Nonmuscle Invasive Research Articles

Fibroblast Growth Factor Receptor 3 Mutation as a Prognostic Indicator in Patients with Urothelial Carcinoma: A Systematic Review and Meta-analysis

BackgroundFibroblast growth factor receptor 3 (FGFR3) mutations have been implicated in urothelial tumorigenesis. FGFR3 inhibitors are being explored in clinical trials. ObjectiveWe aimed to study the association between FGFR3 mutations and survival in urothelial carcinoma. Design, setting, and participantsWe performed a systematic literature search of PubMed, Cochrane, Ovid, and Web of Science from January 1985 to October 2018. The search terms were as follows: targeted therapies, FGFR and its subtypes, urothelial, bladder, and cancer. We included case-control or cohort studies of FGFR3 mutations in urothelial carcinoma. We included studies reporting hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes comparing FGFR3 mutations with FGFR3 wild type. Two reviewers performed article selection. Outcome measurements and statistical analysisWe assessed heterogeneity among study-specific HRs using I2 statistic. We used a random effect model to obtain HR and 95% CI for event-free survival (EFS), composed of recurrence-free and progression-free survival. Statistical tests were two sided. Results and limitationsEleven studies (seven retrospective and four prospective) comprising 2162 patients were included. Analysis was performed for two groups. The first group included 1651 patients with non–muscle-invasive (NMI) urothelial carcinomas (886 [53.6%] had FGFR3 mutations). Compared with FGFR3 wild type, FGFR3 mutation did not influence EFS (HR = 0.99, CI = 0.77–1.28, p = 0.96). There was no significant heterogeneity (I2 = 25%). The second group included 511 patients with NMI and muscle-invasive (MI) urothelial carcinomas (151 [30%] had FGFR3 mutations). FGFR3 mutation was not prognostic (HR = 1.54, CI = 0.41–5.81, p = 0.52). There was heterogeneity (I2 = 91%). ConclusionsThere is no association between FGFR3 mutation and EFS in NMI urothelial carcinoma, and in NMI and MI urothelial carcinoma groups. Patient summaryFibroblast growth factor receptor 3 (FGFR3) mutation is not associated with a worse survival outcome in urothelial carcinoma. This is important as FGFR inhibitors are emerging as a new treatment option.

Relevance of iNOS expression in tumor growth and maintenance of cancer stem cells in a bladder cancer model.

The expression of inducible nitric oxide (NO) synthase (iNOS) in human bladder cancer (BC) is a poor prognostic factor associated with invasion and tumor recurrence. Here, we evaluated the relevance of iNOS expression in BC progression and in cancer stem cell (CSC) maintenance in a murine BC model. Also, iNOS expression and CSC markers were analyzed in human BC samples. iNOS inhibitors (L-NAME or 1400W) or shRNA were used on murine BC model with different iNOS expressions and invasiveness grades: MB49 (iNOS+, non-muscle invasive (NMI)) and MB49-I (iNOS++, muscle invasive (MI)), in order to analyzed cell proliferation, tumor growth, angiogenesis, number of CSC, and pluripotential marker expression. iNOS, SOX2, Oct4, and Nanog expressions were also analyzed in human BC samples by qPCR and immunohistochemistry. iNOS inhibtion reduced parameters associated with tumor progression and reduced the number of CSC, wich resulted higher in MB49-I than in MB49, in concordance with the higher expression of SOX2, Oct4, and Nanog. The expression of SOX2 was notoriously diminished, when iNOS was inhibited only in the MI cell line. Similar results were observed in human samples, where MI tumors expressed higher levels of iNOS and pluripotential genes, in comparison to NMI tumors with a positive correlation between those and iNOS, suggesting that iNOS expression is associated with CSC. iNOS plays an important role in BC progression and CSC maintenance. Its inhibition could be a potential therapeutic target to eradicate CSC, responsible fortumor recurrences. KEY MESSAGES: • iNOS expression is involved in bladder tumor development, growth, and angiogenesis. • iNOS expression is involved in bladder cancer stem cell generation and maintenance, playing an important role regulating their self-renewal capacity, especially in muscle invasive murine bladder cancer cells. • iNOS expression is higher in human muscle invasive tumors, in association with a high expression of pluripotential genes, especially of SOX2.

Abstract B23: FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment?

Abstract Objective: Fibroblast growth factor receptor 3 (FGFR3) is a potentially actionable target in bladder cancer (BC). FGFR3 mutations are associated with favorable prognosis in non-muscle invasive (NMI) BC and MIBC. Overexpression of FGFR3 was reported in up to 40% of FGFR3 wild-type MIBC. p53 alterations rarely coincide with FGFR3 mutations. We analyzed FGFR3 mutations and protein-expression of FGFR3 and p53 and assessed their prognostic value in a multicenter, multilaboratory setting. Methods: We included 1,000 cN0M0, chemotherapy-naive patients who underwent radical cystectomy (RC) with pelvic node dissection. Specimens were reviewed by eight uropathologists. At seven laboratories, FGFR3 mutation status was examined using PCR-SNaPshot. p53 and FGFR3 expression were determined by immunohistochemistry (IHC). FGFR3 mutation status, p53 and FGFR3 protein expression were correlated to each other, clinicopathologic parameters, and disease-specific survival (DSS). Results: FGFR3 mutations were found in 107/1,000 RCs (11%), of which 67 were S249C. Overexpression of FGFR3 was found in 279/1,000 (28%) of tumors. p53 overexpression (cut-off>10%) was found in 638/926 (69%) of available cases. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression. Among FGFR3 wild-type tumors, 22% had FGFR3 overexpression. FGFR3 mutations were associated with lower pT-stage (P<0.001), lower grade (G2-WHO 1973) (P<0.001), absence of CIS (P=0.009), pN0 (P<0.001), normal p53 (P<0.001), and prolonged DSS (Plog-rank=0.001). FGFR3 overexpression was associated with lower pT-stage (P<0.001) and G2 (P<0.001) but not with absence of CIS (P=0.860), pN0 (P=0.230), normal p53, (P=0.330) nor prolonged DSS (Plog-rank=0.204). We found no significant difference in DSS for patients with FGFR3 mutant tumors comparing normal vs. overexpression of FGFR3 (Plog-rank=0.444). Furthermore, we also found no significant difference in DSS for patients with FGFR3 wild-type tumors comparing normal vs. overexpression of FGFR3 (Plog-rank=0.754). Conclusions: FGFR3 mutations identified patients with favorable BC with fewer p53 alterations at RC. FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. Our results suggest that FGFR3 mutations (driver effect) have a distinct functional role than FGFR3 overexpression (passenger effect). Hence, patients with FGFR3 mutations may be more likely to benefit from anti-FGFR3 therapy than patients with only overexpression of FGFR3. Citation Format: Bas van Rhijn, Laura Mertens, Roman Mayr, Peter Bostrom, Mirari Marques, Geert van Leenders, Stefanie Gotz, Michiel van der Heijden, Michael Jewett, Francisco Real, Robert Stohr, Alexandre Zlotta, Markus Eckstein, Yanish Soorojebally, Max Burger, Wolfgang Otto, Francois Radvanyi, Damien Pouessel, Theo van der Kwast, Nuria Malats, Arndt Hartmann, Yves Allory, Deric van der Schoot, Ellen Zwarthoff, Tahlita Zuiverloon. FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment? [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B23.

531 - Prospective validation of vesical imaging-reporting and data system (VI-RADS) for non-muscle invasive (NMI) vs. muscle invasive bladder cancer (MIBC) discrimination in patients candidate for primary transurethral resection of bladder tumors (TURBT)κκκ

531 - Prospective validation of vesical imaging-reporting and data system (VI-RADS) for non-muscle invasive (NMI) vs. muscle invasive bladder cancer (MIBC) discrimination in patients candidate for primary transurethral resection of bladder tumors (TURBT)κκκ

Is it necessary to obtain a second review on outside pathology for patients referred with non-muscle invasive (NMI) bladder cancer?

e17049 Background: Correct pathological staging is paramount in treatment recommendations for patients with non-muscle invasive disease. As a referral center, we sought to evaluate the quality of outside pathology determined by College of American Pathology (CAP) recommendation as well as discordance in AUA risk group stratification. Methods: We retrospectively reviewed our database of patients who originally underwent resection of bladder tumors at external facilities that were subsequently referred to our cancer institute between 2015 and 2018. 75 initial pathologies were overread by one of our GU pathologists all with non-muscle invasive bladder cancer. We evaluated the discordance rate between outside pathology reports and our overread using the CAP criteria for reporting. Additionally, we included the association in risk stratification category as well as the change in risk stratification group following overread. Cohen’s kappa (κ) statistics were used to evaluate concordance in pathology report between LCI and external facilities. Comparisons of risk stratification between LCI and external facilities were analyzed using Fisher’s exact test. Results: 5 criteria for quality were evaluated to assess reporting. A relatively high agreement in reporting tumor grade between LCI and external facilities (κ = 0.65, p < 0.001) and moderate agreement in microscopic extent (κ = 0.41, p < 0.001). LVI was not commented on in 58.7% of outside reports. 6/12 (50%) of patients were upstaged from Low Risk (LR) to Intermediate Risk (IR), 2/11 (18%) from IR to High Risk (HR), and 6/46 (13%) from HR to MIBC (Table). Conclusions: Initial pathology reports from outside facilities were often lacking minimum criteria as recommended by the CAP. Furthermore, a significant number of patients were upstaged after review, including 13% of HR patients being overread as muscle invasive disease. Second review of outside pathology should strongly be considered as re-review may have implications on treatment recommendations. [Table: see text]

Clinical value of texture analysis in differentiation of urothelial carcinoma based on multiphase computed tomography images.

Identification of histologic grading of urothelial carcinoma still depends on histopathologic examination. As an emerging and promising imaging technology, radiomic texture analysis is a noninvasive technique and has been studied to differentiate various tumors. This study explored the value of computed tomography (CT) texture analysis for the differentiation of low-grade urothelial carcinoma (LGUC), high-grade urothelial carcinoma (HGUC), and their invasive properties.Radiologic data were analyzed retrospectively for 94 patients with pathologically proven urothelial carcinomas from November 2016 to April 2019. Pathologic examination demonstrated that tumors were: high grade in 43 cases, and low grade in 51 cases; and nonmuscle invasive (NMI) in 37 cases, and muscle invasive (MI) in 37 cases. Maximum tumor diameters on CT scan were manually outlined as regions of interest and 78 texture features were extracted automatically. Three-phasic CT images were used to measure texture parameters, which were compared with postoperative pathologic grading and invasive results. The independent sample t test or Mann-Whitney U test was used to compare differences in parameters. Receiver-operating characteristic curves for statistically significant parameters were used to confirm efficacy.Of the 78 features extracted from each phase of CT images, 26 (33%), 20 (26%), and 22 (28%) texture parameters were significant (P < .05) for differentiating LGUC from HGUC, while 19 (24%), 16 (21%), and 30 (38%) were significant (P < .05) for differentiating NMI from MI urothelial carcinoma. Highest areas the under curve for differentiating grading and invasive properties were obtained by variance (0.761, P < .001) and correlation (0.798, P < .001) on venous-phase CT images.Texture analysis has the potential to distinguish LGUC and HGUC, or NMI from MI urothelial carcinoma, before surgery.

Diagnostic Accuracy of MCM5 for the Detection of Recurrence in Nonmuscle Invasive Bladder Cancer Followup: A Blinded, Prospective Cohort, Multicenter European Study.

Detection of MCM5 containing cells in urine has been shown to be indicative of the presence of a bladder tumor on primary diagnosis. In this study we evaluate diagnostic performance of ADXBLADDER in patients undergoing cystoscopic surveillance in nonmuscle invasive bladder cancer followup. A multicenter prospective blinded study was performed at 21 European centers with patients undergoing cystoscopy for nonmuscle invasive bladder cancer surveillance, diagnosed in the preceding 2 years. Urine was collected from all eligible patients and ADXBLADDER-MCM5 testing was performed. Performance characteristics were calculated by comparing MCM5 results to the outcome of cystoscopy plus pathological assessment. Of 1,431 eligible patients enrolled 127 were diagnosed with a bladder cancer recurrence. The overall sensitivity for the ADXBLADDER-MCM5 test in detecting bladder cancer recurrence was 44.9% (95% CI 36.1-54) with a 75.6% sensitivity for nonpTaLG tumors (95% CI 59.7-87.6). Specificity was 71.1% (95% CI 68.5-73.5). The overall negative predictive value was 93% (95% CI 91.2-94.5). However, ADXBLADDER was able to rule out the presence of a nonpTaLG recurrent tumor with a negative predictive value of 99.0% (95% CI 98.2-99.5). No statistically significant differences in the performance of ADXBLADDER were observed as a result of age or sex. This large blinded prospective study demonstrates that in the followup of patients with nonmuscle invasive bladder cancer ADXBLADDER is able to exclude the presence of the most aggressive tumors with a negative predictive value of 99%. These results indicate that ADXBLADDER could be incorporated in the followup strategy of nonmuscle invasive bladder cancer.

PD12-05 IMPROVING RATES OF INTRAVESICAL CHEMOTHERAPY FOR LOW GRADE BLADDER CANCER

INTRODUCTION AND OBJECTIVE: Despite advances in urologic research, there is often a disconnect with real-world practice. AUA guidelines recommend consideration of an immediate postoperative instillation of intravesical chemotherapy (IVC) for low grade urothelial cancers, which has been shown to reduce tumor recurrence up to ∼40%. However, rates of postoperative IVC use remains low due to high costs, low availability, and side effects. While Mitomycin C is the standard of care, recent data demonstrates that gemcitabine (Gem) has similar efficacy in reducing tumor recurrences, while being more tolerable and less expensive. We created an implementation protocol to improve usage rates of immediate post-operative Gem. Because histology is not available to the surgeon prior to ordering IVC, the accuracy of visual grading during cystoscopy was determined for our group of surgeons. METHODS: Pre-intervention audits were performed at two hospitals to determine for baseline rates of appropriate use of immediate post-operative IVC in patients with low grade (LG) non-muscle invasive (NMI) urothelial carcinoma (UC) undergoing resection of bladder tumors (TURBT) over a 3-month period. Needs assessment was performed to recognize key stakeholders and identify barriers to use. An intervention protocol was designed and implemented, which included new EMR order sets, education of providers and staff, and establishment of communication checkpoints. A 4 month post-intervention audit was performed. RESULTS: Prior to knowing histology, LG histology was accurately predicted with a PPV of 80%. Pre-intervention rates of appropriate intravesical chemotherapy use were 9% at hospital A and 39% at hospital B. Post-intervention rates were 81% at hospital A and 84% at hospital B. CONCLUSIONS: Prior to knowing histology, our urologists can accurately predict LG histology and thus patients who will require IVC after TURBT. There was a significant improvement in the rates of immediate postoperative Gem at both hospitals. Continued refinement of the protocol will be necessary to further improve and sustain these improved rates. This success indicates that our intervention may be used as a model for other institutions.Source of Funding: Urology Care Foundation Resident Research Award; Kahlert Foundation

MP73-08 INTRAVESICAL GEMCITABINE AND DOCETAXOL IN HEAVILY PRE-TREATED PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)

You have accessJournal of UrologyBladder Cancer: Non-invasive IV (MP73)1 Apr 2020MP73-08 INTRAVESICAL GEMCITABINE AND DOCETAXOL IN HEAVILY PRE-TREATED PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) Adele Caruso*, Roshan Ravishankar, Keith VanArsdalen, and Stanley Malkowicz Adele Caruso*Adele Caruso* More articles by this author , Roshan RavishankarRoshan Ravishankar More articles by this author , Keith VanArsdalenKeith VanArsdalen More articles by this author , and Stanley MalkowiczStanley Malkowicz More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000959.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Therapeutic options are limited for BCG resistant/ refractory NMIBC patients who are unfit or refuse radical cystectomy. Combination chemotherapy is not regularly used due to additive toxicity. The non-desiccant properties of Gemcitabine allow for combined therapy not previously employed. Docetaxol as a single agent demonstrates significant activity with acceptable toxicity. The objective of this study was to evaluate combination intravesical chemotherapy for its initial response and therapeutic durability in those patients heavily pre-treated with BCG. METHODS: Patients who had failed or were intolerant to BCG therapy were offered combination intravesical therapy per the following regimen 1000 mg of GEM in 100 cc’s of saline instilled for two hours followed by bladder emptying and reinstallation of 37.5 mg DOC in 50 mls saline. This was done weekly for 6 weeks. At twelve weeks patients underwent cystoscopy with full bladder mapping and cytology. Cystoscopy was performed every 3 months for one year and at 3 months or 6 months thereafter. Further biopsiy or resection was performed for positive cytology, distinct recurrent tumor or suspicious areas on cystoscopy. Failure was defined as positive cytology, tumor recurrence or distant failure. RESULTS: Between 12/2015 and 6/2019, thirty patients were recruited. 26 are eligible for evaluation and had a mean of 3.2 prior induction courses of intravesical therapy. There were 20 men and 6 women with a mean age of 77 (range 68-94). Twenty four of 26 patients demonstrated an initial negative evaluation. 16/26 patients recurred during this time period with a mean disease free interval of 12.45 months (range 3-34 months). Ten patients are NED for a mean of 9.6 months (range 3-15 months) 11 failures were local (2 muscle invasive progression), 4 cytology only, 1 pelvic lymph node progression. The regimen was well tolerated per patient complaints and AUA voiding scores. CONCLUSIONS: Sequential, combination Gemcitabine and Docetaxol intravesical chemotherapy is an active regimen in BCG pretreated patients who are unfit or unwilling to undergo cystectomy. A near universal initial response with a complete response maintained for over one year in responders suggests a role for maintenance therapy and supports continued study of this intravesical regimen. Source of Funding: NONE © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1124-e1124 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Adele Caruso* More articles by this author Roshan Ravishankar More articles by this author Keith VanArsdalen More articles by this author Stanley Malkowicz More articles by this author Expand All Advertisement PDF downloadLoading ...

MP72-10 THE OUTCOME OF PATIENTS WITH HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER IN SWEDEN

You have accessJournal of UrologyBladder Cancer: Non-invasive III (MP72)1 Apr 2020MP72-10 THE OUTCOME OF PATIENTS WITH HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER IN SWEDEN Eugen Wang*, Ulf Larsson, Truls Gårdmark, and Per-Uno Malmström Eugen Wang*Eugen Wang* More articles by this author , Ulf LarssonUlf Larsson More articles by this author , Truls GårdmarkTruls Gårdmark More articles by this author , and Per-Uno MalmströmPer-Uno Malmström More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000952.010AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: At the time of bladder cancer detection, about 2/3 are non-muscle invasive bladder cancer (NMIBC). The high-risk NMIBC tumor types (TaG3, T1G2,T1G3 or/and Tis) present an increased risk of progression to deep-growing cancer and metastasis. Our aim was to identify this group of patients in the Bladder Cancer Data Base Sweden (BladderBaSe) and analyze the cancer specific survival after different managements. METHODS: BladderBaSe was created in 2015. This database links information from the Swedish National Register of Urinary Bladder Cancer (SNRUBC) from 1997 to 2014, with a number of national health care and demographic registers through the use of the personal identification numbers. The national register has detailed data on 97% of the bladder cancer cases diagnosed in Sweden. In 1997-2014 in Sweden, a total of 26808 patients were diangosed with NMIBC, of whom 10209 were high-risk cancer with median age 71 and 80 % male. 5660 patients were treated with TURBT only, 3862 had inital Bacillus Calmette-Guérin (BCG). Radical cystectomy was performed in 687 patients initially while 399 had delayed cystectomy after BCG. RESULTS: Characteristics of patients with high risk NMIBC is shown in table 1. During the follow-up 5 years, the cancer specific survival chance was higher for the BCG group (85 %) than it was for the initial radical cystectomy (75 %) or TURBT only group (65 %). (Fig.1). In a Cox proportional hazards model younger patients, lower cancer stage, initial treatment with BCG and treatment in high volume university hospital was associated with better survival. CONCLUSIONS: Initial BCG installation with or without delayed cystectomy improved cancer specific survival more than initial cystectomy in high-grade T1 bladder cancer in this population registry. However selection criteria could be a cause for confounding and will be further studied. Source of Funding: Schmekel fund in Urological research © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1077-e1077 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eugen Wang* More articles by this author Ulf Larsson More articles by this author Truls Gårdmark More articles by this author Per-Uno Malmström More articles by this author Expand All Advertisement PDF downloadLoading ...

MP73-19 DEEP LEARNING FOR HISTOPATHOLOGY AND CLINICAL CHARACTERISTICS BASED RECURRENCE PREDICTION IN NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS

You have accessJournal of UrologyBladder Cancer: Non-invasive IV (MP73)1 Apr 2020MP73-19 DEEP LEARNING FOR HISTOPATHOLOGY AND CLINICAL CHARACTERISTICS BASED RECURRENCE PREDICTION IN NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS Marit Lucas*, Ilaria Jansen, Jorg R. Oddens, C. Dilara Savci-Heijink, Ton G. van Leeuwen, Daniel M. de Bruin, and Henk A. Marquering Marit Lucas*Marit Lucas* More articles by this author , Ilaria JansenIlaria Jansen More articles by this author , Jorg R. OddensJorg R. Oddens More articles by this author , C. Dilara Savci-HeijinkC. Dilara Savci-Heijink More articles by this author , Ton G. van LeeuwenTon G. van Leeuwen More articles by this author , Daniel M. de BruinDaniel M. de Bruin More articles by this author , and Henk A. MarqueringHenk A. Marquering More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000959.019AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The EORTC and CUETO are used to assess the risk for recurrence in non-muscle invasive bladder cancer (NMIBC). Low concordance rates with recurrence are reported for those tools, and could be explained a.o. by the subjectivity of the histopathological parameters used in the prediction. By the use of deep learning, we want to objectify the recurrence prediction. This deep learning approach aims to combine clinical characteristics, including histopathological parameters, with the histopathology images. In this abstract, we report on the first steps taken in the development of this deep learning approach. METHODS: All patients that underwent a trans-urethral resection of bladder tumor in the Amsterdam UMC, location AMC, between 2000 and 2018 were included in this study. Histopathological slides of NMIBC patients were retrieved from the archive and digitized by the Philips Ultrafast scanner. A three-stage deep learning approach is proposed to assess the risk of recurrence. The first stage is the detection of the urothelium on the histopathology slides. The second stage selects regions within the urothelium which are most predictive for recurrence. The last step is a deep learning network which combines those regions with the clinical characteristics. The short (1 yr)-term recurrence dataset contained 395 patients, with 26% of recurred patients. The long (5 yr)-term dataset contained 306 patients, with recurrence in 63%. Missing data in clinical characteristics were imputed using a random forest. The three step deep learning approach will be compared with a multivariable logistic regression model based on clinical characteristics only. RESULTS: The first step from the deep learning approach has been completed and resulted in an automated and accurate detection of urothelium. The results from the other two stages will be presented at the AUA Annual Meeting in May. Multivariable logistic regression based on clinical characteristics only shows low predictive power, with a sensitivity of 11% and 72%, specificity of 96% and 35% and AUC of 0.60 and 0.62 for the prediction of recurrence within 1 yr and 5 yr, respectively. CONCLUSIONS: Accurate detection of urothelium is achieved with deep learning, and is the first step in order to create a deep learning approach for recurrence prediction. The next steps consists of the automated detection of regions on histopathology slides predictive for recurrence and at last the incorporation of clinical data into the recurrence prediction of NMIBC patients. Source of Funding: Cure for Cancer Foundation, ITEA3 (ITEA151003) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1129-e1129 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Marit Lucas* More articles by this author Ilaria Jansen More articles by this author Jorg R. Oddens More articles by this author C. Dilara Savci-Heijink More articles by this author Ton G. van Leeuwen More articles by this author Daniel M. de Bruin More articles by this author Henk A. Marquering More articles by this author Expand All Advertisement PDF downloadLoading ...

PD32-07 BARRIERS TO SINGLE-DOSE INTRAVESICAL CHEMOTHERAPY IN NON-MUSCLE INVASIVE BLADDER CANCER: WHAT'S THE PROBLEM?

You have accessJournal of UrologyGeneral & Epidemiological Trends & Socioeconomics: Practice Patterns, Quality of Life and Shared Decision Making III (PD32)1 Apr 2020PD32-07 BARRIERS TO SINGLE-DOSE INTRAVESICAL CHEMOTHERAPY IN NON-MUSCLE INVASIVE BLADDER CANCER: WHAT'S THE PROBLEM? Clint Cary*, Laura Militello, Michael Weiner, Paige DeChant, Richard Frankel, and Michael Koch Clint Cary*Clint Cary* More articles by this author , Laura MilitelloLaura Militello More articles by this author , Michael WeinerMichael Weiner More articles by this author , Paige DeChantPaige DeChant More articles by this author , Richard FrankelRichard Frankel More articles by this author , and Michael KochMichael Koch More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000896.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The intravesical instillation of mitomycin C immediately following surgery for non-muscle invasive bladder cancer has been shown to be efficacious in reducing cancer recurrence. This led the American Urological Association guidelines for non-muscle invasive bladder cancer care to support its use in low to intermediate risk patients. Despite this, urologists’ use of this drug following transurethral resection of a bladder tumor (TURBT) has been reported as low as 5% or less in studies and reasons for this are not well understood. METHODS: Semi-structured interviews were conducted with 13 practicing urologists at 4 geographically distinct practice locations throughout Indiana between 2017 and 2018. Cognitive task analysis was used to explore factors that influence clinician decision making about Mitomycin C use following (TURBT) in specific patient cases. Interview transcripts were coded using immersion/crystallization to identify emergent themes. RESULTS: The median age of the urologists interviewed was 44 (IQR 40-48). Eighty-five percent were male. Approximately 30% had completed urologic fellowship training; 62% were in private practice. Three major themes related to the use of mitomycin C emerged: cumbersome workflow processes, urologists’ fears of side effects, and issues with identifying patients most likely to benefit. We identified significant cumbersome workflow processes and administrative barriers of postoperative chemotherapy following a TURBT. CONCLUSIONS: Workflow, fear, and value are key factors and also represent complexities of translating efficacy into effectiveness for a drug with known benefits to patients. Moving from efficacy to effectiveness requires understanding the context and environment in which the drug is going to be used. Areas of potential intervention development to improve the use of mitomycin C to reduce recurrence of bladder cancer are suggested. Source of Funding: NIH NCI K23 Award: 1K23CA212272 © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e639-e639 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Clint Cary* More articles by this author Laura Militello More articles by this author Michael Weiner More articles by this author Paige DeChant More articles by this author Richard Frankel More articles by this author Michael Koch More articles by this author Expand All Advertisement PDF downloadLoading ...

Lifestyle and Non-muscle Invasive Bladder Cancer Recurrence, Progression, and Mortality: Available Research and Future Directions.

BACKGROUND:A broad, comprehensive review of studies exploring associations between lifestyle factors and non-muscle invasive bladder cancer (NMIBC) outcomes is warranted to consolidate recommendations and identify gaps in research.OBJECTIVE:To summarize the literature on associations between lifestyle factors and clinical outcomes among patients with NMIBC.METHODS:PubMed was systematically queried for articles published through March 2019 regarding lifestyle factors and recurrence, progression, cancer-specific mortality, and all-cause mortality among patients with NMIBC.RESULTS:Notwithstanding many ambiguities, there is good-quality evidence suggesting a benefit of smoking avoidance/cessation, healthy body mass index (BMI), and type II diabetes mellitus prevention and treatment. Lactobacillus casei probiotic supplementation may reduce recurrence. There have been individual studies suggesting a benefit for uncooked broccoli and supplemental vitamin E as well as avoidance of supplemental vitamin B9, areca nut chewing, and a “Western diet” pattern high in fried foods and red meat. Additional studies do not suggest associations between NMIBC outcomes and use of fibrin clot inhibitors; insulin and other oral hypoglycemics; statins; supplemental selenium, vitamin A, vitamin C, and vitamin B6; fluid intake and intake of specific beverages (e.g., alcohol, coffee, green tea, cola); various dietary patterns (e.g., Tex-Mex, high fruit and vegetable, low-fat); and occupational and chemical exposures.CONCLUSIONS:Despite a myriad of publications on lifestyle factors and NMIBC, a need remains for research on unexplored associations (e.g., physical activity) and further studies that can elucidate causal effects. This would inform future implementation strategies for healthy lifestyle change in NMIBC patients.

Evaluation of the Role of Early Second Look Cystoscopy after Complete Resection of Non-Muscle Invasive Bladder Tumors

Abstract Background most of the bladder cancers are non-muscle invasion at the time of diagnosis. Non-Muscle invasive tumors confined to the mucosa and invading the lamina propria are classified as stage Ta and T1, respectively, according to the Tumor, Node, Metastasis (TNM) classification system. Aim of the Study to determine the efficacy of early second look cystoscopy after complete resection of non-muscle invasive urinary bladder tumors and its impact on subsequent treatment policy. Patients and Methods this is a prospective clinical study that was done at Urology Department, Faculty of Medicine, Ain Shams University and Damanhur Oncology Centre. A total of 40 consecutive patients with newly diagnosed non-muscle invasive bladder cancer will be enrolled in this prospective study for second-look cystoscopy with TURBT in two to six weeks after initial TURBT and follow them up in one year. Results Single tumor was found in 22 cases (55%), while multiple tumors were recognized in 18 cases (45%) with average sizes ranging from 12mm to 70mm. Low-grade transitional cell carcinoma (TCC) was found in 26 cases (65%), whereas high-grade TCC was found in 14 cases (35%). Stage PTa tumors was found in 12 cases (30%) while 28 cases (70%) have had tumors of PT1 stage. All cases underwent an early second TURBT after (2-6) weeks which has reviled the following data. The majority of cases (28 cases) representing 70% of whole study population were free with no detection of any tumors either residual or recurrence. Residual tumors were detected in six cases (15%) all of which detected in patient with large primary tumor size exceeding 50mm or patients with multiple tumors. Whole detected residual tumors were found at edges of primary tumors ranging 2-5 mm in size which were completely resected and they were of the same stage and grade as the initial tumor. Conclusion Our findings in this study support the notion that second-look cystoscopy with or without TURBT is a prerequisite in patients with superficial bladder cancers except for patients with solitary, small low-grade pTa tumors. It is particularly highly recommended for patients with extensive and multiple tumors at the first TURBT

Alternative Therapies to Bacillus Calmette-Guérin Shortage for Nonmuscle Invasive Bladder Cancer in Brazil and Other Underdeveloped Countries: Management Considerations.

Bacillus Calmette-Guérin (BCG) plays a cornerstone role in the management of nonmuscle invasive urothelial carcinoma of the bladder. However, there has been a worldwide intermittent BCG shortage in recent years that may affect the care of patients with bladder cancer and pose difficult clinical decisions to urologists and clinical oncologists. This literature review aims to clarify alternatives to BCG during a shortage and propose measures to replace BCG, mainly in Brazil and probably in other low- and middle-income countries, where not all studied and commonly suggested treatments are available.

American Urological Association Nonmuscle Invasive Bladder Cancer Risk Model Validation-Should Patient Age be Added to the Risk Model?

We evaluated the AUA (American Urological Association)/SUO (Society of Urologic Oncology) nonmuscle invasive bladder cancer risk model to predict nonmuscle invasive bladder cancer recurrence and progression prior to death. We performed a retrospective analysis using electronic medical records and cancer registry data of patients with nonmuscle invasive bladder cancer in a multicenter United States patient population. We evaluated recurrence-free and progression-free survival according to the AUA/SUO nonmuscle invasive bladder cancer risk model. We then assessed discriminative performance with the c-index and compared the cumulative incidence of recurrence, progression and death across 4 age groups. We identified 1,297 patients with nonmuscle invasive bladder cancer. Median followup in the cohort was 3.2 years. The c-index of the AUA/SUO recurrence model was 0.62 and for progression it was higher at 0.77. Patients younger than 60 years had a 40% greater probability of recurrent nonmuscle invasive bladder cancer vs death while patients 84 years old or older had a 12% greater probability of death prior to recurrence at 5 years. This study was limited by its retrospective design. The AUA/SUO nonmuscle invasive bladder cancer risk model provides predictive performance of recurrence and progression similar to that of previous similar risk models, such as the models of the European Organization for Research and Treatment of Cancer, the Club Urológico Español de Tratamiento Oncológico and the National Comprehensive Cancer Network®. This work illustrates the need to consider age in predictive tools for clinicians who treat patients with nonmuscle invasive bladder cancer.

Proteome-based classification of Nonmuscle Invasive Bladder Cancer.

DNA/RNA-based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high-resolution proteomics analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype-specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low-risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross-omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value.

Abstract LB-051: Integrative, targeted deep sequencing of bladder tumors reveals novel associations between cancer gene mutations and mutational signatures with major risk factors

Abstract Exome and whole-genome sequencing of muscle-invasive (MI) bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle invasive (NMI) bladder cancer with detailed information on bladder cancer risk factors. We used deep, targeted amplicon sequencing of the coding regions of 44 genes frequently mutated in bladder cancer (average 630x coverage for tumor and 350x for germline DNA) to characterize somatic mutations and the mutational spectrum in 307 formalin fixed paraffin embedded bladder tumors (n=260 NMI and n=47 MI) from a population-based case-control study with detailed information on smoking and other risk factors. Variants identified by mutation calling pipelines were validated by manual review of aligned sequences. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate somatic mutations and risk factors. We used SignatureEstimation to extract the four known single base substitution mutational signatures (COSMIC: Sig1, Sig2, Sig13, ERCC2-Signature) and Poisson regression to calculate risk ratios (RRs) and 95%CIs to evaluate signatures and risk factors. The most frequently mutated gene in NMI tumors was FGFR3 (52% mutated) and in MI tumors was TP53 (51% mutated). FGFR3 (89%), STAG2 (81%), and PIK3CA (78%) mutations were significantly higher in Ta tumors compared to T1 or MI tumors. Mutations in histone/chromatin regulating genes (KDM6A, KMT2D, KMT2C, CREBBP, ARID1A, and EP300) were present at a high frequency in low grade Ta tumors. Non-silent KDM6Amutations were significantly more common in females compared to males (OR=1.79,95%CI:1.03-3.11); in females these mutations largely occurred in Ta tumors (86%). There was striking heterogeneity in the relationship between smoking status (current, former, never) and the established signatures: only current smoking was associated with greater ERCC2-Signature variants compared to both former smoking (p-value=0.015) and never smoking (p-value=0.023); only former smoking was associated with APOBEC-Sig13 variants (RR=1.83,95%CI: 1.10-3.04,p-value=0.019); and only never smoking was associated with the APOBEC-Sig2 variants (RR=1.52,95%CI: 1.15-2.01,p-value=0.003). Further, there was significant evidence that smoking duration, the component of smoking most strongly associated with bladder cancer risk, was associated with ERCC2-Signature variants and APOBEC-Sig13 variants among current (p-trend=0.013) and former smokers (p=0.002), respectively. Exploration of insertion/deletions revealed that both status and duration of smoking was significantly associated with presence of any 1bp deletions (p-trend=0.007); these were enriched for deletions in KDM6A (p=0.0003). In conclusion, these data quantify the contribution of bladder cancer risk factors to mutational burden in a population-based series of tumors and reveal distinct signature contributions among never, former and current smokers. Citation Format: Stella Koutros, Nina Rao, Lee E. Moore, Michael L. Nickerson, Donghyuk Lee, Bin Zhu, Larissa Pardo, Dalsu Baris, Molly Schwenn, Alison Johnson, Kristine Jones, Montserrat Garcia-Closas, Ludmila Prokunina-Olsson, Debra T. Silverman, Nathaniel Rothman, Michael Dean. Integrative, targeted deep sequencing of bladder tumors reveals novel associations between cancer gene mutations and mutational signatures with major risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-051.

Sulforaphane Inhibits Nonmuscle Invasive Bladder Cancer Cells Proliferation through Suppression of HIF-1α-Mediated Glycolysis in Hypoxia.

Bladder cancer is the fourth common cancer among men and more than 70% of the bladder cancer is nonmuscle invasive bladder cancer (NMIBC). Because of its high recurrence rate, NMIBC brings to patients physical agony and high therapy costs to the patients' family and society. It is imperative to seek a natural compound to inhibit bladder cancer cell growth and prevent bladder cancer recurrence. Cell proliferation is one of the main features of solid tumor development, and the rapid tumor cell growth usually leads to hypoxia due to the low oxygen environment. In this study we found that sulforaphane, a natural chemical which was abundant in cruciferous vegetables, could suppress bladder cancer cells proliferation in hypoxia significantly stronger than in normoxia (p < 0.05): 20 μM sulforaphane inhibited bladder cancer cell proliferation by 26.1 ± 4.1% in normoxia, while it inhibited cell proliferation by 39.7 ± 5.2% in hypoxia in RT112 cells. Consistently, sulforaphane inhibited cell proliferation by 29.7 ± 4.6% in normoxia, while it inhibited cell proliferation by 48.3 ± 5.2% in hypoxia in RT4 cells. Moreover, we revealed that sulforaphane decreased glycolytic metabolism in a hypoxia microenvironment by downregulating hypoxia-induced HIF-1α and blocking HIF-1α trans-localization to the nucleus in NMIBC cell lines. This study discovered a food sourced compound inhibiting bladder cancer cells proliferation and provided experimental evidence for developing a new bladder cancer preventive and therapeutic strategy.

Compliance With American Urological Association Guidelines for Nonmuscle Invasive Bladder Cancer Remains Poor: Assessing Factors Associated With Noncompliance and Survival in a Rural State

To identify factors associated with nonmuscle invasive bladder cancer (NMIBC) American Urological Association (AUA) guideline compliance in a rural state, to evaluate compliance rates over time, and to assess the impact of patient and provider rurality on delivery of NMIBC care. We identified 847 Iowans in Surveillance, Epidemiology, and End Results-Medicare from 1992 to 2009 with high-grade NMIBC who survived 2 years and were not treated with cystectomy or radiation during this period. Compliance with AUA guidelines was assessed over time and compared to patient demographic, tumor, and treatment institution variables. Impact of rurality was analyzed using Surveillance, Epidemiology, and End Results ZIP code data travel distance of patient to nearest urologist practice location. Overall compliance with AUA guidelines was low (<1%), and did not markedly improve over the study period. In the multivariable model, only care at an academic medical center (OR 11.68, 95% CI 7.07-19.29) and tumor stage (Tis; OR 3.24, 95% CI 1.86-5.63) increased the odds of compliance. Patients living closer (<10 miles) to their urologists underwent more cystoscopies than patients living further (>30 miles) but distance did not affect compliance with other measures. Compliance was not associated with cancer-specific survival. Compliance with post-Transurethral Resection of Bladder Tumor (TURBT) NMIBC treatment guidelines has improved but remains suboptimal in our rural state, and is highly associated with treatment at an academic cancer center for reasons that could not be fully explained with these data.