Gastrointestinal perforation in metastatic colorectal cancer patients with peritoneal metastases receiving bevacizumab

AIM To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease. METHODS We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts: (1) the AGITG MAX trial (Phase III randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine, bevacizumab and mitomycinC); (2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (any first-line regimen ± bevacizumab); and (3) two cancer centres in New South Wales, Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre (NSWCC) from January 2005 to Decenber 2012, (any first-line regimen ± bevacizumab). For the AGITG MAX trial capecitabine was compared to the other two arms (capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycinC). In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases. Secondary endpoints included progression-free survival, chemotherapy duration, and overall survival. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS Eighty-four MAX, 179 TRACC and 69 NSWCC patients had peritoneal disease. There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts. Of the patients without peritoneal disease in the MAX trial, 4/300 (1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123 (0.8%) in the capecitabine alone arm. In the TRACC registry 3/126 (2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53 (1.9%) in the chemotherapy alone arm. In a further analysis of patients without peritoneal metastases in the TRACC registry, the rate of gastrointestinal perforations was 9/369 (2.4%) in the chemotherapy/bevacizumab group and 5/177 (2.8%) in the chemotherapy alone group. The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts: MAX 6.9 m vs 4.9 m, HR = 0.64 (95%CI: 0.42-1.02); P = 0.063; TRACC 9.1 m vs 5.5 m, HR = 0.61 (95%CI: 0.37-0.86); P = 0.009; NSWCC 8.7 m vs 6.8 m, HR = 0.75 (95%CI: 0.43-1.32); P = 0.32. Chemotherapy duration was similar across the groups. CONCLUSION Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone

A Complete Redesign of the Cardiopulmonary Resuscitation (CPR) and Automated External Defibrillator (AED) Learning Experience

Survival following sudden cardiac arrest in the community can be framed as a complex systems problem for which systems thinking and design methodologies may be applied. Focusing on the subsystem of the learning experience of cardiopulmonary resuscitation and use of an automated external defibrillator (CPR/AED), we used a systems approach to understand the current state of learning and a design methodology to identify improvements. A systems diagnosis identified six elements within the learning experience - need for training, opportunity for training, training class characteristics, perceived competence, anticipated event characteristics, and perceived readiness to act – each of which had positive and negative meanings and outcomes. As the elements are interactive and complex, the expected central property of learning – likelihood to act - may not be realized because of significant conflicts and obstructions. Design methodology identified 250 elements for an ideal CPR/AED learning experience which could be arranged as a containing system with eight interactive categories. Based on a system thinking and design methodology approach we suggested ten changes to improve the current state of the CPR/AED learning experience

Borderline personality traits, rumination and self-injurious behavior: An empirical test of the emotional cascades model in adult male offenders

The aim of the study was to examine whether the emotional cascade model, which suggests that the relationship between emotional and behavioural dysregulation in Borderline Personality Disorder (BPD) is mediated by rumination, applies to a sample of adult male offenders. The study focused on individuals with “BPD traits” and two dysregulated behaviors that are particularly relevant to the prison population: non-suicidal self-injury (NSSI) and suicidality. Participants were 179 adult male offenders detained in a medium-secure prison, all of whom completed a battery of measures and self-reported their actual prison behaviour. The results support the application of the emotional cascade model to adult male offenders, suggesting that emotional cascades may play an important role in NSSI and suicidality in this population, although this relationship needs further exploration. These findings highlight the benefits of targeting rumination to manage risk of NSSI and suicidality within custodial settings

The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection

Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors and their matched recurrent counterparts. Molecular profiling of tumors was performed using multiplexed targeted deep sequencing of 409 well characterized cancer-associated genes, achieving a mean read depth of 1272 x. Three levels of evidence suggested an evolutionary pattern consistent with a response to therapy-mediated selection pressures exists in treated patients: 1) variant burden was reduced in recurrent tumors, 2) neutral evolutionary dynamics apparent in untreated tumors shifted toward a non-neutral mode of evolution in treated patients at recurrence, and 3) the recurrent tumor of one patient displayed an increased mutation rate attributable to a temozolomide-associated hypermutator phenotype. Our observations suggest that current treatment modalities are likely to fail in achieving long term remission with the majority of relapse samples containing distinct mutations when compared to primary diagnostic samples. Oncotarget 2018 9(8):7844-7858

Detection of Group 1 Coronaviruses in Bats in North America

Bats of 2 species harbor group 1 coronaviruses

Mutations in KCTD1 Cause Scalp-Ear-Nipple Syndrome

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2 alpha (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. the identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.National Institutes of Health National Human Genome Research InstituteLife Sciences Discovery FundWashington Research FoundationMassachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USAUniv Washington, Dept Pediat, Seattle, WA 98195 USAUniv Washington, Dept Genome Sci, Seattle, WA 98195 USAUniv Western Sydney Macarthur, Sch Med, Campbelltown, NSW 2560, AustraliaGenet Learning Disabil Serv, Newcastle, NSW 2298, AustraliaJohns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USAUniversidade Federal de São Paulo, Dept Morphol & Genet, Clin Genet Ctr, BR-04021001 São Paulo, BrazilPontificia Univ Catolica Parana, Dept Internal Med, BR-1155 Curitiba, Parana, BrazilWestern Gen Hosp, South East Scotland Clin Genet Serv, Edinburgh EH4 2XU, Midlothian, ScotlandUniv Florence, Dept Genet & Mol Med, I-50132 Florence, ItalyHop Necker Enfants Malad, Dept Genet, INSERM, U781, F-75015 Paris, FranceUniv Paris Descartes Sorbonne Paris Cite, Inst Imagine, F-75015 Paris, FranceHop Cote Nacre, CHU Caen, Serv Genet, F-14033 Caen 9, FranceUniv Connecticut, Ctr Hlth, Dept Reconstruct Sci, Farmington, CT 06030 USABoston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA 02115 USATreuman Katz Ctr Pediat Bioeth, Seattle Childrens Res Inst, Seattle, WA 98101 USAUniversidade Federal de São Paulo, Dept Morphol & Genet, Clin Genet Ctr, BR-04021001 São Paulo, BrazilNational Institutes of Health National Human Genome Research Institute: 1U54HG006493National Institutes of Health National Human Genome Research Institute: 1RC2HG005608National Institutes of Health National Human Genome Research Institute: 5RO1HG004316Life Sciences Discovery Fund: 2065508Life Sciences Discovery Fund: 0905001Web of Scienc

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV