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To develop accurate preoperative nomograms for prediction of muscle-invasive disease and lymph node metastasis in upper tract urothelial carcinoma (UTUC), to assist surgeons in risk stratifying patients and help guide treatment decisions.The National Cancer Database was used to identify all patients from 2004 to 2016 with UTUC who underwent extirpative surgery and lymphadenectomy. Univariate and multivariate logistic regression was performed to identify variables predicting muscle-invasive and node-positive disease. The data set was split 80:20 into a derivation and validation cohort and used to generate and test two nomograms. Nomograms were assessed using area under the curve (AUC) and calibration plots.A total of 6,143 patients met inclusion criteria. Predictors of muscle-invasive disease were age, grade, lymphovascular invasion (LVI), tumor size, and positive clinical lymph node status. Predictors of node-positive disease were grade, LVI, tumor size, and positive clinical lymph node status. The accuracy of the final nomogram predicting muscle-invasive disease was 80.0% (AUC 0.800, corrected C-index 0.813), and the accuracy of the nomogram predicting node-positive disease was 87.8% (AUC 0.878, corrected C-index 0.887).With data readily available after imaging and biopsy (age, tumor grade, LVI status, tumor size, and clinical lymph node status), we developed the first preoperative nomograms to quantitatively predict muscle-invasive disease and lymph node metastasis in UTUC, with an accuracy of 80.0% and 87.8% respectively. This information could be helpful to assist surgeons with pre-operative risk stratification.

Introduction The use of robotic-assisted radical cystectomy (RARC) is becoming more widespread. While its safety is accepted, its oncological efficacy as compared to the current standard, open radical cystectomy (ORC), remains debatable. Materials and methods The aim of this study is to compare the rates of positive soft tissue surgical margins (STSM), between patients treated with RARC or ORC, using a large contemporaneous collaborative database. We included 2,536 patients with urothelial carcinoma of the bladder treated at 26 institutions. A propensity-score matching 1:1 was performed with 3 ORC patients matched to 1 RARC patient. The final cohort included 1,614 patients. Uni- and multivariable logistic regression analyses tested the impact of surgical technique on STSM status, before and after propensity-score matching. Results Overall, 870 (34%) patients underwent RARC and 1,666 (66%) ORC. The overall STSM rate was 11%; 10% in the ORC group and 13% in the RARC group. Within the propensity-score-matched cohort, the positive STSM rate were 14% and 13% in the ORC and RARC group, respectively (P = 0.1). In multivariable analysis, after propensity match RARC approach was not associated with the risk of a positive STSM (P = 0.1). These results were confirmed in the subgroup of patients with pathologic non–organ-confined or organ-confined diseases. Conclusions While treatment with RARC is associated with a higher absolute rate of STSM, the difference did not remain after adjustment for the effects of other established prognostic factors. Results from ongoing trials are awaited to assess the validity of these findings.

Objective Patients with urothelial carcinoma (UC) undergo rigorous surveillance for recurrence. Noninvasive urine tests are not currently recommended by guideline panels owing to insufficient clinical benefit. The objective of this study was to prospectively compare the performance of the Cxbladder Monitor test to other commonly available urine markers and cytology for surveillance of patients with UC. Methods and materials A total of 1,036 urine samples were collected from 803 patients undergoing surveillance for UC. Of these, 1,016 samples were directly assessed using cytology, NMP22 Bladderchek and NMP22 enzyme-linked immunosorbent assay (ELISA), and the clinically validated Cxbladder Monitor test. An exploratory analysis was also performed comparing data from 157 samples where UroVysion fluorescence in situ hybridization analysis was performed locally. Results The sensitivity of Cxbladder Monitor (0.91) significantly outperformed cytology (0.22), NMP22 ELISA (0.26), and NMP22 BladderChek (0.11). The negative predictive value of Cxbladder Monitor was also superior at 0.96 compared with cytology (0.87), NMP22 ELISA (0.87), and NMP22 BladderChek (0.86). All false-negative results ( n = 14) observed using Cxbladder Monitor were also negative for cytology, NMP22 ELISA, and NMP22 BladderChek. In the more limited set, UroVysion fluorescence in situ hybridization also had inferior sensitivity (0.33) and negative predictive value (0.92). Conclusions The Cxbladder Monitor test significantly outperforms current Food and Drug Administration-approved urine-based monitoring tests, as well as cytology, in a large representative population undergoing surveillance for recurrent UC. This supports using Cxbladder Monitor as a confirmatory negative adjunct to cystoscopy or to justify postponing cystoscopic investigations in patients with a low risk of recurrence.

A study was performed to assess the role and prognostic significance of angiostatin, basic fibroblast growth factor (bFGF), and tyrosine endothelial kinase (TEK/Tie2) in transitional cell bladder carcinoma.Angiostatin, bFGF, and TEK serum concentrations were measured in 82 bladder cancer patients and 20 age-matched healthy controls using enzyme-linked immunosorbent assay. Results were compared with clinicopathologic and follow-up data with the Mann-Whitney U test and Kaplan-Meier, univariate and multivariate Cox regression analyses.We found significantly decreased angiostatin and TEK serum levels and mildly elevated bFGF concentrations in samples of bladder cancer patients compared with controls (P.001, P.001, and P = .083, respectively). Furthermore, high TEK serum levels were correlated with poor disease-specific and metastasis-free survival in muscle-invasive bladder cancer (P = .013, P = .018), whereas angiostatin and bFGF concentrations did not show any correlation with patients' prognosis. Multivariate analysis revealed high TEK levels (1.60ng/mL) as borderline significant independent risk-factor of disease-specific survival (HR 1.83, 95% CI 0.97-3.44, P = .061) and metastasis-free survival (HR 2.65, 95% CI 0.93-7.55, P = .069).The characteristic differences in the circulating levels of angiostatin, TEK, and bFGF between patients and controls, suggest the presence of a tumor-induced proangiogenic milieu in bladder cancer. Serum TEK levels may contribute to a more reliable preoperative risk stratification in muscle-invasive bladder cancer and therefore may help to optimize therapeutic decisions.

Bladder cancer is one of the few cancers that have been linked to carcinogens in the environment and tobacco smoke. Of the carcinogens tested in mouse chemical carcinogenesis models, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) is one that reproducibly causes high-grade, invasive cancers in the urinary bladder, but not in any other tissues. However, the basis for such a high-level tissue-specificity has not been explored. Using mutagenesis in lacI (Big Blue™) mice, we show here that BBN is a potent mutagen and it causes high-level of mutagenesis specifically in the epithelial cells (urothelial) of the urinary bladder. After a 2-6-week treatment of 0.05% BBN in the drinking water, mutagenesis in urothelial cells of male and female mice was about two orders of magnitude greater than the spontaneous mutation background. In contrast, mutagenesis in smooth muscle cells of the urinary bladder was about five times lower than in urothelial tissue. No appreciable increase in mutagenesis was observed in kidney, ureter, liver or forestomach. In lacI (Big Blue™) rats, BBN mutagenesis was also elevated in urothelial cells, albeit not nearly as profoundly as in mice. This provides a potential explanation as to why rats are less prone than mice to the formation of aggressive form of bladder cancer induced by BBN. Our results suggest that the propensity to BBN-triggered mutagenesis of urothelial cells underlies its heightened susceptibility to this carcinogen and that mutagenesis induced by BBN represents a novel model for initiation of bladder carcinogenesis.

Objectives: To evaluate if preoperative symptom classification could refine prediction of outcomes for patients with clinically localized upper-tract urothelial carcinoma (UTUC) managed by radical nephroureterectomy (RNU). Methods: Data on 654 patients with localized UTUC who underwent RNU were reviewed. Preoperative symptoms were classified as incidental (S1), local (S2), and systemic (S3). Clinical and pathologic data were compared between the cohorts. Kaplan-Meier analyses and Cox proportional hazard modeling were used to determine recurrence-free and cancer-specific survival amongst the symptom cohorts. Results: Symptom classification was SI in 213 (33%) patients, S2 in 402 (61%), and S3 in 39 (6%). S3 symptoms were associated with advanced pathology, including higher stage, grade, and lymph node (LN) positivity. Five and 10-year recurrence-free and cancer-specific survival estimates were similar for patients with SI and S2 symptoms (P = 0.75 and 0.58, respectively), but was worse for patients with S3 symptoms (P < 0.001 for both). On multivariate analysis adjusting for final pathologic stage, grade, and LN status, S3 symptoms were not an independent predictor of recurrence (HR 1.44, P = 0.19) or death due to disease (HR 1.66, P = 0.07). Addition of symptom classification, however, increased the accuracy of a model consisting of stage, grade, and LNs for prediction of recurrence-free and cancer-specific survival by 1.4% and 1.3%, respectively (P < 0.001 for both). Conclusions: Local symptoms do not confer worse prognosis compared with patients with incidentally detected UTUC. However, systemic symptoms are associated with worse outcomes despite apparently effective RNU. Patients with systemic symptoms may harbor micrometastatic disease and could potentially benefit from a more rigorous metastatic evaluation or perioperative chemotherapy regimens. (C) 2011 Elsevier Inc. All rights reserved.

Objectives Hydronephrosis at the time of diagnosis of bladder cancer is associated with advanced disease and is a predictor of poorer outcomes. There is, however, limited information addressing whether a similar relationship exists for upper-tract urothelial carcinoma (UTUC). We investigate the prognostic impact of hydronephrosis on preoperative axial imaging on clinical outcomes after radical nephroureterectomy. Materials and Methods The records for 106 patients with UTUC who underwent radical nephroureterectomy at 2 medical centers were reviewed. Preoperative computed tomography (CT) images were evaluated for ipsilateral hydronephrosis by radiologists blinded to clinical outcomes. Association of hydronephrosis with pathologic features and oncologic outcomes after surgery was assessed. Results Sixty-seven men and 39 women with a median age of 69 years (range, 36 to 90) were evaluated. One-third of these patients had muscle invasive disease or greater (≥T2), 44% had high grade tumors, and 3% had lymph node (LN) metastases. At a median follow-up of 47 months (range, 1 to 164), 43% of patients experienced disease recurrence, 18% developed metastasis, and 12% died of their cancer. Thirty-nine patients (37%) had hydronephrosis on preoperative axial imaging; 35% of these patients had ureteral tumors, and 27% had multifocal disease. The presence of hydronephrosis was associated with advanced pathologic stage ( P = 0.03) and disease in the ureter (vs. renal pelvis) ( P = 0.007). Hydronephrosis was a predictor of non-organ confined disease on final pathology (hazard ratio [HR] 3.7, P = 0.01). On preoperative multivariable analysis controlling for age, gender, tumor location, ureteroscopic biopsy grade, and urinary cytology, hydronephrosis was independently associated with cancer metastasis (HR 8.2, P = 0.02) and cancer-specific death (HR 12.1, P = 0.03). Conclusions Preoperative hydronephrosis on axial imaging is associated with features of aggressive disease and predicts advanced pathologic stage for UTUC. Hydronephrosis can be a valuable prognostic tool for preoperative planning and counseling regarding disease outcomes.