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Background and Objectives: Previous studies have shown that variability in surgical technique can affect the outcomes of cooperative group trials. We analyzed measures of surgical quality and clinical outcomes in patients enrolled in the p53-MVAC trial. Methods: We performed a post-hoc analysis of patients with pT1-T2N0M0 urothelial carcinoma of the bladder following radical cystectomy (RC) and bilateral pelvic and iliac lymphadenectomy (LND). Measures of surgical quality were examined for associations with time to recurrence (TTR) and overall survival (OS). Results: We reviewed operative and/or pathology reports for 440 patients from 35 sites. We found that only 31% of patients met all suggested trial eligibility criteria of having15 lymph nodes identified in the pathologic specimen (LN#) and having undergone both extended and presacral LND. There was no association between extent of LND, LN#, or presacral LND and TTR or OS after adjustment for confounders and multiple testing. Conclusions: We demonstrated that there was substantial variability in surgical technique within a cooperative group trial. Despite explicit entry criteria, many patients did not undergo per-protocol LNDs. While outcomes were not apparently affected, it is nonetheless evident that careful attention to study design and quality monitoring will be critical to successful future trials. J. Surg. Oncol. fl 2015 Wiley Periodicals, Inc.

Advances in endoscopic imaging technology may improve sensitivity for the detection of bladder cancer and provide a more complete understanding of the urothelial landscape, and it also may lead to improved short-term and long-term cancer control. Fluorescence cystoscopy requires intravesical administration of a photosensitizing agent (5-aminolevulinic acid or hexaminolevulinate), and imaging with a blue-light endoscopy system demonstrably improves the detection of papillary and flat bladder lesions compared with conventional white-light cystoscopy. Prospective phase 3 clinical trials have demonstrated improved diagnostic ability, enhanced tumor resection, and a small but significant reduction in recurrence-free survival. Optical coherence tomography delineates subsurface microarchitecture information about bladder lesions in real time and has the ability to discriminate between noninvasive and invasive cancers. Narrow-band imaging may augment white-light cystoscopy by providing increased contrast between normal and abnormal tissue on the basis of neovascularity. Confocal laser endoscopy has been applied to the urinary tract using thinner probes adapted from use in gastrointestinal malignancies and provides exquisite images at microscopic resolution. More technology is on the horizon that may further enhance our ability to detect and accurately stage bladder tumors and distinguish benign from malignant or dysplastic lesions.

BACKGROUND Clinical trials of radiation after radical cystectomy (RC) and chemotherapy for bladder cancer are in development, but inclusion and stratification factors have not been clearly established. In this study, the authors evaluated and refined a published risk stratification for locoregional failure (LF) by applying it to a multicenter patient cohort. METHODS The original stratification, which was developed using a single-institution series, produced 3 subgroups with significantly different LF risk based on pathologic tumor (pT) classification and the number of lymph nodes identified. This model was then applied to patients in Southwest Oncology Group (SWOG) 8710, a randomized trial of RC with or without chemotherapy. LF was defined as any pelvic failure before or within 3 months of distant failure. RESULTS Patients in the development cohort and the SWOG cohort had significantly different baseline characteristics. The original risk model was not fully validated in the SWOG cohort, because lymph node yield was not as strongly associated with LF as in the development cohort. Regression analysis indicated that margin status could improve the model. A revised stratification using pT classification, margin status, and the number of lymph nodes identified produced 3 subgroups with significantly different LF risk in both cohorts: low risk (≤pT2), intermediate risk (≥pT3 with negative margins AND ≥10 lymph nodes identified), and high risk (≥pT3 with positive margins OR

Context The urinary reconstructive options available after radical cystectomy (RC) for bladder cancer are discussed, as are the criteria for selection of the most appropriate diversion, and the outcomes and complications associated with different diversion options. Objective To critically review the peer-reviewed literature on the function and oncological outcomes, complications, and factors influencing choice of procedure with urinary diversion after RC for bladder carcinoma. Evidence Acquisition A Medline search was conducted to identify original articles, review articles, and editorials on urinary diversion in patients treated with RC. Searches were limited to the English language. Keywords included: ‘bladder cancer’, ‘cystectomy’, ‘diversion’, ‘neobladder’, and ‘conduit’. The articles with the highest level of evidence were selected and reviewed, with the consensus of all of the authors of this paper. Evidence Synthesis Both continent and incontinent diversions are available for urinary reconstruction after RC. In appropriately selected patients, an orthotopic neobladder permits the elimination of an external stoma and preservation of body image without compromising cancer control. However, the patient must be fully educated and committed to the labour-intensive rehabilitation process. He must also be able to perform self-catheterisation if necessary. When involvement of the urinary outflow tract by tumour prevents the use of an orthotopic neobladder, a continent cutaneous reservoir may still offer the opportunity for continence albeit one that requires obligate self-catheterisation. For patients who are not candidates for continent diversion, the ileal loop remains an acceptable and reliable option. Conclusions Both continent and incontinent diversions are available for urinary reconstruction after RC. Orthotopic neobladders optimally preserve body image, while continent cutaneous diversions represent a reasonable alternative. Ileal conduits represent the fastest, easiest, least complication-prone, and most commonly performed urinary diversion.

BACKGROUND There have been no improvements in the treatment of metastatic urothelial cancer in the past several decades. A census of contemporary clinical research in this disease was performed to identify potential barriers and opportunities. METHODS These authors performed a search for clinical trials exploring interventions in muscle-invasive and metastatic urothelial cancer, using the ClinicalTrials.gov registry. Data extracted from the registry included title, recruitment status, interventions, sponsor, phase, enrollment, study design, and study sites. RESULTS Among 120 eligible trials exploring interventions in muscle-invasive and metastatic urothelial cancer, 73% were phase 2 and 73% were nonrandomized. The majority (63%) involved treatment in the metastatic disease state. The median planned enrollment size per trial was 45 patients (interquartile range, 47 patients). The majority of trials (55%) involved ≤ 3 study sites. Trials most commonly explored interventions in the first-line metastatic (30%) or second-line metastatic (37%) settings. Targeted therapeutics were studied in 58% of the trials. Among 56 trials that completed enrollment, the median time to complete accrual was 50 months (range, 10-109 months), and these trials enrolled a median of 40 patients per trial (interquartile range, 44 patients). CONCLUSIONS The majority of contemporary clinical trials in muscle-invasive and metastatic urothelial cancer are small, nonrandomized, phase 2 trials involving 1 to 3 study sites. Enhanced communication and collaboration among the urothelial cancer community, and other stakeholders, is needed to facilitate the design and conduct of trials capable of expediting progress in this disease. Cancer 2013;119:1994–1998. © 2013 American Cancer Society.

What's known on the subject? and What does the study add? Lymphovascular invasion (LVI) is an important step in systemic cancer cell dissemination. LVI has been shown to be an independent predictor of disease recurrence and cancer-specific survival in urothelial carcinoma of the bladder (UCB) for patients with carcinoma invading bladder muscle. Patients with final pathological stage T1N0 UCB who underwent radical cystectomy (RC) have not been separately analysed for influence of LVI on outcomes. Our study shows that LVI predicts disease recurrence and cancer-specific survival in patients with final stage T1 UCB after RC. Objective To determine the outcomes of patients with final pathological stage T1N0 disease after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) and to determine whether lymphovascular invasion (LVI) is an independent predictor of prognosis in these patients. Patients and Methods Records of 958 consecutive patients who underwent RC at three academic centres were reviewed. A total of 101 patients with negative lymph nodes and with final stage (the higher of the pre-RC clinical/transurethral resection [TUR] and post-RC pathological stages) T1 UCB were identified. The median (range) follow-up was 38 (0.4–177) months and the median (range) number of nodes examined was 19 (9–80). Results Overall, 12/101 (11.9%) patients experienced cancer recurrence and 7/101 (6.9%) died from their cancer. The 3-year recurrence-free survival probability (SD) was 0.89 (0.04) and 3-year cancer-specific survival probability (SD) was 0.96 (0.02). Six of 101 (6%) patients had LVI, of whom four experienced disease recurrence and three died from bladder cancer. All recurrences and deaths occurred in patients who had either LVI and/or concomitant carcinoma in situ. On multivariable analysis, LVI (hazard ratio [HR] 4.9, P = 0.01) and higher pathological stage (HR 8.5, P = 0.04) predicted cancer recurrence and LVI (HR 6.7, P = 0.01) predicted cancer-specific survival. Conclusions LVI helps identify patients with final pathological T1N0 UCB who are at significantly increased risk of bladder cancer recurrence and death. These patients should be considered for close monitoring after cystectomy.

What's known on the subject? and What does the study add? Although many tests for identifying patients with new or recurrent bladder cancer have been used, a reliable method has yet to be established. Recently, increasing attention has focused on the role of survivin in bladder cancer detection. Because urine survivin tests have better sensitivity than cytology, urine survivin could potentially replace routine cytology and might be used as an adjunct method for cystoscopy. However, the clinical utility of urine survivin as a bladder tumour marker identified in the present study remains to be elucidated. To determine the clinical utility of urine survivin as a bladder tumour marker we systematically reviewed the available evidence. A comprehensive literature review was performed, from August 1997 to March 2011, using three search engines in English including PubMed, Cochrane Library, and SCOPUS. Two reviewers independently evaluated both trial eligibility and methodological quality and data extraction. We included studies that evaluated urine survivin, used cystoscopy and/or histopathology as the reference standard, and allowed the construction of a 2 × 2 contingency table. Bivariate random effect meta-analyses were used to calculate the summary estimated of sensitivity and specificity and to construct a summary receiver-operating characteristics curve of urine survivin tests. In all, 14 studies were included in the present review; two studies had two subsets of data. There were 2051 subjects, including 1038 in the case group and 1013 in the control group, and heterogeneity was present among diagnostic studies. The pooled sensitivity and specificity for urine survivin tests were 0.772 (95% confidence interval [CI] 0.745-0.797) and 0.918 (95% CI 0.899-0.934), respectively. The area under the curve of urine survivin tests was 0.9392. When a subgroup analysis with six studies was performed, urine survivin tests had better sensitivity than cytology, but did not match cytology for specificity. The clinical utility of urine survivin as a bladder tumour marker identified in the present study remains to be elucidated.

Study Type – Prognosis (retrospective cohort) Level of Evidence 2b OBJECTIVE To externally validate the prognostic value of lymphovascular invasion (LVI) in a large international cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). PATIENTS AND METHODS We collected data from 4257 patients treated with RC and pelvic lymphadenectomy for UCB, without neoadjuvant chemotherapy, at 12 centres. LVI was defined as presence of nests of tumour cells within an endothelium-lined space. RESULTS LVI was detected in 1407 patients (33.1%); the proportion of LVI increased with advancing stage, higher grade, soft-tissue surgical margin involvement, and lymph node metastasis (P < 0.001 for all). In standard multivariate models, LVI was associated with both disease recurrence (hazard ratio 1.43, P < 0.001) and cancer-specific mortality (1.45, P < 0.001). In the entire cohort, adding LVI to a base model that included standard features improved only minimally its predictive accuracy for both recurrence and cancer-specific mortality (by 1.1% and 1.2%, respectively). In 3122 patients with negative lymph nodes, LVI remained independently associated with and improved the predictive accuracy of the standard predictors for recurrence (hazard ratio 1.68, P < 0.001; +2.3%) and cancer-specific mortality (1.70, P < 0.001; +2.4%). By contrast, in 1071 node-positive patients, LVI only marginally improved the prediction of cancer-specific recurrence (hazard ratio 1.20, P < 0.001; +0.2%) and survival (1.23, P < 0.001; +0.5%). CONCLUSIONS LVI is strongly associated with clinical outcome in node-negative patients treated with RC. The assessment of LVI might help to identify patients who could benefit from adjuvant therapy after RC. After confirmation in different populations, LVI should be included in the staging of UCB.

Study Type – Prognosis (inception cohort) Level of Evidence 1b OBJECTIVE To test whether assessing p53 expression could improve the ability to predict disease recurrence and disease-specific survival in a multi-institutional cohort of patients with advanced urothelial carcinoma of the urinary bladder (UCB). PATIENTS AND METHODS The study comprised 692 patients with pT3–4 N0 or pTany N+ UCB treated with radical cystectomy and lymphadenectomy. The predictive accuracy (PA) was quantified using the 200 bootstrap-corrected concordance index. The base model comprised age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of lymph nodes positive, concomitant carcinoma in situ, and adjuvant chemotherapy. RESULTS p53 expression was altered in 341 (49.3%) patients. In multivariable analyses, p53 expression was independently associated with disease recurrence (hazard ratio, 1.66; P

BACKGROUND: In a retrospective study of Southwestern Oncology Group (SWOG)-S8710/INT-0080 (radical cystectomy [RC] alone vs 3 cycles of neoadjuvant chemotherapy [NC] with methotrexate, vinblastine, doxorubicin, and cisplatin before RC for bladder cancer), factors found to be associated with improved overall survival (OS) included pathologic complete response, defined as P0; treatment with NC; completion of RC with negative surgical margins; and � 10 pelvic lymph nodes (LNs) removed. METHODS: The authors used stratified Cox regression to retrospectively study the association of quality of pathologic response after RC with OS in the subset of S8710 patients who received NC and RC with negative surgical margins. RESULTS: Of 154 patients who received NC, 68 (44.2%) were

Conventional front-line platinum-based combination chemotherapy yields high response rates but suboptimal long-term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The profusion of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy before cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biologic agents are reviewed.

The first three papers in this section relate to the use of radical cystectomy in bladder cancer, and each study describes issues which are uncommonly written about, but which are relevant and important to any urologist who manages such patients. There is also a paper from Cleveland describing the rare condition of neuroendocrine tumours in the kidney. This is a large series of cases, and the authors recommend awareness of the condition and the prudent use of immunohistochemical neuroendocrine markers. There are a further six papers on prostate cancer; two of them evaluate high-grade prostatic intraepithelial neoplasia, taking different views on the subject. OBJECTIVE To examine the association between the interval from the last transurethral resection (TUR) to radical cystectomy (RC) and bladder cancer-specific outcome, as the decision to proceed to RC for an individual patient is complex, and recent reports suggest an interval from diagnosis to RC of >3 months is associated with adverse outcomes. PATIENTS AND METHODS The records of 592 patients who had RC were reviewed; the interval from the last TUR was analysed as both a continuous and categorical variable (

BACKGROUND Estrogen receptors (ERs) are known to mediate important physiologic responses as well as the growth of some tumors in response to estradiol stimulation. In a previous study the selective ER modulator raloxifene was shown to induce apoptosis in an ERβ-positive bladder cancer cell line. However, the expression of ERβ in human bladder cancer has not been thoroughly investigated. METHODS ERα and ERβ expression in 224 bladder tumor samples was evaluated using tissue microarray and immunohistochemistry. Levels of ERα and ERβ protein and mRNA expression were determined in several bladder cancer cell lines using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis. The effect of estradiol and antiestrogen treatments on RT4 bladder cancer cell growth was determined by cell proliferation assays. RESULTS Analyses revealed that only 2 human bladder cancers weakly expressed ERα. In contrast, the expression of ERβ was detected in 141 tumors (63%). ERβ was expressed in 58% of WHO Grade 1 and 2 tumors, whereas 70% of Grade 3 tumors demonstrated expression (P=.085). Importantly, although only 53% and 55% of Ta and T1 tumors demonstrated ERβ expression, 80% of T2, 81% of T3, and 75% of T4 tumors showed ERβ expression. The differences in ERβ expression between Ta/T1 and T2/T3/T4 tumors were found to be highly significant (P

BACKGROUND The authors found previously that plasma levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) were elevated in patients with bladder carcinoma and were associated with features of biologically aggressive disease. In the current study, they tested the hypothesis that elevated urinary levels of uPA and uPAR would predict the presence of bladder malignancy by comparing the performance of uPA and uPAR with the performance of bladder wash-out cytology in the noninvasive diagnosis of bladder tumors. METHODS An enzyme-linked immunosorbent assay was used to compare levels of uPA and uPAR in urine that was collected before cystoscopy from 122 patients with bladder carcinoma and from 107 participants in a control group. Seventy-two patients had clinical Tis or Ta transitional cell carcinoma, and 50 patients had invasive disease (≥ T1); 85 patients had clinical Grade 1–2 tumors, and 37 patients had Grade 3 tumors. For cytology, only high grade was considered positive. RESULTS Urinary levels of uPA and uPAR were higher in patients with bladder carcinoma compared with levels in the control group (P < 0.001 and P = 0.016, respectively). However, only uPA levels were elevated in patients with abnormal urinary cytology (P = 0.006). After controlling for cytology (odds ratio [OR], 10.182; 95% confidence interval [95%CI], 4.451–23.291; P < 0.001), uPAR (P for trend = 0.168), and age (P = 0.091), those in the highest quartile for uPA had an increased risk of bladder carcinoma compared with those in the lowest quartile (OR, 3.022; 95%CI, 1.295–7.054; P for trend = 0.031). CONCLUSIONS The current findings suggest that urinary levels of uPA, but not uPAR, are related to the risk of bladder carcinoma. The study confirmed the central role of urinary cytology in the noninvasive diagnosis of bladder carcinoma. Cancer 2002;95:2494–9. © 2002 American Cancer Society. DOI 10.1002/cncr.10989

BACKGROUND The purpose of this study was to describe the expression patterns of transforming growth factor (TGF)-β1 and its receptors in transitional cell carcinoma (TCC) of the bladder, to investigate the relation between the TGF-β1 and its receptors, and to determine whether altered expression of TGF-β or its receptors is associated with disease progression and survival in patients with TCC of the bladder. METHODS Immunohistochemical staining for TGF-β1 and its receptors I and II was conducted on formalin fixed paraffin embedded archival cystectomy specimens of 80 patients with bladder TCC. Immunoreactivity was categorized as either positive or negative in a blinded fashion. RESULTS Expression of TGF-β1, TGF-β-RI, and TGF-β-RII was altered in 51 (64%), 34 (43%), and 38 (48%) specimens, respectively. Sixty (75%) specimens had altered expression of at least 1 of the 3 TGF-βs, and 26 (33%) had altered expression of all 3. Expression of the three TGF-βs was highly concordant (P < 0.018). Loss of expression of TGF-β-RI or TGF-β-RII was associated with invasive tumor stage (P < 0.001), high grade (P < 0.006), and lymphovascular invasion (P < 0.030). Overexpression of TGF-β1 was associated with invasive tumor stage only (P = 0.024). With a median follow-up of 101 months, TGF-β-RI was an independent predictor of both disease progression (P = 0.007) and disease specific survival (P = 0.006) whereas TGF-β1 was an independent predictor of disease progression only (P = 0.050). Transforming growth factor-β-RII was not independently associated with either disease progression or survival. CONCLUSIONS Altered expression of TGF-β1 and its receptors is common in TCC of the bladder. Overexpression of TGF-β1 is associated with the loss of expression of its receptors. Transforming growth factor—β1 and TGF-β-RI are independently associated with clinical outcome in patients with bladder TCC treated by radical cystectomy. Cancer 2001;92:1475–83. © 2001 American Cancer Society.

BACKGROUND Elevated local and circulating levels of transforming growth factor (TGF)-β1 have been associated with cancer invasion, progression, and metastasis. The authors tested the hypothesis that preoperative plasma TGF-β1 levels would independently predict cancer stage and prognosis in patients with transitional cell carcinoma (TCC) of the urinary bladder. METHODS The study group consisted of 51 patients who underwent radical cystectomy for muscle-invasive or intravesical immuno- and/or chemotherapy refractory Tis, Ta, or T1 TCC (median follow-up, 45.7 months). Preoperative plasma levels of TGF-β1 were measured and correlated with pathologic features and clinical outcome. Transforming growth factor-β1 levels also were measured in 44 healthy men without any cancer. RESULTS The mean preoperative plasma TGF-β1 level in patients who eventually developed metastases to distant (11.9 ± 0.9 ng/mL) or regional (9.6 ± 2.4 ng/mL) lymph nodes was significantly higher than that in patients with nonmetastatic muscle-invasive TCC (5.4 ± 1.1 ng/mL), which, in turn, was significantly higher than that in patients with nonmetastatic Tis, Ta, or T1 TCC (4.5 ± 1.2 ng/mL) and healthy subjects (4.5 ± 1.2 ng/mL; P < 0.001). Preoperative plasma TGF-β1 level was an independent predictor of lymphovascular invasion (P = 0.002), metastases to lymph nodes (P = 0.030), disease recurrence (P = 0.009), and disease specific survival (P = 0.015). In a subgroup of patients with muscle-invasive TCC, TGF-β1 level was associated with disease recurrence (P = 0.005) and death from bladder carcinoma (P = 0.001). CONCLUSIONS The authors confirm that plasma TGF-β1 levels are elevated in patients with muscle-invasive TCC before cystectomy. Transforming growth factor-β1 levels are highest in patients with bladder carcinoma metastatic to lymph nodes and are a strong independent predictor of disease recurrence and disease specific mortality. Cancer 2001;92:2985–92. © 2001 American Cancer Society.

Study Type – Therapy (individual cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Patients with urothelial carcinoma of the bladder (UCB) and pathological (p) stage T2N0 disease exhibit a range of clinical outcomes with an overall estimated 10–25% experiencing recurrence and death after radical cystectomy (RC). Nomograms to prognosticate UCB post-RC have been developed in heterogeneous datasets of patients across different stages and do not address factors unique to pT2N0 disease. A user-friendly prognostic risk model was devised for patients with pT2N0 UCB undergoing RC based on residual pathological stage at RC (pT2a, pT2b