tom@pelhamcourt.clara.co.uk Introduction Epigenetic silencing mechanisms are increasingly thought to play a major role in the development of human cancers, including prostate cancer. The two major epigenetic regulatory mechanisms involve alterations in DNA methylation and histone acetylation status. Promoter CpG island hypermethylation and histone hypoacetylation, catalysed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) respectively, are associated with transcriptional repression. Evidence in other cancers suggests the two mechanisms are dynamically linked, yet few studies have examined the potential interaction of the two pathways in prostate cancer. Here we report a synergistic, apoptotic effect of treatment with a demethylating agent and a histone deacetylase inhibitor on cultured prostate cancer cells, with associated re-expression of the putative antiproliferative agent oestrogen receptor beta.Methods LNCaP, DU-145 and PC-3 cells were pre-treated with the DNMT inhibitor 5'-aza-2'-deoxycytidine (5-AZAC) for 72 hours followed by 24 hours combined treatment with 5-AZAC and the HDAC inhibitor trichostatin A (TSA). Following treatment, cells were either processed for cell proliferation, cell toxicity, cell viability and apoptosis assays, or harvested for quantitative real-time RT-PCR gene expression analyses. Assessed target genes were oestrogen receptor beta (ERβ), androgen receptor (AR), progesterone receptor (PGR) and prostate specific antigen (PSA). ResultsIn all cell-lines co-treatment with 5-AZAC and TSA was associated with significantly reduced cell proliferation when compared with control groups (p<0.05); associated reduced cell viability and increased cell death was seen in all cases. Caspase activation was significantly increased in the co-treatment group, indicating that apoptosis was a major mechanism of cell death. Most marked effects were seen in the androgen-dependent, AR-positive LNCaP cell-line. In all cell-lines a marked synergistic re-expression of ERβ was identified in the co-treatment group, a finding which was not seen for either AR or PSA. A similar re-expression of PGR was also identified. ConclusionsAt concentrations associated with gene re-expression, the DNA demethylating agent 5-AZAC and the HDAC inhibitor TSA co-operate in an additive and synergistic way to induce apoptosis in prostate cancer cell-lines. Increased apoptosis in the co-treatment group was associated with marked re-expression of ERβ, which is an intriguing finding, raising the possibility of further targeting of prostate cancer cells with ERβ-selective agents such as phytooestrogens and selective oestrogen receptor modulators (SERMs).

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BackgroundMultiparametric magnetic resonance imaging (mpMRI) is now recommended pre-biopsy in numerous healthcare regions based on the findings of high-quality studies from expert centres. Concern remains about reproducibility of mpMRI to rule-out clinically significant prostate cancer (csPCa) in real-world settings. ObjectiveTo assess the diagnostic performance of mpMRI for csPCa in a real-world setting. Design, Setting, and ParticipantsA multicentre, retrospective cohort study including men referred with a raised PSA or abnormal digital rectal exam who had undergone mpMRI followed by transrectal or transperineal biopsy. Patients could be biopsy naïve or have had previous negative biopsies. Outcome Measurements and Statistical AnalysisThe primary definition for csPCa was defined as ISUP Grade Group 2 or higher (any Gleason >/=7); the accuracy for other definitions was also evaluated. Results and LimitationsAcross 10 sites 2642 men were included (January/2011-November/2018). Mean age and PSA were 65.3 years (SD 7.8 years) and 7.5ng/ml (SD 3.3ng/ml). 35.9% had a 'negative' MRI' (score 1-2). 51.9% underwent transrectal biopsy and 48.1% had transperineal biopsy; with 43.4% diagnosed with csPCa overall. The sensitivity and negative predictive value (NPV) for 5 ISUP GG >/=2 were 87.3% and 87.5%, respectively. The NPV was 87.4% and 88.1% for men undergoing transrectal and transperineal biopsy, respectively. Specificity and positive predictive value of MRI were 49.8% and 49.2%, respectively. The sensitivity and NPV increased to 96.6% and 90.6% when a PSA-density threshold 0.15ng/ml/ml was used in MRI scores 1-2; these metrics increased to 97.5% and 91.2%, respectively, for PSA density 0.12ng/ml/ml. ISUP GG >/=3 (Gleason >/=4+3) was found in 2.4% (15/617) of men with MRI score 1-2. They key limitation of this study is the heterogeneity and retrospective nature of the data. ConclusionsmpMRI when used in real-world settings is able to accurately rule-out csPCa suggesting that about one-third of men might avoid an immediate biopsy. Men should be counselled about the risk of missing some significant cancers.

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Despite limited program evaluations of Medicaid accountable care organizations (ACOs), no studies have examined if cost-saving goals negatively affect quality of life and health care experiences of low-income enrollees. The Hennepin Health ACO uses an integrated care model to address the physical, behavioral, and social needs of Medicaid expansion enrollees. As part of a larger evaluation, we conducted semistructured interviews with 35 primary care using Hennepin Health members enrolled for 2 or more years. Using fuzzy set qualitative comparative analysis, we assessed enrollee complexity and use of the care model and improvements in quality of life. We found improved quality of life was consistently associated with strong bonds to primary care, consistent mental health care, and support from extended care team members. Comprehensive, integrated care models within ACOs may improve quality of life for low-income Medicaid enrollees through coordinated primary and mental health care.

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