Maurer, Matthew J.

Abstract Purpose: Here we assess whether molecular subtyping identifies biological features of tumors that correlate with survival and surgical outcomes of high-grade serous ovarian cancer (HGSOC). Experimental Design: Consensus clustering of pooled mRNA expression data from over 2,000 HGSOC cases was used to define molecular subtypes of HGSOCs. This de novo classification scheme was then applied to 381 Mayo Clinic HGSOC patients with detailed survival and surgical outcome information. Results: Five molecular subtypes of HGSOC were identified. In the pooled dataset, three subtypes were largely concordant with prior studies describing proliferative, mesenchymal, and immunoreactive tumors (concordance > 70%), and the group of tumors previously described as differentiated type was segregated into two new types, one of which (anti-mesenchymal) had downregulation of genes that were typically upregulated in the mesenchymal subtype. Molecular subtypes were significantly associated with overall survival (P < 0.001) and with rate of optimal surgical debulking (≤1 cm, P = 1.9E−4) in the pooled dataset. Among stage III-C or IV Mayo Clinic patients, molecular subtypes were also significantly associated with overall survival (P = 0.001), as well as rate of complete surgical debulking (no residual disease; 16% in mesenchymal tumors compared with >28% in other subtypes; P = 0.02). Conclusions: HGSOC tumors may be categorized into five molecular subtypes that associate with overall survival and the extent of residual disease following debulking surgery. Because mesenchymal tumors may have features that were associated with less favorable surgical outcome, molecular subtyping may have future utility in guiding neoadjuvant treatment decisions for women with HGSOC. Clin Cancer Res; 23(15); 4077–85. ©2017 AACR.

236 Background: Patients (pts) with aggressive lymphoma are generally treated with curative intent and many become long-term survivors. There is little data on health behaviors after lymphoma diagnosis and their effect on QOL and long-term outcomes. Methods: Lymphoma pts were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and systematically followed. We measured QOL (FACT-G) and health behaviors (tobacco/alcohol use; diet/exercise habits) 3 years after diagnosis. For this study, “survivor” was defined as alive at 3 years from diagnosis with no active disease or treatment within the previous year. Results: From 2002-2012, 671 patients with aggressive lymphoma were enrolled, met survivor definition, and completed 3-year QOL and health behavior questionnaires. At 3-years, 31% of female (F) and 48% of male (M) reported a history of tobacco use for 6+ months. Of these, 13% of F and 7% of M were still smoking; 52% reported decreased use from baseline. 66% reported no change in alcohol intake at 3-years while 25% of F and 34% of M reported decreased intake. 60% often chose whole grains and 65% get 2+ servings of vegetables daily. 42% of F and 38% of M “somewhat” believed diet could change the course of their lymphoma. Most pts endorsed no significant change in diet as a result of diagnosis. Those who made changes did so primarily out of concern for “health problems other than cancer”. Overweight/obese responders were 72% pre- and 66% post-treatment. A desire to lose weight was reported by 55% of pts. 14% of F and 23% of M often engaged in regular physical activity (PA). Nearly 50% reported a decrease in PA. Pts with advanced stage (p = 0.006), age > 60 (p = 0.001), ECOG PS > 2 (p = 0.04), and worse prognostic score (p = 0.006) were more likely to report decreased PA since diagnosis. 68% of F and 61% of M intend to become more active in the next months. Regular PA (p = < 0.0001) was associated with higher QOL, while increased alcohol intake was associated with lower QOL (p = 0.009) at 3 years. Conclusions: Many survivors of aggressive NHL strive to adopt healthy behaviors and these behaviors are associated with higher QOL. Interventions aimed at emphasizing these behaviors may have potential to improve long-term outcomes and QOL.

Abstract Purpose: Recent progress in understanding the molecular biology of epithelial ovarian cancer has not yet translated into individualized treatment for these women or improvements in their disease outcome. Gene expression has been utilized to identify distinct molecular subtypes, but there have been no reports investigating whether or not molecular subtyping is predictive of response to bevacizumab in ovarian cancer. Experimental Design: DASL gene expression arrays were performed on FFPE tissue from patients enrolled on the ICON7 trial. Patients were stratified into four TCGA molecular subtypes. Associations between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab were assessed. Results: Molecular subtypes were assigned as follows: 122 immunoreactive (34%), 96 proliferative (27%), 73 differentiated (20%), and 68 mesenchymal (19%). In univariate analysis patients with tumors of proliferative subtype obtained the greatest benefit from bevacizumab with a median PFS improvement of 10.1 months [HR, 0.55 (95% CI, 0.34–0.90), P = 0.016]. For the mesenchymal subtype, bevacizumab conferred a nonsignificant improvement in PFS of 8.2 months [HR 0.78 (95% CI, 0.44–1.40), P = 0.41]. Bevacizumab conferred modest improvements in PFS for patients with immunoreactive subtype (3.8 months; P = 0.08) or differentiated subtype (3.7 months; P = 0.61). Multivariate analysis demonstrated significant PFS improvement in proliferative subtype patients only [HR, 0.45 (95% CI, 0.27–0.74), P = 0.0015]. Conclusions: Ovarian carcinoma molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment that includes bevacizumab. Validation of our findings in an independent cohort could enable the use of bevacizumab for those patients most likely to benefit, thereby reducing side effects and healthcare cost. Clin Cancer Res; 23(14); 3794–801. ©2017 AACR.

Background Sex‐related differences in morbidity and survival in bicuspid aortic valve (BAV) adults are fundamentally unknown. Contemporary studies portend excellent survival for BAV patients identified at early echocardiographic‐clinical stages. Whether BAV adults incur a survival disadvantage throughout subsequent echocardiographic‐clinical stages remains undetermined. Methods and Results Analysis was done of 3 different cohorts of consecutive patients with echocardiographic diagnosis of BAV identified retrospectively: (1) a community cohort of 416 patients with first BAV diagnosis (age 35±21 years, follow‐up 16±7 years), (2) a tertiary clinical referral cohort of 2824 BAV adults (age 51±16 years, follow‐up 9±6 years), and (3) a surgical referral cohort of 2242 BAV adults referred for aortic valve replacement (AVR) (age 62±14 years, follow‐up 6±5 years). For the community cohort, 20‐year risks of aortic regurgitation (AR), AVR, and infective endocarditis were higher in men (all P ≤0.04); for a total BAV‐related morbidity risk of 52±4% vs 35±6% in women ( P =0.01). The cohort's 25‐year survival was identical to that in the general population ( P =0.98). AR independently predicted mortality in women ( P =0.001). Baseline AR was more common in men ( P ≤0.02) in the tertiary cohort, with 20‐year survival lower than that in the general population ( P <0.0001); age‐adjusted relative death risk was 1.16 (95% confidence interval [CI] 1.05‐1.29) for men versus 1.67 (95% CI 1.38‐2.03) for women ( P =0.001). AR independently predicted mortality in women ( P =0.01). Baseline AR and infective endocarditis were higher in men (both ≤0.001) for the surgical referral cohort, with 15‐year survival lower than that in the general population ( P <0.0001); age‐adjusted relative death risk was 1.34 (95% CI 1.22‐1.47) for men versus 1.63 (95% CI 1.40‐1.89) for women ( P =0.026). AR and NYHA class independently predicted mortality in women (both P ≤0.04). Conclusions Within evolving echocardiographic‐clinical stages, the long‐term survival of adults with BAV is not benign, as both men and women incur excess mortality. Although BAV‐related morbidity is higher in men in the community, and AR and infective endocarditis are more prevalent in men, women exhibit a significantly higher relative risk of death in tertiary and surgical referral cohorts, which is independently associated with AR.

The incidence and prevalence of most cardiovascular disorders increase with age, and cardiovascular disease ( CVD ) is the leading cause of death and major disability in adults aged 75 and older. Despite the effect of CVD on quality of life, morbidity, and mortality in older adults, individuals aged 75 and older have been markedly underrepresented in most major cardiovascular trials, and virtually all trials have excluded older adults with complex comorbidities, significant physical or cognitive disabilities, frailty, or residence in nursing homes and assisted living facilities. As a result, current guidelines are unable to provide evidence‐based recommendations for diagnosis and treatment of older adults typical of those encountered in routine clinical practice. The objectives of this scientific statement are to summarize current guideline recommendations as they apply to older adults, identify critical gaps in knowledge that preclude informed evidence‐based decision‐making, and recommend future research to close existing knowledge gaps. To achieve these objectives, a detailed review was conducted of current American College of Cardiology/American Heart Association ( ACC / AHA ) and American Stroke Association ( ASA ) guidelines to identify content and recommendations that explicitly targeted older adults. A pervasive lack of evidence to guide clinical decision‐making in older adults with CVD was found, as well as a paucity of data on the effect of diagnostic and therapeutic interventions on outcomes that are particularly important to older adults, such as quality of life, physical function, and maintenance of independence. Accordingly, there is a critical need for a multitude of large population‐based studies and clinical trials that include a broad spectrum of older adults representative of those seen in clinical practice and that incorporate relevant outcomes important to older adults in the study design. The results of these studies will provide the foundation for future evidence‐based guidelines applicable to older adults and enhance person‐centered care of older individuals with CVD in the United States and around the world.

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event‐free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1‐3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002‐2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re‐treatment, or death due to any cause. OS was compared to age‐and‐sex‐matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78‐4.88; Lyon SMR = 8.74, 95%CI: 5.41‐13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56‐0.94, Lyon SMR = 1.02, 95%CI: 0.58‐1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97‐25.02, Lyon SMR = 19.10, 95%CI:9.86‐33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31‐17.74, Lyon SMR = 7.22, 95%CI:4.13‐11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096–1101, 2016. © 2016 Wiley Periodicals, Inc.