Interventions to reduce suicides at suicide hotspots: a systematic review

BACKGROUND: 'Suicide hotspots' include tall structures (for example, bridges and cliffs), railway tracks, and isolated locations (for example, rural car parks) which offer direct means for suicide or seclusion that prevents intervention. METHODS: We searched Medline for studies that could inform the following question: 'What interventions are available to reduce suicides at hotspots, and are they effective?' RESULTS: There are four main approaches: (a) restricting access to means (through installation of physical barriers); (b) encouraging help-seeking (by placement of signs and telephones); (c) increasing the likelihood of intervention by a third party (through surveillance and staff training); and (d) encouraging responsible media reporting of suicide (through guidelines for journalists). There is relatively strong evidence that reducing access to means can avert suicides at hotspots without substitution effects. The evidence is weaker for the other approaches, although they show promise. CONCLUSIONS: More well-designed intervention studies are needed to strengthen this evidence base.Australian Government Department of Health and AgeingUK National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for the Southwest Peninsul

p21 promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker

The oncolytic adenovirus dl922-947 replicates selectively within and lyses cells with a dysregulated Rb pathway, a finding seen in > 90% human cancers. dl922-947 is more potent than wild type adenovirus and the E1B-deletion mutant dl1520 (Onyx-015). We wished to determine which host cell factors influence cytotoxicity. SV40 large T-transformed MRC5-VA cells are 3-logs more sensitive to dl922-947 than isogenic parental MRC5 cells, confirming that an abnormal G1/S checkpoint increases viral efficacy. The sensitivity of ovarian cancer cells to dl922-947 varied widely: IC50 values ranged from 51 (SKOV3ip1) to 0.03 pfu/cell (TOV21G). Cells sensitive to dl922-947 had higher S phase populations and supported earlier E1A expression. Cytotoxicity correlated poorly with both infectivity and replication, but well with expression of p21 by microarray and western blot analyses. Matched p21+/+ and -/- Hct116 cells confirmed that p21 influences dl922-947 activity in vitro and in vivo. siRNA-mediated p21 knockdown in sensitive TOV21G cells decreases E1A expression and viral cytotoxicity, whilst expression of p21 in resistant A2780CP cells increases virus activity in vitro and in intraperitoneal xenografts. These results highlight that host cell factors beyond simple infectivity can influence the efficacy of oncolytic adenoviruses. p21 expression may be an important biomarker of response in clinical trials

A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases

In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8 + T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases. Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by a multiplex assay, and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation. B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the costimulatory molecule CD86 on antigen-presenting cells. A positive role for B cells in the antitumor response was also supported by B-cell depletion in a syngeneic mouse model of peritoneal metastasis. Our data showed that B cells infiltrating HGSOC omental metastases support the development of an antitumor response. Clin Cancer Res; 1-13. ©2016 AACR

Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma

This research was funded by Swiss Cancer League (BIL KLS-2883-02-2012), the European Research Council (ERC322566), Cancer Research UK (A16354), and Barts and The London Charity (467/1307)

The impact of a supranetwork multidisciplinary team (SMDT) on decision-making in testicular cancers: a 10-year overview of the Anglian Germ Cell Cancer Collaborative Group (AGCCCG)

Abstract: Background: The germ cell supranetwork multidisciplinary team (SMDT) for the Anglian Network covers a population of 7.5 million. Methods: We reviewed 10 years of SMDT discussion and categorised them into five domains ((1) overall outcome, (2) chemotherapy regimens—untreated disease and salvage therapy, (3) radiology, (4) pathology and (5) complex cases) to assess the impact of the SMDT. Results: A total of 2892 new cases were reviewed. In the first 5 years, patients with good prognosis disease had poorer survival in low-volume vs high-volume centres (87.8 vs 95.3, p = 0.02), but the difference was no longer significant in the last 5 years (93.3 vs 95.1, p = 0.30). Radiology review of 3206 scans led to rejection of the diagnosis of progression in 26 cases and a further 10 cases were down-staged. There were 790 pathology reviews by two specialised uropathologists, which lead to changes in 75 cases. 18F-fluorodeoxyglucose (18FDG) PET-CT was undertaken during this time period but did not help to predict who would have viable cancer. A total of 26 patients with significant mental health issues who were unable to give informed consent were discussed. Conclusion: SMDT working has led to an improvement in outcomes and refining of treatment in patients with germ cell tumours

The avoiding late diagnosis of ovarian cancer (ALDO) project; A pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2

Background: Our study aimed to establish â € real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). Methods: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. Results: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-Adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of-£102,496/QALY. Conclusion: OC surveillance for women deferring RRSO in a â € real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers.

We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer.Significance: Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. Cancer Discov; 8(3); 304-19. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 253

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.Peer reviewe