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BACKGROUND - Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) compared with other ADTs.
AIM - To determine if abiraterone was associated with an increased proportion of AT and HF reports among all suspected adverse drug reactions (ADRs) reported in several pharmacovigilance databases compared with enzalutamide, other ADTs and all other drugs.
METHODS - In this observational retrospective pharmacovigilance study, we performed a disproportionality analysis of reports of suspected ADRs in men in the French pharmacovigilance database, the European pharmacovigilance database and the international pharmacovigilance database VigiBase, to evaluate the reporting odds ratios (RORs) of AT and HF for abiraterone compared with enzalutamide, other ADTs and all other drugs.
RESULTS - In the 5,759,781 ADR reports in men in VigiBase, 55,070 pertained to ADTs. The RORs for AT for abiraterone versus enzalutamide, other ADTs and all other drugs were 4.1 (95% confidence interval 3.1-5.3), 3.7 (3-4.5) and 3.2 (2.7-3.7), respectively (P<0.0001 for all). The corresponding RORs for HF were 2.5 (2-3), 1.5 (1.3-1.7) and 2 (1.7-2.3), respectively (P<0.0001 for all). These results were concordant with the French and European pharmacovigilance databases. Mean times to AT and HF onset were shorter with abiraterone (5.2±0.8 and 4.5±0.6 months, respectively) versus other ADTs (13.3±3.2 and 9.2±1.1 months, respectively) (both P<0.05). Cases on abiraterone versus other ADTs were more frequently associated with at least two ADR terms, including AT, HF, hypokalaemia, hypertension and oedema (13.6% vs 6%; P<0.0001). For abiraterone, age, but not dose, was associated with reporting of AT and HF versus any other ADR.
CONCLUSIONS - Compared with other ADTs, abiraterone was associated with higher reporting of AT and HF, associated with hypokalaemia, hypertension and oedema. These findings are consistent with the hypermineralocorticism induced by abiraterone, but not by other ADTs.
Copyright © 2019 Elsevier Masson SAS. All rights reserved.
BACKGROUND - Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based.
METHODS - We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations.
RESULTS - We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination.
CONCLUSIONS - Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.
BACKGROUND - Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.
OBJECTIVES - The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib.
METHODS - This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC (lower end of the IC 95% credibility interval) >0 is significant.
RESULTS - This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases).
CONCLUSIONS - Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215).
Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: email@example.com.
BACKGROUND - Patient-specific and disease-specific factors shape the course of chronic rhinosinusitis (CRS) and its response to treatment, with optimal management involving interventions tailored to these factors. Recent evidence suggests CRS inflammatory signatures depend on age. The objective of this study was to determine whether age also influences quality-of-life (QOL) and postoperative outcomes.
METHODS - Retrospective analysis of prospectively collected QOL data from 403 adults with medically refractory CRS who underwent functional endoscopic sinus surgery (FESS) at a tertiary care medical center between 2014 and 2018 was undertaken. Total and subdomain scores from the 22-item Sino-Nasal Outcome Test (SNOT-22) and the Short Form 8 Health Survey (SF-8) measure of general health completed at preoperative and postoperative visits were reviewed.
RESULTS - Patients were divided into young (18 to 39 years, n = 100), middle-aged (40 to 59 years, n = 172), and elderly (≥60 years, n = 131) groups. Baseline total SNOT-22 scores differed between groups (p = 0.01), with middle-aged patients having the highest symptom burden and elderly patients having the lowest. Similar patterns were observed for SNOT-22 subdomains. Elderly patients reported smaller improvements and were less likely to achieve a minimally important clinical difference. CRS patients had worse SF-8 scores compared to the general population, and elderly patients were the least likely to match population norms following surgery. Age was an independent predictor of QOL outcomes after FESS.
CONCLUSION - Age may play a significant role in CRS pathophysiology, symptom burden, and surgical outcomes. Elderly patients report smaller improvements in disease-specific and general health QOL after surgery. CRS management in the elderly population should incorporate age-dependent differences in symptom burden and expectations into treatment algorithms.
© 2019 ARS-AAOA, LLC.
Background Few data exist on the long-term risk prediction of elevated left ventricular (LV) mass quantified by MRI for cardiovascular (CV) events in a contemporary, ethnically diverse cohort. Purpose To assess the long-term impact of elevated LV mass on CV events in a prospective cohort study of a multiethnic population in relationship to risk factors and coronary artery calcium (CAC) score. Materials and Methods The Multi-Ethnic Study of Atherosclerosis, or MESA (: NCT00005487), is an ongoing prospective multicenter population-based study in the United States. A total of 6814 participants (age range, 45-84 years) free of clinical CV disease at baseline were enrolled between 2000 and 2002. In 4988 participants (2613 [52.4%] women; mean age, 62 years ± 10.1 [standard deviation]) followed over 15 years for CV events, LV mass was derived from cardiac MRI at baseline enrollment by using semiautomated software at a central core laboratory. Cox proportional hazard models, Kaplan-Meier curves, and scores were applied to assess the impact of LV hypertrophy. Results A total of 290 participants had hard coronary heart disease (CHD) events (207 myocardial infarctions [MIs], 95 CHD deaths), 57 had other CV disease-related deaths, and 215 had heart failure (HF). LV hypertrophy was an independent predictor of hard CHD events (hazard ratio [HR]: 2.7; 95% confidence interval [CI]: 1.9, 3.8), MI (HR: 2.8; 95% CI: 1.8, 4.0), CHD death (HR: 4.3; 95% CI: 2.5, 7.3), other CV death (HR: 7.5; 95% CI: 4.2, 13.5), and HF (HR: 5.4; 95% CI: 3.8, 7.5) ( < .001 for all end points). LV hypertrophy was a stronger predictor than CAC for CHD death, other CV death, and HF ( scores: 5.4 vs 3.4, 6.8 vs 2.4, and 9.7 vs 3.2 for LV hypertrophy vs CAC, respectively). Kaplan-Meier analysis demonstrated an increased risk of CV events in participants with LV hypertrophy, particularly after 5 years. Conclusion Elevated left ventricular mass was strongly associated with hard coronary heart disease events, other cardiovascular death, and heart failure over 15 years of follow-up, independent of traditional risk factors and coronary artery calcium score. © RSNA, 2019 See also the editorial by Hanneman in this issue.
PURPOSE - Persistent chemotherapy-related cognitive impairment (pCRCI) is commonly reported following cancer treatment and negatively affects quality of life; however, there is currently no pharmacological treatment indicated for pCRCI. This pilot study obtained preliminary data regarding the use of transdermal nicotine patches as a therapeutic strategy for women with pCRCI to (1) reduce subjective cognitive complaints and (2) enhance objective cognitive performance in breast, colon, lymphoma, or ovarian cancer survivors with pCRCI.
METHODS - Participants were randomized to either placebo (n = 11) or transdermal nicotine (n = 11) for 6 weeks, followed by 2 weeks of treatment withdrawal for a total of 8 weeks. Participants were assessed using both subjective and objective measures of cognitive functioning at five visits before, during, and after treatment.
RESULTS - Over the course of the study, women in both groups improved substantially in severity of self-reported cognitive complaints measured by Functional Assessment of Cancer Therapy-Cognitive Function Perceived Cognitive Impairments regardless of treatment arm. Additionally, objective cognitive performance measures improved in both groups; however, there was no significant difference in improvement between groups.
CONCLUSIONS - Due to a large placebo response, we were unable to determine if a drug effect was present. However, we did observe substantial improvement in self-reported cognitive symptoms, likely resulting from factors related to participation in the trial rather than specific drug treatment effects.
TRIAL REGISTRATION - The study was registered with clinicaltrials.gov (trial registration: NCT02312943).
IMPLICATIONS FOR CANCER SURVIVORS - These results suggest that women with pCRCI can exhibit improvement in subjective cognition, with attention paid to symptoms and close follow-up over a short period of time.
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45ROGZMBKi67) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
We evaluated the associations of subjective (self-reported everyday cognition [ECog]) and objective cognitive measures with regional amyloid-β (Aβ) and tau accumulation in 86 clinically normal elderly subjects from the Alzheimer's Disease Neuroimaging Initiative. Regression analyses were conducted to identify whether individual ECog domains (Memory, Language, Organization, Planning, Visuospatial, and Divided Attention) were equally or differentially associated with regional [F]florbetapir and [F]flortaucipir uptake and how these associations compared to those obtained with objective cognitive measures. A texture analysis, the weighted 2-point correlation, was used as an additional approach for estimating the whole-brain tau burden without positron emission tomography intensity normalization. Although the strongest models for ECog domains included either tau (planning and visuospatial) or Aβ (memory and organization), the strongest models for all objective measures included Aβ. In Aβ-negative participants, the strongest models for all ECog domains of executive functioning included tau. Our results indicate differential associations of individual subjective cognitive domains with Aβ and tau in clinically normal adults. Detailed characterization of ECog may render a valuable prescreening tool for pathological prediction.
Copyright © 2019 Elsevier Inc. All rights reserved.