Citations

Abstract OBJECTIVES: Mutations in ESR1 that are acquired following treatment with aromatase inhibitors commonly underlie resistance to endocrine therapy in breast cancer. ERa-LBD mutations, especially at ESR1 Y537 and D538, confer constitutive activity and partial resistance to selective estrogen receptor modulators (SERMs), such as tamoxifen, and degraders (SERDs) such as fulvestrant in transcription assays. Some ovarian tumors also respond to anti-hormone therapy, and a subset which initially respond subsequently become resistant. The mechanisms of resistance to hormone therapy in ovarian cancer have not been previously described. Comprehensive genomic profiling (CGP) of ovarian tumors was used to analyze ESR1 and correlate responsiveness to aromatase inhibitors in a subset of these patients. METHODS: DNA was extracted from tumor specimens and sequenced using hybridization-capture (FoundationOne) targeting up to 315 genes, plus select introns frequently rearranged in cancer. Demographic and clinicopathologic data will be presented for a subset of patients whose tumors harbor ERa-LBD mutations associated with activation and resistance.. RESULTS: CGP of 3,641 ovarian and peritoneal carcinomas revealed 31 (0.9%) samples with amplification of ESR1 and 16 (0.4%) samples with acquired or de novo mutations affecting the ERa-LBD: Y537S (10), Y537N (1), D638G (4), and S341L (1). Within the 16 samples, ovarian serous carcinoma (10), ovarian endometrioid adenocarcinoma (3), ovarian epithelial carcinoma NOS (2), and peritoneal serous carcinoma (1) were represented. In cases of acquired mutations following prior hormone therapy, there was evidence of clinical benefit to SERM/SERDs. CaseAgeDiseaseESR1 MutationPrior HRTAcquiredSERM/SERD (*post mut if acquired)Clinical Benefit SERM/SERD159Ov serousY537SYYNN/A258Papillary serousY537NNNYY344Endometrioid ov adenoY537SNNYY445HG ov serousD538GNUYU564Endometrioid ov adenoY537SYUNU646LG ov serousY537SYUYU739Papillary serousY537SYUNN/A827LG ov serousY537SYYYY CONCLUSIONS: Acquired activating mutations in ESR1, previously described in breast cancer, can occur in ovarian serous carcinomas and endometrioid carcinomas initially responsive to hormone therapy and suggest a similar mechanism for acquired aromatase inhibitor resistance. However, ERa mutations can occur in gynecologic malignancies even in the absence of prior endocrine therapy. Tumors harboring these mutations may remain responsive to SERM/SERDs. Citation Format: J. A. Elvin, L. Gay, G. Colon-Otero, M. Jorgensen, L. Havrilesky, D. Zajchowski, L Shawver, F. A. Valea, S Aithal, J. S. Ross, M. Markman, S. Gaillard. CONSTITUTIVELY ACTIVE ESTROGEN RECEPTOR–ALPHA LIGAND BINDING DOMAIN (ERA–LBD) MUTATIONS IN OVARIAN CARCINOMA [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-056.

Background: Although sliding occurs frequently in professional baseball, little is known about the epidemiology and effect of injuries that occur during sliding in this population of elite athletes. Purpose: To describe the incidence and characteristics of sliding injuries, determine their effect in terms of time out of play, and identify common injury patterns that may represent appropriate targets for injury prevention programs in the future. Study Design: Descriptive epidemiologic study. Methods: All offensive sliding injuries occurring in Major League Baseball (MLB) and Minor League Baseball (MLB) that resulted in time out of play during a span of 5 seasons (2011-2015) were identified. In addition to player demographics, data extracted included time out of play, location on field where injury occurred, level of play, treatment (surgical vs nonsurgical), direction of slide (head vs feet first), body region injured, and diagnosis. Descriptive statistics were used to describe the distribution of these injuries, and injury rates were calculated per slide. Results: From 2011 to 2015, 1633 injuries occurred as a result of a slide. The total number of days missed per season was 4263. Surgical intervention was required for 134 (8.2%) injuries, and the mean days missed was 66.5 for players treated surgically and 12.3 days for players treated nonoperatively ( P < .001). MLB players were more likely than MiLB players to require surgical intervention (12.3% vs 7.5%, P = .019). Injuries to the hands/fingers represented 25.3% of all injuries and 31.3% of those requiring surgery. Although the majority of injuries occurred at second base (57%), the per-slide injury rate was similar across all bases ( P = .991). The estimated overall frequency of injury in MLB was once per every 336 slides, and the rate of injury for head- and feet-first slides was 1 in 249 and 413 slides, respectively ( P = .119). Conclusion: Injuries occurring while sliding in professional baseball result in a significant amount of time out of play for these elite athletes. Injuries occurring at second base and those occurring to the hands and fingers were most prevalent and may be an appropriate target for future injury prevention programs.

Key Points Complete or partial response at 1 year without secondary systemic treatment provides clinical benefit in patients with chronic GVHD. Success defined by this endpoint is currently observed in fewer than 20% of patients after initial systemic treatment of chronic GVHD.

Magnetic resonance elastography (MRE) is a promising technique for noninvasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. The purpose of this study was to determine the accuracy of MRE for the detection of fibrosis and advanced fibrosis in children with NAFLD and to assess agreement between manual and novel automated reading methods. We performed a prospective, multicenter study of two‐dimensional (2D) MRE in children with NAFLD. MR elastograms were analyzed manually at two reading centers, and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross‐validated. In 90 children with a mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r = 0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ = 0.53; center 2, ρ = 0.55; and automated analysis, ρ = 0.52; P < 0.001). Overall cross‐validated accuracy for detecting any fibrosis was 72.2% for all methods (95% confidence interval [CI], 61.8%‐81.1%). Overall cross‐validated accuracy for assessing advanced fibrosis was 88.9% (95% CI, 80.5%‐94.5%) for center 1, 90.0% (95% CI, 81.9%‐95.3%) for center 2, and 86.7% (95% CI, 77.9%‐92.9%) for automated analysis. Conclusion : 2D MRE can estimate hepatic stiffness in children with NAFLD. Further refinement and validation of automated analysis techniques will be an important step in standardizing MRE. How to best integrate MRE into clinical protocols for the assessment of NAFLD in children will require prospective evaluation. (H epatology 2017;66:1474–1485)

AbstractIntroductionThe objective of this study was to evaluate the relationship between self‐reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers.MethodsIn 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self‐reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression.ResultsNo differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels.DiscussionOur findings indicate a relationship exists between self‐reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.

Abstract Medulloblastoma arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we used mouse medulloblastoma models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive medulloblastoma subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/− mice, which develop SHH-driven medulloblastoma, animals with Atoh1 transgene expression developed highly penetrant medulloblastoma at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH medulloblastoma. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH medulloblastoma. Chromatin immunoprecipitation sequencing and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities. Cancer Res; 77(14); 3766–77. ©2017 AACR.

INTRODUCTION: The Pregnancy Reasonably Excluded Guide (PREG) questionnaire is based on traditional methods of excluding pregnancy including sterilization, menopause, and the World Health Organization criteria. The PREG has been validated and shows a 99-100% negative predictive value for pregnancy (Selected practice recommendations for contraceptive use, 2013: adapted from the world health organization selected practice recommendations for contraceptive use, 2nd edition. MMWR Recomm Rep 2013; 62:1‒60.). Pregnancy testing in our outpatient surgical settings varied by provider. This study compared utilization of pregnancy tests in the outpatient gynecologic surgery setting after implementation of universal PREG administration. METHODS: All women undergoing outpatient gynecologic surgery were prospectively evaluated between March and September 2016. Administration of the PREG to women 18-49, excluding those undergoing procedures related to pregnancy, was implemented in July and rates of pregnancy testing pre- and post-implementation were compared using Fisher’s exact test. RESULTS: 369 patients underwent an outpatient gynecologic procedure during the study period (excluding a two week washout period after implementation). In the pre-implementation group, 136 met inclusion criteria with 45 pregnancy tests performed (33.1%). After implementation, 80 patients met inclusion criteria and 17 pregnancy tests were performed as indicated by PREG response (21.3%), demonstrating over one third reduction in pregnancy test administration (p = 0.086). No pregnancy tests were positive and no false negative evaluations were identified. Physician and nursing staff requested continued use of the PREG after the trial. CONCLUSION: PREG administration on admission for outpatient gynecologic surgery consistently and effectively identifies patients in whom pregnancy testing improves the value of care.