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Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m 2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; pinteraction=0·71) or between-trial heterogeneity (I 2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (

Supplementary Figure 1 from A Gene Expression Signature Associated with Metastatic Outcome in Human Leiomyosarcomas

Supplementary Tables 2 and 3 from A Gene Expression Signature Associated with Metastatic Outcome in Human Leiomyosarcomas

Supplementary Table 1 from A Gene Expression Signature Associated with Metastatic Outcome in Human Leiomyosarcomas

Metastasis is a major factor associated with poor prognosis in cancer, but little is known of its molecular mechanisms. Although the clinical behavior of soft tissue sarcomas is highly variable, few reliable determinants of outcome have been identified. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Here, we have chosen leiomyosarcoma as a model for examining the relationship between gene expression profile and the development of metastasis in soft tissue sarcomas. Using cDNA microarray, we have identified a gene expression signature associated with metastasis in sarcoma that allowed prediction of the future development of metastases of primary tumors (Kaplan-Meier analysis P = 0.001). Our finding may aid the tailoring of therapy for individual sarcoma patients, where the aggressiveness of treatment is affected by the predicted outcome of disease.

For localised prostate cancer, focal therapy offers an organ-sparing alternative to radical treatments (radiotherapy or prostatectomy). Currently, there is no randomised comparative effectiveness data evaluating cancer control of both strategies. Following the eligibility criteria PSA

Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Objective To review of the existing literature, current guidelines and standard of practice related to prostate cancer in transgender women, as the transgender population share many of the same healthcare needs as their cisgender counterparts, but may have additional specialist needs. Materials and methods We performed a non-systematic review of the literature, current guidelines and standard of practice related to prostate cancer in transgender women. Results Our search revealed 10 case reports of prostate cancer in transgender women, four specialist opinion papers, six cohort studies, and four systematic reviews. The information in these publications were assimilated to produce a review of prostate cancer in transgender women. Conclusion The risk of prostate cancer in transgender women who are not on gender-affirming hormone therapy (GAHT) or who have not had gender-affirming surgery (GAS) and gender non-conforming individuals (who may never commence GAHT or have GAS) is the same as that in the cis male population. In these patients, healthcare professionals need to be able to discuss screening, diagnostic and treatment options considering future wishes for gender-affirming treatment. Prostate cancer incidence in transgender women on GAHT or following GAS is lower than age-matched cis-male counterparts, but diagnosis and treatment is more nuanced. The present review discusses the existing literature about development and incidence of prostate cancer in this population, and makes recommendations about screening, the usefulness of diagnostic tools e.g. prostate-specific antigen and magnetic resonance imaging, and considerations when formulating treatment. Potential directions for future research are discussed, which will hopefully lead to development of robust evidence-based guidelines for the diagnosis and management of prostate cancer in transgender women.

IntroductionSurvival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone.MethodsA phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years. Primary outcome: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024.Ethics and disseminationApproved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT03763253; ISCRTN58401737

BACKGROUND Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ���40 ng/mL) or relapsing with high-risk features (���12 months of total ADT with an interval of ���12 months without treatment and PSA concentration ���4 ng/mL with a doubling time of

For localised prostate cancer, focal therapy offers an organ-sparing alternative to radical treatments (radiotherapy or prostatectomy). Currently, there is no randomised comparative effectiveness data evaluating cancer control of both strategies.Following the eligibility criteria PSA 20 ng/mL, Gleason score ≤ 7 and T-stage ≤ T2c, we included 830 radical (440 radiotherapy, 390 prostatectomy) and 530 focal therapy (cryotherapy, high-intensity focused ultrasound or high-dose-rate brachytherapy) patients treated between 2005 and 2018 from multicentre registries in the Netherlands and the UK. A propensity score weighted (PSW) analysis was performed to compare failure-free survival (FFS), with failure defined as salvage treatment, metastatic disease, systemic treatment (androgen deprivation therapy or chemotherapy), or progression to watchful waiting. The secondary outcome was overall survival (OS). Median (IQR) follow-up in each cohort was 55 (28-83) and 62 (42-83) months, respectively.At baseline, radical patients had higher PSA (10.3 versus 7.9) and higher-grade disease (31% ISUP 3 versus 11%) compared to focal patients. After PSW, all covariates were balanced (SMD 0.1). 6-year weighted FFS was higher after radical therapy (80.3%, 95% CI 73.9-87.3) than after focal therapy (72.8%, 95% CI 66.8-79.8) although not statistically significant (p = 0.1). 6-year weighted OS was significantly lower after radical therapy (93.4%, 95% CI 90.1-95.2 versus 97.5%, 95% CI 94-99.9; p = 0.02). When compared in a three-way analysis, focal and LRP patients had a higher risk of treatment failure than EBRT patients (p 0.001), but EBRT patients had a higher risk of mortality than focal patients (p = 0.008).Within the limitations of a cohort-based analysis in which residual confounders are likely to exist, we found no clinically relevant difference in cancer control conferred by focal therapy compared to radical therapy at 6 years.

IntroductionSystemic therapy with androgen deprivation therapy (ADT) and intensification with agents such as docetaxel, abiraterone acetate and enzalutamide has resulted in improved overall survival in men with de novo synchronous metastatic hormone-sensitive prostate cancer (mHSPC). Novel local cytoreductive treatments and metastasis-directed therapy are now being evaluated. Such interventions may provide added survival benefit or delay the requirement for further systemic agents and associated toxicity but can confer additional harm. Understanding men’s preferences for treatment options in this disease state is crucial for patients, clinicians, carers and future healthcare service providers.MethodsUsing a prospective, multicentre discrete choice experiment (DCE), we aim to determine the attributes associated with treatment that are most important to men with mHSPC. Furthermore, we plan to determine men’s preferences for, and trade-offs between, the attributes (survival and side effects) of different treatment options including systemic therapy, local cytoreductive approaches (external beam radiotherapy, cytoreductive radical prostatectomy or minimally invasive ablative therapy) and metastases-directed therapies (metastasectomy or stereotactic ablative body radiotherapy). All men with newly diagnosed mHSPC within 4 months of commencing ADT and WHO performance status 0–2 are eligible. Men who have previously consented to a cytoreductive treatment or have developed castrate-resistant disease will be excluded. This study includes a qualitative analysis component, with patients (n=15) and healthcare professionals (n=5), to identify and define the key attributes associated with treatment options that would warrant trade-off evaluation in a DCE. The main phase component planned recruitment is 300 patients over 1 year, commencing in January 2021, with planned study completion in March 2022.Ethics and disseminationEthical approval was obtained from the Health Research Authority East of England, Cambridgeshire and Hertfordshire Research Ethics Committee (Reference: 20/EE/0194). Project information will be reported on the publicly available Imperial College London website and the Heath Economics Research Unit (HERU website including the HERU Blog). We will use the social media accounts of IP5-MATTER, Imperial Prostate London, HERU and the individual researchers to disseminate key findings following publication. Findings from the study will be presented at national/international conferences and peer-reviewed journals. Authorship policy will follow the recommendations of the International Committee of Medical Journal Editors.Trial registration numberNCT04590976.

Publisher's version (útgefin grein)., Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. Design, setting, and participants: Men aged 40–69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. Outcome measurements and statistical analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. Results and limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65). Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Patient summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening. © 2019 The Authors We demonstrate that after 3 yr of prostate-specific-antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening., We demonstrate that, after four annual PSA screening rounds, BRCA2 mutation carriers have a higher incidence of PrCa, are diagnosed at a younger age, and present with more clinically significant tumours than BRCA2 noncarriers. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. Therefore, these data support the use of systematic PSA screening in male BRCA2 carriers. Author contributions : Rosalind A. Eeles had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design : Aaronson, Ardern-Jones, Bancroft, Bangma, Castro, Dearnaley, Eccles, Evans, Eyfjord, Falconer, Foster, Gronberg, Hamdy, Johannsson, Khoo, Kote-Jarai, Lilja, Lindeman, Lubinski, Mahle, Mikropoulos, Mitra, Moynihan, Page, Rennert, Suri. Acquisition of data: All authors. Analysis and interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis : Page, Bancroft, Brook, Assel, Vickers, Lilja. Obtaining funding : Eeles and all IMPACT collaborating sites obtained their own funding for running the study at their site. Administrative, technical, or material support: All authors. Supervision: Eeles. Other : None. Financial disclosures: Rosalind A. Eeles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hans Lilja holds patents for intact PSA assays, and is named, along with Andrew J. Vickers, on a patent application for a statistical method to detect prostate cancer. The patents have been licensed and commercialised as the 4 Kscore by OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; support from Janssen; honorarium as speaker £1100; University of Chicago invited talk May 2018; honorarium as speaker Rosalind A. Eeles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hans Lilja holds patents for intact PSA assays, and is named, along with Andrew J. Vickers, on a patent application for a statistical method to detect prostate cancer. The patents have been licensed and commercialised as the 4 Kscore by OPKO Health. Drs. Vickers and Lilja receive royalties from sales of this test. Additionally, Dr. Lilja owns stock and Dr. Vickers owns stock options in OPKO. Professor Rosalind Eeles: Royal Marsden Hospital—Nov 2017; support from Janssen; honorarium as speaker £1100; University of Chicago invited talk May 2018; honorarium as speaker $1000. The remaining authors have no other conflict of interest to declare.000. The remaining authors have no other conflict of interest to declare. Funding/Support and role of the sponsor : This research is coordinated by the Institute of Cancer Research, London, UK, and is supported by grants from Cancer Research UK (grant references C5047/A21332, C5047/A13232, and C5047/A17528) and the Ronald and Rita McAulay Foundation. Judith Offman is supported by Cancer Research UK Programme Grant reference C8161/A16892. Mr. and Mrs. Jack Baker are acknowledged for supporting the study in NorthShore University HealthSystem, Evanston, IL, USA and Myriad Genetics Laboratory, Salt Lake City, UT, USA, for providing research BRCA testing rates for NorthShore University HealthSystem patients. We acknowledge funding from the National Institute for Health Research (NIHR) to the Biomedical Research Center at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, at Manchester University Foundation Trust (IS-BRC-1215-20007), the Oxford Biomedical Research Centre Program, and the Cambridge Clinical Research Centre, NIHR Cambridge Biomedical Research Centre. We acknowledge that in Australia, this project was cofunded by Cancer Council Tasmania and Cancer Australia (grant number 1006349 [2011–2013]), Prostate Cancer Foundation of Australia (grant number PCFA PRO4 [2008]), Cancer Councils of Victoria and South Australia (grant number 400048 [2006–2008]), the Victorian Cancer Agency Clinical Trial Capacity CTCB08_14, Cancer Australia and Prostate Cancer Foundation of Australia (2014–2016; grant number 1059423), and Translational grants EOI09_50. The Association of International Cancer Research funded data collection in The Netherlands (AICR 10-0596). We acknowledge funding from the Basser Center for BRCA (to Susan Domchek). This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748), a SPORE grant in Prostate Cancer to Dr. H. Scher (P50-CA92629), the Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation. This work was also supported in part by the NIHR Oxford Biomedical Research Centre Program in UK, the Swedish Cancer Society (CAN 2017/559), the Swedish Research Council (VR-MH project no. 2016-02974), and General Hospital in Malmö Foundation for Combating Cancer. We acknowledge funding from the Slovenian Research Agency, Research programme P3-0352. We thank CERCA Program/Generalitat de Catalunya for their institutional support. Elena Castro acknowledges funding from Prostate Cancer Foundation. We acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad), “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI16/00563, JR18/00011 and CIBERONC), and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). We acknowledge funding support from Fundação para a Ciência e a Tecnologia to the IPO Porto study (project grant PTDC/DTP-PIC/1308/2014 to Manuel R. Teixeira and fellowship grant SFRH/BD/116557/2016 to Marta Cardoso).

Introduction For older patients with glioblastoma (GBM), age, extent of resection, and performance status are prognostic factors. However, an international survey conducted by our Unit found that >40% of neurosurgeons use age alone to discount surgery in older (65+) patients. The aim of this study was to review management in our Unit for 65+ GBM patients, to inform future approaches. Methods Patients 65+ with a new GBM diagnosis in our Unit, between 2014 and 2017, were identified. Demographic data, performance status (PS), comorbidity and frailty indices, together with details of surgical/oncological management and outcome were collected. Results 78 patients were identified. 78% aged 65–74 underwent maximal safe resection, compared with 45% aged 75–84, and 10% aged 85+. Resection was undertaken in 68% PS1, 73% PS2 and 23% PS3 patients. No PS3 patient completed intended radiotherapy, compared with 79% PS1 and 74% PS2 patients. There was a significant difference in frailty scores of patients who completed scheduled oncological therapy compared with those who did not (median score 2 vs 4.5, p=0.0338). Median survival was 10 months for patients 65–74, 4 months for aged 75 -84, and 40 days for 85+ (p Conclusion There is considerable variability in performance status and frailty of 65+ GBM patients. PS3 patients at diagnosis are very unlikely to complete oncological treatment. These factors, rather than age alone, should be used to guide management decisions.

e17046 Background: Sleep disturbances and cancer related fatigue are commonly associated. Prostate cancer patients may suffer from disturbed sleep as a result of their diagnosis and following treatment, especially with androgen deprivation therapy (ADT). Wrist actigraphy is a non-invasive objective method of sleep data collection. This feasibility study compares sleep data obtained by actigraphy with subjective data from sleep questionnaires in order to determine the nature and severity of sleep disturbances in patients with and without ADT use. Methods: A prospective cross-sectional pilot study was conducted on 74 patients with prostate cancer attending a regional oncology clinic. Two validated subjective sleep questionnaires namely the Pittsburgh Sleep Quality Index [PSQI] and the Epworth Sleepiness Scale [ESS] were used. Patients wore actigraphy watches for a minimum of five consecutive days. The parameters of interest included: actual sleep time, sleep efficiency, fragmentation index, daytime napping frequency and duration. The questionnaire and actigraphy data were compared between 20 patients receiving ADT and 41 who were treatment-naive. Results: The compliance rate for completed actigraphy was 85%. Complete data sets with actigraphy and questionnaires were available from 61 patients. Those already receiving ADT were on LHRH analogues for a median duration of 2.35 years. Poor sleep quality as self-identified by patients from the PSQI (cut-off > 5) was 49% in the treatment-naive group which increased to 70% for those on ADT. For daytime sleepiness as assessed by ESS (cut-off > 10) this was 16% and 20% respectively. Actigraphy showed that patients on ADT reported longer sleep duration (7.4 vs 6.5 hours, p = 0.02), higher levels of nocturnal wakings (51.1% vs 36.7%, p = 0.002), with greater daytime napping duration (80.7mins vs 53.0mins, p = 0.04), and frequency (8.6 vs 5.6, p = 0.02) compared to treatment-naive patients. Conclusions: Self-reported poor sleep quality is common in prostate cancer patients, which appears worse for those receiving ADT. In patients receiving ADT, data derived from actigraphy suggests that although they were sleeping for longer at night, the quality of sleep was poor which, in turn, may be responsible for an increase in the frequency and duration of daytime napping. Based on the current findings, we recommend the use of actigraphy to characterise patients’ sleep patterns and to assess if sleep treatment is needed. Actigraphic data may allow for direct comparisons of different hormonal agents on sleep whilst identifying those with specific sleep disorders amenable to therapeutic intervention.

TPS5600 Background: Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit beyond standard systemic therapy in patients with de novo synchronous metastatic prostate cancer. There is accumulating prospective evidence for local cytoreductive therapy. In particular, the phase III study STAMPEDE which demonstrated improved overall survival in a low burden subgroup of men following cytoreductive radiotherapy. Cytoreductive prostatectomy and minimally invasive ablative therapies (MIAT) are now subject to similar trial evaluation. IP2-ATLANTA will evaluate progression-free and overall survival outcomes with the addition of sequential multi-modal local and metastasis-directed treatments in patients with newly diagnosed metastatic prostate cancer compared to standard care alone. Methods: Phase II, multicentre, three-arm randomised controlled trial using a positive comparator arm ( n=918 ). An internal pilot ( n=80) feasibility phase is incorporated. All men with new histologically diagnosed, hormone sensitive, metastatic prostate cancer, within three months of commencing ADT and of PS 0-2 are eligible. Patients are randomised (1:1:1) to: Control (Standard of Care) OR Intervention 1 (Minimally invasive ablative therapy to the prostate +/- pelvic lymph node dissection [PLND]) OR Intervention 2 (prostate radiotherapy +/- lymph nodes OR Radical prostatectomy +/- PLND). Metastatic burden pre-specified by CHAARTED definition. Men with low-burden disease in intervention arms are eligible for metastasis-directed therapy (stereotactic ablative radiotherapy [SABR] or surgery). Standard systemic therapy given in all arms (incl. docetaxel). Follow-up: min. 2-years; max. 4 years. Primary outcome: progression-free survival (PFS). Secondary outcomes: Overall survival; urinary, sexual & rectal side-effects; patient reported outcome measures. HRA ethical approval (Ref: 19/WA0005). To date, 28/80 (35%) patients have been recruited and randomised across 9 open sites in the internal pilot. Median recruitment rate is 85.7% (IQR 55–86). Internal pilot recruitment expected to be complete by April 2020. IP2-ATLANTA addresses an important research gap in the role of local and metastasis-directed therapy in men with newly diagnosed metastatic prostate cancer. Clinical trial information: NCT03763253 .

Background Glioblastoma (GBM) is the most common malignant brain tumour in adults with a median survival from progression of 8 months. A recent phase 1 study of temozolomide (TMZ) and 1:1 CBD:THC (Sativex) offers evidence of efficacy in patients with recurrent GBM (NCT01812603). Methods All patients receiving TMZ & Sativex (75mg/m2 daily d1 – 21 q28; Sativex continuously) for relapsed GBM or grade 3 astrocytoma at our centre were identified. Patient, tumor and treatment characteristics were recorded, and response based on sequential MRI scans using modified RANO criteria assessed. Results 13 patients were treated over 18 months. The median age was 56; 69% were male. All had received initial chemo-radiotherapy (12 patients: 60 or 59.4Gy/30–33#; 1 patient: 45Gy/15#). 6 patients underwent reresection at recurrence. 4 patients were treated at first progression, 7 at second progression, and 2 at third or later progression. The median number of cycles of TMZ and sativex was 2. The combination treatment was tolerated well by all patients treated, with no Grade 3 or 4 toxicities, the only complaints being of discomfort in mouth after spray and ‘spaced out feeling’. Patients stopped treatment due to evidence of progressive disease on sequential MRI sign or physical deterioration. Median Overall Survival (OS) from initiation was 5.9 months (177 days); Progression Free Surival (PFS) at 3 months was 50%. Conclusion These results highlight some discrepancies in OS in comparison to the previous trial (NCT01812603), but our patients were treated at second/ third recurrence. We agree that the combination is well tolerated.

Importance Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. Objective To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. Design, Setting, and Participants This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials. Main Outcomes and Measures Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. Results Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non–small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8;P Conclusions and Relevance Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients’ gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

147 Background: Antibiotic therapy (ATB) may impair efficacy of immune checkpoint inhibitors (ICPI) through modulation of gut microbiota. Evidence is however limited to trial participants with non-small cell (NSCLC) and renal cell carcinoma (RCC). In this multi-centre study, we validated the impact of ATB in patients (pts) treated with ICPI in routine practice, irrespective of tumour site. Methods: We analysed a prospective dataset of pts treated with ICPI in 2 centres. We documented timing and duration of ATB administered within 1 month prior to ICPI treatment (pATB) or concurrently (cATB) until ICPI cessation. We evaluated response and overall survival (OS) across ATB+/-. Results: We enrolled 196 pts with NSCLC (n=119), Melanoma (n=38) and other histotypes (n=39). Most pts were male (n=137, 70%) with performance status 0-1 (n=159, 84%) and a median number of 2 metastatic sites (range 0-7). Pts received mostly anti-PD-1/PD-L1 ICPI (n=189, 96%) as first-line metastatic therapy (n=120, 62%). Twenty-nine patients (15%) received pATB with penicillins (n=22, 75%) for ≤7 days (n=26, 89%). Sixty-eight pts (35%) received penicillin-based (n=49, 72%) cATB for ≤7 days (n=39, 88%). Respiratory infections were the commonest indication for both pATB (n=16, 55%) and cATB (n=38, 85%). pATB (p

Summary Background and Aim: Malignant spinal cord compression (mSCC) is one of the most serious complications of cancer. Recent NICE guidance has aimed to improve patient pathways and outcomes for patients with mSCC. We have examined the current presentations, management and outcomes for patients with mSCC in West London following the implementation of the NICE guidance. Materials and methods: The electronic records and clinical notes were reviewed for all patients assessed for confirmed or potential mSCC at Charing Cross Hospital in 2012. Details on the number of referrals, the proportion with confirmed mSCC, the cancer diagnosis, treatment and outcome were analysed. Results: 191 patients were reviewed with 127 (66%) cases of confirmed mSCC. The commonest tumour types were prostate cancer (26 cases), lung cancer (26), breast cancer (21) and kidney cancer (15). 21% of the patients had no previous cancer diagnosis; mSCC was their presenting diagnostic event. Radiotherapy was the predominant management, 24% of the patients had first line surgical treatment. At presentation 62% of patients were either chair or bed bound. Treatment brought important mobility benefits to all patients groups with 20% of the initially chair or bed bound patients leaving the hospital with independent mobility. Conclusion: Enhanced patients pathways with ease of access, rapid assessment and prompt treatment can improve outcomes. Despite these pathways many patients still present with gross motor impairment and over 20% have no previous diagnosis of cancer. Ongoing work to maintain awareness for patients and primary care of the diagnosis and emergency pathways is essential to optimize outcomes.

What's known on the subject? and What does the study add? Scientists have found a number of genetic factors that increase prostate cancer risk, including heritable mutations in the genes BRCA1 and BRCA2. These mutations are not common but can have major impact, as a BRCA2 mutation increases risk by up to seven-fold while a BRCA1 mutation is thought to double risk in men under 65. The IMPACT study aims to determine whether targeted screening in men with a known BRCA1 or BRCA2 mutation would lead to earlier diagnosis of prostate cancers. This data from the IMPACT study adds to the increasing evidence that BRCA mutation carriers develop more aggressive disease. Although these are early results, it appears that PSA screening is more accurate at predicting potentially aggressive prostate cancer among men at higher risk of the disease due to a genetic predisposition than general population screening. This study provides support for continued screening in men with genetic mutations. OBJECTIVE To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (+/- 5 years) who were negative for the familial mutation. RESULTS In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47 center dot 6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Prostate cancer (PrCa) is a significant public health problem. In the European Union, approximately 200 000 men are diagnosed annually with the disease. There are 35 515 cases (Cancer Research UK, 2009a) per year in the United Kingdom and 10 239 deaths (Cancer Research UK, 2009b). It is now the commonest male non-cutaneous cancer diagnosed in the United Kingdom; the lifetime risk of being diagnosed with PrCa is 1 in 10 (Cancer Research UK, 2009a). Although the increase in population screening is leading to an increase in diagnosis, many men will not develop aggressive disease. However, it is recognised that some PrCa cases have a particularly poor prognosis. Although there are some histological and stage predictors of prognosis (Kattan and Scardino, 2002), until recently, none of them have been related to inherited factors. Multiple aetiologies have been proposed to contribute to the development of PrCa. There is strong evidence that inherited genetic factors are important and exhibit significant familial aggregation in some men, particularly when affected at a young age (Woolf, 1960; Edwards and Eeles, 2004). There is a recognised association of breast cancer with PrCa in families (Thiessen, 1974; Anderson and Badzioch, 1992; Tulinius et al, 1992). Male relatives in breast cancer families in Iceland have a 2–3-fold risk of PrCa (Sigurdsson et al, 1997). The breast cancer predisposition genes BRCA1 and BRCA2 have been reported to increase the risk of PrCa by three-fold and seven-fold, respectively, in male mutation carriers ascertained through a family history of breast cancer (Ford et al, 1994; Struewing et al, 1997; Breast Cancer Linkage Consortium, 1999). Analyses of PrCa relative risks (RR) in male mutation carriers in breast cancer families from the Breast Cancer Linkage Consortium showed an RR of 4.65 (95% CI: 3.48–6.22) of PrCa in male BRCA2 mutation carriers (the RR is 7.33 below the age of 65 years) and of 1.07 (0.75–1.54) in BRCA1 carriers (with an RR of 1.82 (1.01–3.29) for men under 65 years of age) (Thompson and Easton, 2001, 2002). The estimated cumulative incidence of PrCa by the age of 70 years is 7.5–33%. Recent studies have suggested that the risk of PrCa in BRCA2 mutation carriers may be as high as an RR of 23-fold at age 60 years (Edwards et al, 2003). Studies from Iceland have reported that germline mutations in BRCA2 may be involved not only in susceptibility to PrCa but also in the aggressiveness of the disease (Sigurdsson et al, 1997; Tryggvadottir et al, 2007). However, these individuals all carried a common founder mutation (999del5 in BRCA2). Narod et al (2008) have reported that PrCa survival in BRCA2 mutation carriers is much shorter (median survival from diagnosis was 4 years) when compared with BRCA1 carriers' survival (median survival from diagnosis was 8 years). In PrCa, in which the BRCA2 germline mutation status was unknown, allele loss at the BRCA2 locus has been shown to be a prognostic factor for survival on univariate analysis (Edwards et al, 1998), and loss of the wild-type allele would imply a tumour suppressor mechanism in predisposition to this disease in BRCA2 mutation carriers, but it is not known whether this is a surrogate for high grade or is due to mutation per se (Knudson, 1971; Willems et al, 2008). A BRCA2 genomic screening study has previously been undertaken by ourselves, and six potentially pathogenic germline BRCA2 mutations were found in a set of 263 PrCa patients diagnosed at ⩽55 years (2.3%) (Edwards et al, 2003). In this study we report clinical follow-up data and the results of loss of heterozygosity (LOH) analyses on PrCa tumours from the mutation carriers in this report. We then studied a second validation data set of men with germline mutations in the BRCA2 gene from a cancer genetics clinic and assessed their survival to confirm our results in a different UK data set of male BRCA2 mutation carriers with PrCa.

OBJECTIVES: To determine whether low to moderate alcohol intake is protective against cognitive decline in older people. DESIGN: Prospective cohort study. SETTING: Community-based study in Ireland, the Netherlands, and Scotland. PARTICIPANTS: Five thousand eight hundred four people (3,000 women) aged 70 to 82 and randomized to pravastatin or placebo in the Prospective Study of Pravastatin in the Elderly at Risk. MEASUREMENTS: Alcohol consumption was determined at study baseline. Serial measures of cognitive function over 3.2 years mean follow-up included Mini-Mental-State-Examination (MMSE), speed of information processing (Stroop and Letter-Digit Coding tests), and immediate and delayed memory (Picture-Word Learning test). RESULTS: Forty-two percent of women and 71% of men were alcohol drinkers. Cognitive performance was better for female drinkers than nondrinkers for all cognitive domains over the 3.2-year follow-up; no significant effects were seen for men (linear mixed model, including adjusting for possible confounders). The rate of cognitive decline was similar for drinkers and nondrinkers for all cognitive domains, except for MMSE, which declined significantly less in female drinkers than nondrinkers (linear mixed model attenuated rate of decline=0.05 MMSE units per annum, P=.001). CONCLUSION: Drinking low to moderate amounts of alcohol may delay age-associated cognitive decline in older women (including slowing deterioration in global cognitive function), but these apparent benefits were not clearly seen in older men.

Needle biopsies are taken as standard diagnostic specimens for many cancers, but no technique exists for the high-throughput analysis of multiple individual immunohistochemical (IHC) markers using these samples. Here we present a simple and highly reliable technique for constructing tissue microarrays (TMAs) from prostatic needle biopsies. Serial sectioning of the TMAs, called ‘Checkerboard TMAs’, facilitated expression analysis of multiple proteins using IHC markers. In total, 100% of the analysed biopsies within the TMA both preserved their antigenicity and maintained their morphology. Checkerboard TMAs will allow the use of needle biopsies (i) alongside other tissue specimens (trans-urethral resection of prostates and prostatectomies in the case of prostate cancer) in clinical correlation studies when searching for new prognostic markers, and (ii) in a diagnostic context for assessing expression of multiple proteins in cancers from patients prior to treatment.

Background: Variants in the gene encoding the macrophage scavenger receptor 1 (MSR14) protein have been identified in men with prostate cancer, and several small studies have suggested that the 999C>T (R293X) protein-truncating mutation may be associated with an increased risk for this disease. Methods: Using large case-control, cohort, and prostate cancer family studies conducted in several Western countries, we tested for the 999C>T mutation in 2,943 men with invasive prostate carcinoma, including 401 males from multiple-case families, 1,982 cases unselected for age, and 575 men diagnosed before the age of 56 years, and in 2,870 male controls. Risk ratios were estimated by unconditional logistic regression adjusting for country and by a modified segregation analysis. A meta-analysis was conducted pooling our data with published data. Results: The prevalence of MSR1*999C>T mutation carriers was 0.027 (SE, 0.003) in cases and 0.022 (SE, 0.002) in controls, and did not differ by country, ethnicity, or source. The adjusted risk ratio for prostate cancer associated with being a 999C>T carrier was 1.31 [95% confidence interval (CI), 0.93-1.84; P = 0.16]. The modified segregation analysis estimated the risk ratio to be 1.20 (95% CI, 0.87-1.66; P = 0.16). The risk ratio estimated from the meta-analysis was 1.34 (95% CI, 0.94-1.89; P = 0.10). Conclusion: Our large-scale analysis of case and controls from several countries found no evidence that the 999C>T mutation is associated with increased risk of prostate cancer. The meta-analysis suggests it is unlikely that this mutation confers more than a 2-fold increased risk.

We demonstrate that, in human bladder cancer, amplification of the E2F3 gene, located at 6p22, is associated with overexpression of its encoded mRNA transcripts and high levels of expression of E2F3 protein. Immunohistochemical analyses of E2F3 protein levels have established that around one-third (33/101) of primary transitional cell carcinomas of the bladder overexpress nuclear E2F3 protein, with the proportion of tumours containing overexpressed nuclear E2F3 increasing with tumour stage and grade. When considered together with the established role of E2F3 in cell cycle progression, these results suggest that the E2F3 gene represents a candidate bladder cancer oncogene that is activated by DNA amplification and overexpression.

Lymphoepithelioma-like carcinoma (LELC) of the urinary bladder is a rare variant, which can occur in a pure form or in conjunction with transitional cell carcinoma. Owing to the scarcity of reported cases, the optimum treatment is yet to be defined, although the benefits of chemotherapy are increasingly recognised. We present a case of a 64-year-old man with pure LELC, treated with trans-urethral resection of the bladder tumor (TURBT) and primary gemcitabine and platinum-based chemotherapy. He remained free of disease at six-month follow-up cystoscopy. The case adds to the growing evidence for the efficacy of chemotherapy, coupled with TUR, as part of a bladder-preserving treatment option for LELC.

To determine whether low to moderate alcohol intake is protective against cognitive decline in older people.Prospective cohort study.Community-based study in Ireland, the Netherlands, and Scotland.Five thousand eight hundred four people (3,000 women) aged 70 to 82 and randomized to pravastatin or placebo in the Prospective Study of Pravastatin in the Elderly at Risk.Alcohol consumption was determined at study baseline. Serial measures of cognitive function over 3.2 years mean follow-up included Mini-Mental-State-Examination (MMSE), speed of information processing (Stroop and Letter-Digit Coding tests), and immediate and delayed memory (Picture-Word Learning test).Forty-two percent of women and 71% of men were alcohol drinkers. Cognitive performance was better for female drinkers than nondrinkers for all cognitive domains over the 3.2-year follow-up; no significant effects were seen for men (linear mixed model, including adjusting for possible confounders). The rate of cognitive decline was similar for drinkers and nondrinkers for all cognitive domains, except for MMSE, which declined significantly less in female drinkers than nondrinkers (linear mixed model attenuated rate of decline=0.05 MMSE units per annum, P=.001).Drinking low to moderate amounts of alcohol may delay age-associated cognitive decline in older women (including slowing deterioration in global cognitive function), but these apparent benefits were not clearly seen in older men.

Aims: To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging. Methods/Results: The method involves a prostate slicing apparatus comprising a tissue slicer with a series of juxtaposed planar stainless steel blades linked to a support, and a cradle adapted to grip the tissue sample and receive the blades. The fresh prostate gland is held in the cradle and the blades are moved through the cradle slits to produce multiple 4 mm slices of the gland in a plane perpendicular to its posterior surface. One of the resulting slices is preserved in RNAlater TM . The areas comprising tumour and normal glands within this preserved slice can be identified by matching it to the haematoxylin and eosin stained sections of the adjacent slices that are formalin fixed and paraffin wax embedded. Intact RNA can be extracted from the identified tumour and normal glands within the RNAlater preserved slice. Preoperative imaging studies are acquired with the angulation of axial images chosen to be similar to the slicing axis, such that stained sections from the formalin fixed, paraffin wax embedded slices match their counterparts on imaging. Conclusions: A novel method of sampling fresh prostate removed at radical prostatectomy that allows tissue samples to be used both for diagnosis and molecular analysis is described. This method also allows the integration of preoperative imaging data with histopathological and molecular data obtained from the prostate tissue slices.

Metastasis is a major factor associated with poor prognosis in cancer, but little is known of its molecular mechanisms. Although the clinical behavior of soft tissue sarcomas is highly variable, few reliable determinants of outcome have been identified. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Here, we have chosen leiomyosarcoma as a model for examining the relationship between gene expression profile and the development of metastasis in soft tissue sarcomas. Using cDNA microarray, we have identified a gene expression signature associated with metastasis in sarcoma that allowed prediction of the future development of metastases of primary tumors (Kaplan-Meier analysis P = 0.001). Our finding may aid the tailoring of therapy for individual sarcoma patients, where the aggressiveness of treatment is affected by the predicted outcome of disease.

E2F transcription factors, including E2F3, directly modulate expression of EZH2. Recently, overexpression of the EZH2 gene has been implicated in the development of human prostate cancer. In tissue microrarray studies we now show that expression of high levels of nuclear E2F3 occurs in a high proportion (98/147, 67%) of human prostate cancers, but is a rare event in non-neoplastic prostatic epithelium suggesting a role for E2F3 overexpression in prostate carcinogenesis. Patients with prostate cancer exhibiting immunohistochemically detectable nuclear E2F3 expression have poorer overall survival (P=0.0022) and cause-specific survival (P=0.0047) than patients without detectable E2F3 expression. When patients are stratified according to the maximum percentage of E2F3-positive nuclei identified within their prostate cancers (up to 20, 21-40%, etc.), there is an increasingly significant association between E2F3 staining and risk of death both for overall survival (P=0.0014) and for cause-specific survival (P=0.0004). Multivariate analyses select E2F3 expression as an independent factor predicting overall survival (unstratified P=0.0103, stratified P=0.0086) and cause-specific survival (unstratified P=0.0288, stratified P=0.0072). When these results are considered together with published data on EZH2 and on the E2F3 control protein pRB, we conclude that the pRB-E2F3-EZH2 control axis may have a critical role in modulating aggressiveness of individual human prostate cancer.

It has been postulated that telomere dysfunction and telomerase activation have important roles in prostate tumorigenesis. Since the ataxia-telangiectasia mutated gene product (ATM protein) is involved in maintaining telomere length and integrity, we hypothesized that its expression might be altered in prostate tumors and, thus, examined its profile in 49 tumor samples. The majority (32/49) had ATM protein levels higher than those observed in normal tissues, with only 5 of 49 tissue samples showing reduced or absent ATM levels. Three of these were from the group of 6 young-onset or sibling-pair tumors. There was a trend toward higher ATM expression in tumors with a higher Gleason score (23/32 [72%] for grade 8–10 vs 9/17 [53%] for grades 5–7), although this difference was not statistically significant. These findings support our hypothesis that the presence of the ATM protein at the same or a higher level than that in normal prostate cells might have an important role in the maintenance of the shortened telomeres commonly found in prostate cancer cells.

Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were ≤55 years of age. Protein-truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%–5.0%), and all of these mutations were clustered outside the ovarian-cancer cluster region. The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with mutations did not have a family history of breast or ovarian cancer. Twenty-two variants of uncertain significance were also identified. These results confirm that BRCA2 is a high-risk prostate-cancer–susceptibility gene and have potential implications for the management of early-onset prostate cancer, in both patients and their relatives.