Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas

Purpose: Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. Methods: We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. Results: By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non–xenograft-forming gliomas (P = 0.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT, or PTEN mutation or PDGFRA, MET, or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations whereas IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months; P = 0.0011). Conclusion: A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients.Koch Institute Dana Farber/Harvard Cancer Center Bridge Projec

Reducing the duration of untreated psychosis and its impact in the U.S.: the STEP-ED study

Background: Early intervention services for psychotic disorders optimally interlock strategies to deliver: (i) Early Detection (ED) to shorten the time between onset of psychotic symptoms and effective treatment (i.e. Duration of Untreated Psychosis, DUP); and (ii) comprehensive intervention during the subsequent 2 to 5 years. In the latter category, are teams (‘First-episode Services’ or FES) that integrate several empirically supported treatments and adapt their delivery to younger patients and caregivers. There is an urgent need to hasten access to established FES in the U.S. Despite improved outcomes for those in treatment, these FES routinely engage patients a year or more after psychosis onset. The Scandinavian TIPS study was able to effectively reduce DUP in a defined geographic catchment. The guiding questions for this study are: can a U.S. adaptation of the TIPS approach to ED substantially reduce DUP and improve outcomes beyond existing FES? Methods/Design The primary aim is to determine whether ED can reduce DUP in the US, as compared to usual detection. ED will be implemented by one FES (STEP) based in southern Connecticut, and usual detection efforts will continue at a comparable FES (PREPR) serving the greater Boston metropolitan area. The secondary aim is to determine whether DUP reduction can improve presentation, engagement and early outcomes in FES care. A quasi-experimental design will compare the impact of ED on DUP at STEP compared to PREPR over 3 successive campaign years. The campaign will deploy 3 components that seek to transform pathways to care in 8 towns surrounding STEP. Social marketing approaches will inform a public education campaign to enable rapid and effective help-seeking behavior. Professional outreach and detailing to a wide variety of care providers, including those in the healthcare, educational and judicial sectors, will facilitate rapid redirection of appropriate patients to STEP. Finally, performance improvement measures within STEP will hasten engagement upon referral. Discussion STEP-ED will test an ED campaign adapted to heterogeneous U.S. pathways to care while also improving our understanding of these pathways and their impact on early outcomes. Trial registration ClinicalTrials.gov: NCT02069925. Registered 20 February 2014

Solvothermal synthesis of a new 3-D mixed-metal sulfide framework, (H1.33tren)[In2.67Sb1.33S8]∙tren

A new indium(III) antimony(V) sulfide, (H1.33tren)[In2.67Sb1.33S8]∙tren, has been prepared solvothermally at 433 K. The compound crystallises in the tetragonal space group I-42d (lattice parameters, a = 12.6248(5) and c = 19.4387(18) Å at 150 K) and contains adamantane-like T2 supertetrahedral units comprised of corner-sharing InS45- and SbS43- tetrahedra. The adamantane-like units are then linked through sulfur vertices to generate an open, 3-D framework structure containing large pores in which neutral, protonated tren (tris(2-aminoethylene)amine) molecules reside. The presence of the organic components was confirmed by solid-state 13C NMR (10 kHz), combustion and thermogravimetric analysis. The band gap, obtained from UV-vis diffuse reflectance measurements, is 2.7(2) eV. Stirring with either water or alkali-metal salt solution leads to removal of the neutral tren molecules and an ~9 % reduction in unit-cell volume on formation of (H1.33tren)[In2.67Sb1.33S8]∙(H2O)4

Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population

Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Pharmacological Effects of Asiatic acid in Glioblastoma Cells under Hypoxia

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Despite current treatment options including surgery followed by radiation and chemotherapy with temozolomide (TMZ) and cisplatin, the median survival rate remains low (<16 months). Combined with increasing drug resistance and the inability of some compounds to cross the blood brain barrier (BBB), novel compounds are being sought for the treatment of this disease. Here, we aimed to examine the pharmacological effect of Asiatic acid (AA) in glioblastoma under hypoxia. To investigate the effects of AA on cell viability, proliferation, apoptosis and wound healing, SVG p12 fetal glia and U87-MG grade IV glioblastoma cells were cultured under normoxic (21% O2) and hypoxic (1% O2) conditions. In normoxia, AA reduced cell viability in U87-MG cells in a time and concentration-dependent manner. A significant decrease in viability, compared to cisplatin, was observed following 2hrs of AA treatment with no significant changes in cell proliferation or cell cycle progression observed. Under hypoxia, a significantly greater number of cells underwent apoptosis in comparison to cisplatin. While cisplatin showed a reduction in wound healing in normoxia, a significantly greater reduction was observed following AA treatment. An overall reduction in wound healing was observed under hypoxia. The results of this study show that AA has cytotoxic effects on glioma cell lines and has the potential to become an alternative treatment for glioblastoma

COmparing Urolift and Standard Transurethral resection of prostate Ahead of Radiotherapy in men with urinary symptoms secondary to prostate enlargement in Southwest London and North Cumbria (CO-STAR): a study protocol for a randomised feasibility study

Introduction: Patients undergoing prostate radiotherapy with an enlarged prostate can have short-term and long-term urinary complications. Currently, transurethral resection of the prostate (TURP) is the mainstay surgical intervention for men with urinary symptoms due to an enlarged prostate prior to radiotherapy. UroLift (NeoTract, Pleasanton, CA, USA) is a recent minimally invasive alternative, widely used in benign disease but is untested in men with prostate cancer. // Methods and analysis: A multicentre, two-arm study designed in collaboration with a Patient Reference Group to assess the feasibility of randomising men with prostate cancer and coexisting urinary symptoms due to prostate enlargement to TURP or UroLift ahead of radiotherapy. 45 patients will be enrolled and randomised (1:1) using a computer-generated programme to TURP or UroLift. Recruitment and retention will be assessed over a 12 month period. Information on clinical outcomes, adverse events and costs will be collected. Clinical outcomes and patient reported outcome measures will be measured at baseline, 6 weeks postintervention and 3 months following radiotherapy. A further 12 in-depth interviews will be conducted with a subset of patients to assess acceptability using the Theoretical Framework of Acceptability. Descriptive analysis on all outcomes will be performed using Stata (StataCorp V.2021). // Ethics and dissemination: The trial has been approved by the Research Ethics Committee (REC) NHS Health Research Authority (HRA) and Health and Care Research Wales (HCRW). The results will be published in peer-reviewed journals, presented at national meetings and disseminated to patients via social media, charity and hospital websites. // Trial registration number: NCT05840549

Development and validation of a recommended checklist for assessment of surgical videos quality: the LAParoscopic surgery Video Educational GuidelineS (LAP-VEGaS) video assessment tool

Introduction There has been a constant increase in the number of published surgical videos with preference for open-access sources, but the proportion of videos undergoing peer-review prior to publication has markedly decreased, raising questions over quality of the educational content presented. The aim of this study was the development and validation of a standard framework for the appraisal of surgical videos submitted for presentation and publication, the LAParoscopic surgery Video Educational GuidelineS (LAP-VEGaS) video assessment tool. Methods An international committee identified items for inclusion in the LAP-VEGaS video assessment tool and finalised the marking score utilising Delphi methodology. The tool was finally validated by anonymous evaluation of selected videos by a group of validators not involved in the tool development. Results 9 items were included in the LAP-VEGaS video assessment tool, with every item scoring from 0 (item not presented in the video) to 2 (item extensively presented in the video), with a total marking score ranging from 0 to 18. The LAP-VEGaS video assessment tool resulted highly accurate in identifying and selecting videos for acceptance for conference presentation and publication, with high level of internal consistency and generalisability. Conclusions We propose that peer review in adherence to the LAP-VEGaS video assessment tool could enhance the overall quality of published video outputs.[GRAPHICS]