Citations

Abstract Background: Treatment options for women with ovarian cancer remain very limited and acquired resistance to current therapies is very common. Altered DNA repair capability in epithelial ovarian cancer (EOC) may underlie response to both standard therapy and novel treatments, such as PARP inhibitors. Molecular sub-classification of high-grade serous ovarian cancer (HG-SOC) may uncover potential drug targets and possible mechanisms of drug resistance. Understanding the contribution of DNA repair and other driver mutations to drug response and resistance requires the development of molecularly annotated preclinical models reflective of the clinic. Methods: A patient derived xenograft (PDX) cohort has been generated from consecutive, chemotherapy-naïve human HG-SOC and stratified according to in vivo response to standard chemotherapy, DNA repair capability and molecular characteristics, including next generation sequencing by Foundation Medicine. Resistance to therapy is driven by re-treating relapsed PDX in vivo providing invaluable “paired samples” (pre and post drug treatment), which are difficult to obtain from patients, to allow clonal evolution analysis of mechanisms of drug response and resistance. Results: The xenograft success rate was 83%. Of ten HG-SOC PDX, all exhibited mutations in TP53, five in BRCA1/2 (two of which were germline) and two were methylated for BRCA1. In vivo cisplatin response, determined as platinum sensitive (progression-free interval (PFI) ≥100 d, n=4), platinum resistant (PFI <100 d, n=3) or platinum refractory (n=3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDX contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDX overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2). Molecular analysis of this cohort has revealed actionable targets for novel therapeutic strategies. In vivo studies, including with PARP inhibitors, are underway. Conclusion: PDX with histologic, molecular and therapeutic annotation, as well as clinical outcome data allow interrogation of molecular aberrations and drug resistance in vivo. This will inform targeting of novel therapies and the design of clinical trials for women. Citation Format: Monique D. Topp, Lynne Hartley, Michele Cook, Valerie Heong, Emma Boehm, Lauren McShane, Jan Pyman, Orla McNally, Sumi Ananda, Maria I. Harell, Dariush Etemadmoghadam, Laura Galletta, Kathryn Alsop, Gillian Mitchell, Stephen B. Fox, Jeff B. Kerr, Karla J. Hutt, Scott H. Kaufmann, Australian Ovarian Cancer Study (AOCS), Elizabeth M. Swisher, David D. Bowtell, Matthew M. Wakefield, Clare L. Scott. Using molecularly characterized patient-derived models to delineate underlying drivers and vulnerabilities of epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 38. doi:10.1158/1538-7445.CANSUSC14-38

The Food and Drug Administration recently approved topiramate for migraine prevention in adolescents. Given the well-established appetite-suppressant side effects of topiramate, as well as data suggesting a potential comorbidity between migraine and eating disorders, susceptible young migraine patients may be at a greater risk for the development or worsening of eating disorder symptoms with topiramate therapy. This case series comprises 7 adolescent patients in whom serious eating disorders developed or were exacerbated after the initiation of topiramate therapy. Clinical characteristics of these patients are highlighted. In addition, this case series provides guidelines for providers to use in assessing eating disorders before prescribing topiramate for migraine prevention in adolescents.

Context Self‐regulated learning ( SRL ) requires an active learner who has developed a set of processes for managing the achievement of learning goals. Simulation‐based training is one context in which trainees can safely practise learning how to learn. Objectives The purpose of the present study was to evaluate, in the simulation‐based training context, the effectiveness of interventions designed to support trainees in SRL activities. We used the social‐cognitive model of SRL to guide a systematic review and meta‐analysis exploring the links between instructor supervision, supports or scaffolds for SRL , and educational outcomes. Methods We searched databases including MEDLINE and Scopus, and previous reviews, for material published until December 2011. Studies comparing simulation‐based SRL interventions with another intervention for teaching health professionals were included. Reviewers worked independently and in duplicate to extract information on learners, study quality and educational outcomes. We used random‐effects meta‐analysis to compare the effects of supervision (instructor present or absent) and SRL educational supports (e.g. goal‐setting study guides present or absent). Results From 11 064 articles, we included 32 studies enrolling 2482 trainees. Only eight of the 32 studies included educational supports for SRL . Compared with instructor‐supervised interventions, unsupervised interventions were associated with poorer immediate post‐test outcomes (pooled effect size: −0.34, p = 0.09; n = 19 studies) and negligible effects on delayed (i.e. > 1 week) retention tests (pooled effect size: 0.11, p = 0.63; n = 8 studies). Interventions including SRL supports were associated with small benefits compared with interventions without supports on both immediate post‐tests (pooled effect size: 0.23, p = 0.22; n = 5 studies) and delayed retention tests (pooled effect size: 0.44, p = 0.067; n = 3 studies). Conclusions Few studies in the simulation literature have designed SRL training to explicitly support trainees’ capacity to self‐regulate their learning. We recommend that educators and researchers shift from thinking about SRL as learning alone to thinking of SRL as comprising a shared responsibility between the trainee and the instructional designer (i.e. learning using designed supports that help prepare individuals for future learning).

Summary Objective To prospectively evaluate the etiology of new‐onset infantile spasms and evaluate the yield of genetic and metabolic investigations in those without obvious cause after initial clinical evaluation and magnetic resonance imaging ( MRI ). Methods Twenty‐one U.S. pediatric epilepsy centers prospectively enrolled infants with newly diagnosed West syndrome in a central database. Etiology and investigations performed within 3 months of diagnosis were documented. Results From June 2012 to June 2014, a total of 251 infants were enrolled (53% male). A cause was identified in 161 (64.4%) of 250 cases (genetic,14.4%; genetic‐structural, 10.0%; structural‐congenital, 10.8%; structural‐acquired, 22.4%; metabolic, 4.8%; and infectious, 2.0%). An obvious cause was found after initial clinical assessment (history and physical examination) and/or MRI in 138 of 161, whereas further genetic and metabolic studies were revealing in another 23 cases. Of 112 subjects without an obvious cause after initial evaluation and MRI , 81 (72.3%) had undergone genetic testing, which showed a causal abnormality in 23.5% and a variant of unknown significance in 14.8%. Although metabolic studies were done in the majority (serum, 79.5%; urine, 69.6%; and cerebrospinal fluid [ CSF ], 38.4%), these revealed an etiology in only five cases (4.5%). No correlation was found between type of health insurance (public vs. private) and either genetic or metabolic testing. Significance Clinical evaluation and MRI provide a specific diagnosis in 55% of children presenting with West syndrome. We propose that a cost‐effective workup for those without obvious cause after initial clinical evaluation and MRI includes an array comparative genomic hybridization ( aCGH ) followed by an epilepsy gene panel if the microarray is not definitive, serum lactate, serum amino acids, and urine organic acids.

Context The relative advantages and disadvantages of checklists and global rating scales ( GRS s) have long been debated. To compare the merits of these scale types, we conducted a systematic review of the validity evidence for checklists and GRS s in the context of simulation‐based assessment of health professionals. Methods We conducted a systematic review of multiple databases including MEDLINE , EMBASE and S copus to F ebruary 2013. We selected studies that used both a GRS and checklist in the simulation‐based assessment of health professionals. Reviewers working in duplicate evaluated five domains of validity evidence, including correlation between scales and reliability. We collected information about raters, instrument characteristics, assessment context, and task. We pooled reliability and correlation coefficients using random‐effects meta‐analysis. Results We found 45 studies that used a checklist and GRS in simulation‐based assessment. All studies included physicians or physicians in training; one study also included nurse anaesthetists. Topics of assessment included open and laparoscopic surgery ( n = 22), endoscopy ( n = 8), resuscitation ( n = 7) and anaesthesiology ( n = 4). The pooled GRS –checklist correlation was 0.76 (95% confidence interval [ CI ] 0.69–0.81, n = 16 studies). Inter‐rater reliability was similar between scales ( GRS 0.78, 95% CI 0.71–0.83, n = 23; checklist 0.81, 95% CI 0.75–0.85, n = 21), whereas GRS inter‐item reliabilities (0.92, 95% CI 0.84–0.95, n = 6) and inter‐station reliabilities (0.80, 95% CI 0.73–0.85, n = 10) were higher than those for checklists (0.66, 95% CI 0–0.84, n = 4 and 0.69, 95% CI 0.56–0.77, n = 10, respectively). Content evidence for GRS s usually referenced previously reported instruments ( n = 33), whereas content evidence for checklists usually described expert consensus ( n = 26). Checklists and GRS s usually had similar evidence for relations to other variables. Conclusions Checklist inter‐rater reliability and trainee discrimination were more favourable than suggested in earlier work, but each task requires a separate checklist. Compared with the checklist, the GRS has higher average inter‐item and inter‐station reliability, can be used across multiple tasks, and may better capture nuanced elements of expertise.