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PurposeWe evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy.Materials and methodsWe identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings.ResultsWe identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p

Objectives: To evaluate if the obesity paradox, wherein obesity portends worse overall prognosis for a disease but improved outcomes for patients receiving immunotherapy, exists for patients receiving bacillus Calmette–Guérin (BCG) in a contemporary cohort. Patients and Methods: We performed an Institutional Review Board‐approved database review to identify patients with non‐muscle‐invasive bladder cancer (NMIBC) completing at least an induction course of BCG. Clinicopathological variables collected included: body mass index (BMI), medications, and diabetes mellitus (DM). Outcomes of interest included: recurrence‐free (RFS), progression‐free (PFS), cancer‐specific (CSS), and overall survival (OS). Univariate and multivariate modelling were used to evaluate the association between outcomes and clinical factors. Results: A total of 579 patients (median follow‐up 4.6 years) received BCG induction for NMIBC; 90% had high‐grade disease (47.2% clinical stage T1). In all, 75.7% of patients were overweight or obese and 18% had DM. Aspirin, statins, metformin and β‐blockers were used in 34%, 42%, 11%, and 29% of patients, respectively. Overweight and obese patients had improved PFS, CSS and OS. DM was associated with worse RFS. Medications of interest had no association with outcomes. Conclusion: Elevated BMI is associated with improved outcomes in patients with NMIBC treated with BCG immunotherapy. Patients with DM are at increased risk of recurrence. These findings support a potential obesity paradox in bladder cancer. Evaluation of the underlying mechanism and the role of global patient assessment, counselling, and risk factor modification are warranted. [ABSTRACT FROM AUTHOR]

Purpose: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics.Methods: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system.Results: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities.Conclusions: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Patients with cancer are highly concerned about food choices and dietary supplements that may affect their treatment outcomes. Excess folic acid (synthetic folate) from supplements or fortification can lead to accumulation of unmetabolized folic acid in the systemic circulation and urine and may promote cancer growth, especially among those with neoplastic alterations. Objective:We investigated the prospective association between synthetic compared with natural folate intake and clinical outcomes in non-muscle-invasive bladder cancer (NMIBC), which is a highly recurrent disease. Design: In a cohort of 619 NMIBC patients, folate intake at diagnosis was assessed with a previously validated food-frequency questionnaire and categorized according to tertiles. After a median follow-up of 5.2 y, 303 tumor recurrence and 108 progression events were documented from medical record review. Multivariable Cox proportional hazards and logistic models were used to estimate adjusted HRs and ORs with 95% CIs. Results: Synthetic folic acid intake was positively associated with a risk of recurrence among NMIBC patients (medium compared with low intake--HR: 1.72; 95% CI: 1.20, 2.48; P = 0.003; high compared with low intake--HR: 1.80; 95% CI: 1.14, 2.84; P = 0.01). Patients with a higher folic acid intake were more likely to have multifocal tumors at diagnosis (medium or high compared with low-- OR: 2.08; 95% CI: 1.08, 4.02; P = 0.03). In contrast, natural folate intake tended to be inversely associated with the risk of progression (medium or high compared with low--HR: 0.68; 95% CI: 0.44, 1.04; P = 0.08). Conclusions: A high intake of synthetic folic acid, in contrast to the natural forms, is associated with an increased risk of recurrence in NMIBC and multifocal tumors at diagnosis, which suggests that folic acid may be unsafe for NMIBC patients. These findings provide some evidence for nutritional consultation with regard to folate intake among NMIBC patients. [ABSTRACT FROM AUTHOR]

Background: Latent genetic instability has been associated with an increased risk for several cancers. We used the comet assay (single-cell gel electrophoresis) to assess whether genetic instability, as reflected by susceptibility to DNA damage, was associated with the risk of bladder cancer in a case-control study.Methods: We used the comet assay to measure baseline and benzo[a]pyrene diol epoxide (BPDE)- and gamma-radiation-induced DNA damage in individual peripheral blood lymphocytes from 114 incident case patients with bladder cancer and 145 matched healthy control subjects. All subjects provided personal information, including smoking history. DNA damage was visualized with the comet assay and quantified by the Olive tail moment parameter, a relative measure. Multivariable analysis was used to assess relative risks for bladder cancer associated with DNA damage. All statistical tests were two-sided.Results: Baseline levels of DNA damage were statistically significantly higher in case patients (tail moment = 1.40) than in control subjects (tail moment = 1.21) (difference = 0.19, 95% confidence interval [CI] = 0.04 to 0.32; P =.015), as were gamma-radiation-induced (tail moment = 4.76 versus 4.22; difference = 0.54, 95% CI = 0.11 to 0.96; P =.013) and BPDE-induced (tail moment = 4.06 versus 3.45; difference = 0.61, 95% CI = 0.23 to 0.99; P =.002) DNA damage. When data were dichotomized at the median value for DNA damage in control subjects and adjusted for age, sex, ethnicity, and smoking status, an increased estimated relative risk of bladder cancer was statistically significantly associated with DNA damage at baseline (odds ratio [OR] = 1.84, 95% CI = 1.07 to 3.15) and after gamma-radiation (OR = 1.81, 95% CI = 1.04 to 3.14) but not after BPDE treatment (OR = 1.69, 95% CI = 0.98 to 2.93).Conclusion: Latent genetic instability as measured by the comet assay is associated with an increased estimated relative risk of bladder cancer. [ABSTRACT FROM AUTHOR]

Objectives To present a molecular definition of bacille Calmette-Guérin (BCG) failure that incorporates fluorescence in situ hybridization (FISH) testing to predict BCG failure before it becomes clinically evident, which can be used to enhance trial designs for patients with non-muscle-invasive bladder cancer. Patients and Methods We used data from 143 patients who were followed prospectively for 2 years during intravesical BCG therapy, during which time FISH assays were collected and correlated to clinical outcomes. Results Of the 95 patients with no evidence of tumour at 3-month cystoscopy, 23 developed tumour recurrence and 17 developed disease progression by 2 years. Patients with a positive FISH test at both 6 weeks and 3 months were more likely to develop tumour recurrence (17/37 patients [46%] and 16/28 patients [57%], respectively) than patients with a negative FISH test (6/58 patients [10%] and 3/39 patients [8%], respectively; both P < 0.001). Using hazard ratios for recurrence with positive 6-week and 3-month FISH results, we constructed clinical trial scenarios whereby patients with a negative 3-month cystoscopy and positive FISH result could be considered to have 'molecular BCG failure' and could be enrolled in prospective, randomized clinical trials comparing BCG therapy (control) with an experimental intravesical therapy. Conclusions Patients with positive early FISH and negative 3-month cystoscopy results can be considered to have molecular BCG failure based on their high rates of recurrence and progression. This definition is intended for use in designing clinical trials, thus potentially allowing continued use of BCG as an ethical comparator arm. [ABSTRACT FROM AUTHOR]

Objective To assess the incidence and clinical significance of 'skip lesions' that are present in proximal but not in distal ureteric sections, which are occasionally found during the pathological examination of ureteric margins during radical cystectomy ( RC)., Patients and Methods We identified 660 patients who underwent a RC and had at least two permanent margins for a given ureter., In all, 1173 ureters were analysed and classified as follows: 'normal' (no tumour, reactive atypia, mild or moderate dysplasia) or 'abnormal' (severe dysplasia, carcinoma in situ ( CIS), or tumour)., Transitions from 'normal' distal pathology to 'abnormal' on proximal section(s) determined frequency of skip lesions., Fisher's exact test and the log-rank test were used to study correlations., Results Ureteric skip lesions were found in 4.8% patients (2.9% ureters)., Pathology of skip lesions was CIS in 55.9%, transitional cell carcinoma in 23.5% and severe dysplasia in 20.6%., Skip lesions were associated with lymphovascular invasion (34.4% vs 13.7%, P = 0.004) and advanced pT stage ( P = 0.007)., On multivariate analysis, skip lesions correlated with lower median overall survival ( OS) (inestimable vs 8.2 years, P = 0.014) in patients with pT0 or pTa disease and a trend towards lower OS (2.7 vs 8.8 years, P = 0.066) in pTis disease., Concordance between frozen distal margin and permanent proximal margin varied; sensitivity was 80% in those without and 20% in those with skip lesions., Conclusions The presence of a ureteric skip lesion may be associated with lower survival in patients with pT0, pTa or pTis urothelial carcinoma., Thus, while uncommon, ureteric skip lesions should be reported in pathological findings. [ABSTRACT FROM AUTHOR]

Abstract: Background: Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence. Objective: To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence. Design, setting, and participants: This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non–muscle-invasive bladder cancer (NMIBC). Intervention: A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy. Outcome measurements and statistical analysis: We studied the detection of NMIBC (intention to treat [ITT]: n =831; six studies) and recurrence (per protocol: n =634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection. Results and limitations: BL cystoscopy detected significantly more Ta tumours (14.7%; p <0.001; odds ratio [OR]: 4.898; 95% CI, 1.937–12.390) and CIS lesions (40.8%; p <0.001; OR: 12.372; 95% CI, 6.343–24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p <0.001), significant also in patients with primary (20.7%; p <0.001) and recurrent cancer (27.7%; p <0.001), and in patients at high risk (27.0%; p <0.001) and intermediate risk (35.7%; p =0.004). In 26.7% of patients, CIS was detected only by BL (p <0.001) and was also significant in patients with primary (28.0%; p <0.001) and recurrent cancer (25.0%; p <0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p =0.006; RR: 0.761 [0.627–0.924]), and lower in patients with T1 or CIS (p =0.052; RR: 0.696 [0.482–1.003]), Ta (p =0.040; RR: 0.804 [0.653–0.991]), and in high-risk (p =0.050) and low-risk (p =0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used. Conclusions: This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9–12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer. [Copyright &y& Elsevier]

BACKGROUND: Neoadjuvant chemotherapy improves the survival of patients with high-risk urothelial cancer. However, the lack of curative alternatives to cisplatin-based chemotherapy is limiting for patients with neuropathy or hearing loss. Sequential chemotherapy also has not been well studied in the neoadjuvant setting. The authors explored sequential neoadjuvant ifosfamide-based chemotherapy in a patient cohort at high risk of noncurative cystectomy. METHODS: Patients with muscle-invasive cancer and lymphovascular invasion, hydronephrosis, clinical T3b and T4a (cT3b-4a) disease (defined as a 3-dimensional mass on examination under anesthetic or invasion into local organs), micropapillary tumors, or upper tract disease received 3 cycles of combined ifosfamide, doxorubicin, and gemcitabine followed by 4 cycles of combined cisplatin, gemcitabine, and ifosfamide. The primary endpoint was downstaging to pT1N0M0 disease or lower. RESULTS: At a median follow-up of 85.3 months, the 5-year overall survival (OS) and disease-specific survival (DSS) rates for all 65 patients were 63% and 68%, respectively (95% confidence interval: 5-year OS rate, 0.52%-0.76%; 5-year DSS rate, 0.58%-0.81%). Pathologic downstaging to pT1N0 disease or lower occurred in 50% of patients who underwent cystectomy and in 60% of patients who underwent nephroureterectomy and was correlated with the 5-year OS rate (pT1N0 disease or lower, 87%; pT2-pT3aN0 disease, 67%; and pT3b disease or higher or lymph node-negative disease, 27%; P ≤ .001 for pT1 or lower vs pT2 or higher). Variant histology was associated with an inferior 5-year DSS rate (50% vs 83% in pure transitional cell carcinoma; P = .02). The most frequent grade 3 toxicities were infection (38%), febrile neutropenia (22%), and mucositis (18%). There were 3 grade 4 toxicities (myocardial infarction, thrombocytopenia, and vomiting) and 1 grade 5 toxicity in a patient who refused antibiotics for pneumonia. CONCLUSIONS: Sequential therapy was active and maintained the historic expectation of achieving a cure. The current results strongly reinforced previous experience suggesting that pathologic downstaging to pT1N0 disease or less is a useful surrogate for eventual cure in patients with urothelial cancer. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Patients with positive lymph nodes at radical cystectomy have a poor prognosis. The actual outcome of patients varies based on many factors, among which lymph node density has emerged as being more informative than nodal status of TNM staging. We combined clinical data from two major cancer centres in the USA and identified patients with an adequate lymphadenectomy and no perioperative chemotherapy to understand the natural history of the disease. Using this information, we created prognostic tools incorporating lymph node density that can be used for risk stratification, patient counselling and clinical trial design. OBJECTIVE To develop a clinical tool based on lymph node density (LND) for patient counselling after radical cystectomy and for design of clinical trials of adjuvant therapies after radical cystectomy., PATIENTS AND METHODS Using pooled data from two comprehensive cancer centres, we identified patients with lymph node metastases after radical cystectomy who received an adequate lymph node dissection according to existing literature (resection of eight or more nodes)., Only patients who had not received neoadjuvant or adjuvant chemotherapy were included to ensure that prediction models were based on the natural course of the disease., Thresholds for LND ranging from 5% to 35%, in 5% increments, were used to dichotomize the study population. Within each set of two groups, the Kaplan-Meier product-limit estimator was used to estimate disease-specific survival (DSS) for each group, and Cox proportional hazards regression was used to test the significance of differences in DSS between the group with higher LND and the group with lower LND., Tables and graphs showing the relationship between LND categories and 2-year and 5-year estimated DSS were created to aid in clinical decision-making., RESULTS LND was valuable as a tool for stratifying node-positive patients into different risk groups based on expected survival., At each LND threshold from 10% to 35%, patients with higher LND had significantly worse DSS than patients with lower LND ( P≤ 0.001)., As expected, DSS in the higher-LND group worsened with each 5% increase in LND threshold: patients with LND > 35% had a 5-year DSS rate of 4%., Using our data as a tool, multiple cut-offs can be employed to categorize patients into various risk groups with different risk. For example, patients with LND ≤ 10% have an estimated 5-year DSS rate of 61.9%, whereas patients with LND > 15% have an estimated 5-year DSS rate of 19.2%., CONCLUSIONS Patients with node-positive bladder cancer have poor outcomes, and survival varies widely according to LND., Categorical LND should be used to risk-stratify patients for counselling regarding prognosis., Furthermore, categorical LND should be used as a tool for designing and reporting on clinical trials of adjuvant therapies. [ABSTRACT FROM AUTHOR]

Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? A plethora of urinary markers are available with the purported benefit of identifying bladder tumours that evade detection with cystoscopy alone. Clinicians often infer that this translates into earlier detection of invasive disease and helps control costs. This prospective trial suggests that in experienced hands, cystoscopy alone is the most cost-effective strategy to detect recurrence of non-invasive bladder cancer. Using urinary markers in all patients significantly adds to cost and hence must be individualized. OBJECTIVE • To assess the cost-effectiveness of using cytological evaluation, NMP22 BladderChek®, and fluorescence in situ hybridization (FISH) UroVysion® in addition to cystoscopy in patients with a history of bladder cancer undergoing surveillance for recurrence. PATIENTS AND METHODS • In all, 200 consecutive patients with a history of bladder cancer not invading the muscle were prospectively enrolled at The University of Texas MD Anderson Cancer Center. • Five surveillance strategies were compared: (i) cystoscopy alone; (ii) cystoscopy and NMP22; (iii) cystoscopy and FISH; (iv) cystoscopy and cytology; and (v) cystoscopy and positive NMP22 confirmed by positive FISH. • The cost per cancer detected was calculated. • For patients with an initial positive test and negative cystoscopy, tumour detected at first follow-up was assumed to be too small to be visualized at the initial assessment and the biomarker was credited with early detection. RESULTS • Cancer was detected in 13 patients at study entry. • Detection rates for the five surveillance strategies were: (i) 52%, (ii) 56%, (iii) 72%, (iv) 60%, and (v) 56%. • The costs per tumour detected (at the time of initial marker analysis) were (i) $7692; (ii) $12 000; (iii) $26 462; (iv) $11 846; and (v) $10 292. • When early detection of biomarkers was factored in, the CPTD became: (i) $7692; (ii) $11 143; (iii) $19 111; (iv) $10 267; and (v) $9557. • There were 12 new cancers detected at first follow-up (median time, 4.1 months). None of the tumours detected by biomarkers but not by cystoscopy were invasive. CONCLUSIONS • Cystoscopy alone remains the most cost-effective strategy to detect recurrence of bladder cancer not invading the muscle. • The addition of urinary markers adds to cost, without improved detection of invasive disease. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? In a meta-analysis of randomized trials, neoadjuvant platinum-based combination chemotherapy administered before definitive local treatment improved survival of patients with muscle-invasive bladder cancer compared with definitive local treatment alone. However, it was not known whether chemotherapy was equally effective for pure urothelial carcinoma versus urothelial carcinoma with mixed histological features, such as squamous or glandular differentiation. To address this question we performed a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) followed by cystectomy versus cystectomy alone for treatment of locally advanced urothelial cancer of the bladder. Our findings suggest that presence of squamous or glandular differentiation does not confer resistance to combination chemotherapy with MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy. OBJECTIVE • To determine whether the effect of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) on the survival of patients with locally advanced urothelial carcinoma (UC) of the bladder treated with radical cystectomy varies with the presence of non-urothelial components in the tumour. PATIENTS AND METHODS • This is a secondary analysis of the Southwest Oncology Group-directed intergroup randomized trial S8710 of neoadjuvant MVAC followed by cystectomy versus cystectomy alone for treatment of locally advanced UC of the bladder. • For the purpose of these analyses, tumours were classified based on the presence of non-urothelial components as either pure UC ( n= 236) or mixed tumours ( n= 59). Non-urothelial components included squamous and glandular differentiation. • Cox regression models were used to estimate the effect of neoadjuvant MVAC on all-cause mortality for patients with pure UC and for patients with mixed tumours, with adjustment for age and clinical stage. RESULTS • There was evidence of a survival benefit from chemotherapy in patients with mixed tumours (hazard ratio 0.46; 95% CI 0.25-0.87; P= 0.02). Patients with pure UC had improved survival on the chemotherapy arm but the survival benefit was not statistically significant (hazard ratio 0.90; 95% CI 0.67-1.21; P= 0.48). • There was marginal evidence that the survival benefit of chemotherapy in patients with mixed tumours was greater than it was for patients with pure UC (interaction P= 0.09). CONCLUSION • Presence of squamous or glandular differentiation in locally advanced UC of the bladder does not confer resistance to MVAC and in fact may be an indication for the use of neoadjuvant chemotherapy before radical cystectomy. [ABSTRACT FROM AUTHOR]

The phosphoinositide-3 kinase (PI3K)–AKT– mammalian target of rapamycin (mTOR) pathway is an important cellular pathway controlling cell growth, tumorigenesis, cell invasion and drug response. We hypothesized that genetic variations in the PI3K–AKT–mTOR pathway may affect the survival in muscle invasive and metastatic bladder cancer (MiM-BC) patients. We conducted a follow-up study of 319 MiM-BC patients to systematically evaluate 289 single-nucleotide polymorphisms (SNPs) of 20 genes in the PI3K–AKT–mTOR pathway as predicators of survival. In multivariate Cox regression, AKT2 rs3730050, PIK3R1 rs10515074 and RAPTOR rs9906827 were significantly associated with survival. In combined analysis, we found a cumulative effect of these three SNPs on survival. With the increasing number of unfavorable genotypes, there was a significant trend of higher risk of death in multivariate Cox regression (P for trend <0.001) and shorter median survival time in Kaplan–Meier estimates (P log rank <0.001). This is the first study to evaluate the role of germ line genetic variations in the PI3K–AKT–mTOR pathway genes as predictors of MiM-BC clinical outcomes. These findings warrant further replication in independent populations and may provide information on disease management and development of target therapies. [ABSTRACT FROM PUBLISHER]

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To evaluate our experience with urethral recurrences in patients treated by radical cystectomy(RC) and orthotopic neobladder urinary diversion for carcinoma of the bladder. PATIENTS AND METHODS We retrospectively reviewed the records of patients treated with RC and orthotopic urinary diversion between January 1980 and July 2004. RESULTS In all, 260 patients underwent RC with a Studer or Hautmann orthotopic urinary diversion; the median (range) follow-up was 5.1 (0–15.6) years. Six patients (2.3%) developed local recurrence of urothelial cancer (UC) within the urethra after this treatment. The median (range) time to presentation with recurrence after RC was 2.4 (0.7–3.6) years for pT1-4 UC. Recurrences were treated with various methods, including transurethral resection, urethrectomy with conversion of neobladder to continent catheterizable diversion, and chemotherapy. At the last follow-up, four of these six patients were alive without disease, one was alive with disease, and one had died from disease. CONCLUSIONS In our experience, local recurrences involving the urethra are infrequent. Complete surgical excision can provide a good outcome. Neoadjuvant chemotherapy should be considered for recurrences with adverse clinicopathological features. [ABSTRACT FROM AUTHOR]

Abstract: The Bladder Cancer Think Tank III brought together a multidisciplinary group of clinician scientists, patient advocates, representatives from the National Cancer Institute, and Industry leaders to discuss the current state of the field in urothelial cancer and to develop strategies to move forward. This paper summarizes the session devoted to prevention. Experts sought to define primary, secondary, and tertiary prevention and discussed clinical trials performed to date testing retinoids, difluoromethylornithine, celecoxib, and other oral agents in a tertiary prevention setting following transurethral resection with or without intravesical therapy. Urologists practice tertiary prevention in the form of intravesical therapy, and strategies were discussed to identify biomarkers, including urinary cytokines and pathway single nucleotide polymorphism analysis associated with response to treatment. Optimizing delivery of intravesical chemotherapy to the target tissue with simple pharmacologic manipulations or packaging drugs in nanoparticles may improve treatment outcome. Defining a premalignant lesion should be a focus of future research as a strategy for early detection and secondary prevention. Cigarette smoking is the most prevalent risk factor for urothelial cancer, and emphasis was placed on smoking cessation as a powerful tool to reduce the burden of urothelial cancer, and the central role physicians must play in educating patients and providing resources. There is a strong need for research to develop markers of disease initiation and progression. These markers, combined with histories of environmental exposure to bladder carcinogens, may provide a tool to identify patients who will benefit from primary prevention. [Copyright &y& Elsevier]

The article presents a study on the use of stratified Cox regression of the association of quality of pathologic response following the radical cystectomy (RC) with overall survival (OS). Results show that radical cystectomy (RC) is greater or equal than pelvic lymph nodes removed in a retrospective study. It is concluded that a combination of baseline clinical stage and post-RC pathologic stage can be better predict overall survival (OS).

Purpose: Cross-contamination of cell lines is a serious but often unrecognized problem. We describe the authentication of a panel of transitional cell carcinoma cell lines using the short tandem repeat profiling technique to detect cross-contamination. Materials and Methods: Genomic DNA was isolated from UM-UC-1, UM-UC-2, UM-UC-3 (ATCC®), UM-UC-6, UM-UC-9, UM-UC-10, UM-UC-11, UM-UC-13, UM-UC-14, UM-UC-16, T24 and KU7 cell lines. Short tandem repeat loci (D3S1358, D16S539, vWA, FGA, TH01, TPOX, CSF1PO, D5S818, D13S317 and D7S820) and a segment of the X-Y homologous gene amelogenin were co-amplified by polymerase chain reaction. Profiling was done using POP-4TM performance optimized polymer 4 (Applied Biosystems®) with an ABI Prism® 310 genetic analyzer. DNA sequencing of TP53 and immunohistochemistry for p53 were performed in UM-UC-3 and UM-UC-3-GFP. Results: All cell lines had a unique short tandem repeat profile except UM-UC-2 and T24, which were virtually identical. T24 short tandem repeat profiles matched those of early passage number UM-UC-2. Stable transfection of the green fluorescence protein marker gene did not alter UM-UC-6, UM-UC-14 or KU7 profiles. However, the short tandem repeat profile for UM-UC-3-GFP was different from that of UM-UC-3. DNA sequencing showed a difference in TP53 between UM-UC-3 and UM-UC-3-GFP, confirming that UM-UC-3-GFP is not derived from UM-UC-3. Conclusions: Short tandem repeat profiling provides a unique genetic signature of human cell lines that does not significantly change with passage or green fluorescence protein transduction. Using short tandem repeat profiling we noted that the cell line UM-UC-2 is T24. DNA fingerprinting using short tandem repeat profiling is an easy and reliable tool that can be used to verify cell lines. [Copyright &y& Elsevier]

Background Chromosome missegregation and the resulting aneuploidy is a common change in neoplasia. The Aurora kinase A (AURKA) gene, which encodes a key regulator of mitosis, is frequently amplified and/or overexpressed in cancer cells, and the level of AURKA amplification is associated with the level of aneuploidy. We examined whether AURKA gene amplification is a biomarker for the detection of bladder cancer. Methods The effect of ectopic expression of Aurora kinase A (AURKA) using an adenoviral vector in simian virus 40-immortalized urothelial cells (SV-HUC) on centrosome multiplication and chromosome copy number was measured in vitro by immunofluorescence and fluorescence in situ hybridization (FISH), respectively. The FISH test was also used to examine AURKA gene copy number in exfoliated cells in voided urine samples from 23 patients with bladder cancer and 7 healthy control subjects (training set), generating a model for bladder cancer detection that was subsequently validated in an independent set of voided urine samples from 100 bladder cancer patients and 148 control subjects (92 healthy individuals and 56 patients with benign urologic disorders). An AURKA gene score (the proportion of cells with three or more AURKA signals) was used to produce receiver operating characteristic (ROC) curves and to calculate the specificity and sensitivity of the AURKA FISH test. Differences between mean AURKA scores in different pathogenetic groups of bladder cancer stratified according to histological grade and stage were tested by unpaired Mann-Whitney ttests or one-way Wilcoxon tests. All statistical tests were two-sided. Results Forced overexpression of AURKA in urothelial cells induced amplification of centrosomes, chromosome missegregation, and aneuploidy, and natural overexpression was detectable in in situ lesions from patients with bladder cancer. The FISH test for the AURKA gene copy number performed on the validation set yielded a specificity of 96.6% (95% confidence interval [I] = 92.3% to 98.5%) and sensitivity of 87% (95% Cl = 79.0% to 92.2%) and an area under the ROC curve of 0.939 (95% CI = 0.906 to 0.971; P < .001). Conclusion Overexpression of AURKA can cause aneuploidy in urothelial cells, and the AURKA gene copy number is a promising biomarker for detection of bladder cancer. [ABSTRACT FROM AUTHOR]

Bladder cancer results from complex and only partially understood host-environmental interactions. Tobacco smoking is the greatest risk factor for bladder cancer, but the actual risk to an individual reflects not only the amount of exposure to the carcinogens in tobacco smoke but also host susceptibility to these carcinogens and possibly other factors. Lifestyle may have a significant effect on the incidence of this disease. The forms of chemoprevention and their relevance to bladder cancer, the impact of lifestyle and complementary medicine, and the costs of diagnosing and treating bladder cancer are reviewed to provide a base for advances in decreasing the incidence, recurrence and costs of this disease. [ABSTRACT FROM AUTHOR]

Information about several papers discussed at the 2008 International Consultation "Bladder Cancer - From Pathogenesis to Prevention." Topics include the epidemiology and etiology of bladder cancer, screening and prevention of bladder cancer, and histopathological and clinical presentation of bladder urothelial carcinoma. The meeting features Jan Adolfsson, Ziya Kirkali and Paolo Boffetta.

The article presents a study which examines the effects of a panel of 10 potential functional single nucleotide polymorphisms (SNPs) from 7 cell cycle control genes on bladder cancer susceptibility. Results of the Classification and Regression Tree (CART) analysis suggests that cell cycle genetic polymorphisms may affect bladder cancer predisposition by modulation of host genome stability and confirms the importance of studying gene-environment interactions in bladder cancer risk assessment.

The article focuses on a study which investigated the patterns and outcome of recurrence of nonbilharzial squamous cell carcinoma (SCC) of the bladder. A brief overview of nonbilharzial SCC of the bladder is presented. The respondents of the study underwent transurethral resection for diagnostic purposes and bimanual examination. The demographics and clinical characteristics of patients are given. In conclusion, radical cystectomy remains the recommended therapy for nonbilharzial SCC of the bladder in selected patients.

The article focuses on a study about micropapillary bladder cancer. Under the study, records of 100 micropapillary bladder cancer patients at the University of Texas M.D. Anderson Cancer Center in Houston were evaluated. Results indicate that the mean age of patients was 64.7 years and that male:female ratio was 10:1. It concludes that poor prognosis leads to the disease while intravesical therapy proves to be an ineffective treatment.

Tumor recurrence is a hallmark of superficial bladder cancer. Currently, a molecular marker for bladder cancer recurrence is lacking. E-cadherin plays an important role in epithelial development and in the establishment and maintenance of cell–cell adhesion and tissue architecture. The purpose of this study is to investigate the association of an E-cadherin promoter polymorphism (CDH1c-160a) with the risk of bladder cancer recurrence. This study included 302 patients with superficial bladder cancer. Genomic DNA was extracted from peripheral blood lymphocytes and genotyping was performed using Taqman assay. Clinical data were collected by medical chart review. Cox proportional hazard model was used to estimate the hazard ratios (HRs) associated with genotypes while adjusting for age, gender, smoking status, tumor stage and grade where appropriate. During a median follow-up of 27.65 months, 151 patients experienced disease recurrence. Subsequent analyses were restricted to Caucasians only due to the small sample size of other ethnic groups (13 in recurrence group and 15 in non-recurrence group). Among the 274 Caucasian patients, 138 developed recurrence during the same length of follow-up time. In Caucasian patients, having at least one variant A allele conferred a 32% reduction in recurrence risk (adjusted HR: 0.68; 95% CI: 0.48–0.96). The median recurrence-free survival for patients carrying at least one variant A allele was significantly longer than that for patients with a homozygous CC genotype (40.4 vs 12.5 months, p = 0.04). Our findings suggest that the E-cadherin promoter polymorphism may be a valuable molecular marker for bladder cancer recurrence. [ABSTRACT FROM AUTHOR]

Abstract: Chemoprevention of cancer can be accomplished using primary, secondary, or tertiary strategies. Tertiary chemoprevention has been the predominant approach for bladder cancer and addresses the need for preventing the occurrence of second primary cancers in patients who have previously been treated for cancer. Because non–muscle-invasive bladder cancer is associated with a high risk of recurrence, tertiary chemoprevention has been studied in this population. Although considerable preclinical data has demonstrated the feasibility of this approach, application to the clinical setting has met with limited success. This review discusses chemoprevention of bladder cancer and focuses on the drugs used in chemoprevention investigations and clinical study design. [Copyright &y& Elsevier]

The article discusses treatment strategy for monitoring patients with a history of recurrent bladder cancer, which was the focus of a cross-sectional study in the United States. The point-of-care proteomic test is a urine test which measures the nuclear matrix protein NMP22 and could be effective in detecting recurrence. Research methods are detailed, including diagnosis based on cystoscopy with biopsy and blind testing of the NMP22 tumor marker. Statistics are provided on baseline patient characteristics, detection, sensitivity of NMP22 assay and cytologic analysis, as well as specificity of NMP22 assay. The study found that noninvasive point-of-care assay can help detect recurrence quickly.

Abstract: Dietary folate, a water-soluble B vitamin found in a variety of fruits and vegetables, is of particular interest as a chemopreventive agent due to its role in DNA methylation and DNA synthesis and repair. We hypothesized that individuals with low folate intake would be at an increased risk for bladder cancer. Using an ongoing case-control study we assessed dietary folate in 409 incident bladder cancer patients and 451 healthy control subjects. A food-frequency questionnaire was used to estimate naturally occurring food folate (μg/kcal/day), dietary folate equivalents (DFE) from food sources (μg DFE/kcal/day), and DFE from all sources (μg DFE/kcal/day). Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Bladder cancer patients reported a statistically significant lower intake of folate than control subjects for food folate and DFE from food sources (P < 0.001) but not for DFE from all sources (P = 0.061). In the highest quartile of food folate intake there was a 54% reduced risk for bladder cancer (OR = 0.46; 95% CI = 0.29-0.73) after adjusting for age, gender, ethnicity, smoking, and total energy intake. Similarly, the highest quartile of intake was associated with a 59% reduced risk for DFE from food sources (OR = 0.41; 95% CI = 0.26-0.65) and a 35% reduced risk for DFE from all sources (OR = 0.65; 95% CI = 0.42-1.00). In the joint-effects analyses using never smokers with high folate intake as the reference group (OR = 1.0), heavy smokers with low food folate intake had a 2.31-fold (95% CI = 1.11-4.82) increased risk, whereas heavy smokers with high folate intake had a reduced OR of 1.31 (95% CI = 0.53-3.26). Although the ORs were not statistically significant, light smokers and high folate intake exhibited a protective effect (OR = 0.62; 95% CI = 0.20-1.94), whereas an increased risk was observed for light smoking and low folate intake (OR = 1.41; 95% CI = 0.57-3.45). These patterns were consistent for the joint effects of smoking and DFE from food sources and DFE from all sources. In summary, high intake of dietary folate was associated with an overall decrease in bladder cancer risk. These data may have important implications for cancer prevention; however, large, hypothesis-driven, population-based clinical trials will be required to confirm these findings. [ABSTRACT FROM AUTHOR]

Context A combination of methods is used for diagnosis of bladder cancer because no single procedure detects all malignancies. Urine tests are frequently part of an evaluation, but have either been nonspecific for cancer or required specialized analysis at a laboratory. Objective To investigate whether a point-of-care proteomic test that measures the nuclear matrix protein NMP22 in voided urine could enhance detection of malignancy in patients with risk factors or symptoms of bladder cancer. Design, Setting, and Patients Twenty-three academic, private practice, and veterans’ facilities in 10 states prospectively enrolled consecutive patients from September 2001 to May 2002. Participants included 1331 patients at elevated risk for bladder cancer due to factors such as history of smoking or symptoms including hematuria and dysuria. Patients at risk for malignancy of the urinary tract provided a voided urine sample for analysis of NMP22 protein and cytology prior to cystoscopy. Main Outcome Measures The diagnosis of bladder cancer, based on cystoscopy with biopsy, was accepted as the reference standard. The performance of the NMP22 test was compared with voided urine cytology as an aid to cancer detection. Testing for the NMP22 tumor marker was conducted in a blinded manner. Results Bladder cancer was diagnosed in 79 patients. The NMP22 assay was positive in 44 of 79 patients with cancer (sensitivity, 55.7%; 95% confidence interval [CI], 44.1%-66.7%), whereas cytology test results were positive in 12 of 76 patients (sensitivity, 15.8%; 95% CI, 7.6%-24.0%). The specificity of the NMP22 assay was 85.7% (95% CI, 83.8%-87.6%) compared with 99.2% (95% CI, 98.7%-99.7%) for cytology. The proteomic marker detected 4 cancers that were not visualized during initial endoscopy, including 3 that were muscle invasive and 1 carcinoma in situ. Conclusion The noninvasive point-of-care assay for elevated urinary NMP22 protein can increase the accuracy of cystoscopy, with test ... [ABSTRACT FROM AUTHOR]

Tumor free survival after radical cystectomy is stage dependent. In addition, other features such as the presence of angioinvasion or micropapillary histology also indicate a poor outcome. Failures of definitive therapy by radical cystectomy occur most frequently at distant sites and appear to result from occult micrometastases present at the time of surgery. These clinical data strongly suggest that radical cystectomy provides insufficient treatment for a group of patients at high risk for tumor recurrence. Multimodal therapy (chemotherapy and surgery) seems to improve outcome in such patients, whether given in a neoadjuvant or adjuvant mode. This increased probability of improved outcome with multimodal therapy, however, is accompanied by an almost certain risk of increased toxicity. The neoadjuvant strategy can deliver systemic chemotherapy more reliably and may permit bladder salvage, but adjuvant therapy permits patient selection based on pathology results. The most critical issue in multimodal therapy is patient selection. The choice of neoadjuvant or adjuvant therapy will depend on clinical circumstances, resources, and patient and physician preferences. [Copyright &y& Elsevier]

Background: The mitotic kinase-encoding gene STK15/BTAK/ AuroraA is associated with aneuploidy and transformation when overexpressed in mammalian cells. STK15 overexpression activates an unknown oncogenic pathway that involves centrosome amplification and results in missegregation of chromosomes. Because clinical prognosis and tumor aneuploidy are tightly linked in human bladder cancer, we examined whether increased STK15 copy number and protein levels are linked to aneuploidy in bladder cancers.Methods: STK15 protein was visualized by immunohistochemistry in 205 formalin-fixed, paraffin-embedded human bladder tumors. STK15 gene copy number was evaluated in 61 tumors by Southern blot hybridization and in 21 of these 61 tumors by fluorescence in situ hybridization (FISH). Copy numbers of chromosomes 3, 17, 20, and 21 were evaluated by FISH with chromosome-specific probes. STK15 expression levels were related to histologic grade, stage, and DNA ploidy of the tumors and to the patients' follow-up data. The chi-square test for association was used to analyze the relationship between STK15 expression and pathologic features. All statistical tests were two-sided.Results: Tumors with low levels of STK15 amplification (3-4 copies) showed minimal deviation in their chromosome copy number and diploid or near-diploid total nuclear DNA content. Tumors with higher levels of STK15 amplification (>4 copies) had a major increase of chromosome copy number and of their total nuclear DNA content, i.e., exhibited pronounced aneuploidy. Elevated expression of STK15 was strongly associated with parameters of clinical aggressiveness including high histologic grade (P<.001), invasion (P<.001), increased rate of metastasis (P<.001), and decreased metastasis-free (P<.001) and overall (P<.001) survival of patients with bladder cancer.Conclusion: STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer. [ABSTRACT FROM AUTHOR]