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Purpose of Review: The prevalence of obesity has risen dramatically in the general population and among cancer survivors in the last three decades. In this review, we highlight the impact of obesity on carcinogenesis and survival with a focus on bladder cancer and renal cell carcinoma (RCC)., Recent Findings: Obesity presents an established risk factor for an up to 1.8-fold relative risk of RCC. Data with regard to bladder cancer are less abundant but support this association as well. Possible biological mechanisms involved are the insulin/insulin-like growth factor pathway, sex steroids, adipokines and chronic inflammation as well as treatment disparities within normal weight versus obese patients. With regard to survival, no conclusion can be drawn in either tumor entity at this time because of contradictory findings. These can in part be attributed to methodological limitations, while at the same time data exist to support the notion that obese patients exhibit less aggressive tumors., Summary: Obesity drives cancer risk in RCC and potentially bladder cancer. Evidence regarding survival has been contradictory and therefore no clear-cut recommendation can be made regarding weight management in cancer survivors despite to maintain a healthy lifestyle. However, given the future cancer burden that obesity will constitute, physicians should encourage weight loss and help prevent weight gain in the general population.

Purpose: Radical cystectomy and urinary diversion may cause chronic metabolic acidosis, leading to long-term bone loss in patients with bladder cancer. However, the risk of fractures after radical cystectomy has not been defined. We assessed whether radical cystectomy and intestinal urinary diversion are associated with increased risk of fracture., Patients and Methods: Population-based study using SEER-Medicare-linked data from 2000 through 2007 for patients with stage 0-III bladder cancer. We evaluated the association between radical cystectomy and risk of fracture at any site, controlling for patient and disease characteristics., Results: The cohort included 50,520 patients, of whom 4,878 had cystectomy and urinary diversion. The incidence of fracture in the cystectomy group was 6.55 fractures per 100 person-years, compared with 6.39 fractures per 100 person-years in those without cystectomy. Cystectomy was associated with a 21% greater risk of fracture (adjusted hazard ratio, 1.21; 95% CI, 1.10 to 1.32) compared with no cystectomy, controlling for patient and disease characteristics. There was no evidence of an interaction between radical cystectomy and age, sex, comorbidity score, or cancer stage., Conclusion: Patients with bladder cancer who have radical cystectomy and urinary diversion are at increased risk of fracture., (© 2014 by American Society of Clinical Oncology.)

Objectives: Surveillance after radical cystectomy is recommended to detect tumor recurrence and treatment complications. We evaluated adherence to National Comprehensive Cancer Network (NCCN) guidelines using a large population-based database., Methods and Materials: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify patients aged ≥66 years diagnosed with nonmetastatic bladder cancer who had undergone radical cystectomy between 2000 and 2007. Medicare claims information identified recommended surveillance tests for 2 years after cystectomy as outlined in the NCCN guidelines. Adherence was defined as receipt of urine cytology and imaging of the chest, abdomen, and pelvis in each year. We evaluated the effect of patient and provider characteristics on adherence, controlling for demographic and disease characteristics., Results: Of 3,757 patients who had undergone radical cystectomy, 2,990 (80%) were alive after 2 years. Adherence to all recommended investigations was 17% for the first and the second years following surgery. Among patients surviving 2 years, only 9% had complete surveillance in both years. In either year, adherence was less likely in patients with advanced pathologic stage (III/IV) (adjusted odds ratio [AOR] = 0.74, 95% CI: 0.60-0.91) and unmarried patients (AOR = 0.82, 95% CI: 0.68-0.99). Adherence was more likely in patients treated by high-volume surgeons (AOR = 2.00, 95% CI: 1.70-2.36) and those who saw a medical oncologist (AOR = 1.52, 95% CI: 1.27-1.82). We also observed significant geographic variability in adherence., Conclusion: Patterns of surveillance after radical cystectomy deviate considerably from NCCN recommendations. Despite increased utilization of radiographic imaging investigations, the omission of urine cytology significantly contributed to the low rate of overall adherence to surveillance guidelines. Uniform adherence to surveillance guidelines was observed in patients treated by high-volume surgeons. This suggests an important opportunity for quality improvement in bladder cancer care., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Context: Despite the effectiveness of bacillus Calmette-Guérin (BCG) therapy in non-muscle-invasive bladder cancer (NIMBC) to delay recurrence and disease progression, the evidence supporting maintenance treatment and its optimal duration is unkown., Objective: The purposes of this paper are to critically review the evidence supporting the use of maintenance BCG after an initial series of induction instillations and to illustrate the factors contributing to current dilemmas in establishing the optimal duration of BCG treatment., Evidence Acquisition: The following terms were used in Medline database searches for original articles published before February 1, 2013: bladder cancer, urothelial cancer, bacillus Calmette-Guérin, maintenance, and induction. All randomized controlled trials and meta-analyses, including those based on indirect comparisons, were evaluated., Evidence Synthesis: Seven randomized studies compared induction BCG plus maintenance to induction alone, with or without retreatment with BCG on recurrence. All but one of these studies were underpowered and the largest study used a broad, composite end point: worsening-free survival. Seven meta-analyses have been conducted, three of which included data from observational cohort studies. They demonstrated the benefit of maintenance BCG to reduce disease recurrence and delay progression compared to various control groups; however, the analyses were based on suboptimal data. Although there is new evidence that 1 yr of maintenance BCG is sufficient treatment in intermediate-risk patients, the optimal duration of BCG maintenance remains unknown. A new randomized trial is proposed, which includes induction BCG with retreatment on recurrence as a control arm, to study this question., Conclusions: The optimal duration of BCG treatment in patients with NMIBC remains unknown and should be the subject of further studies. We recommend that in addition to 3 yr of maintenance BCG, guideline panels also include 1 yr of therapy and induction BCG with retreatment on recurrence as a possible treatment options for patients with NMIBC, albeit with a lower level of evidence and grade of recommendation., (Copyright © 2013. Published by Elsevier B.V.)

Background: Cigarette smoking is the best-established risk factor for urothelial carcinoma development., Objective: To elucidate the association of pretreatment smoking status, cumulative exposure, and time since smoking cessation on outcomes of patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC)., Design, Setting, and Participants: We retrospectively collected clinicopathologic and smoking variables, including smoking status, number of cigarettes per day (CPD), duration in years, and time since smoking cessation, for 1506 patients treated with RC for UCB. Lifetime cumulative smoking exposure was categorized as light short-term (≤20 CPD for ≤20 yr), light long-term (≤20 CPD for >20 yr), heavy short-term (>20 CPD for ≤20 yr), and heavy long-term (>20 CPD for >20 yr)., Intervention: RC and bilateral lymph node (LN) dissection without neoadjuvant chemotherapy., Outcome Measurements and Statistical Analysis: Logistic regression and competing risk analyses assessed the association of smoking with disease recurrence, cancer-specific mortality, and overall mortality., Results and Limitations: There was no difference in clinicopathologic factors between patients who had never smoked (20%), former smokers (46%), and current smokers (34%). Smoking status was associated with the cumulative incidence of disease recurrence (p=0.004) and cancer-specific mortality (p=0.016) in univariable analyses and with disease recurrence in multivariable analysis (p=0.02); current smokers had the highest cumulative incidences. Among ever smokers, cumulative smoking exposure was associated with advanced tumor stages (p<0.001), LN metastasis (p=0.002), disease recurrence (p<0.001), cancer-specific mortality (p=0.001), and overall mortality (p=0.037) in multivariable analyses that adjusted for standard characteristics; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short-term smokers. Smoking cessation ≥10 yr mitigated the risk of disease recurrence (hazard ratio [HR]: 0.44; p<0.001), cancer-specific mortality (HR: 0.42; p<0.001), and overall mortality (HR: 0.69; p=0.012) in multivariable analyses. The study is limited by its retrospective nature., Conclusions: Smoking is associated with worse prognosis after RC for UCB. This association seems to be dose-dependent, and its effects are mitigated by >10 yr smoking cessation. Health care practitioners should counsel smokers regarding the detrimental effects of smoking and the benefits of smoking cessation on UCB etiology and prognosis., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi-institutional series., Patients and Methods: Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded. Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer-specific mortality and overall mortality. BMI was analysed as a continuous and categorical variable (<25 vs 25-29 vs ≥30 kg/m(2))., Results: Median BMI was 28.8 kg/m(2) (interquartile range 7.9); 25.3% had a BMI <25 kg/m(2), 32.5% had a BMI between 25 and 29.9 kg/m(2), and 42.2% had a BMI ≥30 kg/m(2). Patients with a higher BMI were older (P < 0.001), had higher tumour grade (P < 0.001), and were more likely to have positive soft tissue surgical margins (P = 0.006) compared with patients with lower BMI. In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI >30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.46-1.91, P < 0.001), cancer-specific mortality (HR 1.43, 95% CI 1.24-1.66, P < 0.001), and overall mortality (HR 1.81, CI 1.60-2.05, P < 0.001). Themain limitation is the retrospective design of the study., Conclusions: Obesity is associated with worse cancer-specific outcomes in patients treated with RC for UCB. Focusing on patient-modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB., (© 2012 BJU International.)

Background: Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the standard of care for high-risk non-muscle-invasive and muscle-invasive bladder cancer (BCa)., Objective: To develop a model that allows quantification of the likelihood that a pathologically node-negative patient has, indeed, no positive nodes., Design, Setting, and Participants: We analyzed data from 4335 patients treated with RC and PLND without neoadjuvant chemotherapy at 12 international academic centers., Interventions: Patients underwent RC and PLND., Outcome Measurements and Statistical Analysis: We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a pathologic (postoperative) nodal staging score (pNSS) that represents the probability that a patient is correctly staged as node negative as a function of the number of examined nodes., Results and Limitations: Overall, the probability of missing a positive node decreases with the increasing number of nodes examined (52% if 3 nodes are examined, 40% if 5 are examined, and 26% if 10 are examined). The proportion of having a positive node increased proportionally with advancing pathologic T stage and lymphovascular invasion (LVI). Patients with LVI who had 25 examined nodes would have a pNSS of 80% (pT1), 88% (pT2), and 66% (pT3-T4), whereas 10 examined nodes were sufficient for pNSS exceeding 90% in patients without LVI and pT0-T2 tumors. This study is limited because of its retrospective design and multicenter nature., Conclusions: We developed a tool that estimates the likelihood of lymph node (LN) metastasis in BCa patients treated with RC by evaluating the number of examined nodes, the pathologic T stage, and LVI. The pNSS indicates the adequacy of nodal staging in LN-negative patients. This tool could help to refine clinical decision making regarding adjuvant chemotherapy, follow-up scheduling, and inclusion in clinical trials., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Dissimilarities in management and outcomes exist between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB)., Objective: The aim of this study was to analyze the stage-specific impact of upper or lower urinary tract tumor location on oncologic outcomes., Design, Setting, and Participants: Data were collected from 4335 patients with UCB treated with radical cystectomy (RC) and bilateral pelvic lymphadenectomy (PLND), 877 patients with ureteral UTUC, and 1615 with pelvicalyceal UTUC treated with radical nephroureterectomy (RNU). No patient received preoperative chemotherapy or radiation therapy., Interventions: Patients were treated with RC and bilateral PLND or RNU., Measurements: Outcomes were assessed according to primary tumor location., Results and Limitations: Compared to UTUC patients, UCB patients had more advanced tumor stage and higher grade, and they were more likely to harbor lymphovascular invasion (LVI) and lymph node metastasis (p<0.001). In non-muscle-invasive tumor stages, UCB patients were more likely to experience disease recurrence and mortality compared to renal pelvicalyceal tumor patients (p<0.002) but not ureteral tumors (p>0.05). In pT2 and pT3 tumors, there was no difference in outcomes between the three tumor locations. In pT4 tumors, patients with ureteral and pelvicalyceal tumors were more likely to experience disease recurrence and mortality compared to UCB patients (p<0.004). These stage-specific findings were unchanged after adjustment for the effects of age, gender, tumor grade, LVI, lymph node status, and adjuvant chemotherapy. This study is limited by its retrospective and multicenter nature., Conclusions: Stage-specific differences in outcomes exist between UCB and UTUC. The differentially worse outcomes by stage between UCB and UTUC patients underline the differences between both cancer entities and the need for individualized stage-specific management for each patient., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The extent of lymphadenectomy needed to optimize oncologic outcomes after radical cystectomy (RC) for patients with regionally advanced bladder cancer (BCa) is unclear., Objective: Evaluate the effect of the location of lymph node metastasis on recurrence-free survival (RFS) and cancer-specific survival (CSS) for patients undergoing RC with a mapping pelvic lymph node dissection (PLND)., Design, Setting, and Participants: A study of 591 patients undergoing RC with mapping PLND was completed between 2000 and 2010. Median follow-up was 30 mo., Intervention: RC with mapping PLND., Measurements: We evaluated the impact of lymph node involvement by location on disease outcomes using the 2010 TNM staging system. Survival estimates were described using Kaplan-Meier methods. Gender, age, pathologic stage, histology, number of positive nodes, location of positive nodes, node density, use of perioperative chemotherapy, and grade were evaluated as predictors of RFS and CSS using multivariate Cox proportional hazard regression., Results and Limitations: Overall, 114 patients (19%) had lymph node involvement, and 42 patients (7%) had pN3 disease. On multivariate analysis, the number of positive lymph nodes (one or two or more) was significantly associated with increased risk of cancer-specific death (hazard ratio [HR]: 1.9 [95% confidence interval (CI), 1.04-3.46], p=0.036; versus HR: 4.3 [95% CI, 2.25-8.34], p<0.0005). Positive lymph node location was not an independent predictor of RFS or CSS. Five-year RFS for pN3 patients undergoing RC with PLND was 25% (95% CI, 10-42). This finding was not statistically different from our pN1 and pN2 patients (38% [95% CI, 22-54] and 35% [95% CI, 11-60], respectively). This study is limited by the lack of prospective randomization and a control group., Conclusions: The outcome for patients with involved common iliac lymph nodes was similar to the outcome for patients with primary nodal basin disease. These data support inclusion of the common iliac lymph nodes (pN3) in the nodal staging system for BCa. Lymph node location was not an independent predictor of outcome, whereas the number of positive lymph nodes was an independent predictor of worse oncologic outcome (pN1, pN2). Further refinements of the TNM system to provide improved prognostication are warranted., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Radical cystectomy (RC) with pelvic lymph node dissection (LND) is the standard of care for refractory non-muscle-invasive and muscle-invasive bladder cancer. Although consensus exists on the need for LND, its extent is still debated., Objective: To develop a model that allows preoperative determination of the minimum number of lymph nodes (LNs) needed to be removed at RC to ensure true nodal status., Design, Setting, and Participants: We analyzed data from 4335 patients treated with RC and pelvic LND without neoadjuvant chemotherapy at 12 academic centers located in the United States, Canada, and Europe., Measurements: We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed clinical (preoperative) nodal staging scores (cNSS), which represent the probability that a patient has LN metastasis as a function of the number of examined nodes., Results and Limitations: The probability of missing a positive LN decreased with an increasing number of nodes examined (52% if 3 nodes were examined, 40% if 5 were examined, and 26% if 10 were examined). A cNSS of 90% was achieved by examining 6 nodes for clinical Ta-Tis tumors, 9 nodes for cT1 tumors, and 25 nodes for cT2 tumors. In contrast, examination of 25 nodes provided only 77% cNSS for cT3-T4 tumors. The study is limited due to its retrospective design, its multicenter nature, and a lack of preoperative staging parameters., Conclusions: Every patient treated with RC for bladder cancer needs an LND to ensure accurate nodal staging. The minimum number of examined LNs for adequate staging depends preoperatively on the clinical T stage. Predictive tools can give a preoperative estimation of the likelihood of nodal metastasis and thereby allow tailored decision-making regarding the extent of LND at RC., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: We compared clinical outcomes, and identified predictors of cancer specific and overall survival after radical cystectomy in patients with urothelial carcinoma with squamous differentiation and those with pure squamous cell carcinoma., Materials and Methods: We reviewed data on 2,031 patients treated with radical cystectomy and pelvic lymph node dissection at a single high volume referral center. Of these patients 78 had squamous cell carcinoma and 67 had squamous differentiation. Survival estimates by histological subtype were described using Kaplan-Meier methods. Within histological subtypes pathological stage, nodal invasion, soft tissue margins, age and gender were evaluated as predictors of cancer specific survival and overall survival using univariate Cox regression., Results: Median followup was 44 months. Of 104 patient deaths 60 died of their disease. We did not find a statistically significant difference between survival curves of patients with squamous cell carcinoma and squamous differentiation (log rank overall survival p = 0.6, cancer specific survival p = 0.17). Positive soft tissue margins were associated with worse cancer specific survival (HR 6.92, 95% CI 2.98-16.10, p ≤0.0005) and overall survival (HR 3.68, 95% CI 1.84-7.35, p ≤0.0005) in patients with pure squamous cell carcinoma. Among patients with squamous differentiation, pelvic lymphadenopathy was associated with decreased overall survival (HR 2.52, 95% CI 1.33-4.77, p = 0.004) and cancer specific survival (HR 3.23, 95% CI 1.57-6.67, p = 0.002)., Conclusions: There appears to be no evidence of a difference in cancer specific survival or overall survival between patients with squamous cell carcinoma and those with squamous differentiation treated with radical cystectomy and pelvic lymph node dissection. Patients with squamous differentiation and tumor metastases to pelvic lymph nodes should be followed more closely, and adjuvant treatment should be considered to improve survival. Wide surgical resection is critical to achieve local tumor control and improve survival in patients with squamous cell carcinoma., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Renal transplant recipients have an increased incidence of bladder cancer. It is unknown whether these cancers are more aggressive than those in nontransplanted cases and whether this is also true for cases with end stage renal disease without renal transplantation., Materials and Methods: Surveillance, Epidemiology and End Results-Medicare data identified 97,942 patients with bladder cancer diagnosed between 1988 and 2002. We compared gender, race, tumor stage and histology at diagnosis among patients with a renal transplant, end stage renal disease or neither condition. The statistical significance of differences in the distribution of patient and tumor variables was assessed using the chi-square statistic (categorical variables) and single factor ANOVA tests of difference in means (continuous variables)., Results: Renal transplant recipients (58) were younger at diagnosis than those with end stage renal disease (400) or with neither diagnosis (97,484) (p <0.0001). Muscle invasive disease (stage T2 or greater) at presentation was more common in renal transplant recipients (37%, p = 0.04) and patients with end stage renal disease (33%, p = 0.0001) than in patients without these conditions (24%). Most renal transplant recipients were diagnosed with bladder cancer within 4 years of transplantation. Patients with a renal transplant (17%, p = 0.001) and end stage renal disease (12%, p <0.0001) also had a higher proportion of nonurothelial tumors than the remaining population (6.5%)., Conclusions: Renal transplant recipients and patients with end stage renal disease present with higher stage bladder cancer than those without these conditions despite closer medical supervision. Since most renal transplant recipients were diagnosed with bladder cancer within 4 years of undergoing renal transplantation, consideration should be given to bladder cancer screening of such patients in this period.

Molecular markers have potential as both diagnostics and predictors of progression and patient outcome in urothelial cancer. Advancements in technology have provided an understanding of the molecular mechanisms of carcinogenesis and defined distinct pathways in tumorigenesis and progression. Herein we present a select overview of the molecular underpinning of urothelial carcinogenesis and progression, and discuss the potential for some of the proteins involved in these processes to serve as biomarkers for evaluation of progression risk. Eventual refinement of prognostic methods with the addition of the latter markers will enable clinicians to provide an individualized therapeutic approach for each patient, and discover targets for novel therapeutic agents to disrupt the deregulation underlying the development and progression of urothelial carcinogenesis.