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Background: B7-H3 (CD276) , part of the B7 superfamily of immune checkpoint molecules, has been shown to have an immunomodulatory role. Its regulation, receptor and mechanism of action remain unclear. B7-H3 protein expression correlates with prostate cancer outcomes, and humanized monoclonal antibodies (that is, enoblituzumab) are currently being investigated for therapeutic use. Here we used genomic expression data to examine the relationship between B7-H3 mRNA expression and prostate cancer. Methods: Prostatectomy tissue from 2781 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Pairwise comparisons were used to identify significant associations between B7-H3 expression and clinicopathologic variables, and survival analyses were used to evaluate the prognostic significance of B7-H3 . Pearson’s correlation analyses were performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy at the B7-H3 locus was determined using chromatin immunoprecipitation (ChIP), and androgen-dependent expression changes in B7-H3 was evaluated by quantitative reverse transcription PCR in LNCaP cell lines. Oncomine was queried to evaluate B7-H3 expression in metastatic disease. Results: B7-H3 mRNA expression was positively associated with higher Gleason score ( P <0.001), tumor stage ( P <0.001), and castrate resistant metastatic disease ( P <0.0001). High B7-H3 expression correlated with the development of metastasis and prostate cancer specific mortality, but this was not significant on multi-variable analysis. B7-H3 expression correlated with ERG-positive disease ( r =0.99) and AR expression ( r =0.36). ChIP revealed an AR-binding site upstream of B7-H3 , and the presence of androgens decreased B7-H3 expression in LNCaP suggesting potential direct AR regulation. Gene set enrichment analysis demonstrated an association of B7-H3 with androgen signaling as well as immune regulatory pathways. Conclusions: Higher B7-H3 expression correlates with Gleason grade, prostate cancer stage and poor oncologic outcomes in prostatectomy cohorts. B7-H3 expression appears to be related to androgen signaling as well as the immune reactome.

Background: Due to their varied outcomes, men with biochemical recurrence (BCR) following radical prostatectomy (RP) present a management dilemma. Here, we evaluate Decipher, a genomic classifier (GC), for its ability to predict metastasis following BCR. Methods: The study population included 85 clinically high-risk patients who developed BCR after RP. Time-dependent receiver operating characteristic (ROC) curves, weighted Cox proportional hazard models and decision curves were used to compare GC scores to Gleason score (GS), PSA doubling time (PSAdT), time to BCR (ttBCR), the Stephenson nomogram and CAPRA-S for predicting metastatic disease progression. All tests were two-sided with a type I error probability of 5%. Results: GC scores stratified men with BCR into those who would or would not develop metastasis (8% of patients with low versus 40% with high scores developed metastasis, P <0.001). The area under the curve for predicting metastasis after BCR was 0.82 (95% CI, 0.76–0.86) for GC, compared to GS 0.64 (0.58–0.70), PSAdT 0.69 (0.61–0.77) and ttBCR 0.52 (0.46–0.59). Decision curve analysis showed that GC scores had a higher overall net benefit compared to models based solely on clinicopathologic features. In multivariable modeling with clinicopathologic variables, GC score was the only significant predictor of metastasis ( P =0.003). Conclusions: When compared to clinicopathologic variables, GC better predicted metastatic progression among this cohort of men with BCR following RP. While confirmatory studies are needed, these results suggest that use of GC may allow for better selection of men requiring earlier initiation of treatment at the time of BCR.

PurposeThe goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis to adequately stage and treat the patient. Persistent disease after TUR is not uncommon and is why re-TUR is recommended in T1G3 patients. When there is T1 tumor in the re-TUR specimen, very high risks of progression (82%) have been reported. We analyze the risks of recurrence, progression to muscle-invasive disease and cancer-specific mortality (CSM) according to tumor stage at re-TUR in T1G3 patients treated with BCG.MethodsIn our retrospective cohort of 2451 T1G3 patients, 934 patients (38.1%) underwent re-TUR. 667 patients had residual disease (71.4%): Ta in 378 (40.5%), T1 in 289 (30.9%) patients. Times to recurrence, progression and CSM in the three groups were estimated using cumulative incidence functions and compared using the Cox regression model.ResultsDuring a median follow-up of 5.2 years, 512 patients recurred. The recurrence rate was significantly higher in patients with a T1 at re-TUR (P < 0.001). Progression rates differed according to the pathology at re-TUR, 25.3% in T1, 14.6% in Ta and 14.2% in case of no residual tumor (P < 0.001). Similar trends were seen in both patients with and without muscle in the original TUR specimen.ConclusionsPatients with T1G3 tumors and no residual disease or Ta at re-TUR have better recurrence, progression and CSM rates than previously reported, with a CSM rate of 13.1 and a 25.3% progression rate in re-TUR T1 disease.

Background: Several randomized controlled trials assessed the outcomes of patients treated with neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP). The majority of them included mainly low and intermediate risk prostate cancer (PCa) without specifically assessing PCa-related death (PCRD). Thus, there is a lack of knowledge regarding a possible effect of NHT on PCRD in the high-risk PCa population. We aimed to analyze the effect of NHT on PCRD in a multicenter high-risk PCa population treated with RP, using a propensity-score adjustment. Methods: This is a retrospective multi-institutional study including patients with high-risk PCa defined as: clinical stage T3–4, PSA >20 ng ml −1 or biopsy Gleason score 8–10. We compared PCRD between RP and NHT+RP using competing risks analysis. Correction for group differences was performed by propensity-score adjustment. Results: After application of the inclusion/exclusion criteria, 1573 patients remained for analysis; 1170 patients received RP and 403 NHT+RP. Median follow-up was 56 months (interquartile range 29–88). Eighty-six patients died of PCa and 106 of other causes. NHT decreased the risk of PCRD (hazard ratio (HR) 0.5; 95% confidence interval (CI) 0.32–0.80; P =0.0014). An interaction effect between NHT and radiotherapy (RT) was observed (HR 0.3; 95% CI 0.21–0.43; P <0.0008). More specifically, of patients who received adjuvant RT, those who underwent NHT+RP had decreased PCRD rates (2.3% at 5 year) compared to RP (7.5% at 5 year). The retrospective design and lack of specific information about NHT are possible limitations. Conclusions: In this propensity-score adjusted analysis from a large high-risk PCa population, NHT before surgery significantly decreased PCRD. This effect appeared to be mainly driven by the early addition of RT post-surgery. The specific sequence of NHT+RP and adjuvant RT merits further study in the high-risk PCa population.

PurposeTo evaluate the oncological impact of postponing radical cystectomy (RC) to allow further conservative therapies prior to progression in a large multicentre retrospective cohort of T1-HG/G3 patients initially treated with BCG.MethodsAccording to the time of RC, the population was divided into 3 groups: patients who did not progress to muscle-invasive disease, patients who progressed before radical cystectomy and patients who experienced progression at the time of radical cystectomy. Clinical and pathological outcomes were compared across the three groups.ResultsOf 2451 patients, 509 (20.8%) underwent RC. Patients with tumors > 3 cm or with CIS had earlier cystectomies (HR = 1.79, p = 0.001 and HR = 1.53, p = 0.02, respectively). Patients with tumors > 3 cm, multiple tumors or CIS had earlier T3/T4 or N + cystectomies. In patients who progressed, the timing of cystectomy did not affect the risk of T3/T4 or N + disease at RC. Patients with T3/T4 or N + disease at RC had a shorter disease-specific survival (HR = 4.38, p < 0.001), as did patients with CIS at cystectomy (HR = 2.39, p < 0.001). Patients who progressed prior to cystectomy had a shorter disease-specific survival than patients for whom progression was only detected at cystectomy (HR = 0.58, p = 0.024)ConclusionsPatients treated with RC before experiencing progression to muscle-invasive disease harbor better oncological and survival outcomes compared to those who progressed before RC and to those upstaged at surgery. Tumor size and concomitant CIS at diagnosis are the main predictors of surgical treatment while tumor size, CIS and tumor multiplicity are associated with extravesical disease at surgery.

Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1 , we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo . In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.

BACKGROUND: The aim of the study was to evaluate survival and perioperative outcomes of metastatic prostate cancer (mPCa) patients treated with surgery or androgen deprivation treatment (ADT) only. METHODS: We retrospectively selected 47 metastatic PCa patients treated at a single center (Mayo Clinic, Rochester, MN) by two urologists (RJK and EK) between 2007 and 2014. Overall, 31 (66%) underwent radical prostatectomy (RP) with or without adjuvant therapies and 16 (34%) underwent ADT only. Surgical patients were treated by a single surgeon (RJK). Complications and functional outcomes were recorded for surgery group. Cancer-specific mortality (CSM) was analyzed by Kaplan–Meier estimation. Univariable Cox regression analyses were used to test the risk factors associated with CSM in mPCa patients treated with RP. RESULTS: Median age at diagnosis was 61 years. During median follow-up 38.8 months, 12 deaths were recorded. At 5 years, the overall CSM-free survival rate of the whole cohort was 57.9%. When patients were stratified according to the treatment, CSM-free survival rate at 5 years was 62% and 46% for patients who underwent surgery and ADT, respectively ( P =0.3). Median length of stay was 3 days, with a 30 days readmission rate of 9.7%. The 30-day all complication rate was 29% ( n =9). Specifically, we recorded: 2 lymphoceles (6.5%), 2 wound infection (6.5%), 2 ileus (6.5%), 2 hematoma (6.5%) and 1 anastomosis leak (3.2%). Within 90 days after surgery, 2 (6.5%) and 5 (16.1%) patients needed 1–2 supportive and 3 or more pads, respectively. However, continence was achieved by all treated patients during the follow-up period. CONCLUSIONS: We demonstrated the feasibility of local surgical treatment of primary tumor in mPCa patients. However, in the short term, no survival benefits have been observed for patients treated with surgery when compared with patients treated with ADT only. Further prospective studies are warranted to explore the treatment of M1a/M1b prostate cancer patients.

Background: Prostate cancer overdiagnosis and overtreatment represents a major problem. Many men with low-grade disease on biopsy are undergraded and they harbour high-grade disease at prostatectomy with no reliable way to identify these men. We used a novel urine-based 2-gene methylation test to identify prostate cancers with aggressive features. Methods: Following a proof of concept study in 100 post-radical prostatectomy tissue samples, urine samples were tested from 665 men at multiple U.S. centers undergoing prostate needle biopsy for elevated prostate-specific antigen (2–10 ng ml −1 ). A prediction model was then developed from a combination of clinical factors and the urine-based markers. It was then prospectively tested for accurate prediction of adverse disease (surgical Gleason score ⩾7 and/or a pathological stage ⩾T3a) using urine from a separate cohort of 96 men before radical prostatectomy. Results: Among pre-prostatectomy men with a biopsy Gleason score <7, 41% had adverse disease of which 100% were correctly identified by the test with a negative predictive value of 100% (95% confidence interval, 86–100%). Conclusions: This urine-based test accurately identifies men with clinical low-risk disease who do not have adverse pathology in their prostates and would be excellent candidates for active surveillance.

Background: Data regarding the prognostic significance of tumor volume (TV) in prostate cancer are conflicting. Herein, we evaluated the association of TV with prostate cancer mortality following radical prostatectomy (RP), and assessed the additive prognostic value of TV to an established predictive model. Methods: We identified 13 687 patients who underwent RP without preoperative therapy between 1987 and 2009. TV was estimated using the prolate ellipsoid formula. Survival was estimated using the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of TV with mortality. The ability of TV to enhance the performance of an established prognostic model (Mayo Clinic GPSM (Gleason, PSA, seminal vesicle and margin status) score) was assessed using the c-index. Results: Median TV was 1.57 cm 3 (interquartile range (IQR) 0.48–4.19). Increasing TV was associated with significantly higher risks of seminal vesicle invasion (hazard ratio (HR) 1.58; P <0.0001), positive surgical margins (HR 1.28; P <0.0001) and lymph node involvement (HR 1.26; P <0.0001). Median postoperative follow-up was 9.4 years (IQR 5.0–14.5). Patient grouping into quartiles according to TV resulted in a significant stratification of outcome, as the 15-year cancer-specific survival by TV quartile was 99%, 98%, 95% and 88%, respectively ( P <0.0001). Moreover, on multivariate analysis, greater TV remained associated with significantly increased risks of systemic progression (HR 1.27; P <0.0001), death from prostate cancer (HR 1.29; P <0.0001) and all-cause mortality (HR 1.05; P <0.0001). Meanwhile, addition of TV to the GPSM score increased the c-index for the model’s prediction of prostate cancer mortality from 0.803 to 0.822. Conclusions: TV is associated with survival following RP, and enhances, although modestly, the performance of an established prediction model. As such, TV warrants continued assessment in risk stratification tools.

Background: Atypical small acinar proliferation (ASAP) occurs in approximately 5% of prostate biopsies. Approximately 30–40% of patients with ASAP may develop prostate cancer (PCa) within a 5-year period. Current guidelines recommend a repeat biopsy within 3–6 months after the initial diagnosis. Our objective was to examine the association between ASAP and subsequent diagnosis of high-grade PCa and to evaluate the need for immediate repeat biopsy. Methods: A retrospective multi-institutional review identified 264 patients who underwent prostate biopsy from 2000 to 2013 (Brown), 2008 to 2013 (University of Massachusetts) and 1994 to 2005 (Mayo) and were diagnosed with ASAP. Patients underwent transrectal ultrasound-guided biopsies for elevated PSA and/or abnormal digital rectal exam. Clinicopathologic features were assessed, including rates of subsequent PCa detection of any high-grade (Gleason 7–10) PCa. Comparison was made between those with subsequent PCa on repeat biopsy and those with benign repeat pathology. Results: All 264 patients included underwent repeat biopsy with a median follow-up of 5.4 years (interquartile range: 4.6, 6.7). Of these patients, 89 (34%) were subsequently diagnosed with PCa including 21 (8%) with high-grade PCa. Pre-biopsy PSA was higher among patients subsequently diagnosed with (6.7 vs 5.8, P <0.001). Of those diagnosed with subsequent PCa, 69/89 (78%) had less than or equal to Gleason 3+3 disease and only 15/89 (17%) had Gleason 7 and 6/89 (6%) revealed Gleason ⩾8–10. Radical prostatectomy was performed on 36/89 (40%) patients. Surgical pathology revealed 11 patients ⩾Gleason 8–10 PCa. Conclusions: Although 34% of patients with an initial diagnosis of ASAP who had repeat biopsy were subsequently diagnosed with PCa only, only 22% (8% of the total cohort) were found to have high-grade disease. Higher PSA was associated with increased risk of identifying PCa on repeat biopsy. These findings suggest that immediate repeat biopsy may be omitted in the majority of men with ASAP.