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Systemic therapy is the mainstay of treatment for metastatic urothelial carcinoma (UC). Responses to first-line platinum-based therapy tend to be short-lived with potential toxicity. Despite the approval of checkpoint inhibitors, the long-term prognosis for patients with metastatic UC remains dismal. Herein we report the case of a patient with a solitary pulmonary metastatic lesion of urothelial origin as the only site of metastatic disease who remained free of disease for more than 2 years without systemic therapy after metastasectomy. We review the literature discussing the role of combined surgical and medical management of oligometastatic UC. As our case illustrates, a growing body of evidence suggests a potential role for a multimodal approach in patients with oligometastatic UC.

Background Multiparametric magnetic resonance imaging (mpMRI) for prostate cancer detection without careful patient selection may lead to excessive resource utilization and costs. Objective To develop and validate a clinical tool for predicting the presence of high-risk lesions on mpMRI. Design, setting, and participants Four tertiary care centers were included in this retrospective and prospective study (BiRCH Study Collaborative). Statistical models were generated using 1269 biopsy-naive, prior negative biopsy, and active surveillance patients who underwent mpMRI. Using age, prostate-specific antigen, and prostate volume, a support vector machine model was developed for predicting the probability of harboring Prostate Imaging Reporting and Data System 4 or 5 lesions. The accuracy of future predictions was then prospectively assessed in 214 consecutive patients. Outcome measurements and statistical analysis Receiver operating characteristic, calibration, and decision curves were generated to assess model performance. Results and limitations For biopsy-naive and prior negative biopsy patients (n = 811), the area under the curve (AUC) was 0.730 on internal validation. Excellent calibration and high net clinical benefit were observed. On prospective external validation at two separate institutions (n = 88 and n = 126), the machine learning model discriminated with AUCs of 0.740 and 0.744, respectively. The final model was developed on the Microsoft Azure Machine Learning platform (birch.azurewebsites.net). This model requires a prostate volume measurement as input. Conclusions In patients who are naive to biopsy or those with a prior negative biopsy, BiRCH models can be used to select patients for mpMRI. Patient summary In this multicenter study, we developed and prospectively validated a calculator that can be used to predict prostate magnetic resonance imaging (MRI) results using patient age, prostate-specific antigen, and prostate volume as input. This tool can aid health care professionals and patients to make an informed decision regarding whether to get an MRI.

PURPOSE/OBJECTIVE(S) Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) near AGT associated with late hematuria following radiotherapy (RT) for prostate cancer. AGT encodes angiotensinogen and, in pre-clinical models, angiotensin pathway inhibition protects against late radiation toxicity in some tissues. Effects on the bladder have not been investigated. We tested the hypothesis that angiotensin converting enzyme inhibitors (ACEi) reduce risk of late hematuria following RT. We additionally investigated the effect of genetically-defined hypertension on hematuria. MATERIALS/METHODS Prostate cancer patients (N = 268) undergoing curative RT (alone or with surgery and/or androgen deprivation therapy) were enrolled from each of two cancer centers pre-RT and followed prospectively for development of hematuria for up to four years using patient reported outcome questionnaires. Hematuria was defined as gross bleeding or medication use for hematuria. Demographic, treatment, and medication data were abstracted from medical records. The cumulative probability of hematuria was estimated by Kaplan-Meier methods, and the log rank test assessed differences by ACEi/ARB, use stratified by enrollment center. Multivariable analyses used Cox models of time to onset of hematuria stratified by enrollment center. A polygenic risk score (PRS) comprising 882 SNPs previously associated with blood pressure was tested for association with time to onset of hematuria in our Radiogenomics Consortium GWAS cohorts (N = 3,608). RESULTS The cumulative probability of hematuria among all participants was 17.1% (N = 19) at four years (median follow-up of two years). Hematuria was seen in 1.4% of those taking vs 22.9% in those not taking ACEi (P = 0.01) at the start of RT, resulting in a hazard ratio (HR) of 0.11 (95% CI 0.01 to 0.83). The protective effect of ACEi on hematuria remained when adjusted for factors associated with ACEi use, including body mass index, hypertension, or diabetes. The protective effect also remained after stratifying by risk factors for hematuria, including prior transurethral prostate resection, smoking status, or prior prostatectomy. A blood pressure PRS was strongly associated with hypertension (odds ratio per standard deviation 1.40, 95% CI 1.30 to 1.50, P < 0.001) but not with hematuria (HR per standard deviation 0.97, 95% CI 0.87 to 1.07, P = 0.52). CONCLUSION Our study is the first to show a radioprotective effect of ACEi on bladder toxicity. This effect appears distinct from presence of hypertension, which is not itself a risk factor. These results point to a promising radioprotector readily available for testing in a randomized clinical trial. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects normal tissues to reduce RT toxicity.

Purpose/Objective(s) Pathological T2-4 N1 M0 prostate cancer (Pca) has a heterogeneous natural history. So far, only one randomized control trial has established the current standard of care of immediate androgen deprivation (ADT) after prostatectomy and lymph node dissection. The role of pelvic radiation (RT) for this cohort of patients remains unknown. The purpose of this study is to perform a retrospective review of our institutional experience to provide much-needed information that may improve the outcome of these very high-risk patients. Materials/Methods We identified patients with pT2-4 N1 M0 disease treated in our institution from 2006 to 2016. We reviewed ADT and RT records in addition to patient and disease characteristics. Kaplan-Meier analyses were utilized to evaluate overall survival (OS) and progression-free survival (PFS, defined as either biochemical or clinical evidence of disease recurrence). Results We identified a total of 94 patients with pT2-4N1M0 Pca with patient demographic and disease characteristics shown in the table. A total of 72 patients had postoperative RT with a median follow-up of 85.9 months (range 15 to 175 months). Among patients receiving RT, 54/72 (75%) received ADT concurrently (median duration of 24 months, range 4 -36 months). The median time from prostatectomy to RT initiation was 6 months (range 3-90 months). RT of 7 patients was initiated after PSA progression. For patients without RT, 15/22 (68%) received ADT (median duration of 24 months, range 3 to 96 months); the median follow-up was 91 months (range 9 to 164 months). The estimated 5-year OS for patients with RT and without RT were 100% and 85.7%, respectively (P = 0.04). The estimated 5-year PFS for patients with RT and without RT were 80.9% and 62.8%, respectively (P = 0.19). Among patients who received ADT, the estimated 5-year PFS was 82.3% with RT and 63.8% without RT, respectively (P = 0.26). Conclusion For a select group of patients with pT2-4N1M0 Pca, postoperative pelvic RT in combination with ADT appeared to have prolonged OS. Further investigation to stratify this group of patients, and ultimately prospective clinical trials to establish the effectiveness of combined pelvic RT and systemic treatment is needed for this cohort of high-risk patients.

Trials SWOG 8949 and EORTC 30947 had the same eligibility criteria and established the role of cytoreductive nephrectomy for metastatic renal cell carcinoma. The more recently published CARMENA trial calls into question the need for cytoreductive nephrectomy. A systematic comparison of CARMENA and SWOG 8949 suggests that cytoreductive nephrectomy may be beneficial for patients receiving immunotherapy but not targeted therapy. The approval of immune checkpoint inhibitors for previously untreated metastatic renal cell carcinoma underlines the need for another randomized phase 3 trial of cytoreductive nephrectomy for patients receiving powerful modern immunotherapies.

Background In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) reduced the risk of renal dysfunction compared with radical nephrectomy (RN); however, overall survival was better in the RN arm. Objective To determine whether treatment effect on the risk of renal dysfunction and all-cause mortality differed in magnitude across levels of baseline variables. Design, setting, and participants This was an exploratory subgroup analysis of EORTC 30904, a phase 3 randomized trial conducted in patients with a small (≤5cm) renal mass and normal contralateral kidney. Intervention Patients were randomized to RN ( n =273) or NSS ( n =268). Outcome measurements and statistical analysis End points included follow-up estimated glomerular filtration rate (eGFR) 2 , eGFR 2 , eGFR 2 , and all-cause mortality. Treatment effect was examined within baseline variables: age ( 1.25×upper limit of normal (ULN). Logistic and Cox regression models were used for analysis of renal dysfunction and all-cause mortality, respectively. Results and limitations The median follow-up periods were 6.7 yr for eGFR and 9.3 yr for survival. No variable-by-treatment interactions were significant at alpha=0.05. For patients with baseline creatinine >1.25×ULN ( n =36), estimated mortality hazard ratio (HR) for NSS versus RN reversed its direction (HR=0.76, 95% confidence interval [CI]: 0.17–3.39) relative to the rest of the study cohort (HR=1.56, 95% CI: 1.06–2.29), although this reversal was not statistically significant (interaction p =0.25). This analysis was limited by low power. Conclusions This exploratory analysis did not reveal strong evidence of treatment effect modification in EORTC 30904, but it was limited by low power. Patient summary We aimed to determine whether the effect of partial versus radical nephrectomy on kidney function and overall survival depended on age, sex, and baseline health of patients enrolled in a large clinical trial. Such dependence could not be demonstrated in this analysis.

In recent years, multiparametric magnetic resonance imaging and magnetic resonance/ultrasound fusion targeted biopsy (TB) have become more widely adopted to aid in prostate cancer (PCa) detection. Previously, TB has been found to increase the yield of clinically significant PCa and is more likely to sample the index tumor compared with traditional 12-core extended sextant biopsies. Currently, the prognostic significance of perineural invasion (PNI) when identified on TB (PNI-TB) is unknown. We identified 95 men at 2 tertiary referral centers who underwent TB followed by radical prostatectomy between January 2014 and January 2017. Clinical, radiological, and pathological variables were retrospectively reviewed. PNI was identified on TB in 27 of 95 (28.4%) patients. On multivariable logistic regression, independent predictors of extraprostatic extension were prostate-specific antigen, TB maximum % core involvement, and PNI-TB (all P

The American Urological Association (AUA) introduced evidence-based guidelines for the management of nonmuscle invasive bladder cancer (NMIBC) in 2016. We sought to assess the implementation of these guidelines among members of the Society of Urologic Oncology (SUO) with an aim to identifying addressable gaps.An SUO approved survey was distributed to 747 members from December 28, 2018 to February 2, 2019. This 14-question online survey (Qualtrics, SAP SE, Germany) consisted of 38 individual items addressing specific statements from the AUA NMIBC guidelines within 3 broad categories - initial diagnosis, surveillance, and imaging/biomarkers. Adherence to guidelines was assessed by dichotomizing responses to each item that was related to recommended action statement within the guidelines. Statistical analysis was applied using Pearson's chi-squared test, where a P-value of0.05 was considered statistically significant.A total of 121 (16.2%) members completed the survey. Members reported a mean of 71% guidelines adherence; adherence was higher for the intermediate- and high-risk subgroups (82% and 76%, respectively) compared to low-risk (58%). Specifically, adherence to guideline recommended cystoscopic surveillance intervals for low-risk disease differed based on clinical experience (60.9% [10 years] vs. 36.8% [≥10 years], P = 0.01) and type of fellowship training (55.2% [urologic oncology] vs. 28.0% [none/other], P = 0.02).Adherence to guidelines across risk-categories was higher for intermediate- and high-risk patients. Decreased adherence observed for low-risk patients resulted in higher than recommended use of cytology, imaging, and surveillance cystoscopy. These results identify addressable gaps and provide impetus for targeted interventions to support high-value care, especially for low-risk patients.

The field cancerization effect has been proposed to explain bladder cancer's multifocal and recurrent nature, yet its mechanisms remain unknown. In this work we show that chronic exposure to tumor-derived extracellular vesicles (TEVs) resulted in the neoplastic transformation of non-malignant human SV-HUC urothelial cells. Inhibition of EV uptake prevented transformation. Transformed cells not only possessed several oncogenic properties, such as genome instability, loss of cell-cell contact inhibition, and invasiveness, but also displayed altered morphology where cells show enlarged cytoplasm with disrupted ER alignment and the accumulation of smaller mitochondria. Treatment of SV-HUC cells with TEVs provoked the unfolded protein response of endoplasmic reticulum (UPRER). Prolonged induction of UPRER signaling led to the activation of the survival branch of the UPRER pathway, where cells had elevated expression of the IRE1, NFi«B and the inflammatory cytokine leptin, and loss of CHOP, a pro-apoptotic protein. More importantly, inhibition of ER stress by docosahexaenoic acid prevented TEV-induced transformation. We propose that TEVs promote malignant transformation of predisposed cells by inhibiting pro-apoptotic signals and activating tumor-promoting ER stress-induced unfolded protein response and inflammation. This study provides insight into the mechanisms of the bladder cancer field effect and tumor recurrence. Funding Statement: This work is supported by NCI R01 CA173986 (YF Lee, PI). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: The study was approved by the University of Rochester Committee on Animal Resources, and the mice were kept in a specific pathogen-free environment.

Objective To evaluate the role of antibiotic prophylaxis with oral ciprofloxacin prior to urinary catheter removal after radical prostatectomy in preventing urinary tract infection (UTI). Materials and methods Patients undergoing radical prostatectomy were prospectively enrolled and randomized to either the antibiotic prophylaxis group (2 doses of oral ciprofloxacin prior to urinary catheter removal) or the control group (no antibiotics given prior to urinary catheter removal). Neither patients nor study providers were blinded to the group. The primary objective was to assess for development of UTI. The secondary objective was to assess for development of Clostridium difficile (C diff) enterocolitis. Continuous variables were compared using a 2-sample t test. Categorical variables were compared using Pearson's chi-squared test or Fisher's exact test. Results One hundred seventy-five patients were enrolled and randomized (90 control and 85 antibiotic prophylaxis). After randomization, 4 patients were excluded and 4 patients withdrew voluntarily. One hundred sixty-seven patients (84 control and 83 antibiotic prophylaxis) completed the study and were available for analysis. There were no significant differences in baseline characteristics, perioperative data, or complications. There was no significant difference in the rate of UTI between the control group and antibiotic prophylaxis group (5.95% vs. 6.02%, P = 1). There was also no significant difference in the rates of C diff infection between the control and the antibiotic prophylaxis groups (3.57% vs. 0%, P = 0.21). Conclusions In this prospective, randomized, controlled trial, the use of antibiotic prophylaxis with oral ciprofloxacin prior to urinary catheter removal after radical prostatectomy did not decrease the rate of UTI, and was not associated with an increased incidence of C diff enterocolitis.

Objectives Because bladder cancer (BC) patients often have comorbidities that adversely affect their health, we wanted to determine whether grade and stage of BC at diagnosis are associated with the hazard of death from causes other than BC. Materials and methods Cancer records for 93,033 patients diagnosed with urothelial BC during 1988–2002 were obtained from the Surveillance Epidemiology and End Results (SEER) database. The grade-stage categories were defined as follows: (1) low grade, stage 0/I (Ta/T1, N0/Nx), (2) high grade, stage 0/I (Ta/Tis/T1, N0/Nx), (3) any grade, stage II (T2, N0/Nx), (4) any grade, stage III (T3-T4a, N0/Nx), (5) any grade, stage IV (T4b and/or N+). Patients with known distant metastases at presentation were excluded. Other covariates were age, gender, and race. The outcome measures were defined as the hazard of death from all causes, from BC, and from non-BC causes. Cox regression model was used to estimate the effect of grade-stage categories on over-all and cause-specific hazards with adjustment for covariates. Results The 5-year mortality proportions by grade-stage category were as follows: low grade, stage 0/I: all-causes 25%, BC 3%, non-BC 22%; high grade stage 0/I: all-causes 38%, BC 13%, non-BC 25%; stage II: all-causes 63%, BC 36%, non-BC 27%; stage III: all-causes 69%, BC 45%, non-BC 24%; stage IV: all-causes 83%, BC 68%, non-BC 15%. Using low grade, stage 0/I as a reference category, the hazard ratios for increasing grade-stage categories (high grade 0/I, II, III, IV) were as follows: all-cause mortality 1.30, 2.37, 3.07, 6.14; BC-related hazard 3.31, 10.02, 14.65, 32.04; non-BC-related hazard: 1.05, 1.37, 1.49, 1.65 (all P Conclusion Grade-stage categories were associated with the hazard of death from non-BC causes. However, their influence on BC-related hazard was much greater in magnitude. Because BC (rather than co-morbidities) is the main cause of death in patients with muscle-invasive disease, aggressive BC-directed therapies in these patients, when feasible, are justified.

Objective To report and identify the predictors of early and long-term complications in a large series of extraperitoneal robot-assisted radical prostatectomy using the standardized Martin criteria. MaterialS and Methods A total of 1503 patients underwent extraperitoneal robot-assisted radical prostatectomy for the treatment of clinically localized prostate cancer from July 2003 to August 2010 at a tertiary referral center. The median follow-up was 28.9 months. Fisher’s exact test was used to examine the association of multiple variables in a bivariate analysis with the incidence and types of complications. Independent predictors were also examined in a multivariate analysis using logistic regression models. Results A total of 151 complications were recorded in 127 of 1503 patients (8.45%). Approximately one third (30.5%) were classified as major complications requiring intervention (Clavien grade III and IV). The most commonly encountered complications were lymphocele (1.46%), bladder neck contracture (1.33%), and anastomotic leak (1.20%). The operative time was a significant predictor of all complications and of major complications on multivariate analysis. Surgeon experience was also predictive of complications on multivariate analysis. Conclusion Extraperitoneal robot-assisted radical prostatectomy remains an underused alternative approach for the treatment of localized prostate cancer. Its safety profile is equivalent to that of other approaches in experienced hands.

Objective To evaluate the safety of near infrared fluorescence (NIRF) of intravenously injected indocyanine green (ICG) during open partial nephrectomy, and to demonstrate the feasibility of this technology to identify the renal vasculature and distinguish renal cortical tumors from normal parenchyma. Methods Patients undergoing open partial nephrectomy provided written informed consent for inclusion in this institutional review board-approved study. Perirenal fat was removed to allow visualization of the renal parenchyma and lesions to be excised. The patients received intravenous injections of ICG, and NIRF imaging was performed using the SPY system. Intraoperative NIRF video images were evaluated for differentiation of tumor from normal parenchyma and for renal vasculature identification. Results A total of 15 patients underwent 16 open partial nephrectomies. The mean cold ischemia time was 26.6 minutes (range 20-33). All 14 malignant lesions were afluorescent or hypofluorescent compared with the surrounding normal renal parenchyma. NIRF imaging of intravenously injected ICG clearly identified the renal hilar vessels and guided selective arterial clamping in 3 patients. No adverse reactions to ICG were noted, and all surgical margins were negative on final pathologic examination. Conclusion The intravenous use of ICG combined with NIRF is safe during open renal surgery. This technology allows the surgeon to distinguish renal cortical tumors from normal tissue and highlights the renal vasculature, with the potential to maximize oncologic control and nephron sparing during open partial nephrectomy. Additional study is needed to determine whether this imaging technique will help improve the outcomes during open partial nephrectomy.

The Surveillance, Epidemiology, and End Results (SEER) program is a commonly used data source in cancer research. This article provides an introduction to the SEER database, describes important data items available from SEER on the most commonly diagnosed urologic malignancies (prostate, bladder, and kidney cancers), and reviews limitations of SEER data for urologic oncology research.

Lymph node count has prognostic implications in bladder cancer patients who are treated with radical cystectomy. Lymph nodes that are too small to identify grossly can easily be missed, potentially leading to missed nodal metastases and inaccurate nodal counts, resulting in inaccurate prognoses. We investigated whether there is a benefit to submitting the entire lymph node packet for histological examination to identify additional lymph nodes. We prospectively assessed 61 pelvic lymphadenectomy specimens in 14 consecutive patients undergoing radical cystectomy. The specimens were placed in Carnoy's solution overnight, then analyzed for lymph nodes. The residual tissue was entirely submitted to assess for additional lymph nodes. In 61 specimens, we identified 391 lymph nodes, ranging from 4-44 nodes per patient. We identified 238 (61%) lymph nodes with standard techniques and 153 (39%) lymph nodes in submitted residual tissue. The number of additional lymph nodes found in the residual tissue ranged from 0 to 26 (0-75%) per patient. These lymph nodes ranged in size from 0.05 to 1 cm. All additional lymph nodes were negative for metastatic disease. Submitting the entire specimen for histological examination allowed for identification of more lymph nodes in radical cystectomy pelvic lymphadenectomy specimens. However, as none of the additional lymph nodes contained metastatic disease, it is unclear if there is a clinical benefit in evaluating lymph nodes that are neither visible nor palpable in lymphadenectomy specimens.

The Bladder Cancer Think Tank III brought together a multidisciplinary group of clinician scientists, patient advocates, representatives from the National Cancer Institute, and Industry leaders to discuss the current state of the field in urothelial cancer and to develop strategies to move forward. This paper summarizes the session devoted to prevention. Experts sought to define primary, secondary, and tertiary prevention and discussed clinical trials performed to date testing retinoids, difluoromethylornithine, celecoxib, and other oral agents in a tertiary prevention setting following transurethral resection with or without intravesical therapy. Urologists practice tertiary prevention in the form of intravesical therapy, and strategies were discussed to identify biomarkers, including urinary cytokines and pathway single nucleotide polymorphism analysis associated with response to treatment. Optimizing delivery of intravesical chemotherapy to the target tissue with simple pharmacologic manipulations or packaging drugs in nanoparticles may improve treatment outcome. Defining a premalignant lesion should be a focus of future research as a strategy for early detection and secondary prevention. Cigarette smoking is the most prevalent risk factor for urothelial cancer, and emphasis was placed on smoking cessation as a powerful tool to reduce the burden of urothelial cancer, and the central role physicians must play in educating patients and providing resources. There is a strong need for research to develop markers of disease initiation and progression. These markers, combined with histories of environmental exposure to bladder carcinogens, may provide a tool to identify patients who will benefit from primary prevention.

Initial detection of bladder cancer and surveillance for cancer recurrence and progression are central topics in the field of urologic oncology. A session at the 3rd Annual Bladder Cancer Think Tank Meeting focused on urine-based markers for bladder cancer screening and surveillance. Here, we review the key points from the presentations, as well as the recommendations from a working group tasked with critically evaluating the information discussed in the session. Although the practicality of markers has been challenged, the resounding consensus was that continued research efforts directed at developing and evaluating markers for screening and early detection are warranted.

Vitamin D anti-tumor effect is often found reduced in the late stages of cancer. To uncover vitamin D resistance mechanism, we established a vitamin D-resistant human prostate cancer LNCaP cell line, LNCaP-R, by chronic exposure of cells to 1alpha,25-dihydroxyvitamin D(3) (1,25-VD). The vitamin D receptor (VDR)-mediated transcriptional activity was reduced in LNCaP-R, whereas VDR expression level and DNA-binding capacity were similar compared to parental cells (LNCaP-P). The expressions of the key factors involved in VDR transactivity, including CYP24A1 and VDR-associated proteins are all increased in LNCaP-R cells, and yet treatment with ketoconazole, P450 enzymes inhibitor, as well as trichostatin A (TSA), a histone deacetylase inhibitor, did not sensitize LNCaP-R cells response to vitamin D, suggesting that neither a local 1,25-VD availability, nor VDR-associated proteins are responsible for the vitamin D resistance. Interestingly, nuclear factor-kappaB (NF-kappaB) signaling, which is critical for 1,25-VD/VDR activity was found reduced in LNCaP-R cells, thereby treatment with NF-kappaB activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), can sensitize LNCaP-R vitamin D response. Together, we conclude that NF-kappaB signaling is critical for vitamin D sensitivity, and dysregulation of this pathway would result in vitamin D resistance and disease progression.

Objectives To assess the validity of the American Urological Association guidelines, we investigated 14-year outcomes of men aged ≥50 years who had hematuria detected in a bladder cancer (BC) screening trial, were thoroughly evaluated, and were not found to have urological cancers. The American Urological Association guidelines for follow-up of adults with asymptomatic microhematuria (MH) who have negative evaluations include repeat urinary cytologies, urinalyses, and office visits for several years, primarily to detect BC (Cohen and Brown, N Engl J Med 348: 2330-2338, 2003; and Grossfeld et al, Urology 57:604-610, 2001). Methods Of 1575 screening participants, 258 had MH detected by daily home testing with the Ames hemastix during two 14-day periods. This test has been shown to accurately reflect MH on microscopic urinalysis when each is correctly performed. Any man with at least 1 positive test (≥"trace") underwent a complete evaluation including microscopic urinalysis, culture, cytology, complete blood count, serum creatinine, coagulation profile, intravenous urography or computed tomography scan, and cystoscopy. BC or other urological tumors was not detected in 234 participants. Using Wisconsin state tumor registry and death certificate data, the outcomes of these men were tracked for 14 years since their last testing. Results Two of the 234 men (0.85%) developed BC during the 14-year follow-up, at 6.7 and 11.4 years after their negative evaluations; one died of BC 7.6 years after his last screening. During this follow-up, 0.93% of the screenees who tested negatively for hematuria had BC diagnosed, none within a year of their last testing date. Conclusions Patients who have negative complete evaluations for asymptomatic MH have little chance of subsequently developing BC. The recommended "appropriate" follow-up for these patients may require reconsideration in light of these data.

Objective To assess the safety and effectiveness of AD32, a doxorubicin analogue with little systemic exposure when administered intravesically, in patients with recurrent or refractory superficial urothelial carcinoma (formerly called transitional cell carcinoma [TCC]), or carcinoma in situ (CIS), who have failed prior BCG-based immunotherapy. Methods Eligible patients received six weekly doses (800 mg) of intravesical AD32 and were evaluated at 12-week intervals for 24 months or until date of worsening disease. Primary analysis was the proportion of all patients recurrence-free at 12 months. Treatment-related and GU-specific toxicities were also examined. All participating institutions submitted the protocol for Institutional Review Board (IRB) approval. Results The study was halted due to unavailability of study drug after accrual of 48 of a planned 64 patients; 42 were included in the analysis. Of these, 28 (67%) were still alive after median follow-up of 61.1 months. Of 21 TCC patients, 18 (85.7%) experienced disease recurrence (median time to recurrence, 5.3 months). Of the 5 CIS patients with complete response (CR), 3 (60%) experienced disease recurrence; (median time to recurrence, 37.3 months). Recurrence-free rates at 12 and 24 months were 20% (90% CI, 7.8%, 36.1%) and 15% (90 CI, 4.9%, 30.2%), respectively, for patients with TCC and 80% (90% CI, 31.4%, 95.8%) at both intervals for CIS patients with CR. Infection was the most common treatment-related toxicity; no grade 4 or higher toxicity was observed. The most common GU-specific toxicity was increased frequency/urgency. Conclusions AD32 is safe and active for treatment of recurrent or refractory superficial bladder carcinoma. The agent awaits more complete characterization when drug production problems can be solved.

Objectives To determine whether the survival of patients with squamous cell carcinoma (SCC) is different from that of patients with urothelial carcinoma, after adjusting for stage, grade, demographic factors, and the initial treatment. Methods Information on bladder cancer cases diagnosed from 1988 to 2003 was obtained from the Surveillance, Epidemiology, and End Results database. The tumors were classified by histologic type, grade, and American Joint Committee on Cancer (AJCC) stage. Other covariates included age, sex, race, and information on the initial treatment (cystectomy and radiotherapy). The outcome variables examined were all-cause and bladder cancer-specific mortality within 2 years of diagnosis. Covariate-adjusted mortality differences were computed within each stage using the modified least squares model. Results SCC histologic features were an independent predictor of all-cause and bladder cancer-specific mortality among patients with AJCC Stage I and II tumors who did not undergo cystectomy as a part of their initial treatment and among patients with AJCC Stage III and IV regardless of whether cystectomy was performed. SCC histologic features were not associated with increased mortality among patients with AJCC Stage I and II tumors treated with cystectomy. Conclusions SCC appears to be more aggressive than urothelial carcinoma after adjusting for stage and other prognostic factors, except for cases in which the tumor was confined to the bladder wall and the bladder was removed as a part of the initial treatment.

To investigate the association between parity and exophytic bladder cancer growth in the UPII-SV40T transgenic mouse model of bladder cancer.The UPII-SV40T transgenic mice express the simian virus 40 large T antigen specifically in the urothelium (driven by uroplakin II promoter) and reliably develop bladder cancer. UPII-SV40T transgenic female mice were either never bred (nulliparous; n = 6) or placed in breeding pairs and allowed full-term pregnancies and lactation. Multiparous animals (n = 5) had between 2 and 4 litters. UPII-SV40T transgenic male mice were sham-operated (intact; n = 9) or castrated (n = 8) at 24 weeks of age. Noninvasive, contrast-enhanced, flat panel detector-based, cone beam computed tomographic imaging of animals at 32 weeks of age permitted quantification of bladder cancer volumes.Multiparous animals had significantly smaller bladder cancers than their nulliparous female (P.001) and intact male (P = .007) counterparts but not different from castrated males. Bladder cancer volume in nulliparous females was significantly larger than castrated males (P.001) but not different from intact males.These results suggest that pregnancy, parity, lactation, or a combination of these may play a protective role in bladder cancer by inhibiting tumor growth. This could be an important model system for studying the effects of pregnancy/lactation hormones on bladder cancer, which could lead to identification of additional risk factors of bladder cancer.

Three applications of markers of detection: screening, replacing surveillance cystoscopies, and guiding evaluation of asymptomatic hematuria, are discussed. In one study, repetitive hematuria screening in men age ≥50 effectively shifted the stage of high grade cancers at diagnosis from muscle invasive to earlier ones, reducing bladder cancer, and all cause mortality. This technique is sensitive, but is not terribly specific. Testing other markers alone or in combination with each other and/or hemoglobin screening in similar or higher risk populations is now beginning. Currently, no commercially available marker is sufficiently sensitive to replace all surveillance cystoscopies for low risk bladder cancer, although some cystoscopic examinations can probably be replaced by markers. Available markers are too insensitive for small, high grade cancers to replace any surveillance cystoscopies in this group. No single marker or combination of markers can safely replace cystoscopy in the work-up of patients with microhematuria who are at high risk for harboring bladder cancer. However, markers may be useful for directing which patients age ≤40 with asymptomatic microhematuria without histories of smoking, particularly women, require cystoscopic evaluation.

Prostate cancer is the most prevalent newly diagnosed noncutaneous malignancy in men. With the continued use of prostate-specific antigen screening, there has been a dramatic rise in the number of prostate biopsied performed. Transrectal ultrasonography (TRUS) is an essential tool used for detecting prostate pathology and performing prostate biopsies. This article review the indications and principles of TRUS of the prostate, the technique of TRUS, and controversies pertaining to prostate core biopsy.

Objectives To characterize the voiding function in a transgenic adenocarcinoma of murine prostate (TRAMP) mouse of advanced age, because it might provide a useful model of slow-onset bladder outlet obstruction. Spontaneous death from urinary outlet obstruction occurs in the TRAMP mouse. Methods A metabolic cage without a fecal separation screen was placed above a precision balance that reported the mass of the excreta pan every 100 ms. A computational algorithm identified voids suitable for uroflow assessment from other excretory events. A series of images were obtained automatically before and during the excretory events. Results The TRAMP mouse displayed a pulsatile voiding pattern characterized by a reduction in uroflow, prolongation of voiding, and droplet formation at the tip of the prepuce. Postmortem histologic examination revealed gross enlargement of the prostate, a suburethral tumor, dilation of the lumen of the urethra, and proteinaceous debris in the urethra and bladder. Conclusions The observed changes were consistent with urethral obstruction induced by prostate enlargement and/or suburethral tumor. Additional studies are required to ascertain whether prostate enlargement per se is sufficient to produce urethral obstruction in the TRAMP mouse. This transgenic mouse strain may provide a model of slow-onset outlet obstruction that is more representative of bladder outlet obstruction caused by benign prostatic hyperplasia than is the obstruction produced by urethral ligation.

Contains fulltext : 47839schalken.pdf (Publisher’s version ) (Closed access) This is the first of 2 articles that summarize the findings of the International Consensus Panel on cytology and bladder tumor markers. The objectives of our panel were to reach a consensus on the areas where markers are needed, to define the attributes of an ideal tumor marker, and to identify which marker(s) would be suitable for diagnosis and/or surveillance of bladder cancer. Our panel consisted of urologists and researchers from Europe, Asia, and the United States who reviewed original articles, reviews, and book chapters on individual bladder tumor markers published in the English language mainly using the PubMed search engine. Panel members also met during 3 international meetings to write recommendations regarding bladder tumor markers. The panel found that the most practical use of noninvasive tests is to monitor bladder cancer recurrence, thereby reducing the number of surveillance cystoscopies performed each year. Markers also may be useful in the screening of high-risk individuals for early detection of bladder cancer. However, more prospective studies are needed to strengthen this argument. Case-control and cohort studies show that several markers have a higher sensitivity to detect bladder cancer. However, cytology is the superior marker in terms of specificity, although some markers in limited numbers of studies have shown specificity equivalent to that of cytology. Our panel believes that several bladder tumor markers are more accurate in detecting bladder cancer than prostate-specific antigen (PSA) is in detecting prostate cancer. However, bladder tumor markers are held to a higher standard than PSA. Therefore, use of bladder tumor markers in the management of patients with bladder cancer will require the willingness of both urologists and clinicians to accept them.

The suppressor of cytokine signaling (SOCS) protein family includes a SPRY (repeats in splA and RyR) domain-containing SOCS box protein (SSB) subfamily, which consists of four members, SSB-1, SSB-2, SSB-3, and SSB-4. These proteins contain a central SPRY domain and a C-terminal SOCS box. Although some of the SOCS protein subfamilies function as adaptors for a large family of ubiquitin-protein isopeptide ligases to regulate certain signaling pathways, the function of the SSB subfamily remains to be determined. In our previous studies, we have found that two SPRY domain-containing proteins, RanBP9 and RanBP10, interact with MET through the SPRY domain. In the present study, we explored the function of SSB proteins in the regulation of the hepatocyte growth factor (HGF)-MET signaling. Our results showed that all four SSB proteins also interacted with the MET. The MET interaction with SSB-1 was further investigated. We demonstrated that SSB-1 bound to MET tyrosine kinase domain through its SPRY domain. MET interacted with SSB-1 in both the absence and the presence of HGF, but HGF treatment resulted in the recruitment of more SSB-1 by MET. We showed that overexpression of SSB-1 but not other SSB proteins enhanced the HGF-induced serum response element (SRE)-luciferase activity. Overexpression of SSB-1 exhibited no effect on the basal level or epidermal growth factor-induced SRE-luciferase activity. SSB-1 also enhanced HGF-induced Erk phosphorylation. Suppression of SSB-1 by the RNA interference method down-regulated HGF-induced SRE-luciferase activity and decreased Elk-1 activation. These results suggest that SSB-1 may play an important role in enhancing the HGF-induced Erk-Elk-1-SRE pathway. Furthermore, we demonstrated that in response to HGF stimulation, the SSB-1 protein became phosphorylated at tyrosine residue 31. The phosphorylated SSB-1 protein bound to p120Ras-GTPase-activating protein (GAP) but did not promote the degradation of p120RasGAP, indicating that enhanced HGF-MET signaling by overexpression of SSB-1 was not dependent on p120RasGAP degradation.

Objectives To develop a noninvasive method to measure urinary flow rate in the mouse. This could be useful for the study of bladder outlet obstruction, as well as processes affecting detrusor function in the awake animal. Genetically engineered mice can improve our understanding of a variety of human bladder diseases. Methods A metabolic cage without a fecal separation screen was placed above a precision balance that reported the mass of the excreta pan every 100 ms. A computational algorithm identified voids suitable for assessment of uroflow from other excretory events. These algorithms were verified by comparison with a series of images obtained automatically before and during the excretory events. Intraurethral acetic acid was used to induce urethritis and to verify the sensitivity of the measurement technique. Results Automatic categorization and characterization of uroflow was successful. Brief exposures of the urethra of the female C57BL6/J mouse to 2% acetic acid decreased uroflow and increased the void duration without a change in the voided volume. Conclusions This method will enable studies of urologic function in mice of differing age, sex, strain, and genetic constitution. Murine urethritis can be differentiated from cystitis, known to be associated with a decrease in voided volume. The observed changes were consistent with urethral obstruction induced by local swelling and inflammation.

Testicular microlithiasis (TM) is an entity of unknown etiology that results in the formation of intratubular calcifications. It is of concern to the urologist because of its possible association with intratubular germ cell neoplasia and testicular germ cell cancer. Although commonly present in patients with germ cell tumors, there appears to be no definitive association with TM and cancer. Therefore, follow-up at this time should be dictated based on risk factors for developing testis cancer more than on the presence of TM.

To analyze, retrospectively, the patterns and behavior of metastatic lesions in prostate cancer patients treated with external beam radiotherapy and to investigate whether patients withor =5 lesions had an improved outcome relative to patients with5 lesions.The treatment and outcome of 369 eligible patients with Stage T1-T3aN0-NXM0 prostate cancer were analyzed during a minimal 10-year follow-up period. All patients were treated with curative intent to a mean dose of 65 Gy. The full history of any metastatic disease was documented for each subject, including the initial site of involvement, any progression over time, and patient survival.The overall survival rate for the 369 patients was 75% at 5 years and 45% at 10 years. The overall survival rate of patients who never developed metastases was 90% and 81% at 5 and 10 years, respectively. However, among the 74 patients (20%) who developed metastases, the survival rate at both 5 and 10 years was significantly reduced (p0.0001). The overall survival rate for patients who developed bone metastases was 58% and 27% at 5 and 10 years, respectively, and patients with bone metastases to the pelvis fared worse compared with those with vertebral metastases. With regard to the metastatic number, patients withor =5 metastatic lesions had superior survival rates relative to those with5 lesions (73% and 36% at 5 and 10 years vs. 45% and 18% at 5 and 10 years, respectively; p = 0.02). In addition, both the metastasis-free survival rate and the interval measured from the date of the initial diagnosis of prostate cancer to the development of bone metastasis were statistically superior for patients withor =5 lesions compared with patients with5 lesions (p = 0.01 and 0.02, respectively). However, the survival rate and the interval from the date of diagnosis of bone metastasis to the time of death for patients in both groups were not significantly different, statistically (p = 0.17 and 0.27, respectively).Patients withor =5 metastatic sites had significantly better survival rates than patients with5 lesions. Because existing sites of metastatic disease may be the primary sites of origin for additional metastases, our findings suggest that early detection and aggressive treatment of patients with a small number of metastatic lesions is worth testing as an approach to improving long-term survival.

Many men with newly diagnosed prostate cancer choose not to undergo curative treatment, including patients who cannot be helped by local curative therapies (especially those with metastatic disease) and patients with clinically localized disease who opt for expectant management or noncurative treatments such as androgen ablation. This article reviews the selection of patients for these noncurative approaches, strategies for clinical monitoring, the choices of intervention therapies upon progression, and when to start these therapies.

The history of the use of hormonal therapy to treat prostrate cancer is outlined, focusing on such treatments and disease scenarios as diethylstilboestrol therapy, androgen ablation alone or in conjunction with radiation, and the treatment of minimal disease burdens. Studies have pointed to the benefits of initiating androgen ablation therapy earlier in the treatment of prostate cancer; the greatest benefits of anti-androgen therapy may be gained when only tiny amounts of prostate cancer are present.

Objectives. Bladder hyperpermeability should result in elevated blood levels of intravesically administered agents. Reabsorption from a hyperpermeable bladder should result in prolonged urinary excretion of an agent after parenteral administration. To test these hypotheses, urinary clearance and plasma levels of sodium fluorescein (NaF) were measured in mice before and during cyclophosphamide (CYP) and protamine-induced hemorrhagic cystitis. Methods. To measure the plasma uptake of NaF from the bladder, 10 mg/mL NaF was instilled, either by catheter or retrograde urethral infusion, 15 minutes before retro-orbital or ventricular sampling. The plasma levels were measured 24 hours and 14 days after exposure to CYP 300 mg/kg or 15 minutes after instillation of protamine 10 mg/mL. Hourly urine concentrations were measured immediately after intraperitoneal administration of 10 mg/kg NaF. Pretreatment samples were compared with those obtained 24 hours after intraperitoneal administration of 300 mg/kg CYP. Results. Urinary NaF excretion was delayed in CYP-exposed mice. A bi-exponential model provided an appropriate fit of the data, both before and after CYP administration. The plasma levels of NaF were significantly elevated at 24 hours and 14 days after CYP exposure when sampled by ventricular nick or retro-orbitally. The median concentration of fluorescein in the protamine-treated mice was significantly higher than in the control mice. Conclusions. Fluorescein can be used to measure alterations in bladder permeability after bladder mucosal injury in mice. Urinary excretion of NaF is a bi-exponential process that is delayed after bladder mucosal injury, presumably because of increased mucosal permeability and resorption from the urine into the bloodstream.

Objectives: An intergroup study (SWOG 8795) comparing two forms of adjunctive therapy (immuno and chemo), bacillus Calmette–Guerin (BCG) and mitomycin C (MMC), furnished preregistrat

Purpose: To develop a computer-intelligent planning engine for automated treatment planning and optimization of ultrasound- and template-guided prostate seed implants. Methods and Materials: The genetic algorithm was modified to reflect the 2D nature of the implantation template. A multi-objective decision scheme was used to rank competing solutions, taking into account dose uniformity and conformity to the planning target volume (PTV), dose-sparing of the urethra and the rectum, and the sensitivity of the resulting dosimetry to seed misplacement. Optimized treatment plans were evaluated using selected dosimetric quantifiers, dose–volume histogram (DVH), and sensitivity analysis based on simulated seed placement errors. These dosimetric planning components were integrated into the Prostate Implant Planning Engine for Radiotherapy (PIPER). Results: PIPER has been used to produce a variety of plans for prostate seed implants. In general, maximization of the minimum peripheral dose (mPD) for given implanted total source strength tended to produce peripherally weighted seed patterns. Minimization of the urethral dose further reduced the loading in the central region of the PTV. Isodose conformity to the PTV was achieved when the set of objectives did not reflect seed positioning uncertainties; the corresponding optimal plan generally required fewer seeds and higher source strength per seed compared to the manual planning experience. When seed placement uncertainties were introduced into the set of treatment planning objectives, the optimal plan tended to reach a compromise between the preplanned outcome and the likelihood of retaining the preferred outcome after implantation. The reduction in the volatility of such seed configurations optimized under uncertainty was verified by sensitivity studies. Conclusion: An automated treatment planning engine incorporating real-time sensitivity analysis was found to be a useful tool in dosimetric planning for prostate brachytherapy.

Objectives: To determine the sensitivity and specificity of combining fluorescence in situ hybridization (FISH) measurement of chromosome 9 and DNA cytometry of bladder irrigation specimens in the detection of bladder cancer. Methods: Bladder irrigation specimens were obtained from 37 normal control patients and 317 bladder cancer patients during cystoscopic examinations. Bladder cancer patients were sampled in the absence of observable tumor (256 specimens) and concurrently with tumor (204 specimens). Chromosome 9 copy number was determined on a cellular basis by FISH, and cellular DNA content was determined by Feulgen DNA staining and image cytometry. Results: Sensitivity of chromosome 9 FISH was 42% for all tumors and was not correlated to transitional cell carcinoma tumor grade, while the sensitivity of DNA cytometry was 55% and improved with increasing grade from 38% for grade 1 to 90% for grade 3 tumors. The results of FISH and DNA cytometry were combined, resulting in specificity of 92% and sensitivity of 69% for grade 1, 76% for grade 2, and 97% for grade 3 tumors. Conclusions: The lack of increase with grade in the percentage of positive specimens by FISH supports the hypothesis that chromosome 9 aberrations are critical events in bladder tumorigenesis for many patients. These data demonstrate the presence of cells in irrigation specimens with specific genomic lesions of chromosome 9 and DNA content. Combining FISH on chromosome 9 and DNA cytometry provides an increase in sensitivity to transitional cell carcinoma over either test alone.

To determine if specific symptoms or physical findings were associated with findings on cystoscopic examination under anesthesia in patients participating in the Interstitial Cystitis Data Base (ICDB) Study.Subjects entering the ICDB Study completed symptom questionnaires and underwent physical examinations. Additionally, at the discretion of study investigators, 150 women underwent cystoscopy under anesthesia following a specific protocol of bladder distension at 70 to 80 cm irrigating fluid height and reinspection after capacity was reached and the irrigant drained.Statistically significant (p0.01) associations between bodily pain and urinary urgency with the presence of a Hunner's patch, and urinary frequency and urgency with a reduced bladder capacity under anesthesia were seen. Neither the findings of bloody irrigating fluid nor glomerulations were strongly associated with any symptom, and except for an association of urethral tenderness with Hunner's patch, no physical examination finding was associated with any cystoscopic findings.The strong associations of Hunner's patch and reduced bladder capacity under anesthesia with severe pain and urinary urgency, and urgency and frequency, respectively, indicate not only the importance of these findings in diagnosing interstitial cystitis, but also their potential utility in subclassifying this disease.

While 80% of transitional cell carcinomas (TCC) present as Ta Tl lesions, they account for only 15% of deaths caused by TCC. We have evaluated the ability of DNA ploidy analysis to predict outcome in 228 patients with Ta Tl TCC. All patients were judged to be at increased risk for tumor recurrence due to having two occurrences of Stage TI tumor within 56 weeks, or three or more tumors presenting simultaneously within 16 weeks of registration. Concurrent carcinoma in situ was acceptable. All patients were treated with either bacillus Calmette Guerin (BCG) immunotherapy or mitomycin-C (MMC) intravesical chemotherapy. Patients with nondiploid tumors had higher hazard rates for both tumor progression and death (p = 0.007 and p = 0.016, respectively); however, the prognostic information of DNA ploidy was not additive to tumor grade.

Merkel cell carcinoma of the genitalia is very rare and to date has been found only in vulvar mucosa. We describe an aggressive Merkel cell tumor in the frenulum of the penis with lymph node metastases, local recurrence, and eventually widespread dissemination. The primary tumor was associated with discontiguous squamous cell carcinoma in situ. This is the first report of Merkel cell (neuroendocrine) carcinoma in this anatomic site.