Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH -Mutant Molecular Profiles

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Increasing Minority Participation in Clinical Research

Our goal is to ensure that clinical research supporting 1) the safety and efficacy of products for labeling purposes and 2) the validity of biomarkers commonly used to assess risk and to design therapeutic strategies is based on data sufficient for statistical power and derived from diverse subpopulations. It is widely recognized that data supporting therapeutic options for women and minorities have been deficient because these groups were not previously included in clinical trials. Although the combined efforts of Congress, the Office of Women’s Health at the Food and Drug Administration (FDA), and the Office of Research on Women’s Health

A controlled evaluation of an intensive, peer-led, schools-based, anti-smoking programme

There is increasing interest in health promotion interventions which seek to change behaviour through local cultural diffusion by trained opinion-formers. This study adapted this approach to schools settings. Popular pupils in years 8 and 9 (aged 12 to 14) were recruited for intensive training by specialist staff on how to intervene effectively in everyday situations to promote smoking cessation and prevention of smoking uptake among their peers. Data on smoking behaviour, plus saliva samples for cotinine testing, were collected pre-intervention, immediately post-intervention, and three months post-intervention in two intervention and two control schools. Most differences in behaviour between intervention and control schools were not statistically significant. However, baseline ex-smokers (11 per cent of the sample and a larger group than baseline regular smokers) were significantly more likely still to be abstinent in the intervention, as opposed to the control, schools. Given the relative paucity of evidence of effective anti-smoking programmes in schools, these results are sufficiently encouraging to justify a full-scale randomised controlled trial evaluation

J Affect Disord

Background The literature suggests that cognitive reactivity in bipolar patients can increase relapse vulnerability, is enhanced by depressive mood and dysfunctional attitudes, and could be improved with MBCT. Autobiographical memory (AM) could be involved in cognitive reactivity, and improved with MBCT training. This study aims to investigate the effect of MBCT for bipolar patients on depressive and anxious symptoms, dysfunctional attitudes and AM, and the predictive versus mediating role of AM in the impact of MBCT on clinical symptoms. Methods Sixty-two outpatients diagnosed with bipolar I disorder were assigned to MBCT and were compared to 37 bipolar patients on a waiting list. Affective symptoms and dysfunctional attitudes were explored using self-report inventories (BDI, BAI, DAS) and AM was assessed using the Autobiographical Memory Test. Results Patients receiving MBCT demonstrated significantly decreased depressive symptoms, dysfunctional attitudes, overgeneral memories and omissions, and increased specific memories. General AM and omissions at baseline respectively predicted lower anxiety and dysfunctional attitudes improvement following therapy, but the improvement of AM did not explain the impact of MBCT on depression and dysfunctional attitudes improvement. Limits Further studies should consider patients’ therapeutic adherence and mechanisms involved in MBCT in order to better apprehend how MBCT may reduce dysfunctional attitudes and improve AM in bipolar patients. Conclusion Results are consistent with the hypothesis that MBCT reduces cognitive reactivity and AM impairment in bipolar disorders. Findings suggest that AM training prior to MBCT may influence MBCT efficacy, but that MBCT efficacy on AM and clinical symptoms are non-related phenomena