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1775 EXTERNAL VALIDATION OF EORTC AND CUETO SCORING MODELS TO PREDICT RECURRENCE AND PROGRESSION IN PATIENTS WITH NONMUSCLE INVASIVE BLADDER CANCER TREATED WITH BACILLUS CALMETTE-GUERIN
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THE JOURNAL OF UROLOGY姞
Vol. 187, No. 4S, Supplement, Tuesday, May 22, 2012
CONCLUSIONS: Intravesical instillation of THP 30 mg twice within 24 hours after TUR was effective as prophylactic therapy for non-muscle-invasive bladder cancer with tolerable toxicity problems. Source of Funding: None
1774 INTEROBSERVER AGREEMENT AND ACCURACY OF CONFOCAL LASER ENDOMICROSCOPY FOR IN VIVO DIAGNOSIS OF BLADDER CANCER Timothy Chang*, Jen-Jane Liu, Shelly Hsiao, Ying Pan, Jesse McKenney, Joseph Liao, Stanford, CA
1773 INTEROBSERVER REPRODUCIBILITY OF THE 1973 WHO AND 2004 WHO/ISUP NON-INVASIVE BLADDER CANCER CLASSIFICATIONS AMONG GENERAL AND GENITOURINARY PATHOLOGISTS Eugene W. Lee*, Fang Ming Deng, Jonathan Melamed, Savvas Mendrinos, Kasturi Das, Tsivia Hochman, Samir S. Taneja, William C. Huang, New York, NY INTRODUCTION AND OBJECTIVES: Pathological grade is the most important prognostic indicator used to risk stratify and select treatment for non-invasive urothelial carcinoma (UC). The 1973 World Health Organization (WHO) grading classification has been most widely used, but suffers from unacceptably high interobserver variability. The 2004 WHO/International Society of Urological Pathology (ISUP) revision was developed to reduce variability by providing welldefined histological criteria for each grade. We compared interobserver reproducibility between the 1973 and 2004 systems and between general versus expert genitourinary pathologists. METHODS: 1 general pathologist (GP) and 2 genitourinary pathology specialists (GU1 and GU2) were blinded to patient identity and graded 98 consecutive UC specimens retrospectively using the 1973 and 2004 classifications. Kappa statistics () were used to measure interobserver reproducibility. By convention, values from 0.21 – 0.4 represent “fair” agreement, from 0.41 - 0.6 represent “moderate” agreement, and ⬎ 0.6 represent “substantial” agreement. As an example, values for prostate cancer Gleason score among genitourinary pathologists have been reported to be ⬎ 0.6. RESULTS: Overall agreement was only fair for both systems and while higher for the 2004 system than the 1973, this was not significant (: 0.38 versus 0.26, respectively). Agreement between the two specialists versus agreement between each specialist and the generalist was higher using the 1973 system (: 0.37 vs 0.33 and 0.18) but lower using the 2004 system (: 0.31 vs 0.46 and 0.39). The generalist had better agreement with both specialists using the 2004 system versus the 1973 system (: 0.46 and 0.39 versus 0.33 and 0.18). These findings were not statistically significant. CONCLUSIONS: Reproducibility is not improved by the 2004 WHO/ISUP revision to the 1973 WHO grading system, even among expert genitourinary pathologists. Since management of non-invasive UC is primarily determined by its grade, this limits a clinician’s ability to risk stratify tumor and potentially alters treatment. Our findings underscore the need to identify molecular markers that can provide a more reliable risk stratification system.
INTRODUCTION AND OBJECTIVES: Probe-based confocal laser endomicroscopy (CLE), an emerging optical imaging technology that enables in vivo microscopy, is a promising intraoperative adjunct to white light cystoscopy (WLC) to better characterize bladder lesions. As interobserver variance is well documented in standard histopathology, this study aims to determine the interobserver agreement and accuracy of novice users utilizing CLE to diagnose bladder cancer. METHODS: Urologists and non-clinical researchers with no experience in CLE were recruited to participate in a two-hour computerbased training that consisted of a teaching and validation set of intraoperative WLC and CLE video images from patients undergoing transurethral resection of bladder tumor at the VA Palo Alto Health Care System since 2008. The teaching set included 15 CLE images to train the participants to identify key CLE features observed in benign, low grade and high grade bladder cancers. Participants then reviewed a validation set split into 3 sections: CLE images alone, WLC images alone, and WLC⫹CLE images combined. Each section contained 32 corresponding but randomized images of benign, low grade and high grade cancer. Accuracy was determined by comparing the diagnoses obtained from the participants to histopathologic results. RESULTS: In assessing interobserver agreement for the urologists (n⫽7), statistic and percent agreement was 0.43 and 62% for WLC, 0.44 and 63% for CLE, and 0.49 and 66% for WLC⫹CLE. Accuracy was 60% for WLC, 63% for CLE, and 67% for WLC⫹CLE with significant difference between WLC and WLC⫹CLE (p⬍0.01). In detecting HG carcinoma, sensitivity was 57% for WLC, 63% for CLE, and 73% for WLC⫹CLE with significant increase from both WLC to WLC⫹CLE and CLE to WLC⫹CLE (p⬍0.02), and specificity was 80% for WLC, 80% for CLE, and 79% for WLC⫹CLE. For non-clinical researchers (n⫽4), statistic, percent agreement, and accuracy for CLE was 0.56, 71%, and 63%, respectively. CONCLUSIONS: We have shown that novice users can be trained to interpret CLE images to similar levels of interobserver agreement (moderate) and accuracy as standard WLC after participating in a two-hour training. Also, compared to standard WLC, accuracy improves with the adjunctive use of CLE. Moreover, sensitivity in detecting high grade cancer increases from WLC to WLC⫹CLE with no change in specificity. Interestingly, compared to urologists, non-clinical researchers exhibited a higher level of agreement with similar accuracy for CLE, suggesting that clinical training is not a prerequisite for the accurate interpretation of CLE images. Source of Funding: Supported in part by NIH/National Cancer Institute R01 CA160986.
1775
Agreement () between pathologists using the 1973 WHO versus 2004 WHO/ ISUP classifications for urothelial carcinoma 1973 (95% CI) 2004 (95% CI) Overall 0.26 (0.16-0.39) 0.38 (0.25-0.50)
EXTERNAL VALIDATION OF EORTC AND CUETO SCORING MODELS TO PREDICT RECURRENCE AND PROGRESSION IN PATIENTS WITH NONMUSCLE INVASIVE BLADDER CANCER TREATED WITH BACILLUS CALMETTE-GUERIN Yasuo Kohjimoto*, Hiroki Kusumoto, Nagahide Matsumura, Takeshi Inagaki, Isao Hara, Wakayama, Japan
GU1 vs GU2
0.37 (0.22-0.51)
0.31 (0.16-0.46)
GU1 vs GP
0.33 (0.19-0.48)
0.46 (0.30-0.63)
GU2 vs GP
0.18 (0.07-0.31)
0.39 (0.26-0.54)
By convention, values are interpreted as follows: 0.00-0.20 ⫽ slight agreement, 0.21-0.40 ⫽ fair agreement, 0.41-0.60 ⫽ moderate agreement, 0.61-0.80 ⫽ substantial agreement, 0.81-1.00 ⫽ almost perfect agreement
Source of Funding: None
INTRODUCTION AND OBJECTIVES: Two scoring models have been developed based on large-scale trials to predict recurrence and progression of non-muscle invasive bladder cancer (NMIBC), namely the European Organization for Research and Treatment of Cancer (EORTC) model and the Spanish Urological Club for Oncological Treatment (CUETO) model. Only 6.6% of 2,576 patients analyzed for the EORTC model received Bacillus Calmette-Guerin (BCG) therapy, while all of 1,062 patients for the CUETO model received BCG
Vol. 187, No. 4S, Supplement, Tuesday, May 22, 2012
THE JOURNAL OF UROLOGY姞
therapy. The purpose of the present study was to evaluate the external validity of these two scoring models in patients with NMIBC treated with BCG therapy at our institution. METHODS: We retrospectively reviewed data on 366 patients with primary NMIBC treated with transurethral resection (TUR) and BCG therapy at our institution between 1985 and 2005. Patients were assigned points for recurrence and progression based on the EORTC model and CUETO model and then divided into 4 groups based on total score. Discrimination was assessed using the concordance index (cindex). RESULTS: The CUETO model successfully stratified both the recurrence and progression risks into 4 statistically different groups based on total score (Figure). However, the EORTC model stratified neither recurrence nor progression risks. With respect to the discriminative ability of the EORTC model and CUETO model, c-idices for recurrence were 0.514 and 0.576, respectively, and those for progression were 0.693 and 0.764, respectively. CONCLUSIONS: The CUETO model successfully stratified recurrence and progression risks in Japanese patients with NMIBC treated with TUR and BCG therapy, although the EORTC model did not.
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Source of Funding: None
1777 CENTROSOME AMPLIFICATION IN BLADDER WASHING CYTOLOGY SAMPLES MAY BECOME PROGNOSTIC BIOMARKER IN NON-MUSCLE INVASIVE BLADDER CANCER
Source of Funding: None
1776 E-CADHERIN, N-CADHERIN AND TWIST EXPRESSION IN HIGH RISK BLADDER CANCER Marc Vergnolles*, Gregoire Robert, Philippe Ballanger, Jean-Marie Ferriere, Gilles Pasticier, Alain Ravaud, Nadine Houede, Jean-Christophe Bernhard, Herve Wallerand, Bordeaux, France INTRODUCTION AND OBJECTIVES: Epithelial-mesenchymal transition is a complex process taking place during embryonic development in which cell– cell and cell-extracellular matrix interactions are altered. Malignant cells exploit this “normal” process in order to invade and metastasize with a loss of expression of E-cadherin and neo expression of N-cadherin. Twist is an inhibitor of the expression of E-cadherin and would be an anti-apoptotic agent. Prognosis of high-risk non-muscle-invasive bladder cancer is poor when progressing in muscle-invasive. METHODS: This monocentric retrospective study concerned 123 patients with a primary T1 high grade tumor, single and ⬍3cm. Expression of intercellular adhesion proteins E-cadherin, N-cadherin and Twist were studied with immunochemistry. RESULTS: Loss of expression of E-cadherin was 71.5% and was correlated with CIS (p⫽0.01). Neo expression of N-cadherin (8.9%) was correlated with progression (p⬍0,01) and poor specific survival(p⬍0,01). Twist expression (17.1%) was correlated with progression (p⬍0,02). None of the markers expression increased the risk of recurrence. Combining markers allowed to define favorable profil (E⫹/N-/ T-) and unfavorable (E-/N⫹/T⫹). CONCLUSIONS: Profils E-/N⫹/T⫹ and E-/N⫹ are associated with a high risk of progression and a radical treatment (an early cystectomy) could be proposed. Targeted therapies anti N-cadherin or anti-Twist could reduce the risk of progression and restore chemosensitivity. Larger studies are necessary to validate these markers.
Yoshihiro Miyachika*, Yoshiaki Yamamoto, Hiroaki Matsumoto, June Nishijima, Yoshihisa Kawai, Takahiko Hara, Shigeru Sakano, Hideyasu Matsuyama, ube, Japan INTRODUCTION AND OBJECTIVES: Recent studies have reported that centrosome amplification (CA) detected by using tumor tissue is associated with chromosomal instability and poor prognosis in bladder cancer. However, the relationship between CA in bladder washing cytology samples and clinical outcome remains unclear. In this study, we elucidated the impact of CA in bladder washing cytology for non-muscle invasive bladder cancer. METHODS: 78 non-muscle invasive bladder cancer patients treated by transurethral resection were investigated. We evaluated centrosome amplification both bladder washing cytology and tumor tissue samples from these patients by using immunofluorescent staining. CA is defined as over 5% cells showed the positive staining which has more than 3 centrosomes per each cell. And we analyzed the association between CA and clinical parameters. RESULTS: CA in bladder washing cytology samples was detected in 21 (21.9%) of 78 patients. Disease progression was observed in 9 (11.5%) of 78 patients. All those patients with disease progression had CA. The patients with CA of bladder washing cytology samples showed significantly shorter progression-free survival periods than the patients without its amplification (p ⫽ 0.0038). The correlation coefficient between CA of bladder washing cytology and tumor tissue samples in 78 same patients was 0.56. In univariate analysis, CA, tumor recurrence and positive-washing cytology were significant prognostic factors for tumor progression. In multivariate analysis, CA and tumor recurrence were independent prognostic factors for tumor progression (HR 2.22, p ⫽ 0.022 and HR 2.08, p ⫽ 0.043, respectively). CONCLUSIONS: These data suggest that centrosome amplification in bladder washing cytology samples may provide predictive information about disease progression in non-muscle invasive bladder cancer. Source of Funding: None
THE JOURNAL OF UROLOGY姞
Vol. 187, No. 4S, Supplement, Tuesday, May 22, 2012
CONCLUSIONS: Intravesical instillation of THP 30 mg twice within 24 hours after TUR was effective as prophylactic therapy for non-muscle-invasive bladder cancer with tolerable toxicity problems. Source of Funding: None
1774 INTEROBSERVER AGREEMENT AND ACCURACY OF CONFOCAL LASER ENDOMICROSCOPY FOR IN VIVO DIAGNOSIS OF BLADDER CANCER Timothy Chang*, Jen-Jane Liu, Shelly Hsiao, Ying Pan, Jesse McKenney, Joseph Liao, Stanford, CA
1773 INTEROBSERVER REPRODUCIBILITY OF THE 1973 WHO AND 2004 WHO/ISUP NON-INVASIVE BLADDER CANCER CLASSIFICATIONS AMONG GENERAL AND GENITOURINARY PATHOLOGISTS Eugene W. Lee*, Fang Ming Deng, Jonathan Melamed, Savvas Mendrinos, Kasturi Das, Tsivia Hochman, Samir S. Taneja, William C. Huang, New York, NY INTRODUCTION AND OBJECTIVES: Pathological grade is the most important prognostic indicator used to risk stratify and select treatment for non-invasive urothelial carcinoma (UC). The 1973 World Health Organization (WHO) grading classification has been most widely used, but suffers from unacceptably high interobserver variability. The 2004 WHO/International Society of Urological Pathology (ISUP) revision was developed to reduce variability by providing welldefined histological criteria for each grade. We compared interobserver reproducibility between the 1973 and 2004 systems and between general versus expert genitourinary pathologists. METHODS: 1 general pathologist (GP) and 2 genitourinary pathology specialists (GU1 and GU2) were blinded to patient identity and graded 98 consecutive UC specimens retrospectively using the 1973 and 2004 classifications. Kappa statistics () were used to measure interobserver reproducibility. By convention, values from 0.21 – 0.4 represent “fair” agreement, from 0.41 - 0.6 represent “moderate” agreement, and ⬎ 0.6 represent “substantial” agreement. As an example, values for prostate cancer Gleason score among genitourinary pathologists have been reported to be ⬎ 0.6. RESULTS: Overall agreement was only fair for both systems and while higher for the 2004 system than the 1973, this was not significant (: 0.38 versus 0.26, respectively). Agreement between the two specialists versus agreement between each specialist and the generalist was higher using the 1973 system (: 0.37 vs 0.33 and 0.18) but lower using the 2004 system (: 0.31 vs 0.46 and 0.39). The generalist had better agreement with both specialists using the 2004 system versus the 1973 system (: 0.46 and 0.39 versus 0.33 and 0.18). These findings were not statistically significant. CONCLUSIONS: Reproducibility is not improved by the 2004 WHO/ISUP revision to the 1973 WHO grading system, even among expert genitourinary pathologists. Since management of non-invasive UC is primarily determined by its grade, this limits a clinician’s ability to risk stratify tumor and potentially alters treatment. Our findings underscore the need to identify molecular markers that can provide a more reliable risk stratification system.
INTRODUCTION AND OBJECTIVES: Probe-based confocal laser endomicroscopy (CLE), an emerging optical imaging technology that enables in vivo microscopy, is a promising intraoperative adjunct to white light cystoscopy (WLC) to better characterize bladder lesions. As interobserver variance is well documented in standard histopathology, this study aims to determine the interobserver agreement and accuracy of novice users utilizing CLE to diagnose bladder cancer. METHODS: Urologists and non-clinical researchers with no experience in CLE were recruited to participate in a two-hour computerbased training that consisted of a teaching and validation set of intraoperative WLC and CLE video images from patients undergoing transurethral resection of bladder tumor at the VA Palo Alto Health Care System since 2008. The teaching set included 15 CLE images to train the participants to identify key CLE features observed in benign, low grade and high grade bladder cancers. Participants then reviewed a validation set split into 3 sections: CLE images alone, WLC images alone, and WLC⫹CLE images combined. Each section contained 32 corresponding but randomized images of benign, low grade and high grade cancer. Accuracy was determined by comparing the diagnoses obtained from the participants to histopathologic results. RESULTS: In assessing interobserver agreement for the urologists (n⫽7), statistic and percent agreement was 0.43 and 62% for WLC, 0.44 and 63% for CLE, and 0.49 and 66% for WLC⫹CLE. Accuracy was 60% for WLC, 63% for CLE, and 67% for WLC⫹CLE with significant difference between WLC and WLC⫹CLE (p⬍0.01). In detecting HG carcinoma, sensitivity was 57% for WLC, 63% for CLE, and 73% for WLC⫹CLE with significant increase from both WLC to WLC⫹CLE and CLE to WLC⫹CLE (p⬍0.02), and specificity was 80% for WLC, 80% for CLE, and 79% for WLC⫹CLE. For non-clinical researchers (n⫽4), statistic, percent agreement, and accuracy for CLE was 0.56, 71%, and 63%, respectively. CONCLUSIONS: We have shown that novice users can be trained to interpret CLE images to similar levels of interobserver agreement (moderate) and accuracy as standard WLC after participating in a two-hour training. Also, compared to standard WLC, accuracy improves with the adjunctive use of CLE. Moreover, sensitivity in detecting high grade cancer increases from WLC to WLC⫹CLE with no change in specificity. Interestingly, compared to urologists, non-clinical researchers exhibited a higher level of agreement with similar accuracy for CLE, suggesting that clinical training is not a prerequisite for the accurate interpretation of CLE images. Source of Funding: Supported in part by NIH/National Cancer Institute R01 CA160986.
1775
Agreement () between pathologists using the 1973 WHO versus 2004 WHO/ ISUP classifications for urothelial carcinoma 1973 (95% CI) 2004 (95% CI) Overall 0.26 (0.16-0.39) 0.38 (0.25-0.50)
EXTERNAL VALIDATION OF EORTC AND CUETO SCORING MODELS TO PREDICT RECURRENCE AND PROGRESSION IN PATIENTS WITH NONMUSCLE INVASIVE BLADDER CANCER TREATED WITH BACILLUS CALMETTE-GUERIN Yasuo Kohjimoto*, Hiroki Kusumoto, Nagahide Matsumura, Takeshi Inagaki, Isao Hara, Wakayama, Japan
GU1 vs GU2
0.37 (0.22-0.51)
0.31 (0.16-0.46)
GU1 vs GP
0.33 (0.19-0.48)
0.46 (0.30-0.63)
GU2 vs GP
0.18 (0.07-0.31)
0.39 (0.26-0.54)
By convention, values are interpreted as follows: 0.00-0.20 ⫽ slight agreement, 0.21-0.40 ⫽ fair agreement, 0.41-0.60 ⫽ moderate agreement, 0.61-0.80 ⫽ substantial agreement, 0.81-1.00 ⫽ almost perfect agreement
Source of Funding: None
INTRODUCTION AND OBJECTIVES: Two scoring models have been developed based on large-scale trials to predict recurrence and progression of non-muscle invasive bladder cancer (NMIBC), namely the European Organization for Research and Treatment of Cancer (EORTC) model and the Spanish Urological Club for Oncological Treatment (CUETO) model. Only 6.6% of 2,576 patients analyzed for the EORTC model received Bacillus Calmette-Guerin (BCG) therapy, while all of 1,062 patients for the CUETO model received BCG
Vol. 187, No. 4S, Supplement, Tuesday, May 22, 2012
THE JOURNAL OF UROLOGY姞
therapy. The purpose of the present study was to evaluate the external validity of these two scoring models in patients with NMIBC treated with BCG therapy at our institution. METHODS: We retrospectively reviewed data on 366 patients with primary NMIBC treated with transurethral resection (TUR) and BCG therapy at our institution between 1985 and 2005. Patients were assigned points for recurrence and progression based on the EORTC model and CUETO model and then divided into 4 groups based on total score. Discrimination was assessed using the concordance index (cindex). RESULTS: The CUETO model successfully stratified both the recurrence and progression risks into 4 statistically different groups based on total score (Figure). However, the EORTC model stratified neither recurrence nor progression risks. With respect to the discriminative ability of the EORTC model and CUETO model, c-idices for recurrence were 0.514 and 0.576, respectively, and those for progression were 0.693 and 0.764, respectively. CONCLUSIONS: The CUETO model successfully stratified recurrence and progression risks in Japanese patients with NMIBC treated with TUR and BCG therapy, although the EORTC model did not.
e717
Source of Funding: None
1777 CENTROSOME AMPLIFICATION IN BLADDER WASHING CYTOLOGY SAMPLES MAY BECOME PROGNOSTIC BIOMARKER IN NON-MUSCLE INVASIVE BLADDER CANCER
Source of Funding: None
1776 E-CADHERIN, N-CADHERIN AND TWIST EXPRESSION IN HIGH RISK BLADDER CANCER Marc Vergnolles*, Gregoire Robert, Philippe Ballanger, Jean-Marie Ferriere, Gilles Pasticier, Alain Ravaud, Nadine Houede, Jean-Christophe Bernhard, Herve Wallerand, Bordeaux, France INTRODUCTION AND OBJECTIVES: Epithelial-mesenchymal transition is a complex process taking place during embryonic development in which cell– cell and cell-extracellular matrix interactions are altered. Malignant cells exploit this “normal” process in order to invade and metastasize with a loss of expression of E-cadherin and neo expression of N-cadherin. Twist is an inhibitor of the expression of E-cadherin and would be an anti-apoptotic agent. Prognosis of high-risk non-muscle-invasive bladder cancer is poor when progressing in muscle-invasive. METHODS: This monocentric retrospective study concerned 123 patients with a primary T1 high grade tumor, single and ⬍3cm. Expression of intercellular adhesion proteins E-cadherin, N-cadherin and Twist were studied with immunochemistry. RESULTS: Loss of expression of E-cadherin was 71.5% and was correlated with CIS (p⫽0.01). Neo expression of N-cadherin (8.9%) was correlated with progression (p⬍0,01) and poor specific survival(p⬍0,01). Twist expression (17.1%) was correlated with progression (p⬍0,02). None of the markers expression increased the risk of recurrence. Combining markers allowed to define favorable profil (E⫹/N-/ T-) and unfavorable (E-/N⫹/T⫹). CONCLUSIONS: Profils E-/N⫹/T⫹ and E-/N⫹ are associated with a high risk of progression and a radical treatment (an early cystectomy) could be proposed. Targeted therapies anti N-cadherin or anti-Twist could reduce the risk of progression and restore chemosensitivity. Larger studies are necessary to validate these markers.
Yoshihiro Miyachika*, Yoshiaki Yamamoto, Hiroaki Matsumoto, June Nishijima, Yoshihisa Kawai, Takahiko Hara, Shigeru Sakano, Hideyasu Matsuyama, ube, Japan INTRODUCTION AND OBJECTIVES: Recent studies have reported that centrosome amplification (CA) detected by using tumor tissue is associated with chromosomal instability and poor prognosis in bladder cancer. However, the relationship between CA in bladder washing cytology samples and clinical outcome remains unclear. In this study, we elucidated the impact of CA in bladder washing cytology for non-muscle invasive bladder cancer. METHODS: 78 non-muscle invasive bladder cancer patients treated by transurethral resection were investigated. We evaluated centrosome amplification both bladder washing cytology and tumor tissue samples from these patients by using immunofluorescent staining. CA is defined as over 5% cells showed the positive staining which has more than 3 centrosomes per each cell. And we analyzed the association between CA and clinical parameters. RESULTS: CA in bladder washing cytology samples was detected in 21 (21.9%) of 78 patients. Disease progression was observed in 9 (11.5%) of 78 patients. All those patients with disease progression had CA. The patients with CA of bladder washing cytology samples showed significantly shorter progression-free survival periods than the patients without its amplification (p ⫽ 0.0038). The correlation coefficient between CA of bladder washing cytology and tumor tissue samples in 78 same patients was 0.56. In univariate analysis, CA, tumor recurrence and positive-washing cytology were significant prognostic factors for tumor progression. In multivariate analysis, CA and tumor recurrence were independent prognostic factors for tumor progression (HR 2.22, p ⫽ 0.022 and HR 2.08, p ⫽ 0.043, respectively). CONCLUSIONS: These data suggest that centrosome amplification in bladder washing cytology samples may provide predictive information about disease progression in non-muscle invasive bladder cancer. Source of Funding: None