.nlm.nih.gov/pubmed/24001893)
PUI
  L370338100
DOI
  10.1530/EJE-13-0434
FULL TEXT LINK
  http://dx.doi.org/10.1530/EJE-13-0434
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 356
TITLE
  Thyroid dysfunction as an unintended side effect of anticancer drugs
AUTHOR NAMES
  Torino F.
  Barnabei A.
  Paragliola R.
  Baldelli R.
  Appetecchia M.
  Corsello S.M.
AUTHOR ADDRESSES
  (Torino F.) Department of Systems Medicine, Tor Vergata University of Rome, 
Rome, Italy.
(Barnabei A.; Baldelli R.; Appetecchia M.) Endocrinology Unit, Regina Elena 
National Cancer Institute, Rome, Italy.
(Paragliola R.; Corsello S.M., corsello.sm@mclink.it) Endocrinology Unit, 
Università Cattolica, Via Federico Cesi, 72-I-00193 Roma, Italy.
CORRESPONDENCE ADDRESS
  S.M. Corsello, Endocrinology Unit, Università Cattolica, Via Federico Cesi, 
72-I-00193 Roma, Italy. Email: corsello.sm@mclink.it
SOURCE
  Thyroid (2013) 23:11 (1345-1366). Date of Publication: 1 Nov 2013
ISSN
  1050-7256
  1557-9077 (electronic)
BOOK PUBLISHER
  Mary Ann Liebert Inc., 140 Huguenot Street, New Rochelle, United States.
ABSTRACT
  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. 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-α 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. 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. © Mary Ann Liebert, Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  (3 iodobenzyl)guanidine i 131 (adverse drug reaction, drug combination, drug 
therapy)
  alemtuzumab (adverse drug reaction, drug therapy)
  alpha interferon (adverse drug reaction, drug therapy)
  bevacizumab (adverse drug reaction, drug combination, pharmacology)
  bexarotene (adverse drug reaction, drug therapy, pharmacology)
  bleomycin (adverse drug reaction, drug combination, drug therapy)
  chlormethine (adverse drug reaction, drug combination, drug therapy)
  cisplatin (adverse drug reaction, drug combination, drug therapy)
  dactinomycin (adverse drug reaction, drug combination, drug therapy)
  denileukin diftitox (adverse drug reaction, drug therapy, pharmacology)
  etoposide (adverse drug reaction, drug combination, drug therapy)
  imatinib (adverse drug reaction, drug comparison, drug therapy, 
pharmacology)
  interleukin 2 (adverse drug reaction, drug combination, drug therapy, 
pharmacology, subcutaneous drug administration)
  ipilimumab (adverse drug reaction, drug combination, drug therapy, 
pharmacology)
  lenalidomide (adverse drug reaction, drug combination, drug therapy, 
pharmacology)
  nilotinib (adverse drug reaction, drug comparison, drug therapy, 
pharmacology)
  pazopanib (drug therapy, pharmacology)
  peginterferon alpha2b (adverse drug reaction, drug therapy, 
pharmacokinetics)
  prednisolone (adverse drug reaction, drug combination, drug therapy)
  prednisone (adverse drug reaction, drug combination)
  procarbazine (adverse drug reaction, drug combination, drug therapy)
  protein tyrosine kinase inhibitor (adverse drug reaction)
  sorafenib (adverse drug reaction, drug combination, drug therapy, 
pharmacokinetics, pharmacology)
  sunitinib (adverse drug reaction, drug combination, drug dose, drug therapy, 
pharmacology)
  thalidomide (adverse drug reaction, drug therapy, pharmacology)
  ticilimumab (adverse drug reaction, pharmacology)
  tositumomab (adverse drug reaction, drug combination, drug therapy)
  unindexed drug
  vinblastine (adverse drug reaction, drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  multimodality cancer therapy
  thyroid disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  5q- syndrome (drug therapy)
  advanced cancer (drug therapy)
  antiangiogenic activity
  antineoplastic activity
  autoimmune disease (drug therapy)
  breast cancer (drug therapy)
  cancer adjuvant therapy
  cancer combination chemotherapy
  cancer immunotherapy
  cancer radiotherapy
  cancer survival
  carcinoid (drug therapy)
  chronic lymphatic leukemia (drug therapy)
  chronic myeloid leukemia (drug therapy)
  colitis (side effect)
  colorectal cancer (drug therapy)
  cutaneous melanoma (drug therapy)
  cutaneous T cell lymphoma (drug therapy)
  dermatitis (side effect)
  diarrhea (side effect)
  dose response
  drug approval
  drug clearance
  drug dose increase
  drug efficacy
  drug half life
  drug hypersensitivity (side effect)
  drug mechanism
  drug megadose
  drug potency
  drug receptor binding
  drug specificity
  drug targeting
  drug tolerability
  drug withdrawal
  endocrine disease (side effect)
  endocrine ophthalmopathy (side effect)
  Goodpasture syndrome (side effect)
  graft versus host reaction (drug therapy)
  Graves disease (side effect)
  hematologic malignancy (drug therapy)
  hepatitis (side effect)
  hepatitis B (drug therapy)
  Hodgkin disease (drug therapy)
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  induction chemotherapy
  Kaposi sarcoma (drug therapy)
  kidney carcinoma (drug therapy)
  low drug dose
  lung cancer (drug therapy)
  melanoma (drug therapy)
  metastatic melanoma (drug therapy)
  monotherapy
  multiple myeloma (drug therapy)
  multiple sclerosis (drug therapy)
  neuroblastoma (drug therapy)
  neutropenia (side effect)
  nonhodgkin lymphoma (drug therapy)
  nonhuman
  pancreas cancer (drug therapy)
  pathophysiology
  pheochromocytoma (drug therapy)
  priority journal
  prostate cancer (drug therapy)
  radioimmunotherapy
  renal clearance
  review
  side effect (side effect)
  soft tissue sarcoma (drug therapy)
  solid malignant neoplasm (drug therapy)
  subclinical hyperthyroidism (side effect)
  subclinical hypothyroidism (side effect)
  testis cancer (drug therapy)
  thrombocytopenic purpura (side effect)
  thyroid cancer (drug therapy)
  thyroid function
  thyroiditis (side effect)
  thyrotoxicosis (side effect)
  thyrotropin blood level
  treatment duration
  treatment response
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  (3 iodobenzyl)guanidine i 131 (77679-27-7)
  alemtuzumab (216503-57-0)
  bevacizumab (216974-75-3)
  bexarotene (153559-49-0)
  bleomycin (11056-06-7, 9041-93-4)
  chlormethine (51-75-2, 55-86-7, 82905-71-3)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  dactinomycin (1402-38-6, 1402-58-0, 50-76-0)
  denileukin diftitox (173146-27-5)
  etoposide (33419-42-0)
  imatinib (152459-95-5, 220127-57-1)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  lenalidomide (191732-72-6)
  nilotinib (641571-10-0)
  pazopanib (444731-52-6, 635702-64-6)
  peginterferon alpha2b (215647-85-1)
  prednisolone (50-24-8)
  prednisone (53-03-2)
  procarbazine (366-70-1, 671-16-9)
  sorafenib (284461-73-0)
  sunitinib (341031-54-7, 557795-19-4)
  thalidomide (50-35-1)
  ticilimumab (745013-59-6)
  tositumomab (208921-02-2)
  vinblastine (865-21-4)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013712263
MEDLINE PMID
  23750887 (http://www.ncbi.nlm.nih.gov/pubmed/23750887)
PUI
  L370244392
DOI
  10.1089/thy.2013.0241
FULL TEXT LINK
  http://dx.doi.org/10.1089/thy.2013.0241
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 357
TITLE
  Hypophysitis caused by ipilimumab in cancer patients: Hormone replacement or 
immunosuppressive therapy
AUTHOR NAMES
  Lammert A.
  Schneider H.J.
  Bergmann T.
  Benck U.
  Krämer B.K.
  Gärtner R.
  Metzner C.
  Schöfl C.
  Berking C.
AUTHOR ADDRESSES
  (Lammert A., alexander.lammert@umm.de; Benck U.; Krämer B.K.) Fifth Medical 
Clinic, University Medical Center Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 
Mannheim, Germany.
(Schneider H.J.; Gärtner R.) Division of Endocrinology, Department of 
Medicine IV, Ludwig-Maximilians University, Munich, Germany.
(Bergmann T.; Schöfl C.) Division of Endocrinology and Diabetes, Department 
of Medicine i, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, 
Germany.
(Metzner C.) Department of Medicine i and Clinical Chemistry, University of 
Heidelberg, Heidelberg, Germany.
(Berking C.) Department of Dermatology and Allergology, Ludwig-Maximilians 
University, Munich, Germany.
CORRESPONDENCE ADDRESS
  A. Lammert, Fifth Medical Clinic, University Medical Center Mannheim, 
Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Email: 
alexander.lammert@umm.de
SOURCE
  Experimental and Clinical Endocrinology and Diabetes (2013) 121:10 
(581-587). Date of Publication: 11 Oct 2013
ISSN
  0947-7349
  1439-3646 (electronic)
BOOK PUBLISHER
  Georg Thieme Verlag, Rudigerstrasse 14, Stuttgart, Germany.
ABSTRACT
  Purpose: 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. Methods and Results: 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. 
Conclusion: 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. © J. A. 
Barth Verlag in Georg Thieme Verlag KG Stuttgart New York ISSN 0947-7349.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  corticosteroid (drug therapy)
  dexamethasone (drug therapy, oral drug administration)
  fluocortolone (drug therapy)
  hydrocortisone (drug therapy)
  levothyroxine (drug therapy)
  prednisolone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, drug therapy, side effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  brain metastasis
  cancer patient
  clinical article
  corticosteroid therapy
  diarrhea (side effect)
  drug dose reduction
  drug megadose
  drug withdrawal
  female
  gastrointestinal symptom (side effect)
  hormone substitution
  hospitalization
  human
  human tissue
  hypopituitarism
  immunosuppressive treatment
  male
  priority journal
  prostate cancer
  prostate carcinoma (drug therapy)
  pruritus (side effect)
  rash (side effect)
  treatment duration
  tumor regression
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  fluocortolone (152-97-6)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  prednisolone (50-24-8)
EMBASE CLASSIFICATIONS
  Neurology and Neurosurgery (8)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013766037
MEDLINE PMID
  24122241 (http://www.ncbi.nlm.nih.gov/pubmed/24122241)
PUI
  L52811855
DOI
  10.1055/s-0033-1355337
FULL TEXT LINK
  http://dx.doi.org/10.1055/s-0033-1355337
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 358
TITLE
  Panobinostat Synergistically Enhances the Cytotoxic Effects of Cisplatin, 
Doxorubicin or Etoposide on High-Risk Neuroblastoma Cells
AUTHOR NAMES
  Wang G.
  Edwards H.
  Caldwell J.T.
  Buck S.A.
  Qing W.Y.
  Taub J.W.
  Ge Y.
  Wang Z.
AUTHOR ADDRESSES
  (Wang G.; Taub J.W.; Wang Z., Jwang2@med.wayne.edu) Department of 
Pediatrics, Wayne State University School of Medicine, Detroit, MI, United 
States.
(Wang G.; Ge Y., gey@karmanos.org) College of Life Science, Jilin 
University, Changchun, China.
(Edwards H.; Qing W.Y.; Ge Y., gey@karmanos.org) Department of Oncology, 
Wayne State University School of Medicine, Detroit, MI, United States.
(Edwards H.; Qing W.Y.; Ge Y., gey@karmanos.org) Molecular Therapeutics 
Program, Barbara Ann Karmanos Cancer Institute, Wayne State University 
School of Medicine, Detroit, MI, United States.
(Caldwell J.T.) MD/PhD Program, Wayne State University School of Medicine, 
Detroit, MI, United States.
(Caldwell J.T.) Cancer Biology Program, Wayne State University School of 
Medicine, Detroit, MI, United States.
(Buck S.A.; Taub J.W.; Wang Z., Jwang2@med.wayne.edu) Division of Pediatric 
Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, United 
States.
CORRESPONDENCE ADDRESS
  Y. Ge, College of Life Science, Jilin University, Changchun, China. Email: 
gey@karmanos.org
SOURCE
  PLoS ONE (2013) 8:9 Article Number: e76662. Date of Publication: 30 Sep 2013
ISSN
  1932-6203 (electronic)
BOOK PUBLISHER
  Public Library of Science, 185 Berry Street, Suite 1300, San Francisco, 
United States.
ABSTRACT
  High-risk neuroblastoma remains a therapeutic challenge with a long-term 
survival rate of less than 40%. Therefore, new agents are urgently needed to 
overcome chemotherapy resistance so as to improve the treatment outcome of 
this deadly disease. Histone deacetylase (HDAC) inhibitors (HDACIs) 
represent a novel class of anticancer drugs. Recent studies demonstrated 
that HDACIs can down-regulate the CHK1 pathway by which cancer cells can 
develop resistance to conventional chemotherapy drugs. This prompted our 
hypothesis that combining HDACIs with DNA damaging chemotherapeutic drugs 
for treating neuroblastoma would result in enhanced anti-tumor activities of 
these drugs. Treatment of high-risk neuroblastoma cell lines with a novel 
pan-HDACI, panobinostat (LBH589), resulted in dose-dependent growth arrest 
and apoptosis in 4 high-risk neuroblastoma cell lines. Further, the 
combination of panobinostat with cisplatin, doxorubicin, or etoposide 
resulted in highly synergistic antitumor interactions in the high-risk 
neuroblastoma cell lines, independent of the sequence of drug 
administration. This was accompanied by cooperative induction of apoptosis. 
Furthermore, panobinostat treatment resulted in substantial down-regulation 
of CHK1 and its downstream pathway and abrogation of the G2 cell cycle 
checkpoint. Synergistic antitumor interactions were also observed when the 
DNA damaging agents were combined with a CHK1-specific inhibitor, LY2603618. 
Contrary to panobinostat treatment, LY2603618 treatments neither resulted in 
abrogation of the G2 cell cycle checkpoint nor enhanced cisplatin, 
doxorubicin, or etoposide-induced apoptosis in the high-risk neuroblastoma 
cells. Surprisingly, LY2603618 treatments caused substantial down-regulation 
of total CDK1. Despite this discrepancy between panobinostat and LY2603618, 
our results indicate that suppression of the CHK1 pathway by panobinostat is 
at least partially responsible for the synergistic antitumor interactions 
between panobinostat and the DNA damaging agents in high-risk neuroblastoma 
cells. The results of this study provide a rationale for clinical evaluation 
of the combination of panobinostat and cisplatin, doxorubicin, or etoposide 
for treating children with high-risk neuroblastoma. © 2013 Wang et al.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cisplatin (drug combination, pharmacology)
  doxorubicin (drug combination, pharmacology)
  etoposide (drug combination, pharmacology)
  panobinostat (drug combination, drug comparison, pharmacology)
EMTREE DRUG INDEX TERMS
  checkpoint kinase 1 (endogenous compound)
  cyclin dependent kinase 1 (endogenous compound)
  rabusertib (drug combination, drug comparison, pharmacology)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug cytotoxicity
  drug potentiation
  neuroblastoma
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  apoptosis
  article
  cancer cell culture
  cell cycle arrest
  concentration response
  controlled study
  down regulation
  drug efficacy
  drug indication
  enzyme inhibition
  G2 phase cell cycle checkpoint
  growth inhibition
  human
  human cell
  IC50
  in vitro study
  incubation time
  signal transduction
  Western blotting
DRUG TRADE NAMES
  lbh 589  , United StatesSelleck

  ly 2603618  , United StatesSelleck

DRUG MANUFACTURERS
   (United States)Selleck
   (United States)Sigma Aldrich
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  doxorubicin (23214-92-8, 25316-40-9)
  etoposide (33419-42-0)
  panobinostat (404950-80-7)
  rabusertib (911222-45-2)
EMBASE CLASSIFICATIONS
  Neurology and Neurosurgery (8)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013613970
MEDLINE PMID
  24098799 (http://www.ncbi.nlm.nih.gov/pubmed/24098799)
PUI
  L369919352
DOI
  10.1371/journal.pone.0076662
FULL TEXT LINK
  http://dx.doi.org/10.1371/journal.pone.0076662
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 359
TITLE
  Neurological immune-related adverse events of ipilimumab
AUTHOR NAMES
  Bot I.
  Blank C.U.
  Boogerd W.
  Brandsma D.
AUTHOR ADDRESSES
  (Bot I., i.bot@neuro.umcn.nl; Boogerd W.; Brandsma D.) Department of 
Neurology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, 
Amsterdam, Netherlands.
(Bot I., i.bot@neuro.umcn.nl) Department of Neurology, University Medical 
Centre Nijmegen St Radboud, Nijmegen, Netherlands.
(Blank C.U.) Department of Medical Oncology, Antoni van Leeuwenhoek 
Hospital/Netherlands Cancer Institute, Amsterdam, Netherlands.
CORRESPONDENCE ADDRESS
  I. Bot, Department of Neurology, Antoni van Leeuwenhoek Hospital/Netherlands 
Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, Netherlands. Email: 
i.bot@neuro.umcn.nl
SOURCE
  Practical Neurology (2013) 13:4 (278-280). Date of Publication: August 2013
ISSN
  1474-7758
  1474-7766 (electronic)
BOOK PUBLISHER
  BMJ Publishing Group, Tavistock Square, London, United Kingdom.
ABSTRACT
  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-Barré syndrome. Once an irAE occurs, ipilimumab should be 
stopped and corticosteroids started. Usually, ipilimumabinduced irAE 
symptoms improve within days to weeks, but can be life-threatening if 
unrecognised.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immunologic factor (drug therapy)
  monoclonal antibody (drug therapy)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4
  ipilimumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy)
EMTREE MEDICAL INDEX TERMS
  aged
  article
  case report
  human
  immunology
  male
  middle aged
  neurooncology
  neuropharmacology
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  23487828 (http://www.ncbi.nlm.nih.gov/pubmed/23487828)
PUI
  L369285009
DOI
  10.1136/practneurol-2012-000447
FULL TEXT LINK
  http://dx.doi.org/10.1136/practneurol-2012-000447
COPYRIGHT
  MEDLINE® is the source for the citation and abstract of this record.

RECORD 360
TITLE
  Ipilimumab immune-related adverse reactions: a case report
AUTHOR NAMES
  Anderson L.
  Bhatia V.
AUTHOR ADDRESSES
  (Anderson L.; Bhatia V.) Sanford School of Medicine, University of South 
Dakota, USA
SOURCE
  South Dakota medicine : the journal of the South Dakota State Medical 
Association (2013) 66:8 (315-317). Date of Publication: 1 Aug 2013
ISSN
  0038-3317
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  hydrocortisone (drug therapy)
  ipilimumab
  monoclonal antibody (adverse drug reaction, drug therapy)
  prednisone (drug therapy)
  thyroxine (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  chemically induced
  immunology
  pathology
EMTREE MEDICAL INDEX TERMS
  autoimmune disease
  case report
  complication
  drug effects
  female
  follow up
  human
  hypopituitarism (drug therapy)
  hypothyroidism (drug therapy)
  immunomodulation
  liver tumor (drug therapy)
  lung tumor (drug therapy)
  melanoma
  middle aged
  secondary
  upregulation
CAS REGISTRY NUMBERS
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
  thyroxine (7488-70-2)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  24175496 (http://www.ncbi.nlm.nih.gov/pubmed/24175496)
PUI
  L602438030
COPYRIGHT
  Copyright 2015 Medline is the source for the citation and abstract of this 
record.

RECORD 361
TITLE
  Ipilimumab immune-related adverse reactions: a case report.
AUTHOR NAMES
  Anderson L.
  Bhatia V.
AUTHOR ADDRESSES
  (Anderson L.) Sanford School of Medicine, University of South Dakota, USA.
(Bhatia V.)
CORRESPONDENCE ADDRESS
  L. Anderson, Sanford School of Medicine, University of South Dakota, USA.
SOURCE
  South Dakota medicine : the journal of the South Dakota State Medical 
Association (2013) 66:8 (315-317). Date of Publication: Aug 2013
ISSN
  0038-3317
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  monoclonal antibody (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  hydrocortisone (drug therapy)
  ipilimumab
  prednisone (drug therapy)
  thyroxine (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease
  hypopituitarism (drug therapy)
  melanoma
EMTREE MEDICAL INDEX TERMS
  article
  case report
  chemically induced disorder
  drug effect
  female
  follow up
  human
  hypothyroidism (complication, drug therapy)
  immunology
  immunomodulation
  liver tumor (complication, drug therapy)
  lung tumor (complication, drug therapy)
  metastasis
  middle aged
  pathology
  upregulation
CAS REGISTRY NUMBERS
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
  thyroxine (7488-70-2)
LANGUAGE OF ARTICLE
  English
MEDLINE PMID
  24175496 (http://www.ncbi.nlm.nih.gov/pubmed/24175496)
PUI
  L563016506
COPYRIGHT
  MEDLINE® is the source for the citation and abstract of this record.

RECORD 362
TITLE
  Ipilimumab-induced endocrinopathies: When to start corticosteroids (or not)
AUTHOR NAMES
  Corsello S.M.
  Salvatori R.
  Barnabei A.
  De Vecchis L.
  Marchetti P.
  Torino F.
AUTHOR ADDRESSES
  (Corsello S.M., corsello.sm@mclink.it) Endocrinology Unit, Università 
Cattolica, Rome, Italy.
(Salvatori R.) Pituitary Center, Division of Endocrinology, Johns Hopkins 
University School of Medicine, Baltimore MD, United States.
(Barnabei A.) Endocrinology Unit, Regina Elena National Cancer Institute, 
Rome, Italy.
(De Vecchis L.; Torino F.) Department of Systems Medicine, Tor Vergata 
University of Rome, Rome, Italy.
(Marchetti P.) Department of Clinical and Molecular Medicine, Sant'Andrea 
Hospital, Sapienza University of Rome, Rome, Italy.
CORRESPONDENCE ADDRESS
  S.M. Corsello, Endocrinology Unit, Università Cattolica, Rome, Italy. Email: 
corsello.sm@mclink.it
SOURCE
  Cancer Chemotherapy and Pharmacology (2013) 72:2 (489-490). Date of 
Publication: August 2013
ISSN
  0344-5704
  1432-0843 (electronic)
BOOK PUBLISHER
  Springer Verlag, Tiergartenstrasse 17, Heidelberg, Germany.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  dexamethasone (drug dose, drug therapy, oral drug administration)
  methylprednisolone (drug therapy, intravenous drug administration)
  prednisone (drug therapy, oral drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease (drug therapy, side effect, drug therapy, prevention, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (prevention, side effect)
  cancer chemotherapy
  corticosteroid therapy
  diarrhea (side effect)
  drug dose reduction
  drug eruption (side effect)
  drug indication
  drug megadose
  drug monitoring
  drug safety
  drug withdrawal
  endocrine ophthalmopathy (side effect)
  hormone substitution
  human
  hypophysitis (drug therapy, prevention, side effect)
  hypopituitarism (prevention)
  letter
  priority journal
  side effect (side effect)
  thyroid disease (side effect)
  thyroid function test
  thyroiditis (side effect)
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  2013480638
MEDLINE PMID
  23779068 (http://www.ncbi.nlm.nih.gov/pubmed/23779068)
PUI
  L52639604
DOI
  10.1007/s00280-013-2213-y
FULL TEXT LINK
  http://dx.doi.org/10.1007/s00280-013-2213-y
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 363
TITLE
  Ipilimumab for patients with advanced mucosal melanoma
AUTHOR NAMES
  Postow M.A.
  Luke J.J.
  Bluth M.J.
  Ramaiya N.
  Panageas K.S.
  Lawrence D.P.
  Ibrahim N.
  Flaherty K.T.
  Sullivan R.J.
  Ott P.A.
  Callahan M.K.
  Harding J.J.
  D'Angelo S.P.
  Dickson M.A.
  Schwartz G.K.
  Chapman P.B.
  Gnjatic S.
  Wolchok J.D.
  Stephen Hodi F.
  Carvajal R.D.
AUTHOR ADDRESSES
  (Postow M.A.; Callahan M.K.; Harding J.J.; D'Angelo S.P.; Dickson M.A.; 
Schwartz G.K.; Chapman P.B.; Wolchok J.D.; Carvajal R.D., 
carvajar@mskcc.org) Departments of Medicine, New York, NY, United States.
(Bluth M.J.) Departments of Radiology, New York, NY, United States.
(Panageas K.S.) Departments of Epidemiology and Biostatistics, Memorial 
Sloan-Kettering Cancer Center, New York, NY, United States.
(Luke J.J.; Ibrahim N.; Ott P.A.; Stephen Hodi F.) Department of Medical 
Oncology, Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, MA, 
United States.
(Ramaiya N.) Department of Radiology, Dana-Farber/Brigham and Women's Cancer 
Center, Boston, MA, United States.
(Lawrence D.P.; Flaherty K.T.; Sullivan R.J.) Department of Medicine, 
Massachusetts General Hospital Cancer Center, Boston, MA, United States.
(Gnjatic S.) Ludwig Institute for Cancer Research, New York, NY, United 
States.
(Gnjatic S.) Tisch Cancer Institute, Icahn School of Medicine at Mount 
Sinai, New York, NY, United States.
CORRESPONDENCE ADDRESS
  R. D. Carvajal, Melanoma-Sarcoma Oncology Service, Department of Medicine, 
Memorial Sloan-Kettering Cancer Center, BAIC 1071, New York, NY 10021, 
United States. Email: carvajar@mskcc.org
SOURCE
  Oncologist (2013) 18:6 (726-732). Date of Publication: 2013
ISSN
  1083-7159
  1549-490X (electronic)
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  The outcome of patients with mucosal melanoma treated with ipilimumab is not 
defined. To assess the efficacy and safety of ipilimumab in 
thismelanomasubset,weperformeda 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 immunerelated stable 
disease, and 23 immune-related progressive disease. Immune-related adverse 
events (as graded by CommonTerminology 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 ratewaslow. Additional investigation is necessary to clarify the 
role of ipilimumab in patients with mucosal melanoma. ©AlphaMed Press 2013.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  B Raf kinase (endogenous compound)
  NY ESO 1 antigen (endogenous compound)
  protein p53 (endogenous compound)
  steroid
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  mucosal melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer
  aged
  article
  clinical article
  clinical trial (topic)
  controlled study
  diarrhea (side effect)
  drug efficacy
  drug response
  drug safety
  enzyme linked immunosorbent assay
  female
  fluorescence in situ hybridization
  gene mutation
  hepatitis (side effect)
  human
  hypophysitis (side effect)
  immune response
  male
  multicenter study (topic)
  oncogene N ras
  overall survival
  priority journal
  rash (side effect)
  retrospective study
  thyroiditis (side effect)
  tumor volume
DRUG MANUFACTURERS
   (United States)Bristol Myers Squibb
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01355120)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013406789
MEDLINE PMID
  23716015 (http://www.ncbi.nlm.nih.gov/pubmed/23716015)
PUI
  L369200874
DOI
  10.1634/theoncologist.2012-0464
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2012-0464
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 364
TITLE
  Orbital myositis associated with ipilimumab
ORIGINAL (NON-ENGLISH) TITLE
  Myosite orbitaire associée à un traitement par ipilimumab
AUTHOR NAMES
  Lecouflet M.
  Verschoore M.
  Giard C.
  Gohier P.
  Le Corre Y.
  Milea D.
  Martin L.
AUTHOR ADDRESSES
  (Lecouflet M., marie.lecouflet@gmail.com; Giard C.; Le Corre Y.; Martin L.) 
Service de Dermatologie, Université l'Unam, CHU d'Angers, 4, rue Larrey, 
49933 Angers Cedex 9, France.
(Verschoore M.; Gohier P.; Milea D.) Service d'Ophtalmologie, Université 
l'Unam, CHU d'Angers, 4, rue Larrey, 49933 Angers Cedex 9, France.
CORRESPONDENCE ADDRESS
  M. Lecouflet, Service de Dermatologie, Université l'Unam, CHU d'Angers, 4, 
rue Larrey, 49933 Angers Cedex 9, France. Email: marie.lecouflet@gmail.com
SOURCE
  Annales de Dermatologie et de Venereologie (2013) 140:6-7 (448-451). Date of 
Publication: June-July 2013
ISSN
  0151-9638
BOOK PUBLISHER
  Elsevier Masson SAS, 62 rue Camille Desmoulins, Issy les Moulineaux Cedex, 
France.
ABSTRACT
  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. 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. 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. © 2013 Elsevier 
Masson SAS. Tous droits réservés.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  steroid (drug therapy, oral drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  orbital myositis (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  article
  case report
  clinical examination
  conjunctival hyperemia
  diplopia
  drug megadose
  eyelid edema
  female
  heel melanoma (drug therapy)
  heel melanoma (drug therapy)
  human
  mediastinum metastasis
  melanoma (drug therapy)
  nuclear magnetic resonance imaging
  patient referral
  ptosis
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  French
LANGUAGE OF SUMMARY
  English, French
EMBASE ACCESSION NUMBER
  2013390046
MEDLINE PMID
  23773743 (http://www.ncbi.nlm.nih.gov/pubmed/23773743)
PUI
  L52574735
DOI
  10.1016/j.annder.2013.02.029
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.annder.2013.02.029
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 365
TITLE
  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
AUTHOR NAMES
  Gardiner D.
  Lalezari J.
  Lawitz E.
  DiMicco M.
  Ghalib R.
  Reddy K.R.
  Chang K.-M.
  Sulkowski M.
  Marro S.O.
  Anderson J.
  He B.
  Kansra V.
  McPhee F.
  Wind-Rotolo M.
  Grasela D.
  Selby M.
  Korman A.J.
  Lowy I.
AUTHOR ADDRESSES
  (Gardiner D., david.gardiner@bms.com; Anderson J.; He B.; Grasela D.) 
Bristol-Myers Squibb, Pennington, NJ, United States.
(Lalezari J.) Quest Clinical Research, San Francisco, CA, United States.
(Lawitz E.) Alamo Medical Research, San Antonio, TX, United States.
(DiMicco M.) Advanced Clinical Research Institute, Anaheim, CA, United 
States.
(Ghalib R.) The Liver Institute at Methodist Hospital, Dallas, TX, United 
States.
(Reddy K.R.; Chang K.-M.) University of Pennsylvania School of Medicine, 
Philadelphia, PA, United States.
(Chang K.-M.) Philadelphia Veterans Affairs Medical Center, Philadelphia, 
PA, United States.
(Sulkowski M.) Johns Hopkins University School of Medicine, Baltimore, MD, 
United States.
(Marro S.O.) Springfield Clinic Infectious Diseases, Springfield, IL, United 
States.
(Kansra V.; Wind-Rotolo M.) Bristol-Myers Squibb, Princeton, NJ, United 
States.
(McPhee F.) Bristol-Myers Squibb, Wallingford, CT, United States.
(Selby M.; Korman A.J.) Bristol-Myers Squibb, Milpitas, CA, United States.
(Lowy I.) Regeneron Pharmaceuticals, Tarrytown, NY, United States.
(Kansra V.) TESARO, Waltham, MA, United States.
CORRESPONDENCE ADDRESS
  D. Gardiner, Bristol-Myers Squibb, Pennington, NJ, United States. Email: 
david.gardiner@bms.com
SOURCE
  PLoS ONE (2013) 8:5 Article Number: e63818. Date of Publication: 22 May 2013
ISSN
  1932-6203 (electronic)
BOOK PUBLISHER
  Public Library of Science, 185 Berry Street, Suite 1300, San Francisco, 
United States.
ABSTRACT
  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-naïve 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 
log(10) IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 
log(10) 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 naïve 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.Trial 
Registration:ClinicalTrials.gov NCT00703469. © 2013 Gardiner et al.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  monoclonal antibody (endogenous compound)
  nivolumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacokinetics, pharmacology)
  programmed death 1 receptor (endogenous compound)
EMTREE DRUG INDEX TERMS
  alpha interferon (drug therapy)
  CD19 antigen (endogenous compound)
  cytokine (endogenous compound)
  immunoglobulin (endogenous compound)
  peginterferon alpha (drug therapy)
  placebo
  ribavirin (drug therapy)
  virus RNA (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hepatitis C (drug therapy, drug therapy, etiology)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adult
  area under the curve
  article
  autoimmune thyroiditis
  CD4+ T lymphocyte
  CD8+ T lymphocyte
  controlled study
  coughing (side effect)
  diarrhea (side effect)
  double blind procedure
  drug safety
  drug tolerability
  enzyme linked immunosorbent assay
  fatigue (side effect)
  female
  headache (side effect)
  Hepatitis C virus
  human
  hyperthyroidism (side effect)
  hypothyroidism (side effect)
  ligand binding
  limit of quantitation
  major clinical study
  male
  maximum plasma concentration
  phenotype
  protein expression
  pruritus (side effect)
  randomized controlled trial
  side effect (side effect)
  single drug dose
  sore throat (side effect)
  urticaria (side effect)
  virus load
DRUG TRADE NAMES
  bms 936558
CAS REGISTRY NUMBERS
  immunoglobulin (9007-83-4)
  nivolumab (946414-94-4)
  ribavirin (36791-04-5)
EMBASE CLASSIFICATIONS
  Microbiology: Bacteriology, Mycology, Parasitology and Virology (4)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00703469, NCT01642004, NCT01668784, NCT01673867)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013328166
MEDLINE PMID
  23717490 (http://www.ncbi.nlm.nih.gov/pubmed/23717490)
PUI
  L368973621
DOI
  10.1371/journal.pone.0063818
FULL TEXT LINK
  http://dx.doi.org/10.1371/journal.pone.0063818
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 366
TITLE
  Immune toxicities and long remission duration after ipilimumab therapy for 
metastatic melanoma: Two illustrative cases
AUTHOR NAMES
  Assi H.
  Wilson K.S.
AUTHOR ADDRESSES
  (Assi H., hazem.assi@horizonnb.ca) Division of Hematology-Oncology, Horizon 
Health Network-Zone Moncton, The Moncton Hospital, 135 MacBeath Avenue, 
Moncton, NB E1C 6Z8, Canada.
(Wilson K.S.)
CORRESPONDENCE ADDRESS
  H. Assi, Division of Hematology-Oncology, Horizon Health Network-Zone 
Moncton, The Moncton Hospital, 135 MacBeath Avenue, Moncton, NB E1C 6Z8, 
Canada. Email: hazem.assi@horizonnb.ca
SOURCE
  Current Oncology (2013) 20:2 (e165-e169). Date of Publication: 2013
ISSN
  1198-0052
  1718-7729 (electronic)
BOOK PUBLISHER
  Multimed Inc., 66 Martin Street, Milton, Canada.
ABSTRACT
  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. © 2013 Multimed Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  budesonide (drug dose, oral drug administration)
  methylprednisolone (drug therapy)
  placebo
  prednisone (drug dose, drug therapy)
  testosterone (endogenous compound)
  thyroxine (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunotoxicity (side effect, side effect)
  melanoma (drug therapy, diagnosis, drug therapy, radiotherapy, surgery)
  metastasis (drug therapy, complication, diagnosis, drug therapy)
  scalp melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  alopecia (side effect)
  article
  brain edema
  brain metastasis (complication, diagnosis, drug therapy, radiotherapy, 
surgery)
  brain radiography
  cancer radiotherapy
  cancer regression
  cancer size
  cancer surgery
  case report
  cervical lymphadenopathy
  colitis (drug therapy, side effect)
  colonoscopy
  computer assisted tomography
  craniotomy
  diarrhea (side effect)
  disease severity
  dose response
  drug dose reduction
  drug tolerability
  drug withdrawal
  ear tumor
  female
  headache (side effect)
  human
  human tissue
  hypophysitis (side effect)
  hypopituitarism (drug therapy)
  ileitis (drug therapy, side effect)
  immune response
  induction chemotherapy
  low drug dose
  lung metastasis (complication, diagnosis, drug therapy)
  lymph node metastasis (complication, drug therapy)
  maintenance drug dose
  male
  multiple cycle treatment
  positron emission tomography
  skin biopsy
  skin necrosis
  subcutaneous nodule
  testosterone blood level
  treatment duration
  vitiligo (side effect)
CAS REGISTRY NUMBERS
  budesonide (51333-22-3, 51372-29-3)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
  testosterone (58-22-0)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013223038
PUI
  L368677312
DOI
  10.3747/co.20.1265
FULL TEXT LINK
  http://dx.doi.org/10.3747/co.20.1265
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 367
TITLE
  Endocrine side effects induced by immune checkpoint inhibitors
AUTHOR NAMES
  Corsello S.M.
  Barnabei A.
  Marchetti P.
  De Vecchis L.
  Salvatori R.
  Torino F.
AUTHOR ADDRESSES
  (Corsello S.M., corsello.sm@mclink.it) Endocrinology Unit, Università 
Cattolica, Via Federico Cesi 72, I-00193 Rome, Italy.
(Barnabei A.) Endocrinology Unit, Regina Elena National Cancer Institute, 
00144 Rome, Italy.
(Marchetti P.) Department of Clinical and Molecular Medicine, Medical 
Oncology Division, Sapienza University of Rome, 00189 Rome, Italy.
(De Vecchis L.; Torino F.) Department of Systems Medicine, Tor Vergata 
University of Rome, 00133 Rome, Italy.
(Salvatori R.) Pituitary Center, Division of Endocrinology, Johns Hopkins 
University School of Medicine, Baltimore, MD 21287, United States.
CORRESPONDENCE ADDRESS
  S.M. Corsello, Endocrinology Unit, Università Cattolica, Via Federico Cesi 
72, I-00193 Rome, Italy. Email: corsello.sm@mclink.it
SOURCE
  Journal of Clinical Endocrinology and Metabolism (2013) 98:4 (1361-1375). 
Date of Publication: April 2013
ISSN
  0021-972X
  1945-7197 (electronic)
BOOK PUBLISHER
  Endocrine Society, 8401 Connecticut Ave. Suite 900, Chevy Chase, United 
States.
ABSTRACT
  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 thatareexpressed 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, designatedas "immune-related 
adverse events," mainly including rash, colitis, hepatitis, and 
endocrinopathies. 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." 
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. 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. Copyright © 2013 by The Endocrine Society.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  immune checkpoint inhibitor (adverse drug reaction, pharmacology)
  immunomodulating agent (adverse drug reaction, pharmacology)
EMTREE DRUG INDEX TERMS
  bevacizumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy)
  cancer vaccine (drug combination)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction, 
pharmacology)
  dacarbazine (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug dose, drug therapy)
  fotemustine (adverse drug reaction, clinical trial, drug combination)
  glucocorticoid (drug therapy)
  glycoprotein gp 100 (drug combination, drug therapy)
  immunosuppressive agent (drug therapy)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug dose, drug therapy, intravenous drug administration, 
pharmacology)
  peptide vaccine (adverse drug reaction)
  placebo
  programmed death 1 inhibitor (adverse drug reaction, drug dose, drug 
therapy)
  programmed death 1 ligand inhibitor (adverse drug reaction, drug therapy)
  programmed death 1 receptor (endogenous compound)
  prostate specific antigen vaccine (drug combination)
  recombinant interleukin 2 (adverse drug reaction, drug combination)
  ticilimumab (adverse drug reaction, pharmacology)
  tumor antigen (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine disease (drug therapy, side effect, drug therapy, side effect)
  hypophysitis (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adrenal insufficiency (side effect)
  advanced cancer (drug therapy)
  amnesia (side effect)
  anorexia (side effect)
  arthralgia (side effect)
  arthritis (side effect)
  aseptic meningitis (side effect)
  asthenia (side effect)
  asthma (side effect)
  autoimmune disease (side effect)
  autoimmune thyroiditis (side effect)
  autoinflammatory disease (side effect)
  behavior change
  bone marrow toxicity (side effect)
  cancer survival
  castration resistant prostate cancer (drug therapy)
  cell proliferation
  cellulitis (side effect)
  chill (side effect)
  clinical feature
  colitis (side effect)
  colorectal cancer (drug therapy)
  confusion (side effect)
  constipation (side effect)
  cutaneous melanoma (drug therapy)
  dermatitis (side effect)
  diarrhea (side effect)
  diplopia (side effect)
  dose response
  down regulation
  drug dose escalation
  drug dose reduction
  drug eruption (side effect)
  drug fatality (side effect)
  drug fever (side effect)
  drug induced headache (side effect)
  edema (side effect)
  encephalitis (side effect)
  enterocolitis (side effect)
  enzyme blood level
  euthyroid sick syndrome (side effect)
  fatigue (side effect)
  gastrointestinal hemorrhage (side effect)
  gastrointestinal symptom (drug therapy, side effect)
  giant cell arteritis (side effect)
  hallucination (side effect)
  homeostasis
  hormone substitution
  human
  hyperthyroidism (side effect)
  hypertransaminasemia (side effect)
  hypogonadotropic hypogonadism (side effect)
  hypokalemia (side effect)
  hypopituitarism (side effect)
  hypothyroidism (side effect)
  immunological tolerance
  infusion related reaction (side effect)
  insomnia (side effect)
  intestinal bleeding (side effect)
  intestine perforation (side effect)
  intracellular signaling
  kidney carcinoma (drug therapy)
  libido disorder (side effect)
  liver disease (drug therapy, side effect)
  lymphocytic autoimmune hypophysitis (side effect)
  lymphocytic autoimmune hypophysitis (side effect)
  melanoma (drug therapy)
  morning dosage
  multiple cycle treatment
  multiple organ failure (side effect)
  nausea (side effect)
  neutropenia (side effect)
  non small cell lung cancer (drug therapy)
  overall survival
  pain (side effect)
  pancytopenia (side effect)
  platelet count
  pneumonia (side effect)
  priority journal
  prostate cancer (drug therapy)
  protein function
  protein synthesis inhibition
  pruritus (side effect)
  review
  side effect (side effect)
  skin disease (drug therapy, side effect)
  skin exfoliation (side effect)
  T lymphocyte
  T lymphocyte activation
  temperature sensitivity
  thyroid disease (side effect)
  thyroid function test
  thyroiditis (side effect)
  thyrotropin blood level
  toxic hepatitis (side effect)
  treatment outcome
  triacylglycerol lipase blood level
  uveitis (side effect)
  vasculitis (side effect)
  vertigo (side effect)
  visual impairment (side effect)
  weakness (side effect)
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  dacarbazine (4342-03-4)
  fotemustine (92118-27-9)
  ipilimumab (477202-00-9)
  recombinant interleukin 2 (110942-02-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013244604
MEDLINE PMID
  23471977 (http://www.ncbi.nlm.nih.gov/pubmed/23471977)
PUI
  L368740091
DOI
  10.1210/jc.2012-4075
FULL TEXT LINK
  http://dx.doi.org/10.1210/jc.2012-4075
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 368
TITLE
  PD-L1 on tumor cells is induced in ascites and promotes peritoneal 
dissemination of ovarian cancer through CTL dysfunction
AUTHOR NAMES
  Abiko K.
  Mandai M.
  Hamanishi J.
  Yoshioka Y.
  Matsumura N.
  Baba T.
  Yamaguchi K.
  Murakami R.
  Yamamoto A.
  Kharma B.
  Kosaka K.
  Konishi I.
AUTHOR ADDRESSES
  (Abiko K.; Mandai M., mandai@kuhp.kyoto-u.ac.jp; Hamanishi J.; Yoshioka Y.; 
Matsumura N.; Baba T.; Yamaguchi K.; Murakami R.; Yamamoto A.; Kharma B.; 
Kosaka K.; Konishi I.) Department of Gynecology and Obstetrics, Graduate 
School of Medicine, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku, 
Kyoto 606-8507, Japan.
(Yamaguchi K.) Department of Obstetrics and Gynecology, Japan Baptest 
Hospital, Kyoto, Japan.
CORRESPONDENCE ADDRESS
  M. Mandai, Department of Gynecology and Obstetrics, Graduate School of 
Medicine, Kyoto University, 54 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto 
606-8507, Japan. Email: mandai@kuhp.kyoto-u.ac.jp
SOURCE
  Clinical Cancer Research (2013) 19:6 (1363-1374). Date of Publication: 15 
Mar 2013
ISSN
  1078-0432
  1557-3265 (electronic)
BOOK PUBLISHER
  American Association for Cancer Research Inc., 615 Chestnut Street, 17th 
Floor, Philadelphia, United States.
ABSTRACT
  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 (PDL1) 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. 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. 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. 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. © 2012 AACR.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  programmed cell death 1 ligand 1 protein (endogenous compound)
EMTREE DRUG INDEX TERMS
  gamma interferon (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ascites (complication)
  CD8+ T lymphocyte
  ovary cancer
  peritoneum metastasis (etiology)
EMTREE MEDICAL INDEX TERMS
  animal cell
  animal experiment
  animal model
  article
  ascites fluid cytology
  cancer cell
  cancer survival
  cell mediated cytotoxicity
  controlled study
  correlation analysis
  cytolysis
  degranulation
  female
  flow cytometry
  gene expression profiling
  gene overexpression
  human
  human tissue
  immunohistochemistry
  in vitro study
  in vivo study
  major clinical study
  microarray analysis
  mouse
  nonhuman
  priority journal
  protein expression
  protein function
  T lymphocyte activation
CAS REGISTRY NUMBERS
  gamma interferon (82115-62-6)
EMBASE CLASSIFICATIONS
  General Pathology and Pathological Anatomy (5)
  Obstetrics and Gynecology (10)
  Cancer (16)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013177465
MEDLINE PMID
  23340297 (http://www.ncbi.nlm.nih.gov/pubmed/23340297)
PUI
  L368552615
DOI
  10.1158/1078-0432.CCR-12-2199
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-12-2199
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 369
TITLE
  Detection of early onset of hypophysitis by 18F-FDG PET-CT in a patient with 
advanced stage melanoma treated with ipilimumab
AUTHOR NAMES
  van der Hiel B.
  Blank C.U.
  Haanen J.B.A.G.
  Stokkel M.P.M.
AUTHOR ADDRESSES
  (van der Hiel B.; Blank C.U.; Haanen J.B.A.G.; Stokkel M.P.M.)
CORRESPONDENCE ADDRESS
  B. van der Hiel,
SOURCE
  Clinical Nuclear Medicine (2013). Date of Publication: 28 Feb 2013
ISSN
  0363-9762
BOOK PUBLISHER
  Lippincott Williams & Wilkins, Inc.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  fluorodeoxyglucose f 18
  ipilimumab
EMTREE DRUG INDEX TERMS
  human monoclonal antibody
  receptor
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  human
  hypophysitis
  melanoma
  patient
EMTREE MEDICAL INDEX TERMS
  follow up
  hypophysis
  male
  metastatic melanoma
  parameters
  T lymphocyte
  T lymphocyte activation
  tumor cell
LANGUAGE OF ARTICLE
  English
MEDLINE PMID
  23455528 (http://www.ncbi.nlm.nih.gov/pubmed/23455528)
PUI
  L52468221
DOI
  10.1097/RLU.0b013e3182639765
FULL TEXT LINK
  http://dx.doi.org/10.1097/RLU.0b013e3182639765
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 370
TITLE
  Phase III randomized clinical trial comparing tremelimumab with 
standard-of-care chemotherapy in patients with advanced melanoma
AUTHOR NAMES
  Ribas A.
  Kefford R.
  Marshall M.A.
  Punt C.J.A.
  Haanen J.B.
  Marmol M.
  Garbe C.
  Gogas H.
  Schachter J.
  Linette G.
  Lorigan P.
  Kendra K.L.
  Maio M.
  Trefzer U.
  Smylie M.
  McArthur G.A.
  Dreno B.
  Nathan P.D.
  MacKiewicz J.
  Kirkwood J.M.
  Gomez-Navarro J.
  Huang B.
  Pavlov D.
  Hauschild A.
AUTHOR ADDRESSES
  (Ribas A., aribas@mednet.ucla.edu) Division of Hematology-Oncology, 11-934 
Factor Building, UCLA Medical Center, 10833 Le Conte Ave, Los Angeles, CA 
90095-1782, United States.
(Kefford R.) Westmead Institute for Cancer Research, Melanoma Institute 
Australia, University of Sydney at Westmead Hospital, Sydney, NSW, 
Australia.
(McArthur G.A.) Peter MacCallum Cancer Centre, East Melbourne, VIC, 
Australia.
(Marshall M.A.; Gomez-Navarro J.; Huang B.; Pavlov D.) Pfizer Global 
Research and Development, Groton, CT, United States.
(Punt C.J.A.) Radboud University Nijmegen Medical Center, Nijmegen, 
Netherlands.
(Haanen J.B.) Netherlands Cancer Institute, Amsterdam, Netherlands.
(Marmol M.) Hospital Clinic of Barcelona, Barcelona, Spain.
(Garbe C.) University Hospital Tübingen, Tübingen, Germany.
(Trefzer U.) Skin Cancer Center, Charité Universitätsmedizin Berlin, Berlin, 
Germany.
(Hauschild A.) University of Kiel, Kiel, Germany.
(Gogas H.) University of Athens, Athens, Greece.
(Schachter J.) Sheba Medical Centre, Tel Hashomer, Israel.
(Linette G.) Washington University School of Medicine, St Louis, MO, United 
States.
(Lorigan P.) Christie Hospital, National Health Service Foundation Trust, 
Manchester, United Kingdom.
(Nathan P.D.) Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
(Kendra K.L.) Arthur G. James Cancer Hospital, Richard J. Solve Research 
Institute, Columbus, OH, United States.
(Maio M.) Immunoterapia Oncologica-Azienda Ospedaliera Universitaria Senese, 
Siena, Italy.
(Smylie M.) Cross Cancer Institute, University of Alberta, Edmonton, AB, 
Canada.
(Dreno B.) Centre Hospitalier Universitaire de Nantes-Hôtel Dieu, Clinique 
Dermatologique, Nantes, France.
(MacKiewicz J.) Zaklad Diagnostyki i Immunologii Nowotworow Wielkopolskie 
Centrum Onkologii, University of Medical Sciences, Poznan, Poland.
(Kirkwood J.M.) University of Pittsburgh School of Medicine, Pittsburgh, PA, 
United States.
CORRESPONDENCE ADDRESS
  A. Ribas, Division of Hematology-Oncology, 11-934 Factor Building, UCLA 
Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90095-1782, United 
States. Email: aribas@mednet.ucla.edu
SOURCE
  Journal of Clinical Oncology (2013) 31:5 (616-622). Date of Publication: 10 
Feb 2013
ISSN
  0732-183X
  1527-7755 (electronic)
BOOK PUBLISHER
  American Society of Clinical Oncology, 330 John Carlyle Street, Suite 300, 
Alexandria, United States.
ABSTRACT
  Purpose In phase I/II trials, the cytotoxic T lymphocyte-associated 
antigen-4-blocking monoclonal antibody tremelimumab induced durable 
responses in a subset of patients with advanced melanoma. This phase III 
study evaluated overall survival (OS) and other safety and efficacy end 
points in patients with advanced melanoma treated with tremelimumab or 
standard-of-care chemotherapy. Patients and Methods Patients with 
treatment-naive, unresectable stage IIIc or IV melanoma were randomly 
assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 
days) or physician's choice of standard-of-care chemotherapy (temozolomide 
or dacarbazine). Results In all, 655 patients were enrolled and randomly 
assigned. The test statistic crossed the prespecified futility boundary at 
second interim analysis after 340 deaths, but survival follow-up continued. 
At final analysis with 534 events, median OS by intent to treat was 12.6 
months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 
to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective 
response rates were similar in the two arms: 10.7% in the tremelimumab arm 
and 9.8% in the chemotherapy arm. However, response duration (measured from 
date of random assignment) was significantly longer after tremelimumab (35.8 
v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common 
treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine 
toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy 
arm were considered treatment related by either investigators or sponsor. 
Conclusion This study failed to demonstrate a statistically significant 
survival advantage of treatment with tremelimumab over standard-of-care 
chemotherapy in first-line treatment of patients with metastatic melanoma. © 
2013 by American Society of Clinical Oncology.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ticilimumab (adverse drug reaction, clinical trial, drug comparison, drug 
therapy)
EMTREE DRUG INDEX TERMS
  dacarbazine (adverse drug reaction, drug comparison, drug therapy)
  ipilimumab (drug therapy)
  temozolomide (adverse drug reaction, drug comparison, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug therapy)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adrenal insufficiency (side effect)
  adult
  aged
  appetite disorder (side effect)
  article
  asthenia (side effect)
  body weight loss
  cancer chemotherapy
  cancer mortality
  cancer patient
  cancer survival
  chemotherapy induced nausea and vomiting (side effect)
  colitis (side effect)
  comparative effectiveness
  constipation (side effect)
  controlled study
  coughing (side effect)
  decreased appetite (side effect)
  diarrhea (side effect)
  drug efficacy
  drug fatality (side effect)
  drug safety
  drug withdrawal
  dyspnea (side effect)
  eye infection (side effect)
  eye inflammation (side effect)
  eye irritation (side effect)
  eye swelling (side effect)
  fatigue (side effect)
  female
  fever (side effect)
  headache (side effect)
  health care quality
  hepatitis (side effect)
  human
  hypophysis disease (side effect)
  hypothalamus disease (side effect)
  intention to treat analysis
  major clinical study
  male
  neutropenia (side effect)
  open study
  pancreatitis (side effect)
  peripheral edema (side effect)
  phase 3 clinical trial
  priority journal
  pruritus (side effect)
  randomized controlled trial
  rash (side effect)
  side effect (side effect)
  thrombocytopenia (side effect)
  thyroid disease (side effect)
  treatment duration
  treatment response
CAS REGISTRY NUMBERS
  dacarbazine (4342-03-4)
  ipilimumab (477202-00-9)
  temozolomide (85622-93-1)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00257205)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013197945
MEDLINE PMID
  23295794 (http://www.ncbi.nlm.nih.gov/pubmed/23295794)
PUI
  L368595557
DOI
  10.1200/JCO.2012.44.6112
FULL TEXT LINK
  http://dx.doi.org/10.1200/JCO.2012.44.6112
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 371
TITLE
  Elevated rates of transaminitis during ipilimumab therapy for metastatic 
melanoma
AUTHOR NAMES
  Bernardo S.G.
  Moskalenko M.
  Pan M.
  Shah S.
  Sidhu H.K.
  Sicular S.
  Harcharik S.
  Chang R.
  Friedlander P.
  Saenger Y.M.
AUTHOR ADDRESSES
  (Bernardo S.G.; Pan M.; Shah S.; Harcharik S.) Department of Dermatology, 
Icahn Medical Institute, Mount Sinai School of Medicine, New York, NY, 
United States.
(Moskalenko M.; Friedlander P.; Saenger Y.M., yvonne.saenger@mssm.edu) 
Department of Hematology and Medical Oncology, Icahn Medical Institute, 
Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, 
United States.
(Sidhu H.K.) Department of Pathology, Mount Sinai School of Medicine, New 
York, NY, United States.
(Sicular S.) Department of Radiology, Mount Sinai School of Medicine, New 
York, NY, United States.
(Chang R.) Department of Genetics and Genomic Sciences, Mount Sinai School 
of Medicine, New York, NY, United States.
CORRESPONDENCE ADDRESS
  Y.M. Saenger, Department of Hematology and Medical Oncology, Icahn Medical 
Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 
10029, United States. Email: yvonne.saenger@mssm.edu
SOURCE
  Melanoma Research (2013) 23:1 (47-54). Date of Publication: February 2013
ISSN
  0960-8931
  1473-5636 (electronic)
BOOK PUBLISHER
  Lippincott Williams and Wilkins, 250 Waterloo Road, London, United Kingdom.
ABSTRACT
  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. © 2013 Wolters Kluwer 
Health | Lippincott Williams & Wilkins.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  alanine aminotransferase (endogenous compound)
  aspartate aminotransferase (endogenous compound)
  ipilimumab (adverse drug reaction, drug therapy, drug toxicity)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  dacarbazine
  thyrotropin (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypertransaminasemia (side effect, side effect)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adrenal insufficiency (side effect)
  adult
  alanine aminotransferase blood level
  article
  aspartate aminotransferase blood level
  cancer immunotherapy
  clinical article
  colitis (side effect)
  constipation (side effect)
  corticotropin blood level
  cryotherapy
  diarrhea (side effect)
  disease course
  drug withdrawal
  female
  food and drug administration
  human
  hypophysitis (side effect)
  hypopituitarism (side effect)
  hypothyroidism (side effect)
  liver function test
  liver toxicity
  male
  nausea (side effect)
  overall survival
  patient selection
  priority journal
  pruritus (side effect)
  rash (side effect)
  side effect (side effect)
  systemic therapy
  thyrotropin blood level
  treatment response
  vomiting (side effect)
CAS REGISTRY NUMBERS
  alanine aminotransferase (9000-86-6, 9014-30-6)
  aspartate aminotransferase (9000-97-9)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  dacarbazine (4342-03-4)
  ipilimumab (477202-00-9)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2013023155
MEDLINE PMID
  23262440 (http://www.ncbi.nlm.nih.gov/pubmed/23262440)
PUI
  L368072804
DOI
  10.1097/CMR.0b013e32835c7e68
FULL TEXT LINK
  http://dx.doi.org/10.1097/CMR.0b013e32835c7e68
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 372
TITLE
  Molecular-target therapy for advanced malignant melanoma
AUTHOR NAMES
  Takahashi S.
AUTHOR ADDRESSES
  (Takahashi S.) Department of Medical Oncology, Cancer Institute Hospital, 
Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 
135-8500, Japan.
CORRESPONDENCE ADDRESS
  S. Takahashi, Department of Medical Oncology, Cancer Institute Hospital, 
Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 
135-8500, Japan.
SOURCE
  Japanese Journal of Cancer and Chemotherapy (2013) 40:1 (19-25). Date of 
Publication: January 2013
ISSN
  0385-0684
BOOK PUBLISHER
  Japanese Journal of Cancer and Chemotherapy Publishers Inc., 
ccp@blue.ocn.ne.jp
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  dabrafenib (drug therapy)
  dacarbazine (adverse drug reaction, clinical trial, drug therapy)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy)
  trametinib (drug therapy)
  vemurafenib (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  molecularly targeted therapy
EMTREE MEDICAL INDEX TERMS
  colitis (side effect)
  drug efficacy
  drug eruption (side effect)
  endocrine disease (side effect)
  human
  liver dysfunction (side effect)
  overall survival
  phase 3 clinical trial (topic)
  review
  skin carcinoma (side effect)
  skin toxicity (side effect)
CAS REGISTRY NUMBERS
  dabrafenib (1195765-45-7, 1195768-06-9)
  dacarbazine (4342-03-4)
  ipilimumab (477202-00-9)
  trametinib (1187431-43-1, 871700-17-3)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  Japanese
LANGUAGE OF SUMMARY
  English, Japanese
EMBASE ACCESSION NUMBER
  2013179164
MEDLINE PMID
  23306915 (http://www.ncbi.nlm.nih.gov/pubmed/23306915)
PUI
  L368555085
COPYRIGHT
  Copyright 2016 Elsevier B.V., All rights reserved.

RECORD 373
TITLE
  Exploring novel immune-related toxicities and endpoints with 
immune-checkpoint inhibitors in non-small cell lung cancer
AUTHOR NAMES
  Chow L.Q.
AUTHOR ADDRESSES
  (Chow L.Q.) From the Department of Medicine, Division of Medical Oncology, 
University of Washington, Seattle, WA
SOURCE
  American Society of Clinical Oncology educational book / ASCO. American 
Society of Clinical Oncology. Meeting (2013). Date of Publication: 2013
ISSN
  1548-8756 (electronic)
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  antibody (adverse drug reaction)
  antineoplastic agent (adverse drug reaction)
  CD274 protein, human
  CTLA4 protein, human
  cytotoxic T lymphocyte antigen 4
  PDCD1 protein, human
  programmed death 1 ligand 1
  programmed death 1 receptor
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adverse effects
  antagonists and inhibitors
EMTREE MEDICAL INDEX TERMS
  animal
  apoptosis
  drug effects
  human
  immunology
  immunotherapy
  lung tumor (drug therapy)
  lymphocyte activation
  metabolism
  molecularly targeted therapy
  non small cell lung cancer (drug therapy)
  pathology
  risk factor
  signal transduction
  treatment outcome
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
MEDLINE PMID
  23714523 (http://www.ncbi.nlm.nih.gov/pubmed/23714523)
PUI
  L606787703
DOI
  10.1200/EdBook_AM.2013.33.e280
FULL TEXT LINK
  http://dx.doi.org/10.1200/EdBook_AM.2013.33.e280
COPYRIGHT
  Copyright 2015 Medline is the source for the citation and abstract of this 
record.

RECORD 374
TITLE
  Vemurafenib: Targeted inhibition of mutated BRAF for treatment of advanced 
melanoma and its potential in other malignancies
AUTHOR NAMES
  Sharma A.
  Shah S.R.
  Illum H.
  Dowell J.
AUTHOR ADDRESSES
  (Sharma A., Anant.Sharma@va.gov; Shah S.R.; Illum H.; Dowell J.) VA North 
Texas Health Care System, 4500 South Lancaster Road, Dallas, TX 75216, 
United States.
(Sharma A., Anant.Sharma@va.gov; Illum H.; Dowell J.) University of Texas, 
Southwestern Medical Center, Dallas, TX, United States.
(Shah S.R.) Texas Tech University, Health Sciences Center, School of 
Pharmacy, Dallas, TX, United States.
CORRESPONDENCE ADDRESS
  A. Sharma, VA North Texas Health Care System, 4500 South Lancaster Road, 
Dallas, TX 75216, United States. Email: Anant.Sharma@va.gov
SOURCE
  Drugs (2012) 72:17 (2207-2222). Date of Publication: 2012
ISSN
  0012-6667
  1179-1950 (electronic)
BOOK PUBLISHER
  Springer International Publishing, Gewerbestrasse 11, Cham, Switzerland.
ABSTRACT
  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 0.6295 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. Adis © 2012 Springer International Publishing AG. 
All rights reserved.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  B Raf kinase (endogenous compound)
  vemurafenib (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug dose, drug therapy, oral drug administration, 
pharmacokinetics, pharmacology)
EMTREE DRUG INDEX TERMS
  antihistaminic agent (drug therapy, topical drug administration)
  carboplatin (drug combination, drug therapy)
  cobimetinib (clinical trial, drug combination, drug therapy)
  corticosteroid (drug therapy, topical drug administration)
  cytochrome P450
  dacarbazine (clinical trial, drug combination, drug comparison, drug 
therapy, intravenous drug administration)
  emollient agent (drug therapy)
  fibroblast growth factor receptor 1 (endogenous compound)
  imatinib (clinical trial, drug therapy)
  ipilimumab (clinical trial, drug combination, drug therapy)
  mitogen activated protein kinase (endogenous compound)
  mitogen activated protein kinase inhibitor (clinical trial, drug 
combination, drug therapy)
  n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 
difluorophenyl]propanesulfonamide
  nerve growth factor (endogenous compound)
  nilotinib (clinical trial, drug therapy)
  paclitaxel (drug combination, drug therapy)
  phosphatidylinositol 3 kinase (endogenous compound)
  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (endogenous compound)
  platelet derived growth factor (endogenous compound)
  prednisolone (drug therapy, oral drug administration)
  protein SH2 (endogenous compound)
  protein tyrosine kinase (endogenous compound)
  Raf protein (endogenous compound)
  somatomedin C (endogenous compound)
  sorafenib (adverse drug reaction, drug combination, drug therapy, 
pharmacology)
  tipifarnib (pharmacology)
  unclassified drug
  unindexed drug
  vasculotropin receptor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  advanced cancer (drug therapy, drug resistance, drug therapy, etiology, 
surgery)
  melanoma (drug therapy, drug resistance, drug therapy, etiology, surgery)
EMTREE MEDICAL INDEX TERMS
  alanine aminotransferase blood level
  alopecia (side effect)
  area under the curve
  arthralgia (side effect)
  aspartate aminotransferase blood level
  bilirubin blood level
  blood toxicity (side effect)
  brain metastasis (complication)
  cancer chemotherapy
  cancer combination chemotherapy
  cancer fatigue (side effect)
  cancer patient
  cancer resistance
  cancer survival
  clinical trial (topic)
  confidence interval
  drug mechanism
  drug monitoring
  drug tolerability
  drug withdrawal
  erythema (side effect)
  fever (side effect)
  gene mutation
  genetic association
  hairy cell leukemia (drug therapy, etiology)
  hand foot syndrome (side effect)
  hazard ratio
  human
  hyperkeratosis (side effect)
  IC50
  keratoacanthoma (side effect)
  kidney disease
  liver cell carcinoma (drug therapy)
  liver toxicity (side effect)
  low drug dose
  maximum tolerated dose
  metastatic melanoma (drug therapy)
  molecularly targeted therapy
  nonhuman
  oncogene K ras
  oncogene ras
  overall survival
  palmoplantar keratoderma (side effect)
  pancreatitis (side effect)
  panniculitis (side effect)
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  photosensitivity (side effect)
  phototoxicity (side effect)
  progression free survival
  pruritus (side effect)
  QT prolongation (side effect)
  randomized controlled trial (topic)
  rash (drug therapy, side effect)
  review
  side effect (side effect)
  signal transduction
  skin carcinogenesis (etiology)
  skin carcinoma (side effect)
  skin defect (side effect)
  skin surgery
  statistical significance
  Stevens Johnson syndrome (side effect)
  thyroid carcinoma (drug therapy)
  ultraviolet A radiation
  uveitis (side effect)
DRUG TRADE NAMES
  gdc 0973
  plx 4720
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  cytochrome P450 (9035-51-2)
  dacarbazine (4342-03-4)
  imatinib (152459-95-5, 220127-57-1)
  ipilimumab (477202-00-9)
  mitogen activated protein kinase (142243-02-5)
  n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 
difluorophenyl]propanesulfonamide (918505-84-7)
  nerve growth factor (9061-61-4)
  nilotinib (641571-10-0)
  paclitaxel (33069-62-4)
  phosphatidylinositol 3 kinase (115926-52-8)
  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (210488-47-4)
  prednisolone (50-24-8)
  protein tyrosine kinase (80449-02-1)
  somatomedin C (67763-96-6)
  sorafenib (284461-73-0)
  tipifarnib (192185-68-5, 192185-72-1)
  vasculotropin receptor (301253-48-5)
  vemurafenib (918504-65-1)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01253564, NCT01264380, NCT01271803, NCT01378975, NCT01400451)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012690949
MEDLINE PMID
  23116250 (http://www.ncbi.nlm.nih.gov/pubmed/23116250)
PUI
  L366127639
DOI
  10.2165/11640870-000000000-00000
FULL TEXT LINK
  http://dx.doi.org/10.2165/11640870-000000000-00000
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 375
TITLE
  [Ctla-4 blockade: a new hope for the immunotherapy of malignant melanoma].
AUTHOR NAMES
  Lotem M.
  Merims S.
  Frank S.
  Ospovat I.
  Peretz T.
AUTHOR ADDRESSES
  (Lotem M.) Sharett Institute of Oncology, Hadassah Hebrew University 
Hospital, Jerusalem.
(Merims S.; Frank S.; Ospovat I.; Peretz T.)
CORRESPONDENCE ADDRESS
  M. Lotem, Sharett Institute of Oncology, Hadassah Hebrew University 
Hospital, Jerusalem. Email: mlotem@hadassah.org.il
SOURCE
  Harefuah (2012) 151:10 (585-588, 604). Date of Publication: Oct 2012
ISSN
  0017-7768
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4
  monoclonal antibody (adverse drug reaction, drug administration)
EMTREE DRUG INDEX TERMS
  alkylating agent (drug therapy)
  antineoplastic agent
  dacarbazine (drug therapy)
  ipilimumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunotherapy
  melanoma (therapy)
  skin tumor (therapy)
EMTREE MEDICAL INDEX TERMS
  autoimmunity
  cytotoxic T lymphocyte
  drug antagonism
  drug approval
  drug effect
  drug monitoring
  drug surveillance program
  human
  immunology
  methodology
  pathology
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  proportional hazards model
  review
  treatment outcome
CAS REGISTRY NUMBERS
  dacarbazine (4342-03-4)
  ipilimumab (477202-00-9)
LANGUAGE OF ARTICLE
  Hebrew
MEDLINE PMID
  23316667 (http://www.ncbi.nlm.nih.gov/pubmed/23316667)
PUI
  L368330159
COPYRIGHT
  MEDLINE® is the source for the citation and abstract of this record.

RECORD 376
TITLE
  Ipilimumab-induced immune-related renal failure - A case report
AUTHOR NAMES
  Forde P.M.
  Rock K.
  Wilson G.
  O'Byrne K.J.
AUTHOR ADDRESSES
  (Forde P.M., pforde1@jhmi.edu) Sidney Kimmel Comprehensive Cancer Center, 
Johns Hopkins Hospital, 401 N. Broadway, Baltimore, MD, 21231, United 
States.
(Rock K.; O'Byrne K.J.) Department of Medical Oncology, St James Hospital, 
Dublin, Ireland.
(Wilson G.) Department of Radiology, St James Hospital, Dublin, Ireland.
CORRESPONDENCE ADDRESS
  P.M. Forde, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins 
Hospital, 401 N. Broadway, Baltimore, MD, 21231, United States. Email: 
pforde1@jhmi.edu
SOURCE
  Anticancer Research (2012) 32:10 (4607-4608). Date of Publication: October 
2012
ISSN
  0250-7005
BOOK PUBLISHER
  International Institute of Anticancer Research, 1st km Kapandritiou - 
Kalamou Rd., P.O. Box 22, Kapandriti, Attica, Greece.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  methylprednisolone (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  acute kidney failure (drug therapy, side effect, drug therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  case report
  computer assisted tomography
  drug megadose
  human
  human tissue
  kidney biopsy
  male
  melanoma (drug therapy)
  multiple cycle treatment
  priority journal
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012619400
MEDLINE PMID
  23060594 (http://www.ncbi.nlm.nih.gov/pubmed/23060594)
PUI
  L365895877
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 377
TITLE
  Characteristics and management of immune-related adverse effects associated 
with ipilimumab, a new immunotherapy for metastatic melanoma
AUTHOR NAMES
  Andrews S.
  Holden R.
AUTHOR ADDRESSES
  (Andrews S., stephanie.andrews@moffitt.org) H Lee Moffitt Cancer Center, 
Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, United States.
(Holden R.) St Luke's Hospital, Health Network Cancer Center, Easton, PA, 
United States.
CORRESPONDENCE ADDRESS
  S. Andrews, H Lee Moffitt Cancer Center, Research Institute, 12902 Magnolia 
Drive, Tampa, FL 33612, United States. Email: stephanie.andrews@moffitt.org
SOURCE
  Cancer Management and Research (2012) 4:1 (299-307). Date of Publication: 11 
Sep 2012
ISSN
  1179-1322 (electronic)
BOOK PUBLISHER
  Dove Medical Press Ltd, Beechfield House, Winterton Way, Macclesfield, 
United Kingdom.
ABSTRACT
  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. © 2012 Talreja, 
publisher and licensee Dove Medical Press Ltd.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy, intravenous 
drug administration, pharmacology)
EMTREE DRUG INDEX TERMS
  alpha2b interferon (drug combination, drug therapy)
  cisplatin (drug combination, drug therapy)
  dacarbazine (drug combination, drug therapy)
  infliximab
  interleukin 2 (drug combination, drug therapy)
  methylprednisolone sodium succinate (adverse drug reaction, drug therapy, 
intravenous drug administration)
  prednisone (adverse drug reaction, drug therapy, oral drug administration)
  vemurafenib (drug therapy)
  vinblastine (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  metastatic melanoma (drug therapy, drug therapy, therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  advanced cancer (drug therapy)
  cancer incidence
  cancer mortality
  cancer prognosis
  cancer staging
  cancer survival
  controlled study
  diarrhea (side effect)
  drug approval
  drug dose reduction
  drug efficacy
  drug mechanism
  drug safety
  drug withdrawal
  episcleritis (side effect)
  erythroderma (side effect)
  food and drug administration
  Guillain Barre syndrome (side effect)
  human
  ileus (side effect)
  immunopathology (side effect)
  incontinence (side effect)
  intestine perforation (side effect)
  iritis (side effect)
  major clinical study
  motor neuropathy (side effect)
  muscle weakness (side effect)
  myasthenia gravis (side effect)
  nausea (side effect)
  phase 3 clinical trial
  pruritus (side effect)
  randomized controlled trial
  rash (side effect)
  review
  sensory neuropathy (side effect)
  treatment outcome
  treatment response
  uveitis (side effect)
  vomiting (side effect)
DRUG TRADE NAMES
  remicade  , United StatesCentocor Ortho Biotech

  solu medrol  , United StatesPfizer

  yervoy  , United StatesBristol Myers Squibb

  zelboraf  , United StatesGenentech

DRUG MANUFACTURERS
   (United States)Bristol Myers Squibb
   (United States)Centocor Ortho Biotech
   (United States)Genentech
   (United States)Pfizer
CAS REGISTRY NUMBERS
  alpha2b interferon (99210-65-8)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  dacarbazine (4342-03-4)
  infliximab (170277-31-3)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  methylprednisolone sodium succinate (2375-03-3, 2921-57-5)
  prednisone (53-03-2)
  vemurafenib (918504-65-1)
  vinblastine (865-21-4)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012571279
PUI
  L365720605
DOI
  10.2147/CMAR.S31873
FULL TEXT LINK
  http://dx.doi.org/10.2147/CMAR.S31873
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 378
TITLE
  The outliers become a stampede as immunometabolism reaches a tipping point
AUTHOR NAMES
  Nikolajczyk B.S.
  Jagannathan-Bogdan M.
  Denis G.V.
AUTHOR ADDRESSES
  (Nikolajczyk B.S., bnikol@bu.edu) Departments of Microbiology and Medicine, 
Boston University, Boston, MA, United States.
(Jagannathan-Bogdan M.) Department of Pathology, Boston University, Boston, 
MA, United States.
(Denis G.V.) Cancer Research Center, Boston University School of Medicine, 
Boston, MA, United States.
CORRESPONDENCE ADDRESS
  B.S. Nikolajczyk, Department of Microbiology, Boston University School of 
Medicine, 72 East Concord Street, Boston, MA 02118, United States. Email: 
bnikol@bu.edu
SOURCE
  Immunological Reviews (2012) 249:1 (253-275). Date of Publication: September 
2012
ISSN
  0105-2896
  1600-065X (electronic)
BOOK PUBLISHER
  Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.
ABSTRACT
  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. © 2012 John Wiley & Sons A/S.
EMTREE DRUG INDEX TERMS
  acetylsalicylic acid (drug dose, drug therapy)
  B lymphocyte antibody (endogenous compound)
  biological marker (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immunity
  immunometabolism
  inflammation
  metabolism
  non insulin dependent diabetes mellitus (drug therapy, drug therapy)
  obesity
EMTREE MEDICAL INDEX TERMS
  adipose tissue
  article
  B lymphocyte
  cell function
  disease severity
  human
  immunocompetent cell
  insulin resistance
  low drug dose
  metabolic disorder
  molecular interaction
  nonhuman
  priority journal
  Th17 cell
DRUG TRADE NAMES
  aspirin
CAS REGISTRY NUMBERS
  acetylsalicylic acid (493-53-8, 50-78-2, 53663-74-4, 53664-49-6, 63781-77-1)
EMBASE CLASSIFICATIONS
  Internal Medicine (6)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012495030
MEDLINE PMID
  22889227 (http://www.ncbi.nlm.nih.gov/pubmed/22889227)
PUI
  L365490919
DOI
  10.1111/j.1600-065X.2012.01142.x
FULL TEXT LINK
  http://dx.doi.org/10.1111/j.1600-065X.2012.01142.x
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 379
TITLE
  Management of immune-related adverse events and kinetics of response with 
ipilimumab
AUTHOR NAMES
  Weber J.S.
  Kähler K.C.
  Hauschild A.
AUTHOR ADDRESSES
  (Weber J.S., jeffrey.weber@moffitt.org) H. Lee Moffitt Cancer Center, 
Research Institute, SRB 22045, 12902 Magnolia Dr, Tampa, FL 33612, United 
States.
(Kähler K.C.; Hauschild A.) University of Kiel, Kiel, Germany.
CORRESPONDENCE ADDRESS
  J.S. Weber, H. Lee Moffitt Cancer Center, Research Institute, SRB 22045, 
12902 Magnolia Dr, Tampa, FL 33612, United States. Email: 
jeffrey.weber@moffitt.org
SOURCE
  Journal of Clinical Oncology (2012) 30:21 (2691-2697). Date of Publication: 
20 Jul 2012
ISSN
  0732-183X
  1527-7755 (electronic)
BOOK PUBLISHER
  American Society of Clinical Oncology, 330 John Carlyle Street, Suite 300, 
Alexandria, United States.
ABSTRACT
  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. © 2012 by American Society of Clinical Oncology.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  antipruritic agent (drug therapy, oral drug administration)
  atropine (drug therapy)
  betamethasone (drug therapy, topical drug administration)
  budesonide (drug therapy)
  cytotoxic T lymphocyte antigen 4
  dexamethasone (drug dose, drug therapy)
  diphenhydramine (drug therapy, oral drug administration)
  diphenoxylate (drug therapy, oral drug administration)
  glucocorticoid (drug therapy, topical drug administration)
  hydroxyzine (drug therapy, oral drug administration)
  infliximab (drug therapy)
  methylprednisolone (drug therapy, intravenous drug administration)
  mycophenolate mofetil (drug therapy, oral drug administration)
  prednisone (drug therapy, oral drug administration)
  steroid (oral drug administration)
  ticilimumab (adverse drug reaction)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug induced disease (etiology)
EMTREE MEDICAL INDEX TERMS
  behavior change
  colitis (drug therapy, side effect)
  diarrhea (drug therapy, side effect)
  diplopia (side effect)
  drug dose titration
  episcleritis (drug therapy, side effect)
  Guillain Barre syndrome (side effect)
  headache (side effect)
  hepatitis (side effect)
  human
  hypophysitis (drug therapy, side effect)
  iridocyclitis (side effect)
  liver toxicity (drug therapy)
  lymphadenopathy (side effect)
  metastatic melanoma (drug therapy)
  myasthenia gravis (side effect)
  nausea (side effect)
  nephritis (side effect)
  neuropathy (drug therapy, side effect)
  pancreatitis (side effect)
  priority journal
  pruritus (drug therapy, side effect)
  rash (drug therapy, side effect)
  review
  side effect (side effect)
  Stevens Johnson syndrome (side effect)
  T lymphocyte activation
  toxic epidermal necrolysis (side effect)
  treatment response
  tumor regression
  tumor volume
  uveitis (drug therapy, side effect)
  vertigo (side effect)
  visual disorder (side effect)
  vitiligo (side effect)
  weakness (side effect)
DRUG TRADE NAMES
  cellcept  , United StatesGenentech

  cp 675206  , United StatesPfizer

  yervoy  , United StatesBristol Myers Squibb

DRUG MANUFACTURERS
   (United States)Bristol Myers Squibb
   (United States)Genentech
   (United States)Pfizer
CAS REGISTRY NUMBERS
  atropine (51-55-8, 55-48-1)
  betamethasone (378-44-9)
  budesonide (51333-22-3, 51372-29-3)
  dexamethasone (50-02-2)
  diphenhydramine (147-24-0, 58-73-1)
  diphenoxylate (3810-80-8, 915-30-0)
  hydroxyzine (2192-20-3, 64095-02-9, 68-88-2)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  mycophenolic acid 2 morpholinoethyl ester (116680-01-4, 128794-94-5)
  prednisone (53-03-2)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012427428
MEDLINE PMID
  22614989 (http://www.ncbi.nlm.nih.gov/pubmed/22614989)
PUI
  L365284049
DOI
  10.1200/JCO.2012.41.6750
FULL TEXT LINK
  http://dx.doi.org/10.1200/JCO.2012.41.6750
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 380
TITLE
  Ipilimumab: A novel immunomodulating therapy causing autoimmune 
hypophysitis: A case report and review
AUTHOR NAMES
  Juszczak A.
  Gupta A.
  Karavitaki N.
  Middleton M.R.
  Grossman A.B.
AUTHOR ADDRESSES
  (Juszczak A.; Karavitaki N.; Grossman A.B., ashley.grossman@ocdem.ox.ac.uk) 
Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill 
Hospital, Oxford OX3 7LE, United Kingdom.
(Gupta A.; Middleton M.R.) Department of Oncology, Churchill Hospital, 
Oxford OX3 7LE, United Kingdom.
(Gupta A.; Middleton M.R.) NIHR Biomedical Research Centre, University of 
Oxford, Oxford OX3 7LE, United Kingdom.
CORRESPONDENCE ADDRESS
  A.B. Grossman, Oxford Centre for Diabetes, Endocrinology and Metabolism, 
Churchill Hospital, Oxford OX3 7LE, United Kingdom. Email: 
ashley.grossman@ocdem.ox.ac.uk
SOURCE
  European Journal of Endocrinology (2012) 167:1 (1-5). Date of Publication: 
July 2012
ISSN
  0804-4643
  1479-683X (electronic)
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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. © 2012 European Society of Endocrinology.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  dexamethasone (drug combination, drug therapy)
  docetaxel (drug therapy)
  follitropin (endogenous compound)
  hydrocortisone (endogenous compound)
  levothyroxine (drug combination)
  luteinizing hormone (endogenous compound)
  prolactin (endogenous compound)
  somatomedin C (endogenous compound)
  testosterone (drug combination, endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease (drug therapy, side effect, drug therapy, side effect)
  autoimmune hypophysitis (drug therapy, side effect, drug therapy, side 
effect)
  hypophysitis (drug therapy, side effect, drug therapy, side effect)
  immunomodulation
EMTREE MEDICAL INDEX TERMS
  adult
  brain edema
  cancer chemotherapy
  cancer recurrence
  case report
  computer assisted tomography
  drug dose reduction
  drug substitution
  drug withdrawal
  erectile dysfunction
  follow up
  headache
  hormone substitution
  human
  hypopituitarism
  lethargy
  libido disorder
  lung metastasis
  male
  metastatic melanoma (drug therapy, surgery)
  neuroimaging
  nuclear magnetic resonance imaging
  priority journal
  review
DRUG TRADE NAMES
  yervoy  Bristol Myers Squibb

  yervoy  Medarex

DRUG MANUFACTURERS
  Bristol Myers Squibb
  Medarex
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  docetaxel (114977-28-5)
  follitropin (9002-68-0)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
  somatomedin C (67763-96-6)
  testosterone (58-22-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012362218
MEDLINE PMID
  22495490 (http://www.ncbi.nlm.nih.gov/pubmed/22495490)
PUI
  L365092121
DOI
  10.1530/EJE-12-0167
FULL TEXT LINK
  http://dx.doi.org/10.1530/EJE-12-0167
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 381
TITLE
  Immunostimulant; more assessment needed
AUTHOR ADDRESSES
  SOURCE
  Prescrire International (2012) 21:128 (145-147). Date of Publication: June 
2012
ISSN
  1167-7422
BOOK PUBLISHER
  Association Mieux Prescrire, 83, boulevard Voltaire, Paris, France.
ABSTRACT
  • 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 welldesigned clinical trials designed to 
better assess the survival benefit, serious adverse effects, and the optimal 
dosage. Copyright©Prescrire.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug therapy)
EMTREE DRUG INDEX TERMS
  dacarbazine (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug therapy)
  fotemustine (drug therapy)
  glycoprotein gp 100 (adverse drug reaction, clinical trial, drug 
combination, drug comparison, drug therapy)
  HLA A antigen (endogenous compound)
  interleukin 2 (clinical trial, drug combination, drug comparison, drug 
therapy)
  placebo
  temozolomide (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  antibody production
  brain metastasis (complication, drug therapy)
  cancer chemotherapy
  cancer growth
  cancer patient
  cancer survival
  capillary leak syndrome (side effect)
  cell activation
  cell proliferation
  clinical assessment
  clinical evaluation
  clinical protocol
  dermatitis (side effect)
  diarrhea (side effect)
  drug fatality (side effect)
  drug megadose
  drug treatment failure
  enterocolitis (side effect)
  European Union
  fatigue (side effect)
  Guillain Barre syndrome (side effect)
  hepatitis (side effect)
  human
  hypopituitarism (side effect)
  immunostimulation
  intestine perforation (side effect)
  liver failure (side effect)
  lymphocyte activation
  medical practice
  myelodysplastic syndrome (side effect)
  overall survival
  pregnancy
  primary health care
  pruritus (side effect)
  randomized controlled trial (topic)
  rash (side effect)
  risk benefit analysis
  short survey
  side effect (side effect)
  survival time
  T lymphocyte
  toxic epidermal necrolysis (side effect)
DRUG TRADE NAMES
  yervoy  Bristol

DRUG MANUFACTURERS
  Bristol
  Squibb
CAS REGISTRY NUMBERS
  dacarbazine (4342-03-4)
  fotemustine (92118-27-9)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  temozolomide (85622-93-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012391275
MEDLINE PMID
  22822590 (http://www.ncbi.nlm.nih.gov/pubmed/22822590)
PUI
  L365181111
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 382
TITLE
  Ovarian carcinoma tumor-initiating cells have a mesenchymal phenotype
AUTHOR NAMES
  Ricci F.
  Bernasconi S.
  Perego P.
  Ganzinelli M.
  Russo G.
  Bono F.
  Mangioni C.
  Fruscio R.
  Signorelli M.
  Broggini M.
  Damia G.
AUTHOR ADDRESSES
  (Ricci F.; Bernasconi S.; Ganzinelli M.; Russo G.; Broggini M.; Damia G., 
giovanna.damia@marionegri.it) Department of Oncology, Istituto di Ricerche 
Farmacologiche Mario Negri, Milan, Italy.
(Perego P.; Bono F.) Department of Surgical Pathology, Cytology and Medical 
Genetics, San Gerardo Hospital, University of Milan-Bicocca, Monza, Italy.
(Mangioni C.; Fruscio R.; Signorelli M.) Department of Obstetrics and 
Gynecology, San Gerardo Hospital, University of Milan-Bicocca, Monza, Italy.
CORRESPONDENCE ADDRESS
  G. Damia, Department of Oncology, Istituto di Ricerche Farmacologiche Mario 
Negri, Milan, Italy. Email: giovanna.damia@marionegri.it
SOURCE
  Cell Cycle (2012) 11:10 (1966-1976). Date of Publication: 15 May 2012
ISSN
  1551-4005 (electronic)
  1538-4101
BOOK PUBLISHER
  Taylor and Francis Inc.
ABSTRACT
  Solid tumors appear to contain a subpopulation of cells (tumor-initiating 
cells, TICs) that not only drives and sustains tumor growth, but is possibly 
responsible for recurrence. We isolated, after enzymatic digestion of 
primary ovarian carcinoma samples, a subpopulation of cells propagating as 
non-adherent spheres in medium suitable for tumor stem cells. These cells 
were able to self-renew in vitro, as suggested by PKH-26 staining studies, 
were tumorigenic and acquired an epithelial morphology when grown in 
FBS-supplemented medium, losing their tumorigenic potential. Interestingly, 
the tumorigenic potential of PKH-26(high)- and PKH-26(neg)-sorted cells was 
similar. These TIC-enriched cultures showed higher levels of genes involved 
in stemness than differentiated cells derived from them and were more 
resistant to the cytotoxic effects of some drugs but equally sensitive to 
others. The higher level of ABCG2 efflux pump could explain increased 
resistance to taxol and VP16, and higher levels of genes involved in 
nucleotide excision repair partially explain the resistance to cisplatin. 
These cells express mesenchymal markers and epithelial transition could be 
induced when cultured in differentiating conditions, with a loss of invasive 
potential. These data suggest that ovarian cancer is a stem cell disease and 
should help elucidate the role of these cells in the aggressive phenotype of 
this tumor and find new therapeutic strategies to reduce resistance to 
current chemotherapeutic drugs. © 2012 Landes Bioscience.
EMTREE DRUG INDEX TERMS
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide
  breast cancer resistance protein (endogenous compound)
  cisplatin
  etoposide
  paclitaxel
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer stem cell
  ovary carcinoma (drug resistance)
EMTREE MEDICAL INDEX TERMS
  animal experiment
  animal model
  animal tissue
  article
  cancer cell
  cancer cell culture
  cancer resistance
  carcinogenesis
  carcinogenicity
  cell differentiation
  cell isolation
  cell population
  cell renewal
  cell sorter
  controlled study
  cytotoxicity
  epithelium
  excision repair
  female
  human
  human cell
  in vitro study
  mesenchymal stem cell
  mesenchyme cell
  mouse
  nonhuman
  phenotype
  staining
DRUG TRADE NAMES
  azd 7762  Axon

  vp 16
DRUG MANUFACTURERS
  Axon
CAS REGISTRY NUMBERS
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide 
(1019773-80-8, 860352-01-8)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  etoposide (33419-42-0)
  paclitaxel (33069-62-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012297577
MEDLINE PMID
  22544328 (http://www.ncbi.nlm.nih.gov/pubmed/22544328)
PUI
  L364866385
DOI
  10.4161/cc.20308
FULL TEXT LINK
  http://dx.doi.org/10.4161/cc.20308
COPYRIGHT
  Copyright 2017 Elsevier B.V., All rights reserved.

RECORD 383
TITLE
  Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte 
antigen 4: Challenges from a new cause of a rare disease
AUTHOR NAMES
  Torino F.
  Barnabei A.
  de Vecchis L.
  Salvatori R.
  Corsello S.M.
AUTHOR ADDRESSES
  (Torino F.) Department of Internal Medicine, University of Rome 'Tor 
Vergata', Rome, Italy.
(de Vecchis L.) Department of Neuroscience, University of Rome 'Tor 
Vergata', Rome, Italy.
(Barnabei A.) Endocrinology Unit, National Institute of Cancer 'Regina 
Elena', Rome, Italy.
(Salvatori R.) Pituitary Center, Division of Endocrinology, Johns Hopkins 
University School of Medicine, Baltimore, MD, United States.
(Corsello S.M., corsello.sm@mclink.it) Endocrinology Unit, Università 
Cattolica, Rome, Italy.
CORRESPONDENCE ADDRESS
  S. M. Corsello, Endocrinology Unit, Università Cattolica, Largo A. Gemelli 
8, 00168 Rome, Italy. Email: corsello.sm@mclink.it
SOURCE
  Oncologist (2012) 17:4 (525-535). Date of Publication: 2012
ISSN
  1083-7159
  1549-490X (electronic)
BOOK PUBLISHER
  AlphaMed Press, 318 Blackwell St. Suite 260, Durham, United States.
ABSTRACT
  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. © AlphaMed 
Press.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  cytotoxic T lymphocyte antigen 4 monoclonal antibody
  monoclonal antibody
EMTREE DRUG INDEX TERMS
  bevacizumab (drug combination)
  corticotropin (endogenous compound)
  dacarbazine (clinical trial, drug combination, drug comparison)
  glucocorticoid
  glycoprotein gp 100 (clinical trial, drug combination)
  gonadotropin (endogenous compound)
  granulocyte macrophage colony stimulating factor (clinical trial, drug 
combination)
  granulocyte macrophage colony stimulating factor vaccine (clinical trial, 
drug combination, drug comparison)
  growth hormone (endogenous compound)
  interleukin 2 (clinical trial, drug combination)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
  luteinizing hormone (endogenous compound)
  monophenol monooxygenase (clinical trial, drug combination)
  peptide vaccine (clinical trial, drug combination)
  temozolomide (clinical trial, drug comparison)
  thyrotropin (endogenous compound)
  ticilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adenocarcinoma (drug therapy)
  adrenal insufficiency (side effect)
  arteritis (side effect)
  arthralgia (side effect)
  article
  aseptic meningitis (side effect)
  asthma (side effect)
  B cell lymphoma (drug therapy)
  cancer immunotherapy
  CD8+ T lymphocyte
  cellulitis (side effect)
  colitis (side effect)
  colon cancer (drug therapy)
  constipation (side effect)
  death
  dermatitis (side effect)
  diarrhea (side effect)
  disease classification
  diverticulitis (side effect)
  drug dose escalation
  drug dose reduction
  drug megadose
  edema (side effect)
  encephalitis (side effect)
  enterocolitis (side effect)
  episcleritis (side effect)
  esophageal adenocarcinoma (drug therapy)
  fatigue (side effect)
  fever (side effect)
  gastrointestinal hemorrhage (side effect)
  gastrointestinal toxicity (side effect)
  Guillain Barre syndrome (side effect)
  headache (side effect)
  hepatitis (side effect)
  human
  hypertransaminasemia (side effect)
  hypokalemia (side effect)
  hypopituitarism (side effect)
  hypothyroidism (side effect)
  immune system
  ischemia (side effect)
  kidney carcinoma (drug therapy)
  liver toxicity (side effect)
  lung alveolitis (side effect)
  melanoma (drug therapy)
  metastasis (drug therapy)
  multiple cycle treatment
  multiple organ failure (side effect)
  myasthenia gravis (side effect)
  myocarditis (side effect)
  myositis (side effect)
  nausea (side effect)
  nephritis (side effect)
  neuritis (side effect)
  neuropathy (side effect)
  neutropenia (side effect)
  nonhodgkin lymphoma (drug therapy)
  overall survival
  pain (side effect)
  pancreas adenocarcinoma (drug therapy)
  pancreatitis (side effect)
  pancytopenia (side effect)
  perforation (side effect)
  pneumonia (side effect)
  polyarthritis (side effect)
  priority journal
  prostate cancer (drug therapy)
  pruritus (side effect)
  pure red cell anemia (side effect)
  rash (side effect)
  repeated drug dose
  sarcoidosis (side effect)
  side effect (side effect)
  single drug dose
  skin exfoliation (side effect)
  skin toxicity (side effect)
  stomach adenocarcinoma (drug therapy)
  thrombocytopenia (side effect)
  thyroid disease (side effect)
  thyroiditis (side effect)
  triacylglycerol lipase blood level
  uveitis (side effect)
  vasculitis (side effect)
  vomiting (side effect)
DRUG TRADE NAMES
  cp 675 206  , United StatesPfizer

  mdx 010  , United StatesBristol Myers Squibb

  mdx 010  , United StatesMedarex

DRUG MANUFACTURERS
   (United States)Bristol Myers Squibb
   (United States)Medarex
   (United States)Pfizer
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  dacarbazine (4342-03-4)
  gonadotropin (63231-54-9)
  growth hormone (36992-73-1, 37267-05-3, 66419-50-9, 9002-72-6)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  monophenol monooxygenase (9002-10-2)
  temozolomide (85622-93-1)
  thyrotropin (9002-71-5)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Neurology and Neurosurgery (8)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012235775
MEDLINE PMID
  22477725 (http://www.ncbi.nlm.nih.gov/pubmed/22477725)
PUI
  L364680985
DOI
  10.1634/theoncologist.2011-0404
FULL TEXT LINK
  http://dx.doi.org/10.1634/theoncologist.2011-0404
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 384
TITLE
  Association of ipilimumab therapy for advanced melanoma with secondary 
adrenal insufficiency: A case series
AUTHOR NAMES
  Min L.
  Vaidya A.
  Becker C.
AUTHOR ADDRESSES
  (Min L.; Vaidya A.; Becker C., cbbecker@partners.org) Division of 
Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, 
Harvard Medical School, 221 Longwood Ave, Boston, MA 02115, United States.
CORRESPONDENCE ADDRESS
  C. Becker, Division of Endocrinology, Diabetes, and Hypertension, Brigham 
and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 
02115, United States. Email: cbbecker@partners.org
SOURCE
  Endocrine Practice (2012) 18:3 (351-355). Date of Publication: 1 May 2012
ISSN
  1530-891X
  1934-2403 (electronic)
BOOK PUBLISHER
  Endocrine Practice, 245 Riverside Ave,Suite 200, Jacksonville, United 
States.
ABSTRACT
  Objective: To present a case series of ipilimumab-related secondary adrenal 
insufficiency.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.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.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. Copyright © 2012 AACE.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  hydrocortisone (drug therapy)
  luteinizing hormone (endogenous compound)
  somatomedin C (endogenous compound)
  testosterone (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  adrenal insufficiency (side effect, diagnosis, side effect)
  advanced cancer (drug therapy, drug therapy)
  advanced melanoma (drug therapy, drug therapy)
  drug induced disease (drug therapy, side effect, diagnosis, drug therapy, 
side effect)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  cancer diagnosis
  cause of death
  clinical article
  corticosteroid therapy
  dizziness (side effect)
  drug induced headache (side effect)
  drug withdrawal
  enlarged pituitary (drug therapy, side effect)
  enlarged pituitary (drug therapy, side effect)
  fatigue (side effect)
  female
  free thyroxine index
  hormone substitution
  human
  hypogonadism
  hypophysis
  hypophysis disease (drug therapy, side effect)
  hypophysis function
  hypophysitis (side effect)
  hypopituitarism (side effect)
  male
  neuroimaging
  nuclear magnetic resonance imaging
  organ size
  review
  side effect (side effect)
  treatment duration
  treatment response
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  luteinizing hormone (39341-83-8, 9002-67-9)
  somatomedin C (67763-96-6)
  testosterone (58-22-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012279999
MEDLINE PMID
  22138079 (http://www.ncbi.nlm.nih.gov/pubmed/22138079)
PUI
  L364816607
DOI
  10.4158/EP11273.OR
FULL TEXT LINK
  http://dx.doi.org/10.4158/EP11273.OR
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 385
TITLE
  Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in 
metastatic castration-resistant prostate cancer: A phase 1 dose-escalation 
trial
AUTHOR NAMES
  Madan R.A.
  Mohebtash M.
  Arlen P.M.
  Vergati M.
  Rauckhorst M.
  Steinberg S.M.
  Tsang K.Y.
  Poole D.J.
  Parnes H.L.
  Wright J.J.
  Dahut W.L.
  Schlom J.
  Gulley J.L.
AUTHOR ADDRESSES
  (Madan R.A.; Mohebtash M.; Arlen P.M.; Vergati M.; Rauckhorst M.; Tsang 
K.Y.; Poole D.J.; Schlom J.; Gulley J.L., gulleyj@mail.nih.gov) Laboratory 
of Tumor Immunology and Biology, Center for Cancer Research, National Cancer 
Institute, National Institutes of Health, Bethesda, MD, United States.
(Madan R.A.; Arlen P.M.; Parnes H.L.; Wright J.J.; Dahut W.L.; Gulley J.L., 
gulleyj@mail.nih.gov) Medical Oncology Branch, Center for Cancer Research, 
National Cancer Institute, National Institutes of Health, Bethesda, MD, 
United States.
(Steinberg S.M.) Biostatistics and Data Management Section, Center for 
Cancer Research, National Cancer Institute, National Institutes of Health, 
Bethesda, MD, United States.
CORRESPONDENCE ADDRESS
  J.L. Gulley, Laboratory of Tumor Immunology and Biology, Center for Cancer 
Research, National Cancer Institute, National Institutes of Health, 10 
Center Drive, Bethesda, MD 20892, United States. Email: gulleyj@mail.nih.gov
SOURCE
  The Lancet Oncology (2012) 13:5 (501-508). Date of Publication: May 2012
ISSN
  1470-2045
  1474-5488 (electronic)
BOOK PUBLISHER
  Lancet Publishing Group, Elsevier, The Boulevard, Langford, Kidlington, 
Oxford, United Kingdom.
ABSTRACT
  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. 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 2×10(8) plaque-forming 
units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, 
with subsequent monthly boosts of 1×10(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. 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%. 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. Funding: US National 
Institutes of Health. © 2012 Elsevier Ltd.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug dose, drug therapy, 
intravenous drug administration)
  virus vaccine (adverse drug reaction, clinical trial, drug dose, drug 
therapy, subcutaneous drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer immunotherapy
  castration resistant prostate cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult
  aged
  article
  clinical article
  colitis (side effect)
  dehydration (side effect)
  diarrhea (side effect)
  dose response
  drug dose escalation
  drug safety
  drug tolerability
  drug withdrawal
  fatigue (side effect)
  fever (side effect)
  human
  hyponatremia (side effect)
  hypophosphatemia (side effect)
  hypophysitis (side effect)
  hypotension (side effect)
  hypothyroidism (side effect)
  immunopathology (side effect)
  injection site reaction (side effect)
  male
  neutropenia (side effect)
  phase 1 clinical trial
  priority journal
  rash (side effect)
  side effect (side effect)
  thrombocytopenia (side effect)
  treatment outcome
DRUG MANUFACTURERS
   (United States)Bristol Myers Squibb
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00113984)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012251349
MEDLINE PMID
  22326924 (http://www.ncbi.nlm.nih.gov/pubmed/22326924)
PUI
  L51857446
DOI
  10.1016/S1470-2045(12)70006-2
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(12)70006-2
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 386
TITLE
  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
AUTHOR NAMES
  Van den Eertwegh A.J.M.
  Versluis J.
  Van den Berg H.P.
  Santegoets S.J.A.M.
  Van Moorselaar R.J.A.
  Van der Sluis T.M.
  Gall H.E.
  Harding T.C.
  Jooss K.
  Lowy I.
  Pinedo H.M.
  Scheper R.J.
  Stam A.G.M.
  Von Blomberg B.M.E.
  De Gruijl T.D.
  Hege K.
  Sacks N.
  Gerritsen W.R.
AUTHOR ADDRESSES
  (Van den Eertwegh A.J.M.; Versluis J.; Van den Berg H.P.; Santegoets 
S.J.A.M.; Gall H.E.; Pinedo H.M.; De Gruijl T.D.; Gerritsen W.R., 
winald.gerritsen@vumc.nl) Department of Medical Oncology, VU University 
Medical Centre, Amsterdam, Netherlands.
(Scheper R.J.; Stam A.G.M.; Von Blomberg B.M.E.) Department of Pathology, VU 
University Medical Centre, Amsterdam, Netherlands.
(Van Moorselaar R.J.A.; Van der Sluis T.M.) Department of Urology, VU 
University Medical Centre, Amsterdam, Netherlands.
(Harding T.C.; Jooss K.; Hege K.; Sacks N.) Cell Genesys Inc, San Francisco, 
CA, United States.
(Lowy I.) Medarex, Bloomsbury, NJ/Bristol-Myers Squibb Company, Wallingford, 
CT, United States.
CORRESPONDENCE ADDRESS
  W.R. Gerritsen, Department of Medical Oncology, VU University Medical 
Centre, PO Box 7057, 1007 MB Amsterdam, Netherlands. Email: 
winald.gerritsen@vumc.nl
SOURCE
  The Lancet Oncology (2012) 13:5 (509-517). Date of Publication: May 2012
ISSN
  1470-2045
  1474-5488 (electronic)
BOOK PUBLISHER
  Lancet Publishing Group, Elsevier, The Boulevard, Langford, Kidlington, 
Oxford, United Kingdom.
ABSTRACT
  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). 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 5×10(8) cell 
priming dose of GVAX intradermally on day 1 with subsequent intradermal 
injections of 3×10(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. 
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. 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. Funding: Cell Genesys 
Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), 
and Foundation Stichting VUmc Cancer Center Amsterdam. © 2012 Elsevier Ltd.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  granulocyte macrophage colony stimulating factor vaccine (adverse drug 
reaction, clinical trial, drug combination, drug dose, drug therapy, 
intradermal drug administration)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy, intravenous drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  castration resistant prostate cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult
  aged
  anorexia (side effect)
  article
  body weight
  cancer combination chemotherapy
  cancer immunization
  cancer survival
  clinical article
  colitis (side effect)
  diarrhea (side effect)
  dose response
  drug dose comparison
  drug dose escalation
  drug safety
  drug tolerability
  drug withdrawal
  dysgeusia (side effect)
  fatigue (side effect)
  fever (side effect)
  flu like syndrome (side effect)
  headache (side effect)
  hepatitis (side effect)
  human
  human cell
  hyponatremia (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  injection site pain (side effect)
  injection site reaction (side effect)
  leukopenia (side effect)
  lung alveolitis (side effect)
  malaise (side effect)
  male
  nausea (side effect)
  overall survival
  phase 1 clinical trial
  priority journal
  proctitis (side effect)
  side effect (side effect)
  treatment outcome
  vomiting (side effect)
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT01510288)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012251350
MEDLINE PMID
  22326922 (http://www.ncbi.nlm.nih.gov/pubmed/22326922)
PUI
  L51857447
DOI
  10.1016/S1470-2045(12)70007-4
FULL TEXT LINK
  http://dx.doi.org/10.1016/S1470-2045(12)70007-4
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 387
TITLE
  Autoimmune hypophysitis: Autoantigens and association with CTLA-4 blockade
AUTHOR NAMES
  Caturegli P.
AUTHOR ADDRESSES
  (Caturegli P., pcat@jhmi.edu) Johns Hopkins University, Department of 
Pathology, Endocrinology and Molecular Microbiology and Immunology, Ross 
Building, 720, Rutland Avenue, Baltimore, 21205 MD, United States.
CORRESPONDENCE ADDRESS
  P. Caturegli, Johns Hopkins University, Department of Pathology, 
Endocrinology and Molecular Microbiology and Immunology, Ross Building, 720, 
Rutland Avenue, Baltimore, 21205 MD, United States. Email: pcat@jhmi.edu
SOURCE
  Annales d'Endocrinologie (2012) 73:2 (78). Date of Publication: April 2012
ISSN
  0003-4266
BOOK PUBLISHER
  Elsevier Masson SAS, 62 rue Camille Desmoulins, Issy les Moulineaux Cedex, 
France.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  autoantigen (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
EMTREE DRUG INDEX TERMS
  glucocorticoid (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune hypophysitis (drug therapy, diagnosis, drug therapy)
  hypophysitis (drug therapy, diagnosis, drug therapy)
EMTREE MEDICAL INDEX TERMS
  article
  cell destruction
  clinical feature
  diabetes insipidus
  diagnostic imaging
  differential diagnosis
  disease association
  disease classification
  disease course
  etiology
  histopathology
  hormone substitution
  human
  hyperprolactinemia
  hypophysis
  hypophysis cell
  hypophysis disease
  hypophysis surgery
  hypopituitarism
  immunomodulation
  inflammatory disease
  pathogenesis
  sella turcica tumor
  sellar compression
  surgery
  symptomatology
  treatment duration
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  General Pathology and Pathological Anatomy (5)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  2012275773
MEDLINE PMID
  22537512 (http://www.ncbi.nlm.nih.gov/pubmed/22537512)
PUI
  L51976227
DOI
  10.1016/j.ando.2012.04.006
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ando.2012.04.006
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 388
TITLE
  Ipilimumab: Its potential in non-small cell lung cancer
AUTHOR NAMES
  Tomasini P.
  Khobta N.
  Greillier L.
  Barlesi F.
AUTHOR ADDRESSES
  (Barlesi F., fabrice.barlesi@ap-hm.fr) Service d'Oncologie 
Multidisciplinaire et Innovations Thérapeutique, Hôpital Nord, Chemin des 
Bourrely, 13915 Marseille Cedex 20, France.
(Tomasini P.; Khobta N.; Greillier L.) Multidisciplinary Oncology and 
Therapeutic Innovations Department, Aix Marseille University, Assistance 
Publique Hôpitaux de Marseille, Marseille, France.
CORRESPONDENCE ADDRESS
  F. Barlesi, Service d'Oncologie Multidisciplinaire et Innovations 
Thérapeutique, Hôpital Nord, Chemin des Bourrely, 13915 Marseille Cedex 20, 
France. Email: fabrice.barlesi@ap-hm.fr
SOURCE
  Therapeutic Advances in Medical Oncology (2012) 4:2 (43-50). Date of 
Publication: March 2012
ISSN
  1758-8340
  1758-8359 (electronic)
BOOK PUBLISHER
  SAGE Publications Inc., 2455 Teller Road, Thousand Oaks, United States.
ABSTRACT
  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. © SAGE Publications 2011.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug dose, drug interaction, drug therapy, drug toxicity, 
pharmacokinetics, pharmacology)
  placebo
EMTREE DRUG INDEX TERMS
  belagenpumatucel L (drug therapy)
  budesonide (drug therapy)
  carboplatin (clinical trial, drug combination, drug interaction)
  CD28 antigen (endogenous compound)
  CD69 antigen (endogenous compound)
  CD8 antigen (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  glycoprotein gp 100 (clinical trial, drug combination, drug comparison, drug 
therapy)
  interleukin 2 (endogenous compound)
  interleukin 2 receptor alpha (endogenous compound)
  melanoma antigen 3 (clinical trial, drug therapy)
  paclitaxel (clinical trial, drug combination, drug interaction)
  talactoferrin (clinical trial, drug therapy)
  tecemotide (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  non small cell lung cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adaptive immunity
  adjuvant chemotherapy
  adrenal insufficiency (side effect)
  advanced cancer (drug therapy)
  autoimmune disease (side effect)
  cancer chemotherapy
  cancer immunotherapy
  cancer prognosis
  cancer staging
  castration resistant prostate cancer (drug therapy)
  CD25+ T lymphocyte
  cell expansion
  correlation analysis
  diarrhea (drug therapy, prevention, side effect)
  disease free survival
  DNA sequence
  drug dose increase
  drug efficacy
  drug megadose
  drug tolerability
  enterocolitis (side effect)
  genetic variability
  hepatitis (side effect)
  human
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  kidney metastasis (drug therapy)
  metastatic melanoma (drug therapy)
  molecularly targeted therapy
  monotherapy
  multiple cycle treatment
  overall survival
  phase 1 clinical trial (topic)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  priority journal
  progression free survival
  protein expression
  randomized controlled trial (topic)
  regulatory T lymphocyte
  review
  signal transduction
  T lymphocyte
  toxic epidermal necrolysis (side effect)
  translational research
  treatment response
  tumor immunity
  tumor regression
  uveitis (side effect)
DRUG TRADE NAMES
  lucanix  , United StatesNovaRx

  stimuvax
DRUG MANUFACTURERS
   (United States)NovaRx
CAS REGISTRY NUMBERS
  budesonide (51333-22-3, 51372-29-3)
  carboplatin (41575-94-4)
  emepepimut S (1225284-76-3)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  paclitaxel (33069-62-4)
  talactoferrin (308240-58-6)
EMBASE CLASSIFICATIONS
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00527735, NCT01285609)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012449585
PUI
  L365342077
DOI
  10.1177/1758834011431718
FULL TEXT LINK
  http://dx.doi.org/10.1177/1758834011431718
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 389
TITLE
  Hyponatremia associated with Ipilimumab-induced hypophysitis
AUTHOR NAMES
  Barnard Z.R.
  Walcott B.P.
  Kahle K.T.
  Nahed B.V.
  Coumans J.V.
AUTHOR ADDRESSES
  (Barnard Z.R.; Walcott B.P., walcott.brian@mgh.harvard.edu; Kahle K.T.; 
Nahed B.V.; Coumans J.V.) Department of Neurosurgery, Massachusetts General 
Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United 
States.
CORRESPONDENCE ADDRESS
  B.P. Walcott, Department of Neurosurgery, Massachusetts General Hospital, 
Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. 
Email: walcott.brian@mgh.harvard.edu
SOURCE
  Medical Oncology (2012) 29:1 (374-377). Date of Publication: March 2012
ISSN
  1357-0560
  1559-131X (electronic)
BOOK PUBLISHER
  Humana Press, 999 Riverview Drive, Suite 208, Totowa, United States.
ABSTRACT
  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. © 2011 
Springer Science+Business Media, LLC.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  corticotropin (endogenous compound)
  hydrocortisone (endogenous compound)
  prednisone (drug therapy)
  sodium (endogenous compound)
  sodium chloride
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hyponatremia (diagnosis)
  hypophysitis (side effect, diagnosis, side effect)
  inappropriate vasopressin secretion (drug therapy, complication, diagnosis, 
disease management, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adenohypophysis
  aged
  anamnesis
  article
  cancer staging
  case report
  corticotropin blood level
  disease severity
  drug dose reduction
  female
  fluid therapy
  free thyroxine index
  headache
  human
  hydrocortisone blood level
  hyperosmolarity
  metastatic melanoma (drug therapy)
  multiple cycle treatment
  nuclear magnetic resonance imaging
  pituitary stalk
  priority journal
  radiography
  serum osmolality
  sodium blood level
  sodium urine level
  thyrotropin blood level
  thyroxine blood level
  tissue necrosis
  urine osmolality
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  prednisone (53-03-2)
  sodium (7440-23-5)
  sodium chloride (7647-14-5)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012427161
MEDLINE PMID
  21264545 (http://www.ncbi.nlm.nih.gov/pubmed/21264545)
PUI
  L51246133
DOI
  10.1007/s12032-010-9794-7
FULL TEXT LINK
  http://dx.doi.org/10.1007/s12032-010-9794-7
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 390
TITLE
  Tumour suppressive function and modulation of programmed cell death 4 
(PDCD4) in ovarian cancer
AUTHOR NAMES
  Wei N.
  Liu S.S.
  Chan K.K.L.
  Ngan H.Y.S.
AUTHOR ADDRESSES
  (Wei N.; Liu S.S.; Chan K.K.L.; Ngan H.Y.S., gyonc@hku.hk) Department of 
Obstetrics and Gynaecology, Queen Mary Hospital, the University of Hong 
Kong, Hong Kong, Hong Kong.
CORRESPONDENCE ADDRESS
  H. Y. S. Ngan, Department of Obstetrics and Gynaecology, Queen Mary 
Hospital, the University of Hong Kong, Hong Kong, Hong Kong. Email: 
gyonc@hku.hk
SOURCE
  PLoS ONE (2012) 7:1 Article Number: e30311. Date of Publication: 17 Jan 2012
ISSN
  1932-6203 (electronic)
BOOK PUBLISHER
  Public Library of Science, 185 Berry Street, Suite 1300, San Francisco, 
United States.
ABSTRACT
  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. 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. 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. © 2012 Wei et al.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cell protein (endogenous compound)
  programmed cell death 4 protein (endogenous compound)
EMTREE DRUG INDEX TERMS
  phosphatase (endogenous compound)
  phosphatidylinositol 3 kinase inhibitor
  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (endogenous compound)
  protein kinase B (endogenous compound)
  protein p21 (endogenous compound)
  protein p27 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer control
  cancer inhibition
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  article
  cancer cell
  cell cycle arrest
  cell cycle G1 phase
  cell cycle progression
  cell invasion
  cell migration
  cell proliferation
  controlled study
  cytoplasm
  human
  human cell
  nucleotide sequence
  protein blood level
  protein degradation
  protein depletion
  protein expression
  protein function
  protein localization
  protein transport
  regulatory mechanism
  signal transduction
  upregulation
CAS REGISTRY NUMBERS
  phosphatase (9013-05-2)
  phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (210488-47-4)
  protein kinase B (148640-14-6)
  protein p21 (85306-28-1)
MOLECULAR SEQUENCE NUMBERS
  GENBANK (NM014456)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012034043
MEDLINE PMID
  22272332 (http://www.ncbi.nlm.nih.gov/pubmed/22272332)
PUI
  L364093714
DOI
  10.1371/journal.pone.0030311
FULL TEXT LINK
  http://dx.doi.org/10.1371/journal.pone.0030311
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 391
TITLE
  Low expression and secretion of circulating soluble CTLA-4 in peripheral 
blood mononuclear cells and sera from type 1 diabetic children
AUTHOR NAMES
  Rydén A.
  Bolmeson C.
  Jonson C.-O.
  Cilio C.M.
  Faresjö M.
AUTHOR ADDRESSES
  (Rydén A., anna.ryden@liu.se; Jonson C.-O.; Faresjö M.) Division of 
Paediatrics and Diabetes Research Centre, Department of Molecular and 
Clinical Medicine, Faculty of Health Sciences, Linköping University, 
Linköping, Sweden.
(Bolmeson C.; Cilio C.M.) Cellular Autoimmunity Unit, Department of Clinical 
Sciences, Lund University, Malmö, Sweden.
(Faresjö M.) Department of Natural Science and Biomedicine, School of Health 
Sciences, Jönköping University, Jönköping, Sweden.
CORRESPONDENCE ADDRESS
  A. Rydén, Clinical Experimental Research, Division of Paediatrics, Faculty 
of Health Sciences, Linköping University, S-581 85 Linköping, Sweden. Email: 
anna.ryden@liu.se
SOURCE
  Diabetes/Metabolism Research and Reviews (2012) 28:1 (84-96). Date of 
Publication: January 2012
ISSN
  1520-7552
  1520-7560 (electronic)
BOOK PUBLISHER
  John Wiley and Sons Ltd, Southern Gate, Chichester, West Sussex, United 
Kingdom.
ABSTRACT
  Background: High levels of soluble cytotoxic T-lymphocyte antigen 4 (soluble 
CTLA-4), an alternative splice form of the regulatory T-cell (Treg) 
associated CTLA-4 gene, have been associated with type 1 diabetes (T1D) and 
other autoimmune diseases, such as Grave's disease and myasthenia gravis. At 
the same time, studies have shown soluble CTLA-4 to inhibit T-cell 
activation through B7 binding. This study aimed to investigate the role of 
soluble CTLA-4 in relation to full-length CTLA-4 and other Treg-associated 
markers in T1D children and in individuals with high or low risk of 
developing the disease. Methods: T1D children were studied at 4 days, 1 and 
2 years after diagnosis in comparison to individuals with high or low risk 
of developing the disease. Isolated peripheral blood mononuclear cells were 
stimulated with the T1D-associated glutamic acid decarboxylase 65 and 
phytohaemagglutinin. Subsequently, soluble CTLA-4, full-length CTLA-4, FOXP3 
and TGF-β mRNA transcription were quantified and protein concentrations of 
soluble CTLA-4 were measured in culture supernatant and sera. Results and 
Conclusions: Low protein concentrations of circulating soluble CTLA-4 and a 
positive correlation between soluble CTLA-4 mRNA and protein were seen in 
T1D, in parallel with a negative correlation in healthy subjects. Further, 
low levels of mitogen-induced soluble CTLA-4 were accompanied by low 
C-peptide levels. Interestingly, low mitogen-induced soluble CTLA-4 mRNA and 
low TGF-β mRNA expression were seen in high risk individuals, suggesting an 
alteration in activation and down-regulating immune mechanisms during the 
pre-diabetic phase. © 2011 John Wiley & Sons, Ltd.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
EMTREE DRUG INDEX TERMS
  C peptide
  glutamate decarboxylase 65
  messenger RNA
  nicotinamide (drug therapy)
  phytohemagglutinin
  placebo
  transcription factor FOXP3
  transforming growth factor beta
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  insulin dependent diabetes mellitus (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adolescent
  antigen expression
  article
  cell isolation
  child
  clinical article
  controlled study
  down regulation
  female
  human
  male
  peripheral blood mononuclear cell
  preschool child
  priority journal
  regulatory T lymphocyte
  school child
  supernatant
CAS REGISTRY NUMBERS
  C peptide (59112-80-0)
  nicotinamide (11032-50-1, 98-92-0)
  phytohemagglutinin (9008-97-3)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Pediatrics and Pediatric Surgery (7)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012015208
MEDLINE PMID
  22218756 (http://www.ncbi.nlm.nih.gov/pubmed/22218756)
PUI
  L364039144
DOI
  10.1002/dmrr.1286
FULL TEXT LINK
  http://dx.doi.org/10.1002/dmrr.1286
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 392
TITLE
  Radiologic manifestations of immune-related adverse events in patients with 
metastatic melanoma undergoing anti-CTLA-4 antibody therapy
AUTHOR NAMES
  Bronstein Y.
  Ng C.S.
  Hwu P.
  Hwu W.-J.
AUTHOR ADDRESSES
  (Bronstein Y., yulia.bronstein@mdanderson.org; Ng C.S.) Department of 
Diagnostic Radiology, M. D. Anderson Cancer Center, T. Boone Pickens 
Academic Tower (FCT15.5009), 1515 Holcombe Blvd., Houston, TX 77030, United 
States.
(Hwu P.; Hwu W.-J.) Melanoma Medical Oncology, M. D. Anderson Cancer Center, 
Houston, TX, United States.
CORRESPONDENCE ADDRESS
  Y. Bronstein, Department of Diagnostic Radiology, M. D. Anderson Cancer 
Center, T. Boone Pickens Academic Tower (FCT15.5009), 1515 Holcombe Blvd., 
Houston, TX 77030, United States. Email: yulia.bronstein@mdanderson.org
SOURCE
  American Journal of Roentgenology (2011) 197:6 (W992-W1000). Date of 
Publication: December 2011
ISSN
  0361-803X
  1546-3141 (electronic)
BOOK PUBLISHER
  American Roentgen Ray Society, 44221 Slatestone Court, Leesburg, United 
States.
ABSTRACT
  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. 
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. 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. 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. © American Roentgen Ray Society.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug comparison, drug therapy)
  ticilimumab (adverse drug reaction, drug comparison, drug therapy)
EMTREE DRUG INDEX TERMS
  antinuclear antibody (endogenous compound)
  creatine kinase (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction, drug 
therapy)
  fluorodeoxyglucose f 18
  rheumatoid factor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug response
  immunotoxicity (side effect, diagnosis, side effect)
  melanoma (drug therapy, drug therapy)
  metastasis potential
  radiodiagnosis
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  arthralgia (side effect)
  arthritis (side effect)
  article
  aseptic meningitis (side effect)
  cancer control
  cancer growth
  clinical feature
  colitis (side effect)
  colon dilatation (side effect)
  colon disease (side effect)
  computer assisted tomography
  controlled study
  dermatitis (side effect)
  diarrhea (side effect)
  edema (side effect)
  endocrine ophthalmopathy (side effect)
  exophthalmos (side effect)
  fasciitis (side effect)
  female
  Graves disease (side effect)
  hip pain (side effect)
  histopathology
  human
  human tissue
  hyperthyroidism (side effect)
  hypophysitis (side effect)
  hypothyroidism (side effect)
  image analysis
  joint effusion (side effect)
  knee pain (side effect)
  leukoderma (side effect)
  low drug dose
  lymphadenopathy (side effect)
  major clinical study
  male
  myalgia (side effect)
  myositis (side effect)
  nuclear magnetic resonance imaging
  positron emission tomography
  priority journal
  pruritus (side effect)
  retroperitoneal fat
  retrospective study
  sacroiliitis (side effect)
  sarcoidosis (side effect)
  side effect (side effect)
  subcutaneous fat
  synovitis (side effect)
  thyroiditis (side effect)
  toxic megacolon (side effect)
  uveitis (side effect)
DRUG TRADE NAMES
  cp 675 206  Pfizer

  mdx 010  Bristol Myers Squibb

DRUG MANUFACTURERS
  Bristol Myers Squibb
  Pfizer
CAS REGISTRY NUMBERS
  creatine kinase (9001-15-4)
  fluorodeoxyglucose f 18 (63503-12-8)
  ipilimumab (477202-00-9)
  rheumatoid factor (9009-79-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Radiology (14)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011656058
MEDLINE PMID
  22109345 (http://www.ncbi.nlm.nih.gov/pubmed/22109345)
PUI
  L363011654
DOI
  10.2214/AJR.10.6198
FULL TEXT LINK
  http://dx.doi.org/10.2214/AJR.10.6198
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 393
TITLE
  Thyroid dysfunction from antineoplastic agents
AUTHOR NAMES
  Hamnvik O.-P.R.
  Larsen P.R.
  Marqusee E.
AUTHOR ADDRESSES
  (Hamnvik O.-P.R., ohamnvik@partners.org; Larsen P.R.; Marqusee E.) 
Department of Medicine, Brigham and Women's Hospital, Harvard Medical 
School, 221 Longwood Ave, Boston, MA 02115, United States.
CORRESPONDENCE ADDRESS
  O.-P.R. Hamnvik, Department of Medicine, Brigham and Women's Hospital, 
Harvard Medical School, 221 Longwood Ave, Boston, MA 02115, United States. 
Email: ohamnvik@partners.org
SOURCE
  Journal of the National Cancer Institute (2011) 103:21 (1572-1587). Date of 
Publication: 2 Nov 2011
ISSN
  0027-8874
  1460-2105 (electronic)
BOOK PUBLISHER
  Oxford University Press, Great Clarendon Street, Oxford, United Kingdom.
ABSTRACT
  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-α, 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. © 2011 The Author.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (adverse drug reaction, pharmacology)
EMTREE DRUG INDEX TERMS
  (3 iodobenzyl)guanidine i 131 (adverse drug reaction, drug combination, drug 
therapy, pharmacology)
  alemtuzumab (adverse drug reaction, drug therapy, pharmacology)
  axitinib (adverse drug reaction, pharmacology)
  bevacizumab (drug therapy)
  bexarotene (adverse drug reaction, clinical trial, drug therapy, drug 
toxicity, pharmacology)
  cediranib (adverse drug reaction, pharmacology)
  dasatinib (adverse drug reaction, drug therapy, pharmacology)
  denileukin diftitox (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  imatinib (adverse drug reaction, clinical trial, drug therapy, pharmacology)
  ipilimumab (adverse drug reaction, pharmacology)
  lenalidomide (adverse drug reaction, drug therapy, pharmacology)
  levothyroxine (clinical trial, drug therapy)
  liothyronine (endogenous compound)
  motesanib (adverse drug reaction, pharmacology)
  nilotinib (adverse drug reaction, drug therapy, pharmacology)
  recombinant alpha interferon (adverse drug reaction, pharmacology)
  recombinant interleukin 2 (adverse drug reaction, pharmacology)
  rituximab (drug combination)
  sorafenib (adverse drug reaction, pharmacology)
  sunitinib (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
  thalidomide (adverse drug reaction, drug therapy, pharmacology)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
  ticilimumab (adverse drug reaction, clinical trial, pharmacology)
  tositumomab (adverse drug reaction, pharmacology)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thyroid disease (side effect, side effect)
EMTREE MEDICAL INDEX TERMS
  5q- syndrome (drug therapy)
  arthritis (side effect)
  cancer chemotherapy
  cancer patient
  cancer radiotherapy
  central nervous system tumor (drug therapy, radiotherapy)
  chronic myeloid leukemia (drug therapy)
  cutaneous T cell lymphoma (drug therapy)
  drug mechanism
  drug withdrawal
  enterocolitis (side effect)
  free thyroxine index
  gastrointestinal stromal tumor (drug therapy)
  graft versus host reaction (drug therapy, prevention)
  Graves disease (side effect)
  Hashimoto disease (side effect)
  hepatitis (side effect)
  hormone response
  hormone substitution
  human
  hypophysitis (side effect)
  hypothyroidism (complication, drug therapy, prevention, side effect)
  immunosuppressive treatment
  immunotherapy
  multiple cycle treatment
  multiple myeloma (drug therapy)
  nephritis (side effect)
  nonhodgkin lymphoma (drug therapy)
  nonhuman
  pancreatitis (side effect)
  phase 2 clinical trial (topic)
  phase 3 clinical trial (topic)
  premedication
  priority journal
  review
  skin manifestation (side effect)
  solid malignant neoplasm (drug therapy)
  systematic review
  thyroid cancer (drug therapy)
  thyroid function
  thyroid medullary carcinoma (drug therapy, surgery)
  thyroidectomy
  thyroiditis (side effect)
  thyrotoxicosis (side effect)
  thyrotropin blood level
  thyrotropin release
  uveitis (side effect)
CAS REGISTRY NUMBERS
  (3 iodobenzyl)guanidine i 131 (77679-27-7)
  alemtuzumab (216503-57-0)
  axitinib (319460-85-0)
  bevacizumab (216974-75-3)
  bexarotene (153559-49-0)
  cediranib (288383-20-0, 857036-77-2)
  dasatinib (302962-49-8)
  denileukin diftitox (173146-27-5)
  imatinib (152459-95-5, 220127-57-1)
  ipilimumab (477202-00-9)
  lenalidomide (191732-72-6)
  levothyroxine (51-48-9)
  liothyronine (6138-47-2, 6893-02-3)
  motesanib (453562-69-1, 857876-30-3)
  nilotinib (641571-10-0)
  recombinant interleukin 2 (110942-02-4)
  rituximab (174722-31-7)
  sorafenib (284461-73-0)
  sunitinib (341031-54-7, 557795-19-4)
  thalidomide (50-35-1)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
  ticilimumab (745013-59-6)
  tositumomab (208921-02-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011613529
MEDLINE PMID
  22010182 (http://www.ncbi.nlm.nih.gov/pubmed/22010182)
PUI
  L362886478
DOI
  10.1093/jnci/djr373
FULL TEXT LINK
  http://dx.doi.org/10.1093/jnci/djr373
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 394
TITLE
  Retinal pericytes inhibit activated T cell proliferation
AUTHOR NAMES
  Tu Z.
  Li Y.
  Smith D.S.
  Sheibani N.
  Huang S.
  Kern T.
  Lin F.
AUTHOR ADDRESSES
  (Tu Z.; Li Y.; Lin F., feng.lin@case.edu) Department of Pathology, Case 
Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, United 
States.
(Smith D.S.; Huang S.) Department of Ophthalmology, Case Western Reserve 
University, Cleveland, OH, United States.
(Sheibani N.) Department of Ophthalmology and Visual Sciences, University of 
Wisconsin, Madison, WI, United States.
(Kern T.) Department of Medicine, Case Western Reserve University, 
Cleveland, OH, United States.
CORRESPONDENCE ADDRESS
  F. Lin, Institute of Pathology, Case Western Reserve University, School of 
Medicine, 2085 Adelbert Road, Cleveland, OH 44106, United States. Email: 
feng.lin@case.edu
SOURCE
  Investigative Ophthalmology and Visual Science (2011) 52:12 (9005-9010). 
Date of Publication: November 2011
ISSN
  0146-0404
  1552-5783 (electronic)
BOOK PUBLISHER
  Association for Research in Vision and Ophthalmology Inc., 12300 Twinbrook 
Parkway,Suite 250, Rockville, United States.
ABSTRACT
  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). 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. 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. 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. © 2011 The 
Association for Research in Vision and Ophthalmology, Inc.
EMTREE DRUG INDEX TERMS
  interleukin 10 (endogenous compound)
  programmed death 1 ligand 1 (endogenous compound)
  tumor necrosis factor (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  pericyte
  retina
  T lymphocyte
EMTREE MEDICAL INDEX TERMS
  animal cell
  apoptosis
  article
  cell function
  cell proliferation
  controlled study
  diabetic retinopathy
  endothelium cell
  enzyme linked immunosorbent assay
  flow cytometry
  glycation
  human
  human cell
  hyperglycemia
  mouse
  nonhuman
  priority journal
EMBASE CLASSIFICATIONS
  Ophthalmology (12)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2012396881
MEDLINE PMID
  22003106 (http://www.ncbi.nlm.nih.gov/pubmed/22003106)
PUI
  L365203266
DOI
  10.1167/iovs.11-8008
FULL TEXT LINK
  http://dx.doi.org/10.1167/iovs.11-8008
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 395
TITLE
  Checkpoint kinase inhibitor synergizes with DNA-damaging agents in G (1) 
checkpoint-defective neuroblastoma
AUTHOR NAMES
  Xu H.
  Cheung I.Y.
  Wei X.X.
  Tran H.
  Gao X.
  Cheung N.-K.V.
AUTHOR ADDRESSES
  (Xu H.; Cheung I.Y.; Wei X.X.; Tran H.; Gao X.; Cheung N.-K.V., 
cheungn@mskcc.org) Department of Pediatrics, Memorial Sloan-Kettering Cancer 
Center, 1275 York Avenue, New York, NY 10065, United States.
CORRESPONDENCE ADDRESS
  N.-K.V. Cheung, Department of Pediatrics, Memorial Sloan-Kettering Cancer 
Center, 1275 York Avenue, New York, NY 10065, United States. Email: 
cheungn@mskcc.org
SOURCE
  International Journal of Cancer (2011) 129:8 (1953-1962). Date of 
Publication: 15 Oct 2011
ISSN
  0020-7136
  1097-0215 (electronic)
BOOK PUBLISHER
  Wiley-Liss Inc., 111 River Street, Hoboken, United States.
ABSTRACT
  Checkpoint kinase inhibitors can enhance the cancer killing action of 
DNA-damaging chemotherapeutic agents by disrupting the S/G(2) cell cycle 
checkpoints. The in vitro and in vivo effects of the Chk1/2 inhibitor 
AZD7762 when combined with these agents were examined using neuroblastoma 
cell lines with known p53/MDM2/p14(ARF) genomic status. Four of four p53 
mutant lines and three of five MDM2/p14(ARF) abnormal lines were defective 
in G(1) checkpoint, correlating with failure to induce endogenous p21 after 
treatment with DNA-damaging agents. In cytotoxicity assays, these G(1) 
checkpoint-defective lines were more resistant to DNA-damaging agents when 
compared to G(1) checkpoint intact lines, yet becoming more sensitive when 
AZD7762 was added. Moreover, AZD7762 abrogated DNA damage-induced S/G(2) 
checkpoint arrest both in vitro and in vivo. In xenograft models, a 
significant delay in tumor growth accompanied by histological evidence of 
increased apoptosis was observed, when AZD7762 was added to the DNA-damaging 
drug gemcitabine. These results suggest a therapeutic potential of 
combination therapy using checkpoint kinase inhibitor and chemotherapy to 
reverse or prevent drug resistance in treating neuroblastomas with defective 
G(1) checkpoints. Copyright © 2010 UICC.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  [3 (carbamoylamino) 5 (3 fluorophenyl) n (3 piperidyl)thiophene 2 
carboxamide] (drug combination, drug interaction, drug therapy, 
intraperitoneal drug administration, pharmacology)
  antineoplastic agent (drug combination, drug interaction, drug therapy, 
intraperitoneal drug administration, pharmacology)
  phosphotransferase inhibitor (drug combination, drug interaction, drug 
therapy, intraperitoneal drug administration, pharmacology)
EMTREE DRUG INDEX TERMS
  5 (3 fluorophenyl) n (3 piperidinyl) 3 ureido 2 thiophenecarboxamide
  cisplatin (drug combination, drug interaction, pharmacology)
  cyclin dependent kinase inhibitor 2A (endogenous compound)
  doxorubicin (drug combination, drug interaction, pharmacology)
  etoposide (drug combination, drug interaction)
  firtecan (drug combination, drug interaction, pharmacology)
  gemcitabine (drug combination, drug interaction, drug therapy, intravenous 
drug administration, pharmacology)
  melphalan (drug combination, drug interaction)
  mutant protein (endogenous compound)
  nocodazole
  protein MDM2 (endogenous compound)
  protein p53 (endogenous compound)
  topotecan (drug combination, drug interaction)
  unclassified drug
  vincristine sulfate (drug combination, drug interaction, pharmacology)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  neuroblastoma (drug therapy, drug resistance, drug therapy)
EMTREE MEDICAL INDEX TERMS
  animal experiment
  animal model
  animal tissue
  apoptosis
  article
  cancer combination chemotherapy
  cancer growth
  cancer resistance
  cell assay
  cell cycle arrest
  cell cycle G1 phase
  cell cycle G2 phase
  cell cycle S phase
  chemosensitivity
  controlled study
  DNA damage
  drug cytotoxicity
  drug effect
  drug mechanism
  drug potentiation
  drug treatment failure
  female
  genomics
  histopathology
  human
  human cell
  human tissue
  in vitro study
  in vivo study
  mouse
  multiple cycle treatment
  nonhuman
  priority journal
  protein defect
  tumor xenograft
DRUG TRADE NAMES
  adriamycin  , United StatesBedford

  azd 7762  , United StatesAstra Zeneca

  gemzar  , United StatesLilly

  hycamtin  , United StatesGlaxo SmithKline

  sn 38  , ChinaAbatra Technology

  vincasar  , United StatesSicor

DRUG MANUFACTURERS
   (China)Abatra Technology
   (United States)Astra Zeneca
   (United States)Bedford
   (United States)Glaxo SmithKline
   (United States)Lilly
   (United States)Sicor
  Sigma
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  doxorubicin (23214-92-8, 25316-40-9)
  etoposide (33419-42-0)
  gemcitabine (103882-84-4)
  melphalan (148-82-3)
  nocodazole (31430-18-9)
  topotecan (119413-54-6, 123948-87-8)
  vincristine sulfate (2068-78-2)
EMBASE CLASSIFICATIONS
  Neurology and Neurosurgery (8)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011471385
MEDLINE PMID
  21154747 (http://www.ncbi.nlm.nih.gov/pubmed/21154747)
PUI
  L362403245
DOI
  10.1002/ijc.25842
FULL TEXT LINK
  http://dx.doi.org/10.1002/ijc.25842
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 396
TITLE
  Drug-induced graves disease from CTLA-4 receptor suppression
AUTHOR NAMES
  Borodic G.
  Hinkle D.M.
  Cia Y.
AUTHOR ADDRESSES
  (Borodic G., borodic@aol.com) Massachusetts Eye and Ear Infirmary, Boston, 
United States.
(Hinkle D.M.) Ocular Immunology and Uveitis Foundation, Cambridge, United 
States.
(Borodic G., borodic@aol.com; Hinkle D.M.) Harvard Medical School, Boston, 
MA, United States.
(Cia Y.)
CORRESPONDENCE ADDRESS
  G. Borodic, Harvard Medical School, Massachusetts Eye and Ear Infirmary, 5 
Cambridge Center, Cambridge, MA 02142, United States. Email: borodic@aol.com
SOURCE
  Ophthalmic Plastic and Reconstructive Surgery (2011) 27:4 (e87-e88). Date of 
Publication: July-August 2011
ISSN
  0740-9303
  1537-2677 (electronic)
BOOK PUBLISHER
  Lippincott Williams and Wilkins, 530 Walnut Street,P O Box 327, 
Philadelphia, United States.
ABSTRACT
  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. © 2011 The American Society of Ophthalmic Plastic and 
Reconstructive Surgery, Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  ipilimumab (adverse drug reaction, drug therapy, pharmacology)
EMTREE DRUG INDEX TERMS
  corticosteroid (drug therapy)
  liothyronine (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine ophthalmopathy (drug therapy, side effect, diagnosis, drug 
therapy, side effect)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  cancer chemotherapy
  cancer immunotherapy
  case report
  CD8+ T lymphocyte
  diplopia (side effect)
  exophthalmos (side effect)
  female
  human
  keratitis (side effect)
  melanoma (drug therapy)
  nuclear magnetic resonance imaging
  pathogenesis
  physical disease by body function
  priority journal
  T lymphocyte
  T lymphocyte activation
  tumor cell
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  liothyronine (6138-47-2, 6893-02-3)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Ophthalmology (12)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011398896
MEDLINE PMID
  21242854 (http://www.ncbi.nlm.nih.gov/pubmed/21242854)
PUI
  L51234152
DOI
  10.1097/IOP.0b013e3181ef72a1
FULL TEXT LINK
  http://dx.doi.org/10.1097/IOP.0b013e3181ef72a1
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 397
TITLE
  Synergistic antitumor activity of chemotherapy and immunotherapy in the 
treatment of established rat solid tumors
AUTHOR NAMES
  Feng Q.-M.
  Wu X.
  Liu P.
  Peng M.
  Wang Y.
  Di W.
AUTHOR ADDRESSES
  (Feng Q.-M.; Liu P.; Peng M.) Department of Obstetrics and Gynecology, 
Shanxi Province People's Hospital, Taiyuan 030012, China.
(Wu X.; Di W., diwen163@163.com) Department of Obstetrics and Gynecology, 
School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
(Wang Y.)
CORRESPONDENCE ADDRESS
  W. Di, Department of Obstetrics and Gynecology, School of Medicine, Shanghai 
Jiaotong University, Shanghai 200127, China. Email: diwen163@163.com
SOURCE
  Chinese Journal of Microbiology and Immunology (China) (2011) 31:7 
(632-637). Date of Publication: July 2011
ISSN
  0254-5101
BOOK PUBLISHER
  Society of Microbiology and Immunology, Chaoyangqu, Beijing, China.
ABSTRACT
  Objective: To explore immunotherapy effective combined with active 
immunotherapy in different time according rats bearing-tumor after 
paclitaxel and carboplatin chemotherapy, and to identify the optimization 
time and strategy of vaccine and seek rational chemo-immunotherapy 
strategies in ovarian cancer treatment. Methods: The dynamic immunocytes 
number and function in established tumor treated with paclitaxel and 
carboplatin chemotherapy were investigated. The changes of established tumor 
volume and immune function of different groups were observed according to 
combining different time after chemotherapy and vaccine. Results: 
Lymphopenia was observed and the number of lymphocyte subset decreased 
remarkably on the 6th day, but all cells were found almost recovered on 15th 
day after chemotherapy. There is the process of immune-enhancing from 
post-chemotherapy 6 day to 10 day and reversal of immune suppression 
temporary. The combination post-chemotherapy 6 day with CTL caused a 
significantly delayed tumor growth in both tumor models and induced 
significant the proliferation of T lymphocyte by [H](3) releasing. The 
number of CD8(+)T cell is the highest, but the expression of Tr cell was 
lowest in the group of post-chemotherapy 6 day with CTL. Furthermore, the 
ability of CD8(+)T secretion IFN-γ is the most in the post-chemotherapy 6 
day with immunotherapy groups. Conclusion: Combinational paclitaxel and 
carboplatin chemotherapy has synergistic effects with active immunotherapy 
boosting against tumor during window periods, where 6 days after 
chemotherapy with the most decreased number of lymphocytes in the animal 
periphery might represent the optimal checkpoint for the immune therapy 
against tumors. Therefore, monitoring the immune status of tumor patients 
might become one of the important prerequisites for the effective immune 
therapy when designing the comprehensive therapeutic strategies. Copyright © 
2011 by the Chinese Medical Association.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cancer vaccine (drug combination, drug therapy, drug toxicity)
  carboplatin (drug combination, drug therapy, drug toxicity)
  paclitaxel (drug combination, drug therapy, drug toxicity)
EMTREE DRUG INDEX TERMS
  gamma interferon (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  antineoplastic activity
  cancer chemotherapy
  cancer immunotherapy
  ovary cancer (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  animal experiment
  animal tissue
  article
  cancer inhibition
  cancer size
  CD8+ T lymphocyte
  cell proliferation
  cytokine release
  drug potentiation
  human
  immune function test
  lymphocyte
  lymphocytopenia
  nonhuman
  rat
  regulatory T lymphocyte
  T lymphocyte
CAS REGISTRY NUMBERS
  carboplatin (41575-94-4)
  gamma interferon (82115-62-6)
  paclitaxel (33069-62-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Toxicology (52)
LANGUAGE OF ARTICLE
  Chinese
LANGUAGE OF SUMMARY
  Chinese, English
EMBASE ACCESSION NUMBER
  2013165462
PUI
  L368522666
DOI
  10.3760/cma.j.issn.0254-5101.2011.07.014
FULL TEXT LINK
  http://dx.doi.org/10.3760/cma.j.issn.0254-5101.2011.07.014
COPYRIGHT
  Copyright 2013 Elsevier B.V., All rights reserved.

RECORD 398
TITLE
  CTLA4-antibodies: A new challenge to the management of side effects in the 
treatment of distantly metastasized malignant melanoma
ORIGINAL (NON-ENGLISH) TITLE
  CTLA4-antikörper: Eine neue herausforderung an das nebenwirkungsmanagement 
in der therapie des fernmetastasierten malignen melanoms
AUTHOR NAMES
  Rudolph B.M.
  Grabbe S.
  Loquai C.
AUTHOR ADDRESSES
  (Rudolph B.M., berenice.rudolph@unimedizin-mainz.de; Grabbe S.; Loquai C.) 
Haukrebszentrum Rhein-Main, Hautklinik und Poliklinik, Universitätsmedizin 
der Johannes Gutenberg-Universität Mainz, Langenbeckstraße 1, 55131 Mainz, 
Germany.
CORRESPONDENCE ADDRESS
  B.M. Rudolph, Haukrebszentrum Rhein-Main, Hautklinik und Poliklinik, 
Universitätsmedizin der Johannes Gutenberg-Universität Mainz, 
Langenbeckstraße 1, 55131 Mainz, Germany. Email: 
berenice.rudolph@unimedizin-mainz.de
SOURCE
  Haut (2011) 22:3 (112-115). Date of Publication: June 2011
ISSN
  0938-2216
BOOK PUBLISHER
  Viavital Verlag GmbH, Theodor-Althoff-Strasse 39, Essen, Germany.
ABSTRACT
  CTLA4-antibodies may induce natural immune response by activating T 
lymphocytes and can therefore break through immune tolerance against tumor 
cells. Recently a prolongation of survival time was proofed for the 
CTLA4-antibody Ipilimumab in the treatment of metastatic melanoma. Due to 
their immune-modifying mode of action CTLA4-antibodies show a new profile of 
side effects, so called immune-related adverse events. The effected organs 
are primarily the skin, intestines, liver and endocrine system. Due to the 
wide and complex range of adverse events treating physicians should gain a 
substantiated state of knowledge in diagnosis and management of these 
effects.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction)
EMTREE DRUG INDEX TERMS
  ipilimumab (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  metastasis (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  endocrine disease (side effect)
  enteropathy (side effect)
  human
  immune response
  immunological tolerance
  immunopathology (side effect)
  liver disease (side effect)
  review
  skin disease (side effect)
  survival time
  T lymphocyte activation
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Hematology (25)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  German
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  2011429853
PUI
  L362280335
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 399
TITLE
  Treatment and side effect management of CTLA-4 antibody therapy in 
metastatic melanoma
ORIGINAL (NON-ENGLISH) TITLE
  Behandlung und Nebenwirkungsmanagement des metastasierten Melanoms mit 
CTLA-4-Antikörpern
AUTHOR NAMES
  Kähler K.C.
  Hauschild A.
AUTHOR ADDRESSES
  (Kähler K.C., kckaehler@yahoo.de; Hauschild A.) Department of Dermatology, 
Venerology and Allergology, University of Schleswig, Holstein Hospital, 
Germany.
(Kähler K.C., kckaehler@yahoo.de) Klinik für Dermatologie und Venerologie 
Dermatoonkologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, 
Schittenhelmstraße 7, D-24105 Kiel, Germany.
CORRESPONDENCE ADDRESS
  K. C. Kähler, Klinik für Dermatologie und Venerologie Dermatoonkologie, 
Universitätsklinikum Schleswig-Holstein, Campus Kiel, Schittenhelmstraße 7, 
D-24105 Kiel, Germany. Email: kckaehler@yahoo.de
SOURCE
  JDDG - Journal of the German Society of Dermatology (2011) 9:4 (277-286). 
Date of Publication: April 2011
ISSN
  1610-0379
  1610-0387 (electronic)
BOOK PUBLISHER
  Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, United Kingdom.
ABSTRACT
  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. © Blackwell Verlag GmbH, Berlin.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction, drug 
therapy)
EMTREE DRUG INDEX TERMS
  antipruritic agent (drug therapy)
  betamethasone (drug therapy, topical drug administration)
  budesonide (drug therapy, oral drug administration)
  budesonide (drug therapy)
  dacarbazine (drug combination, drug comparison, drug therapy)
  dexamethasone (drug therapy)
  infliximab (drug therapy)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug dose, drug therapy)
  loperamide (drug therapy)
  methylprednisolone (drug therapy)
  mycophenolate mofetil (drug therapy, intravenous drug administration, oral 
drug administration)
  optiderm
  peptide vaccine (drug combination, drug therapy)
  polidocanol (drug therapy)
  prednisone (drug therapy)
  temozolomide (drug combination, drug comparison, drug therapy)
  ticilimumab (clinical trial, drug comparison, drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, drug therapy)
  metastatic melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  brain metastasis (drug therapy)
  cancer chemotherapy
  cancer survival
  colitis (side effect)
  corticosteroid therapy
  diarrhea (drug therapy, side effect)
  diplopia (side effect)
  dizziness (side effect)
  drug dose comparison
  drug eruption (drug therapy, side effect)
  drug mechanism
  drug megadose
  episcleritis (side effect)
  gastrointestinal disease (side effect)
  Guillain Barre syndrome (side effect)
  headache (side effect)
  human
  hypophysitis (side effect)
  inflammatory hepatotoxicity (drug therapy, side effect)
  inflammatory hepatotoxicity (drug therapy, side effect)
  liver toxicity (drug therapy, side effect)
  meta analysis
  motor neuropathy (side effect)
  myasthenia gravis (side effect)
  nausea (side effect)
  neurologic disease (side effect)
  neurotoxicity (side effect)
  overall survival
  pruritus (side effect)
  review
  sensory neuropathy (side effect)
  skin toxicity (side effect)
  uveitis (side effect)
  visual disorder (side effect)
  weakness (side effect)
DRUG TRADE NAMES
  budenofalk
  cp 675 206  , KazakhstanPfizer

  mdx 010  , United StatesMedarex

  optiderm
  remicade
DRUG MANUFACTURERS
   (Germany)Bristol Myers Squibb
   (United States)Medarex
   (Kazakhstan)Pfizer
CAS REGISTRY NUMBERS
  betamethasone (378-44-9)
  budesonide (51333-22-3)
  dacarbazine (4342-03-4)
  dexamethasone (50-02-2)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  loperamide (34552-83-5, 53179-11-6)
  methylprednisolone (6923-42-8, 83-43-2)
  mycophenolic acid 2 morpholinoethyl ester (116680-01-4, 128794-94-5)
  polidocanol (60828-78-6, 9002-92-0)
  prednisone (53-03-2)
  temozolomide (85622-93-1)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  German, English
LANGUAGE OF SUMMARY
  English, German
EMBASE ACCESSION NUMBER
  2011185187
MEDLINE PMID
  21083648 (http://www.ncbi.nlm.nih.gov/pubmed/21083648)
PUI
  L361545685
DOI
  10.1111/j.1610-0387.2010.07568.x
FULL TEXT LINK
  http://dx.doi.org/10.1111/j.1610-0387.2010.07568.x
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 400
TITLE
  Autoimmunity and treatment outcome in melanoma
AUTHOR NAMES
  Bouwhuis M.G.
  Ten Hagen T.L.M.
  Suciu S.
  Eggermont A.M.M.
AUTHOR ADDRESSES
  (Bouwhuis M.G.; Ten Hagen T.L.M.; Eggermont A.M.M., 
alexander.eggermont@igr.fr) Department of Surgery, Division Surgical 
Oncology, Erasmus University Medical Center, Rotterdam, Netherlands.
(Suciu S.) Statistics Department, EORTC Headquarters, Brussels, Belgium.
(Eggermont A.M.M., alexander.eggermont@igr.fr) Institut de Cancérologie 
Gustave Roussy, Villejuif, France.
CORRESPONDENCE ADDRESS
  A. M. M. Eggermont, Institut de Cancé Rologie Gustave Roussy, Villejuif, 
France. Email: alexander.eggermont@igr.fr
SOURCE
  Current Opinion in Oncology (2011) 23:2 (170-176). Date of Publication: 
March 2011
ISSN
  1040-8746
BOOK PUBLISHER
  Lippincott Williams and Wilkins, 530 Walnut Street, Philadelphia, United 
States.
ABSTRACT
  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. 
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 IFNα. 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. Summary: 
Evidence for an association of immune-related toxicities and response in 
patients receiving IL-2 or IFNα 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? © 2011 Wolters Kluwer Health | 
Lippincott Williams & Wilkins.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 antibody (drug therapy)
  interleukin 2 (adverse drug reaction, drug combination, drug dose, drug 
therapy)
  ipilimumab (adverse drug reaction, drug comparison, drug therapy)
  melanoma vaccine (drug comparison, drug therapy)
  ticilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  alpha interferon (adverse drug reaction, drug therapy)
  alpha2a interferon (drug therapy)
  alpha2b interferon (drug therapy)
  autoantibody (endogenous compound)
  gamma interferon (adverse drug reaction, drug therapy)
  granulocyte macrophage colony stimulating factor (drug combination)
  peginterferon alpha2b (drug therapy, pharmaceutics, pharmacokinetics, 
subcutaneous drug administration)
  recombinant alpha interferon (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmunity
  cancer immunotherapy
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adjuvant therapy
  animal experiment
  animal model
  antibody detection
  article
  autoimmune thyroiditis (complication, diagnosis, side effect)
  dermatitis (side effect)
  diarrhea (side effect)
  drug efficacy
  drug megadose
  drug safety
  fatigue (side effect)
  flu like syndrome (side effect)
  gastrointestinal toxicity (side effect)
  human
  hypothyroidism (side effect)
  major clinical study
  metastasis (complication)
  mouse
  nausea (side effect)
  nonhuman
  priority journal
  prognosis
  pruritus (side effect)
  rash (side effect)
  seroconversion
  solid malignant neoplasm (drug therapy)
  survival
  treatment response
  vitiligo (complication, side effect)
CAS REGISTRY NUMBERS
  alpha2a interferon (76543-88-9)
  alpha2b interferon (99210-65-8)
  gamma interferon (82115-62-6)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  peginterferon alpha2b (215647-85-1)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Pharmacy (39)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011112840
MEDLINE PMID
  21150603 (http://www.ncbi.nlm.nih.gov/pubmed/21150603)
PUI
  L51187721
DOI
  10.1097/CCO.0b013e328341edff
FULL TEXT LINK
  http://dx.doi.org/10.1097/CCO.0b013e328341edff
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 401
TITLE
  RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a 
therapeutic target in neuroblastoma
AUTHOR NAMES
  Cole K.A.
  Huggins J.
  Laquaglia M.
  Hulderman C.E.
  Russell M.R.
  Bosse K.
  Diskin S.J.
  Attiyeh E.F.
  Sennett R.
  Norris G.
  Laudenslager M.
  Wood A.C.
  Mayes P.A.
  Jagannathan J.
  Winter C.
  Mosse Y.P.
  Maris J.M.
AUTHOR ADDRESSES
  (Cole K.A.; Huggins J.; Laquaglia M.; Hulderman C.E.; Russell M.R.; Bosse 
K.; Diskin S.J.; Attiyeh E.F.; Sennett R.; Norris G.; Laudenslager M.; Wood 
A.C.; Mayes P.A.; Jagannathan J.; Winter C.; Mosse Y.P.; Maris J.M., 
maris@chop.edu) Division of Oncology, Children's Hospital of Philadelphia, 
Philadelphia, PA 19104-4318, United States.
(Cole K.A.; Attiyeh E.F.; Winter C.; Mosse Y.P.; Maris J.M., maris@chop.edu) 
Department of Pediatrics, University of Pennsylvania School of Medicine, 
Philadelphia, PA 19104-4318, United States.
(Maris J.M., maris@chop.edu) Abramson Family Cancer Research Institute, 
University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318, 
United States.
CORRESPONDENCE ADDRESS
  J. M. Maris, Division of Oncology, Children's Hospital of Philadelphia, 
Philadelphia, PA 19104-4318, United States. Email: maris@chop.edu
SOURCE
  Proceedings of the National Academy of Sciences of the United States of 
America (2011) 108:8 (3336-3341). Date of Publication: 22 Feb 2011
ISSN
  0027-8424
  1091-6490 (electronic)
BOOK PUBLISHER
  National Academy of Sciences, 2101 Constitution Avenue NW, Washington, 
United States.
ABSTRACT
  Neuroblastoma is a childhood cancer that is often fatal despite intense 
multimodality therapy. In an effort to identify therapeutic targets for this 
disease, we performed a comprehensive loss-offunction screen of the protein 
kinome. Thirty kinases showed significant cellular cytotoxicity when 
depleted, with loss of the cell cycle checkpoint kinase 1 (CHK1/CHEK1) being 
the most potent. CHK1mRNAexpression was higher inMYC-Neuroblastoma-related 
(MYCN)-amplified (P < 0.0001) and high-risk (P = 0.03) tumors. Western 
blotting revealed that CHK1 was constitutively phosphorylated at the ataxia 
telangiectasia response kinase target site Ser345 and the 
autophosphorylation site Ser296 in neuroblastoma cell lines. This pattern 
was also seen in six of eight high-risk primary tumors but not in control 
nonneuroblastoma cell lines or in seven of eight low-risk primary tumors. 
Neuroblastoma cells were sensitive to the two CHK1 inhibitors SB21807 and 
TCS2312, with median IC50 values of 564 nM and 548 nM, respectively. In 
contrast, the control lines had high micromolar IC50 values, indicating a 
strong correlation between CHK1 phosphorylation and CHK1 inhibitor 
sensitivity (P = 0.0004). Furthermore, cell cycle analysis revealed that 
CHK1 inhibition in neuroblastoma cells caused apoptosis during S-phase, 
consistent with its role in replication fork progression. CHK1 inhibitor 
sensitivity correlated with total MYC(N) protein levels, and inducing MYCN 
in retinal pigmented epithelial cells resulted in CHK1 phosphorylation, 
which caused growth inhibition when inhibited. These data show the power of 
a functional RNAi screen to identify tractable therapeutical targets in 
neuroblastoma and support CHK1 inhibition strategies in this disease.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  checkpoint kinase 1 (endogenous compound)
EMTREE DRUG INDEX TERMS
  4' [5 [4 (cyclopropylaminomethyl)phenylamino] 1h pyrazol 3 yl] 1,1' biphenyl 
2,4 diol
  messenger RNA
  protein serine threonine kinase inhibitor
  sb 21807
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  neuroblastoma
EMTREE MEDICAL INDEX TERMS
  animal experiment
  apoptosis
  article
  ataxia telangiectasia
  autophosphorylation
  cell cycle S phase
  cell mediated cytotoxicity
  controlled study
  drug targeting
  enzyme inhibition
  gene expression
  genetic transfection
  growth inhibition
  human
  human cell
  human cell culture
  IC50
  mouse
  neuroblastoma cell
  nonhuman
  priority journal
  protein analysis
  protein phosphorylation
  tumor volume
  Western blotting
DRUG TRADE NAMES
  sb 21807
  tcs 2312
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Neurology and Neurosurgery (8)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011154704
MEDLINE PMID
  21289283 (http://www.ncbi.nlm.nih.gov/pubmed/21289283)
PUI
  L361458200
DOI
  10.1073/pnas.1012351108
FULL TEXT LINK
  http://dx.doi.org/10.1073/pnas.1012351108
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 402
TITLE
  Cross-regulation between oncogenic BRAF(V600E) kinase and the MST1 pathway 
in papillary thyroid carcinoma
AUTHOR NAMES
  Lee S.J.
  Lee M.H.
  Kim D.W.
  Lee S.
  Huang S.
  Ryu M.J.
  Kim Y.K.
  Kim S.J.
  Kim S.J.
  Hwang J.H.
  Oh S.
  Cho H.
  Kim J.M.
  Lim D.-S.
  Jo Y.S.
  Shong M.
AUTHOR ADDRESSES
  (Lee S.J.; Lee M.H.; Kim D.W.; Lee S.; Ryu M.J.; Kim Y.K.; Kim S.J.; Kim 
S.J.; Hwang J.H.; Shong M., minhos@cnu.ac.kr) Department of Internal 
Medicine, Chungnam National University School of Medicine, Daejeon, South 
Korea.
(Huang S.; Kim J.M.) Department of Pathology, Chungnam National University 
School of Medicine, Daejeon, South Korea.
(Lee S.J.; Cho H.) Pharmacology Research Center, Korea Research Institute of 
Chemical Technology, Daejeon, South Korea.
(Hwang J.H.) Animal Model Center, Korea Research Institute of Bioscience and 
Biotechnology, Daejeon, South Korea.
(Oh S.; Lim D.-S.) Department of Biological Sciences, Korea Advanced 
Institute of Science and Technology, Daejeon, South Korea.
(Jo Y.S., ysmrj@cnuh.ac.kr) Research Center for Endocrine and Metabolic 
Diseases, Chungnam National University Hospital, Daejeon, South Korea.
CORRESPONDENCE ADDRESS
  M. Shong, Department of Internal Medicine, Chungnam National University 
School of Medicine, Daejeon, South Korea. Email: minhos@cnu.ac.kr
SOURCE
  PLoS ONE (2011) 6:1 Article Number: e16180. Date of Publication: 2011
ISSN
  1932-6203 (electronic)
BOOK PUBLISHER
  Public Library of Science, 185 Berry Street, Suite 1300, San Francisco, 
United States.
ABSTRACT
  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. 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, whereasaddition 
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. 
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. Copy; 2011 Lee et 
al.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  B Raf kinase (endogenous compound)
  MST1 protein (endogenous compound)
  tumor suppressor protein (endogenous compound)
EMTREE DRUG INDEX TERMS
  protein p21 (endogenous compound)
  protein p27 (endogenous compound)
  Ras association domain family protein 1A (endogenous compound)
  transcription factor FKHRL1 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thyroid papillary carcinoma (etiology)
EMTREE MEDICAL INDEX TERMS
  animal cell
  apoptosis
  article
  cancer cell culture
  carboxy terminal sequence
  carcinogenesis
  cell cycle G1 phase
  cell cycle regulation
  controlled study
  enzyme inhibition
  genetic regulation
  human
  human cell
  mouse
  nonhuman
  phenotype
  protein binding
  protein expression
  protein induction
  signal transduction
  transactivation
  transcription initiation
  transgenic mouse
CAS REGISTRY NUMBERS
  protein p21 (85306-28-1)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  General Pathology and Pathological Anatomy (5)
  Cancer (16)
  Human Genetics (22)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011060494
MEDLINE PMID
  21249150 (http://www.ncbi.nlm.nih.gov/pubmed/21249150)
PUI
  L361180262
DOI
  10.1371/journal.pone.0016180
FULL TEXT LINK
  http://dx.doi.org/10.1371/journal.pone.0016180
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 403
TITLE
  Thyroid autoimmunity and ophthalmopathy related to melanoma biological 
therapy
AUTHOR NAMES
  Min L.
  Vaidya A.
  Becker C.
AUTHOR ADDRESSES
  (Min L.; Vaidya A.; Becker C., cbbecker@partners.org) Division of 
Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, 221 
Longwood Avenue, Boston, MA 02115, United States.
CORRESPONDENCE ADDRESS
  C. Becker, Division of Endocrinology, Diabetes, and Hypertension, Brigham 
and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, United States. 
Email: cbbecker@partners.org
SOURCE
  European Journal of Endocrinology, Supplement (2011) 164:2 (303-307). Date 
of Publication: February 1 2011
ISSN
  0804-4635
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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. 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. 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. 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. © 2011 European Society 
of Endocrinology.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  bevacizumab (adverse drug reaction, drug combination, drug therapy)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  alpha interferon (drug therapy)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  glucocorticoid (drug therapy)
  methylprednisolone sodium succinate (drug dose, drug therapy, intravenous 
drug administration)
  prednisone (drug dose, drug therapy, oral drug administration)
  thyroid antibody (endogenous compound)
  thyrotropin (endogenous compound)
  thyrotropin receptor antibody (endogenous compound)
  thyroxine (endogenous compound)
  tumor cell vaccine (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmunity
  endocrine ophthalmopathy (drug therapy, diagnosis, drug therapy)
  melanoma (drug therapy, drug therapy, radiotherapy, surgery)
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer (drug therapy, radiotherapy, surgery)
  antibody titer
  article
  cancer combination chemotherapy
  cancer immunotherapy
  cancer radiotherapy
  cancer staging
  cancer surgery
  case report
  computer assisted tomography
  conjunctivitis (side effect)
  disease severity
  dose response
  drug dose reduction
  drug megadose
  drug withdrawal
  euthyroidism
  exophthalmos (side effect)
  eye pain (side effect)
  female
  human
  intraocular pressure
  male
  nuclear magnetic resonance imaging
  patient monitoring
  periorbital edema (side effect)
  physical examination
  thyroid function test
  thyroiditis (side effect)
  treatment duration
DRUG TRADE NAMES
  solumedrol
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  ipilimumab (477202-00-9)
  methylprednisolone sodium succinate (2375-03-3, 2921-57-5)
  prednisone (53-03-2)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Ophthalmology (12)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011169715
PUI
  L361503480
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 404
TITLE
  Thyroid autoimmunity and ophthalmopathy related to melanoma biological 
therapy
AUTHOR NAMES
  Min L.
  Vaidya A.
  Becker C.
AUTHOR ADDRESSES
  (Min L.; Vaidya A.; Becker C., cbbecker@partners.org) Division of 
Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, 221 
Longwood Avenue, Boston, MA 02115, United States.
CORRESPONDENCE ADDRESS
  C. Becker, Division of Endocrinology, Diabetes, and Hypertension, Brigham 
and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, United States. 
Email: cbbecker@partners.org
SOURCE
  European Journal of Endocrinology (2011) 164:2 (303-307). Date of 
Publication: 1 Feb 2011
ISSN
  0804-4643
  1479-683X (electronic)
BOOK PUBLISHER
  BioScientifica Ltd., Euro House, 22 Apex Court, Woodlands, Bradley Stoke, 
Bristol, United Kingdom.
ABSTRACT
  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. 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. 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. 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. © 2011 European Society 
of Endocrinology.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  bevacizumab (adverse drug reaction, drug combination, drug therapy)
  ipilimumab (adverse drug reaction, drug combination, drug therapy)
EMTREE DRUG INDEX TERMS
  alpha interferon
  fluorodeoxyglucose f 18
  methylprednisolone (drug therapy, intravenous drug administration)
  methylprednisolone sodium succinate (drug therapy)
  prednisone (drug therapy, oral drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  endocrine ophthalmopathy (drug therapy, diagnosis, drug therapy)
  melanoma (drug therapy, drug therapy)
  thyroiditis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  case report
  clinical feature
  computer assisted tomography
  drug megadose
  drug withdrawal
  female
  human
  laboratory test
  male
  positron emission tomography
  priority journal
  treatment response
CAS REGISTRY NUMBERS
  bevacizumab (216974-75-3)
  fluorodeoxyglucose f 18 (63503-12-8)
  ipilimumab (477202-00-9)
  methylprednisolone (6923-42-8, 83-43-2)
  methylprednisolone sodium succinate (2375-03-3, 2921-57-5)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Ophthalmology (12)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011042475
MEDLINE PMID
  21088057 (http://www.ncbi.nlm.nih.gov/pubmed/21088057)
PUI
  L361139132
DOI
  10.1530/EJE-10-0833
FULL TEXT LINK
  http://dx.doi.org/10.1530/EJE-10-0833
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 405
TITLE
  CUEDC2: An emerging key player in inflammation and tumorigenesis
AUTHOR NAMES
  Man J.
  Zhang X.
AUTHOR ADDRESSES
  (Man J.; Zhang X., xmzhang@nic.bmi.ac.cn) Institute of Basic Medical 
Sciences, National Center of Biomedical Analysis, Beijing 100850, China.
CORRESPONDENCE ADDRESS
  X. Zhang, Institute of Basic Medical Sciences, National Center of Biomedical 
Analysis, Beijing 100850, China. Email: xmzhang@nic.bmi.ac.cn
SOURCE
  Protein and Cell (2011) 2:9 (699-703). Date of Publication: September 2011
ISSN
  1674-8018 (electronic)
  1674-800X
BOOK PUBLISHER
  Higher Education Press
ABSTRACT
  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 α 
(IKKα) and IKKβ and has an inhibitory role in the activation of 
transcription factor nuclear factor-κB. Moreover, CUEDC2 plays an important 
role in downregulating the expression of hormone receptors estrogen 
receptor-α 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. © 2011 Higher Education Press and Springer-Verlag 
Berlin Heidelberg.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  CUE domain containing 2 protein (endogenous compound)
  regulator protein (endogenous compound)
EMTREE DRUG INDEX TERMS
  anaphase promoting complex (endogenous compound)
  biological marker (endogenous compound)
  cell cycle protein 20 (endogenous compound)
  cyclin dependent kinase 1 (endogenous compound)
  cytokine (endogenous compound)
  epidermal growth factor receptor 2 (endogenous compound)
  estrogen receptor alpha (endogenous compound)
  I kappa B kinase alpha (endogenous compound)
  I kappa B kinase beta (endogenous compound)
  immunoglobulin enhancer binding protein (endogenous compound)
  phosphoprotein phosphatase 1 (endogenous compound)
  progesterone receptor (endogenous compound)
  proteasome
  tamoxifen (drug therapy)
  tumor necrosis factor receptor associated factor 2 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  carcinogenesis
  inflammation (etiology)
EMTREE MEDICAL INDEX TERMS
  aneuploidy
  breast cancer (drug resistance, drug therapy, etiology)
  cancer resistance
  cancer risk
  cancer survival
  cell cycle regulation
  cellular secretion
  disease marker
  down regulation
  enzyme activation
  enzyme activity
  enzyme release
  human
  mitosis
  nonhuman
  priority journal
  protein degradation
  protein expression
  protein function
  protein phosphorylation
  protein protein interaction
  protein stability
  review
  signal transduction
  spindle cell
  transcription initiation
  treatment response
  ubiquitination
CAS REGISTRY NUMBERS
  anaphase promoting complex (74812-49-0)
  epidermal growth factor receptor 2 (137632-09-8)
  proteasome (140879-24-9)
  tamoxifen (10540-29-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
  General Pathology and Pathological Anatomy (5)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2011624475
MEDLINE PMID
  21976060 (http://www.ncbi.nlm.nih.gov/pubmed/21976060)
PUI
  L362913035
DOI
  10.1007/s13238-011-1089-z
FULL TEXT LINK
  http://dx.doi.org/10.1007/s13238-011-1089-z
COPYRIGHT
  Copyright 2014 Elsevier B.V., All rights reserved.

RECORD 406
TITLE
  Active immunotherapy induces antibody responses that target tumor 
angiogenesis
AUTHOR NAMES
  Schoenfeld J.
  Jinushi M.
  Nakazaki Y.
  Wiener D.
  Park J.
  Soiffer R.
  Neuberg D.
  Mihm M.
  Hodi F.S.
  Dranoff G.
AUTHOR ADDRESSES
  (Schoenfeld J.; Jinushi M.; Nakazaki Y.; Wiener D.; Park J.; Soiffer R.; 
Hodi F.S.; Dranoff G., glenn_dranoff@dfci.harvard.edu) Department of Medical 
Oncology, Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA, 
United States.
(Schoenfeld J.; Jinushi M.; Nakazaki Y.; Wiener D.; Park J.; Soiffer R.; 
Hodi F.S.; Dranoff G., glenn_dranoff@dfci.harvard.edu) Department of 
Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 
United States.
(Schoenfeld J.) Harvard Radiation Oncology Program, Harvard Medical School, 
Boston, MA, United States.
(Jinushi M.) Research Center for Infection-Associated Cancer, Institute for 
Genetic Medicine, Hokkaido University, Sapporo, Japan.
(Neuberg D.) Department of Biostatistics and Computational Biology, 
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United 
States.
(Mihm M.) Department of Pathology, Massachusetts General Hospital, Harvard 
Medical School, Boston, MA, United States.
CORRESPONDENCE ADDRESS
  G. Dranoff, Department of Medical Oncology, Cancer Vaccine Center, 
Dana-Farber Cancer Institute, Boston, MA, United States. Email: 
glenn_dranoff@dfci.harvard.edu
SOURCE
  Cancer Research (2010) 70:24 (10150-10160). Date of Publication: 15 Dec 2010
ISSN
  0008-5472
  1538-7445 (electronic)
BOOK PUBLISHER
  American Association for Cancer Research Inc., 615 Chestnut Street, 17th 
Floor, Philadelphia, United States.
ABSTRACT
  The inhibition of VEGF signaling with antibodies or small molecules achieves 
clinical benefits in diverse solid malignancies. Nonetheless, therapeutic 
effects are usually not sustained, and most patients eventually succumb to 
progressive disease, indicating that antiangiogenic strategies require 
additional optimization. Vaccination with lethally irradiated, autologous 
tumor cells engineered to secrete granulocyte-macrophage colony stimulating 
factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte-associated 
antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding 
subjects. These reactions are characterized by disrupted tumor blood vessels 
in association with lymphocyte and granulocyte infiltrates and zonal areas 
of ischemic tumor necrosis. However, the mechanisms underlying this 
immune-mediated destruction of the tumor vasculature remain to be clarified. 
Here, we show that GM-CSF-secreting tumor cell vaccines and CTLA-4 blockade 
elicit a functionally important humoral reaction against multiple angiogenic 
cytokines. Antibodies to angiopoietin-1 and angiopoietin-2 block Tie-2 
binding, downstream signaling, endothelial cell tube formation, and 
macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) 
attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) 
production. Together, these results delineate an immunotherapy-induced host 
response that broadly targets the angiogenic network in the tumor 
microenvironment. ©2010 AACR.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antibody (endogenous compound)
EMTREE DRUG INDEX TERMS
  angiopoietin 1 (endogenous compound)
  angiopoietin 2 (endogenous compound)
  angiopoietin receptor (endogenous compound)
  cytokine (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  dacarbazine (drug therapy)
  gelatinase B (endogenous compound)
  granulocyte macrophage colony stimulating factor (clinical trial, drug 
therapy, pharmacology)
  ipilimumab (clinical trial, drug therapy)
  macrophage migration inhibition factor (endogenous compound)
  tumor cell vaccine (clinical trial, drug therapy, pharmacology)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  active immunization
  carcinogenesis
  humoral immunity
  melanoma (drug therapy, drug therapy, radiotherapy)
  non small cell lung cancer (drug therapy, drug therapy)
  ovary carcinoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  angiogenesis
  antibody titer
  article
  attenuation
  binding affinity
  cancer patient
  chemotaxis
  clinical article
  controlled study
  cytokine production
  endothelium cell
  female
  human
  human cell
  immunogenicity
  macrophage
  phase 1 clinical trial
  priority journal
  protein expression
  protein synthesis
  signal transduction
CAS REGISTRY NUMBERS
  angiopoietin 1 (186270-49-5)
  angiopoietin 2 (194368-66-6)
  dacarbazine (4342-03-4)
  gelatinase B (146480-36-6)
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Internal Medicine (6)
  Dermatology and Venereology (13)
  Chest Diseases, Thoracic Surgery and Tuberculosis (15)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2010699661
MEDLINE PMID
  21159637 (http://www.ncbi.nlm.nih.gov/pubmed/21159637)
PUI
  L360197161
DOI
  10.1158/0008-5472.CAN-10-1852
FULL TEXT LINK
  http://dx.doi.org/10.1158/0008-5472.CAN-10-1852
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 407
TITLE
  Ipilimumab: Unleashing the power of the immune system through CTLA-4 
blockade
AUTHOR NAMES
  Boasberg P.
  Hamid O.
  O'Day S.
AUTHOR ADDRESSES
  (Boasberg P., pboasberg@theangelesclinic.org; Hamid O.; O'Day S.) Angeles 
Clinic and Research Institute, 2001 Santa Monica Blvd, Santa Monica, CA 
90404, United States.
CORRESPONDENCE ADDRESS
  P. Boasberg, Angeles Clinic and Research Institute, 2001 Santa Monica Blvd, 
Santa Monica, CA 90404, United States. Email: pboasberg@theangelesclinic.org
SOURCE
  Seminars in Oncology (2010) 37:5 (440-449). Date of Publication: October 
2010
ISSN
  0093-7754
BOOK PUBLISHER
  W.B. Saunders, Independence Square West, Philadelphia, United States.
ABSTRACT
  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. © 2010 Published by Elsevier Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  ipilimumab (adverse drug reaction, drug combination, drug dose, drug 
therapy, pharmacology)
EMTREE DRUG INDEX TERMS
  budesonide (oral drug administration)
  dacarbazine (drug combination, drug therapy)
  glycoprotein gp 100 (drug combination, drug therapy)
  indoleamine 2,3 dioxygenase (endogenous compound)
  infliximab
  loperamide
  messenger RNA (endogenous compound)
  methylprednisolone
  transcription factor FOXP3 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  immune response
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adjuvant therapy
  antineoplastic activity
  brain metastasis (drug therapy)
  cancer staging
  cancer survival
  CD4+ T lymphocyte
  colitis (side effect)
  diarrhea (side effect)
  drug dose comparison
  drug efficacy
  drug mechanism
  drug safety
  drug tolerability
  hormone substitution
  human
  intestinal bleeding (side effect)
  lactate dehydrogenase blood level
  liver toxicity (side effect)
  monotherapy
  nausea and vomiting (side effect)
  nonhuman
  overall survival
  pain (side effect)
  patient compliance
  priority journal
  rash (side effect)
  review
  side effect (side effect)
  single drug dose
  T lymphocyte activation
  treatment response
  tumor associated leukocyte
  tumor biopsy
  tumor volume
CAS REGISTRY NUMBERS
  budesonide (51333-22-3)
  dacarbazine (4342-03-4)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  loperamide (34552-83-5, 53179-11-6)
  methylprednisolone (6923-42-8, 83-43-2)
EMBASE CLASSIFICATIONS
  Internal Medicine (6)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2010631196
MEDLINE PMID
  21074058 (http://www.ncbi.nlm.nih.gov/pubmed/21074058)
PUI
  L359977671
DOI
  10.1053/j.seminoncol.2010.09.004
FULL TEXT LINK
  http://dx.doi.org/10.1053/j.seminoncol.2010.09.004
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 408
TITLE
  The emerging toxicity profiles of antiCTLA-4 antibodies across clinical 
indications
AUTHOR NAMES
  Di Giacomo A.M.
  Biagioli M.
  Maio M.
AUTHOR ADDRESSES
  (Di Giacomo A.M., a.m.digiacomo@ao-siena.toscana.it; Maio M.) Department of 
Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto 
Toscano Tumori, Siena, Italy.
(Biagioli M.) Department of Dermatology, University Hospital of Siena, 
Istituto Toscano Tumori, Siena, Italy.
CORRESPONDENCE ADDRESS
  A. M. Di Giacomo, Medical Oncology and Immunotherapy, University Hospital of 
Siena, Strada delle Scotte 53100, Siena, Italy. Email: 
a.m.digiacomo@ao-siena.toscana.it
SOURCE
  Seminars in Oncology (2010) 37:5 (499-507). Date of Publication: October 
2010
ISSN
  0093-7754
BOOK PUBLISHER
  W.B. Saunders, Independence Square West, Philadelphia, United States.
ABSTRACT
  The promising new class of immunomodulating antibodies directed against 
cytotoxic T-lymphocyte antigen-4 (CTLA-4) has been extensively tested in 
clinical trials and found to be active against cutaneous melanoma and other 
tumor histotypes. Inhibition of CTLA-4 characteristically induces 
well-identified side effects for which the definition "immune-related 
adverse events" (irAEs) has been proposed. IrAEs mainly include 
colitis/diarrhea, dermatitis, hepatitis, and endocrinopathies; uveitis, 
nephritis, and inflammatory myopathy also have been reported occasionally. 
These unique side effects are likely a direct result of breaking immune 
tolerance upon CTLA-4 blockade and are generally mild, reversible, and 
manageable, following specific treatment guidelines that include symptomatic 
therapies or systemic corticosteroids. However, patientphysician 
communication and early treatment are also emerging as critical issues to 
successfully manage irAEs, thus avoiding major complications. The major 
experience in identifying and managing CTLA-4 treatment-related side effects 
has derived from studies in melanoma patients; nevertheless, accumulating 
clinical experiences are clearly demonstrating that irAEs are class-specific 
events, and that they are fully overlapping in patients with tumors of 
different histotypes. This review provides an overview of current safety 
data on CTLA-4 antagonists and of available strategies to optimize their 
clinical use in cancer patients. © 2010 Elsevier Inc. All rights reserved.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy, drug toxicity, intravenous drug administration)
  ticilimumab (adverse drug reaction, drug combination, drug therapy, 
intravenous drug administration)
EMTREE DRUG INDEX TERMS
  antihistaminic agent (drug therapy)
  antiinflammatory agent (drug therapy)
  antineoplastic agent (adverse drug reaction, drug combination, drug therapy)
  budesonide (drug therapy)
  carboplatin (adverse drug reaction, clinical trial, drug combination, drug 
therapy, drug toxicity)
  cimetidine (drug therapy)
  corticosteroid (drug combination, drug dose, drug therapy, intravenous drug 
administration, oral drug administration)
  diphenhydramine (drug therapy)
  exemestane (adverse drug reaction, drug combination, drug therapy)
  glucocorticoid (adverse drug reaction, drug therapy)
  hydroxyzine (drug therapy)
  ibuprofen (drug therapy)
  infliximab (drug therapy, intravenous drug administration)
  levothyroxine (drug therapy)
  mesalazine (drug combination, drug therapy)
  mycophenolic acid (drug therapy, intravenous drug administration)
  paclitaxel (adverse drug reaction, clinical trial, drug combination, drug 
therapy, drug toxicity)
  prednisone (oral drug administration)
  recombinant granulocyte macrophage colony stimulating factor (adverse drug 
reaction, clinical trial, drug combination, drug therapy)
  sunitinib (adverse drug reaction, drug combination)
EMTREE MEDICAL INDEX TERMS
  acute kidney failure (side effect)
  adrenal insufficiency (side effect)
  alanine aminotransferase blood level
  allergic reaction (side effect)
  alopecia areata (side effect)
  arthralgia (drug therapy, side effect)
  aspartate aminotransferase blood level
  asthenia (side effect)
  autoimmune dermatitis (drug therapy)
  autoimmune dermatitis (drug therapy)
  autoimmune disease (drug therapy, side effect)
  autoimmune thyroiditis
  backache (side effect)
  bone pain (drug therapy, side effect)
  breast cancer (drug therapy)
  cancer patient
  clinical trial
  colitis (drug therapy, side effect)
  constipation (side effect)
  creatinine blood level
  decreased appetite (side effect)
  dermatitis (drug therapy, side effect)
  diarrhea (drug therapy, prevention, side effect)
  doctor patient relation
  drug efficacy
  drug eruption (drug therapy, side effect)
  drug megadose
  drug safety
  drug tolerability
  drug withdrawal
  dyspnea (side effect)
  eosinophilia (side effect)
  esophageal adenocarcinoma (drug therapy)
  fatigue (side effect)
  fever (side effect)
  gastrointestinal symptom (side effect)
  hepatitis (drug therapy, side effect)
  histopathology
  human
  hypoadrenalism (side effect)
  hypoadrenalism (side effect)
  hypokalemia (side effect)
  hypophysitis (drug therapy, side effect)
  hypopituitarism (drug therapy, side effect)
  hypothyroidism (side effect)
  idiopathic thrombocytopenic purpura (side effect)
  immune related red blood cell aplasia (side effect)
  immune related red blood cell aplasia (side effect)
  immunohistochemistry
  inflammatory neuropathy (side effect)
  inflammatory neuropathy (side effect)
  kidney cancer (drug therapy)
  limb pain (drug therapy, side effect)
  liver toxicity (drug therapy)
  lung cancer (drug therapy)
  lupus erythematosus nephritis (side effect)
  lymphocytopenia (side effect)
  maculopapular rash (side effect)
  malaise (side effect)
  melanoma (drug therapy)
  metastatic castration resistant prostate cancer (drug therapy)
  metastatic castration resistant prostate cancer (drug therapy)
  mucosa inflammation (side effect)
  myopathy (side effect)
  nausea (side effect)
  neutropenia (side effect)
  non small cell lung cancer (drug therapy)
  nuclear magnetic resonance imaging
  pallor (side effect)
  priority journal
  prostate cancer (drug therapy)
  pruritus (drug therapy, side effect)
  rash (drug therapy, side effect)
  review
  side effect (side effect)
  solid malignant neoplasm (drug therapy)
  stomach adenocarcinoma (drug therapy)
  temporal arteritis (side effect)
  treatment failure
  treatment indication
  treatment response
  ulcerative colitis (side effect)
  vitiligo (side effect)
  vomiting (side effect)
CAS REGISTRY NUMBERS
  budesonide (51333-22-3)
  carboplatin (41575-94-4)
  cimetidine (51481-61-9, 70059-30-2)
  diphenhydramine (147-24-0, 58-73-1)
  exemestane (107868-30-4)
  hydroxyzine (2192-20-3, 64095-02-9, 68-88-2)
  ibuprofen (15687-27-1, 79261-49-7)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  mesalazine (89-57-6)
  mycophenolic acid (23047-11-2, 24280-93-1)
  paclitaxel (33069-62-4)
  prednisone (53-03-2)
  recombinant granulocyte macrophage colony stimulating factor (99283-10-0)
  sunitinib (341031-54-7, 557795-19-4)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Internal Medicine (6)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2010631199
MEDLINE PMID
  21074065 (http://www.ncbi.nlm.nih.gov/pubmed/21074065)
PUI
  L359977674
DOI
  10.1053/j.seminoncol.2010.09.007
FULL TEXT LINK
  http://dx.doi.org/10.1053/j.seminoncol.2010.09.007
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 409
TITLE
  RNAi screening of the kinome identifies modulators of cisplatin response in 
ovarian cancer cells
AUTHOR NAMES
  Arora S.
  Bisanz K.M.
  Peralta L.A.
  Basu G.D.
  Choudhary A.
  Tibes R.
  Azorsa D.O.
AUTHOR ADDRESSES
  (Arora S.; Bisanz K.M.; Peralta L.A.; Basu G.D.; Choudhary A.; Azorsa D.O., 
dazorsa@tgen.org) Pharmaceutical Genomics Division, Translational Genomics 
Research Institute, Scottsdale, AZ 85259, United States.
(Bisanz K.M.; Tibes R.; Azorsa D.O., dazorsa@tgen.org) Clinical 
Translational Research Division, Translational Genomics Research Institute, 
Scottsdale, AZ 85259, United States.
CORRESPONDENCE ADDRESS
  D. O. Azorsa, Clinical Translational Research Division, Translational 
Genomics Research Institute, Scottsdale, AZ 85259, United States. Email: 
dazorsa@tgen.org
SOURCE
  Gynecologic Oncology (2010) 118:3 (220-227). Date of Publication: September 
2010
ISSN
  0090-8258
  1095-6859 (electronic)
BOOK PUBLISHER
  Academic Press Inc., 6277 Sea Harbor Drive, Orlando, United States.
ABSTRACT
  Objective: Ovarian cancer retains a poor prognosis among the female 
gynaecological malignancies. It constitutes about 3% of all malignancies in 
women and accounts for 5% of all female cancer related deaths. A standard 
treatment is cytoreductive surgery followed by adjuvant chemotherapy, and 
re-treatment with platinum based chemotherapy at the time of relapse. In 
order to improve cisplatin response in ovarian cancer cells, we utilized a 
high-throughput RNAi screening to identify kinase modulators. Methods: A 
high-throughput RNAi screen was performed using a siRNA library targeting 
572 kinases to identify potentiators of cisplatin response in the ovarian 
cancer cell line SKOV3. Results: RNAi screening identified at least 55 
siRNAs that potentiated the growth inhibitory effects of cisplatin in SKOV3 
cells. Inhibition of ATR and CHK1 resulted in the greatest modulation of 
cisplatin response. Drug dose response of cisplatin in the presence of siRNA 
validated the effects of these target genes. To show that the siRNA data 
could be successfully translated into potential therapeutic strategies, CHK1 
was further targeted with small molecule inhibitor PD 407824 in combination 
with cisplatin. Results showed that treatment of SKOV3 and OVCAR3 cells with 
CHK1 inhibitor PD 407824 led to sensitization of ovarian cancer cells to 
cisplatin. Conclusions: Our data provides kinase targets that could be 
exploited to design better therapeutics for ovarian cancer patients. We also 
demonstrate the effectiveness of high-throughput RNAi screening as a tool 
for identifying sensitizing targets to known and established 
chemotherapeutic agents. © 2010 Elsevier Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cisplatin (drug combination, drug therapy, pharmacology)
EMTREE DRUG INDEX TERMS
  9 hydroxy 4 phenylpyrrolo[3,4 c]carbazole 1,3(2h,6h) dione (drug 
combination, drug therapy, pharmacology)
  antineoplastic agent (drug therapy, pharmacology)
  platinum
  small interfering RNA (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer (drug therapy, diagnosis, drug therapy)
  RNA interference
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  article
  cancer cell culture
  cancer patient
  cancer screening
  cell strain OVCAR3
  cell strain SKOV3
  cytoreductive surgery
  dose response
  drug inhibition
  female
  gene targeting
  human
  human cell
  priority journal
  treatment response
DRUG MANUFACTURERS
   (United States)EMD Chemicals
   (United States)Tocris
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  platinum (7440-06-4)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2010437108
MEDLINE PMID
  20722101 (http://www.ncbi.nlm.nih.gov/pubmed/20722101)
PUI
  L50940715
DOI
  10.1016/j.ygyno.2010.05.006
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ygyno.2010.05.006
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 410
TITLE
  Prediction and Pathogenesis in Type 1 Diabetes
AUTHOR NAMES
  Ziegler A.-G.
  Nepom G.T.
AUTHOR ADDRESSES
  (Ziegler A.-G., anziegler@lrz.uni-muenchen.de) Forschergruppe Diabetes, 
Klinikum rechts der Isar, Technische Universität München, Kölner Platz 1, 
80804 München, Germany.
(Nepom G.T., nepom@benaroyaresearch.org) Benaroya Research Institute at 
Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101-2795, United States.
CORRESPONDENCE ADDRESS
  A.-G. Ziegler, Forschergruppe Diabetes, Klinikum rechts der Isar, Technische 
Universität München, Kölner Platz 1, 80804 München, Germany. Email: 
anziegler@lrz.uni-muenchen.de
SOURCE
  Immunity (2010) 32:4 (468-478). Date of Publication: April 2010
ISSN
  1074-7613
BOOK PUBLISHER
  Cell Press, 1100 Massachusetts Avenue, Cambridge, United States.
ABSTRACT
  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. © 2010 Elsevier Inc.
EMTREE DRUG INDEX TERMS
  autoantibody (endogenous compound)
  autoantigen (endogenous compound)
  HLA antigen (endogenous compound)
  interferon antibody (drug therapy)
  interleukin 1 receptor blocking agent (clinical trial, drug therapy)
  monoclonal antibody CD3 (drug therapy)
  non receptor protein tyrosine phosphatase 22 (endogenous compound)
  rapamycin
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  diabetogenesis
  insulin dependent diabetes mellitus (drug therapy, drug therapy, etiology)
EMTREE MEDICAL INDEX TERMS
  antigen antibody reaction
  autoimmune disease (etiology)
  CD4+ T lymphocyte
  clinical trial
  disease course
  disease marker
  disease predisposition
  genetic association
  genetic risk
  genetic variability
  genotype
  homeostasis
  human
  immune response
  immunological tolerance
  immunopathogenesis
  immunoregulation
  immunostimulation
  juvenile rheumatoid arthritis (drug therapy)
  nonhuman
  prediction
  priority journal
  review
  systemic lupus erythematosus (drug therapy)
CAS REGISTRY NUMBERS
  rapamycin (53123-88-9)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  General Pathology and Pathological Anatomy (5)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2010265843
MEDLINE PMID
  20412757 (http://www.ncbi.nlm.nih.gov/pubmed/20412757)
PUI
  L358778218
DOI
  10.1016/j.immuni.2010.03.018
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.immuni.2010.03.018
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 411
TITLE
  Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: Serious 
immune related adverse events across a spectrum of cancer subtypes
AUTHOR NAMES
  Dillard T.
  Yedinak C.G.
  Alumkal J.
  Fleseriu M.
AUTHOR ADDRESSES
  (Dillard T.; Fleseriu M., fleseriu@ohsu.edu) Department of Medicine, 
Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health 
and Science University, Portland, OR, United States.
(Yedinak C.G.; Fleseriu M., fleseriu@ohsu.edu) Department of Neurological 
Surgery, Oregon Health and Science University, Portland, OR, United States.
(Alumkal J.) Department of Medicine, Division of Hematology and Oncology, 
Oregon Health and Science University, Portland, OR, United States.
(Fleseriu M., fleseriu@ohsu.edu) Departments of Medicine and Neurological 
Surgery, CH8N, Oregon Health and Science University, 3303 S.W. Bond Avenue, 
Portland, OR 97239, United States.
CORRESPONDENCE ADDRESS
  M. Fleseriu, Departments of Medicine and Neurological Surgery, CH8N, Oregon 
Health and Science University, 3303 S.W. Bond Avenue, Portland, OR 97239, 
United States. Email: fleseriu@ohsu.edu
SOURCE
  Pituitary (2010) 13:1 (29-38). Date of Publication: March 2010
ISSN
  1386-341X
BOOK PUBLISHER
  Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, 
United States.
ABSTRACT
  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. © 
2009 Springer Science+Business Media, LLC.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction, clinical 
trial, drug dose, drug therapy, pharmacology)
EMTREE DRUG INDEX TERMS
  bicalutamide (clinical trial, drug combination, drug therapy)
  dexamethasone (drug dose, drug therapy, intravenous drug administration)
  glucocorticoid (drug dose, drug therapy, intravenous drug administration)
  hydrocortisone (drug therapy)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy, pharmacology)
  leuprorelin (clinical trial, drug combination, drug therapy)
  levothyroxine (drug therapy)
  prednisone (drug dose, drug therapy)
  ticilimumab (clinical trial, pharmacology)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease (drug therapy, side effect, diagnosis, drug therapy, 
etiology, side effect)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, etiology, 
side effect)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (prevention, side effect)
  adverse outcome
  alopecia areata (side effect)
  antineoplastic activity
  arthritis (side effect)
  article
  aseptic meningitis (side effect)
  autoimmune thyroiditis (side effect)
  autoimmunity
  bedtime dosage
  chronic myeloid leukemia (drug therapy)
  clinical trial
  colitis (side effect)
  dermatitis (side effect)
  diabetes insipidus (complication, drug therapy)
  disease course
  dose response
  drug dose comparison
  drug megadose
  drug withdrawal
  enteritis (side effect)
  episcleritis (side effect)
  follow up
  gastritis (side effect)
  hepatitis (side effect)
  histopathology
  human
  hypophysis thyroid system
  hypopituitarism (diagnosis, side effect)
  interstitial nephritis (side effect)
  iritis (side effect)
  kidney carcinoma (drug therapy)
  long term care
  lung alveolitis (side effect)
  lung cancer (drug therapy)
  lymphoma (drug therapy)
  melanoma (drug therapy)
  morning dosage
  multiple cycle treatment
  myelodysplastic syndrome (drug therapy)
  myeloproliferative disorder (drug therapy)
  ovary cancer (drug therapy)
  pancreas cancer (drug therapy)
  pathogenesis
  priority journal
  prostate cancer (drug therapy, radiotherapy)
  pruritus (side effect)
  pure red cell anemia (side effect)
  solid malignant neoplasm (drug therapy)
  thyroiditis (side effect)
  urogenital tract tumor (drug therapy)
  uveitis (side effect)
  vitiligo (side effect)
DRUG TRADE NAMES
  cp 675206  , United StatesPfizer

  mdx 010  , United StatesMedarex

DRUG MANUFACTURERS
   (United States)Medarex
   (United States)Pfizer
CAS REGISTRY NUMBERS
  bicalutamide (90357-06-5)
  dexamethasone (50-02-2)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  leuprorelin (53714-56-0, 74381-53-6)
  levothyroxine (51-48-9)
  prednisone (53-03-2)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Neurology and Neurosurgery (8)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2010158803
MEDLINE PMID
  19639414 (http://www.ncbi.nlm.nih.gov/pubmed/19639414)
PUI
  L50594289
DOI
  10.1007/s11102-009-0193-z
FULL TEXT LINK
  http://dx.doi.org/10.1007/s11102-009-0193-z
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 412
TITLE
  Autoimmune hypophysitis: Expanding the differential diagnosis to CTLA-4 
blockade
AUTHOR NAMES
  Gutenberg A.
  Landek-Salgado M.
  Tzou S.-C.
  Lupi I.
  Geis A.
  Kimura H.
  Caturegli P.
AUTHOR ADDRESSES
  (Landek-Salgado M., mlandek1@jhmi.edu; Tzou S.-C., sctzou.tw@yahoo.com.tw; 
Geis A., abbydawson@hotmail.com; Kimura H., hkimura1@jhmi.edu; Caturegli P., 
pcat@jhmi.edu) Department of Pathology, Johns Hopkins University School of 
Medicine, Baltimore, MD, United States.
(Gutenberg A., agutenberg@med.uni-goettingen.de) Department of Neurosurgery, 
Georg-August University, Goettingen, Germany.
(Lupi I., isabellalupi@yahoo.it) Department of Endocrinology and Metabolism, 
University of Pisa, Pisa, Italy.
(Caturegli P., pcat@jhmi.edu) Feinstone Department of Molecular Microbiology 
and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, 
MD, United States.
CORRESPONDENCE ADDRESS
  P. Caturegli, Department of Pathology, Johns Hopkins University School of 
Medicine, Baltimore, MD, United States. Email: pcat@jhmi.edu
SOURCE
  Expert Review of Endocrinology and Metabolism (2009) 4:6 (681-698). Date of 
Publication: November 2009
ISSN
  1744-6651
BOOK PUBLISHER
  Expert Reviews Ltd., 2 Albert Place, London, United Kingdom.
ABSTRACT
  Autoimmune hypophysitis is an increasingly recognized disorder that enters 
in the differential diagnosis of nonfunctioning pituitary masses. The 
differential diagnosis of these conditions is challenging because of similar 
clinical presentations and radiological signs. This review describes the 
essential features of hypophysitis and the other nonfunctioning pituitary 
masses. It also emphasizes a recently described feature of hypophysitis: its 
appearance with unexpectedly high frequency in patients receiving treatments 
that abrogate the function of cytotoxic T lymphocyte antigen 4. © 2009 
Expert Reviews Ltd.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
EMTREE DRUG INDEX TERMS
  azathioprine (drug therapy)
  forkhead transcription factor (endogenous compound)
  glucocorticoid (drug dose, drug therapy)
  ipilimumab (clinical trial, drug therapy)
  methotrexate (drug therapy)
  prednisolone (drug dose, drug therapy)
  rituximab (drug therapy)
  ticilimumab (clinical trial, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease (drug therapy, diagnosis, drug therapy)
  hypophysitis (drug therapy, diagnosis, drug therapy, surgery)
EMTREE MEDICAL INDEX TERMS
  antigen presenting cell
  arachnoid cyst (diagnosis)
  CD4+ T lymphocyte
  cellular immunity
  clinical feature
  clinical trial
  craniopharyngioma (diagnosis)
  cytotoxicity
  dendritic cell
  differential diagnosis
  diplopia
  drug dose reduction
  drug megadose
  effector cell
  epidermoid cyst (diagnosis, surgery)
  gamma knife radiosurgery
  genetic association
  geographic distribution
  germ cell tumor (diagnosis)
  headache
  human
  hypophysis adenoma (diagnosis)
  hypophysis disease (diagnosis)
  immunosurveillance
  Langerhans cell histiocytosis (diagnosis)
  lymphocyte function
  lymphoma (diagnosis)
  melanoma (drug therapy)
  meningioma (diagnosis)
  nuclear magnetic resonance imaging
  priority journal
  Rathke cleft cyst (diagnosis)
  review
  sarcoidosis (diagnosis)
  sex difference
  stereotactic radiosurgery
  T lymphocyte
  T lymphocyte activation
  tuberculosis (diagnosis)
  visual disorder
  Wegener granulomatosis (diagnosis)
CAS REGISTRY NUMBERS
  azathioprine (446-86-6)
  ipilimumab (477202-00-9)
  methotrexate (15475-56-6, 59-05-2, 7413-34-5)
  prednisolone (50-24-8)
  rituximab (174722-31-7)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2009603069
PUI
  L355675194
DOI
  10.1586/eem.09.37
FULL TEXT LINK
  http://dx.doi.org/10.1586/eem.09.37
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 413
TITLE
  Anti-CTLA-4 therapy-related autoimmune hypophysitis in a melanoma patient
AUTHOR NAMES
  Kaehler K.C.
  Egberts F.
  Lorigan P.
  Hauschilda A.
AUTHOR ADDRESSES
  (Kaehler K.C., kckaehler@yahoo.de; Egberts F.; Hauschilda A.) Department of 
Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, Germany.
(Lorigan P.) Department of Medical Oncology, Christie Hospital NHS 
Foundation Trust, Manchester, United Kingdom.
CORRESPONDENCE ADDRESS
  K. C. Kaehler, Department of Dermatology, University of Kiel, 
Schittenhelmstrasse 7, Kiel 24105, Germany. Email: kckaehler@yahoo.de
SOURCE
  Melanoma Research (2009) 19:5 (333-334). Date of Publication: October 2009
ISSN
  0960-8931
BOOK PUBLISHER
  Lippincott Williams and Wilkins, 250 Waterloo Road, London, United Kingdom.
ABSTRACT
  Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an immunoregulatory 
molecule expressed by activated T cells and resting CD4(+)CD25 (+) T cells. 
In patients with advanced melanoma, anti-CTLA-4 antibody therapy achieves 
cancer regression in 15% of patients. Treatment may be associated with grade 
III/IV autoimmune manifestations that included dermatitis, enterocolitis, 
hepatitis, uveitis, and rarely hypophysitis. Many of these toxicities 
require and respond to brief courses of high-dose corticosteroids. We report 
on a case of autoimmune hypophysitis with severe clinical symptoms that 
resolved rapidly after treatment with steroids. It is important to consider 
both autoimmune hypophysitis and brain metastasis in the differential 
diagnosis of melanoma patients receiving CTLA-4 blockade who present this 
constellation of symptoms. Melanoma Res 19:333-334 © 2009 Wolters Kluwer 
Health | Lippincott Williams & Wilkins.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  alpha2b interferon (drug combination, drug therapy, subcutaneous drug 
administration)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  dacarbazine (drug combination, drug therapy)
  dexamethasone (drug therapy, intravenous drug administration)
  hydrocortisone (drug therapy)
  thyroxine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  brain metastasis (complication, diagnosis, surgery)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, etiology, 
side effect)
  melanoma (drug therapy, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  article
  ataxia (side effect)
  autoimmunity
  cancer immunotherapy
  case report
  clinical feature
  diplopia (side effect)
  headache (side effect)
  human
  immunopathogenesis
  male
  nuclear magnetic resonance imaging
  nystagmus (side effect)
  priority journal
  stereotaxic surgery
  vertigo (side effect)
  vomiting (side effect)
CAS REGISTRY NUMBERS
  alpha2b interferon (99210-65-8)
  dacarbazine (4342-03-4)
  dexamethasone (50-02-2)
  hydrocortisone (50-23-7)
  ipilimumab (477202-00-9)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Neurology and Neurosurgery (8)
  Dermatology and Venereology (13)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2010013255
MEDLINE PMID
  19512947 (http://www.ncbi.nlm.nih.gov/pubmed/19512947)
PUI
  L358037918
DOI
  10.1097/CMR.0b013e32832e0bff
FULL TEXT LINK
  http://dx.doi.org/10.1097/CMR.0b013e32832e0bff
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 414
TITLE
  Ipilimumab-induced hypophysitis: MR imaging findings
AUTHOR NAMES
  Carpenter K.J.
  Murtagh R.D.
  Lilienfeld H.
  Weber J.
  Murtagh F.R.
AUTHOR ADDRESSES
  (Carpenter K.J.; Murtagh R.D., rmurtagh13@gmail.com; Murtagh F.R.) 
Department of Radiology, University of South Florida, Tampa, FL, United 
States.
(Murtagh R.D., rmurtagh13@gmail.com; Murtagh F.R.) University Diagnostic 
Institute, 3301 Alumni Dr, Tampa, FL 33629, United States.
(Murtagh R.D., rmurtagh13@gmail.com; Murtagh F.R.) Department of Diagnostic 
Imaging and Interdisciplinary Oncology, Moffitt Cancer Center and Research 
Institute, Tampa, FL, United States.
(Lilienfeld H.) Department of Endocrinology, Moffitt Cancer Center and 
Research Institute, Tampa, FL, United States.
(Weber J.) Department of Cutaneous Surgery, Moffitt Cancer Center and 
Research Institute, Tampa, FL, United States.
CORRESPONDENCE ADDRESS
  R. D. Murtagh, University Diagnostic Institute, 3301 Alumni Dr, Tampa, FL 
33629, United States. Email: rmurtagh13@gmail.com
SOURCE
  American Journal of Neuroradiology (2009) 30:9 (1751-1753). Date of 
Publication: October 2009
ISSN
  0195-6108
BOOK PUBLISHER
  American Society of Neuroradiology, 2210 Midwest Road, Suite 207, Oak Brook, 
United States.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy)
EMTREE DRUG INDEX TERMS
  levothyroxine (drug combination, drug therapy)
  levothyroxine sodium
  prednisone (drug combination, drug dose, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (drug therapy, side effect, diagnosis, drug therapy, side 
effect)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  anorexia (side effect)
  article
  autoimmunity
  cancer immunotherapy
  case report
  chill (side effect)
  corticosteroid therapy
  drug dose reduction
  drug withdrawal
  fatigue (side effect)
  female
  headache (side effect)
  hormonal therapy
  hot flush (side effect)
  human
  insomnia (side effect)
  male
  melanoma (drug therapy)
  nausea (side effect)
  nuclear magnetic resonance imaging
  pain (side effect)
  positional vertigo (side effect)
  treatment duration
  visual hallucination (side effect)
DRUG TRADE NAMES
  mdx 010
  synthroid
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  levothyroxine sodium (55-03-8)
  prednisone (53-03-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Radiology (14)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2009538662
MEDLINE PMID
  19474123 (http://www.ncbi.nlm.nih.gov/pubmed/19474123)
PUI
  L355419043
DOI
  10.3174/ajnr.A1623
FULL TEXT LINK
  http://dx.doi.org/10.3174/ajnr.A1623
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 415
TITLE
  Dendritic cell vaccination combined with CTLA4 blockade in patients with 
metastatic melanoma
AUTHOR NAMES
  Ribas A.
  Comin-Anduix B.
  Chmielowski B.
  Jalil J.
  De La Rocha P.
  McCannel T.A.
  Ochoa M.T.
  Seja E.
  Villanueva A.
  Oseguera D.K.
  Straatsma B.R.
  Cochran A.J.
  Glaspy J.A.
  Hui L.
  Marincola F.M.
  Wang E.
  Economou J.S.
  Gomez-Navarro J.
AUTHOR ADDRESSES
  (Ribas A., aribas@mednet.ucla.edu; Chmielowski B.; Seja E.; Villanueva A.; 
Oseguera D.K.; Glaspy J.A.) Department of Medicine, Division of 
Hematology/Oncology, University of California at Los Angeles, Los Angeles, 
CA, United States.
(Ribas A., aribas@mednet.ucla.edu; Comin-Anduix B.; Jalil J.; De La Rocha 
P.; Cochran A.J.; Economou J.S.) Department of Surgery, Division of Surgical 
Oncology, University of California at Los Angeles, Los Angeles, CA, United 
States.
(Ribas A., aribas@mednet.ucla.edu; Cochran A.J.; Glaspy J.A.; Economou J.S.) 
Jonsson Comprehensive Cancer Center, University of California at Los 
Angeles, Los Angeles, CA, United States.
(McCannel T.A.; Straatsma B.R.) Department of Ophthalmology, Jules Stein Eye 
Institute, University of California at Los Angeles, Los Angeles, CA, United 
States.
(Ochoa M.T.) Department of Medicine, Division of Dermatology, University of 
California at Los Angeles, Los Angeles, CA, United States.
(Cochran A.J.) Department of Pathology and Laboratory Medicine, University 
of California at Los Angeles, Los Angeles, CA, United States.
(Hui L.; Marincola F.M.; Wang E.) Center for Human Immunology, Department of 
Transfusion Medicine, NIH, Bethesda, MD, United States.
(Gomez-Navarro J.) Pfizer Global Research and Development, New London, CT, 
United States.
(Ribas A., aribas@mednet.ucla.edu) Division of Hematology-Oncology, 11-934 
Factor Building, University of California at Los Angeles Medical Center, 
10833 Le Conte Avenue, Los Angeles, CA 90095-1782, United States.
CORRESPONDENCE ADDRESS
  A. Ribas, Division of Hematology-Oncology, 11-934 Factor Building, 
University of California at Los Angeles Medical Center, 10833 Le Conte 
Avenue, Los Angeles, CA 90095-1782, United States. Email: 
aribas@mednet.ucla.edu
SOURCE
  Clinical Cancer Research (2009) 15:19 (6267-6276). Date of Publication: 1 
Oct 2009
ISSN
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., 615 Chestnut Street, 
Philadelphia,17th floor, United States.
ABSTRACT
  Purpose: Tumor antigen-loaded dendritic cells (DC) are believed to activate 
antitumor immunity by stimulating T cells, and CTL-associated antigen 4 
(CTLA4)-blocking antibodies should release a key negative regulatory pathway 
on T cells. The combination was tested in a phase I clinical trial in 
patients with advanced melanoma. Experimental Design: Autologous DC were 
pulsed with MART-1(26-35) peptide and administered with a dose escalation of 
the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to 
five dose levels. Primary end points were safety and immune effects; 
clinical efficacy was a secondary end point. Results: Dose-limiting 
toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of 
three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had 
an objective tumor response, two partial responses and two complete 
responses, all melanoma free between 2 and 4 years after study initiation. 
There was no difference in immune monitoring results between patients with 
an objective tumor response and those without a response. Exploratory gene 
expression analysis suggested that immune-related gene signatures, in 
particular for B-cell function, may be important in predicting response. 
Conclusion: The combination of MART-1 peptide-pulsed DC and tremelimumab 
results in objective and durable tumor responses at the higher range of the 
expected response rate with either agent alone. © 2009 American Association 
for Cancer Research.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  melan A (clinical trial, intradermal drug administration)
  ticilimumab (adverse drug reaction, clinical trial, intravenous drug 
administration)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4
  dendritic cell vaccine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma
  metastasis
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  B lymphocyte
  cell function
  clinical trial
  controlled study
  diarrhea (side effect)
  drug dose escalation
  drug efficacy
  female
  gene expression
  human
  human cell
  hypophysitis (side effect)
  male
  phase 1 clinical trial
  priority journal
CAS REGISTRY NUMBERS
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
CLINICAL TRIAL NUMBERS
  ClinicalTrials.gov (NCT00090896)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2009526192
MEDLINE PMID
  19789309 (http://www.ncbi.nlm.nih.gov/pubmed/19789309)
PUI
  L355379159
DOI
  10.1158/1078-0432.CCR-09-1254
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-09-1254
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 416
TITLE
  Melan-a-specific cytotoxic T cells are associated with tumor regression and 
autoimmunity following treatment with anti-CTLA-4
AUTHOR NAMES
  Klein O.
  Ebert L.M.
  Nicholaou T.
  Browning J.
  Russell S.E.
  Zuber M.
  Jackson H.M.
  Dimopoulos N.
  Tan B.S.
  Hoos A.
  Luescher I.F.
  Davis I.D.
  Chen W.
  Cebon J.
AUTHOR ADDRESSES
  (Klein O.; Ebert L.M.; Nicholaou T.; Browning J.; Russell S.E.; Zuber M.; 
Jackson H.M.; Dimopoulos N.; Tan B.S.; Hoos A.; Chen W.; Cebon J., 
Jonathan.cebon@ludwig.edu.au) Ludwig Institute for Cancer Research 
(Melbourne Centre for Clinical Sciences), Heidelberg, VIC, Australia.
(Luescher I.F.) Bristol-Myers Squibb, Wallingford, CT.
(Davis I.D.) Ludwig Institute for Cancer Research, Lausanne, Switzerland.
(Cebon J., Jonathan.cebon@ludwig.edu.au) Ludwig Institute for Cancer 
Research (Melbourne Centre for Clinical Sciences), Austin Health, Studley 
Rd., Heidelberg, VIC 3084, Australia.
CORRESPONDENCE ADDRESS
  J. Cebon, Ludwig Institute for Cancer Research (Melbourne Centre for 
Clinical Sciences), Heidelberg, VIC, Australia. Email: 
Jonathan.cebon@ludwig.edu.au
SOURCE
  Clinical Cancer Research (2009) 15:7 (2507-2513). Date of Publication: 1 Apr 
2009
ISSN
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., 615 Chestnut Street, 
Philadelphia,17th floor, United States.
ABSTRACT
  Purpose: Ipilimumab is a monoclonal antibody that blocks the 
immune-inhibitory interaction between CTL antigen 4 (CTLA-4) and its ligands 
onTcells. 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. 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-positiveTcells in his peripheral blood, in regressing tumortissue, and 
at the site of an immune-mediated skin rash were investigated. Results: 
Regressing tumor tissue was infiltrated with CD8-positiveTcells, a high 
proportion of which were specific for Melan-A. The skin rash was similarly 
infiltrated with Melan-A-specific CD8-positiveTcells, 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. 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-positiveTcells 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. © 2009 
American Association for Cancer Research.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, clinical trial, drug dose, drug therapy, 
pharmacology)
  melan A (endogenous compound)
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4 antibody
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmunity
  cancer regression
  CD8+ T lymphocyte
EMTREE MEDICAL INDEX TERMS
  advanced cancer (drug therapy)
  antigen specificity
  article
  clinical trial
  controlled clinical trial
  controlled study
  cytotoxicity
  double blind procedure
  drug dose comparison
  drug mechanism
  human
  human tissue
  immune response
  immunohistochemistry
  melanoma (drug therapy)
  metastasis (drug therapy)
  multiple cycle treatment
  phase 2 clinical trial
  phenotype
  priority journal
  randomized controlled trial
  rash (side effect)
DRUG MANUFACTURERS
  Bristol Myers Squibb
CAS REGISTRY NUMBERS
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2009195945
MEDLINE PMID
  19318477 (http://www.ncbi.nlm.nih.gov/pubmed/19318477)
PUI
  L354504822
DOI
  10.1158/1078-0432.CCR-08-2424
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-08-2424
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 417
TITLE
  CTLA4 blockade with ipilimumab to treat relapse of malignancy after 
allogeneic hematopoietic cell transplantation
AUTHOR NAMES
  Bashey A.
  Medina B.
  Corringham S.
  Pasek M.
  Carrier E.
  Vrooman L.
  Lowy I.
  Solomon S.R.
  Morris L.E.
  Holland H.K.
  Mason J.R.
  Alyea E.P.
  Soiffer R.J.
  Ball E.D.
AUTHOR ADDRESSES
  (Bashey A., abashey@bmtga.com; Medina B.; Corringham S.; Carrier E.; Ball 
E.D.) Division of Blood and Marrow Transplantation, University of 
California, San Diego Moores Cancer Center, La Jolla.
(Bashey A., abashey@bmtga.com; Pasek M.; Vrooman L.; Solomon S.R.; Morris 
L.E.; Holland H.K.) Blood and Marrow Transplant Group of Georgia, Northside 
Hospital, Atlanta.
(Lowy I.) Medarex, Bloomsbury, NJ.
(Mason J.R.) BMT, Scripps Clinic, La Jolla, CA.
(Alyea E.P.; Soiffer R.J.) Dana-Farber Cancer Institute, Boston, MA.
(Bashey A., abashey@bmtga.com) Blood and Marrow Transplant Group of Georgia, 
Northside Hospital, 5670 Peachtree Dunwoody Road NE, Atlanta, GA 30342.
CORRESPONDENCE ADDRESS
  A. Bashey, Blood and Marrow Transplant Group of Georgia, Northside Hospital, 
5670 Peachtree Dunwoody Road NE, Atlanta, GA 30342. Email: abashey@bmtga.com
SOURCE
  Blood (2009) 113:7 (1581-1588). Date of Publication: 12 Feb 2009
ISSN
  0006-4971
  1528-0020 (electronic)
BOOK PUBLISHER
  American Society of Hematology, 1900 M Street, Suite 2000, Washington, 
United States.
ABSTRACT
  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. © 2009 by The 
American Society of Hematoloty.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4
  ipilimumab (adverse drug reaction, clinical trial, drug concentration, drug 
dose, drug therapy)
EMTREE DRUG INDEX TERMS
  corticosteroid (adverse drug reaction, drug therapy)
  gemcitabine (drug therapy)
  infliximab (drug therapy)
  meprednisone (drug therapy)
  mycophenolate mofetil (drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  acute myeloid leukemia (complication, drug therapy)
  allogeneic hematopoietic stem cell transplantation
  breast cancer (complication, drug therapy)
  chronic lymphatic leukemia (complication, drug therapy)
  chronic myeloid leukemia (complication, drug therapy)
  Hodgkin disease (complication, drug therapy)
  kidney carcinoma (complication, drug therapy)
  leukemia relapse (complication, drug therapy)
  mantle cell lymphoma (complication, drug therapy)
  myeloma (complication, drug therapy)
  pneumonia (side effect, drug therapy, prevention, side effect)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  adult
  agitation
  alanine aminotransferase blood level
  alkaline phosphatase blood level
  anemia (side effect)
  anxiety
  article
  aspartate aminotransferase blood level
  backache (side effect)
  blister (side effect)
  blood level
  blurred vision (side effect)
  bone pain (side effect)
  bronchitis (side effect)
  cancer recurrence
  cancer regression
  cellulitis (side effect)
  chill (side effect)
  clinical article
  clinical trial
  cohort analysis
  colitis (side effect)
  constipation (side effect)
  coughing (side effect)
  creatinine blood level
  desquamation (side effect)
  diarrhea (side effect)
  dizziness (side effect)
  drug dose escalation
  drug efficacy
  drug infusion
  drug safety
  dry skin (side effect)
  dyspnea (drug therapy, side effect)
  fatigue (side effect)
  febrile neutropenia (side effect)
  female
  fever (side effect)
  graft rejection (side effect)
  graft versus host reaction (side effect)
  graft versus leukemia effect
  headache (side effect)
  heart palpitation (side effect)
  hip fracture (side effect)
  human
  hypercalcemia (side effect)
  hyperglycemia (side effect)
  hypernatremia (side effect)
  hyperthyroidism (side effect)
  hypocalcemia (side effect)
  hypokalemia (side effect)
  hyponatremia (side effect)
  hypotension (side effect)
  hypothyroidism (side effect)
  infection (side effect)
  insomnia (side effect)
  knee swelling (side effect)
  knee swelling (side effect)
  leukocytosis (side effect)
  male
  mucosa inflammation (side effect)
  multicenter study
  muscle cramp (side effect)
  nausea (side effect)
  neutropenia (side effect)
  night sweat (side effect)
  petechia (side effect)
  pharyngitis (side effect)
  photophobia (side effect)
  polyarthritis (side effect)
  priority journal
  pruritus (side effect)
  rash (side effect)
  remission
  rheumatoid arthritis (side effect)
  sensory neuropathy (side effect)
  shoulder pain (side effect)
  side effect (side effect)
  swelling (side effect)
  tachycardia (side effect)
  thorax pain (side effect)
  thrombocytopenia (side effect)
  urine retention (side effect)
  vaginitis (side effect)
  vomiting (side effect)
DRUG MANUFACTURERS
   (United States)National Cancer Institute
CAS REGISTRY NUMBERS
  gemcitabine (103882-84-4)
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
  meprednisone (1247-42-3)
  mycophenolic acid 2 morpholinoethyl ester (116680-01-4, 128794-94-5)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Hematology (25)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2009120218
MEDLINE PMID
  18974373 (http://www.ncbi.nlm.nih.gov/pubmed/18974373)
PUI
  L354286702
DOI
  10.1182/blood-2008-07-168468
FULL TEXT LINK
  http://dx.doi.org/10.1182/blood-2008-07-168468
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 418
TITLE
  CTLA-4 blockade with monoclonal antibodies in patients with metastatic 
cancer: Surgical issues
AUTHOR NAMES
  Phan G.Q.
  Weber J.S.
  Sondak V.K.
AUTHOR ADDRESSES
  (Phan G.Q.; Weber J.S.; Sondak V.K., vernon.sondak@moffitt.org) Division of 
Cutaneous Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, 
Tampa, FL 33612, United States.
(Weber J.S.; Sondak V.K., vernon.sondak@moffitt.org) Donald A. Adam 
Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center, 12902 
Magnolia Drive, Tampa, FL 33612, United States.
(Weber J.S.; Sondak V.K., vernon.sondak@moffitt.org) Department of Oncologic 
Sciences, University of South Florida College of Medicine, Tampa, FL, United 
States.
(Sondak V.K., vernon.sondak@moffitt.org) Department of Surgery, University 
of South Florida College of Medicine, Tampa, FL, United States.
CORRESPONDENCE ADDRESS
  V. K. Sondak, Division of Cutaneous Oncology, H. Lee Moffitt Cancer Center, 
12902 Magnolia Drive, Tampa, FL 33612, United States. Email: 
vernon.sondak@moffitt.org
SOURCE
  Annals of Surgical Oncology (2008) 15:11 (3014-3021). Date of Publication: 
November 2008
ISSN
  1068-9265
  1534-4681 (electronic)
BOOK PUBLISHER
  Springer New York, 233 Springer Street, New York, United States.
ABSTRACT
  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. 
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. 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. 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. © 2008 Society of Surgical Oncology.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction, 
pharmacology)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy, intravenous drug administration, pharmacology)
  ticilimumab (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
EMTREE DRUG INDEX TERMS
  antibiotic agent (drug therapy, intravenous drug administration)
  antidiarrheal agent (drug therapy)
  antipruritic agent (drug therapy)
  atropine plus diphenoxylate (drug therapy)
  budesonide (drug therapy)
  corticosteroid (drug therapy, oral drug administration)
  dacarbazine (drug combination, drug therapy)
  dexamethasone (drug therapy, intravenous drug administration)
  hydrocortisone (drug therapy, oral drug administration)
  hydroxyzine
  infliximab (drug combination, drug therapy)
  interleukin 2 (drug combination, drug therapy, intravenous drug 
administration)
  levothyroxine (drug therapy)
  loperamide (drug therapy)
  methylprednisolone (drug therapy)
  peptide vaccine (drug therapy)
  prednisone (drug therapy, oral drug administration)
  testosterone
  tumor necrosis factor (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy)
  metastasis (drug therapy)
EMTREE MEDICAL INDEX TERMS
  abdominal pain (side effect)
  alopecia areata (side effect)
  anus pain (side effect)
  anus pain (side effect)
  arthritis (side effect)
  article
  cancer immunization
  clinical trial
  colitis (side effect)
  colon perforation (side effect, surgery)
  colon resection
  constipation (side effect)
  dermatitis (drug therapy, side effect)
  diarrhea (drug therapy, side effect)
  drug dose escalation
  enterocolitis (drug therapy, side effect)
  episcleritis (side effect)
  erythema (side effect)
  eye toxicity (side effect)
  fever (side effect)
  hepatitis (side effect)
  human
  hypophysitis (drug therapy, side effect)
  hypothyroidism (drug therapy, side effect)
  immunotoxicity (side effect)
  lymphocytic infiltration (side effect)
  medical literature
  meningitis (side effect)
  nausea and vomiting (side effect)
  nephritis (side effect)
  oncology
  pain (side effect)
  pancreatitis (side effect, therapy)
  rash (side effect)
  rectum hemorrhage (side effect)
  temporal arteritis (side effect)
  thyroid disease (side effect)
  tumor regression (side effect)
  ulcer (side effect)
  uveitis (side effect)
  vitiligo (side effect)
DRUG TRADE NAMES
  entocort
  imodium
  lomotil
  remicade  , United StatesCentocor

DRUG MANUFACTURERS
   (United States)Bristol Myers Squibb
   (United States)Centocor
   (United States)Medarex
   (United States)Pfizer
CAS REGISTRY NUMBERS
  atropine plus diphenoxylate (55840-97-6)
  budesonide (51333-22-3)
  dacarbazine (4342-03-4)
  dexamethasone (50-02-2)
  hydrocortisone (50-23-7)
  hydroxyzine (2192-20-3, 64095-02-9, 68-88-2)
  infliximab (170277-31-3)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  levothyroxine (51-48-9)
  loperamide (34552-83-5, 53179-11-6)
  methylprednisolone (6923-42-8, 83-43-2)
  prednisone (53-03-2)
  testosterone (58-22-0)
  ticilimumab (745013-59-6)
EMBASE CLASSIFICATIONS
  Internal Medicine (6)
  Dermatology and Venereology (13)
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2008513529
MEDLINE PMID
  18716842 (http://www.ncbi.nlm.nih.gov/pubmed/18716842)
PUI
  L50247891
DOI
  10.1245/s10434-008-0104-y
FULL TEXT LINK
  http://dx.doi.org/10.1245/s10434-008-0104-y
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 419
TITLE
  Expression of CD86 on human islet endothelial cells facilitates T cell 
adhesion and migration
AUTHOR NAMES
  Lozanoska-Ochser B.
  Klein N.J.
  Huang G.C.
  Alvarez R.A.
  Peakman M.
AUTHOR ADDRESSES
  (Lozanoska-Ochser B.; Alvarez R.A.; Peakman M., mark.peakman@kcl.ac.uk) 
Department of Immunobiology, King's College London, Guy's Hospital, Great 
Maze Pond, London SE1 9RT, United Kingdom.
(Klein N.J.) Infectious Diseases and Microbiology Unit, Institute of Child 
Health, University College, London, United Kingdom.
(Huang G.C.) King's College London, Diabetes Research Group, London, United 
Kingdom.
(Peakman M., mark.peakman@kcl.ac.uk) National Institute for Health Research 
Biomedical Research Centre, Guy's and St. Thomas' National Health Service 
Foundation Trust, King's College, London, United Kingdom.
CORRESPONDENCE ADDRESS
  M. Peakman, Department of Immunobiology, King's College London, Guy's 
Hospital, Great Maze Pond, London SE1 9RT, United Kingdom. Email: 
mark.peakman@kcl.ac.uk
SOURCE
  Journal of Immunology (2008) 181:9 (6109-6116). Date of Publication: 1 Nov 
2008
ISSN
  0022-1767
  1550-6606 (electronic)
BOOK PUBLISHER
  American Association of Immunologists, 9650 Rockville Pike, Bethesda, United 
States.
ABSTRACT
  Pancreatic islet endothelial cells (ECs) form the barrier across which 
autoreactive T cells transmigrate during the development of islet 
inflammation in type 1 diabetes. Little is known about the immune phenotype 
of islet ECs that might shape their molecular interaction with autoreactive 
T cells before and during the development of islet inflammation. In this 
study we examined the expression and functional significance of 
costimulatory molecules by human islet ECs. Freshly isolated human islet ECs 
constitutively expressed CD86 (B7-2) and ICOS ligand but not CD80 (B7-1) or 
CD40 costimulatory molecules. The functional activity of islet EC-expressed 
CD86 was examined by coculture of resting islet ECs with CD4 T cells 
stimulated by CD3 ligation alone. Marked T cell proliferation in the 
coculture was completely abrogated by mAb blockade of CD86, confirming that 
costimulatory properties are conferred on ECs by CD86 expression. In view of 
its location on the vasculature, we hypothesized a role for CD86 in T cell 
adhesion/transmigration. In keeping with this, adhesion/transmigration of 
activated (CD3 ligated) memory (CD45R0(+)) CD4 T cells across islet ECs was 
completely inhibited in the presence of CD86 blocking mAb. Identical results 
were obtained for T cell adhesion using either CTLA-4 blocking mAb or 
CTLA-4Ig (abatacept), indicating CTLA-4 as the T cell ligand for these 
CD86-mediated effects. These data suggest a novel role for CD86 expression 
on the microvasculature, whereby ligation of CTLA-4 on CD4 T cells by CD86 
on islet ECs is key to the adhesion of recently activated T cells. Copyright 
© 2008 by The American Association of Immunologists, Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  CD86 antigen (endogenous compound)
EMTREE DRUG INDEX TERMS
  abatacept (pharmacology)
  B7 antigen (endogenous compound)
  CD3 antigen (endogenous compound)
  CD40 antigen (endogenous compound)
  CD45RO antigen (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody (pharmacology)
  monoclonal antibody (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cell adhesion
  cell migration
  endothelium cell
  pancreas islet cell
  T lymphocyte
EMTREE MEDICAL INDEX TERMS
  article
  CD4+ T lymphocyte
  cell activation
  cell isolation
  cell proliferation
  cell stimulation
  coculture
  controlled study
  drug mechanism
  enzyme activity
  human
  human cell
  ligation
  memory T lymphocyte
  microvasculature
  priority journal
  protein expression
  protein function
  vascularization
CAS REGISTRY NUMBERS
  abatacept (332348-12-6)
EMBASE CLASSIFICATIONS
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2009583472
MEDLINE PMID
  18941200 (http://www.ncbi.nlm.nih.gov/pubmed/18941200)
PUI
  L355585016
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 420
TITLE
  Pituitary autoimmunity: 30 years later
AUTHOR NAMES
  Caturegli P.
  Lupi I.
  Landek-Salgado M.
  Kimura H.
  Rose N.R.
AUTHOR ADDRESSES
  (Caturegli P., pcat@jhmi.edu; Landek-Salgado M.; Kimura H.; Rose N.R.) 
Department of Pathology, The Johns Hopkins University School of Medicine, 
Baltimore, MD, United States.
(Caturegli P., pcat@jhmi.edu; Rose N.R.) Feinstone Department of Molecular 
Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public 
Health, Baltimore, MD, United States.
(Lupi I.) Department of Endocrinology and Metabolism, University of Pisa, 
Pisa, Italy.
CORRESPONDENCE ADDRESS
  P. Caturegli, Department of Pathology, The Johns Hopkins University School 
of Medicine, Baltimore, MD, United States. Email: pcat@jhmi.edu
SOURCE
  Autoimmunity Reviews (2008) 7:8 (631-637). Date of Publication: September 
2008
ISSN
  1568-9972
BOOK PUBLISHER
  Elsevier, P.O. Box 211, Amsterdam, Netherlands.
ABSTRACT
  Pituitary autoimmunity encompasses a spectrum of conditions ranging from 
histologically proven forms of lymphocytic hypophysitis to the presence of 
pituitary antibodies in apparently healthy subjects. Hypophysitis is a rare 
but increasingly recognized disorder that typically presents as a mass in 
the sella turcica. It mimics clinically and radiologically other 
non-functioning sellar masses, such as the more common pituitary adenoma. 
Hypophysitis shows a striking temporal association with pregnancy, and it 
has been recently described during immunotherapies that block CTLA-4. 
Several candidate pituitary autoantigens have been described in the last 
decade, although none has proven useful as a diagnostic tool. This review 
summarizes the advances made in the field since the publication of the first 
review on pituitary autoimmunity, and the challenges that await 
clarification. © 2008 Elsevier B.V. All rights reserved.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  hormone antibody (endogenous compound)
EMTREE DRUG INDEX TERMS
  alpha enolase (endogenous compound)
  autoantigen (endogenous compound)
  cancer vaccine (drug therapy)
  corticotropin (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  furin (endogenous compound)
  glucocorticoid (drug dose, drug therapy)
  gonadotropin (endogenous compound)
  growth hormone (endogenous compound)
  hydrocortisone (endogenous compound)
  hypophysis hormone (endogenous compound)
  melanoma antigen (drug therapy)
  pituitary gland specific factor 1a (endogenous compound)
  pituitary gland specific factor 2 (endogenous compound)
  prohormone convertase 1 (endogenous compound)
  prolactin (endogenous compound)
  protein (endogenous compound)
  secretogranin II (endogenous compound)
  secretogranin V (endogenous compound)
  thyrotropin (endogenous compound)
  tudor domain containing protein 6 (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease (diagnosis, drug therapy, etiology)
  hypophysis disease (diagnosis, drug therapy, etiology)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency
  autoimmunity
  clinical feature
  diagnostic value
  drug megadose
  empty sella syndrome
  gonadotropin deficiency
  growth hormone deficiency
  histopathology
  hormone deficiency
  hormone substitution
  human
  hypophysis
  hypophysis adenoma
  hypophysitis (diagnosis, drug therapy)
  hypopituitarism (etiology)
  immunotherapy
  lymphocyte
  lymphocytic infiltration
  melanoma (drug therapy)
  nonhuman
  pregnancy
  review
  sella turcica
  thyrotropin deficiency
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  gonadotropin (63231-54-9)
  growth hormone (36992-73-1, 37267-05-3, 66419-50-9, 9002-72-6)
  hydrocortisone (50-23-7)
  hypophysis hormone (85883-81-4)
  prolactin (12585-34-1, 50647-00-2, 9002-62-4)
  protein (67254-75-5)
  thyrotropin (9002-71-5)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Internal Medicine (6)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2008412378
MEDLINE PMID
  18774118 (http://www.ncbi.nlm.nih.gov/pubmed/18774118)
PUI
  L50140960
DOI
  10.1016/j.autrev.2008.04.016
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.autrev.2008.04.016
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 421
TITLE
  BCL-2 family proteins: Critical checkpoints of apoptotic cell death
AUTHOR NAMES
  Danial N.N.
AUTHOR ADDRESSES
  (Danial N.N., nika_danial@dfci.harvard.edu) Department of Pathology, Harvard 
Medical School, Boston, MA, United States.
(Danial N.N., nika_danial@dfci.harvard.edu) Department of Cancer Biology, 
Dana-Farber Cancer Institute, Boston, MA, United States.
(Danial N.N., nika_danial@dfci.harvard.edu) Department of Cancer Biology, 
Dana-Farber Cancer Institute, 44 Binney Street, Smith 756, Boston, MA 02115, 
United States.
CORRESPONDENCE ADDRESS
  N.N. Danial, Department of Cancer Biology, Dana-Farber Cancer Institute, 44 
Binney Street, Smith 756, Boston, MA 02115, United States. Email: 
nika_danial@dfci.harvard.edu
SOURCE
  Clinical Cancer Research (2007) 13:24 (7254-7263). Date of Publication: 15 
Dec 2007
ISSN
  1078-0432
BOOK PUBLISHER
  American Association for Cancer Research Inc., 615 Chestnut Street, 
Philadelphia,17th floor, United States.
ABSTRACT
  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. © 2007 
American Association for Cancer Research.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  protein bcl 2 (endogenous compound)
EMTREE DRUG INDEX TERMS
  4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 
(phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide (drug 
therapy, pharmacology)
  antineoplastic agent (drug therapy, pharmacology)
  BH3 protein (endogenous compound)
  cyclophosphamide (drug combination, drug therapy)
  doxorubicin (drug combination)
  gossypol (drug therapy)
  obatoclax (pharmacology)
  prednisone (drug combination, drug therapy)
  protein Bak (endogenous compound)
  protein Bax (endogenous compound)
  tw 37 (drug combination, drug therapy, pharmacology)
  unclassified drug
  vincristine (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  apoptosis
  cell death
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  B cell lymphoma (drug therapy)
  chronic lymphatic leukemia (drug therapy)
  conformational transition
  drug protein binding
  human
  leukemia (drug therapy)
  lymphoma (drug therapy)
  mitochondrion
  molecular interaction
  priority journal
  review
  small cell lung cancer (drug therapy)
DRUG TRADE NAMES
  abt 737
  gx 15 070
  tw 37
CAS REGISTRY NUMBERS
  cyclophosphamide (50-18-0)
  doxorubicin (23214-92-8, 25316-40-9)
  gossypol (303-45-7)
  obatoclax (803712-67-6, 803712-79-0)
  prednisone (53-03-2)
  protein Bak (166801-28-1)
  protein bcl 2 (219306-68-0)
  vincristine (57-22-7)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Hematology (25)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2008002056
MEDLINE PMID
  18094405 (http://www.ncbi.nlm.nih.gov/pubmed/18094405)
PUI
  L351006327
DOI
  10.1158/1078-0432.CCR-07-1598
FULL TEXT LINK
  http://dx.doi.org/10.1158/1078-0432.CCR-07-1598
COPYRIGHT
  Copyright 2010 Elsevier B.V., All rights reserved.

RECORD 422
TITLE
  Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell 
cancer associated with enteritis and hypophysitis
AUTHOR NAMES
  Yang J.C.
  Hughes M.
  Kammula U.
  Royal R.
  Sherry R.M.
  Topalian S.L.
  Suri K.B.
  Levy C.
  Allen T.
  Mavroukakis S.
  Lowy I.
  White D.E.
  Rosenberg S.A.
AUTHOR ADDRESSES
  (Yang J.C., JamesYang@mail.nih.gov; Hughes M.; Kammula U.; Royal R.; Sherry 
R.M.; Topalian S.L.; Suri K.B.; Levy C.; Allen T.; Mavroukakis S.; White 
D.E.; Rosenberg S.A.) Surgery Branch, Center for Cancer Research, National 
Cancer Institute, Bethesda, MD, United States.
(Lowy I.) Medarex Corp., Princeton, NJ, United States.
(Yang J.C., JamesYang@mail.nih.gov) 9000 Rockville Pike, Bethesda, MD 20892, 
United States.
(Topalian S.L.) Johns Hopkins School of Medicine, Baltimore, MD, United 
States.
CORRESPONDENCE ADDRESS
  J.C. Yang, 9000 Rockville Pike, Bethesda, MD 20892, United States. Email: 
JamesYang@mail.nih.gov
SOURCE
  Journal of Immunotherapy (2007) 30:8 (825-830). Date of Publication: 
November/December 2007
ISSN
  1524-9557
BOOK PUBLISHER
  Lippincott Williams and Wilkins, 530 Walnut Street, Philadelphia, United 
States.
ABSTRACT
  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. © 2007 Lippincott Williams & Wilkins, Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  ipilimumab (adverse drug reaction, drug therapy, drug toxicity, intravenous 
drug administration)
EMTREE DRUG INDEX TERMS
  dexamethasone
  interleukin 2
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  kidney cancer (drug therapy)
EMTREE MEDICAL INDEX TERMS
  adrenal insufficiency (side effect)
  adult
  aged
  arthralgia (side effect)
  article
  aseptic meningitis (side effect)
  cancer regression
  colitis (side effect)
  confidence interval
  controlled study
  dermatitis (side effect)
  enteritis (side effect)
  female
  human
  hypophysitis
  hypopituitarism (side effect)
  immunotherapy
  male
  metastasis
  priority journal
  treatment response
  tumor regression
DRUG MANUFACTURERS
   (United States)Medarex
CAS REGISTRY NUMBERS
  dexamethasone (50-02-2)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2007618939
MEDLINE PMID
  18049334 (http://www.ncbi.nlm.nih.gov/pubmed/18049334)
PUI
  L350295361
DOI
  10.1097/CJI.0b013e318156e47e
FULL TEXT LINK
  http://dx.doi.org/10.1097/CJI.0b013e318156e47e
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 423
TITLE
  Gateways to clinical trials
AUTHOR NAMES
  Bayés M.
  Rabasseda X.
  Prous J.R.
AUTHOR ADDRESSES
  (Bayés M., mbayes@prous.com; Rabasseda X.; Prous J.R.) Prous Science, S.A., 
P.O. Box 540, 08080 Barcelona, Spain.
CORRESPONDENCE ADDRESS
  M. Bayés, Prous Science, S.A., P.O. Box 540, 08080 Barcelona, Spain. Email: 
mbayes@prous.com
SOURCE
  Methods and Findings in Experimental and Clinical Pharmacology (2007) 29:7 
(467-509). Date of Publication: September 2007
ISSN
  0379-0355
BOOK PUBLISHER
  Prous Science, P.O. Box 540, Barcelona, Spain.
ABSTRACT
  Gateways to Clinical Trials are a guide to the most recent clinical trials 
in current literature and congresses. The data in the following tables has 
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: 12B75, 
274150; Abacavir sulfate/lamivudine, Abatacept, Ad2/HIF-1alpha, Adalimumab, 
Adefovir, Adefovir dipivoxil, AGN-201904-Z, AIDSVAX, Albinterferon alfa-2b, 
Alemtuzumab, Aliskiren fumarate, Alvimopan hydrate, Amlodipine 
besylate/atorvastatin calcium, Amlodipine besylate/Olmesartan medoxomil, 
Ammonium tetrathiomolybdate, Amodiaquine, Apaziquone, Aprepitant, Arsenic 
trioxide, Artesunate/Amodiaquine, Ascorbic acid, Atazanavir sulfate, 
Atazanavir/ritonavir, Atomoxetine hydrochloride, Atrigel-Leuprolide, 
Axitinib; Bevacizumab, Binodenoson, Bortezomib, Bovine lactoferrin; 
Calcipotriol/ betamethasone dipropionate, Carisbamate, Certolizumab pegol, 
Ciclesonide, Conivaptan hydrochloride, CP-690550, CP-751871, Cypher; 
Dapivirine, Darbepoetin alfa, Darunavir, Dasatinib, del-1 Genemedicine, 
Denosumab, Desloratadine, Dexlansoprazole, DiabeCell, 
Drospirenone/ethinylestradiol, DTaP-HepB-IPV, Duloxetine hydrochloride, 
Dutasteride; Eculizumab, Eldecalcitol, Eletriptan, Emtricitabine, Entecavir, 
Eritoran tetrasodium, Ertapenem sodium, Escitalopram oxalate, 
Eslicarbazepine acetate, Esomeprazole magnesium, Estradiol acetate, 
Eszopiclone, ETEC vaccine, Etoricoxib, Exenatide, Ezetimibe; Fluticasone 
furoate, Fosmidomycin, Fosmidomycin/clindamycin; Glutamine; Heat Shock 
Protein 10, Hepatitis B hyperimmunoglobulin, HIV vaccine, Hochuekkito, Human 
Albumin, Human papillomavirus vaccine; Immune globulin subcutaneous [human], 
IMP-321, Interferon omega, ISIS-301012, Istaroxime; Japanese encephalitis 
virus vaccine; Latanoprost/timolol maleate, Lenalidomide, Linaclotide 
acetate, Lumiracoxib, LY-517717; Malaria vaccine, MAS-063D, Meningitis B 
vaccine, Mepolizumab, Methylnaltrexone bromide, Micafungin sodium, MK-0822A, 
Morphine glucuronide, Morphine hydrochloride, Mycophenolic acid sodium salt; 
Natalizumab, Nesiritide, Norelgestromin/ethinyl estradiol, NT-201; 
Oblimersen sodium, Olmesartan medoxomil, Olmesartan 
medoxomil/hydrochlorothiazide, Omalizumab, Otamixaban; Paclitaxel 
nanoparticles, Panitumumab, Panobinostat, Parathyroid hormone (human 
recombinant), Parecoxib sodium, Pegfilgrastim, Peginterferon alfa-2a, 
Peginterferon alfa-2b, Pegvisomant, PI-88, Pimecrolimus, Pneumococcal 
7-valent conjugate vaccine, Pneumococcal 9-valent conjugate vaccine, 
Pneumococcal conjugate vaccine, Poloxamer-188, Prasugrel, Pregabalin, 
Prulifloxacin; R-109339, Ramipril/amlodipine, Ranolazine, Rasburicase, rHA 
influenza vaccine, Ro-50-3821, Rosuvastatin calcium, Rotavirus vaccine, 
Rotigotine, Ruboxistaurin mesilate hydrate; Satavaptan, SC-75416, 
Solifenacin succinate, Sorafenib, Sugammadex sodium, Sunitinib malate, 
Synthetic conjugated estrogens B; Tadalafil, Talnetant, Taxus, Tegaserod 
maleate, Telbivudine, Temsirolimus, Tenofovir disoproxil fumarate, 
Tetomilast, Tiotropium bromide, Tipifarnib, Tofimilast, Tremelimumab, 
Trimethoprim; Udenafil, Urocortin 2; Valdecoxib, Vernakalant hydrochloride; 
XP-828L. © 2007 Prous Science. All rights reserved.
EMTREE DRUG INDEX TERMS
  alemtuzumab (clinical trial, drug combination, drug therapy, intravenous 
drug administration)
  ancrod (drug combination, drug therapy)
  antiarrhythmic agent (clinical trial, drug therapy, intravenous drug 
administration)
  atorvastatin (clinical trial, drug comparison, drug therapy)
  coumarin (drug combination, drug therapy)
  cyclosporine (clinical trial, drug combination, drug therapy, oral drug 
administration)
  danaparoid (drug combination, drug therapy)
  diphenhydramine (clinical trial, drug combination, drug therapy)
  dobutamine (clinical trial, drug therapy, intravenous drug administration)
  eculizumab (clinical trial, drug therapy)
  hydroxymethylglutaryl coenzyme A reductase inhibitor (adverse drug reaction, 
clinical trial, drug combination, drug therapy)
  inotropic agent (clinical trial, drug therapy, intravenous drug 
administration)
  istaroxime (clinical trial, drug therapy, intravenous drug administration)
  mepolizumab (clinical trial, drug therapy, intravenous drug administration)
  nesiritide (clinical trial, drug therapy, intravenous drug administration)
  paclitaxel (clinical trial, drug comparison, drug therapy)
  paracetamol (clinical trial, drug combination, drug therapy)
  pentamidine (clinical trial, drug therapy)
  placebo
  prednisone (clinical trial, drug therapy)
  ranolazine (adverse drug reaction, clinical trial, drug combination, drug 
therapy, oral drug administration)
  rapamycin (clinical trial, drug combination, drug comparison, drug therapy, 
oral drug administration)
  recombinant erythropoietin (clinical trial, drug therapy, intraperitoneal 
drug administration)
  rosuvastatin (clinical trial, drug comparison, drug therapy, oral drug 
administration)
  simvastatin (clinical trial, drug comparison, drug therapy)
  thymocyte antibody (clinical trial, drug combination, drug therapy, 
intravenous drug administration)
  unclassified drug
  unindexed drug
  valaciclovir (clinical trial, drug combination, drug therapy)
  vernakalant (clinical trial, drug therapy, intravenous drug administration)
  warfarin (drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cardiovascular disease (drug therapy)
  hematologic disease (drug therapy)
  lymphatic system disease (drug therapy)
EMTREE MEDICAL INDEX TERMS
  absence of side effects (side effect)
  angina pectoris (drug therapy)
  aplastic anemia (drug therapy)
  artery occlusion (drug therapy)
  atrial fibrillation (drug therapy)
  chronic kidney failure (drug therapy)
  clinical trial
  combination chemotherapy
  congestive heart failure (drug therapy)
  controlled clinical trial
  coronary artery disease (drug therapy)
  drug efficacy
  drug eluting stent
  drug safety
  drug withdrawal
  heart failure (drug therapy)
  heparin induced thrombocytopenia (drug therapy)
  human
  hypereosinophilic syndrome (drug therapy)
  meta analysis
  monotherapy
  paroxysmal nocturnal hemoglobinuria (drug therapy)
  randomized controlled trial
  review
  systematic review
  treatment outcome
  unspecified side effect (side effect)
CAS REGISTRY NUMBERS
  alemtuzumab (216503-57-0)
  ancrod (9046-56-4)
  atorvastatin (134523-00-5, 134523-03-8)
  coumarin (91-64-5)
  cyclosporin A (59865-13-3, 63798-73-2)
  danaparoid (83513-48-8)
  diphenhydramine (147-24-0, 58-73-1)
  dobutamine (34368-04-2, 52663-81-7)
  eculizumab (219685-50-4)
  istaroxime (203737-93-3)
  mepolizumab (196078-29-2)
  nesiritide (124584-08-3, 189032-40-4)
  paclitaxel (33069-62-4)
  paracetamol (103-90-2)
  pentamidine (100-33-4)
  prednisone (53-03-2)
  ranolazine (95635-55-5)
  rapamycin (53123-88-9)
  rosuvastatin (147098-18-8, 147098-20-2)
  simvastatin (79902-63-9)
  valaciclovir (124832-26-4)
  vernakalant (748810-28-8, 794466-70-9)
  warfarin (129-06-6, 2610-86-8, 3324-63-8, 5543-58-8, 81-81-2)
EMBASE CLASSIFICATIONS
  Cardiovascular Diseases and Cardiovascular Surgery (18)
  Hematology (25)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2007570930
MEDLINE PMID
  17982511 (http://www.ncbi.nlm.nih.gov/pubmed/17982511)
PUI
  L350157135
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 424
TITLE
  Apoptotic signal transduction and T cell tolerance
AUTHOR NAMES
  Gatzka M.
  Walsh C.M.
AUTHOR ADDRESSES
  (Gatzka M.; Walsh C.M.) Department of Molecular Biology and Biochemistry, 
Center for Immunology, University of California, Irvine, CA, United States.
CORRESPONDENCE ADDRESS
  M. Gatzka, Department of Molecular Biology and Biochemistry, Center for 
Immunology, University of California, Irvine, CA, United States.
SOURCE
  Autoimmunity (2007) 40:6 (442-452). Date of Publication: September 2007
  Signal Transduction, Book Series Title:
ISSN
  0891-6934
  1607-842X (electronic)
BOOK PUBLISHER
  Taylor and Francis Ltd., 4 Park Square, Milton Park, Abingdon, Oxfordshire, 
United Kingdom.
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS
  apoptosis inducing factor (endogenous compound)
  BIM protein (endogenous compound)
  caspase 10 (endogenous compound)
  caspase 3 (endogenous compound)
  caspase 6 (endogenous compound)
  caspase 7 (endogenous compound)
  caspase 8 (endogenous compound)
  caspase 9 (endogenous compound)
  cytochrome c (endogenous compound)
  endonuclease G (endogenous compound)
  Fas associated death domain protein (endogenous compound)
  Fas ligand (endogenous compound)
  FLICE inhibitory protein (endogenous compound)
  major histocompatibility antigen (endogenous compound)
  mitogen activated protein kinase (endogenous compound)
  protein Bak (endogenous compound)
  protein Bax (endogenous compound)
  protein bcl 2 (endogenous compound)
  protein bcl xl (endogenous compound)
  protein Bid (endogenous compound)
  protein kinase ZAP 70 (endogenous compound)
  protein Noxa (endogenous compound)
  protein p53 (endogenous compound)
  second mitochondrial activator of caspase (endogenous compound)
  serine proteinase Omi (endogenous compound)
  T lymphocyte receptor (endogenous compound)
  toll like receptor 3 (endogenous compound)
  tumor necrosis factor receptor superfamily member 6 (endogenous compound)
  tumor necrosis factor related apoptosis inducing ligand (endogenous 
compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  apoptosis
  autoimmune disease (etiology)
  immunological tolerance
  signal transduction
  T lymphocyte
EMTREE MEDICAL INDEX TERMS
  autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (etiology)
  cell death
  clonal anergy
  diabetes mellitus (etiology)
  enzyme activation
  gene mutation
  human
  immunopathogenesis
  immunoreactivity
  lymphoproliferative disease (etiology)
  multiple sclerosis (etiology)
  nonhuman
  pathophysiology
  protein function
  protein phosphorylation
  regulatory T lymphocyte
  review
  rheumatoid arthritis (etiology)
  systemic lupus erythematosus (etiology)
  T lymphocyte activation
  virus immunity
CAS REGISTRY NUMBERS
  Fas associated death domain protein (391972-52-4)
  caspase 10 (189088-85-5)
  caspase 3 (169592-56-7)
  caspase 6 (182372-15-2)
  caspase 7 (189258-14-8)
  caspase 9 (180189-96-2)
  cytochrome c (9007-43-6, 9064-84-0)
  mitogen activated protein kinase (142243-02-5)
  protein Bak (166801-28-1)
  protein Bid (260235-79-8)
  protein bcl 2 (219306-68-0)
  protein bcl xl (151033-38-4)
  protein kinase ZAP 70 (148047-34-1)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Microbiology: Bacteriology, Mycology, Parasitology and Virology (4)
  Neurology and Neurosurgery (8)
  Hematology (25)
  Immunology, Serology and Transplantation (26)
  Arthritis and Rheumatism (31)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2007428419
MEDLINE PMID
  17729038 (http://www.ncbi.nlm.nih.gov/pubmed/17729038)
PUI
  L47343356
DOI
  10.1080/08916930701464962
FULL TEXT LINK
  http://dx.doi.org/10.1080/08916930701464962
COPYRIGHT
  Copyright 2008 Elsevier B.V., All rights reserved.

RECORD 425
TITLE
  UCN-01 in combination with topotecan in patients with advanced recurrent 
ovarian cancer: A study of the Princess Margaret Hospital Phase II 
consortium
AUTHOR NAMES
  Welch S.
  Hirte H.W.
  Carey M.S.
  Hotte S.J.
  Tsao M.-S.
  Brown S.
  Pond G.R.
  Dancey J.E.
  Oza A.M.
AUTHOR ADDRESSES
  (Welch S.; Tsao M.-S.; Brown S.; Pond G.R.; Oza A.M.) Princess Margaret 
Hospital, Toronto, Ont., M56 2M9, Canada.
(Hirte H.W., hal.hirte@hrcc.on.ca; Hotte S.J.) Juravinski Cancer Centre, 699 
Concession St, Hamilton, Ont. L8V 5C2, Canada.
(Carey M.S.) London Regional Cancer Program, London, Ont. N6A 4L6, Canada.
(Dancey J.E.) Cancer Therapy Evaluation Program, National Cancer Institute, 
Bethesda, MD 20852, United States.
CORRESPONDENCE ADDRESS
  H.W. Hirte, Juravinski Cancer Centre, 699 Concession St, Hamilton, Ont. L8V 
5C2, Canada. Email: hal.hirte@hrcc.on.ca
SOURCE
  Gynecologic Oncology (2007) 106:2 (305-310). Date of Publication: August 
2007
ISSN
  0090-8258
  1095-6859 (electronic)
BOOK PUBLISHER
  Academic Press Inc., 6277 Sea Harbor Drive, Orlando, United States.
ABSTRACT
  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. 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. 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%). 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. © 2007 Elsevier Inc. All rights reserved.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  7 hydroxystaurosporine (adverse drug reaction, clinical trial, drug 
combination, drug dose, drug therapy, pharmacokinetics)
  topotecan (adverse drug reaction, clinical trial, drug combination, drug 
dose, drug therapy, intravenous drug administration)
EMTREE DRUG INDEX TERMS
  paclitaxel (clinical trial, drug combination, drug therapy)
  platinum (clinical trial, drug combination, drug therapy)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer (drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer
  aged
  anemia (side effect)
  article
  cancer fatigue (side effect)
  cancer grading
  cancer growth
  cancer pain (side effect)
  cancer recurrence
  cancer survival
  clinical article
  clinical trial
  controlled clinical trial
  controlled study
  drug dose reduction
  drug efficacy
  drug half life
  drug tolerability
  febrile neutropenia (side effect)
  female
  human
  hyperglycemia (side effect)
  infection (side effect)
  lymphocytopenia (side effect)
  multiple cycle treatment
  neutropenia (side effect)
  phase 2 clinical trial
  priority journal
  thrombocytopenia (side effect)
  treatment duration
  tumor biopsy
DRUG TRADE NAMES
  ucn 01
CAS REGISTRY NUMBERS
  7 hydroxystaurosporine (112953-11-4)
  paclitaxel (33069-62-4)
  platinum (7440-06-4)
  topotecan (119413-54-6, 123948-87-8)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2007359716
MEDLINE PMID
  17537491 (http://www.ncbi.nlm.nih.gov/pubmed/17537491)
PUI
  L47096653
DOI
  10.1016/j.ygyno.2007.02.018
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.ygyno.2007.02.018
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 426
TITLE
  Image in endocrinology: Transient hypophysitis after cytotoxic T 
lymphocyte-associated antigen 4 (CTLA4) blockade
AUTHOR NAMES
  Shaw S.A.
  Camacho L.H.
  McCutcheon I.E.
  Waguespack S.G.
AUTHOR ADDRESSES
  (Shaw S.A.; Waguespack S.G., swagues@mdanderson.org) Department of Endocrine 
Neoplasia and Hormonal Disorders, University of Texas, M. D. Anderson Cancer 
Center, Houston, TX 77030, United States.
(Camacho L.H.) Phase I Program, University of Texas, M. D. Anderson Cancer 
Center, Houston, TX 77030, United States.
(McCutcheon I.E.) Department of Neurosurgery, University of Texas, M. D. 
Anderson Cancer Center, Houston, TX 77030, United States.
(Waguespack S.G., swagues@mdanderson.org) Department of Endocrine Neoplasia 
and Hormonal Disorders, University of Texas, M.D. Anderson Cancer Center, 
1400 Holcombe Boulevard, Houston, TX 77030, United States.
CORRESPONDENCE ADDRESS
  S.G. Waguespack, Department of Endocrine Neoplasia and Hormonal Disorders, 
University of Texas, M.D. Anderson Cancer Center, 1400 Holcombe Boulevard, 
Houston, TX 77030, United States. Email: swagues@mdanderson.org
SOURCE
  Journal of Clinical Endocrinology and Metabolism (2007) 92:4 (1201-1202). 
Date of Publication: April 2007
ISSN
  0021-972X
  0021-972X (electronic)
BOOK PUBLISHER
  Endocrine Society, 8401 Connecticut Ave. Suite 900, Chevy Chase, United 
States.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (drug therapy, pharmacology)
  ticilimumab (adverse drug reaction, drug therapy, pharmacology)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  hypophysitis (side effect, side effect)
  melanoma (drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  antigen binding
  antineoplastic activity
  article
  case report
  cytotoxic T lymphocyte
  fatigue (side effect)
  follow up
  headache (side effect)
  human
  immunotherapy
  libido disorder (side effect)
  male
  nuclear magnetic resonance imaging
  priority journal
  treatment outcome
DRUG TRADE NAMES
  cp 675 206
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
EMBASE ACCESSION NUMBER
  2007171873
MEDLINE PMID
  17409339 (http://www.ncbi.nlm.nih.gov/pubmed/17409339)
PUI
  L46556385
DOI
  10.1210/jc.2006-2484
FULL TEXT LINK
  http://dx.doi.org/10.1210/jc.2006-2484
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 427
TITLE
  Ticilimumab. Anti-CTLA-4 antibody, oncolytic
AUTHOR NAMES
  Wang Y.
AUTHOR ADDRESSES
  (Wang Y.) 8106 Runnymeade Dr., Frederick, MD 21702, United States.
CORRESPONDENCE ADDRESS
  Y. Wang, 8106 Runnymeade Dr., Frederick, MD 21702, United States.
SOURCE
  Drugs of the Future (2007) 32:4 (337-340). Date of Publication: April 2007
ISSN
  0377-8282
BOOK PUBLISHER
  Prous Science, P.O. Box 540, Barcelona, Spain.
ABSTRACT
  Ticilimumab (tremelimumab, CP-675206), a fully human IgG(2) monoclonal 
antibody targeting CTLA-4, has been developed to boost the body's immune 
system to target tumor cells. Ticilimumab showed antitumor activity and an 
acceptable safety profile in preclinical studies. Phase I clinical trials 
demonstrated that it can be safely administered to patients with advanced 
melanoma at up to 15 mg/kg i.v. Dose-limiting toxicities and autoimmune 
phenomena included diarrhea, dermatitis and hypothyroidism. Antitumor 
responses in patients with melanoma who received ticilimumab were attributed 
to improved T-cell immunity. Clinical trials are ongoing in melanoma, renal 
cell carcinoma, colorectal adenocarcinoma and non-small cell lung cancer 
(NSCLC). Copyright © 2007 Prous Science.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antineoplastic agent (clinical trial, drug combination, drug comparison, 
drug concentration, drug dose, drug therapy, intravenous drug 
administration, pharmacokinetics, pharmacology)
  ticilimumab (adverse drug reaction, clinical trial, drug combination, drug 
comparison, drug concentration, drug dose, drug therapy, intravenous drug 
administration, pharmacokinetics, pharmacology)
EMTREE DRUG INDEX TERMS
  dacarbazine (clinical trial, drug comparison, drug therapy)
  interleukin 10 (endogenous compound)
  interleukin 12 (endogenous compound)
  melan A (drug combination, drug therapy)
  sunitinib (clinical trial, drug combination, drug therapy)
  temozolomide (clinical trial, drug comparison, drug therapy)
  ticilimumab
  tumor necrosis factor receptor (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  article
  cancer recurrence
  cancer survival
  cell infiltration
  cellular immunity
  clinical trial
  colorectal carcinoma (drug therapy)
  combination chemotherapy
  continuous infusion
  cytokine production
  cytotoxic T lymphocyte
  dermatitis (side effect)
  diarrhea (side effect)
  drug blood level
  drug dose escalation
  drug efficacy
  drug half life
  drug mechanism
  drug megadose
  drug safety
  drug tolerability
  gene expression
  human
  hypothyroidism (side effect)
  kidney carcinoma (drug therapy)
  melanoma (drug therapy)
  non small cell lung cancer (drug therapy)
  pruritus (side effect)
  urticaria (side effect)
DRUG TRADE NAMES
  cp 675206
CAS REGISTRY NUMBERS
  dacarbazine (4342-03-4)
  interleukin 12 (138415-13-1)
  sunitinib (341031-54-7, 557795-19-4)
  temozolomide (85622-93-1)
  ticilimumab (745013-59-6)
  tumor necrosis factor receptor (129203-93-6, 184595-01-5)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2007321887
PUI
  L47019674
DOI
  10.1358/dof.2007.032.04.1089088
FULL TEXT LINK
  http://dx.doi.org/10.1358/dof.2007.032.04.1089088
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 428
TITLE
  Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus 
in a family-based study
AUTHOR NAMES
  Graham D.S.C.
  Wong A.K.
  McHugh N.J.
  Whittaker J.C.
  Vyse T.J.
AUTHOR ADDRESSES
  (Graham D.S.C.; Wong A.K.; Vyse T.J., t.vyse@imperial.ac.uk) Imperial 
College, Molecular Genetics and Rheumatology Section, Hammersmith Hospital, 
Du Cane Road, London W12 0NN, United Kingdom.
(McHugh N.J.) Royal National Hospital for Rheumatic Diseases, Bath BA1 1RL, 
United Kingdom.
(Whittaker J.C.) Department of Epidemiology and Population Health, London 
School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, 
United Kingdom.
CORRESPONDENCE ADDRESS
  T.J. Vyse, Imperial College, Molecular Genetics and Rheumatology Section, 
Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Email: 
t.vyse@imperial.ac.uk
SOURCE
  Human Molecular Genetics (2006) 15:21 (3195-3205). Date of Publication: 1 
Nov 2006
ISSN
  0964-6906
  1460-2083 (electronic)
BOOK PUBLISHER
  Oxford University Press, Great Clarendon Street, Oxford, United Kingdom.
ABSTRACT
  CD28, CTLA4 (cytotoxic T lymphocyte-associated protein 4) and ICOS 
(inducible T cell co-stimulator) are good candidate genes for systemic lupus 
erythematosus (SLE) because of their role in regulating T cell activation. 
CTLA4 inhibits CD28-mediated T cell activation. CTLA4 is expressed on CD4+ 
and CD8+ activated T cells, and also B cells, but CD28 and ICOS are largely 
restricted to T cells. An interval encompassing the CD28-CTLA4-ICOS locus on 
chromosome 2q33 was linked to lupus in two genome-wide linkage scans. This 
large family-based association study in 532 UK SLE families represents the 
first high-density genetic screen of 80 SNPs at this locus. There are seven 
haplotype blocks across the locus. In CTLA4, the strongest signal comes from 
two variants, located 2.1 kb downstream from the 3′-UTR. These 
polymorphisms, rs231726 (SNP 43) and rs231726 (SNP 44), are in complete 
linkage disequilibrium (LD) (r(2) = 1) and are associated with SLE P = 
0.0008 (GH) and P = 0.01 (family-based association test). There is also a 
signal in the distal 3′ flanking region of CTLA4/ICOS promoter (P = 0.003). 
There was no confirmation of published associations for SLE in the promoter 
or coding region of CTLA4. These SLE risk alleles are more distal than those 
identified in Graves' disease and are in LD with Graves' disease protective 
alleles identified in both of these regions of CTLA4 (Ueda et al. 2003). 
These factors suggest an SLE-specific pattern of association. The functional 
consequences of the associated polymorphisms are likely to influence CTLA4 
expression, although it is possible that genetically modulated ICOS 
expression is involved in SLE susceptibility. © Copyright 2006 Oxford 
University Press.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  CD28 antigen (endogenous compound)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  immunoglobulin receptor (endogenous compound)
  inducible T cell costimulator (endogenous compound)
EMTREE DRUG INDEX TERMS
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gene locus
  systemic lupus erythematosus (etiology)
EMTREE MEDICAL INDEX TERMS
  3' untranslated region
  article
  controlled study
  DNA flanking region
  family study
  gene expression
  gene frequency
  gene identification
  gene linkage disequilibrium
  gene location
  genetic association
  genetic code
  genetic risk
  genetic screening
  genetic susceptibility
  genetic variability
  Graves disease
  haplotype
  human
  major clinical study
  nucleotide sequence
  priority journal
  promoter region
  signal transduction
  single nucleotide polymorphism
  United Kingdom
MOLECULAR SEQUENCE NUMBERS
  GENBANK (RS231726)
EMBASE CLASSIFICATIONS
  Human Genetics (22)
  Immunology, Serology and Transplantation (26)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2006515447
MEDLINE PMID
  17000707 (http://www.ncbi.nlm.nih.gov/pubmed/17000707)
PUI
  L44605499
DOI
  10.1093/hmg/ddl395
FULL TEXT LINK
  http://dx.doi.org/10.1093/hmg/ddl395
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 429
TITLE
  Enterocolitis in patients with cancer after antibody blockade of cytotoxic 
T-lymphocyte-associated antigen 4
AUTHOR NAMES
  Beck K.E.
  Blansfield J.A.
  Tran K.Q.
  Feldman A.L.
  Hughes M.S.
  Royal R.E.
  Kammula U.S.
  Topalian S.L.
  Sherry R.M.
  Kleiner D.
  Quezado M.
  Lowy I.
  Yellin M.
  Rosenberg S.A.
  Yang J.C.
AUTHOR ADDRESSES
  (Yang J.C., James_Yang@nih.gov) Surgery Branch, National Cancer Institute, 
National Institutes of Health, 10 Center Dr, Bethesda, MD 20892-1201, United 
States.
(Beck K.E.; Blansfield J.A.; Tran K.Q.; Feldman A.L.; Hughes M.S.; Royal 
R.E.; Kammula U.S.; Topalian S.L.; Sherry R.M.; Kleiner D.; Quezado M.; Lowy 
I.; Yellin M.; Rosenberg S.A.)
CORRESPONDENCE ADDRESS
  J.C. Yang, Surgery Branch, National Cancer Institute, National Institutes of 
Health, 10 Center Dr, Bethesda, MD 20892-1201, United States. Email: 
James_Yang@nih.gov
SOURCE
  Journal of Clinical Oncology (2006) 24:15 (2283-2289). Date of Publication: 
20 May 2006
ISSN
  0732-183X
BOOK PUBLISHER
  American Society of Clinical Oncology, 330 John Carlyle Street, Suite 300, 
Alexandria, United States.
ABSTRACT
  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. Patients and Methods: We treated 198 patients with metastatic 
melanoma (MM) or renal cell carcinoma (RCC) with ipilimumab. 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). 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 antibody (clinical trial, drug therapy, 
intravenous drug administration)
  ipilimumab (adverse drug reaction, clinical trial, drug combination, drug 
therapy, intravenous drug administration)
  monoclonal antibody (clinical trial, drug therapy)
EMTREE DRUG INDEX TERMS
  corticosteroid derivative (drug therapy)
  cytotoxic T lymphocyte antigen 4
  infliximab (drug therapy)
  steroid (drug therapy)
  tumor necrosis factor
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  enterocolitis (side effect, diagnosis, drug resistance, drug therapy, side 
effect)
  melanoma (drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  arthritis (side effect)
  article
  aseptic meningitis (side effect)
  cancer patient
  cancer regression
  clinical feature
  clinical trial
  colon biopsy
  colon perforation (complication, surgery)
  colon resection
  controlled clinical trial
  controlled study
  cytotoxic T lymphocyte
  dermatitis (side effect)
  drug dose escalation
  drug megadose
  endoscopy
  female
  hepatitis (side effect)
  histopathology
  human
  hypophysitis (side effect)
  kidney carcinoma (drug therapy)
  lymphocytic infiltration
  major clinical study
  male
  metastasis (drug therapy)
  nephritis (side effect)
  neutrophil chemotaxis
  priority journal
  randomized controlled trial
  single drug dose
  treatment duration
  treatment response
  uveitis (side effect)
DRUG TRADE NAMES
  mdx 010
CAS REGISTRY NUMBERS
  infliximab (170277-31-3)
  ipilimumab (477202-00-9)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
  Gastroenterology (48)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2007198033
MEDLINE PMID
  16710025 (http://www.ncbi.nlm.nih.gov/pubmed/16710025)
PUI
  L46630658
DOI
  10.1200/JCO.2005.04.5716
FULL TEXT LINK
  http://dx.doi.org/10.1200/JCO.2005.04.5716
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 430
TITLE
  Gateways to clinical trials
AUTHOR NAMES
  Bayés M.
  Rabasseda X.
  Prous J.R.
AUTHOR ADDRESSES
  (Bayés M., mbayes@prous.com) Prous Science, S.A., P.O. Box 540, 08080 
Barcelona, Spain.
(Rabasseda X.; Prous J.R.)
CORRESPONDENCE ADDRESS
  M. Bayés, Prous Science, S.A., P.O. Box 540, 08080 Barcelona, Spain. Email: 
mbayes@prous.com
SOURCE
  Methods and Findings in Experimental and Clinical Pharmacology (2006) 28:4 
(233-277). Date of Publication: May 2006
ISSN
  0379-0355
BOOK PUBLISHER
  Prous Science, P.O. Box 540, Barcelona, Spain.
ABSTRACT
  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/β-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. γ-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. © 2006 Prous Science. All rights reserved.
EMTREE DRUG INDEX TERMS
  acetylsalicylic acid (clinical trial, drug combination, drug therapy)
  aliskiren (clinical trial, drug therapy)
  atenolol (clinical trial, drug therapy, oral drug administration)
  caspofungin (clinical trial, drug therapy)
  cilostazol (clinical trial, drug combination, drug therapy)
  clopidogrel (clinical trial, drug combination, drug therapy)
  conivaptan (clinical trial, drug therapy, intravenous drug administration, 
oral drug administration)
  diuretic agent (clinical trial, drug combination, drug therapy, intravenous 
drug administration)
  etoricoxib (clinical trial, drug therapy, oral drug administration)
  glyceryl trinitrate (clinical trial, drug combination, drug therapy, 
intravenous drug administration)
  heparin (clinical trial, drug therapy, intravenous drug administration)
  immunoglobulin (clinical trial, drug therapy, intravenous drug 
administration)
  ivabradine (clinical trial, drug therapy, oral drug administration)
  levocetirizine (clinical trial, drug therapy, oral drug administration)
  mepolizumab (clinical trial, drug therapy, intravenous drug administration)
  nesiritide (clinical trial, drug therapy, intravenous drug administration)
  paclitaxel (clinical trial, drug combination, drug therapy)
  pegaptanib (clinical trial)
  placebo
  prasterone (clinical trial, drug therapy)
  prasugrel (clinical trial, drug combination, drug therapy)
  ranibizumab (clinical trial)
  rapamycin (clinical trial, drug therapy)
  recombinant erythropoietin (clinical trial, drug therapy, subcutaneous drug 
administration)
  recombinant erythropoietin (clinical trial, drug therapy, subcutaneous drug 
administration)
  tadalafil (clinical trial, drug therapy)
  tecadenoson (clinical trial, drug therapy, intravenous drug administration)
  tg 100115 (clinical trial, drug therapy)
  unclassified drug
  unindexed drug
  urodilatin (clinical trial, drug therapy, intravenous drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  drug research
EMTREE MEDICAL INDEX TERMS
  anemia (drug therapy)
  angina pectoris (drug therapy)
  asthma (drug therapy)
  atherosclerosis (drug therapy)
  cardiovascular disease (drug therapy, therapy)
  clinical trial
  congestive heart failure (drug therapy)
  conjunctivitis (drug therapy)
  coronary artery disease (drug therapy)
  diabetes mellitus (drug therapy)
  drug eluting stent
  eczema (drug therapy)
  edema
  eosinophilia (drug resistance)
  erectile dysfunction (drug therapy)
  eye allergy (drug therapy)
  granulomatosis (drug therapy)
  heart failure (drug therapy)
  heart infarction (drug therapy)
  hemophilia
  human
  hypereosinophilic syndrome (drug therapy)
  hypertension (drug therapy)
  hyponatremia (drug therapy)
  hypopituitarism (drug therapy)
  ischemia (drug therapy)
  macular degeneration
  neutropenia (drug therapy)
  percutaneous transluminal angioplasty
  retinopathy
  review
  rhinitis (drug therapy)
  subretinal neovascularization
  tachycardia (drug therapy)
  urticaria (drug therapy)
  vasculitis (drug therapy)
  Wegener granulomatosis (drug therapy)
DRUG TRADE NAMES
  aspirin
  tg 100115
CAS REGISTRY NUMBERS
  acetylsalicylic acid (493-53-8, 50-78-2, 53663-74-4, 53664-49-6, 63781-77-1)
  aliskiren (173334-57-1, 173334-58-2, 173399-03-6)
  atenolol (29122-68-7)
  caspofungin (189768-38-5)
  cilostazol (73963-72-1)
  clopidogrel (113665-84-2, 120202-66-6, 90055-48-4, 94188-84-8)
  conivaptan (168626-94-6, 210101-16-9)
  etoricoxib (202409-33-4, 202409-40-3)
  glyceryl trinitrate (55-63-0)
  heparin (37187-54-5, 8057-48-5, 8065-01-8, 9005-48-5)
  immunoglobulin (9007-83-4)
  ivabradine (148849-67-6, 148870-80-8, 155974-00-8)
  levocetirizine (130018-77-8)
  mepolizumab (196078-29-2)
  nesiritide (124584-08-3, 189032-40-4)
  paclitaxel (33069-62-4)
  pegaptanib (222716-86-1)
  prasterone (53-43-0)
  prasugrel (389574-19-0)
  ranibizumab (347396-82-1)
  rapamycin (53123-88-9)
  recombinant erythropoietin (113427-24-0, 122312-54-3, 130455-76-4, 
879555-13-2)
  tadalafil (171596-29-5)
  tecadenoson (204512-90-3)
  urodilatin (115966-23-9)
EMBASE CLASSIFICATIONS
  General Pathology and Pathological Anatomy (5)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2006324391
MEDLINE PMID
  16801985 (http://www.ncbi.nlm.nih.gov/pubmed/16801985)
PUI
  L44013394
COPYRIGHT
  Copyright 2011 Elsevier B.V., All rights reserved.

RECORD 431
TITLE
  Testicular germ cell tumours: The paradigm of chemo-sensitive solid tumours
AUTHOR NAMES
  Di Pietro A.
  De Vries E.G.E.
  Gietema J.A.
  Spierings D.C.J.
  De Jong S.
AUTHOR ADDRESSES
  (Di Pietro A.; De Vries E.G.E.; Gietema J.A.; Spierings D.C.J.; De Jong S., 
s.de.jong@int.umcg.nl) Department of Medical Oncology, University of 
Groningen, University Medical Center Groningen, 9713 GZ Hanzeplein 1, 
Groningen, Netherlands.
(Di Pietro A.) Oncology Residency School, Università Cattolica Del Sacro 
Cuore, Rome, Italy.
CORRESPONDENCE ADDRESS
  S. De Jong, Department of Medical Oncology, University of Groningen, 
University Medical Center Groningen, 9713 GZ Hanzeplein 1, Groningen, 
Netherlands. Email: s.de.jong@int.umcg.nl
SOURCE
  International Journal of Biochemistry and Cell Biology (2005) 37:12 
(2437-2456). Date of Publication: December 2005
ISSN
  1357-2725
BOOK PUBLISHER
  Elsevier Ltd, Langford Lane, Kidlington, Oxford, United Kingdom.
ABSTRACT
  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. © 2005 Elsevier Ltd. All rights reserved.
EMTREE DRUG INDEX TERMS
  alkylating agent
  antineoplastic agent (pharmacology)
  bleomycin (pharmacology)
  camptothecin (pharmacology)
  cisplatin (pharmacology)
  cytotoxic agent (pharmacology)
  death receptor
  doxorubicin (pharmacology)
  imatinib
  melphalan (pharmacology)
  protein MDM2
  protein p21
  protein p53
  taxane derivative (pharmacology)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  chemosensitivity
  germ cell tumor (epidemiology)
  solid malignant neoplasm (epidemiology)
  testis cancer
EMTREE MEDICAL INDEX TERMS
  apoptosis
  cancer chemotherapy
  cause of death
  cell cycle G1 phase
  cell cycle S phase
  DNA damage
  drug efficacy
  drug mechanism
  genetics
  germ cell
  human
  male
  metastasis
  mitochondrion
  nonhuman
  protein expression
  protein function
  regulatory mechanism
  review
  transactivation
  wild type
DRUG TRADE NAMES
  gleevec
CAS REGISTRY NUMBERS
  bleomycin (11056-06-7)
  camptothecin (7689-03-4)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  doxorubicin (23214-92-8, 25316-40-9)
  imatinib (152459-95-5, 220127-57-1)
  melphalan (148-82-3)
  protein p21 (85306-28-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Urology and Nephrology (28)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2005445876
MEDLINE PMID
  16099193 (http://www.ncbi.nlm.nih.gov/pubmed/16099193)
PUI
  L41400315
DOI
  10.1016/j.biocel.2005.06.014
FULL TEXT LINK
  http://dx.doi.org/10.1016/j.biocel.2005.06.014
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 432
TITLE
  Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune 
hypophysitis in patients with metastatic melanoma and renal cancer
AUTHOR NAMES
  Blansfield J.A.
  Beck K.E.
  Tran K.
  Yang J.C.
  Hughes M.S.
  Kammula U.S.
  Royal R.E.
  Topalian S.L.
  Haworth L.R.
  Levy C.
  Rosenberg S.A.
  Sherry R.M.
AUTHOR ADDRESSES
  (Blansfield J.A.; Beck K.E.; Tran K.; Yang J.C.; Hughes M.S.; Kammula U.S.; 
Royal R.E.; Topalian S.L.; Haworth L.R.; Levy C.; Rosenberg S.A.; Sherry 
R.M., Richard_Sherry@nih.gov) Surgery Branch, National Cancer Institute, 
National Institutes of Health, Bethesda, MD, United States.
(Sherry R.M., Richard_Sherry@nih.gov) Surgery Branch, National Cancer 
Institute, National Institutes of Health CRC, 10 Center Drive, Bethesda, MD 
20892-1201, United States.
CORRESPONDENCE ADDRESS
  R.M. Sherry, Surgery Branch, National Cancer Institute, National Institutes 
of Health CRC, 10 Center Drive, Bethesda, MD 20892-1201, United States. 
Email: Richard_Sherry@nih.gov
SOURCE
  Journal of Immunotherapy (2005) 28:6 (593-598). Date of Publication: 
November/December 2005
ISSN
  1524-9557
BOOK PUBLISHER
  Lippincott Williams and Wilkins, 530 Walnut Street, Philadelphia, United 
States.
ABSTRACT
  Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an immunoregulatory 
molecule expressed by activated T cells and resting CD4(+)CD25 (+) T cells. 
In patients with advanced melanoma, our group reported that administration 
of anti-CTLA-4 antibody mediated objective cancer regression in 13% of 
patients. This study also established that the blockade of CTLA-4 was 
associated with grade III/IV autoimmune manifestations that included 
dermatitis, enterocolitis, hepatitis, uveitis, and a single case of 
hypophysitis. Since this initial report, 7 additional patients with 
anti-CTLA-4 antibody-induced autoimmune hypophysitis have been accumulated. 
The characteristics, clinical course, laboratory values, radiographic 
findings, and treatment of these 8 patients are the focus of this report. 
Copyright © 2005 by Lippincott Williams & Wilkins.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  monoclonal antibody (adverse drug reaction, clinical trial, drug therapy, 
pharmacology)
EMTREE DRUG INDEX TERMS
  CD4 antigen (endogenous compound)
  corticotropin (endogenous compound)
  cytotoxic T lymphocyte antigen 4 monoclonal antibody (adverse drug reaction, 
clinical trial, drug therapy, pharmacology)
  hormone (drug therapy)
  hydrocortisone (endogenous compound)
  interleukin 2 (drug therapy)
  interleukin 2 receptor alpha (endogenous compound)
  ipilimumab
  steroid (drug therapy)
  testosterone (endogenous compound)
  thyrotropin (endogenous compound)
  thyroxine (endogenous compound)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmune disease (drug therapy, side effect)
  hypophysitis (drug therapy, side effect)
  kidney cancer (drug therapy)
  melanoma (drug therapy)
  metastasis (complication, drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  advanced cancer (drug therapy)
  article
  cancer immunotherapy
  cancer regression
  clinical feature
  clinical trial
  controlled clinical trial
  controlled study
  dermatitis (side effect)
  disease course
  enterocolitis (side effect)
  female
  hepatitis (side effect)
  human
  laboratory diagnosis
  lymphocyte activation
  major clinical study
  male
  priority journal
  radiography
  uveitis (side effect)
DRUG TRADE NAMES
  mdx 010  Medarex

DRUG MANUFACTURERS
  Medarex
CAS REGISTRY NUMBERS
  corticotropin (11136-52-0, 9002-60-2, 9061-27-2)
  hydrocortisone (50-23-7)
  interleukin 2 (85898-30-2)
  ipilimumab (477202-00-9)
  testosterone (58-22-0)
  thyrotropin (9002-71-5)
  thyroxine (7488-70-2)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Urology and Nephrology (28)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2005487280
MEDLINE PMID
  16224277 (http://www.ncbi.nlm.nih.gov/pubmed/16224277)
PUI
  L41533093
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 433
TITLE
  A dominant interfering Bub1 mutant is insufficient to induce or alter thymic 
tumorigenesis in vivo, even in a sensitized genetic background
AUTHOR NAMES
  Cowley D.O.
  Muse G.W.
  Van Dyke T.
AUTHOR ADDRESSES
  (Cowley D.O.; Muse G.W.; Van Dyke T., tvdlab@med.unc.edu) Department of 
Genetics, Lineberger Comprehensive Cancer Center, University of North 
Carolina, Chapel Hill, NC 27599, United States.
(Van Dyke T., tvdlab@med.unc.edu) Lineberger Comprehensive Cancer Center, 
University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, 
NC 27599, United States.
CORRESPONDENCE ADDRESS
  T. Van Dyke, Lineberger Comprehensive Cancer Center, University of North 
Carolina, Chapel Hill School of Medicine, Chapel Hill, NC 27599, United 
States. Email: tvdlab@med.unc.edu
SOURCE
  Molecular and Cellular Biology (2005) 25:17 (7796-7802). Date of 
Publication: September 2005
ISSN
  0270-7306
BOOK PUBLISHER
  American Society for Microbiology, 1752 N Street N.W., Washington, United 
States.
ABSTRACT
  Aneuploidy is a common feature of human tumors, often correlating with poor 
prognosis. The mitotic spindle checkpoint is thought to play a major role in 
aneuploidv suppression. To investigate the role of the spindle checkpoint in 
tumor suppression in vivo, we developed transgenic mice in which thymocytes 
express a dominant interfering fragment of Bubl, a kinase regulator of the 
spindle checkpoint. We report that, despite high-level expression of 
dominant-negative Bub1 (Bub1DN), a protein known to inhibit spindle 
checkpoint activity in cultured cells, thymocytes show no evidence of 
spindle checkpoint impairment. Transgenic animals also failed to show an 
increased predisposition to spontaneous tumors. Moreover, the Bub1DN 
transgene failed to alter the timing or characteristics of thymic lymphoma 
development in p53 heterozygous or homozygous null backgrounds, indicating 
that the lack of tumorigenesis is not due to suppression by p53-dependent 
checkpoints. These results indicate that overexpression of a Bub1 N-terminal 
fragment is insufficient to impair the spindle checkpoint in vivo or to 
drive tumorigenesis in the highly susceptible murine thymocyte system, 
either alone or in combination with G(1) checkpoint disruption. Copyright © 
2005, American Society for Microbiology. All Rights Reserved.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  Bub1 protein
  phosphotransferase
EMTREE DRUG INDEX TERMS
  mutant protein
  protein p53
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  carcinogenesis
  gene mutation
  genetic predisposition
  thymoma (etiology)
EMTREE MEDICAL INDEX TERMS
  amino terminal sequence
  aneuploidy
  animal cell
  animal experiment
  animal model
  animal tissue
  article
  cancer inhibition
  cell cycle G1 phase
  controlled study
  embryo
  heterozygosity
  homozygosity
  human
  human cell
  in vivo study
  mitosis spindle
  mouse
  nonhuman
  priority journal
  prognosis
  protein expression
  thymocyte
  transgenic mouse
  tumor suppressor gene
CAS REGISTRY NUMBERS
  phosphotransferase (9031-09-8, 9031-44-1)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Human Genetics (22)
  Clinical and Experimental Biochemistry (29)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2005377774
MEDLINE PMID
  16107724 (http://www.ncbi.nlm.nih.gov/pubmed/16107724)
PUI
  L41170139
DOI
  10.1128/MCB.25.17.7796-7802.2005
FULL TEXT LINK
  http://dx.doi.org/10.1128/MCB.25.17.7796-7802.2005
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 434
TITLE
  Pituitary tumour transforming gene (PTTG) induces genetic instability in 
thyroid cells
AUTHOR NAMES
  Kim D.S.
  Pemberton H.
  Stratford A.L.
  Buelaert K.
  Watkinson J.C.
  Lopes V.
  Franklyn J.A.
  McCabe C.J.
AUTHOR ADDRESSES
  (Kim D.S., daekim72@yahoo.co.uk; Pemberton H.; Stratford A.L.; Buelaert K.; 
Watkinson J.C.; Lopes V.; Franklyn J.A.; McCabe C.J.) Division of Medical 
Sciences, IBR, University of Birmingham, Edgbaston, Birmingham B12 5TT, 
United Kingdom.
CORRESPONDENCE ADDRESS
  D.S. Kim, Division of Medical Sciences, IBR, University of Birmingham, 
Edgbaston, Birmingham B12 5TT, United Kingdom. Email: daekim72@yahoo.co.uk
SOURCE
  Oncogene (2005) 24:30 (4861-4866). Date of Publication: 14 Jul 2005
ISSN
  0950-9232
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  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 (R(2) = 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 μg DNA/six-well plate) PTTG = 15.3% ± 1.7 versus high 
dose (3 μg 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. © 2005 Nature Publishing 
Group. All rights reserved.
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  genetic stability
  hypophysis tumor
  thyroid cell
EMTREE MEDICAL INDEX TERMS
  article
  blood sampling
  DNA damage
  gene
  gene expression regulation
  gene induction
  gene mutation
  human
  human cell
  mutator gene
  polymerase chain reaction
  priority journal
  pttg gene
  thyroid cancer
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  General Pathology and Pathological Anatomy (5)
  Human Genetics (22)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2005345812
MEDLINE PMID
  15897900 (http://www.ncbi.nlm.nih.gov/pubmed/15897900)
PUI
  L41076304
DOI
  10.1038/sj.onc.1208659
FULL TEXT LINK
  http://dx.doi.org/10.1038/sj.onc.1208659
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 435
TITLE
  Survivin expression in pituitary adenomas
AUTHOR NAMES
  Wasko R.
  Jankowska A.
  Waligorska-Stachura J.
  Andrusiewicz M.
  Jaskula M.
  Sowinski J.
AUTHOR ADDRESSES
  (Wasko R., rwasko@amp.edu.pl; Waligorska-Stachura J.; Jaskula M.; Sowinski 
J.) University of Medical Sciences, Department of Endocrinology, Metabolism 
and Internal Diseases, ul. Przybyszewskiego 49, 60-355 Poznan, Poland.
(Jankowska A.; Andrusiewicz M.) University of Medical Sciences, Department 
of Radiobiology and Cell Biology, ul. Przybyszewskiego 49, 60-355 Poznan, 
Poland.
CORRESPONDENCE ADDRESS
  R. Wasko, University of Medical Sciences, Department of Endocrinology, 
Metabolism and Internal Diseases, ul. Przybyszewskiego 49, 60-355 Poznan, 
Poland. Email: rwasko@amp.edu.pl
SOURCE
  Neuroendocrinology Letters (2005) 26:3 (209-212). Date of Publication: June 
2005
ISSN
  0172-780X
BOOK PUBLISHER
  Maghira and Maas Publications, P.O. Box 26132, Stockholm, Sweden.
ABSTRACT
  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. 
Objectives: The aim of our study was to determine the survivin expression in 
different types of pituitary adenomas. 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. 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. Conclusions: Based on these findings, we conclude that the 
estimation of survivin expression in human pituitary tumours may help 
predict tumour growth and prognosis. © Neuroendocrinology Letters.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  survivin (endogenous compound)
EMTREE DRUG INDEX TERMS
  complementary DNA (endogenous compound)
  long acting drug (drug therapy)
  messenger RNA (endogenous compound)
  octreotide (drug therapy)
  tumor antigen (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gene expression
  hypophysis adenoma (diagnosis, drug therapy, surgery)
EMTREE MEDICAL INDEX TERMS
  acromegaly
  article
  clinical article
  clinical feature
  controlled study
  DNA synthesis
  gene amplification
  human
  human tissue
  hypophysis function
  malignant transformation
  nucleotide sequence
  prediction
  preoperative care
  prognosis
  prolactinoma (diagnosis, surgery)
  reverse transcription polymerase chain reaction
  RNA extraction
  tumor classification
  tumor growth
DRUG TRADE NAMES
  sandostatin
CAS REGISTRY NUMBERS
  octreotide (83150-76-9)
  survivin (195263-98-0)
MOLECULAR SEQUENCE NUMBERS
  GENBANK (AF077350, X00351)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Neurology and Neurosurgery (8)
  Cancer (16)
  Human Genetics (22)
  Clinical and Experimental Biochemistry (29)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2005313945
MEDLINE PMID
  15990723 (http://www.ncbi.nlm.nih.gov/pubmed/15990723)
PUI
  L40975098
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 436
TITLE
  Osteogenic PTHs and vascular ossification - Is there a danger for 
osteoporotics?
AUTHOR NAMES
  Whitfield J.F.
AUTHOR ADDRESSES
  (Whitfield J.F., pthosteo@rogers.com) Institute for Biological Sciences, 
National Research Council of Canada, Montreal Road Campus, Ottawa, Ont. K1A 
0R6, Canada.
CORRESPONDENCE ADDRESS
  J.F. Whitfield, Institute for Biological Sciences, National Research Council 
of Canada, Montreal Road Campus, Ottawa, Ont. K1A 0R6, Canada. Email: 
pthosteo@rogers.com
SOURCE
  Journal of Cellular Biochemistry (2005) 95:3 (437-444). Date of Publication: 
1 Jun 2005
ISSN
  0730-2312
BOOK PUBLISHER
  Wiley-Liss Inc., 111 River Street, Hoboken, United States.
ABSTRACT
  Inflammation in vascular (mostly arterial) walls and heart valves triggered 
bythetrans-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 
(Forteo™), 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 G(1)/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. © 
2005 Wiley-Liss, Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  parathyroid hormone (endogenous compound)
EMTREE DRUG INDEX TERMS
  low density lipoprotein
  parathyroid hormone receptor 1 (endogenous compound)
  parathyroid hormone receptor 2 (endogenous compound)
  parathyroid hormone[1-34]
  retinoblastoma protein (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  blood vessel calcification
  ossification
  osteoporosis
EMTREE MEDICAL INDEX TERMS
  animal model
  atheroma
  cardiovascular disease
  cell cycle G1 phase
  cell cycle S phase
  cell differentiation
  cell proliferation
  diabetes mellitus
  fibroblast
  heart valve
  human
  inflammation
  mouse
  nonhuman
  nuclear localization signal
  osteoblast
  pericyte
  priority journal
  protein expression
  protein phosphorylation
  receptor upregulation
  review
  vascular smooth muscle
DRUG TRADE NAMES
  forteo  Lilly

DRUG MANUFACTURERS
  Lilly
CAS REGISTRY NUMBERS
  parathyroid hormone (12584-96-2, 68893-82-3, 9002-64-6)
  parathyroid hormone[1-34] (12583-68-5, 52232-67-4)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Cardiovascular Diseases and Cardiovascular Surgery (18)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2005454317
MEDLINE PMID
  15786490 (http://www.ncbi.nlm.nih.gov/pubmed/15786490)
PUI
  L41420174
DOI
  10.1002/jcb.20424
FULL TEXT LINK
  http://dx.doi.org/10.1002/jcb.20424
COPYRIGHT
  Copyright 2012 Elsevier B.V., All rights reserved.

RECORD 437
TITLE
  Histone deacetylase inhibitors induce G(2)-checkpoint arrest and apoptosis 
in cisplatinum-resistant ovarian cancer cells associated with overexpression 
of the Bcl-2-related protein Bad
AUTHOR NAMES
  Strait K.A.
  Warnick C.T.
  Ford C.D.
  Dabbas B.
  Hammond E.H.
  Ilstrup S.J.
AUTHOR ADDRESSES
  (Strait K.A., ldkstrai@ihc.com; Ford C.D.) Department of Medicine, 
Laboratory for Molecular Oncology, LDS Hospital, 325 8th Avenue, Salt Lake 
City, UT 84143, United States.
(Warnick C.T.; Dabbas B.; Hammond E.H.; Ilstrup S.J.) Department of 
Pathology, Laboratory for Molecular Oncology, LDS Hospital, 325 8th Avenue, 
Salt Lake City, UT 84143, United States.
CORRESPONDENCE ADDRESS
  K.A. Strait, Cancer Research Laboratory, Department of Medicine, LDS 
Hospital, 325 8th Avenue, Salt Lake City, UT 84143, United States. Email: 
ldkstrai@ihc.com
SOURCE
  Molecular Cancer Therapeutics (2005) 4:4 (603-611). Date of Publication: 
April 2005
ISSN
  1535-7163
BOOK PUBLISHER
  American Association for Cancer Research Inc., 150 South Independence Mall 
West, Philadelphia, United States.
ABSTRACT
  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 G(1), 
resulting in predominant G(2)-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 G(1) 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 call cycle arrest from the G(1) to the G(2) checkpoint and reactivation 
of the intrinsic mitochondrial apoptotic cascade. Copyright © 2005 American 
Association for Cancer Research.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  protein BAD (endogenous compound)
  trichostatin A (drug comparison, pharmacology)
EMTREE DRUG INDEX TERMS
  cisplatin (pharmacology)
  hexamethylenebisacetamide (drug comparison, pharmacology)
  histone deacetylase (endogenous compound)
  histone deacetylase inhibitor (drug comparison, pharmacology)
  lipocortin 5
  protein bcl 2 (endogenous compound)
  protein p53 (endogenous compound)
  tacedinaline (drug comparison, pharmacology)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary cancer
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  apoptosis
  article
  cancer cell culture
  cancer resistance
  cell cycle G1 phase
  cell cycle G2 phase
  cell differentiation
  cell junction
  cell ultrastructure
  cell viability
  controlled study
  drug exposure
  drug sensitivity
  enzyme inhibition
  fibroblast
  human
  human cell
  microvillus
  mitochondrion
  mitosis inhibition
  phenotype
  priority journal
  protein expression
  protein induction
  Western blotting
DRUG TRADE NAMES
  ci 994  , United StatesPfizer

DRUG MANUFACTURERS
   (United States)Calbiochem
   (United States)Pfizer
   (United States)Sigma
CAS REGISTRY NUMBERS
  4 n acetyldinaline (112522-64-2)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  hexamethylenebisacetamide (3073-59-4)
  histone deacetylase (9076-57-7)
  lipocortin 5 (111237-10-6)
  protein bcl 2 (219306-68-0)
  trichostatin A (58880-19-6)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Clinical and Experimental Biochemistry (29)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2005200013
MEDLINE PMID
  15827334 (http://www.ncbi.nlm.nih.gov/pubmed/15827334)
PUI
  L40601842
DOI
  10.1158/1535-7163.MCT-04-0107
FULL TEXT LINK
  http://dx.doi.org/10.1158/1535-7163.MCT-04-0107
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 438
TITLE
  Mechanisms underlying the synergistic effect of SU5416 and cisplatin on 
cytotoxicity in human ovarian tumor cells.
AUTHOR NAMES
  Zhong X.
  Li X.
  Wang G.
  Zhu Y.
  Hu G.
  Zhao J.
  Neace C.
  Ding H.
  Reed E.
  Li Q.Q.
AUTHOR ADDRESSES
  (Zhong X.; Li X.; Wang G.; Zhu Y.; Hu G.; Zhao J.; Neace C.; Ding H.; Reed 
E.; Li Q.Q.) 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.
CORRESPONDENCE ADDRESS
  X. Zhong, 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.
SOURCE
  International journal of oncology (2004) 25:2 (445-451). Date of 
Publication: Aug 2004
ISSN
  1019-6439
ABSTRACT
  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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  angiogenesis inhibitor (drug therapy, drug toxicity, pharmacology)
  antineoplastic agent (drug therapy, drug toxicity, pharmacology)
  cisplatin (drug therapy, drug toxicity, pharmacology)
  indole derivative (drug therapy, drug toxicity, pharmacology)
  pyrrole derivative (drug therapy, drug toxicity, pharmacology)
EMTREE DRUG INDEX TERMS
  CDKN1A protein, human
  cell cycle protein
  cyclin dependent kinase inhibitor 1A
  cyclin dependent kinase inhibitor 1B
  I kappa B
  I kappa B kinase alpha
  I kappa B kinase alpha
  mitogen activated protein kinase kinase
  mitogen activated protein kinase kinase 4
  oncoprotein
  protein p53
  semaxanib
  stress activated protein kinase
  transcription factor AP 1
  tumor suppressor protein
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  ovary tumor (drug therapy)
EMTREE MEDICAL INDEX TERMS
  apoptosis
  article
  cell line
  drug potentiation
  female
  human
  metabolism
  upregulation
CAS REGISTRY NUMBERS
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  mitogen activated protein kinase kinase (142805-58-1)
  semaxanib (186610-95-7)
  stress activated protein kinase (155215-87-5)
LANGUAGE OF ARTICLE
  English
MEDLINE PMID
  15254743 (http://www.ncbi.nlm.nih.gov/pubmed/15254743)
PUI
  L39687807
COPYRIGHT
  MEDLINE® is the source for the citation and abstract of this record.

RECORD 439
TITLE
  The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ 
regulatory T cells.
AUTHOR NAMES
  Boden E.
  Tang Q.
  Bour-Jordan H.
  Bluestone J.A.
AUTHOR ADDRESSES
  (Boden E.; Tang Q.; Bour-Jordan H.; Bluestone J.A.) UCSF Diabetes Center, 
University of California, San Francisco, 513 Parnassus Avenue, Box 0540, HSW 
Room 1114, San Francisco, CA 94143-0540, USA.
CORRESPONDENCE ADDRESS
  E. Boden, UCSF Diabetes Center, University of California, San Francisco, 513 
Parnassus Avenue, Box 0540, HSW Room 1114, San Francisco, CA 94143-0540, 
USA.
SOURCE
  Novartis Foundation symposium (2003) 252 (55-63; discussion 63-66, 106-114). 
Date of Publication: 2003
ISSN
  1528-2511
ABSTRACT
  CD4+CD25+ T cells regulate a variety of autoimmune and alloimmune responses 
including the development of autoimmune diabetes in non-obese diabetic (NOD) 
mice. We have examined the role of CD28/CTLA4/B7 interactions in the 
expansion and survival of CD4+CD25+ regulatory T cells (T(reg)) in this 
setting. CD28/ B7 interactions are essential in the development of T(reg) in 
the thymus and for their survival in the periphery. The CD28-mediated 
homeostasis of these cells is independent of Il2, OX40, CD40L, and survival 
factor Bcl-XI. In addition, analysis of T(reg) from CTLA4-deficient mice 
suggests that CTLA4 expression is not required for their development or 
function. However, non-activating anti-CTLA4 antibodies blocked the 
suppressor activity of regulatory cells in vitro. Thus, clinical application 
of co-stimulatory blockade using agents such as CTLA4Ig in the treatment of 
autoimmune disease may result in complicated outcomes.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  CD28 antigen
  CD4 antigen
  differentiation antigen
  interleukin 2 receptor
EMTREE DRUG INDEX TERMS
  cytotoxic T lymphocyte antigen 4
  cytotoxic T lymphocyte antigen 4
  leukocyte antigen
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  T lymphocyte
EMTREE MEDICAL INDEX TERMS
  animal
  gene deletion
  genetics
  homeostasis
  human
  immunology
  insulin dependent diabetes mellitus
  mouse
  mouse mutant
  nude mouse
  review
LANGUAGE OF ARTICLE
  English
MEDLINE PMID
  14609212 (http://www.ncbi.nlm.nih.gov/pubmed/14609212)
PUI
  L137593247
COPYRIGHT
  MEDLINE® is the source for the citation and abstract of this record.

RECORD 440
TITLE
  CTLA-4 AT-Repeat Polymorphism Reduces the Inhibitory Function of CTLA-4 in 
Graves' Disease
AUTHOR NAMES
  Takara M.
  Kouki T.
  DeGroot L.J.
AUTHOR ADDRESSES
  (Takara M.; Kouki T.; DeGroot L.J., ldegroot@medicine.bsd.uchicago.edu) 
Thyroid Study Unit/MC3090, Department of Medicine, University of Chicago, 
Chicago, IL, United States.
(DeGroot L.J., ldegroot@medicine.bsd.uchicago.edu) Thyroid Study Unit, Mail 
Code 3090, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 
60637, United States.
CORRESPONDENCE ADDRESS
  L.J. DeGroot, Thyroid Study Unit, Mail Code 3090, University of Chicago, 
5841 South Maryland Avenue, Chicago, IL 60637, United States. Email: 
ldegroot@medicine.bsd.uchicago.edu
SOURCE
  Thyroid (2003) 13:12 (1083-1089). Date of Publication: December 2003
ISSN
  1050-7256
BOOK PUBLISHER
  Mary Ann Liebert Inc., 140 Huguenot Street, New Rochelle, United States.
ABSTRACT
  Graves' disease (GD) is thought to be an autoimmune disease with a strong 
genetic component. Candidate genes include human leukocyte antigen (HLA) 
class II genes and CTLA-4. The CTLA-4 gene has a variable length AT-repeat 
polymorphism in the 3′-untranslated region. We previously found that the 
AT-repeat of 104 bp or longer was associated with GD. In this study, we 
categorized patients with GD and normal controls (NC) by genotyping the 
CTLA-4 AT-repeat and investigated the function of CTLA-4. Peripheral blood 
mononuclear cells (PBMC) and DNA were prepared from adult Caucasians (NC = 
34, GD = 37). Genotypes of the AT-repeat polymorphism were divided into 
three groups according to their alleles. We related the CTLA-4 polymorphism 
in each genotype to augmentation of T-cell proliferation induced by a 
soluble anti-CTLA-4 antibody during incubation with irradiated Epstein-Barr 
virus (EBV)-transformed B cells. Proliferation of T cells from subjects with 
the 86/86 bp (shorter) allele was less than T cells from patients with 
longer alleles. The length of the AT-repeat allele correlated inversely with 
augmentation of proliferation after CTLA-4 blockade in subjects with GD. The 
CTLA-4 AT-repeat polymorphism affects the inhibitory function of CTLA-4. The 
long AT-repeat allele is associated with reduced control of T-cell 
proliferation and thus contributes to the pathogenesis of GD.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
EMTREE DRUG INDEX TERMS
  DNA (endogenous compound)
  HLA antigen class 2 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  CTLA 4 gene
  gene
  genetic polymorphism
  Graves disease (etiology)
EMTREE MEDICAL INDEX TERMS
  3' untranslated region
  adult
  allele
  antigen function
  article
  autoimmune disease
  B lymphocyte
  clinical article
  controlled study
  genotype
  human
  human cell
  lymphocyte proliferation
  pathogenesis
  peripheral blood mononuclear cell
  priority journal
  T lymphocyte
CAS REGISTRY NUMBERS
  DNA (9007-49-2)
EMBASE CLASSIFICATIONS
  Endocrinology (3)
  Human Genetics (22)
  Immunology, Serology and Transplantation (26)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2004012266
MEDLINE PMID
  14751028 (http://www.ncbi.nlm.nih.gov/pubmed/14751028)
PUI
  L38032393
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 441
TITLE
  Cancer regression and autoimmunity induced by cytotoxic T 
lymphocyte-associated antigen 4 blockade in patients with metastatic 
melanoma
AUTHOR NAMES
  Phan G.Q.
  Yang J.C.
  Sherry R.M.
  Hwu P.
  Topalian S.L.
  Schwartzentruber D.J.
  Restifo N.P.
  Haworth L.R.
  Seipp C.A.
  Freezer L.J.
  Morton K.E.
  Mavroukakis S.A.
  Duray P.H.
  Steinberg S.M.
  Allison J.P.
  Davis T.A.
  Rosenberg S.A.
AUTHOR ADDRESSES
  (Phan G.Q.; Yang J.C.; Sherry R.M.; Hwu P.; Topalian S.L.; Schwartzentruber 
D.J.; Restifo N.P.; Haworth L.R.; Seipp C.A.; Freezer L.J.; Morton K.E.; 
Mavroukakis S.A.; Rosenberg S.A., sar@nih.gov) Surgery Branch, National 
Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United 
States.
(Duray P.H.) Laboratory of Pathology, National Cancer Institute, National 
Institutes of Health, Bethesda, MD 20892, United States.
(Steinberg S.M.) Biostatist./Data Management Section, National Cancer 
Institute, National Institutes of Health, Bethesda, MD 20892, United States.
(Allison J.P.) Howard Hughes Medical Institute, Dept. of Molecular and Cell 
Biology, University of California, Berkeley, CA 94720, United States.
(Davis T.A.) Medarex, Inc., Princeton, NJ 08540, United States.
CORRESPONDENCE ADDRESS
  S.A. Rosenberg, Surgery Branch, National Cancer Institute, National 
Institutes of Health, Bethesda, MD 20892, United States. Email: sar@nih.gov
SOURCE
  Proceedings of the National Academy of Sciences of the United States of 
America (2003) 100:14 (8372-8377). Date of Publication: 8 Jul 2003
ISSN
  0027-8424
BOOK PUBLISHER
  National Academy of Sciences, 2101 Constitution Avenue NW, Washington, 
United States.
ABSTRACT
  Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical 
immunoregulatory molecule (expressed on activated T cells and a subset of 
regulatory T cells) capable of down-regulating T cell activation. Blockade 
of CTLA-4 has been shown in animal models to improve the effectiveness of 
cancer immunotherapy. We thus treated 14 patients with metastatic melanoma 
by using serial i.v. administration of a fully human anti-CTLA-4 antibody 
(MDX-010) in conjunction with s.c. vaccination with two modified 
HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, 
gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced 
grade III/IV autoimmune manifestations in six patients (43%), including 
dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated 
objective cancer regression in three patients (21%; two complete and one 
partial responses). This study establishes CTLA-4 as an important molecule 
regulating tolerance to "self" antigens in humans and suggests a role for 
CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer 
immunotherapy.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cytotoxic T lymphocyte antigen 4 (adverse drug reaction, drug combination, 
drug therapy, intravenous drug administration, subcutaneous drug 
administration)
  HLA A antigen (adverse drug reaction, drug combination, drug therapy, 
intravenous drug administration, subcutaneous drug administration)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  autoimmunity
  cancer regression
  immunological tolerance
  melanoma (drug therapy)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer immunotherapy
  clinical article
  controlled study
  dermatitis (side effect)
  disease classification
  drug mechanism
  enterocolitis (side effect)
  female
  hepatitis (side effect)
  human
  hypophysitis (side effect)
  male
  priority journal
EMBASE CLASSIFICATIONS
  Cancer (16)
  Immunology, Serology and Transplantation (26)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2003286028
MEDLINE PMID
  12826605 (http://www.ncbi.nlm.nih.gov/pubmed/12826605)
PUI
  L36842552
DOI
  10.1073/pnas.1533209100
FULL TEXT LINK
  http://dx.doi.org/10.1073/pnas.1533209100
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 442
TITLE
  The attractive Achilles heel of germ cell tumours: An inherent sensitivity 
to apoptosis-inducing stimuli
AUTHOR NAMES
  Spierings D.C.J.
  de Vries E.G.E.
  Vellenga E.
  de Jong S.
AUTHOR ADDRESSES
  (Spierings D.C.J.; de Vries E.G.E., e.g.e.de.vries@int.azg.nl; Vellenga E.; 
de Jong S.) Department of Medical Oncology, University of Groningen, 
Hanzeplein 1, 9713 GZ Groningen, Netherlands.
CORRESPONDENCE ADDRESS
  E.G.E. de Vries, Department of Medical Oncology, University Hospital 
Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands. Email: 
e.g.e.de.vries@int.azg.nl
SOURCE
  Journal of Pathology (2003) 200:2 (137-148). Date of Publication: 1 Jun 2003
ISSN
  0022-3417
BOOK PUBLISHER
  John Wiley and Sons Ltd, Southern Gate, Chichester, West Sussex, United 
Kingdom.
ABSTRACT
  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. 
Copyright © 2003 John Wiley & Sons, Ltd.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cisplatin (drug interaction, pharmacology)
EMTREE DRUG INDEX TERMS
  antineoplastic agent (pharmacology)
  bleomycin
  caspase 3 (endogenous compound)
  caspase 8 (endogenous compound)
  DNA (endogenous compound)
  etoposide
  Fas ligand (endogenous compound)
  ifosfamide
  protein Bak (endogenous compound)
  protein bcl 2 (endogenous compound)
  protein MDM2 (endogenous compound)
  protein p21 (endogenous compound)
  protein p53 (endogenous compound)
  retinoblastoma protein (endogenous compound)
  retinoic acid (drug interaction, pharmacology)
  tumor necrosis factor receptor superfamily member 6 (endogenous compound)
  vinblastine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  apoptosis
  germ cell tumor
  testis cancer
EMTREE MEDICAL INDEX TERMS
  antineoplastic activity
  autocrine effect
  cell cycle G1 phase
  cell cycle S phase
  cell differentiation
  DNA damage
  drug sensitivity
  gametogenesis
  gene mutation
  gene overexpression
  human
  male
  mitochondrion
  nonhuman
  paracrine signaling
  priority journal
  protein function
  review
  signal transduction
  spermatogenesis
CAS REGISTRY NUMBERS
  DNA (9007-49-2)
  bleomycin (11056-06-7)
  caspase 3 (169592-56-7)
  cisplatin (15663-27-1, 26035-31-4, 96081-74-2)
  etoposide (33419-42-0)
  ifosfamide (3778-73-2)
  protein Bak (166801-28-1)
  protein bcl 2 (219306-68-0)
  protein p21 (85306-28-1)
  retinoic acid (302-79-4)
  vinblastine (865-21-4)
EMBASE CLASSIFICATIONS
  General Pathology and Pathological Anatomy (5)
  Cancer (16)
  Urology and Nephrology (28)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2003249113
MEDLINE PMID
  12754734 (http://www.ncbi.nlm.nih.gov/pubmed/12754734)
PUI
  L36748022
DOI
  10.1002/path.1373
FULL TEXT LINK
  http://dx.doi.org/10.1002/path.1373
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 443
TITLE
  Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody 
blockade in previously vaccinated metastatic melanoma and ovarian carcinoma 
patients
AUTHOR NAMES
  Hodi F.S.
  Mihm M.C.
  Soiffer R.J.
  Haluska F.G.
  Butler M.
  Seiden M.V.
  Davis T.
  Henry-Spires R.
  MacRae S.
  Willman A.
  Padera R.
  Jaklitsch M.T.
  Shankar S.
  Chen T.C.
  Korman A.
  Allison J.P.
  Dranoff G.
AUTHOR ADDRESSES
  (Hodi F.S.; Soiffer R.J.; Butler M.; Henry-Spires R.; MacRae S.; Willman A.; 
Dranoff G., glenn_dranoff@dfci.harvard.edu) Department of Adult Oncology, 
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, 
United States.
(Mihm M.C.) Department of Pathology, Massachusetts General Hospital, Harvard 
Medical School, Boston, MA 02114, United States.
(Haluska F.G.; Seiden M.V.) Department of Medicine, Massachusetts General 
Hospital, Harvard Medical School, Boston, MA 02114, United States.
(Davis T.; Korman A.) Medarex, Inc., Annandale, NJ 08801, United States.
(Padera R.) Department of Pathology, Brigham and Women's Hospital, Harvard 
Medical School, Boston, MA 02115, United States.
(Jaklitsch M.T.) Department of Surgery, Brigham and Women's Hospital, 
Harvard Medical School, Boston, MA 02115, United States.
(Shankar S.) Department of Radiology, Dana-Farber Cancer Institute, Harvard 
Medical School, Boston, MA 02115, United States.
(Chen T.C.) Massachusetts Eye and Ear Infirmary, Harvard Medical School, 
Boston, MA 02114, United States.
(Allison J.P.) Howard Hughes Medical Institute, Cancer Research Lab., 
University of California, Berkeley, CA 94720, United States.
CORRESPONDENCE ADDRESS
  G. Dranoff, Department of Adult Oncology, Brigham and Women's Hospital, 
Harvard Medical School, Boston, MA 02115, United States. Email: 
glenn_dranoff@dfci.harvard.edu
SOURCE
  Proceedings of the National Academy of Sciences of the United States of 
America (2003) 100:8 (4712-4717). Date of Publication: 15 Apr 2003
ISSN
  0027-8424
BOOK PUBLISHER
  National Academy of Sciences, 2101 Constitution Avenue NW, Washington, 
United States.
ABSTRACT
  A large number of cancer-associated gene products evoke immune recognition, 
but host reactions rarely impede disease progression. The weak 
immunogenicity of nascent tumors contributes to this failure in host 
defense. Therapeutic vaccines that enhance dendritic cell presentation of 
cancer antigens increase specific cellular and humoral responses, thereby 
effectuating tumor destruction in some cases. The attenuation of T cell 
activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further 
limits the potency of tumor immunity. In murine systems, the administration 
of antibodies that block CTLA-4 function inhibits the growth of moderately 
immunogenic tumors and, in combination with cancer vaccines, increases the 
rejection of poorly immunogenic tumors, albeit with a loss of tolerance to 
normal differentiation antigens. To gain a preliminary assessment of the 
biologic activity of antagonizing CTLA-4 function in humans, we infused a 
CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced 
cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with 
lymphocyte and granulocyte infiltrates in three of three metastatic melanoma 
patients and the reduction or stabilization of CA-125 levels in two of two 
metastatic ovarian carcinoma patients previously vaccinated with irradiated, 
autologous granulocyte-macrophage colony-stimulating factor-secreting tumor 
cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic 
melanoma patients previously immunized with defined melanosomal antigens. No 
serious toxicities directly attributable to the antibody were observed, 
although five of seven melanoma patients developed T cell reactivity to 
normal melanocytes. These findings suggest that CTLA-4 antibody blockade 
increases tumor immunity in some previously vaccinated cancer patients.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  antibody (adverse drug reaction, clinical trial, intravenous drug 
administration, pharmacology)
  cancer vaccine (clinical trial, drug therapy)
  cytotoxic T lymphocyte antigen 4 (endogenous compound)
  cytotoxic T lymphocyte antigen 4 antibody (adverse drug reaction, clinical 
trial, intravenous drug administration, pharmacology)
  mdx ctla 4 antibody (adverse drug reaction, clinical trial, intravenous drug 
administration, pharmacology)
EMTREE DRUG INDEX TERMS
  CA 125 antigen (endogenous compound)
  ganglioside GM2 (clinical trial, drug therapy)
  granulocyte macrophage colony stimulating factor receptor (endogenous 
compound)
  qs 21 (clinical trial, drug therapy)
  unclassified drug
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  melanoma (drug therapy, radiotherapy)
  metastasis
  ovary carcinoma (drug therapy, radiotherapy)
  tumor immunity
EMTREE MEDICAL INDEX TERMS
  adult
  anorexia (side effect)
  antineoplastic activity
  arthralgia (side effect)
  article
  autoimmunity
  blood level
  cancer immunization
  cancer radiotherapy
  cell infiltration
  clinical article
  clinical trial
  controlled clinical trial
  controlled study
  coughing (side effect)
  drug activity
  drug effect
  fatigue (side effect)
  female
  granulocyte
  human
  hypersensitivity (side effect)
  hypotension (side effect)
  irradiation
  liver function
  lymphocytic infiltration
  male
  melanocyte
  myalgia (side effect)
  nausea (side effect)
  nose obstruction (side effect)
  priority journal
  secretory cell
  side effect (side effect)
  T lymphocyte
  treatment outcome
  tumor cell
  tumor growth
  tumor necrosis
CAS REGISTRY NUMBERS
  ganglioside GM2 (19600-01-2)
  qs 21 (141256-04-4)
EMBASE CLASSIFICATIONS
  Cancer (16)
  Clinical and Experimental Pharmacology (30)
  Drug Literature Index (37)
  Adverse Reactions Titles (38)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2003163399
MEDLINE PMID
  12682289 (http://www.ncbi.nlm.nih.gov/pubmed/12682289)
PUI
  L36457795
DOI
  10.1073/pnas.0830997100
FULL TEXT LINK
  http://dx.doi.org/10.1073/pnas.0830997100
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 444
TITLE
  Caffeine and the G2/M block override: A concept resulting from a misleading 
cell kinetic delay, independent of functional p53
AUTHOR NAMES
  Deplanque G.
  Céraline J.
  Mah-Becherel M.C.-M.
  Cazenave J.-P.
  Bergerat J.-P.
  Klein-Soyer C.
AUTHOR ADDRESSES
  (Deplanque G.; Mah-Becherel M.C.-M.; Bergerat J.-P.; Klein-Soyer C., 
claudine.soyer@ircad.u-strasbg.fr) Laboratoire de Cancérologie Expérimentale 
et de Radiobiologie, Institut de Recherche Contre les Cancers de l'Appareil 
Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
(Céraline J.) UPR 9003-CNRS Cancérogenèse et Mutagenèse Moléculaire et 
Structurale, ESBS, Illkirch, France.
(Cazenave J.-P.) INSERM U. 311, Etablissement Français du Sang-Alsace, 
Strasbourg, France.
(Klein-Soyer C., claudine.soyer@ircad.u-strasbg.fr) Laboratoire de 
Cancérologie Expérimentale et de Radiobiologie, Institut de Recherche Contre 
les Cancers de l'Appareil Digestif, Hôpitaux Universitaires de Strasbourg, 
B.P. 426, 67091 Strasbourg, France.
CORRESPONDENCE ADDRESS
  C. Klein-Soyer, Lab. de Cancerologie Experimentale, Inst. de Rech. contre 
les Cancers, Hopitaux Univ. de Strasbourg, B.P. 426, 67091 Strasbourg, 
France. Email: claudine.soyer@ircad.u-strasbg.fr
SOURCE
  International Journal of Cancer (2001) 94:3 (363-369). Date of Publication: 
1 Nov 2001
ISSN
  0020-7136
BOOK PUBLISHER
  Wiley-Liss Inc., 111 River Street, Hoboken, United States.
ABSTRACT
  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 γ- 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 GI 
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. © 2001 
Wiley-Liss, Inc.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  caffeine
  protein p53 (endogenous compound)
EMTREE DRUG INDEX TERMS
  DNA
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  thyroid carcinoma
  tumor suppressor gene
EMTREE MEDICAL INDEX TERMS
  article
  cancer cell culture
  cell cycle G2 phase
  cell cycle S phase
  cell kinetics
  cell proliferation
  controlled study
  DNA damage
  DNA repair
  gamma radiation
  human
  human cell
  phenotype
  priority journal
CAS REGISTRY NUMBERS
  DNA (9007-49-2)
  caffeine (58-08-2)
EMBASE CLASSIFICATIONS
  General Pathology and Pathological Anatomy (5)
  Endocrinology (3)
  Cancer (16)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  2001341785
MEDLINE PMID
  11745415 (http://www.ncbi.nlm.nih.gov/pubmed/11745415)
PUI
  L32906066
DOI
  10.1002/ijc.1478
FULL TEXT LINK
  http://dx.doi.org/10.1002/ijc.1478
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 445
TITLE
  Growth suppression of human ovarian cancer cell lines by the introduction of 
a p16 gene via a recombinant adenovirus
AUTHOR NAMES
  Wolf J.K.
  Kim T.-E.
  Fightmaster D.
  Bodurka D.
  Gershenson D.M.
  Mills G.
  Wharton J.T.
AUTHOR ADDRESSES
  (Wolf J.K.; Kim T.-E.; Fightmaster D.; Bodurka D.; Gershenson D.M.; Wharton 
J.T.) Department of Gynecologic Oncology, University of Texas, M. D. 
Anderson Cancer Center, Houston, TX 77030, United States.
(Mills G.) Department of Molecular Genetics, University of Texas, M. D. 
Anderson Cancer Center, Houston, TX 77030, United States.
CORRESPONDENCE ADDRESS
  G. Mills, Department of Gynecologic Oncology, Texas Univ. M. D. Anderson 
Can. Ctr., Houston, TX 77030, United States.
SOURCE
  Gynecologic Oncology (1999) 73:1 (27-34). Date of Publication: April 1999
ISSN
  0090-8258
BOOK PUBLISHER
  Academic Press Inc., 6277 Sea Harbor Drive, Orlando, United States.
ABSTRACT
  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). Methods. Cells lines used were SKOV(3), 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 β-galactosidase gene (Ad5CMV-β-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. 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. 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  protein p16
EMTREE DRUG INDEX TERMS
  beta galactosidase
  virus vector
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  cancer inhibition
  cancer therapy
  ovary cancer (therapy)
EMTREE MEDICAL INDEX TERMS
  apoptosis
  article
  cancer cell culture
  cancer growth
  cell count
  cell cycle G1 phase
  cell selection
  female
  gene therapy
  human
  human cell
  priority journal
  protein expression
EMBASE CLASSIFICATIONS
  General Pathology and Pathological Anatomy (5)
  Obstetrics and Gynecology (10)
  Cancer (16)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  1999134759
MEDLINE PMID
  10094876 (http://www.ncbi.nlm.nih.gov/pubmed/10094876)
PUI
  L29177595
DOI
  10.1006/gyno.1998.5259
FULL TEXT LINK
  http://dx.doi.org/10.1006/gyno.1998.5259
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.

RECORD 446
TITLE
  Sporadic CDKN2 (MTS1/p16(ink4)) gene alterations in human ovarian tumours
AUTHOR NAMES
  Schuyer M.
  Van Staveren I.L.
  Klijn J.G.M.
  V.D. Burg M.E.L.
  Stoter G.
  Henzen-Logmans S.C.
  Foekens J.A.
  Berns E.M.J.J.
AUTHOR ADDRESSES
  (Schuyer M.; Van Staveren I.L.; Klijn J.G.M.; V.D. Burg M.E.L.; Stoter G.; 
Foekens J.A.; Berns E.M.J.J.) Division of Endocrine Oncology, Dr. Daniel den 
Hoed Cancer Center, Rotterdam, Netherlands.
(Henzen-Logmans S.C.) Department of Pathology, Dr. Daniel den Hoed Cancer 
Center, Rotterdam, Netherlands.
(Berns E.M.J.J.) Division of Endocrine Oncology, Dr. Danel den Hoed Cancer 
Center, PO Box 5201, 3008 AE Rotterdam, Netherlands.
CORRESPONDENCE ADDRESS
  E.M.J.J. Berns, Division of Endocrine Oncology, Dr. Danel den Heed Cancer 
Center, PO Box 5201, 3008 AE Rotterdam, Netherlands.
SOURCE
  British Journal of Cancer (1996) 74:7 (1069-1073). Date of Publication: 1996
ISSN
  0007-0920
BOOK PUBLISHER
  Nature Publishing Group, Houndmills, Basingstoke, Hampshire, United Kingdom.
ABSTRACT
  The cell cycle regulatory proteins p16 and p21 cause cell cycle arrest at 
the G(1) 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.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
  cyclin dependent kinase (endogenous compound)
EMTREE DRUG INDEX TERMS
  cycline (endogenous compound)
  protein p21 (endogenous compound)
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
  gene mutation
  ovary cancer (etiology)
EMTREE MEDICAL INDEX TERMS
  adult
  aged
  article
  cancer cell culture
  cell cycle G1 phase
  chromosome 9p
  clinical article
  controlled study
  exon
  female
  gene deletion
  gene expression regulation
  gene mapping
  gene sequence
  human
  human cell
  human tissue
  metastasis
  ovary adenocarcinoma
  polymerase chain reaction
  prevalence
  priority journal
  prognosis
  single strand conformation polymorphism
  stop codon
CAS REGISTRY NUMBERS
  cyclin dependent kinase (150428-23-2)
  protein p21 (85306-28-1)
EMBASE CLASSIFICATIONS
  Obstetrics and Gynecology (10)
  Cancer (16)
  Human Genetics (22)
LANGUAGE OF ARTICLE
  English
LANGUAGE OF SUMMARY
  English
EMBASE ACCESSION NUMBER
  1996306434
MEDLINE PMID
  8855976 (http://www.ncbi.nlm.nih.gov/pubmed/8855976)
PUI
  L26333908
COPYRIGHT
  Copyright 2009 Elsevier B.V., All rights reserved.