Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease.

Front Neurosci. 2018;12:230

Authors: Ibanez L, Dube U, Davis AA, Fernandez MV, Budde J, Cooper B, Diez-Fairen M, Ortega-Cubero S, Pastor P, Perlmutter JS, Cruchaga C, Benitez BA

Abstract
Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established. Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients. Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP), Presenilin 1 and 2 (PSEN1, PSEN2), and Granulin (GRN) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status. Results: Known AD pathogenic mutations in the PSEN1 (p.A79V) and PSEN2 (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10-4), independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site. Conclusions: Pathogenic mutations in the Alzheimer disease-causing genes (PSEN1 and PSEN2) are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects.

PMID: 29692703 [PubMed]

[Neuroendocrine tumors of the breast: Myth or reality? A systematic review].

Bull Cancer. 2018 Apr;105(4):431-439

Authors: Cheymol C, Abramovici O, Do Cao C, Dumont A, Robin YM, El Hajbi F, Dansin E, Bonneterre J, Lauridant G

Abstract
Primary neuroendocrine breast carcinomas are rare and little-known tumors. Only a limited number of studies on neuroendocrine breast carcinomas have been reported in the literature, and the vast majority of them are small retrospective series or case reports. According to the World Health Organization (WHO), they account for only 2 % to 5 % of breast cancers. Their diagnosis relies on the presence of a neuroendocrine architecture and the expression of neuroendocrine markers (chromogranin A and/or synaptophysin). The revised 2012 WHO classification subdivides them into three categories: (i) well-differentiated neuroendocrine carcinomas, (ii) poorly differentiated neuroendocrine carcinomas or small-cell carcinomas, and (iii) invasive breast carcinomas with neuroendocrine differentiation. Their clinical features and radiological characteristics are not different from those of other types of breast cancer. Because of discordant results, their clinical outcome is still poorly defined. So far, no standard treatment has been established, and most clinicians draw on their experience of invasive ductal cancer. The role of specific treatments like platinum-based chemotherapy, somatostatin analogues, peptide receptor radionucleide therapy or temozolomide remains unclear. A better knowledge of the molecular pathways involved in their carcinogenesis could help to identify new potential therapeutic targets. The efficacy of targeted therapies has to be studied.

PMID: 29567279 [PubMed - indexed for MEDLINE]

Capacities and Competences for Drug Evaluation in European Neonatal Intensive Care Units: A Survey and Key Issues for Improvement.

Am J Perinatol. 2018 May;35(6):589-598

Authors: Elie V, Neyro V, Ha P, Aurich B, Leroux S, Jacqz-Aigrain E

Abstract
BACKGROUND:  Multicenter neonatal clinical trials aim to provide evidence-based drug evaluation, but recruiting neonates requires collaboration, standard procedures, and trained neonatologists.
METHODS:  A questionnaire based on a previous Delphi study was sent to European neonatal intensive care units (NICUs) to collect their research experience and identify areas for improvement.
RESULTS: Of 247 NICUs,79 (32%) responded: 69 were level III units and 10 were level II units. In level III centers, 62% had medical staff dedicated to research and 65% conducted regular in-house audits. Similarities were observed in the median number of trials per year (level II: 2; level III: 5), Good Clinical Practice training (level II: 78%; level III: 66%), and standard operating procedures (level II: 63%; level III: 71%). Most NICUs had access to scientific advice for trial design, conduct, data management, and regulatory aspects. Involvement of patient advocacy groups was more common in level II units (level II: 75%; level III: 59%). A "quality" score of 34 "quality" research items was calculated for all centers (mean: 23.2 ± 6.2; range: 6-34).
CONCLUSION:  Research experience and processes vary across Europe. Harmonizing research practices and setting standards will allow building a European neonatal network for effective, safe, and quality neonatal drug development.

PMID: 29695003 [PubMed - in process]

Association of Inhaled Corticosteroids and Long-Acting β-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma: A Systematic Review and Meta-analysis.

JAMA. 2018 04 10;319(14):1485-1496

Authors: Sobieraj DM, Weeda ER, Nguyen E, Coleman CI, White CM, Lazarus SC, Blake KV, Lang JE, Baker WL

Abstract
Importance: Combined use of inhaled corticosteroids and long-acting β-agonists (LABAs) as the controller and the quick relief therapy termed single maintenance and reliever therapy (SMART) is a potential therapeutic regimen for the management of persistent asthma.
Objective: To conduct a systematic review and meta-analysis of the effects of SMART in patients with persistent asthma.
Data Sources and Study Selection: The databases of MEDLINE via OVID, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched from database inception through August 2016 and updated through November 28, 2017. Two reviewers selected randomized clinical trials or observational studies evaluating SMART vs inhaled corticosteroids with or without a LABA used as the controller therapy and short-acting β-agonists as the relief therapy for patients aged 5 years or older with persistent asthma and reporting on an outcome of interest.
Data Extraction and Synthesis: Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs), risk differences (RDs), and mean differences with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength of evidence grading were completed by 2 independent reviewers.
Main Outcomes and Measures: Asthma exacerbations.
Results: The analyses included 16 randomized clinical trials (N = 22 748 patients), 15 of which evaluated SMART as a combination therapy with budesonide and formoterol in a dry-powder inhaler. Among patients aged 12 years or older (n = 22 524; mean age, 42 years; 14 634 [65%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.68 [95% CI, 0.58 to 0.80]; RD, -6.4% [95% CI, -10.2% to -2.6%]) and a higher dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.77 [95% CI, 0.60 to 0.98]; RD, -2.8% [95% CI, -5.2% to -0.3%]). Similar results were seen when SMART was compared with inhaled corticosteroids alone as the controller therapy. Among patients aged 4 to 11 years (n = 341; median age, 8 [range, 4-11] years; 69 [31%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids as the controller therapy (RR, 0.55 [95% CI, 0.32 to 0.94]; RD, -12.0% [95% CI, -22.5% to -1.5%]) or the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.38 [95% CI, 0.23 to 0.63]; RD, -23.2% [95% CI, -33.6% to -12.1%]).
Conclusions and Relevance: In this meta-analysis of patients with persistent asthma, the use of single maintenance and reliever therapy compared with inhaled corticosteroids as the controller therapy (with or without a long-acting β-agonist) and short-acting β-agonists as the relief therapy was associated with a lower risk of asthma exacerbations. Evidence for patients aged 4 to 11 years was limited.

PMID: 29554195 [PubMed - indexed for MEDLINE]

Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma: A Systematic Review and Meta-analysis.

JAMA. 2018 04 10;319(14):1473-1484

Authors: Sobieraj DM, Baker WL, Nguyen E, Weeda ER, Coleman CI, White CM, Lazarus SC, Blake KV, Lang JE

Abstract
Importance: Long-acting muscarinic antagonists (LAMAs) are a potential adjunct therapy to inhaled corticosteroids in the management of persistent asthma.
Objective: To conduct a systematic review and meta-analysis of the effects associated with LAMA vs placebo or vs other controllers as an add-on therapy to inhaled corticosteroids and the use of a LAMA as add-on therapy to inhaled corticosteroids and long-acting β-agonists (LABAs; hereafter referred to as triple therapy) vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma.
Data Sources: MEDLINE, EMBASE, Cochrane databases, and clinical trial registries (earliest date through November 28, 2017).
Study Selection: Two reviewers selected randomized clinical trials or observational studies evaluating a LAMA vs placebo or vs another controller as an add-on therapy to inhaled corticosteroids or triple therapy vs inhaled corticosteroids and LABA in patients with uncontrolled, persistent asthma reporting on an outcome of interest.
Data Extraction and Synthesis: Meta-analyses using a random-effects model was conducted to calculate risk ratios (RRs), risk differences (RDs), and mean differences (MDs) with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength-of-evidence grading were completed by 2 independent reviewers.
Main Outcomes and Measures: Asthma exacerbations.
Results: Of 1326 records identified, 15 randomized clinical trials (N = 7122 patients) were included. Most trials assessed adding LAMA vs placebo or LAMA vs LABA to inhaled corticosteroids. Adding LAMA vs placebo to inhaled corticosteroids was associated with a significantly reduced risk of exacerbation requiring systemic corticosteroids (RR, 0.67 [95% CI, 0.48 to 0.92]; RD, -0.02 [95% CI, -0.04 to 0.00]). Compared with adding LABA, adding LAMA to inhaled corticosteroids was not associated with significant improvements in exacerbation risk (RR, 0.87 [95% CI, 0.53 to 1.42]; RD, 0.00 [95% CI, -0.02 to 0.02]), or any other outcomes of interest. Triple therapy was not significantly associated with improved exacerbation risk vs inhaled corticosteroids and LABA (RR, 0.84 [95% CI, 0.57 to 1.22]; RD, -0.01 [95% CI, -0.08 to 0.07]).
Conclusions and Relevance: In this systematic review and meta-analysis, the use of LAMA compared with placebo as add-on therapy to inhaled corticosteroids was associated with a lower risk of asthma exacerbations; however, the association of LAMA with benefit may not be greater than that with LABA. Triple therapy was not associated with a lower risk of exacerbations.

PMID: 29554174 [PubMed - indexed for MEDLINE]

Structure of Transmembrane Helix 8 and Possible Membrane Defects in CFTR.

Biophys J. 2018 Apr 24;114(8):1751-1754

Authors: Corradi V, Gu RX, Vergani P, Tieleman DP

Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that regulates the flow of anions across epithelia. Mutations in CFTR cause cystic fibrosis. CFTR belongs to the ATP-binding cassette transporter superfamily, and gating is controlled by phosphorylation and ATP binding and hydrolysis. Recently obtained ATP-free and ATP-bound structures of zebrafish CFTR revealed an unwound segment of transmembrane helix (TM) 8, which appears to be a unique feature of CFTR not present in other ATP-binding cassette transporter structures. Here, using μs-long molecular dynamics simulations, we investigate the interactions formed by this TM8 segment with nearby helices in both ATP-free and ATP-bound states. We highlight ATP-dependent interactions as well as the structural role of TM8 in maintaining the functional architecture of the pore via interactions common to both the ATP-bound and ATP-free state. The results of the molecular dynamics simulations are discussed in the context of the gating mechanism of CFTR.

PMID: 29694855 [PubMed - in process]

Association between hypovitaminosis D and frequency of pulmonary exacerbations in children and adolescents with cystic fibrosis.

Einstein (Sao Paulo). 2018;16(1):eAO4143

Authors: Ongaratto R, Rosa KMD, Eloi JC, Epifanio M, Marostica P, Pinto LA

Abstract
Objective We evaluated the association between vitamin D levels and nutritional status, pulmonary function and pulmonary exacerbations in children and adolescents with cystic fibrosis. Methods 25-hydroxyvitamin D (25(OH)D) levels of 37 children and adolescents were retrospectively evaluated. Pulmonary function, body mass index, height for age, and pulmonary exacerbations episodes were associated with vitamin D levels divided into two groups: sufficient (≥30ng/mL) and hypovitaminosis (<30ng/mL). Results Hypovitaminosis D (25(OH)D <30ng/mL) was observed in 54% of subjects. The mean level of 25(OH)D was 30.53±12.14ng/mL. Pulmonary function and nutritional status were not associated with vitamin D levels. Pulmonary exacerbations over a 2-year period (p=0.007) and the period from measurement up to the end of the follow-up period (p=0.002) were significantly associated with vitamin D levels. Conclusion Hypovitaminosis D was associated with higher rates of pulmonary exacerbations in this sample of children and adolescents with cystic fibrosis. Hypovitaminosis D should be further studied as a marker of disease severity in cystic fibrosis. Further prospective and randomized studies are necessary to investigate causality of this association.

PMID: 29694616 [PubMed - in process]

Intrapulmonary Percussive Ventilation as an Airway Clearance Technique in Subjects With Chronic Obstructive Airway Diseases.

Respir Care. 2018 Apr 24;:

Authors: Reychler G, Debier E, Contal O, Audag N

Abstract
BACKGROUND: Airway clearance techniques are regularly proposed as a part of the treatment in chronic obstructive airway diseases. Intrapulmonary percussive ventilation (IPV) is used as an airway clearance technique in patients affected by excessive lung secretions. The aim of this systematic review is to summarize the physiological and clinical effects related to the use of IPV as an airway clearance technique in chronic obstructive airway diseases.
METHODS: This systematic review followed the PRISMA guidelines. Randomized, controlled, comparative, and cohort studies investigating IPV as an airway clearance technique were identified and reviewed from 3 databases. Two reviewers independently assessed study quality and reviewed the selected studies.
RESULTS: 278 subjects from 12 studies were included in the final analysis, with 3 diseases studied. Only one of the included studies had a sample size > 50 subjects. The main findings showed that IPV improves gas exchange during exacerbation and could reduce the hospital length of stay for patients with COPD. In subjects with cystic fibrosis, neither lung function nor other parameters were improved.
CONCLUSIONS: The systematic use of IPV as an airway clearance technique in chronic obstructive airway diseases is not supported by sufficiently strong evidence to recommend routine use in this patient population.

PMID: 29692351 [PubMed - as supplied by publisher]

Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis.

Pancreas. 2016 Oct;45(9):1347-52

Authors: Palermo JJ, Lin TK, Hornung L, Valencia CA, Mathur A, Jackson K, Fei L, Abu-El-Haija M

Abstract
OBJECTIVES: The aim of this study was to determine if comprehensive genetic testing was useful to identify genetic variants that discriminate chronic pancreatitis (CP) from acute recurrent pancreatitis (ARP) in a pediatric population.
METHODS: We conducted a retrospective review of 50 patients enrolled in our institutional pancreatitis registry between April 2013 and January 2015. Genetic analysis of PRSS1, CFTR, SPINK1, and CTRC classified variants as mutations or variants of unknown clinical significance and the minor allele frequency of variants in our cohort was obtained.
RESULTS: Genetic testing was obtained in 16/16 (100%) of CP and 29/34 (85%) of ARP patients. A total of 39 genetic variants were found in 27 (60%) of 45 subjects tested with 5 (11%) subjects having 2 different genes affected. Variant frequency was greatest in patients for CFTR (17/45, 38%) followed by SPINK1 (11/44, 25%), CTRC (2/27, 7%), and PRSS1 (2/44, 4%). CFTR variants were more likely in those with CP compared to ARP (63% and 24%, P = 0.01).
CONCLUSIONS: This study is the first to find a higher rate of CFTR mutations in CP versus ARP groups using comprehensive genetic testing in a pediatric population.

PMID: 27171515 [PubMed - indexed for MEDLINE]

Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles.

Eur J Hum Genet. 2018 Apr 25;:

Authors: Qian J, Nguyen NMP, Rezaei M, Huang B, Tao Y, Zhang X, Cheng Q, Yang H, Asangla A, Majewski J, Slim R

Abstract
Recurrent hydatidiform moles (RHM) are aberrant human pregnancies characterized by absence of, or abnormal, embryonic development, hydropic degeneration of chorionic villi, and hyperproliferation of the trophoblast. Biallelic mutations in two maternal-effect genes, NLRP7 and KHDC3L, underlie the causation of RHM in 60% of patients. We performed exome sequencing on a patient with six pregnancy losses, two miscarriages and four HM, and found no variants that affect the functions of the known genes. We found biallelic missense variants that affect conserved amino acids in PADI6 and segregate with the disease phenotype in the family. PADI6 is another maternal-effect gene and a member of the subcortical maternal complex that has been shown to have recessive variants that affect the gene function in four unrelated women with infertility who also experienced early embryonic arrest during preimplantation development after IVF. We demonstrated that PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos and reviewed the morphology and genotypes of four products of conception from our patient. Our data expand the involvement of PADI6 to other forms of reproductive loss and highlight the commonality between infertility, miscarriages, and molar pregnancies, in some cases.

PMID: 29693651 [PubMed - as supplied by publisher]

Phenotype risk scores identify patients with unrecognized Mendelian disease patterns.

Science. 2018 03 16;359(6381):1233-1239

Authors: Bastarache L, Hughey JJ, Hebbring S, Marlo J, Zhao W, Ho WT, Van Driest SL, McGregor TL, Mosley JD, Wells QS, Temple M, Ramirez AH, Carroll R, Osterman T, Edwards T, Ruderfer D, Velez Edwards DR, Hamid R, Cogan J, Glazer A, Wei WQ, Feng Q, Brilliant M, Zhao ZJ, Cox NJ, Roden DM, Denny JC

Abstract
Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach that aggregates phenotypes on the basis of patterns described by Mendelian diseases. We mapped the clinical features of 1204 Mendelian diseases into phenotypes captured from the electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In an initial validation, PheRS distinguished cases and controls of five Mendelian diseases. Applying PheRS to 21,701 genotyped individuals uncovered 18 associations between rare variants and phenotypes consistent with Mendelian diseases. In 16 patients, the rare genetic variants were associated with severe outcomes such as organ transplants. PheRS can augment rare-variant interpretation and may identify subsets of patients with distinct genetic causes for common diseases.

PMID: 29590070 [PubMed - indexed for MEDLINE]

HABP2 p.G534E variant in patients with family history of thyroid and breast cancer.

Oncotarget. 2017 Jun 20;8(25):40896-40905

Authors: Pinheiro M, Drigo SA, Tonhosolo R, Andrade SCS, Marchi FA, Jurisica I, Kowalski LP, Achatz MI, Rogatto SR

Abstract
Familial Papillary Thyroid Carcinoma (PTC) has been described as a hereditary predisposition cancer syndrome associated with mutations in candidate genes including HABP2. Two of 20 probands from families with history of PTC and breast carcinoma (BC) were evaluated by whole exome sequencing (WES) revealing HABP2 p.G534E. Sanger sequencing was used to confirm the involvement of this variant in three families (F1: 7 relatives; F2: 3 and F3: 3). The proband and his sister (with no malignant tumor so far) from F1 were homozygous for the variant whereas one relative with PTC from F2 was negative for the variant. Although the proband of the F3 with PTC was HABP2 wild type, three relatives presented the variant. Five of 170 healthy Brazilian individuals with no family history of BC or PTC and three of 50 sporadic PTC presented the p.G534E. These findings suggested no association of this variant with our familial PTC cases. Genes potentially associated with deregulation of the extracellular matrix organization pathway (CTSB, TNXB, COL4A3, COL16A1, COL24A1, COL5A2, NID1, LOXL2, MMP11, TRIM24 and MUSK) and DNA repair function (NBN and MSH2) were detected by WES, suggesting that other cancer-associated genes have pathogenic effects in the risk of familial PTC development.

PMID: 28402931 [PubMed - indexed for MEDLINE]

In response to: "Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning".

Eur J Clin Pharmacol. 2018 02;74(2):251

Authors: Harmouche E, Howland MA, K Su M

PMID: 29159489 [PubMed - indexed for MEDLINE]

Knowledge, Attitude and Practice Regarding Pharmacovigilance and Consumer Pharmacovigilance among Consumers at Lalitpur District, Nepal.

J Nepal Health Res Counc. 2017 Jan;15(35):31-37

Authors: Jha N, Rathore DS, Shankar PR, Bhandary S, Alshakka M, Gyawali S

Abstract
BACKGROUND: Adverse drug reactions (ADRs) can be a big threat to the health of people in Nepal as a variety of medicines are consumed in the country. Involving consumers in pharmacovigilance can strengthen ADR reporting. The study aims to find out knowledge, attitude and practice regarding pharmacovigilance and consumer pharmacovigilance among consumers at Lalitpur district, Nepal Methods: It was carried out in outpatients visiting in KIST Medical College and Teaching Hospital, Lalitpur, Nepal. Participant's knowledge, attitude and practice were measured by noting their agreement with a set of 21 statements along with multiple choice and open ended questions.
RESULTS: A total of 157 outpatients were surveyed. The knowledge scores for males (12) was better compared to the females (11), but the scores for attitude and practice were same for both groups. The maximum score for knowledge was 29, attitude was 6 and practice was 10. The overall KAP scores was 45. The total scores for knowledge, attitude and practice for males (24) were better compared to female (22) respondents. Seventy-one patients (68%) who participated in this study favoured establishing a consumer centre for obtaining information about ADRs.
CONCLUSIONS: Knowledge scores among consumers regarding pharmacovigilance is low and require advocacy and improvement.

PMID: 28714489 [PubMed - indexed for MEDLINE]

Data-mining for detecting signals of adverse drug reactions of fluoxetine using the Korea Adverse Event Reporting System (KAERS) database.

Psychiatry Res. 2017 Oct;256:237-242

Authors: Kim S, Park K, Kim MS, Yang BR, Choi HJ, Park BJ

Abstract
Selective serotonin reuptake inhibitors (SSRIs) have become one of the most broadly used medications in psychiatry. Fluoxetine is the first representative antidepressant SSRI drug approved by the Food and Drug Administration (FDA) in 1987. Safety information on fluoxetine use alone was less reported than its combined use with other drugs. There were no published papers on adverse drug reactions (ADRs) of fluoxetine analyzing spontaneous adverse events reports. We detected signals of the adverse drug reactions of fluoxetine by data mining using the Korea Adverse Events Reporting System (KAERS) database. We defined signals in this study by the reporting odds ratios (ROR), proportional reporting ratios (PRR), and information components (IC) indices. The KAERS database included 860,224 AE reports, among which 866 reports contained fluoxetine. We compared the labels of fluoxetine among the United States, UK, Germany, France, China, and Korea. Some of the signals, including emotional lability, myositis, spinal stenosis, paradoxical drug reaction, drug dependence, extrapyramidal disorder, adrenal insufficiency, and intracranial hemorrhage, were not labeled in the six countries. In conclusion, we identified new signals that were not known at the time of market approval. However, certain factors should be required for signal evaluation, such as clinical significance, preventability, and causality of the detected signals.

PMID: 28646789 [PubMed - indexed for MEDLINE]

Amiodarone-induced thyroid dysfunction and a perturbed N-desethyl-amiodarone to amiodarone ratio: could a drug-induced toxicity be regulating exposure to the offending agent?

Eur J Clin Pharmacol. 2017 08;73(8):1051-1052

Authors: Rowland A, Rowland A, Sorich MJ, Mangoni AA

PMID: 28470396 [PubMed - indexed for MEDLINE]

Response: Amiodarone-induced thyroid dysfunction and a perturbed N-desethyl-amiodarone to amiodarone ratio; could a drug-induced toxicity be regulating exposure to the offending agent?

Eur J Clin Pharmacol. 2017 08;73(8):1053-1054

Authors: Takada M, Yamato M, Wada K, Fujimoto M, Hosomi K, Hayashi T, Oita A

PMID: 28456822 [PubMed - indexed for MEDLINE]

Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP).

J Immunother Cancer. 2017;5:19

Authors: King J, de la Cruz J, Lutzky J

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.

PMID: 28344807 [PubMed - indexed for MEDLINE]

Sudden hearing loss in a melanoma patient on pembrolizumab: an etiology not to be omitted in the differential diagnosis.

J Immunother Cancer. 2017;5:24

Authors: Nader ME, Myers JN, Gidley PW

Abstract
Immune checkpoint inhibitors have emerged as a promising therapeutic option for metastatic cancers. However, they have been associated with inflammatory adverse reactions in various organ systems. A recent article reported a case of sudden bilateral hearing loss that occurred in a patient with metastatic melanoma being treated with pembrolizumab. The authors attributed that complication to an autoimmune reaction secondary to the treatment. This commentary discusses the importance of considering the diagnosis of leptomeningeal metastasis in patients with metastatic melanoma who present with new cranial nerve deficits.

PMID: 28331614 [PubMed - indexed for MEDLINE]

Interstitial nephritis in melanoma patients secondary to PD-1 checkpoint inhibitor.

J Immunother Cancer. 2017;5:3

Authors: Escandon J, Peacock S, Trabolsi A, Thomas DB, Layka A, Lutzky J

Abstract
BACKGROUND: Immune checkpoint inhibitors have become the first line therapy in melanoma treatment and their use is extending to other malignancies. However, we are still learning about immune side effects produced by these drugs and their severity especially in patients with history of inflammatory diseases.
CASE PRESENTATION: We present two cases of metastatic melanoma treated with nivolumab and pembrolizumab (anti PD-1). Both patients developed acute interstitial nephritis during immune checkpoint therapy. We emphasize the causal association between immune checkpoint inhibitors and the nephritis. The timing of drug administration and appearance of nephritis is suggestive of a causal relation between the checkpoint inhibitor therapy and this adverse event.
CONCLUSIONS: Although uncommon, some side effects from checkpoint inhibitors can be severe and may need to be addressed with immunosuppression. Given the increasing frequency of immunotherapy use, awareness should be raised in regards to immune side effects and their appropriate management.

PMID: 28105370 [PubMed - indexed for MEDLINE]