Search

Objective To determine the relationship between prostate gland and tumor volume in men undergoing radical prostatectomy (RP) for prostate cancer. We hypothesized that larger tumors within smaller prostate glands are associated with more aggressive disease characteristics. Methods Records of patients undergoing RP from 2000-2008 at a single institution were reviewed retrospectively. The dominant nodule was considered to be the largest focus of cancer within the prostate, and the dominant nodule-to-prostate volume ratio (DNVR) was calculated according to the ratio of the dominant nodule volume to the gland weight. Cox regression was performed to assess the relationship between DNVR and both pathologic outcomes (Cancer of the Prostate Risk Assessment post-Surgical score) and biochemical recurrence (BCR). Results At a median follow-up of 3.7 years, 174 patients (7.2%) suffered BCR. There was no linear correlation between tumor volume and gland size (R = -0.09). DNVR above the median (≥0.033 cc/gm) was closely associated with high clinicopathologic risk as measured by Cancer of the Prostate Risk Assessment post-Surgical score (hazard ratio, 35.53; 95% confidence interval, 14.42-87.55 for high- vs low-risk groups). In the univariable analysis, both tumor diameter and DNVR were associated with increased risk of BCR. However, in the multivariable model, only tumor diameter remained a significant predictor of BCR (hazard ratio, 2.02; 95% confidence interval, 1.04-3.91). Conclusion Increased DNVR appears to be a characteristic of aggressive prostate tumors, although it did not predict BCR in the present study. However, these data support the association between tumor diameter and BCR after RP for prostate cancer independent of other key clinicopathologic features. [ABSTRACT FROM AUTHOR]

Summary: Small cell neuroendocrine carcinoma of the prostate is a rare variant of prostatic cancer that shares morphologic similarity with prostatic adenocarcinoma of Gleason 5 pattern. It has also been considered morphologically and immunohistochemically indistinguishable from small cell neuroendocrine carcinomas of other origins. CD44 is a cell-surface molecule proposed to identify cancer stem/progenitor cells in prostate cancer. We performed immunohistochemical study for CD44 expression in 11 cases of prostatic small cell neuroendocrine carcinoma and compared its patterns of expression with 73 cases of prostatic adenocarcinoma and 47 cases of small cell neuroendocrine carcinomas of other organs. Strong and diffuse membrane staining for CD44 was observed in 100% of the prostatic small cell neuroendocrine carcinomas. In conventional adenocarcinomas of the prostate, positive staining was only seen in rare, scattered tumor cells; and CD44 staining was negative in most of the small cell neuroendocrine carcinomas of nonprostate origin. The difference in CD44 expression between small cell neuroendocrine carcinomas of the prostate and those of other organs are statistically significant (P < .001). Our study demonstrates the utility of immunohistochemical staining for CD44 in distinguishing prostatic small cell neuroendocrine carcinoma from its mimickers including prostatic adenocarcinoma of Gleason 5 pattern and small cell neuroendocrine carcinomas of other organs. CD44 is the first marker that shows a high degree of tissue/organ specificity for small cell neuroendocrine carcinomas. Because CD44 is a putative marker of prostate cancer stem cells, the strong and diffuse expression of CD44 and the lack of expression of prostate luminal differentiation markers androgen receptor and prostatic specific antigen in prostatic small cell neuroendocrine carcinomas suggest that the tumor cells may retain cancer stem cell features. [Copyright &y& Elsevier]

Abstract: Objectives: To describe the cancer-specific outcomes of patients with pathologic carcinoma in situ (CIS) only at radical cystectomy. Methods: The records of 812 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for bladder transitional cell carcinoma at three U.S. academic centers were reviewed. Of the 812 patients, 99 (12%) had CIS only at radical cystectomy. Results: The distribution of clinical stage for the 99 patients with CIS only at radical cystectomy was as follows: 47% of patients had CIS only, 8% had cT1, 15% had cT1 plus CIS, 10% had cT2, 13% had cT2 plus CIS, 6% had cTa, and 1% had Ta plus CIS. Two patients had lymphovascular invasion in the radical cystectomy specimen, and three had metastases to the lymph nodes. The actuarial recurrence-free survival estimates were 89.8% (95% confidence interval [CI] 83.0% to 96.6%) at 3 years and 83.0% (95% CI 73.2% to 92.8%) at 5 and 7 years after radical cystectomy. Six patients (6%) had died of bladder cancer at analysis and 13 (13%) had died of other causes without evidence of disease recurrence. The actuarial disease-specific survival estimates were 95.8% (95% CI 91.2% to 99.9%) at 3 years, 90.7% (95% CI 82.4% to 98.9%) at 5 years, and 87.2% (95% CI 76.8% to 97.5%) at 7 years after surgery. On univariate Cox regression analyses, only metastasis to lymph nodes was associated with bladder cancer recurrence and death (P <0.001). Conclusions: Disease control seemed durable for patients with pathologic CIS only at radical cystectomy in the absence of metastases to the lymph nodes, even in the case of failure after intravesical therapy. [Copyright &y& Elsevier]

Abstract: Objectives: The finding of bladder cancer invading the detrusor muscle on transurethral resection (TUR) is one of the clearest indications for radical cystectomy. To the extent that detrusor invasion is, in practical effect, a binary variable, the variety of outcomes after radical cystectomy in these patients belies the simplicity of this approach. In this context, we assessed bladder cancer recurrence-free survival among patients noted to have muscle-invasive urothelial carcinoma (transitional cell cancer [TCC]) on staging TUR subsequently found to have non-muscle-invasive TCC at radical cystectomy (downstaged). Methods: The records of 248 consecutive patients who underwent radical cystectomy for TCC at a single academic institution from 1994 to 2002 were retrospectively reviewed. Of these patients, 112 (45%) had documented muscle-invasive disease by TUR and were clear of gross residual tumor on cystoscopy before radical cystectomy. Results: Of the 112 patients, 25 (22.3%) were downstaged to non-muscle-invasive disease (Stage pT1 or less) at cystectomy and 87 (77.7%) had persistent muscle-invasive disease (Stage pT2 or greater) at cystectomy. Recurrence occurred in 4 downstaged patients (16.0%) compared with 29 patients (33.3%) who were not downstaged (P = 0.094). Kaplan-Meier analysis demonstrated a statistically significant improvement in recurrence-free survival with downstaging (log-rank P = 0.008). Multivariate analysis demonstrated a threefold reduction in recurrence risk with tumor downstaging (hazard ratio 0.33, 95% confidence interval 0.10 to 1.12) that approached statistical significance (P = 0.075). Nodal status was the strongest predictor of RFS. Conclusions: Downstaging from muscle-invasive TCC on TUR to non-muscle-invasive TCC at radical cystectomy can be associated with a reduced risk of recurrence even after adjusting for lymph node status and adjuvant chemotherapy. [Copyright &y& Elsevier]

Objective: To morphometrically measure to muscle mass which may reflect physical components of frailty. Hence, we evaluated the association between L4 total psoas area (TPA) and operative outcome after radical cystectomy (RC) for bladder cancer.Methods: In a retrospective single-center study, bladder cancer patients who underwent RC and urinary diversion between 2007 and 2012 were enrolled. TPA was evaluated in the cross-sectional imaging. The psoas muscles were normalized with the height. Male patients with a psoas mass index ≤7.4 cm2/m2 and female patients with a psoas mass index ≤5.2 cm2/m2 were classified as sarcopenic. Outcome measures were 30- and 90-day readmission and complications, and survival. Multivariable logistic and Cox proportional-hazards regression models were used to determine relevant predictors.Results: The median age of the 441 participants and follow up time was 68 years (IQR 59-75) and 1.2 years (IQR 0.5-1.9), respectively. One hundred forty-three patients (32.4%) were sarcopenic. The 30-day readmission and the complication rates were 13.8% and 44.7%, respectively. The 90-day readmission and complication rates were 23.9% and 53.1%, respectively. The 1-year mortality rate was 11.6% (95%CI 8.7-15.4). Multivariable logistic regression analysis revealed an association between increased TPA and lower odds of 30-day complications after RC (OR 0.95, 95%CI 0.92-0.99, P = .02); similarly, an increase in TPA was of prognostic value, although not statistically significant in the multivariable model (P = .05) once adjusting for other patient factors.Conclusion: Sarcopenia predicted early complications and showed an informative trend for overall survival after RC, and thus may inform models predicting postsurgical outcomes. [ABSTRACT FROM AUTHOR]

Despite the great promise for therapies using antisense oligonucleotides (ASOs), their adverse effects, which include pro-inflammatory effects and thrombocytopenia, have limited their use. Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO degradation in plasma. The main aim of this study was to assess the impact of the nucleic acid portion of an ASO-type drug on platelets and determine if it may contribute to thrombosis or thrombocytopenia. Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo. Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6–8 fold greater than control; p < 0.001). The observed nucleic acid (NA) effects on platelets were toll-like receptor (TLR) -7 subfamily dependent. Injection of a p-Selectin inhibitor significantly (p = 0.02) reduced the formation of oligonucleotide-associated pulmonary microthrombosis in vivo. Our results suggest that platelet exposure to nucleic acids independent of the presence of a PS modification leads to a generation of hypersensitive platelets and requires TLR-7 subfamily receptors. ASO studies conducted in cancer patients may benefit from testing the ASO effects on platelets ex vivo before initiation of patient treatment. [ABSTRACT FROM AUTHOR]

The potential for low-grade (grade group 1 [GG1]) prostate cancer (PCa) to progress to high-grade disease remains unclear. To interrogate the molecular and biological features of low-grade PCa serially over time. Nested longitudinal cohort study in an academic active surveillance (AS) program. Men were on AS for GG1 PCa from 2012 to 2017. Electronic tracking and resampling of PCa using magnetic resonance imaging/ultrasound fusion biopsy. ERG immunohistochemistry (IHC) and targeted DNA/RNA next-generation sequencing were performed on initial and repeat biopsies. Tumor clonality was assessed. Molecular data were compared between men who upgraded and those who did not upgrade to GG ≥ 2 cancer. Sixty-six men with median age 64 yr (interquartile range [IQR], 59–69) and prostate-specific antigen 4.9 ng/mL (IQR, 3.3–6.4) underwent repeat sampling of a tracked tumor focus (median interval, 11 mo; IQR, 6–13). IHC-based ERG fusion status was concordant at initial and repeat biopsies in 63 men (95% vs expected 50%, p < 0.001), and RNAseq-based fusion and isoform expression were concordant in nine of 13 (69%) ERG+ patients, supporting focal resampling. Among 15 men who upgraded with complete data at both time points, integrated DNA/RNAseq analysis provided evidence of shared clonality in at least five cases. Such cases could reflect initial undersampling, but also support the possibility of clonal temporal progression of low-grade cancer. Our assessment was limited by sample size and use of targeted sequencing. Repeat molecular assessment of low-grade tumors suggests that clonal progression could be one mechanism of upgrading. These data underscore the importance of serial tumor assessment in men pursuing AS of low-grade PCa. We performed targeted rebiopsy and molecular testing of low-grade tumors on active surveillance. Our findings highlight the importance of periodic biopsy as a component of monitoring for cancer upgrading during surveillance. Targeted rebiopsy and molecular assessment of low-grade prostate cancers often revealed clonally related tumors. These findings highlight the importance of serial tumor sampling during active surveillance and suggest that clonal progression could be one mechanism of upgrading. [ABSTRACT FROM AUTHOR]

While circulating tumor cell (CTC)–based detection of AR-V7 has been demonstrated to predict patient response to second-generation androgen receptor therapies, the rarity of AR-V7 expression in metastatic castrate-resistant prostate cancer (mCRPC) suggests that other drivers of resistance exist. We sought to use a multiplex gene expression platform to interrogate CTCs and identify potential markers of resistance to abiraterone and enzalutamide. 37 patients with mCRPC initiating treatment with enzalutamide (n = 16) or abiraterone (n = 21) were prospectively enrolled for CTC collection and gene expression analysis using a panel of 89 prostate cancer–related genes. Gene expression from CTCs was correlated with PSA response and radioclinical progression-free survival (PFS) using Kaplan-Meier and Cox regression analyses. Twenty patients (54%) had detectable CTCs. At a median follow-up of 11.3 months, increased expression of the following genes was significantly associated with shorter PSA PFS and radioclinical PFS: AR , AR-V7 , PSA , PSCA , TSPAN8 , NKX3.1 , and WNT5B. Additionally, high SPINK1 expression was associated with increased PFS. A predictive model including all eight genes gave an area under the curve (AUC) of 0.84 for PSA PFS and 0.86 for radioclinical PFS. In comparison, the AR-V7 only model resulted in AUC values of 0.65 and 0.64.These data demonstrate that clinically relevant information regarding gene expression can be obtained from whole blood using a CTC-based approach. Multigene classifiers in this setting may allow for the development of noninvasive predictive biomarkers to guide clinical management. [ABSTRACT FROM AUTHOR]

Abstract Background Intermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design. Objective To identify a potential ICE for men receiving PORT. Design, setting, and participants We performed an institutional review board–approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013. The median follow-up was 8.2 yr. Outcome measurements and statistical analysis Biochemical failure (BF), distant metastases (DM), and castrate-resistant prostate cancer (CRPC) were evaluated for correlation with OS and assessed as time-dependent variables in a multivariable Cox proportional hazards model and in landmark analyses at 1, 3, 5, and 7 yr after PORT. Cross-validated concordance (c) indices were used to assess model discrimination. Results and limitations OS at 1, 3, 5, and 7 yr after PORT was 98%, 95%, 90%, and 82%, respectively. In a time-varying model controlling for clinical and pathologic variables, BF (hazard ratio [HR] 2.32, 95% confidence interval [CI] 1.45–3.71; p < 0.001), DM (HR 6.52, 95% CI 4.20–10.1; p < 0.001), and CRPC (HR 2.47, 95% CI 1.56–3.92; p < 0.001) were associated with OS. In landmark analyses, 5-yr DM had the highest c index when adjusting for baseline covariates (0.78), with 5-yr DM also providing the greatest increase in discriminatory power over a model only including baseline covariates. These findings require validation in prospective randomized data. Conclusions While limited by the retrospective nature of the data, 5-yr DM is associated with lower OS following PORT, outperforming the prognostic capability of BF and CRPC at 1, 3, 5, or 7 yr after treatment. Confirmation of this ICE as a surrogate for OS is needed from randomized trial data so that it can be incorporated into future clinical trial design. Patient summary We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival. Take Home Message We assessed potential intermediate clinical endpoints prognostic for overall survival in a cohort of men receiving radiotherapy after prostatectomy. We identified the development of metastatic disease within 5 yr after treatment as the strongest predictor of overall survival. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether incidental pathologic T3a (pT3a) upstaging after partial nephrectomy (PN) for clinical T1 disease results in inferior oncologic outcomes compared to pT1a-b disease.Materials and Methods: Retrospective chart review was completed at the University of Michigan and Moffitt Cancer Center to identify patients undergoing PN for clinical T1 masses between 1995 and 2015. A total of 1955 patients were identified, of which 95 had pT3a upstaging. Median follow-up was 38.2 months. Patients with pT3a disease were individually matched by clinicopathologic features with patients undergoing PN with pT1a-b disease in a 1:2 ratio. Kaplan-Meier analysis and univariate and multivariable Cox proportional hazards regression analysis were performed. Primary endpoint was recurrence-free survival (RFS). Secondary endpoints were all-cause mortality, cancer-specific survival (CSS), and rates of local and distant recurrence.Results: Recurrence rates were significantly higher in pT3a disease compared to pT1a-b controls (P <.01). In those patients with pT3a upstaging, 3- and 5-year RFS were 81% and 58%, compared to 86% and 75% in pT1a-b controls (P = .01). CSS at 3 and 5 years were 91% and 90% in pT3a disease and 100% and 97% in pT1a-b controls (P <.01). All-cause mortality at 3 and 5 years were 82% and 71% in pT3a disease and 93% and 80% in pT1a-b controls (P = .04). Univariate and multivariable analysis of pT3a disease demonstrated no association between demographic or pathologic characteristics and RCC recurrence.Conclusion: Patients with pT3a upstaging following PN experience a significantly reduced RFS and CSS when compared to pT1 disease. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether shortened inpatient length of stay (LOS) after radical cystectomy (RC) is associated with increased complication rates after hospital discharge.Materials and Methods: The analytic cohort comprised 484 consecutive patients with 90-day follow-up who underwent RC at our institution from 2005 to 2012 and with LOS ≤9 days. Patients were categorized according to LOS as short (s-LOS; ≤5 days) or routine (r-LOS; 6-9 days). The primary outcome was major complications (Clavien-Dindo grades 3-5) occurring within 90 days after discharge. A Cox proportional hazards model was used to determine the association between LOS and post-discharge major complications. Hospital readmission was a secondary outcome.Results: Patients in the s-LOS cohort had fewer comorbidities (P < .01), less frequently received neoadjuvant chemotherapy (P = .02), and more often underwent robotic RC (P < .01). Major outpatient complications occurred in 18.1% of s-LOS patients vs 11.2% of r-LOS patients, and s-LOS was associated with a significant independent increase in the risk of major outpatient complications (hazard ratio 1.91, 95% confidence interval 1.03-3.56, P = .04). There was also a statistically significant association between s-LOS and readmission (hazard ratio 1.60, 95% confidence interval 1.01-2.44, P = .048).Conclusion: Early discharge post RC appears to be associated with an increased risk of major outpatient complications, suggesting that attempts to reduce LOS may need to be supplemented by additional outpatient services to diminish this effect. Further attention should be given to understanding how to better support patients discharged after a short LOS. [ABSTRACT FROM AUTHOR]

Objective: To review our clinical T1a renal mass active surveillance (AS) cohort to determine whether renal mass biopsy was associated with maintenance of AS.Materials and Methods: From our prospectively maintained database we identified patients starting AS from June 2009 to December 2011 who had at least 5 months of radiologic follow-up, unless limited by unexpected death or delayed intervention. The primary outcome was delayed intervention. Clinical, radiologic, and pathologic variables were compared. We constructed Kaplan-Meier survival curves for maintenance of AS. Cox multivariable regression analysis was performed to assess predictors of delayed intervention.Results: We identified 118 patients who met criteria for inclusion with a median radiologic follow-up of 29.5 months. The delayed intervention group had greater initial mass size and faster growth rate compared to those who continued AS. Rate of renal mass biopsy was similar between the 2 groups. In the multivariable analysis, size >2 cm (hazard ratio [HR] 3.65, 95% confidence interval [CI] 1.28-10.38, P = .015), growth rate (continuous by mm/year: HR 1.26, 95% CI 1.12-1.41, P < .001), but not renal biopsy (HR 1.52, 95% CI 0.70-3.30, P = .29), were associated with increased risk of delayed intervention. Time-to-event curves also showed that size was closely associated with delayed intervention whereas renal mass biopsy was not.Conclusion: At our institution, growth rate and initial tumor size appear to be more influential than renal mass biopsy results in determining delayed intervention after a period of AS. Further analysis is required to determine the role of renal biopsy in the management of patients being considered for AS. [ABSTRACT FROM AUTHOR]

Objective: To compare the accuracies of renal mass biopsy (RMB) and R.E.N.A.L. nephrometry score (RNS) nomograms for predicting benign vs malignant disease, and low- vs high-risk renal tumors.Materials and Methods: We included 281 renal masses in 277 patients who had complete RNS, preoperative RMB, and final pathology from renal surgery for clinically localized renal tumors. RMB and final pathology were determined to be benign or malignant, and malignancies were classified as low-risk (Fuhrman grade I/II) or high-risk (Fuhrman grade III/IV) (benign included in low-risk group). Previously published RNS nomograms were used to determine probabilities of any cancer and high-risk cancer. The gamma statistic was used to assess strength of association between RMB or RNS with final pathology.Results: Of the 281 masses, 13 (5%) and 268 (95%) were confirmed benign and malignant, respectively, and 155 (55%) and 126 (45%) were confirmed low-risk and high-risk, respectively, on final pathology. The areas under the curve of the RNS nomograms for benign vs malignant disease and for low-risk vs high-risk renal tumors were 0.56 and 0.64, respectively. Concordances for predicting benign vs malignant disease were 99% for RMB (P < .01, gamma 0.99) and 29% for RNS nomogram (P = .16, gamma 0.38). Concordances for predicting low-risk vs high-risk renal tumors were 67% for RMB (P < .01, gamma 0.97) and 61% for RNS nomogram (P < .01, gamma 0.47), respectively.Conclusion: Although RNS nomograms are useful for discriminating between benign vs malignant renal masses, and low-risk vs high-risk renal tumors, they are outperformed by RMB. [ABSTRACT FROM AUTHOR]

A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status (+ or -), which identified MET expression as markedly increased in AR- samples. In vitro, AR signaling inhibition in AR+ CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR+ CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR- disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR- prostate cancer. [ABSTRACT FROM AUTHOR]

Background Limited data exist to guide the use of androgen deprivation therapy (ADT) for men treated with radiation therapy (RT) after radical prostatectomy (RP). The optimal duration of ADT in this setting is unknown. Objective To determine if the duration of ADT influences clinical outcomes for men receiving post-RP RT. Design, setting, and participants A total of 680 men who received adjuvant radiation therapy ( n = 105) or salvage radiation therapy ( n = 575) between 1986 and 2010 at a single tertiary care institution were reviewed retrospectively. Median follow-up post-RT was 57.8 mo. Intervention RT was delivered using three-dimensional conformal or intensity-modulated RT in 1.8-Gy fractions. For patients treated with ADT, >80% were treated with a gonadotropin-releasing hormone agonist with or without a nonsteroidal antiandrogen. Outcome measurements and statistical analysis Biochemical failure (BF), distant metastasis (DM), prostate cancer–specific mortality (PCSM), and overall mortality were assessed using Kaplan-Meier analysis and propensity score analysis. Results and limitations Overall, 144 patients (21%) received ADT with post-RP RT, most of whom had high-risk disease features such as Gleason score 8–10, seminal vesicle invasion, or pre-RT prostate-specific antigen >1 ng/ml. Median ADT duration was 12 mo (interquartile range: 6.0–23.7). Patients who received <12 mo of ADT had an association with increased BF (hazard ratio [HR]: 2.27; p = 0.003) and DM (HR: 2.48; p = 0.03) compared with patients receiving ≥12 mo of ADT. The 5-yr rates of DM were 6.0% and 23% for ≥12 and <12 mo of ADT, respectively. On propensity score analysis controlling for pretreatment and treatment-related factors, each month of ADT was associated with a decreased risk for BF (HR: 0.95; p = 0.0004), DM (HR: 0.88; p = 0.0004), and PCSM (HR: 0.90; p = 0.037). These findings are limited by the retrospective nature of our analysis. Conclusions For men with high-risk disease features receiving ADT with post-RP RT, the duration of ADT is associated with clinical outcomes. Our findings suggest that for these men an extended course of ADT ≥12 mo may be preferable. Validation of our findings is needed. Patient summary We evaluated outcomes for men with high-risk disease features treated with androgen deprivation therapy (ADT) and radiotherapy after radical prostatectomy. Longer durations of ADT resulted in improved patient outcomes. [ABSTRACT FROM AUTHOR]

Platelets have been long postulated to play a critical role in the pathogenesis of prostate cancer, although relatively little is known regarding the precise mechanisms involved. Androgen deprivation therapy (ADT) for prostate cancer eventually fails with relapse occurring in the form of castration-resistant prostate cancer (CRPC). CRPC tumors typically overexpress androgen receptor (AR), demonstrating continued dependence upon AR signaling. Platelets have been previously demonstrated to contain androgens, and we sought to explore the contribution of platelet-derived androgens in CRPC. In this study, we examined the role of platelet-derived androgens using in vitro platelets from men with CRPC, men with high-risk prostate cancer, and healthy male donors. A series of in vitro assays was performed to elucidate the impact of platelet-derived androgens on androgen-sensitive prostate tumor cells. By examining platelet-derived androgen effects on AR signaling in prostate tumor cells, we found that platelets, from men with CRPC and on ADT, strongly induce AR target genes and tumor cell proliferation. Moreover, we show a fully intact testosterone (T) biosynthetic pathway within platelets from its precursor cholesterol and demonstrate that platelets of CRPC patients with ADT resistance are able to generate T. Overall, our findings reveal an unknown capacity of platelets to synthesize T at functionally relevant levels in patients with lethal prostate cancer. Importantly, it suggests a novel paracrine mechanism of T production that may act to sustain CRPC state and potentiate therapeutic resistance. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the maximum tumor diameter (MTD) of the dominant prostate cancer nodule in the radical prostatectomy specimen as a prognostic factor for outcome in patients treated with salvage external beam radiation therapy (SRT) for a rising prostate-specific antigen (PSA) value after radical prostatectomy. Methods and Materials: From an institutional cohort of 575 patients treated with SRT, data on MTD were retrospectively collected. The impact of MTD on biochemical failure (BF), metastasis, and prostate cancer-specific mortality (PCSM) was assessed on univariate and multivariate analysis using Kaplan-Meier and Cox proportional hazards models. Results: In the 173 patients with MTD data available, median follow-up was 77 months (interquartile range, 47-104 months) after SRT, and median MTD was 18 mm (interquartile range, 13-22 mm). Increasing MTD correlated with increasing pT stage, Gleason score, presence of seminal vesicle invasion, and lymph node invasion. Receiver operating characteristic curve analysis identified MTD of >14 mm to be the optimal cut-point. On univariate analysis, MTD >14 mm was associated with an increased risk of BF (P=.02, hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.8), metastasis (P=.002, HR 4.0, 95% CI 2.1-7.5), and PCSM (P=.02, HR 8.0, 95% CI 2.9-21.8). On multivariate analysis MTD >14 mm remained associated with increased BF (P=.02, HR 1.9, 95% CI 1.1-3.2), metastasis (P=.02, HR 3.4, 95% CI 1.2-9.2), and PCSM (P=.05, HR 9.7, 95% CI 1.0-92.4), independent of extracapsular extension, seminal vesicle invasion, positive surgical margins, pre-RT PSA value, Gleason score, and pre-RT PSA doubling time. Conclusions: For patients treated with SRT for a rising PSA value after prostatectomy, MTD at time of radical prostatectomy is independently associated with BF, metastasis, and PCSM. Maximum tumor diameter should be incorporated into clinical decision making and future clinical risk assessment tools for those patients receiving SRT. [Copyright &y& Elsevier]

Background: To evaluate the association between urinary MyProstateScore (MPS) and pathologic grade group (GG) at surgery in men diagnosed with GG1 prostate cancer (PCa) on biopsy.Methods: Using an institutional biospecimen protocol, we identified men with GG1 PCa on biopsy and PSA ≤10 ng/ml who underwent radical prostatectomy (RP) at the University of Michigan. MPS was retrospectively calculated using prospectively collected, post-DRE urine samples. The primary outcome was upgrading on RP pathology, defined as GG ≥ 2. The associations of MPS, PSA, and PSA density (PSAD) with upgrading were assessed on univariable logistic regression, and the predictive accuracy of each marker was estimated by the area under the receiver operating characteristic curve (AUC).Results: There were 52 men with urinary specimens available that met study criteria, based on biopsy Gleason Grade and specimen collection. At RP, 17 men (33%) had GG1 cancer and 35 (67%) had GG ≥ 2 cancer. Preoperative MPS was significantly higher in patients with GG ≥ 2 cancer at surgery (median 37.8 [IQR, 22.2-52.4]) as compared to GG1 (19.3 [IQR, 9.2-29.4]; P = 0.001). On univariable logistic regression, increasing MPS values were significantly associated with upgrading (odds ratio 1.07 per one-unit MPS increase, 95% confidence interval 1.02-1.12, P = 0.004), while PSA and PSAD were not significantly associated with upgrading. Similarly, the discriminative ability of the MPS model (AUC 0.78) for upgrading at RP was higher compared to models based on PSA (AUC 0.52) and PSAD (AUC 0.62).Conclusions: In men diagnosed with GG1 PCa who underwent surgery, MPS was significantly associated with RP cancer grade. In this limited cohort of men, these findings suggest that MPS could help identify patients with undetected high-grade cancer. Additional studies are needed to better characterize this association. [ABSTRACT FROM AUTHOR]

One in five cancer clinical trials fails with another third failing to meet enrollment goals. Prior efforts to improve enrollment focus on patient facing interventions, but geographic factors such as regional cancer incidence may doom trials before they even begin. For these reasons, we examined associations of regional prostate cancer incidence with trial termination, and identified scientifically-underserved areas where future trials might thrive. We merged US phase 2–3 prostate cancer clinical trial data from ClinicalTrials.gov with prostate cancer incidence data from statecancerprofiles.cancer.gov. We matched trial information from 293 closed and 560 active trials with incidence data for 2947 counties. Using multivariable logistic regression, we identified associations with trial termination. We identified 'scientifically-underserved' counties with the highest cancer incidence quintile (>61 annual cases) but lowest active trials quintile (0 or 1 trial). Of 293 closed trials, one in three was terminated (n = 96, 32.8%). On multivariable analysis, only lower regional prostate cancer incidence was associated with higher likelihood of premature trial termination (OR 0.98, 95% CI [0.96–0.99] for every 100 cases, p = 0.03). We identified 188 counties with >61 annual prostate cancer cases but 0 or 1 active trials, indicating potential scientifically-underserved areas. In this novel study, we found prostate cancer trials in areas with low prostate cancer incidence were more likely to fail. We also identified scientifically-underserved areas where trials might thrive. Our findings provide a more nuanced understanding of clinical trial feasibility and upstream opportunities for improvement. [ABSTRACT FROM AUTHOR]

Objectives: Urothelial tumors that invade the lamina propria but not the muscularis propria are a particularly problematic clinical entity. The aim of the present study was to assess the pathologic features and clinical outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma (UCBC) treated with radical cystectomy. Methods: We reviewed the records of 958 consecutive patients who underwent radical cystectomy and pelvic lymphadenectomy for bladder cancer at three U.S. academic centers. Of these patients, 167 (median age, 66.7 years) underwent radical cystectomy for clinical stage T1 grade 3 UCBC. Results: The median follow-up was 33.8 months (mean ± standard deviation: 45.9 ± 39.2 months, range, 0.4 to 177.1) for patients alive at last follow-up. Disease recurred in 48 of 167 of patients (29.4%) and 30 of 162 patients (18.5%) died from bladder cancer. A total of 29 of 166 patients (17.5%) had lymph nodal metastases. Of 167 patients, 84 (50%) were pathologically upstaged and 167 (27.5%) had extravesical disease. Patients with disease upstaging had poorer survival (P <0.001). A greater than 3-month delay between cystectomy and last transurethral resection showed a trend toward upstaging (P = 0.06). Presence of carcinoma in situ (CIS) was the only precystecomy factor that predicted disease recurrence (hazard ratio [HR]: 2.13, 95% confidence interval [CI]: 1.14 to 3.98) and mortality (HR: 2.75, 95% CI: 1.17 to 6.46). Conclusions: A large proportion of patients undergoing cystectomy for clinical T1 grade 3 disease have adverse pathological features. The recurrence and survival outcomes in this group are suboptimal. Presence of CIS precystectomy predicts outcomes. Better markers are needed to identify patients at high risk for adverse outcomes. [Copyright &y& Elsevier]

Objective: To understand potential harms associated with delaying resection of small renal masses (SRMs) in patients ultimately treated, and whether these patients have factors associated with adverse pathology.Methods: Patients with SRMs (≤4cm) who underwent surgical resection at our institution (2009-2015) were classified as undergoing early resection or initial surveillance with delayed resection (defined by a time from presentation to intervention of at least 6mo). Demographic and clinical variables were compared among groups. Using multivariable logistic regression, we examined the association between delayed resection and adverse pathology (Fuhrman grade 3-4, papillary type 2, sarcomatoid histology, angiomyolipoma with epithelioid features, or stage≥pT3). For patients who underwent delayed intervention, we used similar methods to examine the association between SRM growth rate and adverse pathology.Results: Overall, 401 (81%) and 94 (19%) patients underwent early and delayed resection, respectively. Median time to resection was 84 days (interquartile range: 59-121) and 386 days (interquartile range: 272-702) (P<0.001). Patients undergoing delayed resection were older (62 vs. 58y, P = 0.01) and had smaller masses (2.3 vs. 2.7cm, P<0.001) at initial presentation. Utilization of partial vs. radical nephrectomy was similar regardless of resection timing (P = 0.5). Delayed resection was not associated with adverse pathology (P = 0.8); however, male sex was independently associated with adverse pathology (odds ratio: 1.7, 95% CI: 1.1-2.4, P = 0.009). In patients on surveillance, increasing annual SRM growth rate was associated with adverse pathology (odds ratio: 1.2, 95% CI: 1.03-1.3mm/y, P = 0.02).Conclusions: Delayed resection was not associated with adverse pathology. Patients on surveillance with increased SRM growth rates had a modest but significant increase in the risk of adverse pathology. [ABSTRACT FROM AUTHOR]

Purpose: Numerous definitions of adverse pathology at radical prostatectomy (RP) have been proposed and implemented for both research and clinical care, and there is tremendous variation in the specific criteria used to define adverse pathology in these settings. Given the current landscape in which magnetic resonance imaging criteria and biomarker cutoffs are validated for disparate adverse pathology definitions, we sought to identify which of these is most closely tied to biochemical recurrence (BCR) after RP.Materials and Methods: A total of 2,837 patients who underwent RP at a single institution for localized prostate cancer (PCa) were included. We evaluated the following existing definitions of adverse pathology at RP: (1) Gleason score ≥7, (2) primary Gleason pattern ≥4, (3) Gleason score ≥7 or pathologic stage T3-4, (4) pathologic stage T3-4, (5) primary Gleason pattern ≥4 or pathologic stage T3-4. The primary outcome measure was BCR. Multiple statistical techniques were used to assess BCR prediction.Results: Of the 5 definitions assessed, 1 (primary Gleason pattern ≥4 or pathologic stage T3-4, 540 patients [19% of cohort]) consistently outperformed the other definitions across all statistical measures. Additionally, a total of only 13 (6.6%) and 34 (10.3%) men with very-low-risk and low-risk cancer per National Comprehensive Cancer Network guideline, respectively, met this definition of adverse pathology at the time of RP.Conclusions: Varying definitions of adverse pathology differ in their prognostic performance. The criteria defined by either primary Gleason pattern ≥4 or pT3-4 disease appears to most accurately predict BCR in this subset of patients with lower risk PCa at the time of diagnosis. Additionally, men with very-low-risk or low-risk PCa per National Comprehensive Cancer Network guidelines are relatively unlikely to have adverse pathology at the time of surgical resection. These data may help inform the use of imaging and molecular markers as well as the intensity of surveillance in men with newly diagnosed PCa. [ABSTRACT FROM AUTHOR]