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Purpose: Alternative, noninvasive, cost-effective methods to complement or serve as substitutes to current standard-of-care (SOC) procedures in NMIBC follow-up are needed. Uromonitor is a urine biomarker test detecting bladder cancer recurrence through the screening of TERT , FGFR3 , and KRAS hotspot mutations. The aim of this study was to assess Uromonitor performance by comparing it with the current SOC methods., Materials and Methods: Four hundred thirty-nine patients with 528 NMIBC surveillances were enrolled in this study. All patients underwent SOC methods and provided a urine sample for Uromonitor analysis before undergoing cystoscopy. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for recurrence and compared with the gold-standard cystoscopy plus transurethral resection of bladder tumor histopathology., Results: Uromonitor displayed a sensitivity of 87% (95% CI, 74-95), with only 6 of 47 recurrences failing to be detected; specificity of 99% (98-100); PPV of 93% (82-98); and a NPV of 99% (97-99). Cystoscopy showed a total of 22 false positives (32%) not confirmed by transurethral resection of bladder tumor, whereas Uromonitor presented only 3 positive tests where no lesions were found. Overall recurrence rate was 8.9% (n = 47) among 528 total screenings. Sensitivity, specificity, PPV, and NPV values for Uromonitor remained high across all NMIBC grades and stages., Conclusions: Uromonitor represents a reliable tool in the detection of NMIBC recurrence in patients undergoing routine surveillance, regardless of stage and grade. To our knowledge, this is the largest single-center study assessing Uromonitor's performance, thus validating its usefulness in clinical practice.

Purpose: We determined whether restaging resection before initiating induction intravesical bacillus Calmette-Guérin improves the recurrence-free rate in patients with high risk nonmuscle invasive bladder cancer., Materials and Methods: We retrospectively analyzed data on 1,021 patients treated at our institution with intravesical bacillus Calmette-Guérin for nonmuscle invasive high risk bladder cancer. All patients underwent a second resection except those already receiving bacillus Calmette-Guérin at the time of initial consultation and those who refused restaging resection. All patients were assessed every 3 to 12 months for a minimum of 5 years. Univariate and multivariate regression was used to identify predictors of 5-year recurrence., Results: Restaging transurethral resection was performed in 894 patients (87.5%). At restaging resection viable tumor was found in 496 patients (55.5%). At 3 months patients with a single resection had a 44.3% recurrence rate compared to 9.6% in those with restaging resection (p <0.01). On multivariate analysis a single transurethral resection was the only predictor of recurrence at 5 years (OR 2.1, 95% CI 1.3-3.3, p = 0.01). Time to recurrence in patients with a single resection was significantly shorter than in those with restaging resection (median 22 vs 36 months, p <0.001)., Conclusions: Failure to repeat resection before initiating intravesical bacillus Calmette-Guérin therapy for high risk nonmuscle invasive bladder cancer significantly increases the risk of recurrence. Therefore, we believe that restaging resection should be performed before initiating bacillus Calmette-Guérin therapy in all patients with high risk nonmuscle invasive bladder cancer., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: KLF4 is a transcription factor with divergent functions in different malignancies. We analyzed KLF4 expression and DNA methylation, and their clinical relevance and biological function in urothelial cancer., Materials and Methods: Immunohistochemistry and Sequenom™ MassARRAY® were done to detect the expression and promoter methylation of KLF4 in urothelial cancer tissues. The association of the recurrence-free survival rate and decreased KLF4 or KLF4 methylation status was analyzed by the Kaplan-Meier method, Cox regression analysis and ROC assay. Lentivirus based KLF4 over expression and dsRNA mediated knockdown were used to detect KLF4 functions in urothelial cancer in vitro and in vivo., Results: KLF4 was down-regulated in urothelial cancer due to promoter hypermethylation. Each correlated with recurrence-free survival in patients with nonmuscle invasive bladder cancer after transurethral resection of bladder cancer, which potentiates them as valuable predictive biomarkers for early recurrence. Moreover, in and ex vivo experiments showed that KLF4 suppressed urothelial cancer cell growth, migration and invasion inhibited the epithelial-to-mesenchymal transition., Conclusions: KLF4 may function as a tumor suppressor gene in urothelial cancer since down-regulation of KLF4 by promoter hypermethylation would promote cancer progression. In addition, decreased expression of KLF4 or its promoter hypermethylation may have predictive value for early recurrence in patients with nonmuscle invasive bladder cancer., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We estimate the annual incidence of bladder cancer in Spain and describe the clinical profile of patients with bladder cancer enrolled in a population based study., Materials and Methods: Using the structure of the Spanish National Health System as a basis, in 2011 the AEU (Spanish Association of Urology) conducted this study with a representative sample from 26 public hospitals and a reference population of 10,146,534 inhabitants, comprising 21.5% of the Spanish population., Results: A total of 4,285 episodes of bladder cancer were diagnosed, of which 2,476 (57.8%) were new cases and 1,809 (42.2%) were cases of recurrence, representing an estimated 11,539 new diagnoses annually in Spain. The incidence of bladder cancer in Spain, age adjusted to the standard European population, was 20.08 cases per 100,000 inhabitants (95% CI 13.9, 26.3). Of patients diagnosed with a first episode of bladder cancer 84.3% were male, generally older than 59 years (81.7%) with a mean ± SD age of 70.5 ± 11.4 years. Of these patients 87.5% presented with some type of clinical symptom, with macroscopic hematuria (90.8%) being the most commonly detected. The majority of primary tumors were nonmuscle invasive (76.7%) but included a high proportion of high grade tumors (43.7%). According to the ISUP (International Society of Urologic Pathology)/WHO (2004) classification 51.1% was papillary high grade carcinoma. Carcinoma in situ was found in 2.2% of primary and 5.8% of recurrent cases., Conclusions: The incidence of bladder cancer in Spain, age adjusted to the standard European population, confirms that Spain has one of the highest incidences in Europe. Most primary nonmuscle invasive bladder cancer corresponded to high risk patients but with a low detected incidence of carcinoma in situ., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We validated the performance of our previously reported test for bladder cancer based on urine gene expression patterns using an independent cohort. We also ascertained whether alternative models could achieve better accuracy., Materials and Methods: Gene expression patterns of the previously reported 48 genes, including the 12 + 2 genes of the signature, were analyzed by TaqMan® arrays in an independent set of 207 urine samples. We pooled all samples analyzed to date to obtain a larger training set of 404 and used it to search for putative improved new models., Results: Our 12 + 2 gene expression signature had overall 80% sensitivity with 86% specificity (AUC 0.914) to discriminate between bladder cancer and control samples. It had 75% sensitivity and 75% specificity (AUC 0.83) to predict tumor aggressiveness in the validation set of urine samples. After grouping all samples 3 new signatures for diagnosis containing 2, 5 and 10 genes, respectively, and 1 containing 6 genes for prognosis were designed. Diagnostic performance of the 2, 5, 10 and 12-gene signatures was maintained or improved in the enlarged sample set (AUC 0.913, 0.941, 0.949 and 0.944, respectively). Performance to predict aggressiveness was also improved in the 14 and 6-gene signatures (AUC 0.855 and 0.906, respectively)., Conclusions: This validation study confirms the accuracy of the 12 + 2 gene signature as a noninvasive tool for assessing bladder cancer. We present improved models with fewer genes that must be validated in future studies., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Despite being one of the most important clinical outcomes in nonmuscle invasive bladder cancer, there is currently no standard definition of disease progression. Major clinical trials and meta-analyses have used varying definitions or have failed to define this end point altogether. A standard definition of nonmuscle invasive bladder cancer progression as determined by reproducible and reliable procedures is needed. We examine current definitions of nonmuscle invasive bladder cancer progression, and propose a new definition that will be more clinically useful in determining patient prognosis and comparing treatment options., Materials and Methods: The IBCG (International Bladder Cancer Group) analyzed published clinical trials and meta-analyses that examined nonmuscle invasive bladder cancer progression as of December 2012. The limitations of the definitions of progression used in these trials were considered, as were additional parameters associated with the advancement of nonmuscle invasive bladder cancer., Results: The most commonly used definition of nonmuscle invasive bladder cancer progression is an increase in stage from nonmuscle invasive to muscle invasive disease. Although this definition is clinically important, it fails to include other important parameters of advancing disease such as progression to lamina propria invasion and increase in grade., Conclusions: The IBCG proposes the definition of nonmuscle invasive bladder cancer progression as an increase in T stage from CIS or Ta to T1 (lamina propria invasion), development of T2 or greater or lymph node (N+) disease or distant metastasis (M1), or an increase in grade from low to high. Investigators should consider the use of this new definition to help standardize protocols and improve the reporting of progression., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Perioperative instillation of intravesical chemotherapy after bladder tumor resection is supported by level I evidence showing a 30% decrease in tumor recurrence. However, studies of administrative data sets show poor use in practice., Materials and Methods: We prospectively evaluated the use of perioperative intravesical chemotherapy in a multipractice quality improvement collaborative. Cases were categorized as ideal for intravesical chemotherapy (1 or 2 papillary tumors, cTa/cT1 and completely resected) and nonideal. The reasons for not administering intravesical chemotherapy in ideal cases were classified as appropriate or modifiable. Before and after comparative feedback and educational interventions we calculated judicious use of intravesical chemotherapy (nonuse in nonideal cases plus use in ideal cases plus appropriate nonuse in ideal cases) and quality improvement potential (use in nonideal cases plus nonuse in ideal cases attributable to modifiable factors)., Results: We accrued a total of 2,794 cases at the 5 sites in 22 months. The rate of use in ideal cases was 38% before and 34.8% after intervention (p=0.36), while use in nonideal cases decreased from 15% to 12% (p=0.08). Overall, intravesical chemotherapy was used judiciously in 83.0% to 85.7% of cases, while the remaining 14.3% to 17.0% represented quality improvement potential., Conclusions: Judicious use of perioperative intravesical chemotherapy is relatively high in routine practice. Most instances of nonuse represent appropriate clinical judgment. Utilization did not change after quality improvement interventions, suggesting that there may a ceiling effect that makes it difficult to improve care that is high quality at baseline. Moreover, decreasing unnecessary use of an intervention may be easier than encouraging appropriate use of potentially toxic therapy., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We report our experience with intravesical gemcitabine for bladder cancer after failed bacillus Calmette-Guérin treatment., Materials and Methods: We retrospectively reviewed the records of patients at our cancer center treated with intravesical gemcitabine after bacillus Calmette-Guérin failure. We estimated progression-free, recurrence-free and cancer specific survival using the cumulative incidence function, considering death from another cause as a competing risk. Comparisons were made using the Gray test. Overall survival was estimated using the Kaplan-Meier method and differences were compared with the log rank test., Results: Of 69 patients treated with intravesical gemcitabine 37 had bacillus Calmette-Guérin refractory disease. Median followup in progression-free patients was 3.3 years. Progression-free and cancer specific survival were similar in patients with refractory disease and those with other types of bacillus Calmette-Guérin failure. Overall survival was lower in patients with refractory disease (58% vs 71%) but this was not statistically significant (p=0.096). Of the patients 27 patients experienced a complete response. Progression-free, cancer specific and overall survival did not differ significantly between patients with and without a complete response. Cystectomy was subsequently performed in 20 patients. Those with a complete response had a delayed time to cystectomy and no muscle invasive bladder cancer at cystectomy. There were no serious adverse events and only a minority of patients discontinued treatment due to adverse events., Conclusions: In our experience intravesical gemcitabine should be considered after bacillus Calmette-Guérin failure in patients with bladder cancer who refuse radical cystectomy or who are not candidates for major surgery., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the effectiveness of photodynamic therapy using Radachlorin in patients with high grade, nonmuscle invasive bladder cancer refractory or intolerant to bacillus Calmette-Guérin therapy who refused radical cystectomy., Materials and Methods: Between July 2009 and December 2011 photodynamic therapy was performed in 22 men and 12 women. Radachlorin (0.5 to 0.6 mg/kg) was injected intravenously 2 to 3 hours before photodynamic therapy. After complete transurethral resection, a diffuser using a 22Fr cystoscope was placed in the bladder for irradiation with a 662 nm laser. Output beam power was adjusted to 1.8 W and the light dose was 15 J/cm(2). Photodynamic therapy was performed for 16 to 30 minutes. Recurrence after photodynamic therapy was followed by regular cystoscopy at 1, 2 and 3 months, and at 3-month intervals thereafter for up to 2.8 years. Efficacy was assessed by cystoscopy, cytology and histology, and defined as the number of patients who were tumor free after initial photodynamic therapy., Results: Mean ± SD patient age was 62.94 ± 8.71 years. Average followup was 26.74 ± 6.34 months (median 28.12). As the primary efficacy outcome, the recurrence-free rate was 90.9% at 12 months, 64.4% at 24 months and 60.1% at 30 months. As the secondary efficacy outcome, there was no statistical difference in mass size, carcinoma in situ, number of previous bacillus Calmette-Guérin administrations, number of transurethral bladder resections or tumor multiplicity on Kaplan-Meier analysis (each p >0.05). No evidence of severe adverse effects was detected after photodynamic therapy., Conclusions: Photodynamic therapy with Radachlorin is a safe, effective treatment for nonmuscle invasive bladder cancer refractory or intolerant to bacillus Calmette-Guérin therapy in select patients., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the usefulness of routine upper tract imaging in patients followed for nonmuscle invasive bladder cancer., Materials and Methods: A retrospective review of patients treated for nonmuscle invasive bladder cancer between 2000 and 2006 was conducted. Kaplan-Meier curves were calculated to determine upper tract urothelial carcinoma-free probability for stage Ta and T1 disease. Bladder cancer stage was included as a time dependent covariate. Descriptive statistics were used to report rates of imaging studies used and the efficacy in diagnosing upper tract urothelial carcinoma., Results: Of 935 patients treated and followed for nonmuscle invasive bladder cancer 51 were diagnosed with upper tract urothelial carcinoma. Median followup was 5.5 years. The 5-year upper tract urothelial carcinoma-free probability among patients with Ta and T1 disease was 98% and 93%, respectively. The 10-year upper tract urothelial carcinoma-free probability among patients with Ta and T1 disease was 94% and 88%, respectively. Only 15 (29%) patients were diagnosed on routine imaging while the others were diagnosed after symptoms developed. Overall 3,074 routine imaging scans were conducted for an overall efficacy of 0.49%., Conclusions: Upper tract recurrence is a lifelong risk in patients with bladder cancer, but most cases will be missed on routine upper tract imaging. The majority of upper tract urothelial carcinoma can be diagnosed using a combination of thorough history taking, physical examination, urine cytology and sonography, indicating that routine surveillance imaging may not be the most efficient way to detect upper tract recurrence., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Bacillus Calmette-Guérin and intravesical chemotherapy represent viable adjuvant options for intermediate risk nonmuscle invasive bladder cancer. Although bacillus Calmette-Guérin is perceived as less tolerable than intravesical chemotherapy, to our knowledge no comparative studies have addressed quality of life issues. We compared the quality of life of patients with nonmuscle invasive bladder cancer who received adjuvant intravesical gemcitabine or 1/3 dose bacillus Calmette-Guérin., Materials and Methods: Our multicenter, prospective, randomized, phase II study included 120 patients with intermediate risk nonmuscle invasive bladder cancer. Of these patients 88 remained assessable at 1-year followup. Only 1 patient was withdrawn because of adverse events. Overall 61 patients received 2,000 mg/50 cc gemcitabine weekly for 6 weeks (maintenance monthly for 1 year) while 59 received 1/3 dose bacillus Calmette-Guérin Connaught weekly for 6 weeks (maintenance 3 weekly instillations at 3, 6 and 12 months). Quality of life was measured by the EORTC QLQ-C30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 version 3.0) and QLQ-BLS24 (Quality of Life Superficial Bladder Cancer-Specific 24) questionnaires. Group differences were calculated using ANOVA (ANOVA/MANOVA)., Results: Treatment was well tolerated in both groups, although local and systemic side effects were more frequently reported in the bacillus Calmette-Guérin arm. Multivariate analyses showed no significant differences between the 2 groups in all quality of life dimensions. No significant changes over time in quality of life domains were detected for patients on bacillus Calmette-Guérin and gemcitabine except for physical functioning, which decreased significantly in both groups (p = 0.002). No significant differences were detected in terms of recurrence and progression between the 2 groups at 1-year followup., Conclusions: While a higher rate of side effects, albeit mild to moderate, was detected with 1/3 dose bacillus Calmette-Guérin compared to gemcitabine, our study failed to show significant differences between the 2 drugs in terms of quality of life., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: A phase I trial of intravesical recombinant adenovirus mediated interferon-α2b gene therapy (rAd-IFNα) formulated with the excipient SCH Syn3 was conducted in patients with nonmuscle invasive bladder cancer who had disease recurrence after treatment with bacillus Calmette-Guérin. The primary objective was to determine the safety of rAd-IFNα/Syn3. Secondary end points were demonstrated effective rAd-IFNα gene expression and preliminary evidence of clinical activity at 3 months., Materials and Methods: A total of 17 patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin treatment were enrolled in the study. A single treatment of rAd-IFNα (3 × 10(9) to 3 × 10(11) particles per ml) formulated with the excipient Syn3 was administered. Patient safety was evaluated for 12 or more weeks. Efficacy of gene transfer was determined by urine IFNα protein concentrations. Preliminary drug efficacy was determined at 3 months., Results: Intravesical rAd-IFNα/Syn3 was well tolerated as no dose limiting toxicity was encountered. Urgency was the most common adverse event and all cases were grade 1 or 2. rAd-IFNα DNA was not detected in the blood. However, transient low serum IFNα and Syn3 levels were measured. High and prolonged dose related urine IFNα levels were achieved with the initial treatment. Of the 14 patients treated at doses of 10(10) or more particles per ml with detectable urine IFNα, 6 (43%) experienced a complete response at 3 months and 2 remained disease-free at 29.0 and 39.2 months, respectively., Conclusions: Intravesical rAd-IFNα/Syn3 was well tolerated with no dose limiting toxicity encountered. Dose dependent urinary IFNα concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFNα/Syn3 demonstrated clinical activity in nonmuscle invasive bladder cancer recurring after bacillus Calmette-Guérin., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To our knowledge the impact of body mass index on oncologic outcomes in nonmuscle invasive bladder cancer has not been evaluated. We hypothesized that higher body mass index is associated with worse outcomes in patients with clinical primary T1 high grade urothelial carcinoma of the bladder., Materials and Methods: We retrospectively analyzed data from 892 patients with primary nonmuscle invasive bladder cancer from 7 centers. Patients were treated with transurethral resection of the bladder with or without intravesical therapy. Body mass index was analyzed as a continuous and a categorical variable (nonobese-body mass index less than 30 kg/m(2) vs obese-body mass index 30 kg/m(2) or greater). Disease progression was defined as the development of T2 or higher tumor stage., Results: Median followup was 42.8 months (IQR 56). Of the patients 44.3% were obese and median body mass index was 29.2 kg/m(2) (IQR 8). On univariable analyses higher body mass index and age were associated with an increased risk of disease recurrence, progression, cancer specific mortality and any cause mortality (all p ≤ 0.001). On multivariable analyses that adjusted for the effects of gender, concomitant carcinoma in situ, tumor size, number of tumors and intravesical therapy, higher body mass index and age remained independent predictors of disease recurrence, progression, cancer specific mortality and any cause mortality (all p <0.05). This study was limited by its design (ie lack of data on repeat transurethral resection of the bladder and intravesical therapy protocol)., Conclusions: Patients diagnosed with clinical T1 high grade urothelial carcinoma of the bladder who are obese have worse cancer specific outcomes compared to their nonobese counterparts. Further work is needed to improve our understanding of clinical T1 high grade outcomes in the growing population of obese patients., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)