The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
Immune checkpoint inhibitors (ICI) are now routinely used in multiple cancers but may induce autoimmune-like side effects known as immune-related adverse events (irAE). Although classical autoimmune diseases have well-known risk factors, including age, gender, and seasonality, the clinical factors that lead to irAEs are not well-defined. To explore these questions, we assessed 455 patients with advanced melanoma treated with ICI at our center and a large pharmacovigilance database (VigiBase). We found that younger age was associated with a similar rate of any irAEs but more frequent severe irAEs and more hospitalizations (OR, 0.97 per year). Paradoxically, however, older patients had more deaths and increased length of stay (LOS) when hospitalized. This was partially due to a distinct toxicity profile: Colitis and hepatitis were more common in younger patients, whereas myocarditis and pneumonitis had an older age distribution both in our center and in VigiBase. This pattern was particularly apparent with combination checkpoint blockade with ipilimumab and nivolumab. We did not find a link between gender or seasonality on development of irAEs in univariate or multivariate analyses, although winter hospitalizations were associated with marginally increased LOS. This study identifies age-specific associations of irAEs.
©2020 American Association for Cancer Research.
BACKGROUND - Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer's disease (AD) pathology and neurodegeneration.
OBJECTIVE - This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration.
METHODS - Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognition (NC), mild cognitive impairment (MCI)).
RESULTS - Higher LVEF related to decreased CSF Aβ42 levels (β= -6.50, p = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p = 0.004) and p-tau levels (p = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= -9.74, p = 0.01) and p-tau in the NC (β= -1.41, p = 0.003) but not MCI participants (p-values>0.13).
CONCLUSIONS - Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life.
BACKGROUND - Systemic sclerosis (SSc) is a rare disease with studies limited by small sample sizes. Electronic health records (EHRs) represent a powerful tool to study patients with rare diseases such as SSc, but validated methods are needed. We developed and validated EHR-based algorithms that incorporate billing codes and clinical data to identify SSc patients in the EHR.
METHODS - We used a de-identified EHR with over 3 million subjects and identified 1899 potential SSc subjects with at least 1 count of the SSc ICD-9 (710.1) or ICD-10-CM (M34*) codes. We randomly selected 200 as a training set for chart review. A subject was a case if diagnosed with SSc by a rheumatologist, dermatologist, or pulmonologist. We selected the following algorithm components based on clinical knowledge and available data: SSc ICD-9 and ICD-10-CM codes, positive antinuclear antibody (ANA) (titer ≥ 1:80), and a keyword of Raynaud's phenomenon (RP). We performed both rule-based and machine learning techniques for algorithm development. Positive predictive values (PPVs), sensitivities, and F-scores (which account for PPVs and sensitivities) were calculated for the algorithms.
RESULTS - PPVs were low for algorithms using only 1 count of the SSc ICD-9 code. As code counts increased, the PPVs increased. PPVs were higher for algorithms using ICD-10-CM codes versus the ICD-9 code. Adding a positive ANA and RP keyword increased the PPVs of algorithms only using ICD billing codes. Algorithms using ≥ 3 or ≥ 4 counts of the SSc ICD-9 or ICD-10-CM codes and ANA positivity had the highest PPV at 100% but a low sensitivity at 50%. The algorithm with the highest F-score of 91% was ≥ 4 counts of the ICD-9 or ICD-10-CM codes with an internally validated PPV of 90%. A machine learning method using random forests yielded an algorithm with a PPV of 84%, sensitivity of 92%, and F-score of 88%. The most important feature was RP keyword.
CONCLUSIONS - Algorithms using only ICD-9 codes did not perform well to identify SSc patients. The highest performing algorithms incorporated clinical data with billing codes. EHR-based algorithms can identify SSc patients across a healthcare system, enabling researchers to examine important outcomes.
Importance - Endotracheal intubation and mechanical ventilation are life-saving treatments for acute respiratory failure but are complicated by significant rates of dyspnea and dysphonia after extubation. Unilateral vocal fold immobility (UVFI) after extubation can alter respiration and phonation, but its incidence, risk factors, and pathophysiology remain unclear.
Objectives - To determine the incidence of UVFI after prolonged (>12 hours) mechanical ventilation in a medical intensive care unit and investigate associated clinical risk factors for UVFI after prolonged mechanical ventilation.
Design, Setting, and Participants - This subgroup analysis of a prospective cohort study was conducted in a single-center medical intensive care unit from August 17, 2017, through May 31, 2018, among 100 consecutive adult patients who were intubated for more than 12 hours. Patients were identified within 36 hours of extubation and recruited for study enrollment. Those with an established tracheostomy prior to mechanical ventilation, known laryngeal or tracheal pathologic characteristics, or a history of head and neck radiotherapy were excluded.
Exposure - Invasive mechanical ventilation via an endotracheal tube.
Main Outcomes and Measures - The incidence of UVFI as determined by flexible nasolaryngoscopy.
Results - One hundred patients (62 men [62%]; median age, 58.5 years [range, 19.0-87.0 years]) underwent endoscopic evaluation after extubation. Seven patients had UVFI, of which 6 cases (86%) were left sided. Patients with hypotension while intubated (odds ratio [OR], 10.8; 95% CI, 1.6 to ∞), patients requiring vasopressors while intubated (OR, 16.7; 95% CI, 2.4 to ∞), and patients with a preadmission diagnosis of peripheral vascular disease (OR, 6.2; 95% CI, 1.2-31.9) or coronary artery disease (OR, 5.1; 95% CI, 1.0-25.5) were more likely to develop UVFI.
Conclusions and Relevance - Unilateral vocal fold immobility occurred in 7 of 100 patients in the medical intensive care unit who were intubated for more than 12 hours. Unilateral vocal fold immobility was associated with inpatient hypotension and preadmission vascular disease, suggesting that ischemia of the recurrent laryngeal nerve may play a role in disease pathogenesis.
Literature suggests vascular endothelial growth factor A (VEGFA) is protective among those at highest risk for Alzheimer's disease (AD). Apolipoprotein E (APOE) ε4 allele carriers represent a highly susceptible population for cognitive decline, and VEGF may confer distinct protection among APOE-ε4 carriers. We evaluated interactions between cortical expression of 10 VEGF gene family members and APOE-ε4 genotype to clarify which VEGF genes modify the association between APOE-ε4 and cognitive decline. Data were obtained from the Religious Orders Study and Rush Memory and Aging Project (N = 531). Linear regression assessed interactions on global cognition. VEGF genes NRP1 and VEGFA interacted with APOE-ε4 on cognitive performance (p.fdr < 0.05). Higher NRP1 expression correlated with worse outcomes among ε4 carriers but better outcomes among ε4 noncarriers, suggesting NRP1 modifies the risk for poor cognitive scores based on APOE-ε4 status. NRP1 regulates angiogenesis, and literature suggests vessels in APOE-ε4 brains are more prone to leaking, perhaps placing young vessels at risk for ischemia. Results suggest that future therapeutics targeting brain angiogenesis should also consider ε4 allele status.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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.
PURPOSE - Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon.
EXPERIMENTAL DESIGN - Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases.
RESULTS - Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months.
CONCLUSION - We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy.
IMPLICATIONS FOR PRACTICE - Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.
© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.