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Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (n ¼ 164) had distinctive molecular features when compared with NC4 (n ¼ 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed PTEN and MAP3K7 losses and gains at 3q; (ii) increased SPOP mut and ATM mut ; (iii) enrichment for mTORC1 and MYC pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with SPOP mut (n ¼ 38) and PTEN loss (n ¼ 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years; n ¼ 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS).Implications: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.

Does the presence of human papillomavirus (HPV) in semen impact seminal parameters and sperm DNA quality in white European men seeking medical help for primary couple's infertility? SUMMARY ANSWER: HPV seminal infections involving high-risk (HR) genotypes are associated with impaired sperm progressive motility and sperm DNA fragmentation (SDF) values.WHAT IS KNOWN ALREADY: HPV is commonly present in semen samples. However, whether the presence of HPV in semen is actually associated with impaired sperm parameters and SDF values have yet to be elucidated. STUDY DESIGN, SIZE, DURATION:In this cross-sectional study, complete demographic, clinical and laboratory data from 729 infertile men were analysed.PARTICIPANTS/MATERIALS, SETTING, METHODS: Health-significant comorbidities were scored with the Charlson comorbidity index (CCI). Serum hormones and SDF index (measured by the sperm chromatin structure assay [SCSA]) were measured in every patient (SDF ≥30% was defined as pathological). Semen analysis was based on 2010 World Health Organisation reference criteria. Amplification by nested PCR was used to detect HPV-DNA sequences in semen samples. Descriptive statistics and linear regression models were used to test the association between the presence of HPV and clinical and seminal characteristics in the whole cohort. MAIN RESULTS AND THE ROLE OF CHANCE:The overall rate of HPV positivity was 15.5% (113/729). Overall, 78/729 (10.7%) and 35/729 (4.8%) patients had HR HPV+ and low-risk HPV+, respectively. HPV16 was the most prevalent type (22.1%), followed by HPV43 (10.6%), HPV56 and HPV42 (both 8.8%). No differences were found in terms of clinical and hormonal characteristics between patients with or without seminal HPV. Sperm progressive motility was significantly lower (P = 0.01) while SDF values were higher (P = 0.005) in HPV+ men compared to those with no HPV. In particular, HR HPV+ men had lower sperm progressive motility (P = 0.007) and higher SDF values (P = 0.003) than those with a negative HPV test. Univariable analysis showed that HR HPV+ was associated with impaired sperm progressive motility (P = 0.002) and SDF values (P = 0.003). In the multivariable analysis, age, FSH levels and testicular volume were significantly associated with impaired sperm progressive motility (all P ≤ 0.04). Conversely BMI, CCI, smoking habits and HPV status were not.

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Background:Bacillus Calmette-Guérin (BCG) unresponsive/relapsing patients with non-muscle invasive bladder cancer (NMIBC) who prefer bladder preservation over radical cystectomy (RC) or those who do not qualify for surgery may be offered intravesical therapies. Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH).Objective:To evaluate experience with GEM/DOCE, to confirm safety of the regimen, to identify populations that may benefit most, and to consider the appropriate endpoints for judging efficacy of second line therapies.Methods:Thirty-three patients who received full induction GEM/DOCE since 2011, per the protocol adapted from U. Iowa, were identified and characterized. Multivariable logistic regression was used to determine factors associated with recurrence. Cox proportional hazard models evaluated risk factors for disease-free survival (DFS) and high-grade recurrence-free survival (HG-RFS).Results:There were no serious adverse effects of therapy. Across all patients, median follow-up time was 18.6 months with a median DFS of 6.5 months, 42% 1-year, and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2-year HG-RFS. Among patients initially presenting with HG-NMIBC, 46% (13/28) had HG recurrence. BCG unresponsive/relapsing patients (N = 25) displayed 49% 1-year HG-RFS and 34% 2-year HG-RFS. In total, there were 5 LG and 16 HG recurrences, with 5 progressions and 8 cystectomies among these.Conclusions:GEM/DOCE is a well-tolerated therapy that deserves further study as an alternative to immediate RC for highly selected patients with HG-NMIBC. BCG naïve patients responded more effectively than BCG unresponsive/relapsing patients. As anticipated, GEM/DOCE efficacy was improved for HG only patients.

Background: Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in the PURE-01 study (NCT02736266). Patients and methods: We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out. Results: After a median [interquartile range (IQR)] follow-up of 23 (15-29) months, 12-and 24-month EFS were 84.5% [95% confidence interval (CI): 78.5-90.9] and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypNþ (N ¼ 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P ¼ 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months . The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes. Conclusions: The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.

Summary Recently, the cohort of men from the European Male Ageing Study has been stratified into different categories distinguishing primary, secondary and compensated hypogonadism. A similar classification has not yet been applied to the infertile population. We performed a cross‐sectional study enrolling 786 consecutive Caucasian‐European infertile men segregated into eugonadal [normal serum total testosterone (≥3.03 ng/mL) and normal luteinizing hormone (≤9.4 mU/mL)], secondary (low total testosterone, low/normal luteinizing hormone), primary (low total testosterone, elevated luteinizing hormone) and compensated hypogonadism (normal total testosterone; elevated luteinizing hormone). In this cross‐sectional study, logistic regression models tested the association between semen parameters, clinical characteristics and the defined gonadal status. Eugonadism, secondary, primary and compensated hypogonadism were found in 80, 15, 2, and 3% of men respectively. Secondary hypogonadal men were at highest risk for obesity [OR (95% CI): 3.48 (1.98–6.01)]. Primary hypogonadal men were those at highest risk for azoospermia [24.54 (6.39–161.39)] and testicular volume <15 mL [12.80 (3.40–83.26)]. Compensated had a similar profile to primary hypogonadal men, while their risk of azoospermia [5.31 (2.25–13.10)] and small testicular volume [8.04 (3.17–24.66)] was lower. The risk of small testicular volume [1.52 (1.01–2.33)] and azoospermia [1.76 (1.09–2.82)] was increased, although in a milder fashion, in secondary hypogonadal men as well. Overall, primary and compensated hypogonadism depicted the worst clinical picture in terms of impaired fertility. Although not specifically designed for infertile men, European Male Ageing Study categories might serve as a clinical stratification tool even in this setting.