Citations

Significance Glioblastoma Multiforme (GBM) is the most common and deadliest primary brain tumor in adults. As the median survival is approximately 14 mo there is an urgent need for novel therapies. Epigenetic modulators such as bromodomain and extraterminal (BET) proteins are important therapeutic targets in GBM. Bromodomain inhibitors (including I-BET151) suppress proliferation by repressing oncogenes and inducing tumor suppressor genes through unidentified pathways. Here we demonstrate that HOTAIR (HOX transcript antisense RNA) is overexpressed in GBM, where it is crucial to sustain tumor cell proliferation, and that inhibition of HOTAIR by I-BET151 is necessary to induce cell cycle arrest in GBM cells. Our study outlines the mechanism of action underlying the antiproliferative activity of I-BET151, showing for the first time, to our knowledge, that the oncogenic long noncoding RNA HOTAIR is a major target.

OBJECT The primary goals of this study were: 1) to examine the influence of disease and treatment on headache in patients with sporadic vestibular schwannoma (VS); and 2) to identify clinical predictors of long-term headache disability. METHODS This was a cross-sectional observational study with international multicenter enrollment. Patients included those with primary sporadic < 3-cm VS and a separate group of general population control subjects without tumors. Interventions included a postal survey incorporating the Headache Disability Inventory (HDI), the Hospital Anxiety and Depression Scale, and a VS symptom questionnaire. The main outcome measures were univariate and multivariable associations with HDI total score. RESULTS The overall survey response rate was 79%. Data from 538 patients with VS were analyzed. The mean age at time of survey was 64 years, 56% of patients were female, and the average duration between treatment and survey was 7.7 years. Twenty-seven percent of patients received microsurgery, 46% stereotactic radiosurgery, and 28% observation. Patients with VS who were managed with observation were more than twice as likely to have severe headache disability compared with 103 control subjects without VS. When accounting for baseline differences, there was no statistically significant difference in HDI outcome between treatment modalities at time of survey. Similarly, among the microsurgery cohort, the long-term risk of severe headache disability was not different between surgical approaches. Multivariable regression demonstrated that younger age, greater anxiety and depression, and a preexisting diagnosis of headache were the primary predictors of severe long-term headache disability, while tumor size and treatment modality had little influence. CONCLUSIONS At a mean of almost 8 years following treatment, approximately half of patients with VS experience headaches of varying frequency and severity. Patient-driven factors including age, sex, mental health, and preexisting headache syndrome are the strongest predictors of long-term severe headache disability. Tumor size and treatment modality have less impact. These data may assist with patient counseling regarding long-term expectations following diagnosis and treatment.

Purpose To determine long-term outcomes in a clinical trial evaluating the role of taxane type and schedule in operable breast cancer and evaluate the impact of obesity and black race on outcome. Patients and Methods A total of 4,954 eligible women with stage II to III breast cancer treated with four cycles of doxorubicin plus cyclophosphamide were randomly assigned to receive paclitaxel or docetaxel every 3 weeks for four doses or weekly for 12 doses using a 2 × 2 factorial design. The primary end point was disease-free survival (DFS). Results are expressed as hazard ratios (HRs) from Cox proportional hazards models. All P values are two sided. Results When compared with the standard every-3-week paclitaxel arm, after a median follow-up of 12.1 years, DFS significantly improved and overall survival (OS) marginally improved only for the weekly paclitaxel (HR, 0.84; P = .011 and HR, 0.87; P = .09, respectively) and every-3-week docetaxel arms (HR, 0.79; P = .001 and HR, 0.86; P = .054, respectively). Weekly paclitaxel improved DFS and OS (HR, 0.69; P = .010 and HR, 0.69; P = .019, respectively) in triple-negative breast cancer. For hormone receptor–positive, human epidermal growth factor receptor 2–nonoverexpressing disease, no experimental arm improved OS, and black race and obesity were associated with increased risk of breast cancer recurrence and death. Conclusion Improved outcomes initially observed for weekly paclitaxel were qualitatively similar but quantitatively less pronounced with longer follow-up, although exploratory analysis suggested substantial benefit in triple-negative disease. Further research is required to understand why obesity and race influence clinical outcome in hormone receptor–positive disease.

AbstractBackgroundStudies reveal that ileal pouch‐anal anastomosis (IPAA) has long‐term success. These reports, however, use well‐selected cohorts and exclude patients presenting with fulminant colitis (FC). Herein, we aimed to characterize long‐term functional outcomes in patients with fulminant ulcerative colitis (UC) undergoing IPAA.MethodsA prospective database identified patients who underwent IPAA between 1998 and 2008. Patients with FC and chronic UC were matched by age, gender, date of surgery, and follow‐up duration. Clinical and laboratory parameters, immunomodulator use at the time of surgery, and functional outcomes were compared.ResultsForty patients with FC and 73 patients with chronic UC were identified. Preoperative albumin, hemoglobin, leukocyte count, and steroid dose were significantly different for those with FC. Average survey follow‐up was 5.2 years for FC and 6.7 years for chronic UC patients. Functional outcomes were not significantly different. The 3‐year fistula‐free rate was 91.4 versus 98.6 % and the 3‐year stricture‐free rate was 79.3 versus 87.2 % for FC versus chronic UC patients, respectively.ConclusionPatients undergoing colectomy for FC secondary to UC have similar long‐term functional outcomes after IPAA despite significantly worse presentation. This study confirms that IPAA is an appropriate and durable treatment for patients with FC.

Medicine is increasingly focused on team‐based practice as interprofessional cooperation leads to better patient care. Thus, it is necessary to teach teamwork and collaboration with other health care professionals in undergraduate medical education to ensure that trainees entering the workforce are prepared to work in teams. Gross anatomy provides an opportunity to expose students to interprofessional education (IPE) early in their training. The purpose of this study is to describe an IPE experience and report if the experience has lasting influence on the participating students. The Readiness for Interprofessional Learning Scale (RIPLS) questionnaire was administered to first year medical (MD) and physical therapy (PT) students at Mayo Medical School and Mayo School of Health Sciences. Results demonstrated an openness on the part of the students to IPE. Interprofessional education experiences were incorporated into gross anatomy courses in both medical and PT curricula. The IPE experiences included a social event, peer‐teaching, and collaborative clinical problem‐solving sessions. These sessions enhanced gross anatomy education by reinforcing previous material and providing the opportunity to work on clinical cases from the perspective of two healthcare disciplines. After course completion, students again completed the RIPLS. Finally, one year after course completion, students were asked to provide feedback on their experience. The post‐curricular RIPLS, similar to the pre‐curricular RIPLS, illustrated openness to IPE from both MD and PT students. There were however, significant differences in MD and PT perceptions of roles and responsibilities. One‐year follow‐up indicated long‐term retention of lessons learned during IPE. Anat Sci Educ 8: 317–323. © 2015 American Association of Anatomists.

Background Patient sex and age may influence rates of death after receiving an implantable cardioverter‐defibrillator for primary prevention. Differences in outcomes other than mortality and whether these differences vary by heart failure symptoms, etiology, and left ventricular ejection fraction are not well characterized. Methods and Results We studied 2954 patients with left ventricular ejection fraction ≤0.35 undergoing first‐time implantable cardioverter‐defibrillator for primary prevention within the Cardiovascular Research Network; 769 patients (26%) were women, and 2827 (62%) were aged >65 years. In a median follow‐up of 2.4 years, outcome rates per 1000 patient‐years were 109 for death, 438 for hospitalization, and 111 for heart failure hospitalizations. Procedure‐related complications occurred in 8.36%. In multivariable models, women had significantly lower risks of death (hazard ratio 0.67, 95% CI 0.56 to 0.80) and heart failure hospitalization (hazard ratio 0.82, 95% CI 0.68 to 0.98) and higher risks for complications (hazard ratio 1.38, 95% CI 1.01 to 1.90) than men; patients aged >65 years had higher risks of death (hazard ratio 1.55, 95% CI 1.30 to 1.86) and heart failure hospitalization (hazard ratio 1.25, 95% CI 1.05 to 1.49) than younger patients. Age and sex differences were generally consistent in strata according to symptoms, etiology, and severity of left ventricular systolic dysfunction, except the higher risk of complications in women, which differed by New York Heart Association classification ( P =0.03 for sex–New York Heart Association interaction), and the risk of heart failure hospitalization in older patients, which differed by etiology of heart failure ( P =0.05 for age–etiology interaction). Conclusions The burden of adverse outcomes after receipt of an implantable cardioverter‐defibrillator for primary prevention is substantial and varies according to patient age and sex. These differences in outcome generally do not vary according to baseline heart failure characteristics.

Background: Parkinson’s disease (PD) patients with 20 years or more survival (PD-20) are not well characterized. Objective: To evaluate PD-20 patient characteristics and identify areas for improvement of their health care. Methods: The international, multicenter National Parkinson’s Foundation Quality Improvement Initiative (NPF-QII) study database was queried to identify PD-20 subjects. Demographic and clinical data were analyzed. Results: We identified 187 PD-20 subjects (55% men) representing 4% (187/4,619) of all NPF-QII participants. Subjects were mean age 69.5 years; mean age at PD onset was 44.0 years. The majority (75%) had 20-25 years of PD duration, the longest duration being 49 years. They were median Hoehn and Yahr stage 3, and 75% had motor fluctuations. Half (54%) reported exercising. The majority (89%) were living at home and required a caregiver (88%). They were mildly cognitively impaired for age (Montreal Cognitive Assessment estimate 22.6±3.7), with most deficits in verbal fluency and delayed recall. Quality of life (Parkinson’s Disease Quality of Life Questionnaire index 36±15%) was mild to moderately impaired, with most impairment in mobility and activities of daily living. Caregiver strain measured by the Multidimensional Caregiver Strain Index (27±16%), recorded highest subscores in social constraint. PD-20 subjects aged <70 years versus ≥70 only differed significantly by worse cognition ( P < 0.0001). Conclusions: PD-20 subjects reflect an elite group of PD survivors with early-onset disease and relatively mild cognitive disability despite long disease duration. Interventions for caregivers, mobility, and activities of daily living are areas that could improve caregiver burden and patient quality of life.