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Currently, voided urine cytology (VUC) serves as the gold standard for the detection of bladder cancer (BCa) in urine. Despite its high specificity, VUC has shortcomings in terms of sensitivity. Therefore, alternative biomarkers are being searched, which might overcome these disadvantages as a useful adjunct to VUC. The aim of this study was to evaluate the diagnostic potential of the urinary levels of selected microRNAs (miRs), which might represent such alternative biomarkers due to their BCa-specific expression. Expression levels of nine BCa-associated microRNAs (miR-21, -96, -125b, -126, -145, -183, -205, -210, -221) were assessed by quantitative PCR in urine sediments from 104 patients with primary BCa and 46 control subjects. Receiver operating characteristic (ROC) curve analyses revealed a diagnostic potential for miR-96, -125b, -126, -145, -183, and -221 with area under the curve (AUC) values between 0.605 and 0.772. The combination of the four best candidates resulted in sensitivity, specificity, positive and negative predictive values (NPV), and accuracy of 73.1%, 95.7%, 97.4%, 61.1%, and 80.0%, respectively. Combined with VUC, sensitivity and NPV could be increased by nearly 8%, each surpassing the performance of VUC alone. The present findings suggested a diagnostic potential of miR-125b, -145, -183, and -221 in combination with VUC for non-invasive detection of BCa in urine., Competing Interests: The authors declare no conflict of interest.

Purpose: There is no consensus on the best comorbidity measure in candidates for radical cystectomy. The aim of this study was to identify tool best suited to identify patients at risk for 90-day or premature long-term non-bladder cancer mortality., Methods: We studied 1268 patients who underwent radical cystectomy to identify patients at risk for 90-day and later-than-90-day mortality, respectively. Six classifications were investigated as possible predictors of both types of mortality. Multivariable models including age as continuous variable and each classification separately were calculated. A heuristic ranking was based on the evaluation of the hazard ratios, p values, Akaike's information criteria, and concerning the logit models also the areas under the curve., Results: The median follow-up was 5.7 years. Within 90 days after surgery, the mortality rate was 4.2%. The greatest independent contribution concerning the prediction of 90-day mortality was seen with the American Society of Anesthesiologists (ASA) physical status classification (classes 3-4 versus 1-2: hazard ratio 7.98, 95% confidence interval 3.54-18.01, p < 0.0001). In the longer term, countable diseases (Canadian Cardiovascular Society classification of angina pectoris, conditions contributing the Charlson score) were of greater importance. The results of heuristic ranking were confirmed by multivariate analyses including age and all classifications together., Conclusions: Besides to chronological age, clinicians should pay particular attention to the ASA classification to identify patients at risk for 90-day mortality after radical cystectomy, whereas long-term mortality is more determined by countable comorbid diseases.

Objective: To investigate the impact of socioeconomic status-related parameters on competing (non-bladder cancer) mortality after radical cystectomy., Patients and Methods: A total of 1,268 consecutive patients who underwent radical cystectomy for urothelial or undifferentiated bladder cancer at our institution between 1993 and 2016 with a mean age of 69 years (median 70 years) were studied. The mean -follow-up of the censored patients was 7.2 years (median 5.7 years). Proportional hazard models for competing risk were used to identify predictors of non-bladder cancer (competing) mortality. The following parameters were included into multivariate analyses: age, American Society of Anesthesiologists physical status classification, Charlson score, gender, level of education, smoking status, marital status, local tumour stage, lymph node status, adjuvant and neoadjuvant chemotherapy., Results: Besides age and both comorbidity classifications, the socioeconomic status-related parameters gender (female versus male, hazard ratio [HR] 0.58, 95% CI 0.40-0.84, p = 0.0042), level of education (university degree or master craftsman versus others, HR 0.76, 95% CI 0.56-0.1.03, p = 0.0801), smoking status (current smoking versus others, HR 1.47, 95% CI 1.10-1.96, p = 0.0085) and marital status (married versus others, HR 0.68, 95% CI 0.50-0.92, p = 0.0133) were independent predictors of competing mortality after radical cystectomy. If considered in combination (multiplication of HRs), the prognostic impact of socioeconomic parameters superseded that of the investigated comorbidity classifications., Conclusion: Socioeconomic status-related parameters may provide important information on the long-term competing mortality risk after radical cystectomy supplementary to chronological age and comorbidity., (© 2019 S. Karger AG, Basel.)

Objective: To investigate the capability of a modified self-administrable comorbidity index recommended in the standard sets for neoplastic diseases published by the International Consortium for Health Outcomes Measurement (ICHOM) to predict 90-day and long-term mortality after radical cystectomy., Methods: A single-center series of 1,337 consecutive patients who underwent radical cystectomy for muscle-invasive or high-risk non-muscle-invasive urothelial or undifferentiated bladder cancer were stratified by the modified self-administrable comorbidity index and Charlson score, respectively. Multivariate logit models (for 90-day mortality) and proportional-hazards models (for overall and non-bladder cancer mortality) were used for statistical workup., Results: Considering 90-day mortality, both comorbidity indexes contributed independent information when analyzed together with age (p < 0.0001). The Charlson score performed slightly better (area under the curve [AUC] 0.74 vs. 0.72 for the ICHOM-recommended comorbidity index). Considering 5-year overall mortality in 727 patients with complete observation, the performance of both measures was similar (AUC 0.63 vs. 0.62, including age AUC 0.66 for both indexes). With 6-sided stratifications, the modified self-administrable comorbidity index separated the risk groups slightly better (p values for directly neighboring curves: 0.0068-0.1043 vs. 0.0001-0.8100)., Conclusion: The ICHOM-recommended modified self-administrable comorbidity index is capable of predicting 90-day mortality and long-term non-bladder cancer mortality after radical cystectomy similarly to the commonly used Charlson score., (© 2020 S. Karger AG, Basel.)

Background: Cell-free DNA (cfDNA) is proposed to be a valuable source of biomarkers in liquid biopsies for various diseases as it is supposed to partially originate from tumor cells. However, data about the diagnostic implications of cfDNA in urine for the detection of bladder cancer (BCa) is sparse., Methods: We evaluated the usability of urinary cfDNA for diagnostic purposes compared to urine sediment DNA (sDNA) in 53 BCa patients and 36 control subjects by analyzing two abundant point-mutations (C228T/C250T) in the TERT promoter using Next-Generation Sequencing., Results: Mutations were detected in 77% of the urinary sDNA compared to 63% of the cfDNA samples. Moreover, the TERT mutation allele frequencies (MAF) were highly correlated in cfDNA and sDNA. In comparison, the accuracy of the TERT assay was higher in sDNA (84%) compared to cfDNA or voided urine cytology (both 77%). Interestingly, MAFs from leukocyte-rich urines were higher in cfDNA than in sDNA, indicating a diagnostic advantage of cfDNA in such urines., Conclusions: Urine-based mutation detection has the ability to augment and surpass voided urine cytology as the current gold-standard for the non-invasive detection and surveillance of BCa. The analysis of cell-free DNA provides no general diagnostic advantage compared to urine sediment DNA., (Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Radical cystectomy bears a considerable perioperative mortality risk particularly in elderly patients. In this study, we searched for predictors of perioperative and long-term competing (non-bladder cancer) mortality in elderly patients selected for radical cystectomy., Methods: We stratified 1184 consecutive patients who underwent radical cystectomy for high risk superficial or muscle-invasive urothelial or undifferentiated carcinoma of bladder into two groups (age < 80 years versus 80 years or older). Multivariable and cox proportional hazards models were used for data analysis., Results: Whereas Charlson score and the American Society of Anesthesiologists (ASA) physical status classification (but not age) were independent predictors of 90-day mortality in younger patients, only age predicted 90-day mortality in patients aged 80 years or older (odds ratio per year 1.24, p = 0.0422). Unlike in their younger counterparts, neither age nor Charlson score or ASA classification were predictors of long-term competing mortality in patients aged 80 years or older (hazard ratios 1.07-1.10, p values 0.21-0.77)., Conclusions: This data suggest that extrapolations of perioperative mortality or long-term mortality risks of younger patients to octogenarians selected for radical cystectomy should be used with caution. Concerning 90-day mortality, chronological age provided prognostic information whereas comorbidity did not.

Background: Data on the impact of gender on mortality after radical cystectomy is conflicting. We investigated a large single center sample with long-term follow-up in order to determine the relationship between gender and outcome., Patients and Methods: A total of 1,184 consecutive patients who underwent radical cystectomy for high risk superficial or muscle-invasive urothelial or undifferentiated bladder cancer between 1993 and 2015 were stratified by gender. Demographic data was compared using Mann-Whitney U test, chi-square test, or Fisher exact test. Cox proportional hazard models were used for the analysis of competing risks and logit models were used for the prediction of the receipt of adjuvant cisplatin-based chemotherapy., Results: Female patients were older, healthier, less frequently current smokers and had more extravesical tumors. In the multivariate analyses, female gender was an independent predictor of (lower) non-bladder cancer (competing) mortality (hazards ratio [HR] 0.68, 95% CI 0.49-0.95, p = 0.0248) but no predictor of bladder cancer-specific mortality (HR in the full model 1.20, 95% CI 0.94-1.54, p = 0.15). Gender was no predictor of the receipt of adjuvant cisplatin-based chemotherapy., Conclusions: Female gender was associated with an increased risk of extravesical disease but was no independent predictor of bladder cancer-specific mortality. Anatomical differences might be a plausible explanation for these observations., (© 2018 S. Karger AG, Basel.)

Purpose: Cytokeratin 20 (CK20) and insulin-like growth factor 2 (IGF2) were previously proposed to be elevated in clinical samples from patients with bladder cancer (BCa). A two cohort design validation study was used to assess the relevance for BCa detection by transcript quantitation of both markers in urine samples. Their diagnostic value was assessed in comparison with voided urine cytology (VUC)., Methods: RNA isolation was carried out using cellular sediments of urine samples from 196/103 histologically positive BCa patients, as well as 97/50 control subjects for the test (TC) and validation cohort (VC), respectively. Urinary transcript levels of CK20 and IGF2 were determined by qPCR., Results: Relative transcript levels were significantly elevated 3.4/11-fold for CK20 and 188/64-fold for IGF2 (p < 0.001) in urine sediments of BCa patients compared to controls in the TC and VC, respectively. In a combined analysis, the resulting sensitivity (SN) (SN TC : 77.9; SN VC : 90.3%) and specificity (SP) (SP TC : 88.0; SP VC : 84.0%) were similar to that of VUC. The sensitivity of VUC in combination with CK20 and IGF2 was considerably increased (SN TC : 94.6; SN VC : 93.2%) while specificity was reduced (SP TC : 72.0; SP VC : 82.0%) compared to VUC alone in the test and validation cohort., Conclusions: Transcript levels of IGF2 and CK20 enabled the detection of BCa with a diagnostic performance similar to VUC. Combined analysis of voided urine cytology together with altered transcript levels of CK20 and IGF2 enhanced sensitivity, but did not improve overall test performance.

Purpose: There is no generally accepted instrument to measure comorbidity in patients with cancer. We determined which single comorbid conditions are independently associated with competing mortality after radical prostatectomy or radical cystectomy in order to develop a mortality index., Methods: The study samples consisted of 2,961 consecutive patients who underwent radical prostatectomy between 1992 and 2007 for clinically localized prostate cancer and 932 consecutive patients who underwent radical cystectomy between 1993 and 2012 for high-risk non-muscle-invasive or muscle-invasive urothelial or undifferentiated bladder cancer. Competing mortality was the study endpoint. Proportional hazard models for the subdistribution of competing risks were used for analysis., Results: Age, angina pectoris, peripheral vascular disease, cerebrovascular disease, chronic lung disease, diabetes mellitus, moderate or severe renal disease, current smoking, and American Society of Anesthesiologists (ASA) physical status class 3 to 4 were independent predictors of competing mortality after radical prostatectomy. After identifying radical cystectomy, age, angina pectoris, chronic lung disease, diabetes mellitus, current smoking, ASA class 3 to 4, and male sex as independent predictors of competing mortality, a combined mortality index using the conditions independently associated with competing mortality in both samples stratified the patients into risk groups with 0% 10-year competing mortality in the lowest and approximately 50% in the highest-risk classes., Conclusions: This simple and plausible combined mortality index based on age, ASA class, smoking status, and the presence of the conditions such as angina pectoris, chronic lung disease, and diabetes mellitus may be used to predict competing mortality in candidates for radical prostatectomy or radical cystectomy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Radical cystectomy (RC) is a major surgical procedure accompanied with meaningful complications and countable perioperative mortality. To identify the risk factors predicting the perioperative morbidity and mortality is essential. The study aimed to identify relevant, patient-specific factors associated with 90-day mortality following RC, which may serve as a foundation for improving healthcare delivery to patients with bladder cancer., Methods: We investigated a sample of 1015 consecutive patients in order to identify predictors of 90-day mortality after RC. Beside tumor-related parameters, ASA classification, NYHA, Canadian Cardiovascular Society classification of angina pectoris, Charlson score, age, gender and the single conditions contributing to the Charlson score were included in the multivariable analyses. The patient data were collected retrospectively, except the ASA score that was obtained prospectively., Results: We identified a model containing the parameters age (OR 1.05, p = 0.023), ASA classification of 3-4 (OR 6.19, p < 0.001) and Charlson score (OR 1.22, p = 0.003) to predict 90-day mortality. Among the single conditions to the Charlson score, moderate or severe renal disease (OR 3.94, p < 0.001) and liver disease (OR 3.24, p = 0.037) were most closely related to 90-day mortality., Conclusions: Age, ASA classification and Charlson score as well as moderate or severe renal disease and liver disease appear to be independent predictors of 90-day mortality after RC. Given the highly significant association of ASA score with 90-day mortality and the relative ease and width disposability of this measure, this classification should be, after external validation, incorporated into daily clinical practice in treatment of patients planned to RC.

Unlabelled: Adding chemotherapy to radical cystectomy (RC) may improve outcome. Neoadjuvant treatment is advocated by guidelines based on meta-analysis data but is severely underused in clinical practice. Adjuvant treatment of patients at risk could be an alternative. We analyzed a sample of 798 patients who underwent RC between 1993 and 2011 for high-risk superficial or muscle-invasive urothelial or undifferentiated bladder cancer, of which 23% received adjuvant cisplatin-based chemotherapy and %5 received neoadjuvant chemotherapy. The use of adjuvant chemotherapy was an independent predictor of decreased overall mortality (hazard ratio [HR]: 0.50; 95% confidence interval [CI], 0.38-0.66; p<0.0001) and bladder cancer-specific mortality (HR: 0.71; 95% CI, 0.52-0.97; p=0.0321), but it was not associated with competing mortality. Similar figures were obtained when analyzing the number of cisplatin-containing cycles administered or when restricting the analysis to patients with lymph node-positive or extravesical but lymph node-negative disease, suggesting a mortality-reducing treatment effect after adjusting for several patient- and tumor-related confounders. Future trials should directly compare the concepts of neoadjuvant and adjuvant application of chemotherapy in candidates for RC., Patient Summary: Adjuvant chemotherapy may decrease overall and bladder cancer-specific mortality after radical cystectomy (RC). Future trials should directly compare the concepts of neoadjuvant and adjuvant application of chemotherapy in candidates for RC., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: Radical cystectomy is the preferred standard treatment for patients with muscle-invasive bladder cancer. With improvements in intra- and perioperative care lower complication rates have been reported. We retrospectively evaluated our series of patients who underwent radical cystectomy for advanced bladder cancer for perioperative complications as well as operative time, postoperative hospital stay and transfusion rates., Patients and Methods: Between April 1993 and August 2005, 516 radical cystectomies were performed for muscle infiltrating transitional cell carcinoma and other types of neoplastic diseases of the bladder at our institution. The average age was 66.3 yr (31-89)., Results: The perioperative mortality rate was 0.8%. A total of 141 patients (27.3%) developed at least one perioperative complication. The most frequent medical complications were subileus in 20 (3.9%) patients, deep venous thrombosis in 24 (4.7%), and enterocolitis in 10 (1.9%). Surgical complications included pelvic lymphoceles in 42 (8.1%) patients, wound dehiscence in 46 (8.9%), pelvic hematoma in 4 (0.8%), peritonitis in 4 (0.8%) and small bowel obstruction in 4 (0.8%). The total early reoperation rate was 6.2%. Operative time, postoperative hospital stay and average number of blood units transfused decreased over the period 1993-2005., Conclusions: Radical cystectomy today is a procedure with an acceptable rate of perioperative morbidity and mortality. Improvements in surgical technique and anaesthesia as well as increased quality of perioperative care in recent years have resulted in reduced morbidity and shorter hospital stay.