415 Records downloaded - Tue Jul 18 13:39:16 UTC 2017
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
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
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 4
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
EMTREE DRUG INDEX TERMS
carbimazole
cytotoxic T lymphocyte antigen 4
cytotoxic T lymphocyte antigen 4 antibody
endogenous compound
ipilimumab
thyroid hormone
thyrotropin
thyrotropin receptor antibody
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
Graves disease
EMTREE MEDICAL INDEX TERMS
adult
adverse drug reaction
case report
clinical trial
complication
diagnosis
disease duration
drug therapy
endocrine system
family study
gene inactivation
human
human tissue
male
metastatic melanoma
middle aged
relapse
safety
side effect
thyroid function
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 5
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
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 6
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
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 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
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
programmed death 1 receptor
EMTREE DRUG INDEX TERMS
endogenous compound
glucocorticoid
levothyroxine
messenger RNA
programmed death 1 ligand 1
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
case study
clinical feature
thyroiditis
thyrotoxicosis
EMTREE MEDICAL INDEX TERMS
adverse drug reaction
clinical article
clinical trial
controlled clinical trial
controlled study
diagnosis
drug combination
drug therapy
female
Graves disease
human
hypothyroidism
immunological tolerance
Japan
male
phase 3 clinical trial
postmarketing surveillance
prevention
protein expression
reverse transcription polymerase chain reaction
side effect
substitution therapy
thyroid gland tissue
Western blotting
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
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 10
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
PUI
L616954875
DOI
10.1007/s11912-017-0609-2
FULL TEXT LINK
http://dx.doi.org/10.1007/s11912-017-0609-2
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 11
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
EMTREE DRUG INDEX TERMS
autoantibody
methylprednisolone
muscle enzyme
pyridostigmine
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
myasthenia gravis
squamous cell lung carcinoma
EMTREE MEDICAL INDEX TERMS
adverse drug reaction
aged
asthenia
awareness
case report
clinical trial
diagnosis
diplopia
disease course
drug therapy
family study
head
human
immunotherapy
infusion
male
mechanical ventilator
myositis
plasmapheresis
ptosis
respiratory failure
side effect
stress
symptom
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170491556
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 12
TITLE
Endocrine dysfunction following immune checkpoint inhibitor therapy
AUTHOR NAMES
Konda B.
Nabhan F.
Shah M.H.
AUTHOR ADDRESSES
(Konda B.) aDivision of Medical Oncology, Department of Internal Medicine
bDivision of Endocrinology, Diabetes, and Metabolism, The Ohio State
University and Arthur G. James Cancer Center, Columbus, Ohio, USA *Bhavana
Konda and Fadi Nabhan contributed equally to the article.
(Nabhan F.; Shah M.H.)
CORRESPONDENCE ADDRESS
B. Konda, aDivision of Medical Oncology, Department of Internal Medicine
bDivision of Endocrinology, Diabetes, and Metabolism, The Ohio State
University and Arthur G. James Cancer Center, Columbus, Ohio, USA *Bhavana
Konda and Fadi Nabhan contributed equally to the article.
SOURCE
Current Opinion in Endocrinology, Diabetes and Obesity (2017). Date of
Publication: 28 Jun 2017
ISSN
1752-2978 (electronic)
1752-296X
BOOK PUBLISHER
Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
PURPOSE OF REVIEW: Immune checkpoint inhibitors (ICI) represent an important
milestone in the modern era of antineoplastic therapy and have ushered
optimism amongst oncologists and patients alike. These agents, however, are
associated with significant potential toxicities, the importance of which
cannot be overstated. The clinical presentation, diagnosis, and management
strategies of immune-related endocrinopathies associated with ICI use are
described in this case-based review. RECENT FINDINGS: An increasing number
of ICI have shown promise in the management of various malignancies in the
recent years. These include cytotoxic T lymphocyte antigen-4 inhibitors,
programed death 1 antibodies, and programed death-ligand 1 antibodies.
Several endocrinopathies, including hypophysitis, thyroid dysfunction,
hyperglycemia, and primary adrenal insufficiency, have been associated with
the use of these agents. Toxicities may range from mild transient laboratory
abnormalities to potentially life-threatening ones, warranting immediate
therapeutic intervention. Combination ICI therapies may be associated with a
greater risk of endocrine dysfunction when compared with monotherapy. The
clinical presentation and laboratory assessment of these patients often pose
a diagnostic challenge as they may be confused by the symptoms related to
their underlying malignancy or potential associated acute illnesses.
SUMMARY: ICI use is associated with serious endocrinopathies that may have a
nonspecific initial presentation. A constant eye for these symptoms and a
systematic approach to diagnosis are essential for prompt initiation of
therapy and prevention of significant complications.
EMTREE DRUG INDEX TERMS
antibody
cytotoxic T lymphocyte antigen 4
endogenous compound
ligand
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
Addison disease
EMTREE MEDICAL INDEX TERMS
cancer epidemiology
case report
case study
congenital malformation
controlled study
death
diagnosis
female
human
hyperglycemia
hypophysitis
male
monotherapy
oncologist
optimism
prevention
symptom
thyroid disease
toxicity
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170468715
PUI
L617067626
DOI
10.1097/MED.0000000000000357
FULL TEXT LINK
http://dx.doi.org/10.1097/MED.0000000000000357
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 13
TITLE
Targeting DNA repair and replication stress in the treatment of ovarian
cancer
AUTHOR NAMES
Murai J.
AUTHOR ADDRESSES
(Murai J., junko.murai@nih.gov) Developmental Therapeutics Branch and
Laboratory of Molecular Pharmacology, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, United States.
CORRESPONDENCE ADDRESS
J. Murai, Developmental Therapeutics Branch and Laboratory of Molecular
Pharmacology, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, Bethesda, United States. Email:
junko.murai@nih.gov
SOURCE
International Journal of Clinical Oncology (2017) (1-10). Date of
Publication: 22 Jun 2017
ISSN
1437-7772 (electronic)
1341-9625
BOOK PUBLISHER
Springer Tokyo, orders@springer.jp
ABSTRACT
Approximately half of high-grade serous epithelial ovarian cancers incur
alterations in genes of homologous recombination (BRCA1, BRCA2, RAD51C,
Fanconi anemia genes), and the rest incur alterations in other DNA repair
pathways at high frequencies. Such cancer-specific gene alterations can
confer selective sensitivity to DNA damaging agents such as cisplatin and
carboplatin, topotecan, etoposide, doxorubicin, and gemcitabine. Originally
presumed to inhibit DNA repair, PARP inhibitors that have recently been
approved by the FDA for the treatment of advanced ovarian cancer also act as
DNA damaging agents by inducing PARP–DNA complexes. These DNA damaging
agents induce different types of DNA lesions that require various DNA repair
genes for the repair, but commonly induce replication fork slowing or
stalling, also referred to as replication stress. Replication stress
activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further
DNA damage. Hence, targeting DNA repair genes or DNA repair checkpoint genes
augments the anti-tumor activity of DNA damaging agents. This review
describes the rational basis for using DNA repair and DNA repair checkpoint
inhibitors as single agents. The review also presents the strategies
combining these inhibitors with DNA damaging agents for ovarian cancer
therapy based on specific gene alterations.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
ATR protein
checkpoint kinase 1
cisplatin
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase
inhibitor
topotecan
EMTREE DRUG INDEX TERMS
BRCA1 protein
BRCA2 protein
carboplatin
doxorubicin
endogenous compound
etoposide
gemcitabine
Rad51 protein
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
cell cycle checkpoint
DNA damage
DNA repair
female
homologous recombination
lethality
ovary carcinoma
stress
EMTREE MEDICAL INDEX TERMS
antineoplastic activity
cancer susceptibility
cancer therapy
drug therapy
Fanconi anemia
gene activation
human
mutation
rest
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170453183
PUI
L616956737
DOI
10.1007/s10147-017-1145-7
FULL TEXT LINK
http://dx.doi.org/10.1007/s10147-017-1145-7
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 14
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
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
weight reduction
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 15
TITLE
Autoimmune diabetes induced by PD-1 inhibitor—retrospective analysis and
pathogenesis: a case report and literature review
AUTHOR NAMES
Gauci M.-L.
Laly P.
Vidal-Trecan T.
Baroudjian B.
Gottlieb J.
Madjlessi-Ezra N.
da Meda L.
Madelaine-Chambrin I.
Bagot M.
Basset-Seguin N.
Pages C.
Mourah S.
Boudou P.
Lebbé C.
Gautier J.-F.
AUTHOR ADDRESSES
(Gauci M.-L., marie-lea.gauci@hotmail.fr; Laly P.; Baroudjian B.; Gottlieb
J.; Madjlessi-Ezra N.; da Meda L.; Bagot M.; Basset-Seguin N.; Pages C.;
Lebbé C.) AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue
Claude Vellefaux, Paris Cedex 10, France.
(Gauci M.-L., marie-lea.gauci@hotmail.fr; Laly P.; Baroudjian B.; Gottlieb
J.; Madjlessi-Ezra N.; da Meda L.; Madelaine-Chambrin I.; Bagot M.;
Basset-Seguin N.; Pages C.; Mourah S.; Lebbé C.) INSERM U976, Université
Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris, France.
(Boudou P.) AP-HP Hormonology Department, Saint-Louis Hospital, Paris,
France.
(Boudou P.) Université Paris Diderot-Paris VII, Sorbonne Paris Cité, Paris,
France.
(Vidal-Trecan T.; Gautier J.-F.) AP-HP Diabetology Department, Lariboisière
Hospital, Paris, France.
(Vidal-Trecan T.; Gautier J.-F.) INSERM U1138, Université Paris
Diderot-Paris VII, Sorbonne Paris Cité, Paris, France.
(Madelaine-Chambrin I.) AP-HP Pharmacology Department, Saint-Louis Hospital,
Paris, France.
(Mourah S.) AP-HP Pharmacogenomic Laboratory, Saint-Louis Hospital, Paris,
France.
CORRESPONDENCE ADDRESS
M.-L. Gauci, AP-HP Dermatology Department, Saint-Louis Hospital, 1 avenue
Claude Vellefaux, Paris Cedex 10, France. Email: marie-lea.gauci@hotmail.fr
SOURCE
Cancer Immunology, Immunotherapy (2017) (1-12). Date of Publication: 20 Jun
2017
ISSN
1432-0851 (electronic)
0340-7004
BOOK PUBLISHER
Springer Science and Business Media Deutschland GmbH, info@springer-sbm.com
ABSTRACT
Anti-PD-1 antibody treatment is approved in advanced melanoma and provides
median overall survival over 24 months. The main treatment-related side
effects are immune-related adverse events, which include rash, pruritus,
vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a
case of autoimmune diabetes related to nivolumab treatment. A 73-year-old
man was treated in second line with nivolumab at 3 mg/kg every two weeks for
metastatic melanoma. At 6 weeks of treatment, he displayed diabetic
ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was
initiated, enabling a normalization of glycaemia and the disappearance of
symptoms. Laboratory investigations demonstrated the presence of islet cell
autoantibodies, while C-peptide was undetectable. Retrospective explorations
on serum banked at week 0 and 3 months before the start of nivolumab,
already showed the presence of autoantibodies, but normal insulin, C-peptide
secretion and glycaemia. Partial response was obtained at month 3, and
nivolumab was then resumed at the same dose. The clinical context and
biological investigations before, at and after nivolumab initiation suggest
the autoimmune origin of this diabetes, most likely induced by anti-PD-1
antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well
known in the pathogenesis of type 1 diabetes. Therefore, this rare side
effect can be expected in a context of anti-PD-1 treatment. Glycaemia should
be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies
before treatment could identify individuals at risk of developing diabetes,
but systematic titration may not be relevant considering the rarity of this
side effect.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
autoantibody
programmed death 1 receptor
EMTREE DRUG INDEX TERMS
C peptide
endogenous compound
nivolumab
programmed death 1 ligand 1
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
diabetic ketoacidosis
metastatic melanoma
EMTREE MEDICAL INDEX TERMS
adverse drug reaction
aged
case report
chemical binding
disease course
drug therapy
glucose blood level
human
human tissue
insulin dependent diabetes mellitus
insulin treatment
male
pancreas islet cell
side effect
symptom
titrimetry
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170448110
PUI
L616899059
DOI
10.1007/s00262-017-2033-8
FULL TEXT LINK
http://dx.doi.org/10.1007/s00262-017-2033-8
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 16
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 17
TITLE
Immune-related Neurological Symptoms in an Adolescent Patient Receiving the
Checkpoint Inhibitor Nivolumab
AUTHOR NAMES
Tchapyjnikov D.
Borst A.J.
AUTHOR ADDRESSES
(Tchapyjnikov D.) *Division of Pediatric Neurology †Division of Pediatric
Hematology-Oncology, Duke University Medical Center, Durham, NC
(Borst A.J.)
CORRESPONDENCE ADDRESS
D. Tchapyjnikov, *Division of Pediatric Neurology †Division of Pediatric
Hematology-Oncology, Duke University Medical Center, Durham, NC
SOURCE
Journal of Immunotherapy (2017). Date of Publication: 9 Jun 2017
ISSN
1537-4513 (electronic)
1524-9557
BOOK PUBLISHER
Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
Immune checkpoint inhibitors are a novel group of immunotherapeutic agents
for the treatment of cancer. Immune-related adverse events, including
neurological symptoms, have been associated with these agents. We present
the case of an adolescent with refractory Hodgkin lymphoma treated with
nivolumab, a PD1 inhibitor, who developed Hashimoto thyroiditis, posterior
reversible encephalopathy syndrome causing seizures, as well as urinary
retention, truncal/appendicular spasticity, dysphagia, and a progressive
encephalopathy that was clinically consistent with a diagnosis of
progressive encephalopathy with rigidity and myoclonus, a
stiff-person-syndrome spectrum disorder. He showed response and ultimately
full recovery to a combination of intravenous steroids, intravenous
immunoglobulin, and plasma exchange. To our knowledge, this is the first
documented report of an immune-related neurological reaction to nivolumab in
an adolescent patient and expands the spectrum of known nivolumab-associated
toxicities.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
nivolumab
EMTREE DRUG INDEX TERMS
human immunoglobulin
steroid
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
posterior reversible encephalopathy syndrome
EMTREE MEDICAL INDEX TERMS
adolescent
case report
diagnosis
drug therapy
dysphagia
Hashimoto disease
Hodgkin disease
human
male
myoclonus
plasma exchange
rigidity
seizure
spasticity
stiff man syndrome
toxicity
urine retention
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170429121
PUI
L616798311
DOI
10.1097/CJI.0000000000000177
FULL TEXT LINK
http://dx.doi.org/10.1097/CJI.0000000000000177
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 18
TITLE
Severe Ocular Myositis After Ipilimumab Treatment for Melanoma: A Report of
2 Cases
AUTHOR NAMES
Pushkarevskaya A.
Neuberger U.
Dimitrakopoulou-Strauss A.
Enk A.
Hassel J.C.
AUTHOR ADDRESSES
(Pushkarevskaya A.) Departments of *Dermatology and National Center for
Tumor Diseases (NCT) †Diagnostic Radiology, University Hospital Heidelberg
‡German Cancer Research Center, Clinical Cooperation Unit Nuclear Medicine,
Heidelberg, Germany
(Neuberger U.; Dimitrakopoulou-Strauss A.; Enk A.; Hassel J.C.)
CORRESPONDENCE ADDRESS
A. Pushkarevskaya, Departments of *Dermatology and National Center for Tumor
Diseases (NCT) †Diagnostic Radiology, University Hospital Heidelberg ‡German
Cancer Research Center, Clinical Cooperation Unit Nuclear Medicine,
Heidelberg, Germany
SOURCE
Journal of Immunotherapy (2017). Date of Publication: 9 Jun 2017
ISSN
1537-4513 (electronic)
1524-9557
BOOK PUBLISHER
Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
Ipilimumab binds and blocks cytotoxic T-lymphocyte-associated antigen-4,
causing enhanced T-cell reaction, antitumor response, and significant
improvement of the overall survival of patients with metastatic melanoma.
Patients treated with ipilimumab can develop immune-related adverse effects,
primarily dermatitis, colitis, hepatitis, and hypophysitis. Although, in
phase I–III studies, 64.2% of all patients suffered from immune-related
adverse effects, ocular adverse effects occurred in 1.3% only. In the cases
reported below, 2 patients with metastatic melanoma developed severe ocular
myositis after treatment with ipilimumab. These are the first 2 reports of
successful treatment of this condition by use of a combination of
methylprednisolone and mycophenolate mofetil, and, in 1 of the cases,
additional medication with intravenous immunoglobulin.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
ipilimumab
EMTREE DRUG INDEX TERMS
human immunoglobulin
methylprednisolone
mycophenolate mofetil
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
metastatic melanoma
myositis
EMTREE MEDICAL INDEX TERMS
adverse drug reaction
case report
clinical trial
drug combination
drug therapy
female
human
male
side effect
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170428941
PUI
L616797803
DOI
10.1097/CJI.0000000000000178
FULL TEXT LINK
http://dx.doi.org/10.1097/CJI.0000000000000178
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 19
TITLE
Molecularly targeted agents in oculoplastic surgery
AUTHOR NAMES
Allen R.C.
AUTHOR ADDRESSES
(Allen R.C.) Section of Ophthalmology, Department of Head and Neck Surgery,
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
CORRESPONDENCE ADDRESS
R.C. Allen, Section of Ophthalmology, Department of Head and Neck Surgery,
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
SOURCE
Current Opinion in Ophthalmology (2017). Date of Publication: 8 Jun 2017
ISSN
1531-7021 (electronic)
1040-8738
BOOK PUBLISHER
Lippincott Williams and Wilkins, kathiest.clai@apta.org
ABSTRACT
PURPOSE OF REVIEW: Significant advances have been made in oncology and
rheumatology with the introduction of molecularly targeted agents (MTAs).
MTAs consist of monoclonal antibodies and small molecule inhibitors. The
purpose of this manuscript is to review the recent applications of MTAs to
orbital, lacrimal, and eyelid disease. RECENT FINDINGS: The use of
monoclonal antibodies has been described in the treatment of orbital
vascular lesions, lymphoma, and squamous cell carcinoma. Inflammatory
conditions treated with monoclonal antibodies include thyroid eye disease,
IgG4 disease, and granulomatosis with polyangiitis. Immunotherapy with
checkpoint inhibitors has also found applications to orbital disease. Use of
small molecule inhibitors has been described in the treatment of basal cell
carcinoma, squamous cell carcinoma, and Erdheim–Chester disease. There are
many orbital, lacrimal, and eyelid side effects of MTAs with which the
oculoplastic surgeon should be familiar, including hypertrichosis, edema,
and orbital and eyelid inflammation. SUMMARY: MTAs represent the future of
treatment of oncologic and inflammatory conditions. Application of these
agents to orbital, lacrimal, and eyelid disease will continue to expand.
Elucidating the molecular mechanisms of oculoplastic disorders will
facilitate additional potential pathways that could be targeted for therapy.
EMTREE DRUG INDEX TERMS
antibody
endogenous compound
immunoglobulin G4
EMTREE MEDICAL INDEX TERMS
basal cell carcinoma
blepharitis
edema
endocrine ophthalmopathy
eyelid disease
human
hypertrichosis
immunotherapy
lymphoma
orbit disease
publication
surgeon
surgery
vascular lesion
Wegener granulomatosis
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170425797
PUI
L616783968
DOI
10.1097/ICU.0000000000000403
FULL TEXT LINK
http://dx.doi.org/10.1097/ICU.0000000000000403
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 20
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
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 21
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 22
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
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 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
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
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
PUI
L616744325
DOI
10.2217/imt-2017-0020
FULL TEXT LINK
http://dx.doi.org/10.2217/imt-2017-0020
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 26
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
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 27
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
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 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, kunden.service@thieme.de
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
PUI
L616574332
DOI
10.1055/s-0043-101212
FULL TEXT LINK
http://dx.doi.org/10.1055/s-0043-101212
COPYRIGHT
Copyright 2017 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
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
PUI
L616104559
DOI
10.1186/s12885-017-3313-6
FULL TEXT LINK
http://dx.doi.org/10.1186/s12885-017-3313-6
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 31
TITLE
Clival chordoma: a single-centre outcome analysis
AUTHOR NAMES
Jägersberg M.
El Rahal A.
Dammann P.
Merkler D.
Weber D.C.
Schaller K.
AUTHOR ADDRESSES
(Jägersberg M., max.jaegersberg@hcuge.ch; El Rahal A.; Dammann P.; Schaller
K.) Division of Neurosurgery, Geneva University Hospitals and University of
Geneva, 4, rue Gabrielle-Perret-Gentil, Geneva, Switzerland.
(Dammann P.) Department of Neurosurgery, Essen University Hospital,
University of Duisburg-Essen, Essen, Germany.
(Merkler D.) Department of Pathology and Immunology, Division of Clinical
Pathology, Geneva University Hospitals of Geneva, Geneva, Switzerland.
(Weber D.C.) Centre for Proton Therapy, Paul Scherrer Institute, Villigen,
Switzerland.
CORRESPONDENCE ADDRESS
M. Jägersberg, Division of Neurosurgery, Geneva University Hospitals and
University of Geneva, 4, rue Gabrielle-Perret-Gentil, Geneva, Switzerland.
Email: max.jaegersberg@hcuge.ch
SOURCE
Acta Neurochirurgica (2017) (1-9). Date of Publication: 7 May 2017
ISSN
0942-0940 (electronic)
0001-6268
BOOK PUBLISHER
Springer-Verlag Wien, michaela.bolli@springer.at
ABSTRACT
Background: The treatment of clival chordomas remains challenging. Total
tumour resection is often impossible without hampering adjacent anatomical
structures and causing functional sequelae. On the other hand, chordomas
show limited response to non-surgical treatment modalities. Up to now, no
well-established interdisciplinary treatment algorithms for clival chordomas
exist. In this regard, we analysed the data from all patients that underwent
interdisciplinary treatment for clival chordoma in our institution over the
last 10 years. Method: Retrospective report of all patients treated at the
authors’ institution from 2005 to 2015. Results: Thirteen patients underwent
24 surgeries, of which 2 (8%) were gross total resections and 22 (92%)
incomplete resections. Neurological deterioration, endocrinological
disturbances and other surgical complications were observed in six (25%),
three (13%) and nine (38%) cases, respectively. Three surgeries (13%) led to
an improvement of the initial preoperative neurological condition. All
patients were discussed on the interdisciplinary tumour board and all
underwent one type of radiotherapy following initial surgery: proton beam in
11 cases (85%) and photon beam in two (15%) cases. In the course of their
recurrent disease, three patients (23%) received systemic therapy (imatinib,
pazopanib and nivolumab). One patient received a personalised cellular
immunotherapy. One patient (8%) was lost to follow-up. Of the remaining 12
patients, four patients (33%) died in the period of analysis; all deaths
were chordoma-related. The 5-year cumulative survival rate was 83% (52–97%,
CI 95%), 5-year progression-free survival rate was 53% (26-79%, CI 95%). The
eight patients (66%) still alive had favourable outcome (KPS, 90 ± 10.7%).
SF36 analysis among the survivors revealed 43 points for the Physical
Component Summary (12% above, 38% at and 50% below the general population
norm) and 47 points for the Mental Component Summary (25% above, 38% at and
38% below). Conclusions: Our patients show a low rate of gross total
resection but an outcome well comparable to other published results. This
emphasises the importance of interdispiplinary treatment strategies, with
surgery supplying maximal safe resection and avoiding severe neurological
deficit, allowing patients to undergo adjusted radiotherapy and other
treatment options in a good condition.
EMTREE DRUG INDEX TERMS
imatinib
nivolumab
pazopanib
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
chemotherapy
chordoma
radiosurgery
systemic therapy
EMTREE MEDICAL INDEX TERMS
clinical article
clinical trial
death
drug therapy
female
follow up
human
immunotherapy
male
mental health
neurologic disease
peroperative complication
photon
population
progression free survival
proton radiation
radiotherapy
recurrent disease
Short Form 36
surgery
survival rate
survivor
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170326852
PUI
L615979374
DOI
10.1007/s00701-017-3163-7
FULL TEXT LINK
http://dx.doi.org/10.1007/s00701-017-3163-7
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 32
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
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 33
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)
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)
weight reduction
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
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 34
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
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 35
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 36
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
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 37
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 38
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
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 39
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 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
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
The experience of immune checkpoint inhibitors in Chinese patients with
metastatic melanoma: a retrospective case series
AUTHOR NAMES
Wen X.
Ding Y.
Li J.
Zhao J.
Peng R.
Li D.
Zhu B.
Wang Y.
Zhang X.
Zhang X.
AUTHOR ADDRESSES
(Wen X.; Ding Y.; Li J.; Zhao J.; Peng R.; Li D.; Zhu B.; Wang Y.; Zhang X.;
Zhang X., zhangxsh@sysucc.org.cn) Biotherapy Center, State Key Laboratory of
Oncology in South China, Collaborative Innovation Center for Cancer
Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
CORRESPONDENCE ADDRESS
X. Zhang, Biotherapy Center, State Key Laboratory of Oncology in South
China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen
University Cancer Center, Guangzhou, China. Email: zhangxsh@sysucc.org.cn
SOURCE
Cancer Immunology, Immunotherapy (2017) (1-10). Date of Publication: 25 Apr
2017
ISSN
1432-0851 (electronic)
0340-7004
BOOK PUBLISHER
Springer Science and Business Media Deutschland GmbH, info@springer-sbm.com
ABSTRACT
Melanomas in Chinese patients show relatively higher rates of acral and
mucosal types than in other populations. However, the efficacy of checkpoint
inhibitor therapies against these melanoma subtypes is not well defined. We
analyzed 52 patients treated with ipilimumab, pembrolizumab, or a
combination of both to evaluate the efficacy and safety of checkpoint
inhibitors in Chinese patients with advanced melanoma, particularly those
with acral and mucosal types. The objective response rates (ORRs) were 0,
25, and 20% for ipilimumab, pembrolizumab, and pembrolizumab plus
ipilimumab, respectively. Pembrolizumab contained therapy was as effective
in acral and mucosal melanoma patients (ORR 26.7 and 20%, respectively) as
in non-acral cutaneous melanoma patients (ORR 26.7%). Baseline lactate
dehydrogenase levels and relative lymphocyte counts were independent
prognostic factors for PFS and OS. The incidences of grade 3–4 adverse
events were 14% in the two monotherapy groups and 30% in the combined
therapy group. The most frequent adverse events were elevation of
aminotransferase, skin toxicity, thyroid dysfunction, pyrexia, and fatigue.
Treatment-related rash or vitiligo was associated with a better prognosis.
In summary, pembrolizumab-based therapy resulted in meaningful efficacy and
good tolerability in Chinese patients with melanoma, including those with
acral and mucosal types.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
ipilimumab
pembrolizumab
EMTREE DRUG INDEX TERMS
aminotransferase
endogenous compound
lactate dehydrogenase
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
case study
Chinese
cutaneous melanoma
metastatic melanoma
mucosal melanoma
EMTREE MEDICAL INDEX TERMS
adverse drug reaction
clinical trial
comparative effectiveness
drug combination
drug therapy
fatigue
fever
gene expression
human
lymphocyte count
major clinical study
monotherapy
pharmacokinetics
prognosis
safety
side effect
skin toxicity
thyroid disease
vitiligo
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170301433
PUI
L615702407
DOI
10.1007/s00262-017-1989-8
FULL TEXT LINK
http://dx.doi.org/10.1007/s00262-017-1989-8
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 44
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 45
TITLE
Prevalence of hypophysitis in a cohort of patients with metastatic melanoma
and prostate cancer treated with ipilimumab
AUTHOR NAMES
Brilli L.
Danielli R.
Ciuoli C.
Calabrò L.
Di Giacomo A.M.
Cerase A.
Paffetti P.
Sestini F.
Porcelli B.
Maio M.
Pacini F.
AUTHOR ADDRESSES
(Brilli L.; Ciuoli C.; Paffetti P.; Sestini F.; Pacini F., pacini8@unisi.it)
Section of Endocrinology, Department of Medical, Surgical and Neurological
sciences, University of Siena, Siena, Italy.
(Danielli R.; Calabrò L.; Di Giacomo A.M.; Maio M.) Medical Oncology and
Immunotherapy Unit, Department of Oncology, Istituto Toscano Tumori,
University of Siena, Siena, Italy.
(Cerase A.) Unit of Neuroimaging and Neurointervention, Department of
Neurological and Sensorineural Sciences, Azienda Ospedaliera Universitaria
Senese, Siena, Italy.
(Porcelli B.) Department of Medical Biotechnologies, Biochemistry Division,
University of Siena, UOC Laboratorio Patologia Clinica, Azienda Ospedaliera
Universitaria Senese, Siena, Italy.
CORRESPONDENCE ADDRESS
F. Pacini, Section of Endocrinology, Department of Medical, Surgical and
Neurological sciences, University of Siena, Siena, Italy. Email:
pacini8@unisi.it
SOURCE
Endocrine (2017) (1-7). Date of Publication: 12 Apr 2017
ISSN
1559-0100 (electronic)
1355-008X
BOOK PUBLISHER
Humana Press Inc., humana@humanapr.com
ABSTRACT
Objective: Ipilimumab is a human monoclonal antibody directed against
cytotoxic T-lymphocyte antigen-4, that has been shown to significantly
improve survival in patients with metastatic melanoma. Blocking cytotoxic
T-lymphocyte antigen-4 elicits T cell activation, proliferation and
anti-tumor response, but can also trigger immune-related adverse events.
Among immune-related endocrinopathies, hypophysitis represents the most
frequent, with an incidence up to 17% in patients treated with ipilimumab.
Design and methods: We report nine cases of ipilimumab-induced hypophysitis
in a cohort of 273 patients treated with ipilimumab between 2006 and 2015,
as part of clinical trials or after its marketing. Thyroid function tests
were scheduled at screening and during follow up (every 21 days) in all
patients. Cortisol, adrenocorticotropic hormone, follicle-stimulating
hormone, luteinizing hormone, and estradiol (for females) or testosterone
(for males), prolactin, growth hormone, insulin-like growth factor 1 were
measured only in case of clinical suspicion. Results: The incidence of
hypophysitis was 3.3%. The most frequent pituitary failure was
adrenocorticotropic hormone and thyroid stimulating hormone secretion with a
complete recovery of thyroid stimulating hormone, but not of
adrenocorticotropic hormone during follow up. All patients had negative
pituitary antibodies. The main symptoms at diagnosis were fatigue and
headache. Conclusion: Clinicians should be aware about the risk of
hypophysitis during treatment with immune check-point inhibitors and the
necessity of investigating pituitary function during therapy. Pituitary
magnetic resonance imaging does not seem pivotal for a definite diagnosis if
not performed at the onset of disease.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
cytotoxic T lymphocyte antigen 4
ipilimumab
EMTREE DRUG INDEX TERMS
corticotropin
endogenous compound
estradiol
follitropin
growth hormone
hydrocortisone
luteinizing hormone
prolactin
somatomedin C
testosterone
thyrotropin
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
hypophysitis
metastatic melanoma
prevalence
prostate cancer
EMTREE MEDICAL INDEX TERMS
adverse drug reaction
clinical trial
diagnosis
drug therapy
fatigue
female
follow up
headache
human
hypophysis function
hypopituitarism
major clinical study
male
marketing
nuclear magnetic resonance imaging
remission
screening
side effect
symptom
thyroid function test
thyrotropin release
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170275178
PUI
L615377498
DOI
10.1007/s12020-017-1289-2
FULL TEXT LINK
http://dx.doi.org/10.1007/s12020-017-1289-2
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 46
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 47
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 48
TITLE
CAR T Cells Administered in Combination with Lymphodepletion and PD-1
Inhibition to Patients with Neuroblastoma
AUTHOR NAMES
Heczey A.
Louis C.U.
Savoldo B.
Dakhova O.
Durett A.
Grilley B.
Liu H.
Wu M.F.
Mei Z.
Gee A.
Mehta B.
Zhang H.
Mahmood N.
Tashiro H.
Heslop H.E.
Dotti G.
Rooney C.M.
Brenner M.K.
AUTHOR ADDRESSES
(Heczey A., axheczey@txch.org; Louis C.U.) Texas Children's Cancer Center,
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
(Savoldo B.; Dotti G.) Department of Microbiology and Immunology, School of
Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
(Dakhova O.; Durett A.; Grilley B.; Mei Z.; Gee A.; Mehta B.; Zhang H.;
Tashiro H.; Heslop H.E.; Rooney C.M.; Brenner M.K.) Center for Cell and Gene
Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston
Methodist Hospital, Houston, TX 77030, USA
(Liu H.; Wu M.F.) Biostatistics and Informatics Group, Shared Resources, Dan
L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston,
TX 77030, USA
(Mahmood N.) Department of Radiology, Baylor College of Medicine, Houston,
TX 77030, USA
CORRESPONDENCE ADDRESS
A. Heczey, Andras Heczey, Texas Children's Cancer Center, Baylor College of
Medicine, 1102 Bates Street, Suite C1760.10, Houston, TX 77030, USA Email:
axheczey@txch.org
SOURCE
Molecular Therapy (2017). Date of Publication: 3 Apr 2017
ISSN
1525-0024 (electronic)
1525-0016
BOOK PUBLISHER
American Society of Gene and Cell Therapy
ABSTRACT
Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells
expressing a first-generation chimeric antigen receptor (CAR) was safe, but
the cells had poor expansion and long-term persistence. We developed a
third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells
(CARTs) would be safe and effective. This phase 1 study enrolled relapsed or
refractory NB patients in three cohorts. Cohort 1 received CART alone,
cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and
cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1)
inhibitor. Eleven patients were treated with CARTs. The infusions were safe,
and no dose-limiting toxicities occurred. CARTs were detectable in cohort 1,
but the lymphodepletion induced by Cy/Flu increased circulating levels of
the homeostatic cytokine interleukin (IL)-15 (p = 0.003) and increased CART
expansion by up to 3 logs (p = 0.03). PD-1 inhibition did not further
enhance expansion or persistence. Antitumor responses at 6 weeks were
modest. We observed a striking expansion of CD45/CD33/CD11b/CD163(+) myeloid
cells (change from baseline, p = 0.0126) in all patients, which may have
contributed to the modest early antitumor responses; the effect of these
cells merits further study. Thus, CARTs are safe, and Cy/Flu can further
increase their expansion. The outcome of children with relapsed or
refractory neuroblastoma remains poor. Because GD2 is a validated
immunotherapeutic target of NB, we tested T cells expressing a
third-generation GD2-CAR (GD2-CAR3) in three cohorts of patients with
relapsed or refractory NB. Eleven patients were treated, the infusions were
safe, and no dose-limiting toxicities occurred. CAR T cell expansion
improved, and the OS of patients was longer after salvage therapies in
Cy/Flu cohorts. A striking expansion of CD45/CD33/CD11b/CD163(+) myeloid
cells was detected in all patients, which may have contributed to the modest
early antitumor responses; the effect of these cells merits further study.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
chimeric antigen receptor
programmed death 1 receptor
EMTREE DRUG INDEX TERMS
CD11b antigen
CD33 antigen
CD45 antigen
cyclophosphamide
endogenous compound
fludarabine
interleukin 15
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
female
gene inactivation
immunotherapy
male
neuroblastoma
T lymphocyte
EMTREE MEDICAL INDEX TERMS
bone marrow cell
cell expansion
child
clinical article
clinical trial
controlled clinical trial
controlled study
drug therapy
human
infusion
phase 1 clinical trial
salvage therapy
toxicity
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170415460
PUI
L616691761
DOI
10.1016/j.ymthe.2017.05.012
FULL TEXT LINK
http://dx.doi.org/10.1016/j.ymthe.2017.05.012
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 49
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
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 50
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 51
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 52
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 53
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
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 54
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)
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
weight reduction
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
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 55
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
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 56
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 57
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
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)
weight reduction
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
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 58
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
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 59
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 60
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
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 61
TITLE
Role of TIM-3 in ovarian cancer
AUTHOR NAMES
Xu Y.
Zhang H.
Huang Y.
Rui X.
Zheng F.
AUTHOR ADDRESSES
(Xu Y., czyunxu@163.com; Huang Y.; Rui X.; Zheng F.) Department of
Gynecology, The Third Affiliated Hospital of Soochow University, 185 Juqian
Street, Changzhou, China.
(Zhang H.) Department of Epidemiology and Biostatistics, College of Public
Health, University of South Florida, Tampa, United States.
CORRESPONDENCE ADDRESS
Y. Xu, Department of Gynecology, The Third Affiliated Hospital of Soochow
University, 185 Juqian Street, Changzhou, China. Email: czyunxu@163.com
SOURCE
Clinical and Translational Oncology (2017) (1-5). Date of Publication: 29
Mar 2017
ISSN
1699-3055 (electronic)
1699-048X
BOOK PUBLISHER
Springer-Verlag Italia s.r.l., springer@springer.it
ABSTRACT
Evidences have suggested that immunotherapy for ovarian cancer is effective.
Immune checkpoints have emerged in the field of cancer immunotherapy.
Multiple studies have shown negative regulation of TIM-3 expression on
CD4(+) and CD8(+) T cells and other immunocytes. Overexpression of TIM-3 in
innate immune cells has been found in certain types of tumor. The blockade
of TIM-3 leads to sustained anti-tumor reactions. TIM-3 plays an inhibitive
role for immunity in ovarian cancer. TIM-3 is involved in the development of
various subtypes of ovarian cancer and thus has the potential to be a
therapeutic target for treatment of ovarian cancer.
EMTREE DRUG INDEX TERMS
CD4 antigen
endogenous compound
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
female
ovary cancer
EMTREE MEDICAL INDEX TERMS
cancer immunotherapy
CD8+ T lymphocyte
gene expression regulation
gene overexpression
human
immunocompetent cell
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170237247
PUI
L615089618
DOI
10.1007/s12094-017-1656-8
FULL TEXT LINK
http://dx.doi.org/10.1007/s12094-017-1656-8
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 62
TITLE
Durable Response to Immune Checkpoint Blockade in a Platinum-Refractory
Patient With Nonseminomatous Germ Cell Tumor
AUTHOR NAMES
Chi E.A.
Schweizer M.T.
AUTHOR ADDRESSES
(Chi E.A.; Schweizer M.T., schweize@uw.edu) Division of Oncology, Department
of Medicine, University of Washington/Fred Hutchinson Cancer Research
Center, Seattle, WA
CORRESPONDENCE ADDRESS
M.T. Schweizer, University of Washington, 825 Eastlake Ave E, MS G6-075,
Seattle, WA 98109 Email: schweize@uw.edu
SOURCE
Clinical Genitourinary Cancer (2017). Date of Publication: 28 Mar 2017
ISSN
1938-0682 (electronic)
1558-7673
BOOK PUBLISHER
Elsevier Inc., usjcs@elsevier.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
nivolumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
immunotherapy
male
non seminomatous germinoma
testis cancer
EMTREE MEDICAL INDEX TERMS
human
LANGUAGE OF ARTICLE
English
EMBASE ACCESSION NUMBER
20170315016
PUI
L615847516
DOI
10.1016/j.clgc.2017.04.005
FULL TEXT LINK
http://dx.doi.org/10.1016/j.clgc.2017.04.005
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 63
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
priority journal
pruritus (drug therapy, side effect)
rash (side effect)
thrombocyte count
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 64
TITLE
Molecular mechanisms of therapy resistance in solid tumors: chasing “moving”
targets
AUTHOR NAMES
Tafe L.J.
AUTHOR ADDRESSES
(Tafe L.J., Laura.J.Tafe@hitchcock.org) One Medical Center Drive, Department
of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center,
Lebanon, United States.
CORRESPONDENCE ADDRESS
L.J. Tafe, One Medical Center Drive, Department of Pathology and Laboratory
Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, United States. Email:
Laura.J.Tafe@hitchcock.org
SOURCE
Virchows Archiv (2017) (1-10). Date of Publication: 10 Mar 2017
ISSN
1432-2307 (electronic)
0945-6317
BOOK PUBLISHER
Springer Verlag, service@springer.de
ABSTRACT
The goal of personalized cancer therapy is to treat tumors based on genomic
aberrations that drive their survival and progression. Most patients who
receive targeted therapies typically develop resistance and disease
progression within a year’s time. This review focuses on the heterogeneous
mechanisms of therapy resistance to tyrosine kinase inhibitors,
endocrine/hormone therapy and checkpoint blockade using non-small cell lung
cancer, breast and castration-resistant prostate cancer, and melanoma as
classical examples, respectively. In addition, testing for resistance
mechanisms and therapeutic approaches to overcoming resistance is addressed.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
epidermal growth factor receptor
estrogen receptor alpha
EMTREE DRUG INDEX TERMS
endogenous compound
protein tyrosine kinase inhibitor
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
breast cancer
castration resistant prostate cancer
epithelial mesenchymal transition
female
male
mutation
non small cell lung cancer
EMTREE MEDICAL INDEX TERMS
cancer epidemiology
drug therapy
endocrine system
hormonal therapy
human
melanoma
molecularly targeted therapy
tumor resistance
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170183375
PUI
L614736159
DOI
10.1007/s00428-017-2101-7
FULL TEXT LINK
http://dx.doi.org/10.1007/s00428-017-2101-7
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 65
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 66
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 67
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
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 68
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
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 69
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
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 70
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 71
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 72
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 73
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
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 74
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)
foxl2 protein (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 75
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 76
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
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 77
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
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 78
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 79
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 80
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 81
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)
peptides and proteins (endogenous compound)
programmed death 1 ligand 1 (endogenous compound)
programmed death 1 receptor (endogenous compound)
protein IDO 1 (endogenous compound)
protein TIA 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
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 82
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 83
TITLE
Nivolumab, a new immunomodulatory drug, a new adverse effect; adrenal crisis
AUTHOR NAMES
Akarca F.K.
Can O.
Yalcinli S.
Altunci Y.A.
AUTHOR ADDRESSES
(Akarca F.K., fkarbek2003@yahoo.com; Can O.; Yalcinli S.; Altunci Y.A.) Ege
University, Faculty of Medicine, Department of Emergency Medicine, Izmir,
Turkey
CORRESPONDENCE ADDRESS
F.K. Akarca, Emergency Medicine Department, Ege University Faculty of
Medicine, 35100, Izmir, Turkey Email: fkarbek2003@yahoo.com
SOURCE
Turkish Journal of Emergency Medicine (2017). Date of Publication: 6 Feb
2017
ISSN
2452-2473 (electronic)
BOOK PUBLISHER
Emergency Medicine Association of Turkey, ersin.aksay@gmail.com
ABSTRACT
Owing to the advancements in medicine, new information is obtained regarding
cancer, new antineoplastic agents are developed. Frequent use of these new
pharmacological agents emergency physicians to be vigilant about their side
effects. We present a case of adrenal crisis in a patient with non-small
cell lung cancer (NSCLC), caused by an immunomodulatory drug; nivolumab.
While adverse events are related to other immunomodulatory drugs have been
reported in literature, our case is the first nivolumab-related adrenal
failure to be reported. A patient with lung cancer presented to the
emergency room(ER) with nausea and vomiting. Hyponatremia, hyperkalemia,
persistent hypoglycemia led to the diagnosis of adrenal crisis. Having
direct effect on the immune system, these drugs were claimed to be highly
reliable. However, there is no reliable data on the side effect profile of
these agents. It should be kept in mind that life-threatening auto-immune
reactions may occur.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
cytotoxic T lymphocyte antigen 4
nivolumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
adrenal insufficiency
immunomodulation
EMTREE MEDICAL INDEX TERMS
adverse drug reaction
case report
diagnosis
emergency ward
female
human
hyperkalemia
hypoglycemia
hyponatremia
immunity
male
nausea and vomiting
non small cell lung cancer
side effect
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170446942
PUI
L616896548
DOI
10.1016/j.tjem.2017.05.007
FULL TEXT LINK
http://dx.doi.org/10.1016/j.tjem.2017.05.007
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 84
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 85
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 86
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
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 87
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 88
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 89
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 90
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)
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
weight gain
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
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 91
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 92
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
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 93
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 94
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 95
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 96
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
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 97
TITLE
Aggravation of diabetes, and incompletely deficient insulin secretion in a
case with type 1 diabetes-resistant human leukocyte antigen DRB1*15:02
treated with nivolumab
AUTHOR NAMES
Matsumura K.
Nagasawa K.
Oshima Y.
Kikuno S.
Hayashi K.
Nishimura A.
Okubo M.
Uruga H.
Kishi K.
Kobayashi T.
Mori Y.
AUTHOR ADDRESSES
(Matsumura K.; Nagasawa K.; Oshima Y.; Kikuno S.; Hayashi K.; Nishimura A.;
Okubo M.; Mori Y., ymori-metab@toranomon.gr.jp) Department of Endocrinology
and Metabolism Toranomon Hospital Tokyo Japan
(Okubo M.; Uruga H.; Kishi K.; Kobayashi T.; Mori Y.,
ymori-metab@toranomon.gr.jp) Okinaka Memorial Institute for Medical Research
Tokyo Japan
(Uruga H.; Kishi K.) Department of Respiratory Medicine Respiratory Center
Toranomon Hospital Tokyo Japan
CORRESPONDENCE ADDRESS
Y. Mori, Department of Endocrinology and Metabolism Toranomon Hospital Tokyo
Japan Email: ymori-metab@toranomon.gr.jp
SOURCE
Journal of Diabetes Investigation (2017). Date of Publication: 2017
ISSN
2040-1124 (electronic)
2040-1116
BOOK PUBLISHER
Blackwell Publishing, info@asia.blackpublishing.com.au
ABSTRACT
Anti-programmed cell death-1 (PD-1) antibody therapy induces various adverse
effects, especially in the endocrine system. Several cases of acute-onset
insulin-dependent diabetes after anti-PD-1 antibody therapy have been
reported. Many of these cases have a susceptible human leukocyte antigen
(HLA) genotype for type 1 diabetes, possibly suggesting that HLA might be
involved in the onset of diabetes with anti-PD-1 therapy. We describe an
atypical case of hyperglycemia after anti-PD-1 antibody administration. A
68-year-old Japanese man with pancreatic diabetes and steroid diabetes was
given nivolumab three times for chemoresistant adenocarcinoma of the lung.
On day 5 after the third infusion of nivolumab, he had hyperglycemia (blood
glucose 330 mg/dL and hemoglobin A1c 8.0%) without ketosis and with
incompletely deficient insulin secretion. The patient had both type 1
diabetes susceptible (HLA-A*24:02 and -DRB1*09:01) and resistant
(HLA-DRB1*15:02) HLA genotypes. These HLA genotypes differ from those
previously reported in anti-PD-1 antibody-induced diabetes, and might have
influenced the preservation of insulin secretion after nivolumab
administration in the present case.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
HLA DRB3 antigen
nivolumab
programmed death 1 receptor
EMTREE DRUG INDEX TERMS
endogenous compound
hemoglobin A1c
HLA A antigen
HLA DRB1 antigen
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
insulin dependent diabetes mellitus
insulin release
leukocyte
EMTREE MEDICAL INDEX TERMS
aged
case report
genetic susceptibility
genotype
human
hyperglycemia
infusion
Japanese (citizen)
ketoacidosis
lung adenocarcinoma
male
pancreas
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170424693
PUI
L616778976
DOI
10.1111/jdi.12679
FULL TEXT LINK
http://dx.doi.org/10.1111/jdi.12679
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 98
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 99
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 100
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
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 101
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
PUI
L616519972
DOI
10.1097/CJI.0000000000000173
FULL TEXT LINK
http://dx.doi.org/10.1097/CJI.0000000000000173
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 102
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
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 103
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
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 104
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
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 105
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
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 106
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
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 2016 Elsevier B.V., All rights reserved.
RECORD 107
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
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)
weight reduction
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 108
TITLE
CD70 and PD-L1 in anaplastic thyroid cancer - promising targets for
immunotherapy
AUTHOR NAMES
Zwaenepoel K.
Jacobs J.
De Meulenaere A.
Silence K.
Smits E.
Siozopoulou V.
Hauben E.
Rolfo C.
Rottey S.
Pauwels P.
AUTHOR ADDRESSES
(Zwaenepoel K., karen.zwaenepoel@uza.be; Jacobs J.; Siozopoulou V.; Pauwels
P.) Department of Pathology Antwerp University Hospital Edegem Belgium
(Zwaenepoel K., karen.zwaenepoel@uza.be; Jacobs J.; Smits E.; Siozopoulou
V.; Pauwels P.) Center for Oncological Research Antwerp University of
Antwerp Wilrijk Belgium
(De Meulenaere A.; Rottey S.) Department of Medical Oncology Ghent
University Hospital Ghent Belgium
(Silence K.) arGEN-X BVBA Ghent Belgium
(Smits E.) Laboratory of Experimental Hematology Vaccine and Infectious
Disease Institute University of Antwerp Wilrijk Belgium
(Hauben E.) Translational Cell and Tissue Research Leuven University
Hospital Leuven Belgium
(Rolfo C.) Department of Oncology Antwerp University Hospital Edegem Belgium
(Rolfo C.) Phase 1-Early Clinical Trials Unit Antwerp University Hospital
Edegem Belgium
CORRESPONDENCE ADDRESS
K. Zwaenepoel, Center for Oncological Research Antwerp University of Antwerp
Wilrijk Belgium Email: karen.zwaenepoel@uza.be
SOURCE
Histopathology (2017). Date of Publication: 2017
ISSN
1365-2559 (electronic)
0309-0167
BOOK PUBLISHER
Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
ABSTRACT
Aims: During recent years, immune checkpoint inhibition has proved to be
effective in several solid malignancies. The aim of this study was to
identify novel targets for immunotherapy in anaplastic thyroid cancer by
analysis of the expression of tumour antigens for which therapeutic agents
are available. Method and results: By immunohistochemistry we observed
tumoral expression of CD70 in 49% of cases. Expression of its receptor,
CD27, was present mainly in lymphocytes surrounding and infiltrating the
tumour and observed only rarely in tumour cells. CD70 expression was
associated with the presence of a precursor papillary thyroid carcinoma and
the presence of BRAF V600E mutations in the anaplastic thyroid cancer
lesion. Furthermore, the expression of CD70 seems stable during progression
of the disease. Tumoral expression of programmed cell death ligand 1 (PD-L1)
was found in 28.6% of the anaplastic thyroid cancer cases. Programmed cell
death 1 (PD-1), the receptor of PD-L1, was not expressed on the tumour
cells. No association between CD70 expression and PD-L1 expression could be
demonstrated. Conclusion: These data suggest that targeted immunotherapy for
CD70/CD27 and PD-L1/PD-1 might be promising in anaplastic thyroid cancer.
However, as a low amount of tumour-infiltrating lymphocytes was observed in
most lesions, combined therapy with agents enhancing the invasion of
lymphocytes in the tumour region needs to be considered.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
B Raf kinase
CD70 antigen
programmed death 1 ligand 1
EMTREE DRUG INDEX TERMS
CD27 antigen
endogenous compound
ligand
programmed death 1 receptor
tumor antigen
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
anaplastic thyroid cancer
immunotherapy
EMTREE MEDICAL INDEX TERMS
apoptosis
gene expression
gene mutation
human
human experiment
human tissue
immunohistochemistry
precursor
thyroid papillary carcinoma
tumor associated leukocyte
tumor cell
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170439491
PUI
L616865592
DOI
10.1111/his.13230
FULL TEXT LINK
http://dx.doi.org/10.1111/his.13230
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 109
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 110
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 111
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 112
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 113
TITLE
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate
040): An open-label, non-comparative, phase 1/2 dose escalation and
expansion trial
AUTHOR NAMES
El-Khoueiry A.B.
Sangro B.
Yau T.
Crocenzi T.S.
Kudo M.
Hsu C.
Kim T.-Y.
Choo S.-P.
Trojan J.
Welling T.H.
Meyer T.
Kang Y.-K.
Yeo W.
Chopra A.
Anderson J.
dela Cruz C.
Lang L.
Neely J.
Tang H.
Dastani H.B.
Melero I.
AUTHOR ADDRESSES
(El-Khoueiry A.B., elkhouei@med.usc.edu) USC Norris Comprehensive Cancer
Center, Los Angeles, CA, USA
(Sangro B.) Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain
(Yau T.) University of Hong Kong, Hong Kong Special Administrative Region,
China
(Crocenzi T.S.) Providence Cancer Center, Portland, OR, USA
(Kudo M.) Kindai University Faculty of Medicine, Osaka, Japan
(Hsu C.) National Taiwan University Hospital, Taipei, Taiwan
(Kim T.-Y.) Seoul National University Hospital, Seoul, South Korea
(Choo S.-P.) National Cancer Center, Singapore
(Trojan J.) Goethe University Hospital and Cancer Center, Frankfurt, Germany
(Welling T.H.) University of Michigan School of Medicine, Ann Arbor, MI, USA
(Meyer T.) Royal Free Hospital, London, UK
(Kang Y.-K.) Asan Medical Center, University of Ulsan, Seoul, South Korea
(Yeo W.) Chinese University of Hong Kong, Hong Kong Special Administrative
Region, China
(Chopra A.) Johns Hopkins Singapore International Medical Centre, Singapore
(Anderson J.; dela Cruz C.; Lang L.; Neely J.; Tang H.; Dastani H.B.)
Bristol-Myers Squibb, Princeton, NJ, USA
(Melero I.) Biomedical Research Network in Oncology (CIBERONC), Pamplona,
Spain
(Melero I.) Center for Applied Medical Research (CIMA), Pamplona, Spain
CORRESPONDENCE ADDRESS
A.B. El-Khoueiry, USC Norris Comprehensive Cancer Center, Los Angeles, CA
90033, USA Email: elkhouei@med.usc.edu
SOURCE
The Lancet (2017). Date of Publication: 2017
ISSN
1474-547X (electronic)
0140-6736
BOOK PUBLISHER
Lancet Publishing Group, cususerv@lancet.com
ABSTRACT
Background: For patients with advanced hepatocellular carcinoma, sorafenib
is the only approved drug worldwide, and outcomes remain poor. We aimed to
assess the safety and efficacy of nivolumab, a programmed cell death
protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced
hepatocellular carcinoma with or without chronic viral hepatitis. Methods:
We did a phase 1/2, open-label, non-comparative, dose escalation and
expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with
histologically confirmed advanced hepatocellular carcinoma with or without
hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was
allowed. A dose-escalation phase was conducted at seven hospitals or
academic centres in four countries or territories (USA, Spain, Hong Kong,
and Singapore) and a dose-expansion phase was conducted at an additional 39
sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea,
Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less
(Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh
A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group
performance status of 1 or less. Patients with HBV infection had to be
receiving effective antiviral therapy (viral load <100 IU/mL); antiviral
therapy was not required for patients with HCV infection. We excluded
patients previously treated with an agent targeting T-cell costimulation or
checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg
every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg
was given every 2 weeks in the dose-expansion phase to patients in four
cohorts: sorafenib untreated or intolerant without viral hepatitis,
sorafenib progressor without viral hepatitis, HCV infected, and HBV
infected. Primary endpoints were safety and tolerability for the escalation
phase and objective response rate (Response Evaluation Criteria In Solid
Tumors version 1.1) for the expansion phase. This study is registered with
ClinicalTrials.gov, number NCT01658878. Findings: Between Nov 26, 2012, and
Aug 8, 2016, 262 eligible patients were treated (48 patients in the
dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262
patients have completed treatment and follow-up is ongoing. During dose
escalation, nivolumab showed a manageable safety profile, including
acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued
treatment, 42 (88%) due to disease progression. Incidence of
treatment-related adverse events did not seem to be associated with dose and
no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4
treatment-related adverse events. Three (6%) patients had treatment-related
serious adverse events (pemphigoid, adrenal insufficiency, liver disorder).
30 (63%) of 48 patients in the dose-escalation phase died (not determined to
be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose
expansion. The objective response rate was 20% (95% CI 15-26) in patients
treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI
6-28) in the dose-escalation phase. Interpretation: Nivolumab had a
manageable safety profile and no new signals were observed in patients with
advanced hepatocellular carcinoma. Durable objective responses show the
potential of nivolumab for treatment of advanced hepatocellular carcinoma.
Funding: Bristol-Myers Squibb.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
nivolumab
EMTREE DRUG INDEX TERMS
endogenous compound
programmed death 1 receptor
sorafenib
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
liver cell carcinoma
EMTREE MEDICAL INDEX TERMS
adrenal insufficiency
adult
adverse drug reaction
antiviral therapy
Canada
cancer epidemiology
Child Pugh score
chronic hepatitis B
clinical trial
controlled clinical trial
controlled study
disease course
drug therapy
follow up
funding
Germany
hepatitis C
Hong Kong
human
human versus animal comparison
Italy
Japan
major clinical study
maximum tolerated dose
nonhuman
oncology
pemphigoid
pharmacokinetics
phase 1 clinical trial
phase 2 clinical trial
response evaluation criteria in solid tumors
safety
screening
side effect
Singapore
South Korea
Spain
T lymphocyte activation
Taiwan
virus load
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170293361
PUI
L615612852
DOI
10.1016/S0140-6736(17)31046-2
FULL TEXT LINK
http://dx.doi.org/10.1016/S0140-6736(17)31046-2
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 114
TITLE
Assessment of programmed death-ligand 1 expression and tumor-associated
immune cells in pediatric cancer tissues
AUTHOR NAMES
Majzner R.G.
Simon J.S.
Grosso J.F.
Martinez D.
Pawel B.R.
Santi M.
Merchant M.S.
Geoerger B.
Hezam I.
Marty V.
Vielh P.
Daugaard M.
Sorensen P.H.
Mackall C.L.
Maris J.M.
AUTHOR ADDRESSES
(Majzner R.G.; Mackall C.L.) Department of PediatricsStanford
UniversityStanford, California
(Simon J.S.; Grosso J.F.) Bristol-Myers SquibbPrinceton, New Jersey
(Martinez D.; Pawel B.R.; Santi M.) Department of Pathology and Laboratory
MedicineChildren's Hospital of PhiladelphiaPhiladelphia, Pennsylvania
(Martinez D.; Pawel B.R.; Santi M.; Maris J.M., maris@chop.edu) Perelman
School of MedicineUniversity of PennsylvaniaPhiladelphia, Pennsylvania
(Merchant M.S.) Pediatric Oncology Branch, National Cancer
InstituteBethesda, Maryland
(Geoerger B.; Hezam I.) Department of Pediatric and Adolescent
MedicineGustave Roussy InstituteVillejuif France
(Marty V.; Vielh P.) Department of Medical Biology and PathologyGustave
Roussy InstituteVillejuif France
(Daugaard M.) Vancouver Prostate CenterVancouver, British Columbia Canada
(Daugaard M.) Department of Urologic SciencesUniversity of British
ColumbiaVancouver, British Columbia Canada
(Sorensen P.H.) British Columbia Cancer AgencyVancouver, British Columbia
Canada
(Maris J.M., maris@chop.edu) Department of PediatricsUniversity of
PennsylvaniaPhiladelphia Pennsylvania
CORRESPONDENCE ADDRESS
J.M. Maris, Department of Pediatrics, Division of Oncology, Children's
Hospital of Philadelphia, Perelman School of Medicine at the University of
Pennsylvania, Colket Translational Research Building, 3501 Civic Center
Boulevard, No. 3060 4399, Philadelphia, PA 19104 Email: maris@chop.edu
SOURCE
Cancer (2017). Date of Publication: 2017
ISSN
1097-0142 (electronic)
0008-543X
BOOK PUBLISHER
John Wiley and Sons Inc., P.O.Box 18667, Newark, United States.
ABSTRACT
BACKGROUND: Programmed death 1 (PD-1) signaling in the tumor
microenvironment dampens immune responses to cancer, and blocking this axis
induces antitumor effects in several malignancies. Clinical studies of PD-1
blockade are only now being initiated in pediatric patients, and little is
known regarding programmed death-ligand 1 (PD-L1) expression in common
childhood cancers. The authors characterized PD-L1 expression and
tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in
common pediatric cancers. METHODS: Whole slide sections and tissue
microarrays were evaluated by immunohistochemistry for PD-L1 expression and
for the presence of TAICs. TAICs were also screened for PD-L1 expression.
RESULTS: Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at
least 1% of tumor cells. The highest frequency histotypes comprised Burkitt
lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14
tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was
associated with inferior survival among patients with neuroblastoma
(P=.004). Seventy-four percent of tumors contained lymphocytes and/or
macrophages. Macrophages were significantly more likely to be identified in
PD-L1-positive versus PD-L1-negative tumors (P<.001). CONCLUSIONS: A subset
of diagnostic pediatric cancers exhibit PD-L1 expression, whereas a much
larger fraction demonstrates infiltration with tumor-associated lymphocytes.
PD-L1 expression may be a biomarker for poor outcome in neuroblastoma.
Further preclinical and clinical investigation will define the predictive
nature of PD-L1 expression in childhood cancers both at diagnosis and after
exposure to chemoradiotherapy.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
ligand
programmed death 1 ligand 1
programmed death 1 receptor
EMTREE DRUG INDEX TERMS
biological marker
endogenous compound
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
cancer tissue
childhood cancer
gene expression
immunotherapy
neuroblastoma
tumor associated leukocyte
EMTREE MEDICAL INDEX TERMS
Burkitt lymphoma
chemoradiotherapy
child
diagnosis
exposure
female
glioblastoma
human
human tissue
immunohistochemistry
major clinical study
male
preclinical study
radiotherapy
survival
tissue microarray
tumor cell
LANGUAGE OF ARTICLE
English
LANGUAGE OF SUMMARY
English
EMBASE ACCESSION NUMBER
20170425172
PUI
L616780880
DOI
10.1002/cncr.30724
FULL TEXT LINK
http://dx.doi.org/10.1002/cncr.30724
COPYRIGHT
Copyright 2017 Elsevier B.V., All rights reserved.
RECORD 115
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 116
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 117
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 118
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)
synaptophysin (endogenous compound)
thyroid transcription factor 1 (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 119
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 120
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
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 121
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 122
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 123
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 124
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 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
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
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
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
weight gain
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
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
PUI
L612333629
DOI
10.1097/WCO.0000000000000391
FULL TEXT LINK
http://dx.doi.org/10.1097/WCO.0000000000000391
COPYRIGHT
Copyright 2017 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
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 135
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 136
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 137
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
PUI
L612344355
DOI
10.1097/CJI.0000000000000143
FULL TEXT LINK
http://dx.doi.org/10.1097/CJI.0000000000000143
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
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
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 140
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
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 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
PUI
L612705910
DOI
10.1634/theoncologist.2016-0055
FULL TEXT LINK
http://dx.doi.org/10.1634/theoncologist.2016-0055
COPYRIGHT
Copyright 2016 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
PUI
L613013529
DOI
10.1530/ERC-16-0169
FULL TEXT LINK
http://dx.doi.org/10.1530/ERC-16-0169
COPYRIGHT
Copyright 2016 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
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
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 147
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 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)
cyclosporin (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 2016 Elsevier B.V., All rights reserved.
RECORD 150
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 151
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 152
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)
navelbine (125317-39-7, 71486-22-1)
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
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 2016 Elsevier B.V., All rights reserved.
RECORD 153
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 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)
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
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 2016 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
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
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
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)
weight reduction
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
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 159
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 160
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 2016 Elsevier B.V., All rights reserved.
RECORD 161
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
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 162
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 163
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 164
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
PUI
L610202292
DOI
10.1097/CCO.0000000000000293
FULL TEXT LINK
http://dx.doi.org/10.1097/CCO.0000000000000293
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 165
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
PUI
L611205798
DOI
10.1111/ddg.13047
FULL TEXT LINK
http://dx.doi.org/10.1111/ddg.13047
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 166
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
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 167
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 168
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
PUI
L611220417
DOI
10.1634/theoncologist.2015-0509
FULL TEXT LINK
http://dx.doi.org/10.1634/theoncologist.2015-0509
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 169
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
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 170
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 171
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
PUI
L610258882
DOI
10.1097/CCO.0000000000000291
FULL TEXT LINK
http://dx.doi.org/10.1097/CCO.0000000000000291
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 172
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 173
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
PUI
L611333751
DOI
10.1200/JOP.2016.013367
FULL TEXT LINK
http://dx.doi.org/10.1200/JOP.2016.013367
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 174
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
PUI
L610202191
DOI
10.1097/CCO.0000000000000296
FULL TEXT LINK
http://dx.doi.org/10.1097/CCO.0000000000000296
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 175
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 176
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
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 177
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)
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)
weight reduction
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 178
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 179
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
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
weight reduction
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 180
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 181
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 182
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 183
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 184
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
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)
weight reduction
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
PUI
L609239328
DOI
10.1007/s10637-016-0347-6
FULL TEXT LINK
http://dx.doi.org/10.1007/s10637-016-0347-6
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 185
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 186
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 187
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 188
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
PUI
L610767487
DOI
10.18632/oncotarget.8698
FULL TEXT LINK
http://dx.doi.org/10.18632/oncotarget.8698
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 189
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 190
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 191
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
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 192
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
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 193
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 194
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)
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)
weight reduction
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
PUI
L610277152
DOI
10.18632/oncotarget.8216
FULL TEXT LINK
http://dx.doi.org/10.18632/oncotarget.8216
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 195
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
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 196
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 197
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 2016 Elsevier B.V., All rights reserved.
RECORD 198
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 199
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 200
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 201
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 202
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 cancer (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
PUI
L610625590
DOI
10.18632/oncotarget.7839
FULL TEXT LINK
http://dx.doi.org/10.18632/oncotarget.7839
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 203
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
PUI
L610251722
DOI
10.1634/theoncologist.2015-0498
FULL TEXT LINK
http://dx.doi.org/10.1634/theoncologist.2015-0498
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 204
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
PUI
L610625442
DOI
10.18632/oncotarget.7277
FULL TEXT LINK
http://dx.doi.org/10.18632/oncotarget.7277
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 205
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 206
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 207
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 208
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 209
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 210
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 211
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 212
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 213
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 214
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 215
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 216
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 217
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 218
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 219
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 220
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 221
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 222
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 223
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 224
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
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
weight reduction
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 225
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 226
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 227
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 228
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 229
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 230
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 231
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 232
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
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
weight reduction
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 233
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 234
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
PUI
L613412620
DOI
10.18632/oncotarget.12077
FULL TEXT LINK
http://dx.doi.org/10.18632/oncotarget.12077
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 235
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 236
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
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 237
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)
K ras protein (endogenous compound)
Notch1 receptor (endogenous compound)
Notch2 receptor (endogenous compound)
phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase (endogenous compound)
protein MSH2 (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 238
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
PUI
L612718447
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 239
TITLE
Case of metastatic uveal melanoma in which an antitumor effect appeared
after ipilimumab discontinuation due to autoimmune hypophysitis
AUTHOR NAMES
Ohnuma T.
Matsuzawa T.
Kinoshita M.
Sano S.
Kawamura T.
Shimada S.
Inozume T.
AUTHOR ADDRESSES
(Ohnuma T.; Matsuzawa T.; Kinoshita M.; Sano S.; Kawamura T.; Shimada S.;
Inozume T., tinozume@yamanashi.ac.jp) Department of Dermatology University
of Yamanashi Chuo Japan
CORRESPONDENCE ADDRESS
T. Inozume, Department of Dermatology, University of Yamanashi, 1110
Shimokato, Chuo, Yamanashi 409- 3878, Japan Email: tinozume@yamanashi.ac.jp
SOURCE
Journal of Dermatology (2016). Date of Publication: 2016
ISSN
1346-8138 (electronic)
0385-2407
BOOK PUBLISHER
Blackwell Publishing Ltd, customerservices@oxonblackwellpublishing.com
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
ipilimumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
antineoplastic activity
autoimmune hypophysitis
metastatic uvea melanoma
EMTREE MEDICAL INDEX TERMS
case report
human
LANGUAGE OF ARTICLE
English
EMBASE ACCESSION NUMBER
20160910184
PUI
L613684765
DOI
10.1111/1346-8138.13692
FULL TEXT LINK
http://dx.doi.org/10.1111/1346-8138.13692
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 240
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
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 241
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 242
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 243
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
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 244
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 245
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)
CD45 antigen (endogenous compound)
CD8 antigen (endogenous compound)
growth hormone (endogenous compound)
prolactin (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
PUI
L613490669
DOI
10.18632/oncotarget.12088
FULL TEXT LINK
http://dx.doi.org/10.18632/oncotarget.12088
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 246
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 247
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 248
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 249
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 250
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 251
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 252
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 253
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 254
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
PUI
L607487157
COPYRIGHT
Copyright 2016 Elsevier B.V., All rights reserved.
RECORD 255
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 256
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 257
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 258
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 259
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 260
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 261
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 262
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 263
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 264
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 265
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©, 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 266
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 267
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 268
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 cancer (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 269
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 270
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 271
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 272
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 273
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 274
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 275
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 276
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 277
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 278
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 279
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 280
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 281
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 282
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
rash (side effect)
thrombocyte count
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 283
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 284
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 285
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 286
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 287
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 288
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 289
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
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
weight gain
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 290
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 291
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 292
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 293
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 294
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 295
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 296
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
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 297
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 298
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 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
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 301
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 302
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 303
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 304
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 305
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 306
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 307
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 308
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 309
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 310
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 311
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+ 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+ 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 312
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
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)
weight gain
weight reduction
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 313
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-L1high and the remaining as
PD-L1low. Results: PD-L1high 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-L1high 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-L1high 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 314
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 315
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 316
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 317
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 318
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 319
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 320
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 321
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 322
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 323
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
priority journal
pruritus (side effect)
thrombocyte count
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 324
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 325
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 326
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 327
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 328
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 329
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 330
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
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)
weight gain
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 331
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 332
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 333
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 334
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 335
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
CD45 antigen (endogenous compound)
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)
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 336
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 337
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 338
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 339
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 340
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 341
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 342
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 343
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 344
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 345
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 346
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 347
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 348
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 349
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 350
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 351
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 352
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 353
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 354
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)
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
thrombocyte count
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 355
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 356
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 357
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 358
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 359
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 360
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 361
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 362
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 363
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 364
ORIGINAL (NON-ENGLISH) TITLE
Lymfocytær hypofysitis på baggrund af behandling med ipilimumab
AUTHOR NAMES
Thomsen H.H.
AUTHOR ADDRESSES
(Thomsen H.H., hehoth@gmail.com) Medicinsk Endokrinologisk Afdeling, Aarhus
Universitetshospital, Denmark.
CORRESPONDENCE ADDRESS
H.H. Thomsen, Medicinsk Endokrinologisk Afdeling, Aarhus
Universitetshospital, Nørrebrogade 44, 8000 Aarhus C, Denmark. Email:
hehoth@gmail.com
SOURCE
Ugeskrift for Laeger (2012) 174:26 (1829-1830). Date of Publication: 2012
ISSN
0041-5782
BOOK PUBLISHER
Almindelige Danske Laegeforening, Tromdhjemsgade 9, Copenhagen, Denmark.
EMTREE DRUG INDEX TERMS (MAJOR FOCUS)
antineoplastic agent (adverse drug reaction, drug therapy, pharmacokinetics)
monoclonal antibody (adverse drug reaction, drug therapy, pharmacokinetics)
EMTREE DRUG INDEX TERMS
immunologic factor (adverse drug reaction, drug therapy, pharmacokinetics)
ipilimumab
EMTREE MEDICAL INDEX TERMS (MAJOR FOCUS)
hypophysis disease
melanoma (drug therapy)
metastasis (drug therapy)
EMTREE MEDICAL INDEX TERMS
aged
article
case report
chemically induced disorder
fatality
human
immunopathology
male
pathology
tumor recurrence (drug therapy)
CAS REGISTRY NUMBERS
ipilimumab (477202-00-9)
LANGUAGE OF ARTICLE
Danish
MEDLINE PMID
22735122 (http://www.ncbi.nlm.nih.gov/pubmed/22735122)
PUI
L365359131
COPYRIGHT
MEDLINE® is the source for the citation and abstract of this record.
RECORD 365
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 366
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 367
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 368
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 369
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 370
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 371
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 372
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 373
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 374
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 375
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 376
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 377
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 378
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 379
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 380
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 381
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 382
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 383
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 384
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)
budenofalk (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 385
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 386
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 387
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 388
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 389
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 390
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 391
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 392
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 393
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 394
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 395
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 396
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 397
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 398
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 399
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 400
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 401
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 antigen (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 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 402
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 403
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 404
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)
novel erythropoiesis stimulating protein (clinical trial, drug therapy,
subcutaneous 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)
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 405
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 406
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 407
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 408
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 409
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 410
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 411
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 412
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 antigen (endogenous compound)
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)
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 413
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 414
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 415
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.