Phase I Study of the Focal Adhesion Kinase Inhibitor BI 853520 in Japanese and Taiwanese Patients with Advanced or Metastatic Solid Tumors.

Target Oncol. 2019 Feb 06;:

Authors: Doi T, Yang JC, Shitara K, Naito Y, Cheng AL, Sarashina A, Pronk LC, Takeuchi Y, Lin CC

Abstract
BACKGROUND: Focal adhesion kinase (FAK) inhibitors have demonstrated anti-tumor activity preclinically and are currently being evaluated in humans. A first-in-human study evaluating the novel FAK inhibitor BI 853520 in a predominantly Caucasian population with advanced or metastatic non-hematologic malignancies demonstrated acceptable tolerability and favorable pharmacokinetics.
OBJECTIVE: This study was undertaken to investigate the safety, tolerability, and maximum tolerated dose (MTD) of BI 853520 in Japanese and Taiwanese patients with advanced solid tumors.
PATIENTS AND METHODS: In this open-label, phase I, dose-finding study, BI 853520 was administered once daily (QD) in a continuous daily dosing regimen with 28-day cycles and escalating doses to sequential cohorts of patients. Twenty-one patients (62% male; median age 65 years) were treated at two sites in Japan and Taiwan.
RESULTS: The median duration of treatment was 1.2 months (range 0.2-7.7). As no dose-limiting toxicities were observed during cycle 1 in the 50, 100, or 200 mg cohorts, the MTD of BI 853520 was determined to be 200 mg QD. Drug-related adverse events were reported in 19 patients (90%), and all except one were of grade 1 or 2. Pharmacokinetic parameters were supportive of a once-daily dosing schedule. A confirmed objective response rate of 5% and disease control rate of 29% were achieved; median duration of disease control was 3.7 months.
CONCLUSIONS: This trial demonstrated a manageable and acceptable safety profile, favorable pharmacokinetics, and potential anti-tumor activity of BI 853520 in pretreated Japanese and Taiwanese patients with advanced or metastatic solid tumors.
CLINICAL TRIALS REGISTRATION: NCT01905111.

PMID: 30725402 [PubMed - as supplied by publisher]

Phase I dose-escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors.

Cancer Sci. 2019 Feb 06;:

Authors: Esaki T, Hirai F, Makiyama A, Seto T, Bando H, Naito Y, Yoh K, Ishihara K, Kakizume T, Natsume K, Myers A, Doi T

Abstract
Capmatinib is a highly specific, potent, and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics, and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose-limiting toxicities (DLTs) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [qd] to 600 mg twice daily [bid]) and 15 received tablets (200 mg bid and 400 mg bid). DLTs occurred in 2 patients: grade 2 suicidal ideation (600 mg bid capsule) and grade 3 depression (400 mg bid tablet). MTD was not reached. The highest studied dose determined to be safe as tablets was 400 mg bid, whereas it is not yet determined for capsules. Most common adverse events suspected to be drug related were blood creatinine increased, nausea, decreased appetite, vomiting, and diarrhea. Following repeated daily dosing up to day 15 by qd or bid regimen using capsules, median time to reach maximum plasma drug concentration (Tmax ) was 1.0-4.0 hours; absorption was more rapid after dosing using tablets, with median Tmax of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib. This article is protected by copyright. All rights reserved.

PMID: 30724423 [PubMed - as supplied by publisher]

Addressing the under-reporting of adverse drug reactions in public health programs controlling HIV/AIDS, Tuberculosis and Malaria: A prospective cohort study.

PLoS One. 2018;13(8):e0200810

Authors: Avong YK, Jatau B, Gurumnaan R, Danat N, Okuma J, Usman I, Mordi D, Ukpabi B, Kayode GA, Dutt S, El-Tayeb O, Afolabi B, Ambrose I, Agbaji O, Osakwe A, Ibrahim A, Ogar C, Nosiri H, Avong EB, Adekanmbi V, Uthman O, Abimiku A, Oni YO, Mensah CO, Dakum P, Mberu KE, Ogundahunsi OAT

Abstract
BACKGROUND: Adverse Drug Reactions (ADRs) are a major clinical and public health problem world-wide. The prompt reporting of suspected ADRs to regulatory authorities to activate drug safety surveillance and regulation appears to be the most pragmatic measure for addressing the problem. This paper evaluated a pharmacovigilance (PV) training model that was designed to improve the reporting of ADRs in public health programs treating the Human Immunodeficiency Virus (HIV), Tuberculosis (TB) and Malaria.
METHODS: A Structured Pharmacovigilance and Training Initiative (SPHAR-TI) model based on the World Health Organization accredited Structured Operational Research and Training Initiative (SOR-IT) model was designed and implemented over a period of 12 months. A prospective cohort design was deployed to evaluate the outcomes of the model. The primary outcomes were knowledge gained and Individual Case Safety Reports (ICSR) (completed adverse drug reactions monitoring forms) submitted, while the secondary outcomes were facility based Pharmacovigilance Committees activated and health facility healthcare workers trained by the participants.
RESULTS: Fifty-five (98%) participants were trained and followed up for 12 months. More than three quarter of the participants have never received training on pharmacovigilance prior to the course. Yet, a significant gain in knowledge was observed after the participants completed a comprehensive training for six days. In only seven months, 3000 ICSRs (with 100% completeness) were submitted, 2,937 facility based healthcare workers trained and 46 Pharmacovigilance Committees activated by the participants. Overall, a 273% increase in ICSRs submission to the National Agency for Food and Drug Administration and Control (NAFDAC) was observed.
CONCLUSION: Participants gained knowledge, which tended to increase the reporting of ADRs. The SPHAR-TI model could be an option for strengthening the continuous reporting of ADRs in public health programs in resource limited settings.

PMID: 30133453 [PubMed - indexed for MEDLINE]

Inhibitor development, safety, and efficacy of Advate® in previously untreated patients with hemophilia A in a postmarketing surveillance in Japan.

Int J Hematol. 2019 Jan;109(1):70-78

Authors: Taki M, Fukutake K, Matsushita T, Nogami K, Shima M, Yoshioka A, Takamatsu J, Arai M, Takagi H, Uchikawa H, Engl W, Shirahata A

Abstract
Rurioctocog alfa (recombinant Factor VIII: AdvateⓇ) is available for the control of bleeding in patients with hemophilia A in Japan. To evaluate the immunogenicity, safety, and efficacy of prophylactic and on-demand use of rurioctocog alfa, postmarketing surveillance was conducted on 114 previously untreated Japanese patients aged 0-82 years with ≤ 3 exposure days under the conditions of routine clinical practice. A post-hoc comparison of mean annualized bleeding rates between patients in the regular prophylaxis group (7.4 bleeds/year) and in the on-demand treatment group (15.7 bleeds/year) using a negative binomial model found a statistically significant difference (P = 0.0164) in the subset of patients with severe hemophilia A. Favorable prophylactic and on-demand hemostatic efficacy ("excellent" or "good") was shown in 71.4-88.5% across all treatment regimens. A total of 31 events of adverse drug reactions were reported. Of 114 patients, 21 (18.4%) developed de novo FVIII inhibitor; of these, 17 occurred within 50 exposures. One death was reported. A family history of positive inhibitors was significantly associated with inhibitor development (Fisher exact P value = 0.0004); no other risk factors were identified. Rurioctocog alfa was found to be well-tolerated and effective in previously untreated Japanese patients with hemophilia A in this postmarketing surveillance of routine clinical practice.

PMID: 30043332 [PubMed - indexed for MEDLINE]

Grading the potential safety risk of medications used in hospital care.

Farm Hosp. 2018 03 01;42(2):53-61

Authors: Vicente Oliveros N, Pérez Menéndez Conde C, Álvarez Díaz AM, Bermejo Vicedo T, Martín-Aragón Álvarez S, Montero Errasquín B, Calleja López JL, Gálvez Múgica MA, Nieto Gómez G, García Menéndez G, Chamarro Rubio S, Delgado Silveira E

Abstract
OBJECTIVE: The aim of this study was to stratify medications used in hospital  care according to their potential risk.
METHOD: The RAND/UCLA Appropriateness Method was used. Anatomical Therapeutic Chemical subgroups were classified according to their potential risk. A literature search, bulletins, and alerts issued by patient safety organizations were used to identify the potential safety risk of  these subgroups. Nine experts in patient/medication safety were selected to score the subgroups for their appropriateness in the classification. Two evaluation rounds were conducted: the first by email and the second by a  panel meeting.
RESULTS: A total of 298 Anatomical Therapeutic Chemical subgroups were  evaluated. They were classified into three scenarios (low, medium, and high  risk). In the first round, 266 subgroups were classified as appropriate to the  assigned scenario, 32 were classified as uncertain, and none were classified as  inappropriate. In the second round, all subgroups were classified as appropriate.  The most frequent subgroups in the low-risk scenario belonged to  group A "Alimentary tract and metabolism" (44%); the most frequent in the  medium-risk scenario belonged to group J "Antiinfectives for systemic use"  (32%); and the most frequent in the high-risk scenario belonged to group L  "Antineoplastic and immunomodulating agents" (29%) and group N "Nervous  system" (26%).
CONCLUSIONS: Based on the RAND/UCLA appropriateness method, Anatomical  Therapeutic Chemical subgroups used in hospital care were classified according  to their potential risk (low, medium, or high). These lists can be incorporated  into a risk-scoring tool for future patient/medication safety studies.

PMID: 29501056 [PubMed - indexed for MEDLINE]

Combination of Metformin and Lifestyle Intervention for Antipsychotic-Related Weight Gain: A Meta-Analysis of Randomized Controlled Trials.

Pharmacopsychiatry. 2019 Jan;52(1):24-31

Authors: Zheng W, Zhang QE, Cai DB, Yang XH, Ungvari GS, Ng CH, Wu RR, Xiang YT

Abstract
INTRODUCTION: Weight gain is a common antipsychotic (AP)-related adverse drug reaction (ADR) that can increase the risk of cardiovascular diseases and premature mortality. This meta-analysis examined the efficacy and tolerability of combining metformin and lifestyle intervention for AP-related weight gain in schizophrenia.
METHODS: Randomized controlled trials (RCTs) with meta-analyzable data were searched and retrieved by 2 independent investigators. RevMan software (version 5.3) was used to synthesize data, and to calculate the standardized or weighted mean differences and risk ratio with their 95% confidence intervals.
RESULTS: Six RCTs (n=732) were included and meta-analyzed. The metformin and lifestyle combination (MLC) group had significant reduction in weight and body mass index compared with the metformin group, lifestyle group, and placebo group. There was less frequent weight gain of≥7% in the MLC group over placebo. No other group differences in ADRs, total psychopathology, and all-cause discontinuation were found. In terms of study quality, 5 RCTs were open-labelled, 1 RCT had low risk allocation concealment, and 3 RCTs specifically described randomization methods.
CONCLUSION: Combining metformin and lifestyle intervention shows significant effect in reducing AP-related weight gain. Higher quality and larger RCTs are needed to confirm these findings.Review registration: CRD42017059198.

PMID: 29486513 [PubMed - indexed for MEDLINE]

Minocycline-induced transient depersonalization: A case report.

SAGE Open Med Case Rep. 2019;7:2050313X18823827

Authors: Shamout Y, Sigal A, Litvinov IV

Abstract
Minocycline is a medication commonly used for the treatment of acne vulgaris. The central nervous system-induced side effects of minocycline include headaches, pseudotumor cerebri, ataxia, and vestibular dysfunction. Many minocycline-related side effects have been presented in the literature, however, reports of depersonalization symptoms induced by the medication are rare. We present the case of a 37-year-old female diagnosed with perioral dermatitis treated with minocycline, who within 1 week suffered from severe depersonalization symptoms. The pathophysiologic mechanism of depersonalization induced by minocycline is unclear but various hypotheses include hypersensitivity of the serotonin system, drug-related metabolic encephalopathy, substance-induced temporal disintegration, and panic-disorder-related etiology. Depersonalization is a potentially severe and important side effect of minocycline that should be documented, further investigated, and recognized by clinicians.

PMID: 30719316 [PubMed]

Negative and positive self-thoughts predict subjective quality of life in people with schizophrenia.

Neuropsychiatr Dis Treat. 2019;15:293-301

Authors: Takeda T, Nakataki M, Ohta M, Hamatani S, Matsuura K, Yoshida R, Kameoka N, Tominaga T, Umehara H, Kinoshita M, Watanabe S, Numata S, Sumitani S, Ohmori T

Abstract
Purpose: Recently, cognitive variables such as negative and positive self-belief and thoughts have attracted much attention because they are associated with functional outcomes and quality of life (QOL). However, it is unclear how cognitive variables affect subjective and objective QOL. This study aimed to investigate the relationship of negative and positive self-belief and thoughts with subjective and objective QOL.
Participants and methods: Thirty-six people with schizophrenia participated in this study. Subjective and objective QOL were assessed with the Schizophrenia Quality of Life Scale (SQLS) and Quality of Life Scale (QLS), respectively. Neurocognitive function was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Clinical symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale for Schizophrenia. Side effects were assessed with the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS). Negative and positive self-belief and thoughts were assessed with the Defeatist Performance Belief Scale and Automatic Thoughts Questionnaire-Revised. A generalized linear model was tested, with subjective and objective QOL as the response variable and symptoms, neurocognitive function, and cognitive variables that were significantly correlated with subjective and objective QOL as explanatory variables.
Results: In the schizophrenia group, the common objects score on the QLS was predicted by the composite BACS score, and the total QLS score was predicted by the DIEPSS score. Motivation and Energy, Psychosocial, and Symptoms and Side effects scores on the SQLS were predicted by depression and by negative automatic thought (NAT) and positive automatic thought (PAT).
Conclusion: Our results indicated that key targets for improving objective and subjective QOL in people with schizophrenia are side effects, neurocognitive function, depression, and NAT and PAT.

PMID: 30718955 [PubMed]

Using a Consensus Docking Approach to Predict Adverse Drug Reactions in Combination Drug Therapies for Gulf War Illness.

Int J Mol Sci. 2018 Oct 26;19(11):

Authors: Jaundoo R, Bohmann J, Gutierrez GE, Klimas N, Broderick G, Craddock TJA

Abstract
Gulf War Illness (GWI) is a chronic multisymptom illness characterized by fatigue, musculoskeletal pain, and gastrointestinal and cognitive dysfunction believed to stem from chemical exposures during the 1990⁻1991 Persian Gulf War. There are currently no treatments; however, previous studies have predicted a putative multi-intervention treatment composed of inhibiting Th1 immune cytokines followed by inhibition of the glucocorticoid receptor (GCR) to treat GWI. These predictions suggest the use of specific monoclonal antibodies or suramin to target interleukin-2 and tumor necrosis factor α , followed by mifepristone to inhibit the GCR. In addition to this putative treatment strategy, there exist a variety of medications that target GWI symptomatology. As pharmaceuticals are promiscuous molecules, binding to multiple sites beyond their intended targets, leading to off-target interactions, it is key to ensure that none of these medications interfere with the proposed treatment avenue. Here, we used the drug docking programs AutoDock 4.2, AutoDock Vina, and Schrödinger's Glide to assess the potential off-target immune and hormone interactions of 43 FDA-approved drugs commonly used to treat GWI symptoms in order to determine their putative polypharmacology and minimize adverse drug effects in a combined pharmaceutical treatment. Several of these FDA-approved drugs were predicted to be novel binders of immune and hormonal targets, suggesting caution for their use in the proposed GWI treatment strategy symptoms.

PMID: 30373189 [PubMed - indexed for MEDLINE]

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/02/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2019/02/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Improving drug allergy management in Australia: education, communication and accurate information.

Med J Aust. 2019 Feb;210(2):62-64

Authors: Lucas M, Loh RK, Smith WB

PMID: 30712299 [PubMed - in process]

First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity.

Eur J Cancer. 2019 Jan 31;109:103-110

Authors: Postel-Vinay S, Herbschleb K, Massard C, Woodcock V, Soria JC, Walter AO, Ewerton F, Poelman M, Benson N, Ocker M, Wilkinson G, Middleton M

Abstract
BACKGROUND: Bromodomain and extraterminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC- or BRD4-driven diseases. A first-in-human study investigated the safety, pharmacokinetics, maximum tolerated dose and recommended phase II dose of the BET inhibitor BAY 1238097 in patients with advanced malignancies.
MATERIAL AND METHODS: In this phase I, open-label, non-randomised, multicentre study, patients with cytologically or histologically confirmed advanced refractory malignancies received oral BAY 1238097 twice weekly in 21-day cycles using an adaptive dose-escalation design at a starting dose of 10 mg/week. Model-based dose-response analysis was performed to guide dose escalation. Safety, pharmacokinetics, pharmacodynamics and tumour response were evaluated.
RESULTS: Eight patients were enrolled at three dose levels (10 mg/week, n = 3; 40 mg/week, n = 3; 80 mg/week, n = 2). Both patients receiving 80 mg/week had dose-limiting toxicities (DLTs) (grade 3 vomiting, grade 3 headache and grade 2/3 back pain). The most common adverse events were nausea, vomiting, headache, back pain and fatigue. Pharmacokinetic analysis indicated a linear dose response with increasing dose. Two patients displayed prolonged stable disease; no responses were observed. Biomarker evaluation of MYC and HEXIM1 expression demonstrated an emerging pharmacokinetic/pharmacodynamic relationship, with a trend towards decreased MYC and increased HEXIM1 expression in response to treatment.
CONCLUSION: The study was prematurely terminated because of the occurrence of DLTs at a dose below targeted drug exposure. Pharmacokinetic modelling indicated that an alternate dosing schedule whereby DLTs could be avoided while reaching efficacious exposure was not feasible. Registration number: NCT02369029.

PMID: 30711772 [PubMed - as supplied by publisher]

Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival.

EBioMedicine. 2019 Jan 30;:

Authors: Hallberg P, Smedje H, Eriksson N, Kohnke H, Daniilidou M, Öhman I, Yue QY, Cavalli M, Wadelius C, Magnusson PKE, Landtblom AM, Wadelius M, Swedegene

Abstract
BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.
METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.
FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.
INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

PMID: 30711515 [PubMed - as supplied by publisher]

Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1.

Eur J Cancer. 2019 Jan 29;109:92-102

Authors: Montemurro F, Ellis P, Anton A, Wuerstlein R, Delaloge S, Bonneterre J, Quenel-Tueux N, Linn SC, Irahara N, Donica M, Lindegger N, Barrios CH

Abstract
BACKGROUND: Many patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) are candidates for trastuzumab emtansine (T-DM1) treatment sometime in their disease history. KAMILLA evaluated safety of T-DM1 in patients with previously treated HER2-positive locally advanced or metastatic BC (advanced BC).
METHODS: KAMILLA (NCT01702571) is a single-arm, open-label, international, phase IIIb safety study of patients with HER2-positive advanced BC with progression after prior treatment with chemotherapy and a HER2-directed agent for MBC or within 6 months of completing adjuvant therapy. Patients received T-DM1 (3.6 mg/kg every 3 weeks) until unacceptable toxicity, withdrawal or disease progression.
RESULTS: Among 2002 treated patients, median age was 55 years (range, 26-88; 373 [18.6%] aged ≥65 years), 1321 (66.0%) received ≥2 prior metastatic treatment lines and 398 (19.9%) had baseline central nervous system metastases. Adverse events (AEs) and serious AEs occurred in 1862 (93.0%) and 427 (21.3%) patients, respectively. Grade ≥3 AEs occurred in 751 (37.5%) patients; the three most common (individual Medical Dictionary for Regulatory Activity terms) were anaemia (3.0%), thrombocytopaenia (2.7%) and fatigue (2.5%). Median progression-free survival (PFS) was 6.9 months (95% confidence interval [CI], 6.0-7.6). Median overall survival (OS) was 27.2 months (95% CI, 25.5-28.7). With increasing lines of prior advanced therapy (0-1 versus 4+), median PFS and OS decreased numerically from 8.3 to 5.6 months and from 31.3 to 22.5 months, respectively.
CONCLUSIONS: KAMILLA is the largest cohort of T-DM1-treated patients studied to date. Results are consistent with prior randomised studies, thereby supporting T-DM1 as safe, tolerable and efficacious treatment for patients with previously treated HER2-positive advanced BC.

PMID: 30708264 [PubMed - as supplied by publisher]

Factors influencing the use of extended adjuvant endocrine therapy.

Breast Cancer Res Treat. 2019 Jan 31;:

Authors: Kadakia KC, Kidwell KM, Barton DL, Schott AF, Hayes DF, Griggs JJ, Henry NL

Abstract
PURPOSE: Extending adjuvant endocrine therapy (ET) beyond 5 years has been shown to improve outcomes in breast cancer; however, limited data are available about if and why women pursue extended ET. The primary objective was to estimate the proportion of women who were willing to receive extended ET if recommended by their physician and secondarily, to determine what factors were associated with this decision.
METHODS: This descriptive cross-sectional study surveyed 131 women with AJCC 7th Edition stages I-III breast cancer who had been taking adjuvant ET for 3-5 years. The survey inquired about the willingness to continue ET, quality of life (FACT-ES), and beliefs about medications (BMQ). Logistic regression was used to test for associations between clinical and disease factors, FACT-ES, BMQ, and the primary outcome.
RESULTS: One hundred and twelve (85%) patients reported "moderate" (n = 30, 23%), "quite a bit" (n = 41, 31%), or "extreme" (n = 41, 31%) willingness to pursue extended ET; 19 (14%) patients were "not at all" or were "unlikely" to be willing to take extended ET. On univariate analysis, lower total and social well-being FACT-ES scores, and lower perceived necessity and higher concerns on BMQ were associated with lower willingness to pursue extended ET. On multivariable analysis, greater patient perception of necessity of ET was the only factor associated with willingness to pursue extended ET (OR 1.34, 95% CI 1.15-1.57, p = 0.0005).
CONCLUSIONS: Most women who have taken ET for multiple years report being willing to pursue extended ET if recommended. When discussing extended ET, the data from this study support exploring patients' belief of medication necessity.

PMID: 30706190 [PubMed - as supplied by publisher]

[Necrotic leg ulcers after topical application of chlormethine].

Ann Dermatol Venereol. 2019 Jan 28;:

Authors: Gary C, Gautier V, Lazareth I, Bagot M, Asgari R, Priollet P

Abstract
BACKGROUND: Topical chlormethine has been widely used in the early stages of mycosis fungoides for many years. Cutaneous reactions (skin irritation and itch) are the most frequent adverse effects. Herein we report a rare side effect: severe necrotic leg ulcers.
PATIENTS AND METHODS: An 82-year-old woman with a history of high blood pressure developed hyperalgesic necrotic ulcers on the lower limbs following local trauma one month after initiation of topical chlormethine (Valchlor®) to treat mycosis fungoides. Aetiological examination showed moderate peripheral arterial disease which, while constituting an aggravating factor, did not account fully for these skin ulcers. Moreover, drug-induced ulcer was suspected on account of the chronology. Dermal corticoids and topical treatment were prescribed in place of chlormethine and led to a favourable outcome.
CONCLUSION: Incrimination of chlormethine was based on the chronological and semiological criteria. This is the first published case of leg ulceration induced by Valchlor®.

PMID: 30704945 [PubMed - as supplied by publisher]

Liver Toxicity with Cancer Checkpoint Inhibitor Therapy.

Semin Liver Dis. 2018 Nov;38(4):366-378

Authors: Nadeau BA, Fecher LA, Owens SR, Razumilava N

Abstract
Immune checkpoint inhibition targeted against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has shown clinically significant survival benefit when used to treat multiple types of advanced cancer. These drugs have gained approval by the US Food and Drug Administration and their indications continue to increase. Checkpoint inhibitor therapy is associated with a unique side-effect profile characterized as immune-related adverse events (irAEs), which can result in significant morbidity and rarely mortality. Hepatotoxicity from checkpoint inhibitors is a less common irAE and often mild, while its incidence and severity vary based on the class and dose of checkpoint inhibitor, monotherapy versus combination therapy, and the type of cancer. Histological assessment of suspected irAEs is nonspecific and can show a variety of features. Hepatic irAEs can require discontinuation of checkpoint inhibitor therapy and treatment with immunosuppressive agents.

PMID: 30357774 [PubMed - indexed for MEDLINE]

Association between HLA-B*15:02 and oxcarbazepine-induced cutaneous adverse reaction: a meta-analysis.

Pharmacogenomics. 2018 04;19(6):547-552

Authors: Liu Y, Yu Y, Nie X, Zhao L, Wang X

Abstract
AIM: HLA-B*15:02 has been demonstrated as a key risk factor for carbamazepine-induced severe cutaneous adverse reaction (sCAR), especially in Asian population. Oxcarbazepine (OXC) is a drug that has a similar structure of carbamazepine. However, the relationship between HLA-B*15:02 and induced cutaneous adverse reaction (cADR) remains unknown. This study aims to analyze this association in the published literature.
METHOD: After filtering studies, eight studies were finally included for meta-analysis, including 32 sCAR cases, 112 mild cutaneous adverse reaction (mcADR) cases, 281 OXC tolerant control and 946 population control cases.
RESULT: In the tolerant control group, an association was found between HLA-B*15:02 genotype and OXC-induced sCAR (odds ratio [OR]: 18.13; 95% CI: 6.77-48.56), but not in mcADR (OR: 1.43; 95% CI: 0.56-3.64). In population control group, an association was found between HLA-B*15:02 genotype and OXC-induced sCAR, (OR: 8.22; 95% CI: 3.03-22.34), but not in mcADR (OR: 2.06; 95% CI: 0.91-4.67).
DISCUSSION: Our study demonstrates that the genetic risk factor HLA-B*15:02 may be a factor in OXC-induced sCAR.

PMID: 29629814 [PubMed - indexed for MEDLINE]

A Phase 1 Randomized Study of Single Intravenous Infusions of the Novel Nitroxyl Donor BMS-986231 in Healthy Volunteers.

J Clin Pharmacol. 2019 Jan 31;:

Authors: Cowart D, Venuti RP, Lynch K, Guptill JT, Noveck RJ, Foo SY

Abstract
Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first-in-human study for BMS-986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS-986231 after 24- and 48-hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS-986231 0.1, 0.33, 1, 3, 5, 10, and 15 μg/kg/min or placebo, infused over 24 hours. An additional cohort (stratum B) received 10 μg/kg/min or placebo, infused over 48 hours. Adverse events (AEs) were reported for 30 days after completion of infusion. Blood/urine samples were collected at regular intervals; other parameters (blood pressure, heart rate/rhythm, cardiac index) were also assessed. Headaches were the most commonly reported drug-related AE (48%) in those who received BMS-986231, although their severity was reduced by hydration. No other significant drug-related AEs were noted. BMS-986231 was associated with dose-dependent and well-tolerated reductions in systolic and diastolic blood pressure versus baseline; cardiac index, as measured noninvasively, was increased. BMS-986231 had no clinically significant effect on heart rate/rhythm or laboratory parameters. Its mean elimination half-life was 0.7-2.5 hours. BMS-986231 was safe and well-tolerated for up to 24 hours (15 μg/kg/min) or 48 hours (10 μg/kg/min), with a favorable hemodynamic profile observed. Ongoing studies continue to evaluate the potential benefit of BMS-986231 in patients with acute heart failure.

PMID: 30703258 [PubMed - as supplied by publisher]