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Introduction: A few studies addressed predictive factors of cancer-specific mortality (CSM) in patients with recurrent renal cell carcinoma (RCC) following surgery. Time to recurrence (TTR) is an important predictor of CSM in various types of cancers. The aim of our study was to describe the course of RCC following disease recurrence and to identify prognostic factors that influence CSM with a special focus on TTR., Materials and Methods: Retrospective analysis of 331 patients who experienced disease recurrence after radical nephrectomy (n = 307) or partial nephrectomy (n = 24) with curative intent. A Cox proportional hazards regression model addressed the association between various clinicopathologic features and CSM after disease recurrence. TTR was defined as time from surgery to occurrence of disease recurrence., Results: Of the 331 patients, 232 (70%) were male, and 99 (30%) were female. The median age at surgery was 62 years (interquartile range, 53-69 years). Median time from nephrectomy to disease recurrence was 1.2 years (interquartile range, 0.5-3.3 years). Of the recurrences, 63 (19%) were local, and 268 (81%) were distant. Shorter time to recurrence (P = .0008), female gender (P = .035), and distant versus local recurrence location (P < .0001) were found to be independently associated with CSM following disease recurrence., Conclusions: In patients experiencing disease recurrence after nephrectomy for presumably localized RCC, shorter TTR, female gender, and distant recurrence were found to be associated with worse CSM. The inclusion of these factors into risk-stratification tools may help patient counseling and decision-making regarding type and regimen of salvage treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To evaluate whether age affects the clinical benefit afforded by immediate postoperative intravesical instillation of mitomycin C in a contemporary cohort of patients with NMIBC., Patients and Methods: A total of 4,258 patients with NMIBC treated with transurethral resection of the bladder with (n = 2,605, 61%) or without (n = 1,652, 39%) one immediate instillation of mitomycin C from 5 institutions (study period: 2000-2007) were included. No patients received adjuvant instillations. A multivariable Cox proportional hazards regression model adjusting for standard clinical and pathological features tested the potential interaction term between age and administration of mitomycin C with regard to disease recurrence., Results: A total of 2,063 patients experienced disease recurrence with a median follow-up of 48 months for those who did not recur. In multivariable Cox regression analysis, immediate postoperative instillation of mitomycin C (HR: 0.62; 95% CI: 0.56-0.68; P<0.0001) and age (HR: 1.04; 95% CI: 1.00-1.09; P = 0.036) were associated with disease recurrence. We observed only slight decreases in recurrence-free survival with age irrespective of treatment administration of mitomycin C or not., Conclusion: We confirmed reduced disease recurrence rates associated with 1 immediate postoperative intravesical instillation of mitomycin C in NMIBC patients. The benefit on recurrence-free survival of a postoperative intravesical instillation was preserved across all ages and therefore age by itself should not be taken into consideration when deciding to use it., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To characterize outcomes of patients with TaT1 urothelial carcinoma of the bladder stratified by the European Association of Urology (EAU) categories and to compare them with European Organization for Research and Treatment of Cancer (EORTC) risk groups to assess the rate and effect of reclassification., Patients and Methods: A multi-institutional database of 5,122 patients with TaT1 urothelial carcinoma of the bladder who underwent transurethral resection of the bladder with or without adjuvant therapy at 8 institutions between 1996 and 2007. Multivariable Cox-regression analyses addressed factors associated with disease recurrence and progression. The net reclassification index was used to compare the performance of the EAU categories with the EORTC scoring system., Results: Of 5,122 patients, 632 (12.3%), 2,302 (45.0%), and 2,188 (42.7%) were assigned to the low-, intermediate-, and high-risk EAU category, respectively. Within a median follow-up of 62 months (interquartile range: 27-97), 2,365 (46.2%) and 516 (10.1%) patients experienced disease recurrence and progression, respectively. In multivariable Cox-regression analyses, EAU intermediate- and high-risk categories were associated with a higher risk of disease recurrence (P<0.001) and progression (P<0.001) compared to low-risk patients. Application of the EAU categories reclassified 1,940 (37.9%) patients into a higher risk group for recurrence. Likewise, 602 (11.8%) patients were reclassified to a higher and 278 (5.4%) to a lower risk group for progression. The net reclassification index of the EAU risk stratification was 0.1% (95% CI: -3.1% to 3.2%) for recurrence and 10.1% (95% CI: -8.0% to 12.0%) for progression, respectively., Conclusions: Compared to EORTC risk stratification, the EAU categories reclassifies 37.9% patients into a higher risk group of recurrence and 11.8% into a higher risk of progression. However, the novel risk stratification assigns most patients to the same treatment as the more complex EORTC tables and can be regarded as an alternative tool for treatment decision-making., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: We sought to externally validate our pathologic nodal staging score (pNSS) model, which allows for quantification of the likelihood that a pathologically node-negative patient will not have lymph node (LN) metastasis after radical prostatectomy for prostate cancer (PCa) in a population-based cohort., Patients and Methods: We analyzed data from 50,598 patients treated with radical prostatectomy and pelvic LN dissection using the Surveillance, Epidemiology, and End Results database. We estimated the sensitivity of pathologic nodal staging using a β-binomial model and developed a novel pNSS model, which represents the probability that a patient's PCa has been correctly staged as node negative as a function of the number of examined LNs. These findings were compared against those from the original cohort of 7135 patients., Results: The mean and median number of LNs removed was 6.5 and 5, respectively (range, 1-89; interquartile range, 2-8), and 96.9% of the patients (n = 49,020) had stage pN0. Similar to the original cohort, the probability of missing a positive LN decreased with the increasing number of LNs examined. In both the validation and the original cohort, the number of LNs needed to correctly stage a patient's disease as node negative increased with more advanced tumor stage, higher Gleason sum, positive surgical margins, and higher preoperative prostate-specific antigen levels., Conclusion: We have confirmed that the number of examined LNs needed for adequate nodal staging in PCa depends on the pathologic tumor stage, Gleason sum, surgical margins status, and preoperative prostate-specific antigen. We externally validated our pNSS in a population-based cohort, which could help to refine decision-making regarding the administration of adjuvant therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To externally validate our previously developed pathological nodal staging model (pNSS) that allows quantification of the likelihood that a patient with pathologic node-negative status has, indeed, no lymph node metastasis (LNM)., Patients and Methods: We analyzed data from 2,768 patients treated with radical nephroureterectomy (RNU) and lymph node dissection (LND) using the Surveillance, Epidemiology, and End Results database from 1988 to 2010. We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a new pNSS. Then, we compared these findings with those of the initial cohort., Results: The mean and median numbers of lymph node (LN) removed were 5 and 2, respectively (interquartile range = 5) in the validation cohort, though 66.5% of the patients (n = 1814) were pN0. Similar to the development cohort, the probability of missing a LNM decreased as the number of nodes examined increased in the validation cohort. If only a single node was examined, 35% of patients would be misclassified as pN0 while harboring LNM. Even when 5 nodes were examined, 8% would be misclassified. The probability of having a positive node increased with advancing pathological T stage in both the cohorts. Patients with pT0-Ta-Tis-T1 disease in both cohorts would have more than a 95% chance of a correct pathologic nodal staging with 2 examined nodes. However, if a patient has pT3-T4 disease, more than 12 examined LNs are needed to reach 95% accuracy., Conclusions: We confirmed that the number of examined nodes needed for adequate staging depends on pT category. We externally validated our previous pNSS in a population-based database, which could help in the clinical decision-making regarding adjuvant chemotherapy administration., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The neutrophil-to-lymphocyte ratio (NLR) and the C-reactive protein (CRP) are markers of systemic inflammatory response, which have been associated with the prognosis of multiple malignancies, but their relationships with oncologic outcomes of non-muscle-invasive bladder cancer (NMIBC) have not been well studied yet., Patients and Methods: We retrospectively reviewed the medical records of 1,117 patients with NMIBC who underwent a transurethral resection of the bladder. Univariable and multivariable competing risk regression models were used to assess the association of preoperative NLR and CRP with disease recurrence and progression to muscle-invasive disease. The median follow-up was 64 months., Results: In total, 360 patients (32.2%) had a high NLR (≥2.5) and 145 (13.0%) had a high CRP (≥5mg/l). On multivariable analyses, a high NLR was associated with both disease recurrence (subhazard ratio [SHR] = 1.27, P = 0.013) and progression (SHR = 1.72, P = 0.007), and high CRP was associated with disease progression (SHR = 1.72, P = 0.031). Adding NLR and CRP to the multivariable model predicting disease progression lead to a relevant change in discrimination (+2.0%). In a subgroup analysis of 300 patients treated with bacillus Calmette-Guerin, both high NLR and high CRP were associated with disease progression (SHR = 2.80, P = 0.026 and SHR = 3.51, P = 0.021, respectively), and NLR was associated with disease recurrence (SHR = 1.46, P = 0.046). There was also an increase in the discrimination of the model predicting progression after bacillus Calmette-Guerin following the inclusion of both markers (+2.4%)., Conclusion: In patients with NMIBC, markers of systemic inflammation response are associated with disease recurrence and progression. The inclusion of such markers in prognostic models does enhance their accuracy., (Copyright © 2016. Published by Elsevier Inc.)

Objective: To identify risk factors for perioperative complications and morbidity in renal cell cancer (RCC) surgery with tumor thrombus invasion (TTI)., Patients and Methods: Retrospective single-center analysis of 128 patients who underwent open (n = 97) or laparoscopic (n = 31) radical nephrectomy (NT) for RCC between 1999 and 2010. TTI was at Mayo-Level 0, I, II, III, IV in 88, 7, 10, 4, and 19 cases, respectively. Cavotomy was performed in 27, liver mobilisation in 20, and cardiovascular bypass in 17 patients., Results: The rate of any early postoperative complication (PC) by Clavien-Dindo classification was 58.6%, while the severe early PC rate was 29.7%. There was a statistically significant difference in multivariate analysis in the incidence of any early PC and of severe early PC by Charlson score (OR:1.584 (95%CI:1.141-2.199), p = 0.006; OR:3.065 (95%CI:1.218-7.714), p = 0.017) and by tumor thrombus level TNM-UICC 2010 T3a/T3c (OR:10.668 (95%CI:1.266-89.871), p = 0.029; OR:10.502 (95%CI:2.981-36.992), p < 0.001). In pT3a cases open NT was associated with a higher early (57.9% vs. 25.8%) and severe (24.6% vs. 9.7%) PC rate compared to laparoscopic NT. The 30-day mortality rate was 0%. The 90-day mortality rate was 6.3% but 100% cancer-related. In Cox regression analysis tumor thrombus level was not predictive for overall survival., Conclusions: The strongest risk factor for early and severe PC in patients with TTI is a supradiaphragmatic tumor thrombus. In cases with severe PC, this fact persists when comparing Mayo-Levels II-III and Level IV. In pT3a cases open NT shows a 2-fold higher early PC rate compared to laparoscopic NT., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: To test the hypothesis that perioperative blood transfusion (PBT)impacts oncologic outcomes of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC)., Methods: Retrospective analysis of 2492 patients with UTUC treated at 23 institutions with RNU between 1987 and 2007.Cox regression models addressed the association of PBT with disease recurrence, cancer-specific mortality and any-cause mortality., Results: A total of 510 patients (20.5%) patients received PBT. Within a median follow-up of 36 months (Interquartile range: 55 months), 663 (26.6%) patients experienced disease recurrence, 545 patients (21.9%) died of UTUC and 884 (35.5%) patients died from any cause. Patients who received PBT were at significantly higher risk of disease recurrence, cancer-specific mortality and overall mortality than patients not receiving PBT in univariable Cox regression analyses. In multivariable Cox regression analyses that adjusted for the effects of standard clinicopathologic features, PBT did not remain associated with disease recurrence (HR: 1.11; 95% CI 0.92-1.33, p = 0.25), cancer-specific mortality (HR: 1.09; 95% CI 0.89-1.33, p = 0.41) or overall mortality (HR: 1.09; 95% CI 0.93-1.28, p = 0.29)., Conclusions: In patients undergoing RNU for UTUC, PBT is associated with disease recurrence, cancer-specific survival or overall survival in univariable, but not in multivariable Cox regression analyses., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: ABO blood type is an inherited characteristic that has been associated with the prognosis of several malignancies, but there is little evidence in urothelial carcinoma of the bladder (UCB). The purpose of this study was to evaluate the effect of ABO blood type on mortality in patients with UCB treated with radical cystectomy (RC)., Methods: Multi-institutional data from 7,906 patients with UCB treated with RC between 1979 and 2012 were retrospectively analyzed. The effect of ABO blood type on UCB-related mortality was evaluated with univariable and multivariable competing-risks regression models., Results: ABO blood type was O in 3,728 (47%), A in 2,748 (35%), B in 888 (11%), and AB in 532 (7%) patients. Blood type B was associated with a greater likelihood of lymphovascular invasion (P = 0.010) and positive soft tissue margins (P = 0.008). The median follow-up was 41 months. The 5-year cumulative UCB-related mortality rates for blood type O, A, B, and AB were 29.5%, 30.5%, 33.2%, and 25.8%, respectively. In univariable competing-risks regression, patients with blood type B had worse UCB-related mortality than those with blood type O (P = 0.026) and AB (P = 0.020). In multivariable analysis, however, blood type lost its statistical significance., Conclusions: Among patients treated with RC, ABO blood type is associated with a statistically significant but clinically insignificant difference in UCB-related mortality. This association was not present in multivariable analysis. Our data therefore suggest no relevant association of ABO blood type with UCB-related prognosis., (© 2013 Published by Elsevier Inc.)

Objectives: Tissue-based markers improve the accuracy of prediction models in urothelial carcinoma of the bladder (UCB). Current smoking status and cumulative exposure also affect outcomes. To evaluate whether the combination of molecular markers and smoking features further improved the prognostication of patients who underwent radical cystectomy (RC) for UCB., Materials and Methods: A total of 588 patients underwent RC and bilateral lymphadenectomy for UCB from 1995 to 2005. Immunohistochemistry for p53, p21, pRB, p27, Ki-67, and survivin was performed on tissue microarrays from the RC specimen. Smoking features were routinely assessed at diagnosis. Multivariable Cox regression models assessed time to disease recurrence and cancer-specific mortality., Results: Of the 588 patients, 128 were never (22%), 283 former (48%), and 177 current smokers (30%). In total, 227 patients experienced disease recurrence, whereas 190 died of UCB. Smoking status was independently associated with both outcomes (hazard ratio [HR] = 1.48 and 2.62, for former and current vs. never smokers, respectively, P<0.001). All markers were significantly associated with both outcomes (P<0.05) except for survivin. The combination of the 4 cell cycle markers p53, p21, pRB, and p27 increased the discrimination of clinicopathologic model for former and current vs. never smokers with c-indices 0.779 and 0.780, respectively (base model c-indices of 0.741 and 0.740 for former and current vs. never smokers, respectively). The further addition of smoking features and biomarker status improved the discrimination of the model (c-indices of 0.783 and 0.786 for former and current vs. never smokers, respectively)., Conclusions: We confirmed that smoking information and tissue markers status improve prognostication of UCB outcomes after RC; the combination of both reaching the highest level of discrimination., (© 2013 Published by Elsevier Inc.)

Objectives: Bladder cancer detection and surveillance includes cystoscopy and cytology. Urinary cytology is limited by its low sensitivity for low-grade tumors. Urine markers have been extensively studied to help improve the diagnosis of bladder cancer with the goal of complementing or even replacing cystoscopy. However, to date, no marker has reached widespread use owing to insufficient evidence for clinical benefit., Material and Methods: Pubmed/Medline search was conducted to identify original articles, review articles, and editorials regarding urine-based biomarkers for screening, early detection, and surveillance of urothelial carcinoma of the bladder. Searches were limited to the English language, with a time frame of 2000 to 2013. Keywords included urothelial carcinoma, bladder cancer, transitional cell carcinoma, biomarker, marker, urine, diagnosis, recurrence, and progression., Results: Although several urinary markers have shown higher sensitivity compared with cytology, it remains insufficient to replace cystoscopy. Moreover, most markers suffer from lower specificity than cytology. In this review, we aimed to summarize the current knowledge on commercially available and promising investigational urine markers for the detection and surveillance of bladder cancer., Conclusions: Well-designed protocols and prospective, controlled trials are needed to provide the basis to determine whether integration of biomarkers into clinical decision making will be of value for bladder cancer detection and screening in the future., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Urothelial carcinoma of the bladder (UCB) is a highly heterogeneous malignancy that causes significant morbidity and mortality. Standard pathologic features (stage, grade, and nodal status) are insufficient to predict accurately a patient's outcome. Biomarkers could help clinicians provide individualized prognostications and allow risk-stratified clinical decision making regarding surgical and medical treatment. This review summarizes the existing tissue- and blood-based biomarkers in UCB., Material and Methods: A PubMed/Medline search was conducted to identify original articles regarding molecular biomarkers and UCB. Searches were limited to papers published in English. Keywords included urothelial carcinoma, bladder cancer, transitional cell, biomarker, marker, staining, cystectomy, recurrence or progression, survival, prediction, and prognosis., Results: The articles with the highest level of evidence were selected and reviewed, with the consensus of all the authors of this paper., Conclusions: There is no doubt that a panel of biomarkers would eventually improve our clinical decision making regarding treatment and follow-up. However, to date, no biomarker panel is yet validated for daily clinical practice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: Evidence suggests a detrimental effect of diabetes mellitus (DM) on cancer incidence and outcomes. To date, the effect of DM and its treatment on prognosis in upper tract urothelial carcinoma (UTUC) remains uninvestigated. We tested the hypothesis that DM and metformin use impact oncologic outcomes of patients treated with radical nephroureterectomy (RNU) for UTUC., Methods: Retrospective analysis of 2492 patients with UTUC treated at 23 institutions with RNU without neoadjuvant therapy. Cox regression models addressed the association of DM and metformin use with disease recurrence, cancer-specific mortality and any-cause mortality., Results: A total of 365 (14.3%) patients had DM and 194 (7.8%) patients used metformin. Within a median follow-up of 36 months, 663 (26.6%) patients experienced disease recurrence, 545 patients (21.9%) died of UTUC and 884 (35.5%) patients died from any cause. Diabetic patients who did not use metformin were at significantly higher risk of disease recurrence and cancer-specific death compared to non-diabetic patients and diabetic patients who used metformin. In multivariable Cox regression analyses, DM treated without metformin was associated with worse recurrence-free survival (HR: 1.44, 95% CI 1.10-1.90, p = 0.009) and cancer-specific mortality (HR: 1.49, 95% CI 1.11-2.00, p = 0.008)., Conclusions: Diabetic UTUC patients without metformin use have significantly worse oncologic outcomes than diabetics who used metformin and non-diabetics. The possible mechanism behind the impact of DM on UTUC biology and the potentially protective effect of metformin need further elucidation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: Evidence suggests a positive effect of metformin on cancer incidence and outcome. To date, the effect of metformin use on prognosis in urothelial carcinoma of the bladder (UCB) remains uninvestigated. We tested the hypothesis that metformin use affects oncologic outcomes of patients treated with radical cystectomy for UCB., Methods and Materials: We retrospectively evaluated 1,502 patients treated at 4 institutions with radical cystectomy and pelvic lymphadenectomy without neoadjuvant therapy. Cox regression models addressed the association of diabetes mellitus (DM) and metformin use with disease recurrence, cancer-specific mortality, and any-cause mortality., Results: A total of 200 patients (13.3%) had DM, 80 patients (5.3%) used metformin. Within a median follow-up of 34 months, 509 patients (33.9%) experienced disease recurrence, 402 patients (26.8%) died of UCB, and 551 patients (36.7%) died from any cause. In univariable Cox regression analyses, DM without metformin use was associated with increased risk of disease recurrence (hazard ratio [HR]: 1.40, 95% confidence interval [CI] 1.05-1.87, P = 0.02), cancer-specific mortality (HR: 1.60, 95% CI 1.17-2.17, P = 0.003), and any-cause mortality (HR: 1.55, 95% CI 1.18-2.03, P = 0.002), whereas metformin use was associated with decreased risk of disease recurrence (HR: 0.61, 95% CI 0.37-0.98, P = 0.04), cancer-specific mortality (HR: 0.56, 95% CI 0.33-0.97, P = 0.04), and any-cause mortality (HR: 0.54, 95% CI 0.33-0.88, P = 0.01). In multivariable Cox regression analyses, DM treated without metformin use remained associated with worse cancer-specific mortality (HR: 1.53, 95% CI 1.12-2.09, P = 0.007) and any-cause mortality (HR: 1.52, 95% CI 1.16-2.00, P = 0.003) but not disease recurrence., Conclusions: Diabetic patients who do not use metformin appear to be at higher risk of cancer-specific and any-cause mortality than patients without DM. It remains unclear, whether the severity of DM in this group of patients or the use of metformin itself affects outcomes of UCB. The mechanisms behind the effect of DM on patients with UCB and the potential protective effect of metformin need further elucidation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To determine if the number of lymph nodes (LNs) removed is an independent predictor of biochemical recurrence (BCR) in patients without LN metastases undergoing radical prostatectomy (RP)., Material and Methods: Retrospective analysis of 7,310 patients treated at 7 centers with RP and pelvic LN dissection for clinically localized prostate cancer between 2000 and 2011. Patients with LN metastases (n = 398) and other reasons (stated later in the article) (n = 372) were excluded, which left 6,540 patients for the final analyses., Results: Overall, median biopsy and RP Gleason score were both 7; median prostate specific antigen level was 6 ng/ml (interquartile range [IQR]: 5); and median number of LNs removed was 6 (IQR: 8). A total of 3,698 (57%), 2,064 (32%), and 508 (8%) patients had ≥ 6, ≥ 10, and ≥ 20 LNs removed, respectively. Patients with more LNs removed were older, had a higher prostate specific antigen level, had higher clinical and pathologic T stage, and had higher RP Gleason score (all P<0.002). Within a median follow-up of 21 (IQR: 16) months, more LNs removed was associated with an increased risk of BCR (continuous: P = 0.021; categorical: P = 0.014). In multivariable analyses that adjusted for the effects of standard clinicopathologic factors, none of the nodal stratifications predicted BCR., Conclusions: The number of LNs did not have any prognostic significance in our contemporary cohort of patients with LN-negative prostate cancer. This suggests that the risk of missed clinically significant micrometastasis may be minimal in patients currently treated with RP and having a lower LN yield., (Copyright © 2014 Elsevier Inc. All rights reserved.)