Transurethral en bloc submucosal hydrodissection vs conventional resection for resection of non-muscle-invasive bladder cancer (HYBRIDBLUE): a randomised, multicentre trial.

OBJECTIVE: To determine whether transurethral en bloc submucosal hydrodissection of bladder tumours (TUEB) improves the quality of the resection compared to conventional transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A randomised, multicentre trial (HYBRIDBLUE) was conducted with a superiority design. Six German academic centres participated between September 2012 and August 2015. Based on literature analysis, a sample size for accurate histopathological assessment concerning muscle invasion was assumed to be feasible in 50% (P0 = 0.5) of TURBT and 80% of TUEB cases. After pre-screening of a total of 305 patients, participants were allocated to two study arms: Group I: hexaminolevulinate (HAL)-guided TUEB; Group II: conventional HAL-guided TURBT. The primary endpoint was the proportion of specimens that could be reliably evaluated pathologically concerning muscle invasiveness. Secondary endpoints included rates of histopathological completeness of the resection, muscularis propria content, recurrence, and complication rates. RESULTS: A total of 115 patients (TUEB 56; TURBT 59) were eligible for final analysis. Adequate histopathological assessment, which included muscularis propria content and tumour margins (R0 vs R1), was present in 48/56 (86%) TUEB patients compared to 37/59 (63%; P = 0.006) in the TURBT group. R0 was confirmed in 30/56 TUEB patients (57%) and five of 59 TURBT patients (9%; P < 0.001). No complications of Grade ≥III were observed in both arms. At 3 and 12 months, three and 19 patients recurred in the TUEB group vs seven and 11 patients in the TURBT group, respectively (P = 0.33 and P = 0.08). CONCLUSIONS: In this randomised study, TUEB was shown to be clinically safe regarding perioperative endpoints. An adequate histopathological assessment concerning muscle invasion was significantly better assessable in the TUEB arm compared to standard TURBT. This finding indicates the clinical potential for reducing the rate of early re-resections. Yet, a larger study with recurrence-free survival as the primary endpoint is needed to assess the oncological efficacy between both techniques.

Prognostic Features for Objectively Defined Urinary Continence after Radical Cystectomy and Ileal Orthotopic Neobladder in a Contemporary Cohort.

PURPOSE: We objectively quantified daytime and nocturnal continence rates, and defined predictive features for favorable continence outcomes after radical cystectomy and orthotopic ileal neobladder creation. MATERIALS AND METHODS: At 1 institution 1,012 cystectomies were performed between 2004 and 2015. Questionnaires evaluating the continence status were sent to 244 patients. To objectify postoperative urine loss daytime and nocturnal pad tests were performed. Continence was defined as the need for up to 1 safety pad and urine loss 10 gm or less per test. Predefined associative features were tested for an influence on continence outcomes. Statistical analysis was done with the Fisher exact and Mann-Whitney U tests, and linear logistic regression models. Significance was considered at p <0.05. RESULTS: A total of 188 patients (77.0%) returned the questionnaires. Median followup was 61 months. Median daytime pad use was 1 pad per day (range 0 to 9). Median daily urine loss based on standardized pad testing was 8 gm (range 0 to 2,400). During the night a median of 1 pad (range 0 to 7) was used and median nocturnal urine loss was 28.5 gm (range 0 to 1,220). The continence rate was 54.3% during the day and 36.3% at night. On multivariate analysis good preoperative ECOG (Eastern Cooperative Oncology Group) status (OR 2.987, p = 0.010), retained sensation of bladder filling (OR 6.462, p = 0.003) and preoperative coronary heart disease (OR 0.036, p = 0.002) were independent predictors of daytime success. Based on preoperative risk factors a simple predictive score for daytime continence was created (AUC 0.725, p <0.001). CONCLUSIONS: Continence rates after orthotopic ileal neobladder creation are lower than previously described when objective continence definitions are applied. Patients with good performance status, without coronary heart disease and with retained sensation of orthotopic ileal neobladder filling have better daytime continence outcomes.

Prospective evaluation of health-related quality of life after radical cystectomy: focus on peri- and postoperative complications.

OBJECTIVES: To analyse the impact of perioperative complications and complex treatment courses on postoperative health-related quality of life (HRQOL) after radical cystectomy (RC) and continent (ONB) or incontinent (IC) urinary diversion at multiple prospective time points. METHODS: A total of 121 consecutive patients underwent RC with curative intent between 2013 and 2014. HRQOL was prospectively assessed preoperatively, after 3 and 12 months, using the QLQ-C30 questionnaire. The impact of complex perioperative treatment courses including cases requiring surgical re-interventions was retrospectively assessed using Martin criteria and the Clavien-Dindo scale. Urinary continence was determined using the validated ICIQ-SF questionnaire. Statistical analysis included Kruskal-Wallis ANOVA, Spearman's rank correlation, and ordinal regression models (p < 0.05). RESULTS: A total of 100 patients underwent further analysis. Physical functioning (PF), role functioning (RF), and global health status (GHS) scores were higher in the ONB subgroup both preoperatively (p < 0.001, 0.010, 0.048) and 3 months after RC (p = 0.003, 0.048, 0.019). Clavien complications ≥III led to reduced PF levels after 3 months (p = 0.050) without effect on GHS (p = 0.825). Operating time and length of critical care monitoring correlated with 3 months pain scores in the ONB subgroup (p = 0.003, 0.009) without affecting GHS (p = 0.603, 0.653). Continent urinary diversion was an independent predictor of increased HRQOL after 3 months (p = 0.021), however, not after 12 months (p = 0.803). CONCLUSIONS: Patients receiving an IC have lower PF, RF, and GHS scores than those receiving ONB. Perioperative complications and complicated treatment courses can affect HRQOL subdomains but do not significantly impact the GHS. ONB is an independent predictor for better overall HRQOL 3 months, but not 12 months after RC.

Fibroblast growth factor receptor (FGFR) gene amplifications are rare events in bladder cancer.

AIMS: Activating point mutations and protein overexpression of fibroblast growth factor receptors (FGFRs), especially FGFR3, are frequent events in bladder cancer. Little is known about gene amplifications, therefore we characterized amplification of FGFR1-3 by fluorescence in-situ hybridization (FISH). METHODS AND RESULTS: Tumours of 153 patients (n = 65 pTa low-grade, n = 15 pTa high-grade, n = 37 pT1, n = 20 pT2, n = 10 pT3, n = 6 pT4) were analysed by FISH for FGFR1-3 copy numbers and screened for FGFR3 mutations and immunohistochemical protein expression. Amplifications of FGFR1 were found in 1.6% (two of 122), FGFR2 in 0.8% (one of 121) and FGFR3 in 3.4% (five of 145). All amplifications were high-level amplifications, not overlapping with polysomy. Amplifications were found in papillary/papillary-invasive tumour parts, and predominantly in tumours with enhanced Ki67 index (>10%), aberrant CK20 expression, and low p53 expression. All FGFR3-amplified samples showed concomitant FGFR3 mutations and FGFR3 protein overexpression. FGFR amplifications were not associated significantly with gender, age, grade or stage in statistical analyses. CONCLUSIONS: FGFR amplifications are rare events in bladder cancer, with FGFR3 amplification being the most prevalent (3.4% of cases). Concomitant FGFR3 mutations and protein overexpression indicate that FGFR3-mediated signalling in these tumours would probably be highly active. This patient subgroup may be particularly suited to FGFR-targeted pharmacotherapy.

Prognostic Value of the Preoperative Platelet-to-leukocyte Ratio for Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer.

BACKGROUND: Currently, stratification of patients with bladder cancer (BC) mainly relies on histopathologic and clinical staging. Furthermore, inflammation plays an important role in the pathogenesis of BC. With the preoperative platelet-to-leukocyte ratio (PLR), we introduce a novel prognostic marker based on routine hematologic values in patients undergoing radical cystectomy (RC). PATIENTS AND METHODS: In our cohort of 665 patients undergoing RC (2004-2015) for urothelial carcinoma of the bladder (UCB), we analyzed a variety of preoperative hematologic parameters. We investigated the effect of thrombocytosis, leukocytosis, and the PLR on the oncologic outcomes, including cancer-specific survival (CSS), progression-free survival (PFS), and overall survival (OS). Both univariate (log-rank test) and multivariate (Cox regression) analysis were performed. The prevalence of thrombocytosis and leukocytosis and differences in the PLR was assessed using the Mann-Whitney U test. The cutoff levels for leukocytosis, thrombocytosis, and the PLR were defined using receiver operating characteristic curve analysis, with the 5-year CSS as the binary classifier. RESULTS: A PLR of ≤ 28 (CSS, P = .033; OS, P = .029) and leukocytosis (CSS, P = .01; OS, P = .001; PFS, P = .003) were significantly associated with adverse oncologic outcomes using the log-rank test. On multivariate regression analysis, the PLR (CSS, P = .022; OS, P = .025) remained a significant prognostic marker among the standard staging variables and hemoglobin level. Advanced BC disease was significantly more prevalent in the patient subgroup with a low PLR (pT2-pT4, 35%; vs. pT ≤ 1, 24%; P = .006) and leukocytosis (pT2-pT4, 46%; vs. pT ≤ 1, 30%; P < .001; pN+, 49%; vs. pN0, 39%; P < .047). CONCLUSION: To the best of our knowledge, the present study is the first report of the preoperative PLR as a prognostic factor in patients undergoing RC for UCB. Compared with other inflammatory markers in BC, the PLR can be assessed without additional effort. External validation and its combination with other parameters might improve current prognostication systems for UCB.

Follow-up of high-risk bladder cancer-Is it safe to perform fluorescence endoscopy multiple times in the same patient?

PURPOSE: As the use of fluorescence endoscopy is recommended today by different guidelines during the follow-up of high-grade non-muscle-invasive bladder cancer, the aim of this study is to analyze whether the multiple use of hexylaminolevulinate (HAL) for TUR-BT can be performed safely within the same patient over a time interval. METHODS: Data of patients diagnosed and treated with HAL-TUR-B at our institute between 2008 and 2013 were analyzed. Special interest was given to side effects observed during the instillation of the substance, on the whole day of the instillation and during the entire hospital stay. We focussed on side effects associated with the use of HAL, such as allergic reactions, urinary tract infections, photosensitization of the skin, and relevant changes in blood pressure. RESULTS: In the time between 2008 and 2013, 2480 HAL-TUR-BTs were performed in total at our institute. In 80 patients, HAL-TUR-BT was used at least 2 times, and on average 4 times (2-12 times). Only patients with multiple uses were included for our final analysis. We observed no allergizations in any of the treated patients. Minor side effects were urinary tract infections (n = 4), dysuria (n = 4), pollakisuria (n = 9), and bladder spasms (n = 17). CONCLUSION: In our study cohort, the multiple use of HAL-TUR-BT within the same patient caused no major side effects or an induction of allergization against the substance. We, therefore, conclude that HAL-TUR-BT can be performed safely in the same patient during the follow-up of aggressive tumors as recommended by different guidelines today.

Dramatic impact of blood transfusion on cancer-specific survival after radical cystectomy irrespective of tumor stage.

OBJECTIVE: The aim of the present study was to determine the influence of intraoperative and postoperative blood transfusion on cancer-specific outcome. MATERIALS AND METHODS: Follow-up data were collected from 722 patients undergoing radical cystectomy for urothelial carcinoma of the bladder (UCB) between 2004 and 2014. Median follow-up was 26 months (interquartile range 12-61 months). Outcome was analyzed in relation to the amount of intraoperative and postoperative blood transfusion and different tumor stages. The primary endpoint was cancer-specific survival (CSS) after cystectomy. Kaplan-Meier analysis with log-rank test and Cox regression models were used. RESULTS: Intraoperative blood transfusion was given in 36% (263/722) and postoperative blood transfusion in 18% (132/722). In patients with and without intraoperative blood transfusion, 5 year CSS was 48% and 67%, respectively (p < .001). In patients with and without postoperative blood transfusion, 5 year CSS was 48% and 63%, respectively (p < .001). The number of transfused red blood cell (RBC) units [intraoperatively: hazard ratio (HR) = 1.08, 95% confidence interval (CI) 1.01-1.15, p = .023; postoperatively: HR = 1.14, 95% CI 1.07-1.21, p < .001] was an independent prognostic factor for CSS. The dose-dependent negative effect of transfusions was also found in favorable subgroups (pT1 tumor, hemoglobin ≥13 mg/dl, p = .004) and in a high-volume surgeon subgroup (n = 244, p < .001). CONCLUSIONS: Blood transfusions during and after radical cystectomy were independent prognostic factors for CSS in this retrospective study. Therefore, efforts should be made to reduce the necessity of intraoperative and postoperative blood transfusion in cystectomy patients.