Summary There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, FLI1) or mutations (SPOP, FOXA1, IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1-mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process.

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Background: Accumulating evidence shows that tumor cell-specific genomic changes can influence the cross talk between cancer cells and the surrounding tumor microenvironment (TME). Loss of the PTEN tumor suppressor gene is observed in 20% to 30% of prostate cancers (PCa) when first detected and the rate increases with PCa progression and advanced disease. Recent findings implicate a role for PTEN in cellular type I interferon response and immunosuppression in PCa. However, the way that PTEN inactivation alters antitumor immune response in PCa is poorly understood. Materials and Methods:To investigate the changes associated with PTEN loss and an immunosuppressive TME in PCa, we used CIBERSORT to estimate the relative abundance of 22 immune-cell types from 741 primary and 96 metastatic tumors. Our in silico findings were then validated by immunohistochemical analysis of immune cells and IDO1 and PDL1 checkpoint proteins in a cohort of 94 radical prostatectomy specimens.Results: FoxP3+ T regulatory cells (Tregs) were significantly increased in PTENdeficient PCa in all three public domain cohorts. Loss of PTEN in bone metastases was associated with lower CD8+ T-cell abundance, but in liver metastasis, FoxP3+ Tregs were present at higher levels. PTEN-deficient lymph node metastasis had a distinct profile, with high levels of CD8+ T cells. Moreover, we found that metastatic PCa presents higher abundance of FoxP3+ Treg when compared to primary lesions. Since PTEN-deficient tumors are likely to be immunosuppressed as a consequence of increased FoxP3+ Tregs, we then evaluated the localization and expression of IDO1, PDL1 immune checkpoints, and the corresponding density of FoxP3+ Treg and CD8+ T cells using our validation cohort (n = 94). We found that IDO1 protein expression and FoxP3+ Treg density were higher in neoplastic glands compared with benign adjacent tissue. Moreover, higher densities of FoxP3+ Treg cells in both stromal The Prostate. 2019;79:969-979.wileyonlinelibrary.com/journal/pros

INTRODUÇÃOA incontinência urinária pode ser definida de várias formas. Entretanto, para que possamos comparar resultados de diversos trabalhos científicos e realizar estudos populacionais confiá-veis, é necessário uniformizar conceitos e definições. A Sociedade Internacional de Incontinência define incontinência urinária como a condição na qual a perda involuntária de urina é um problema social ou higiênico e é objetivamente demonstrada. A incontinência urinária é muitas vezes erroneamente interpretada como parte natural do envelhecimento. Alterações que comprometem o convívio social como vergonha, depressão e isolamento, freqüentemente fazem parte do quadro clínico, causando grande transtorno aos pacientes e familiares 1 .Estudos revelam que a prevalência da incontinência urinária no idoso varia de 8 a 34% 2,3 . Essa variação da prevalência pode ser parcialmente explicada pelos diferentes tipos de questionários aplicados, pelas amostras populacionais distintas, pela falta de uniformização nas definições, pela ausência de seguimento a longo prazo das populações estudadas e pelo desconhecimento da história natural da incontinência urinária. Devemos lembrar que a incontinência urinária é um estado anormal e que se realizarmos uma abordagem adequada, é na maioria dos casos resolvida ou minorada. Em qualquer faixa etária, a continência urinária não depende somente da integridade do trato urinário inferior. Alterações da motivação, da destreza manual, da mobilidade, da lucidez e a existência de doenças associadas (diabetes mellitus e insuficiência cardíaca, entre outras) estão entre os fatores que podem ser responsáveis pela incontinência urinária, sem que haja comprometimento significativo do trato urinário inferior. Embora essas alterações sejam raras nos pacientes jovens, são freqüentemente encontradas no idoso e podem agravar ou causar incontinência urinária. NosO trato urinário inferior apresenta alterações relacionadas ao envelhecimento, que ocorrem mesmo na ausência de doenças. A força de contração da musculatura detrusora, a capacidade vesical e a habilidade de adiar a micção aparentemente diminuem, no homem e na mulher. Contrações involuntárias da musculatura vesical e o volume residual pós-miccional aumentam com a idade em ambos os sexos. Entretanto, a pressão máxima de fechamento uretral, o comprimento uretral e as células da musculatura estriada do esfíncter alteram-se predominantemente nas mulheres 6,7 .Além das alterações decorrentes da senilidade dos tecidos, doenças próprias do indivíduo idoso também contribuem para o desenvolvimento de incontinência urinária. A hiperplasia prostática benigna, que está presente em aproximadamente 50% dos homens aos 50 anos de idade, em metade dos quais causa obstrução ao fluxo urinário e acarreta alterações significativas do trato urinário inferior 8 , como a instabilidade do músculo detrusor. A presença de instabilidade detrusora em muitos indivíduos idosos continentes sugere que a relação entre urge-incontinência e instabilidade detrusora seja mais fraca em pessoas ...

Mutations in PTEN activate the phosphoinositide 3-kinase (PI3K) signalling network, leading to many of the characteristic phenotypic changes of cancer. However, the primary effects of this gene on oncogenesis through control of the PI3K–AKT–mammalian target of rapamycin (mTOR) pathway might not be the only avenue by which PTEN affects tumour progression. PTEN has been shown to regulate the antiviral interferon network and thus alter how cancer cells communicate with and are targeted by immune cells. An active, T cell-infiltrated microenvironment is critical for immunotherapy success, which is also influenced by mutations in DNA damage repair pathways and the overall mutational burden of the tumour. As PTEN has a role in the maintenance of genomic integrity, it is likely that a loss of PTEN affects the immune response at two different levels and might therefore be instrumental in mediating failed responses to immunotherapy. In this review, we summarise findings that demonstrate how the loss of PTEN function elicits specific changes in the immune response in several types of cancer. We also discuss ongoing clinical trials that illustrate the potential utility of PTEN as a predictive biomarker for immune checkpoint blockade therapies.

BackgroundProstate cancer is the most common cancer in older men in the United States (USA) and Western Europe. Androgen deprivation (AD) constitutes, in most cases, the first-line of treatment for these cases. The negative impact of CAD in quality of life, secondary to the adverse events of sustained hormone deprivation, plus the costs of this therapy, motivated the intermittent treatment approach. The objective of this study is to to perform a systematic review and meta-analysis of all randomized controlled trials that compared the efficacy and adverse events profile of intermittent versus continuous androgen deprivation for locally advanced, recurrent or metastatic hormone-sensitive prostate cancer.MethodsSeveral databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The endpoints were overall survival (OS), cancer-specific survival (CSS), time to progression (TTP) and adverse events. We performed a meta-analysis (MA) of the published data. The results were expressed as Hazard Ratio (HR) or Risk Ratio (RR), with their corresponding 95% Confidence Intervals (CI 95%).ResultsThe final analysis included 13 trials comprising 6,419 patients with hormone-sensitive prostate cancer. TTP was similar in patients who received intermittent androgen deprivation (IAD) or continuous androgen deprivation (CAD) (fixed effect: HR = 1.04; CI 95% = 0.96 to 1.14; p = 0.3). OS and CSS were also similar in patients treated with IAD or CAD (OS: fixed effect: HR = 1.02; CI 95% = 0.95 to 1.09; p = 0.56 and CSS: fixed effect: HR = 1.06; CI 95% = 0.96 to 1.18; p = 0.26).ConclusionOverall survival was similar between IAD and CAD in patients with locally advanced, recurrent or metastatic hormone-sensitive prostate cancer. Data on CSS are weak and the benefits of IAD on this outcome remain uncertain. Impact in QoL was similar for both groups, however, sexual activity scores were higher and the incidence of hot flushes was lower in patients treated with IAD.

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