Citations

Background: Patients with combined post- and precapillary pulmonary hypertension due to left heart disease have a worse prognosis compared with isolated postcapillary. However, it remains unclear whether increased mortality in combined post- and precapillary pulmonary hypertension is simply a result of higher total right ventricular load. Pulmonary effective arterial elastance (Ea) is a measure of total right ventricular afterload, reflecting both resistive and pulsatile components. We aimed to test whether pulmonary Ea discriminates survivors from nonsurvivors in patients with pulmonary hypertension due to left heart disease and if it does so better than other hemodynamic parameters associated with combined post- and precapillary pulmonary hypertension. Methods and Results: We combined 3 large heart failure patient cohorts (n=1036) from academic hospitals, including patients with pulmonary hypertension due to heart failure with preserved ejection fraction (n=232), reduced ejection fraction (n=335), and a mixed population (n=469). In unadjusted and 2 adjusted models, pulmonary Ea more robustly predicted mortality than pulmonary vascular resistance and the transpulmonary gradient. Along with pulmonary arterial compliance, pulmonary Ea remained predictive of survival in patients with normal pulmonary vascular resistance. The diastolic pulmonary gradient did not predict mortality. In addition, in a subset of patients with echocardiographic data, Ea and pulmonary arterial compliance were better discriminators of right ventricular dysfunction than the other parameters. Conclusions: Pulmonary Ea and pulmonary arterial compliance more consistently predicted mortality than pulmonary vascular resistance or transpulmonary gradient across a spectrum of left heart disease with pulmonary hypertension, including patients with heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, and pulmonary hypertension with a normal pulmonary vascular resistance.

Abstract Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n = 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR = 1.9; P = 0.012). Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients. Clin Cancer Res; 24(14); 3433–46. ©2018 AACR.

Abstract In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six‐stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker‐based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker‐based research should not be considered a template for all research into age‐related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β‐amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

Background: Palliative care is associated with improved survival and quality of life, but its use among patients with colorectal cancer varies nationwide and the determinants of those variations are not clear. Objective: To determine the factors associated with palliative care use among patients who died of colorectal cancer. Methods: Deceased patients treated for colorectal cancer (2004-2013) were identified within the National Cancer Database. Multivariable logistic regression was used to evaluate patient and institutional characteristics associated with palliative care use. Patients were classified based on their length of survival (<6 months, 6-24 months, and 24+ months) to provide timing context. Results: A total of 287 923 patients were analyzed. Overall, 4.3% of the patients received palliative care. Patients who received palliative care were more likely to be younger, recently diagnosed, treated at academic hospitals, and have stage IV disease. Patients living in Mountain and Pacific regions had higher odds of palliative care receipt than those in the East Coast. Patients without insurance had higher odds of palliative care if they survived <24 months. Insurance coverage through Medicaid was associated with increased palliative care use among patients who survived 6 to 24 months. Patients who survived <6 months and lived >9 miles from the institution received more palliative care. Conclusion: Palliative care use among patients with colorectal cancer is associated with a younger age, a more recent year of diagnosis, insurance status, academic hospitals, and living in Mountain and Pacific regions.

Background Despite substantial evidence demonstrating clear benefit, rates of preemptive kidney transplantation (PreKTx) remain low in the United States. Our goal was to identify barriers to PreKTx. Methods Using a telephone-administered questionnaire including questions about barriers, timing of referral, timing of education, we retrospectively studied first living donor kidney transplant recipients (2006-2010) at Mayo Clinic, Rochester, MN. Of 235 patients, 145 (62%) responded to the questionnaire (74 PreKTx and 71 non-PreKTx). We compared categorical data with Fisher exact test and median times with Wilcoxon rank sum test. Results Polycystic kidney disease (PCKD), longer median time between diagnosis and transplant, and time between education about transplant and transplant correlated with PreKTx (P < 0.01). The presence of at least 1 patient-identified barrier (lack of referral, financial barriers, medical barriers, no identified living donor and donor evaluation delays) was associated with non-PreKTx (0.034) though no single barrier predominated. Age, education level, insurance status and source of referral (primary care, nephrology, and nonphysician referral) were not associated with the rate of PreKTx. Univariate logistic regression identified white race, PCKD, and increased time from diagnosis as factors favoring PreKTx; PCKD and increased time remained significant factors after multivariate analysis. Conclusions Even among a patient population that is primarily white, educated, and has a spouse or first-degree relative donor, PreKTx rates remain concerningly low. Increased time between diagnosis or education and transplant are predictors of PreKTx. Greater emphasis on transplant education earlier in the stages of chronic kidney disease and community outreach from transplant centers may help to increase the rate of PreKTx.

Objectives/HypothesisHuman papillomavirus (HPV)‐positive and HPV‐negative oropharyngeal squamous cell carcinoma (OPSCC) are distinct disease entities. Prognostic factors specific to each entity have not been adequately explored. Goals for this study were: 1) to determine whether HPV‐positive and HPV‐negative OPSCCs have distinct prognostic factors, and 2) to explore the prognostic significance of sex and race in OPSCC after HPV stratificationStudy DesignRetrospective case series.MethodsA retrospective review of 239 incident OPSCC patients from 1995 to 2012, treated at Johns Hopkins and University of California–San Francisco was conducted. Women and nonwhite races were oversampled. All analyses were stratified by tumor HPV in situ hybridization status. The effects of sex and race on survival were considered in Kaplan‐Meier and unadjusted and adjusted Cox regression models.ResultsOne hundred thirty‐four (56.1%) OPSCC patients were HPV positive. On univariate analysis, women had better overall survival than men among HPV‐positive (hazard ratio [HR]: 0.47, 95% confidence interval [CI]: 0.20‐1.07; P = .06) but not HPV‐negative (HR: 0.73, 95% CI: 0.43‐1.24; P = .24) OPSCCs. On multivariate analysis, women with HPV‐positive OPSCCs remained at lower risk of death (adjusted hazard ratio [aHR]: 0.34, 95% CI: 0.12‐0.96; P = .04). Survival did not vary significantly by race among HPV‐positive patients. Among HPV‐negative patients, Hispanic patients had significantly better survival in unadjusted (HR: 0.27, 95% CI: 0.08‐0.91; P = .04) but not adjusted (aHR: 0.93, 95% CI: 0.11‐7.36; P = .94) analysis.ConclusionsWomen with HPV‐positive OPSCC may have improved overall survival compared to men. Sex does not play a prognostic role in HPV‐negative OPSCC. There are no differences in prognosis by race among HPV‐positive or HPV‐negative patients.Level of Evidence4 Laryngoscope, E288–E296, 2018

Background— Women have higher rates of all-cause mortality after percutaneous coronary intervention. Whether this is because of greater age and comorbidity burden or a sex-specific factor remains unclear. Methods and Results— We retrospectively assessed cause-specific long-term mortality after index percutaneous coronary intervention over 3 time periods (1991–1997, 1998–2005, and 2006–2012). Cause of death was determined using telephone interviews, medical records, and death certificates. We performed competing risks analyses of cause-specific mortality. A total of 6847 women and 16 280 men survived index percutaneous coronary intervention hospitalization 1991 to 2012. Women were older (mean±SD: 69.4±12 versus 64.8±11.7 years; P <0.001) with more comorbidities (mean±SD: Charlson index 2.1±2.1 versus 1.9±2.1; P <0.001). Across the 3 time periods, both sexes exhibited a decline in cardiac deaths at 5 years (26% relative decrease in women, 17% in men, trend P <0.001 for each). Although women had higher all-cause mortality compared with men in all eras, the excess mortality was because of noncardiac deaths. In the contemporary era, only a minority of deaths were cardiac (33.8% in women, 38.0% in men). After adjustment, there was no evidence for a sex-specific excess of risk for cardiac or noncardiac mortality. The commonest causes of death were chronic diseases and heart failure in women (5-year cumulative mortality, 5.4% and 3.9%) but cancer and myocardial infarction/sudden death in men (5.4% and 4.3%). Conclusions— The higher mortality after percutaneous coronary intervention in women is because of death from noncardiac causes. This is accounted for by baseline age and comorbidities rather than an additional sex-specific factor. These findings have implications for sex-specific clinical care and trial design.