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  • Bladder Cancer
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  • 1
    Language: English
    In: Oncology Letters, 11/2017, Vol.14(5), pp.5513-5518
    Description: Treatment failure in metastatic bladder cancer is commonly caused by acquisition of resistance to chemotherapy in association with tumor progression. Since alterations of integrins can influence the adhesive and invasive behaviors of urothelial bladder cancer cell lines, the present study aimed to evaluate the role of integrins in bladder cancer cells with acquired resistance to standard first-line chemotherapy with gemcitabine, and cisplatin. Therefore, four gemcitabine- and four cisplatin-resistant sublines out of a panel of four parental urothelial bladder cancer cell lines (TCC-SUP, HT1376, T24, and 5637) were used. Expression of integrin subunits α3, α5, α6, β1, β3, and β4 was detected using flow cytometry. Adhesion and chemotaxis were analyzed. For functional assays, integrin β1 was attenuated with a blocking antibody. In untreated cells, chemotaxis was upregulated in 3/4 gemcitabine-resistant sublines. In cisplatin-resistant cells, chemotaxis was enhanced in 2/4 cell lines. Acquired chemoresistance induced the upregulation of integrin β1 in all four tested gemcitabine-resistant sublines, as well as an upregulation in 3/4 cisplatin-resistant sublines compared with parental cell lines. Following the inhibition of integrin β1, adhesion to extracellular matrix components was downregulated in 3/4 gemcitabine-resistant sublines and in all four tested cisplatin-resistant sublines. Since integrin β1 is frequently upregulated in chemoresistant urothelial cancer cell lines and inhibition of integrin β1 may influence adhesion, further studies are warranted to evaluate integrin β1 as a potential therapeutic target for bladder cancer in vivo .
    Keywords: Adhesion ; Acquired Resistance ; Cancer Cell Line Collection ; Chemotaxis ; Cisplatin ; Gemcitabine ; Integrin Β1 ; Urothelial Cancer
    ISSN: 1792-1074
    E-ISSN: 1792-1082
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  • 2
    In: BJU International, February 2016, Vol.117(2), pp.272-279
    Description: Byline: Atiqullah Aziz, Shahrokh F. Shariat, Florian Roghmann, Sabine Brookman-May, Christian G. Stief, Michael Rink, Felix K. Chun, Margit Fisch, Vladimir Novotny, Michael Froehner, Manfred P. Wirth, Marco J. Schnabel, Hans-Martin Fritsche, Maximilian Burger, Armin Pycha, Antonin Brisuda, Marko Babjuk, Stefan Vallo, Axel Haferkamp, Jan Roigas, Joachim Noldus, Regina Stredele, Bjorn Volkmer, Patrick J. Bastian, Evanguelos Xylinas, Matthias May Keywords: bladder cancer; radical cystectomy; mortality; nomograms; outcome Objective To externally validate the pT4a-specific risk model for cancer-specific survival (CSS) proposed by May etal. (Urol Oncol 2013; 31: 1141-1147) and to develop a new pT4a-specific nomogram predicting CSS in an international multicentre cohort of patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) Patients and Methods Data from 856 patients with pT4a UCB treated with RC at 21 centres in Europe and North-America were assessed. The risk model proposed by May etal., which includes female gender, presence of positive lymphovascular invasion (LVI) and lack of adjuvant chemotherapy administration as adverse predictors for CSS, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver-operating characteristic-derived area under the curve. A nomogram for predicting CSS in pT4a UCB after RC was developed after internal validation based on multivariable Cox proportional hazards regression analysis evaluating the impact of clinicopathological variables on CSS. Decision-curve analyses were applied to determine the net benefit derived from the two models. Results The estimated 5-year-CSS after RC was 34% in our cohort. The risk model devised by May etal. predicted individual 5-year-CSS with an accuracy of 60.1%. In multivariable Cox proportional hazards regression analysis, female gender (hazard ratio [HR] 1.45), LVI (HR 1.37), lymph node metastases (HR 2.54), positive soft tissue surgical margins (HR 1.39), neoadjuvant (HR 2.24) and lack of adjuvant chemotherapy (HR 1.67, all P 〈 0.05) were independent predictors of an adverse CSS rate and formed the features of our nomogram with a predictive accuracy of 67.1%. Decision-curve analyses showed higher net benefits for the use of the newly developed nomogram in our cohort over all thresholds. Conclusions The risk model devised by May etal. was validated with moderate discrimination and was outperformed by our newly developed pT4a-specific nomogram in the present study population. Our nomogram might be particularly suitable for postoperative patient counselling in the heterogeneous cohort of patients with pT4a UCB. Article Note: A.A. and S.F.S. contributed equally to the study.
    Keywords: Bladder Cancer ; Radical Cystectomy ; Mortality ; Nomograms ; Outcome
    ISSN: 1464-4096
    E-ISSN: 1464-410X
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  • 3
    Language: English
    In: Oncology Letters, 06/2017, Vol.13(6), pp.4085-4092
    Description: Nanoparticle albumin-bound (nab)-paclitaxel appears to exhibit better response rates in patients with metastatic urothelial cancer of the bladder whom are pretreated with nab-paclitaxel compared with conventional paclitaxel. Paclitaxel may induce multidrug resistance in patients with cancer, while the mechanisms of resistance against paclitaxel are manifold. These include reduced function of pro-apoptotic proteins, mutations of tubulin and overexpression of the drug transporter adenosine 5′-triphosphate-binding cassette transporter subfamily B, member 1 (ABCB1). To evaluate the role of ABCB1 in nab-paclitaxel resistance in urothelial cancer cells, the bladder cancer cell lines T24 and TCC-SUP, as well as sub-lines with acquired resistance against gemcitabine (T24 r GEMCI 20 and TCC-SUP r GEMCI 20 ) and vinblastine (T24 r VBL 20 and TCC-SUP r VBL 20 ) were examined. For the functional inhibition of ABCB1, multi-tyrosine kinase inhibitors with ABCB1-inhibiting properties, including cabozantinib and crizotinib, were used. Additional functional assessment was performed with cell lines stably transduced with a lentiviral vector encoding for ABCB1, and protein expression was determined by western blotting. It was indicated that cell lines overexpressing ABCB1 exhibited similar resistance profiles to nab-paclitaxel and paclitaxel. Cabozantinib and crizotinib sensitized tumor cells to nab-paclitaxel and paclitaxel in the same dose-dependent manner in cell lines overexpressing ABCB1, without altering the downstream signaling of tyrosine kinases. These results suggest that the overexpression of ABCB1 confers resistance to nab-paclitaxel in urothelial cancer cells. Additionally, small molecules may overcome resistance to anticancer drugs that are substrates of ABCB1.
    Keywords: Abcb1 ; Acquired Resistance ; Bladder Cancer ; Cabozantinib ; Cancer Cell Line Collection ; Crizotinib ; Nanoparticle Albumin-Bound Paclitaxel
    ISSN: 1792-1074
    E-ISSN: 1792-1082
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  • 4
    Language: English
    In: Cancer Epidemiology, February 2018, Vol.52, pp.63-69
    Description: Incidence rates for urothelial carcinoma (UC) have been reported to differ between countries within the European Union (EU). Besides occupational exposure to chemicals, other substances such as tobacco and nitrite in groundwater have been identified as risk factors for UC. We investigated if regional differences in UC incidence rates are associated with agricultural, industrial and residential land use. Newly diagnosed cases of UC between 2003 and 2010 were included. Information within 364 administrative districts of Germany from 2004 for land use factors were obtained and calculated as a proportion of the total area of the respective administrative district and as a smoothed proportion. Furthermore, information on smoking habits was included in our analysis. Kulldorff spatial clustering was used to detect different clusters. A negative binomial model was used to test the spatial association between UC incidence as a ratio of observed versus expected incidence rates, land use and smoking habits. We identified 437,847,834 person years with 171,086 cases of UC. Cluster analysis revealed areas with higher incidence of UC than others (p = 0.0002). Multivariate analysis including significant pairwise interactions showed that the environmental factors were independently associated with UC (p 〈 0.001). The RR was 1.066 (95% CI 1.052–1.080), 1.066 (95% CI 1.042–1.089) and 1.067 (95% CI 1.045–1.093) for agricultural, industrial and residential areas, respectively, and 0.996 (95% CI 0.869–0.999) for the proportion of never smokers. This study displays regional differences in incidence of UC in Germany. Additionally, results suggest that socioeconomic factors based on agricultural, industrial and residential land use may be associated with UC incidence rates.
    Keywords: Environmental Exposure ; Socioeconomic Factor ; Smoking ; Incidence Rates ; Urothelial Carcinoma ; Medicine ; Public Health
    ISSN: 1877-7821
    E-ISSN: 1877-783X
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  • 5
    Language: English
    In: BMC research notes, 27 September 2016, Vol.9(1), pp.454
    Description: Systemic chemotherapy with gemcitabine and cisplatin is standard of care for patients with metastatic urothelial bladder cancer. However, resistance formation is common after initial response. The protein Src is known as a proto-oncogene, which is overexpressed in various human cancers. Since there are controversial reports about the role of Src in bladder cancer, we evaluated the efficacy of the Src kinase inhibitor dasatinib in the urothelial bladder cancer cell line RT112 and its gemcitabine-resistant sub-line RT112GEMCI in vitro and in vivo. RT112 urothelial cancer cells were adapted to growth in the presence of 20 ng/ml gemcitabine (RT112GEMCI) by continuous cultivation at increasing drug concentrations. Cell viability was determined by MTT assay, cell growth kinetics were determined by cell count, protein levels were measured by western blot, and cell migration was evaluated by scratch assays. In vivo tumor growth was tested in a murine orthotopic xenograft model using bioluminescent imaging. Dasatinib exerted similar effects on Src signaling in RT112 and RT112GEMCI cells but RT112GEMCI cells were less sensitive to dasatinib-induced anti-cancer effects (half maximal inhibitory concentration (IC) of dasatinib in RT112 cells: 349.2 ± 67.2 nM; IC of dasatinib in RT112GEMCI cells: 1081.1 ± 239.2 nM). Dasatinib inhibited migration of chemo-naive and gemcitabine-resistant cells. Most strikingly, dasatinib treatment reduced RT112 tumor growth and muscle invasion in orthotopic xenografts, while it was associated with increased size and muscle-invasive growth in RT112GEMCI tumors. Dasatinib should be considered with care for the treatment of urothelial cancer, in particular for therapy-refractory cases.
    Keywords: Acquired Resistance ; Cancer Cell Line Collection ; Dasatinib ; Gemcitabine ; Orthotopic Xenograft Model ; Urothelial Bladder Cancer
    E-ISSN: 1756-0500
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  • 6
    Language: English
    In: World Journal of Urology, 2015, Vol.33(3), pp.343-350
    Description: Byline: Matthias May (1), Atiqullah Aziz (2,5), Sabine Brookman-May (3), Florian Roghmann (4), Joachim Noldus (4), Michael Rink (5), Felix Chun (5), Margit Fisch (5), Vladimir Novotny (6), Manfred Wirth (6), Roman Mayr (2,7), Armin Pycha (7), Antonin Brisuda (8), Bjorn Volkmer (9), Regina Stredele (9), Christopher Dechet (10), Stefan Vallo (11), Axel Haferkamp (11), Marco Schnabel (2), Stefan Denzinger (2), Jan Roigas (12), Christian G. Stief (3), Christian Gilfrich (1), Patrick J. Bastian (13), Jorg B. Engel (14), Maximilian Burger (2), Hans-Martin Fritsche (2) Keywords: Urothelial carcinoma; Bladder cancer; Radical cystectomy; Vaginal invasion; Uterine invasion; Prognosis Abstract: Purpose To evaluate for the first time the prognostic significance of female invasive patterns in stage pT4a urothelial carcinoma of the bladder in a large series of women undergoing anterior pelvic exenteration. Patients and methods Our series comprised of 92 female patients in total of whom 87 with known invasion patterns were eligible for final analysis. Median follow-up for evaluation of cancer-specific mortality (CSM) was 38 months (interquartile ranges, 21--82 months). The impact on CSM was evaluated using multivariable Cox proportional-hazards regression analysis predictive accuracy (PA) was assessed by receiver operating characteristic analysis. Results Vaginal invasion was noted in 33 patients (37.9 % group VAG), uterine invasion in 20 patients (23 % group UT), and infiltration of both vagina and uterus in 34 patients (39.1 % group VAG + UT). Groups VAG and UT significantly differed from group VAG + UT with regard to the presence of positive soft tissue margins (STM) only. Five-year-cancer-specific survival probabilities in the groups VAG, UT, and VAG + UT were 21, 20, and 21 %, respectively (p = 0.955). On multivariable analysis, only STM status (HR = 2.02, p = 0.023) independently influenced CSM. C-indices of multivariable models for CSM with and without integration of invasive patterns were 0.570 and 0.567, respectively (PA gain 0.3 %, p = 0.526). Conclusions Infiltration of the vagina, the uterus or both is associated with poor 5-year survival rates. With regard to CSM, no difference was detectable between patients with different invasion patterns, thus justifying further collectively including these invasive patterns as stage pT4a. Author Affiliation: (1) Department of Urology, St. Elisabeth Medical Centre Straubing, Straubing, Germany (2) Department of Urology, Caritas St. Josef Medical Centre, University of Regensburg, Regensburg, Germany (3) Department of Urology, Ludwig-Maximilians-University Munich, Munich, Germany (4) Department of Urology, Marienhospital Herne, Ruhr-University Bochum, Herne, Germany (5) Department of Urology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany (6) Department of Urology, University Hospital "Carl Gustav Carus", Dresden Technical University, Dresden, Germany (7) Department of Urology, General Hospital of Bolzano, Bolzano, Italy (8) Department of Urology, 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic (9) Department of Urology, Kassel Medical Centre, Kassel, Germany (10) Division of Urology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA (11) Department of Urology, Goethe-University Frankfurt, Frankfurt am Main, Germany (12) Department of Urology, Vivantes Medical Centre Im Friedrichshain and Am Urban, Berlin, Germany (13) Department of Urology, Paracelsus Medical Centre Golzheim, Dusseldorf, Germany (14) Department of Gynecology and Obstetrics, Caritas St. Josef Medical Centre, University of Regensburg, Regensburg, Germany Article History: Registration Date: 22/04/2014 Received Date: 18/03/2014 Accepted Date: 22/04/2014 Online Date: 10/05/2014 Article note: Matthias May and Atiqullah Aziz have contributed equally to this work.
    Keywords: Urothelial carcinoma ; Bladder cancer ; Radical cystectomy ; Vaginal invasion ; Uterine invasion ; Prognosis
    ISSN: 0724-4983
    E-ISSN: 1433-8726
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  • 7
    Language: English
    In: Urologia Internationalis, July 2018, Vol.101(1), pp.16-24
    Description: Background/Aims/Objectives: To evaluate the influence of body mass index (BMI) on complications and oncological outcomes in patients undergoing radical cystectomy (RC). Methods: Clinical and histopathological parameters of patients have been prospectively collected within the “PROspective MulticEnTer RadIcal Cystectomy Series 2011”. BMI was categorized as normal weight (〈25 kg/m2), overweight (≥25–29.9 kg/m2) and obesity (≥30 kg/m2). The association between BMI and clinical and histopathological endpoints was examined. Ordinal logistic regression models were applied to assess the influence of BMI on complication rate and survival. Results: Data of 671 patients were eligible for final analysis. Of these patients, 26% (n = 175) showed obesity. No significant association of obesity on tumour stage, grade, lymph node metastasis, blood loss, type of urinary diversion and 90-day mortality rate was found. According to the ­American Society of Anesthesiologists score, local lymph node (NT) stage and operative case load patients with higher BMI had significantly higher probabilities of severe complications 30 days after RC (p = 0.037). The overall survival rate of obese patients was superior to normal weight patients (p = 0.019). Conclusions: There is no evidence of correlation between obesity and worse oncological outcomes after RC. While obesity should not be a parameter to exclude patients from cystectomy, surgical settings need to be aware of higher short-term complication risks and obese patients should be counselled ­accordingly.
    Keywords: Original Paper ; Urothelial Carcinoma ; Bladder Cancer ; Obesity ; Radical Cystectomy ; Prognosis ; Survival ; Medicine
    ISSN: 0042-1138
    E-ISSN: 1423-0399
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  • 8
    Language: English
    In: World Journal of Urology, 2015, Vol.33(11), pp.1753-1761
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00345-015-1502-y Byline: Vladimir Novotny (1), Michael Froehner (1), Matthias May (2), Chris Protzel (3), Katrin Hergenrother (3), Michael Rink (4), Felix K. Chun (4), Margit Fisch (4), Florian Roghmann (5), Rein-Juri Palisaar (5), Joachim Noldus (5), Michael Gierth (6), Hans-Martin Fritsche (6), Maximilian Burger (6), Danijel Sikic (7), Bastian Keck (7), Bernd Wullich (7), Philipp Nuhn (8), Alexander Buchner (8), Christian G. Stief (8), Stefan Vallo (9), Georg Bartsch (9), Axel Haferkamp (9), Patrick J. Bastian (10), Oliver W. Hakenberg (3), Stefan Propping (1), Atiqullah Aziz (4) Keywords: Bladder cancer; Radical cystectomy; Recurrence; Outcome Abstract: Purpose To externally validate the Christodouleas risk model incorporating pathological tumor stage, lymph node (LN) count and soft tissue surgical margin (STSM) and stratifying patients who develop locoregional recurrence (LR) after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). In addition, we aimed to generate a new model including established clinicopathological features that were absent in the Christodouleas risk model. Methods Prospectively assessed multicenter data from 565 patients undergoing RC for UCB in 2011 qualified for final analysis. For the purpose of external validation, risk group stratification according to Christodouleas was performed. Competing-risk models were calculated to compare the cumulative incidences of LR after RC. Results After a median follow-up of 25 months (interquartile range 19--29), the LR-rate was 11.5 %. The Christodouleas model showed a predictive accuracy of 83.2 % in our cohort. In multivariable competing-risk analysis, tumor stage a[yen]pT3 (HR 4.32, p 〈 0.001), positive STSM (HR 2.93, p = 0.005), lymphovascular invasion (HR 3.41, p 〈 0.001), the number of removed LNs 〈10 (HR 2.62, p 〈 0.001) and the administration of adjuvant chemotherapy (HR 0.40, p = 0.008) independently predicted the LR-rate. The resulting risk groups revealed significant differences in LR-rates after 24 months with 4.8 % for low-risk patients, 14.7 % for intermediate-risk patients and 38.9 % for high-risk patients (p 〈 0.001 for all), with a predictive accuracy of 85.6 %, respectively. Conclusions The Christodouleas risk model has been successfully externally validated in the present prospective series. However, this analysis finds that overall model performance may be improved by incorporating lymphovascular invasion. After external validation of the newly proposed risk model, it may be used to identify patients who benefit from an adjuvant therapy and suit for inclusion in clinical trials. Author Affiliation: (1) Department of Urology, University Hospital "Carl Gustav Carus", Dresden, Germany (2) Department of Urology, St. Elisabeth Hospital, Straubing, Germany (3) Department of Urology, University Medical Center Rostock, Rostock, Germany (4) Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany (5) Department of Urology, Marienhospital Herne, Ruhr-University Bochum, Herne, Germany (6) Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany (7) Department of Urology, University Hospital Erlangen, Erlangen, Germany (8) Department of Urology, Ludwig-Maximilians-University Munich, Munich, Germany (9) Department of Urology, Goethe-University Frankfurt, Frankfurt am Main, Germany (10) Department of Urology, Paracelsus Medical Center Golzheim, Dusseldorf, Germany Article History: Registration Date: 27/01/2015 Received Date: 02/12/2014 Accepted Date: 25/01/2015 Online Date: 08/02/2015
    Keywords: Bladder cancer ; Radical cystectomy ; Recurrence ; Outcome
    ISSN: 0724-4983
    E-ISSN: 1433-8726
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  • 9
    Language: English
    In: Urologic Oncology: Seminars and Original Investigations, October 2016, Vol.34(10), pp.432.e1-432.e8
    Description: To evaluate the prognostic relevance of different prostatic invasion patterns in pT4a urothelial carcinoma of the bladder (UCB) after radical cystectomy. Our study comprised a total of 358 men with pT4a UCB. Patients were divided in 2 groups—group A with stromal infiltration of the prostate via the prostatic urethra with additional muscle-invasive UCB ( = 121, 33.8%) and group B with continuous infiltration of the prostate through the entire bladder wall ( = 237, 66.2%). The effect of age, tumor grade, carcinoma in situ, lymphovascular invasion, soft tissue surgical margin, lymph node metastases, administration of adjuvant chemotherapy, and prostatic invasion patterns on cancer-specific mortality (CSM) was evaluated using competing-risk regression analysis. Decision curve analysis was used to evaluate the net benefit of including the variable invasion pattern within our model. The estimated 5-year CSM-rates for group A and B were 50.1% and 66.0%, respectively. In multivariable competing-risk analysis, lymph node metastases (hazard ratio [HR] = 1.73, 〈0.001), lymphovascular invasion (HR = 1.62, = 0.0023), soft tissue surgical margin (HR = 1.49, = 0.026), absence of adjuvant chemotherapy (HR = 2.11, 〈0.001), and tumor infiltration of the prostate by continuous infiltration of the entire bladder wall (HR = 1.37, = 0.044) were significantly associated with a higher risk for CSM. Decision curve analysis showed a net benefit of our model including the variable invasion pattern. Continuous infiltration of the prostate through the entire bladder wall showed an adverse effect on CSM. Besides including these patients into clinical trials for an adjuvant therapy, we recommend including prostatic invasion patterns in predictive models in pT4a UCB in men.
    Keywords: Bladder Cancer ; Radical Cystectomy ; Mortality ; Outcome ; Prostatic Invasion Pattern ; Medicine
    ISSN: 1078-1439
    E-ISSN: 1873-2496
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  • 10
    Language: English
    In: Clinical Genitourinary Cancer, October 2017, Vol.15(5), pp.e809-e817
    Description: This prospective multicenter study analyzed the effect of hospital and surgeon case volume on perioperative quality of care and short-term complications and mortality in 479 patients undergoing radical cystectomy for bladder cancer. We found that hospital volume might represent an at least equally important factor regarding postoperative complications as the surgeon case volume itself at European tertiary care centers. Case volume has been suggested to affect surgical outcomes in different arrays of procedures. We aimed to delineate the relationship between case volume and surgical outcomes and quality of care criteria of radical cystectomy (RC) in a prospectively collected multicenter cohort. This was a retrospective analysis of a prospectively collected European cohort of patients with bladder cancer treated with RC in 2011. We relied on 479 and 459 eligible patients with available information on hospital case volume and surgeon case volume, respectively. Hospital case volume was divided into tertiles, and surgeon volume was dichotomized according to the median annual number of surgeries performed. Binomial generalized estimating equations controlling for potential known confounders and inter-hospital clustering assessed the independent association of case volume with short-term complications and mortality, as well as the fulfillment of quality of care criteria. The high-volume threshold for hospitals was 45 RCs and, for high-volume surgeons, was 〉 15 cases annually. In adjusted analyses, high hospital volume remained an independent predictor of fewer 30-day (odds ratio, 0.34;  = .002) and 60- to 90-day (odds ratio, 0.41;  = .03) major complications but not of fulfilling quality of care criteria or mortality. No difference between surgeon volume groups was noted for complications, quality of care criteria, or mortality after adjustments. The coordination of care at high-volume hospitals might confer a similar important factor in postoperative outcomes as surgeon case volume in RC. This points to organizational elements in high-volume hospitals that enable them to react more appropriately to adverse events after surgery.
    Keywords: High Volume ; Postoperative Complications ; Quality of Health Care ; Urinary Bladder Neoplasms ; Volume-Outcome Relationship ; Medicine
    ISSN: 1558-7673
    E-ISSN: 1938-0682
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