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The association between tea consumption and bladder cancer has been confirmed in several animal studies, but one epidemiological study in 2001 showed no association between them. In order to provide an accurate assessment of this, we conducted a meta-analysis on tea consumption and bladder cancer risk. Studies were identified by a literature search in PubMed from January 1980 to March 2012 and the reference lists of relevant studies. Random effect models were used to calculate relative risk estimates (RR) and their corresponding 95% confidence intervals (CI) based on high contrast to low intake values. Twenty-four publications (6 cohort studies and 18 case-control studies) based on consumption of overall tea, black tea, and green tea to bladder cancer risk were included in this analysis. For overall tea, the RR indicated no association between tea consumption and bladder cancer (RR= 1.09, 95%CI: 0.85-1.40). In subgroup analyses, we found a moderate increase of bladder cancer risk in smoking group (RR= 1.77, 95%CI: 1.04-3.01). In the black tea group, no statistically significant association was observed (RR= 0.84, 95%CI: 0.70-1.01). Interestingly, in the subgroup of sex, a protective effect was observed between tea consumption and bladder cancer risk in females (RR= 0.61, 95%CI: 0.38-0.98). For green tea group, there was no relationship associated with bladder cancer risk (RR= 1.03, 95%CI: 0.82-1.31). In conclusion, our data suggest that high overall tea intake in smokers increased the risk of bladder cancer, and high black tea intake in females may reduce the risk of bladder cancer. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is associated with increased risk of cancer at several sites, but its association with risk of bladder cancer is still controversial. We examined this association by conducting a systematic review and meta-analysis of cohort studies. Methods: Studies were identified by searching PubMed, EMBASE, Scopus, Web of Science, Cochrane register, and Chinese National Knowledge Infrastructure (CNKI) databases through April 29, 2012. Summary relative risks (SRRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. Results: A total of fifteen cohort studies were included in this meta-analysis. Analysis of all studies showed that diabetes was associated with a borderline statistically significant increased risk of bladder cancer (RR 1.11, 95% CI 1.00–1.23; p<0.001 for heterogeneity; I2 = 84%). When restricting the analysis to studies that had adjusted for cigarette smoking (n = 6) or more than three confounders (n = 7), the RRs were 1.32 (95% CI 1.18–1.49) and 1.20 (95% CI 1.02–1.42), respectively. There was no significant publication bias (p = 0.62 for Egger’s regression asymmetry test). Conclusions: Our findings support that diabetes was associated with an increased risk of bladder cancer. More future studies are warranted to get a better understanding of the association and to provide convincing evidence for clinical practice in bladder cancer prevention. [ABSTRACT FROM AUTHOR]

Purpose: We determined the risk of disease specific mortality in patients with primary, low risk, noninvasive (G1pTa) bladder cancer and compared it to disease specific mortality in age and gender matched general populations. Materials and Methods: We identified all patients with primary low risk cancer at our institution. We excluded those with adverse pathological features and then matched histopathology, pharmacy, hospital episode and Cancer Registry records. We reviewed case notes on patients with subsequent muscle invasion (progression) or disease specific mortality. Patients underwent post-resection surveillance and treatment using standard regimens. National and regional disease specific mortality rates were calculated from appropriate data. Results: A total of 699 patients met study inclusion criteria. Median followup was 61 months (IQR 24–105). Of the patients 17 (2.4%) died of bladder cancer, including 13 of 14 with progression to muscle invasion and 4 of 19 with grade progression to high grade, nonmuscle invasive disease. On Cox regression analyses low grade dysplasia in the initial resection specimen and tumor weight were associated with disease specific mortality (p <0.003). Disease specific mortality in these patients was 5 times the background rate in matched populations. Limitations of this study include its retrospective nature and the low frequency of adverse events. Conclusions: Patients with low risk bladder cancer rarely progress to muscle invasion but they are at higher risk for disease specific mortality than the general population. Current surveillance regimens appear ineffective for detecting progression in time to alter prognosis. [ABSTRACT FROM AUTHOR]

Background Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations. Methods We obtained data from the Colon Cancer Family Registry for a cohort of 127 women who had a diagnosis of endometrial cancer and who carried a mutation in one of four MMR genes (30 carried a mutation in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2). We used the Kaplan-Meier method to estimate 10- and 20-year cumulative risks for each cancer. We estimated the age-, country-, and calendar period–specific standardized incidence ratios (SIRs) for each cancer, compared with the general population. Results Following endometrial cancer, women carrying MMR gene mutations had the following 20-year risks of other cancer cancers: colorectal cancer (48%, 95% confidence interval [CI] = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%). Compared with the general population, these women were at statistically significantly elevated risks of colorectal cancer (SIR = 39.9, 95% CI = 27.2 to 58.3), cancer of the kidney, renal pelvis, or ureter (SIR = 28.3, 95% CI = 11.9 to 48.6), urinary bladder cancer (SIR = 24.3, 95% CI = 8.56 to 42.9), and breast cancer (SIR = 2.51, 95% CI = 1.17 to 4.14). Conclusions Women with Lynch syndrome who are diagnosed with endometrial cancer have increased risks of several cancers, including breast cancer. [ABSTRACT FROM PUBLISHER]

Objective: To study the effect of smoking status at diagnosis on recurrence in intermediate-risk non–muscle-invasive bladder carcinoma treated by transurethral resection (TUR) of the bladder and early intravesical chemotherapy. Methods: Tumor characteristics and smoking status were recorded in 395 patients entered in a randomized multicenter trial comparing 2 different schedules of early intravesical chemotherapy. All patients received intravesical epirubicin (80 mg/50 mL) within 6 hours after TUR, followed by 5 more weekly instillations with (arm B) or without (arm A) monthly instillations for 1 year. Smoking habit was investigated at diagnosis through a structured questionnaire. Multivariate statistical analysis was performed to study the recurrence-free survival (RFS) and the recurrence-free rate (RFR) in relation to smoking status. Results: Ninety-seven (24.6%) patients never smoked and 298 (75.4%) were smokers. At a median follow-up of 48 months, 117 patients (29.6%) recurred, 63 in arm A and 54 in arm B (P = .43). Ten patients (2.5%) progressed. The 3-year RFS, RFR, and median time to first recurrence of smokers and patients who never smoked were 64.0% and 71.3% (P = .08), 69.1% and 74.2% (P = .16), and 13.6 and 14.2 months (P = .27), respectively. The multivariate analysis identified previous history (P = .01) and smoking status (P = .04) as the main prognostic factors for recurrence in these patients. No difference in recurrence risk at 3 years was detected between current and former smokers. Conclusion: In intermediate-risk non–muscle-invasive bladder carcinoma treated by early intravesical chemotherapy, smoking status influences significantly the 3-year RFS. No difference was detected between current and former smokers. [ABSTRACT FROM AUTHOR]

Objective: To investigate the existence of predictive factors for concomitant, primary UUT-UCC and BC. Upper urinary tract urothelial cell carcinoma (UUT-UCC) is a pan-urothelial disease of the transitional epithelial cells. Although several studies have shown the association of bladder recurrence following UUT-UCC, little is known on the incidence of concomitant UUT-UCC and bladder cancer (BC) without previous BC. Materials and methods: A retrospective review of 673 patients diagnosed and treated for UUT-UCC was performed. Patients with history of BC were excluded. We investigated age, sex, location of the upper tract tumor (calyx, renal pelvis, upper ureter, mid-ureter, lower ureter), multifocality, clinical symptoms, tumor grade and pathological stage. Contingency tables and chi-square test were used for categorical variables and analysis of variance (ANOVA) for quantitative variables. Results: 450 patients eligible for inclusion were identified. Of these, 76 (17 %) presented concomitant primary UUT-UCC and BC. Location of primary UUT-UCC was in calyx and/or renal pelvis in 25 patients (34 %), upper ureter 8 (11 %) and lower ureter 37 (49 %). In 6 patients (8 %), data were missing. Concomitant BC was found in 10, 18, and 33 % of patients with primary caliceal/renal pelvis, upper ureter and lower ureter UUT-UCC, respectively. On multivariate analysis, location of UUT-UCC was the only predictive factor for concomitant bladder tumor (OR: 1.7; 95 % CI, 1.007-2.906 p = 0.047). Conclusions: Our findings suggest that the possibility of concomitant BC in primary diagnosed patient with UUT-UCC is as high as 33 % and mainly depends on upper tract tumor location. [ABSTRACT FROM AUTHOR]

Objective: This meta-analysis of cohort and case-control studies was undertaken to evaluate the relationship between cruciferous vegetables intake and risk of bladder cancer. Methods: Eligible studies were retrieved via both computer searches and review of references. The summary relative risks (RRs) with 95% confidence interval (CI) for the highest versus the lowest intake of cruciferous vegetables were calculated. Heterogeneity and publication bias were also evaluated. Results: Five cohort and five case-control studies were included. A significantly decreased risk with bladder cancer was observed in overall cruciferous vegetables intake group (RR = 0.80; 95% CI 0.69-0.92) and subgroup of case-control studies (RR = 0.78; 95% CI, 0.67-0.89), but not in cohort studies (RR = 0.86; 95% CI, 0.61-1.11). No heterogeneity and publication bias were detected across studies. Conclusion: Our findings support that cruciferous vegetables intake was related to the decreased risk of bladder cancer. Because of the limited number of studies, further well-designed prospective studies are needed to explore the protective effect of cruciferous vegetables on bladder cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Matrix metalloproteinases (MMPs) are expressed in melanocytes and their overexpression has been linked to tumor development, progression, and metastasis. At the genetic level, following functional promoter polymorphisms are known to modify the gene transcription: −1306 C > T, −735 C > T in MMP2, and 799 C > T in MMP8 gene. Hence we hypothesize that functional polymorphisms in the 2 MMP SNPs in promoter region may modulate the risk for bladder cancer (BC) progression in North Indian population. Materials and methods: Genotyping for these polymorphisms were done in a group of 200 BC and 200 age matched, similar ethnicity unrelated healthy controls using PCR-based methods. Two-sided χ2, Cox-regression was utilized to evaluate the associations between genotype and various clinical and epidemiologic factors. Multivariate analyses were conducted using logistic regression, adjusting for known BC confounders such as age and gender. Survival analysis was done using the Kaplan-Meier method and differences in survival were assessed using the log rank test. Results: Individuals with MMP2 (−1306) TT genotype as well as T allele were at higher risk of BC (P, 0.042; OR, 2.85; P, 0.001; OR, 1.76). This effect was even more apparent in case of CT+TT (P < 0.001; OR, 2.61). In MMP2 (735), CT+TT demonstrated significant risk (P, 0.034; OR, 1.66). In MMP8 (799), reduced risk was observed with TT genotype (P, 0.006; OR, 0.27). Haplotype analysis showed that individuals with haplotype 735C-1306T and 735T-1306C were at 1.9- and 1.5-fold higher risk. MMP2 −1306CC in combination with MMP8 799CT genotype showed protective effect. The genotype CT and CT+TT of MMP2 1306C > T were associated with high risk of recurrence in BCG treated patients (HR, 4.32; P, 0.006 and HR, 2.06; P, 0.047) thus showing reduced recurrence free survival (CT+TT/CC = 34/45 months; log rank P, 0.039). Conclusion: Our data suggested that variant allele of MMP2 1306C > T was associated with high risk of tumor recurrence and reduced recurrence free survival in superficial BC patients. [Copyright &y& Elsevier]

Abstract: Context: Urothelial bladder cancer (UBC) is a disease of significant morbidity and mortality. It is important to understand the risk factors of this disease. Objective: To describe the incidence, prevalence, and mortality of UBC and to review and interpret the current evidence on and impact of the related risk factors. Evidence acquisition: A literature search in English was performed using PubMed. Relevant papers on the epidemiology of UBC were selected. Evidence synthesis: UBC is the 7th most common cancer worldwide in men and the 17th most common cancer worldwide in women. Approximately 75% of newly diagnosed UBCs are noninvasive. Each year, approximately 110 500 men and 70 000 women are diagnosed with new cases and 38 200 patients in the European Union and 17 000 US patients die from UBC. Smoking is the most common risk factor and accounts for approximately half of all UBCs. Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons are other important risk factors. The impact of diet and environmental pollution is less evident. Increasing evidence suggests a significant influence of genetic predisposition on incidence. Conclusions: UBC is a frequently occurring malignancy with a significant impact on public health and will remain so because of the high prevalence of smoking. The importance of primary prevention must be stressed, and smoking cessation programs need to be encouraged and supported. [Copyright &y& Elsevier]

Background: Increasing evidence suggests that diabetes mellitus (DM) may be associated with an increased risk of bladder cancer. To provide a quantitative assessment of this association, we evaluated the relation between DM and incidence and mortality of bladder cancer in an updated meta-analysis of cohort studies. Methods We identified cohort studies by searching the EMBASE and MEDLINE databases, through 31 March 2012. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with random-effects models. Results: A total of 29 cohort studies (27 articles) were included in this meta-analysis. DM was associated with an increased incidence of bladder cancer (RR 1.29, 95% CI: 1.08–1.54), with significant evidence of heterogeneity among these studies (p<0.001, I2 = 94.9%). In stratified analysis, the RRs of bladder cancer were 1.36 (1.05–1.77) for diabetic men and 1.28 (0.75–2.19) for diabetic women, respectively. DM was also positively associated with bladder cancer mortality (RR 1.33, 95% CI: 1.14–1.55), with evident heterogeneity between studies (p = 0.002, I2 = 63.3%). The positive association was observed for both men (RR 1.54, 95% CI: 1.30–1.82) and women (RR 1.50, 95% CI: 1.05–2.14). Conclusion: These findings suggest that compared to non-diabetic individuals, diabetic individuals have an increased incidence and mortality of bladder cancer. [ABSTRACT FROM AUTHOR]

Backgrounds. TSP-1 is a glycoprotein that functions in the biology of bladder cancer. We investigated the relationship between the distribution of TSP-1-1223A/G polymorphism (rs2169830) and the clinical characteristics of bladder cancer. Materials and Methods. TaqMan assay was performed to determine the genotype of 609 cases and 670 control subjects in a Chinese population. Logistic regression was used to assess the association between the polymorphism and the risk of bladder cancer. Quantitative real-time polymerase chain reaction was performed to determine TSP-1 mRNA expression. Survival curves were generated using the Kaplan-Meiermethod. Results. No significant differences were detected in the genotype frequencies of healthy control subjects and patients with bladder cancer. By contrast, the time until the first recurrence differed significantly between genotypes (P = 0.017). The expression of TSP-1 mRNA in bladder cancer tissues was lower in patients with an AG genotype than in those with an AA genotype. The lowest expression was observed in patients with a GG genotype. Conclusions. In conclusion, TSP-1-1223 A/G polymorphism may contribute to the recurrence of bladder cancer in Chinese population. [ABSTRACT FROM AUTHOR]

Much evidence show that over-expression of epidermal growth factor receptor (EGFR) plays an important role in regulating carcinogenesis. Genetic variations in 3′ untranslated region (3′UTR) of gene have been reported to affect gene expression by interfering with microRNAs (miRNAs), which are thought to function as either tumour suppressors or oncogenes by binding to their target mRNA. In this study, we investigated the association between the EGFR 3′UTR 774T>C polymorphism and bladder cancer risk. We used the TaqMan technology to genotype this genetic variant in a hospital-based case–control study of 908 bladder cancer patients and 1239 controls in a Chinese population. We found that the 774CC genotype was associated with a statistically significantly increased risk of bladder cancer [adjusted odds ratio = 1.29, 95% confidence interval = 1.05–1.58], compared with the 774TT/TC genotype, and this increased risk was more pronounced among subgroups of age > 65 years, non-smokers and patients’ tumour invasive stage. Furthermore, luciferase assays in T24 cell showed that EGFR 3′UTR 774 T to C substitution could increase the expression of EGFR, which was consistent with the association study finding. Additionally, we also provide evidence that 774T>C polymorphism increasing EGFR expression was not regulated by hsa-miR-214 binding. These findings suggested that EGFR 3′UTR 774T>C polymorphism may contribute to susceptibility to bladder cancer. [ABSTRACT FROM PUBLISHER]

Despite the good quality of treatment expected with optimized transurethral resection (TUR) and adjuvant Bacillus Calmette-Guérin (BCG) regimen, many high-risk non-muscle invasive bladder cancer (NMIBC) patients recur and progress. According to the EORTC Tables of risk, cases with a score of 10-17 and those with a score of 7-23 should be considered as being at high risk of recurrence and progression, respectively. AUA and NCCN consider all T1 stage tumors, high grade Ta and CIS at high risk of recurrence and progression. Long-term follow-up shows that T1,G3 patients treated with BCG will suffer from up to 45% and 17% rate of recurrence and progression, respectively. Consequently, EAU, AUA and NCCN Guidelines for bladder cancer recommend radical cystectomy as a first treatment option for those patients who failed after two cycles of adjuvant BCG. However, to date, there is no definitive evidence that in this special subgroup of patients an early radical cystectomy is better than any additional salvage strategy, in terms of oncologic outcome. On the other hand, it is well accepted that radical cystectomy is burdened with consistent reduction of overall post-operative quality of life. The reluctance of patient to accept (and of surgeon to recommend) this major extirpative surgery may explain the reduced disease-free survival rate, well documented when radical cystectomy has been extremely delayed. Defining the criteria for the selection of BCG-failure patients for whom any conservative procedure should be definitively abandoned in favor of a timely radical cystectomy has become of critical importance. Recently, clinical, laboratory and pathologic acquisitions allowed the development of more accurate predictive factors for tumor progression in NMIBC. Among these factors, clinical type of BCG-failure, morphology and tumor growth patterns, pathologic sub-staging and immunohistochemistry will play a paramount role in decision-making with these patients in routine practice. [ABSTRACT FROM AUTHOR]

The term 'Non-muscle invasive bladder cancer' identifies a heterogeneous disease due to different natural history of its various appearances. T1 stage represents a non-predictable population, which might respond to non-operative treatment strategies or to the need of a more aggressive treatment, in order to avoid the progression to invasive, and possibly to metastatic stages. In the first year following transurethral resection of bladder (TURB), tumor recurrence is seen in up to 45% of the population; of this, 15% may progress to muscle invasive or metastatic disease, or both. In order to control the recurrence and progression and identify invasive tumors at the earliest possible stage, it is strongly necessary to define individual patient risk assessment follow-up. To obtain exact staging, besides a proper transurethral resection of bladder, a restaging transurethral resection of bladder should be performed in T1 patients. Data from literature support the immediate postoperative intravesical instillation of different chemotherapeutic agents in low-risk patients. Multifocal papillary lesions might require a more intensive adjuvant regimen, whereas intravesical im-munotherapy using Bacillus Calmette-Guérin is recommended in patients at high risk of progression. Early cystectomy should be considered in patients with recurrent T1 tumors or refractory carcinoma in situ to avoid unfavorable tumor progression. [ABSTRACT FROM AUTHOR]

Risk factors analysis in bladder cancer should consider not only the clinical and pathological features of the tumor but also environmental and lifestyle factors. They may play, in fact, a relevant role not only in the pathogenesis but also in the biological behavior of the tumor. The association between cigarette smoking and bladder cancer has been consistently confirmed in several case-control and cohort studies. The risk of bladder cancer seems to increase with duration and intensity of smoking. Another environmental risk factor, although not definitively proved, is water supply. Chlorination or water pollution by pesticides and other chemical factors is considered a relevant risk factor. Familiarity and genetic predisposition, diet and individual risk factors should be taken into account. [ABSTRACT FROM AUTHOR]

Background Previous evidence suggests that 25-hydroxyvitamin D3 [25(OH)D3 ] protects against several cancers. However, little is known regarding urothelial bladder cancer (UBC). We analyzed the association between plasma 25(OH)D3 and overall risk of UBC, as well as according to stage and FGFR3 molecular subphenotypes. Methods Plasma concentrations of 25(OH)D3 in 1125 cases with UBC and 1028 control subjects were determined by a chemiluminescence immunoassay. FGFR3 mutational status and expression in tumor tissue were assessed. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression adjusting for potential confounders. Analyses were further stratified by tumor invasiveness and grade, FGFR3 expression, and smoking status. Cell proliferation was measured in human UBC cell lines cultured with 1α,25-dihydroxyvitamin D3. Results A statistically significantly increased risk of UBC was observed among subjects presenting the lowest concentrations of 25(OH)D3 (ORadj 1.83; 95% CI = 1.19 to 2.82; P= .006), showing a dose-response effect (Ptrend = .004).The association was stronger for patients with muscle-invasive tumors, especially among Iow-FGFR3 expressers (ORadj = 5.94; 95% CI = 1.72 to 20.45; P= .005).The biological plausibility of these associations is supported by the fact that, in vitro, 1α,25-dihydroxyvitamin D3 upregulates FGFR3 expression in UBC cell lines with low levels of wild-type FGFR3. Conclusion These findings support a role of vitamin D in the pathogenesis of UBC and show that 25(OH)D3 levels are associated with FGFR3 expression in the tumor. Because FGFR3 mutation and overexpression are markers of better outcome, our findings suggest that individuals with low levels of plasma 25(OH)D3may be at high risk of more aggressive forms of UBC. [ABSTRACT FROM AUTHOR]

Purpose: Bladder cancer is frequently diagnosed during a workup for hematuria. However, most patients with microscopic hematuria and many with gross hematuria are not appropriately referred to urologists. We hypothesized that in patients presenting with asymptomatic hematuria the risk of having bladder cancer can be predicted with high accuracy. Toward this end, we analyzed risk factors in patients with asymptomatic hematuria and developed a nomogram for the prediction of bladder cancer presence. Methods: Data from 1,182 consecutive subjects without a history of bladder cancer undergoing initial evaluation for asymptomatic hematuria were collected at three centers. Clinical risk factors including age, gender, smoking status, and degree of hematuria were recorded. All subjects underwent standard workup including voided cytology, upper tract imaging, and cystourethroscopy. Factors associated with the presence of bladder cancer were evaluated by univariable and multivariable logistic regression analyses. The multivariable analysis was used to construct a nomogram. Internal validation was performed using 200 bootstrap samples. Results: Of the 1,182 subjects who presented with asymptomatic hematuria, 245 (20.7 %) had bladder cancer. Increasing age (OR = 1.03, p < 0.0001), smoking history (OR = 3.72, p < 0.0001), gross hematuria (OR = 1.71, p = 0.002), and positive cytology (OR = 14.71, p < 0.0001) were independent predictors of bladder cancer presence. The multivariable model achieved 83.1 % accuracy for predicting the presence of bladder cancer. Conclusions: Bladder cancer presence can be predicted with high accuracy in patients who present with asymptomatic hematuria. We developed a nomogram to help optimize referral patterns (i.e., timing and prioritization) of patients with asymptomatic hematuria. [ABSTRACT FROM AUTHOR]

Purpose: Despite standard treatment with transurethral resection (TUR) and adjuvant bacillus Calmette-Guérin (BCG), many high-risk bladder cancers (HRBCs) recur and some progress. Based on a review of the literature, we aimed to establish the optimal current approach for the early diagnosis and management of HRBC. Methods: A MEDLINE® search was conducted to identify the published literature relating to early identification and treatment for non-muscle-invasive bladder cancer. Particular attention was paid to factors such as quality of TUR, importance of second TUR, substaging, and CIS. In addition, studies on urinary markers, photodynamic diagnosis, predictive clinical and molecular factors for recurrence and progression after BCG, and best management practice were analysed. Results and conclusions: Good quality of TUR and the implementation of photodynamic diagnosis in selected cases provide a more accurate diagnosis and reduce the risk of residual tumour in HRBC. Although insufficient evidence is available to warrant the use of new urinary molecular markers in isolation, their use in conjunction with cytology and cystoscopy may improve early diagnosis and follow-up. BCG plus maintenance for at least 1 year remains the standard adjuvant treatment for HRBC. Moreover, there is enough evidence to consider the implementation of new specific risk tables for patients treated with BCG. In HRBC patients with poor prognostic factors after TUR, early cystectomy should be considered. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To examine associations between urinary bladder cancer risk and polymorphisms of the gene encoding the catechol estrogen-metabolizing enzyme, catechol-O-methyltransferase (COMT), among Egyptian women and men. Materials and methods: We used questionnaire and genotype data from a case-control study in Egypt. This analysis focused on South Egypt cases with confirmed urothelial (UC) or squamous cell (SCC) carcinoma of the bladder, and controls frequency-matched on sex, 5-year age-group, and residence governorate. Real-time PCR on blood specimen DNA was used to determine COMT genotypes encoding for Val/Val, Val/Met, and Met/Met, the enzyme forms associated with high, intermediate, or low activity, respectively. Results: The study sample, which included 255 women and 666 men, consisted of 394 cases with histologically confirmed UC (225) or SCC (n = 169), and 527 controls. The odds of having either type of bladder cancer were lower among men with genotypes encoding Val/Met or Met/Met than among those with the genotype encoding Val/Val, even after adjustment for other factors, such as smoking and schistosomiasis history [adjusted odds ratio (AOR): 0.64; 95% confidence interval (CI): 0.43, 0.96]; however, the association was statistically significant for SCC (AOR 0.57; 95% CI: 0.34, 0.96) but marginal for UC (AOR: 0.64; 95% CI: 0.39, 1.02). No significant associations were detected between bladder cancer risk and COMT genotypes among postmenopausal women. Conclusions: These findings suggest that even after controlling for established risk factors, the involvement of COMT genotypes in bladder cancer risk differs among men compared with women in South Egypt. [Copyright &y& Elsevier]

OBJECTIVE--Available evidence supports the emerging hypothesis that metabolic syndrome may be associated with the risk of some common cancers. We did a systematic review and meta-analysis to assess the association between metabolic syndrome and risk of cancer at different sites. RESEARCH DESIGN AND METHODS--We conducted an electronic search for articles published through October 2011 without restrictions and by reviewing reference lists from retrieved articles. Every included study was to report risk estimates with 95% CIs for the association between metabolic syndrome and cancer. RESULTS--We analyzed 116 datasets from 43 articles, including 38,940 cases of cancer. In cohort studies in men, the presence of metabolic syndrome was associated with liver (relative risk 1.43, P < 0.0001), colorectal (1.25, P < 0.001), and bladder cancer (1.10, P = 0.013). In cohort studies in women, the presence of metabolic syndrome was associated with endometrial (1.61, P = 0.001), pancreatic (1.58, P<0.0001), breast postmenopausal (1.56, P = 0.017), rectal (1.52, P = 0.005), and colorectal (1.34, P = 0.006) cancers. Associations with metabolic syndrome were stronger in women than in men for pancreatic (P = 0.01) and rectal (P = 0.01) cancers. Associations were different between ethnic groups: we recorded stronger associations in Asia populations for liver cancer (P = 0.002), in European populations for colorectal cancer in women (P = 0.004), and in U.S. populations (whites) for prostate cancer (P = 0.001). CONCLUSIONS--Metabolic syndrome is associated with increased risk of common cancers; for some cancers, the risk differs between sexes, populations, and definitions of metabolic syndrome. [ABSTRACT FROM AUTHOR]

Abstract: o-Toluidine is a monocyclic aromatic amine present in the formulation of some materials that contact drinking water. NSF/ANSI 61 Annex A (2011) and US EPA (2005a) risk assessment guidelines were used to determine an acceptable drinking water level. Occupational exposure to o-toluidine is associated with an increased risk of bladder cancer but human disease rates could not be used to establish risk values due to inadequate exposure data and coexposures in the epidemiology cohorts. Chronic dietary exposure to o-toluidine hydrochloride was associated with benign and malignant tumors in both sexes of F344 rats and B6C3F1 mice. o-Toluidine is genotoxic in vitro and in vivo. A 10−5 cancer risk level was extrapolated from the human equivalent BMDL10 of 13mg/kg-day for the combined incidence of papillomas and carcinomas of the bladder transitional epithelium in female rats. Considering varying susceptibility to tumor development at different life stages, the unit risk was modified to incorporate potency adjustments for early-life exposures. A framework for lifestage adjustment is presented that makes assumptions evident. For this assessment, the lifetime unit risk derived was ∼2-fold greater than the unadjusted adult lifetime unit risk, and the resulting Total Allowable Concentration in drinking water is 20μg/L. [Copyright &y& Elsevier]

Chemicals can increase the risk of cancer by either directly damaging DNA (DNA reactive) or increasing cell proliferation. DNA reactive carcinogens involve activation to reactive metabolites, forming DNA adducts which are mutagenic. The presence of numerous cellular repair processes suggest that these could have a threshold. The issues involved are described for 2-acetylamino‰uorene urinary bladder carcinogenicity. Chemicals that act by increasing cell proliferation involve either increased cell births or decreased cell deaths, leading to an accumulation of cells. Multiple mechanisms can produce these eŠects, most of which have threshold processes. Arsenicals appear to act by inducing cellular cytotoxicity with regenerative proliferation, induced by generation of reactive trivalent forms which interact with critical sulfhydryl groups in cells. A more definitive threshold response is illustrated for the formation of urinary solids, either calculi (melamine) amorphous calcium phosphate-containing precipitate (sodium saccharin) or crystalluria (PPARg agonists). Increasing evidence strongly supports the concept of thresholds in carcinogenesis, not only for chemicals acting by increasing cell proliferation but also for those acting by DNA reactivity. [ABSTRACT FROM AUTHOR]

Cigarette smoking is a risk factor for bladder cancer. Since urothelial cells express phase I and II enzymes these cells are able to metabolize precarcinogens into DNA reactive intermediates. Cigarette smoke is a complex mixture containing at least 80 known carcinogens. In this context especially aromatic amines and polycyclic aromatic hydrocarbons are discussed as being responsible for bladder-carcinogenicity. Cell cultures of primary porcine urinary bladder epithelial cells (PUBEC) have been useful models for studies on bladder-specific effects. These cells are metabolically competent and found to be a valuable tool for examining effects of cigarette smoke constituents. In the present study PUBEC were utilized to investigate the effects of the complex mixture cigarette smoke condensate total particulate matter (CSC TPM) with emphasis on induction of cytochrome P-450 1A1 (CYP1A1) and genotoxic effects. CYP1A1 induction was investigated by Western blot and flow cytometry. The most pronounced effects were found after 24 h of incubation with 1–10 μg/ml CSC TPM. Maximal induction was observed at 5 μg/ml by flow cytometry and at 10 μg/ml by Western blot analysis. Genotoxic effects were investigated by means of alkaline single-cell gel electrophoresis (“comet assay”) with and without the use of the DNA repair enzyme formamidopyrimidine-DNA glycosylase (Fpg) and the micronucleus (MN) test. A numerical concentration-dependent increase in Fpg-sensitive sites indicating oxidative DNA damage and a quantitative rise in MN formation were noted. The CSC utilized in this study contained low amounts of benzo[a]pyrene, 4-aminobiphenyl, and 2-naphthylamine. With regard to the observed CYP1A1 induction, these substances cannot explain the CYP1A1 inducing effect of CSC TPM. It is possible that other compounds within CSC TPM contribute to CYP1A1 induction in our cellular model. [ABSTRACT FROM PUBLISHER]

Background: There is growing concern regarding the increased incidence of bladder cancer in diabetic patients using pioglitazone. This study aimed to investigate the association between bladder cancer and the use of pioglitazone in Korean diabetics. Methods: This retrospective, matched case-control study included a case group (n = 329) of diabetic patients with bladder cancer who presented at the Severance Hospital from November 2005 to June 2011. The control group consisted of patients without bladder cancer (1:2 ratio matching for sex and age, n = 658) who were listed on the Severance Hospital diabetes registry. Results: The percentage of subjects who had ever used pioglitazone was significantly lower in the case group than in the control group (6.4% vs. 15.0%, P<0.001). Multivariate conditional logistic analysis revealed that independent factors affecting bladder cancer were smoking (odds ratio [OR], 11.64; 95% confidence interval [CII, 6.56 to 20.66; P<0.001), coexisting cancer (OR, 6.11; 95% CI, 2.25 to 16.63; P<0.001), and hemoglobin levels (OR, 0.78; 95% CI, 0.69 to 0.88; P<0.001). The OR of the history of pioglitazone use was 2.09 and was not significantly different between the two groups (95% CI, 0.26 to 16.81; P=0.488). Conclusion: A relationship between pioglitazone use and incidence of bladder cancer was not observed in Korean diabetic patients. This suggests that the risk for bladder cancer in Korean diabetic subjects treated with pioglitazone might be different from that of Caucasian populations. Large-scale, well-designed and multi-center studies are needed to further evaluate this relationship. [ABSTRACT FROM AUTHOR]

Recently, rs11892031[A] has been identified in a genome-wide association study (GWAS) to confer increased risk of urinary bladder cancer (UBC). To confirm this association and additionally study a possible relevance of exposure to urinary bladder carcinogens, we investigated the IfADo UBC study group, consisting of eight case-control series from different regions including 1,805 cases and 2,141 controls. This analysis was supplemented by a meta-analysis of all published data, including 13,395 cases and 54,876 controls. Rs11892031 A/A was significantly associated with UBC risk in the IfADo case-control series adjusted to cigarette smoking, gender, age and ethnicity (OR = 1.18; 95% CI = 1.02-1.37; P = 0.026). In the meta-analysis, a convincing association with UBC risk was obtained (OR = 1.19; 95% Cl = 1.12-1.26; P < 0.0001). Interestingly, the highest odds ratios were obtained for individual case-control series with a high degree of occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines: cases with suspected occupational UBC (OR = 1.41) and cases from the highly industrialized Ruhr area (OR = 1.98) compared with Ruhr area controls (all combined OR = 1.46). Odds ratios were lower for study groups with no or a lower degree of occupational exposure to bladder carcinogens, such as the Hungary (OR = 1.02) or the ongoing West German case-control series (OR = 1.06). However, the possible association of rs11892031[A] with exposure to bladder carcinogens still should be interpreted with caution, because in contrast to the differences between the individual study groups, interview-based data on occupational exposure were not significantly associated with rs11892031. In conclusion, the association of rs11892031[A] with UBC risk could be confirmed in independent study groups. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1, and VEGF gene polymorphisms as possible risk factors contributing to the development of bladder cancer among the population from Canary Islands, Spain. Materials and methods: The genotypes were determined by PCR-based methods in a hospital-based case-control study consisting of 119 cases and 110 controls. The socio-demographic and clinicopathologic data were collected, including the smoking habits of the population covered in the study. Results: The observed allelic frequencies were (%): GSTM1-GSTT1, (positive) 54 and (null) 46 in cases, and 65 and 35, respectively, in controls (P = 0.144); MDR1 C3435T, (C) 57 and (T) 43 in cases, and 54 and 46, respectively, in controls (P = 0.633); VEGF A2578C, (A) 40 and (C) 60 in cases, and 51 and 49, respectively, in controls (P = 0.221). Among Canary Islands subjects, GSTT1-null genotype appeared as a significant risk factor for bladder cancer (odds ratio (OR) 2.0; 95% confidence interval (CI), 1.0–3.7; P = 0.041), in multivariate analysis adjusted by age and smoking habits. No statistical changes in genotype distribution of GSTM1, MDR1 C3435T, and VEGF A2578C gene polymorphisms were observed between cases and controls. The distribution of the initial clinical stage, clinical grade, or recurrence status was not significantly different among the polymorphic variants in the case group (P = NS). Conclusions: Subjects with the GSTT1-null genotype might be at an increased risk of bladder cancer in Canary Islands, Spain. However, extensive studies are required for accurate confirmation of these results. [Copyright &y& Elsevier]

Purpose: Cigarette smoking is a recognized risk factor for kidney cancer, bladder cancer and erectile dysfunction. However, little is known regarding patient knowledge of these associations. We evaluated awareness of smoking as a risk factor for genitourinary disease and identified variables associated with awareness. Materials and Methods: We performed a cross-sectional study in a convenience sample of 535 patients who presented to a urology clinic at a major public hospital between 2009 and 2011. Patient demographics and knowledge were captured in a self-reported questionnaire evaluating awareness of smoking as a risk factor for bladder, kidney and lung cancer, and erectile dysfunction. Factors associated with the awareness of smoking and genitourinary disease were identified by multivariable logistic regression. Results: Urology patients generally had low overall awareness of smoking related genitourinary disease. Only 33.5%, 25.2% and 24.2% of patients identified smoking as a risk factor for kidney cancer, bladder cancer and erectile dysfunction, respectively, compared to 94.0% who identified it as a risk factor for lung cancer. Patients from ethnic minorities and current smokers consistently showed a more pronounced lack of awareness of the link between smoking and these diseases. Generally Hispanic and black patients were 2 to 3 times more likely than white patients to be unaware of the association of smoking with the diseases (p = 0.0019 to 0.059). Smokers were twice as likely as nonsmokers to be unaware of the link of smoking with kidney and bladder cancer (p = 0.025 and 0.0509, respectively). Conclusions: Our study highlights the need for increased awareness of smoking related genitourinary diseases, especially among minority patients and smokers. This study draws attention to an opportunity for urologists to provide smoking cessation assistance and education for this patient population. [Copyright &y& Elsevier]

Abstract: Background: A number of studies have examined the association between coffee consumption and risk of bladder cancer, but uncertainty about the dose–response relationship remains. Materials and methods: A comprehensive search was performed to identify all observational studies providing quantitative estimates between bladder cancer risk and coffee consumption. Dose–response relationship was assessed by restricted cubic spline model and bivariate random-effect meta-regression. Results: 23 case–control studies with 7690 cases and 13,507 controls, and 5 cohort studies with 700 cases and 229,099 participants, met the inclusion criteria. Compared with non-drinkers and for case–control studies, the pooled smoking-adjusted RRs(95% CI) of bladder cancer were 1.07(1.02–1.13) for 1 cup/day, 1.15(1.05–1.26) for 2 cups/day, 1.22(1.08–1.38) for 3 cups/day, and 1.29(1.12–1.48) for 4 cups/day. For cohort studies, the pooled smoking-adjusted RRs of bladder cancer were 1.09(95% CI, 0.89–1.34) for 1 cup/day, 1.13(95% CI, 0.82–1.55) for 2 cups/day, 1.09(95% CI, 0.77–1.56) for 3 cups/day, and 1.01(95% CI, 0.69–1.48) for 4 cups/day. Conclusions: Although data from case–control studies suggested that coffee was a risk factor for bladder cancer, there was no conclusive evidence on this association because of inconsistencies between case–control and cohort studies. [Copyright &y& Elsevier]

Glutathione S-transferase T1 ( GSTT1) is implicated in the inactivation of procarcinogens that contribute to cancer progression. However, studies investigating the association between GSTT1 polymorphism and bladder cancer (BC) risk have reported conflicting results; therefore, a meta-analysis was conducted. Fifty studies with 10,805 cases and 13,332 controls were recruited. The overall odds ratio for the GSTT1 null genotype was 1.1502 (95% CI=1.0384-1.2741). When stratified by ethnicity, significantly increased risk was only found for Caucasians. In Asians subgroup, interestingly, decreased BC risks were found in the Korean and Japanese populations but not in the Chinese population. When stratified by control sources, a slightly elevated risk was found in population-based but not in hospital-based studies. Besides, smoking was not found to modify the association between the GSTT1 null genotype and BC risk. When combined with the GSTM1 null genotype, a remarkably increased risk was found for BC. In general, our results suggest that the GSTT1 null genotype is associated with an increased risk of BC. Smoking did not modify the association between the GSTT1 null genotype and BC risk. Furthermore, a strong association was observed between the combination of GSTT1 null and GSTM1 null genotype and risk of BC. Further epidemiological studies will be needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer is the fourth most common malignancy in men and the eighth most common in women. It causes 8% of all malignancies in men and 3% of all malignancies in women. The trend of bladder cancer is increasing in Iran. This study was conducted to estimate the survival rate of bladder cancer based on life table method. Materials and Methods: In this study, at first, data were collected based on individual variables of 514 patients suffering from bladder cancer and referred them to cancer registry center of Shiraz University of Medical Sciences from 2001-2009. Data were collected at two stages and analyzed by life table method and Wilcox on test. Significant level considered at 0.05. Results: Our findings showed that probability of survival accumulation at the end of 1, 3, 5, 10 years in patients with bladder cancer were equal to 0.8989, 0.7132, 0.5752 and 0.2459 respectively. There was significant difference in survival rate among age groups and treatment types (P < 0.05). However, we did not observe any difference in survival time based on smoking (P = 0.578), alcohol (P = 0.419) and education level (P = 0.371) of patients. Conclusion: The overall survival rate of bladder cancer in the present study was less than other areas. Patients' age and treatment type were the influential factor in survival time. So continuous screening for early diagnosis suggested for older people. [ABSTRACT FROM AUTHOR]

Prolonged ingestion of arsenic in drinking water can increase the risks of dying of lung and bladder cancer, particularly for smokers. In a survey of arsenic hotspots in the United States, we elicited individuals' subjective mortality risks related to the presence of arsenic in drinking water. Using this data, we address whether smokers perceive mortality risks from this source differently from non-smokers. We find that those who have smoked at some point in their life have significantly higher perceived arsenic mortality risks than those who have never smoked, on average. We also find that the sample group of current smokers has higher average perceived arsenic mortality risks than those who have quit smoking. We model the decision to treat water for arsenic and find some evidence that current smokers are less likely to engage in this mitigating behavior than are ex-smokers or non-smokers even though their perceived risk is higher. We infer that smokers are either less risk averse or have a higher rate of time preference than non-smokers and ex-smokers. ( JEL I0, D81, Q53) [ABSTRACT FROM AUTHOR]

Abstract: Several evidences have been published linking polymorphism in genes involved in chronic or recurrent inflammation with increased tumor risk and progression. Nevertheless the influence of innate immune receptors in urothelial cancer risk and characteristics has not been sufficient explored. We studied the possible association of polymorphisms in genes encoding NOD2, RIPK2, TLR10 and C13ORF31 with the risk, clinical/pathological characteristics and outcomes of urothelial cancer. We have found association between RIPK2 (rs42490) and cancer risk (AA vs AT&TT, p =0042). In addition, we found statistical differences in TLR10 (rs4129009) gen between low and high tumor infiltration stage (p =0.033). NOD2 (rs9302752) and RIPK2 (rs42490) were found to be associated with development of lymph node metastasis (p =0.011 and p =0.015). Importantly we detect association of TLR10 (Log Rank=0.035) and RIPK2 (Log Rank=0040) with overall survival. Multivariate Cox analysis revealed that both SNPs were survival prognosis factor independent of tumor stage and grade. Our results indicate that innate immunity receptors play a role in modulating urothelial cancer risk and progression. [Copyright &y& Elsevier]

Background:Despite many studies on diet and bladder cancer, there are areas that remain unexplored including meat mutagens, specific vegetable groups, and vitamins from diet.Methods:We conducted a population-based case-control study of bladder cancer in Maine, New Hampshire, and Vermont. A total of 1171 cases were ascertained through hospital pathology records and cancer registries from 2001 to 2004. Overall, 1418 controls were identified from the Department of Motor Vehicles (<65 years) and Center for Medicaid and Medicare Services (65-79 years) and were frequency-matched to cases by state, sex, and age (within 5 years). Diet was assessed with a self-administered Diet History Questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).Results:Processed meat intake was positively associated with bladder cancer (highest vs lowest quartile OR: 1.28; 95% CI: 1.00-1.65; Ptrend=0.035), with a stronger association for processed red meat (OR: 1.41; 95% CI: 1.08-1.84; Ptrend=0.024). There were no associations between intake of fruits or vegetables and bladder cancer. We did, however, observe an inverse association with vitamin B12 intake (OR: 0.77; 95% CI: 0.61-0.99; P=0.019).Conclusion:Vitamin B12 from diet may be protective against bladder cancer, whereas consuming processed meat may increase risk. [ABSTRACT FROM AUTHOR]

Abstract: Selenoproteins with genetically encoded selenium (Se) are very important in response to oxidative stress, redox balance and regulation of various metabolic and developmental processes. Although increased circulating Se has been associated with 33% risk reduction of bladder cancer, there are little data on selenoprotein expression at the protein and genetic level from both human and animal studies. Data from the Mammalian Gene Collection (MGC) Project clearly showed that highest mRNA expression in human urinary epithelium for TRXR1 (thioredoxin reductase 1), GPX1 (glutathione peroxidase 1), SEP15 (15kDa selenoprotein), SELT (selenoprotein T) and SEPW1 (selenoprotein W1). Although bladder tumor has been characterized by increased Se, GPX and TRXR activity, circulating Se and GPX was interestingly decreased in these cancer patients. As such, selenoprotein expression in urinary epithelium may be involved in bladder cancer (development, progression and recurrence) and may play a significant role in chemotherapeutic intervention. Despite these findings, the role of selenoproteins in bladder cancer has rarely been investigated and the significance of selenoproteins in normal and malignant uroepithelium remains poorly understood. [Copyright &y& Elsevier]

In the 1990s, an uncommonly high percentage of glutathione S-transferase M1 (GSTM1) negative bladder cancer cases (70%) was reported in the greater Dortmund area. The question arose as to whether this uncommonly high percentage of GSTM1 negative bladder cancer cases was due to environmental and/or occupational exposure decades ago. Thus, 15 years later, another study on bladder cancer was performed in the same area after the coal, iron, and steel industries had finally closed in the 1990s. In total 196 bladder cancer patients from the St.-Josefs-Hospital Dortmund-Hörde and 235 controls with benign urological diseases were assessed by questionnaire and genotyped for GSTM1, glutathione S-transferase T1 (GSTT1), and the N-acetyltransferase 2 (NAT2) tag SNP rs1495741. The frequency of the GSTM1 negative genotype was 52% in bladder cancer cases and thus lower compared to a previous study performed from 1992 to 1995 in the same area (70%). NAT2 genotypes were distributed equally among cases and controls (63% slow acetylators). Fewer GSTT1 negative genotypes were present in cases (17%) than in controls (20%). [ABSTRACT FROM AUTHOR]

Abstract: Arsenic is associated with bladder cancer risk even at low exposure levels. Genetic variation in enzymes involved in xenobiotic and arsenic metabolism may modulate individual susceptibility to arsenic-related bladder cancer. Through a population-based case-control study in NH (832 cases and 1191 controls), we investigated gene-environment interactions between arsenic metabolic gene polymorphisms and arsenic exposure in relation to bladder cancer risk. Toenail arsenic concentrations were used to classify subjects into low and high exposure groups. Single nucleotide polymorphisms (SNPs) in GSTP1, GSTO2, GSTZ1, AQP3, AS3MT and the deletion status of GSTM1 and GSTT1 were determined. We found evidence of genotype-arsenic interactions in the high exposure group; GSTP1 Ile105Val homozygous individuals had an odds ratio (OR) of 5.4 [95% confidence interval (CI): 1.5–20.2; P for interaction=0.03] and AQP3 Phe130Phe carriers had an OR=2.2 (95% CI: 0.8–6.1; P for interaction=0.10). Bladder cancer risk overall was associated with GSTO2 Asn142Asp (homozygous; OR=1.4; 95% CI: 1.0–1.9; P for trend=0.06) and GSTZ1 Glu32Lys (homozygous; OR=1.3; 95% CI: 0.9–1.8; P for trend=0.06). Our findings suggest that susceptibility to bladder cancer may relate to variation in genes involved in arsenic metabolism and oxidative stress response and potential gene-environment interactions requiring confirmation in other populations. [Copyright &y& Elsevier]

Purpose: We studied the safety and efficacy of multiple adjuvant apaziquone instillations in patients with high risk nonmuscle invasive bladder cancer. Materials and Methods: Patients with high risk nonmuscle invasive urothelial carcinoma of the bladder underwent transurethral resection of all bladder tumor(s), and received 6 weekly adjuvant intravesical apaziquone instillations of 4 mg in 40 ml. Patients with carcinoma in situ received 3 further maintenance instillations at months 3, 6 and 12. Followup consisted of cystoscopy, urine cytology and observation of adverse events every 3 months for 18 months. Results: A total of 53 patients were enrolled in the study. Although all patients were high risk according to the definitions used when the study was initiated, according to most recent guideline criteria, 80% and 20% of these patients would now be considered intermediate and high risk for recurrence, and 50% and 44% would be considered intermediate and high risk for progression, respectively. Intent to treat analysis of 49 patients with papillary tumors showed recurrent tumors in 34.7% and 44.9% at 12 and 18 months, respectively. One patient had progression to T2 or greater urothelial carcinoma after 9 months. There were 4 patients with carcinoma in situ who had complete responses at 3 months but discontinued treatment due to cystitis, recurrent papillary disease, urinary incontinence and dysuria. Most other side effects were mild (grade 1 to 2). Conclusions: Adjuvant intravesical instillations of apaziquone are generally well tolerated. The recurrence rates of 34.7% after 12 months and 44.9% after 18 months in these patients can be considered encouraging, and warrant further study. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified a SNP, rs2294008, on 8q24.3 within the prostate stem cell antigen (PSCA) gene, as a risk factor for bladder cancer. To fine-map this region, we imputed 642 SNPs within 100 Kb of rs2294008 in addition to 33 markers genotyped in one of the reported genome-wide association study in 8,652 subjects. A multivariable logistic regression model adjusted for rs2294008 revealed a unique signal, rs2978974 (r2 = 0.02, D′ = 0.19 with rs2294008). In the combined analysis of 5,393 cases and 7,324 controls, we detected a per-allele odds ratio (OR) = 1.11 [95% confidence interval (CI) = 1.06-1.17, P = 5.8 × 10-5] for rs2294008 and OR = 1.07 (95% CI = 1.02-1.13, P = 9.7 × 10-3) for rs2978974. The effect was stronger in carriers of both risk variants (OR = 1.24, 95% CI = 1.08-1.41, P = 1.8 × 10-3) and there was a significant multiplicative interaction (P = 0.035) between these two SNPs, which requires replication in future studies. The T risk allele of rs2294008 was associated with increased PSCA mRNA expression in two sets of bladder tumor samples (n = 36, P = 0.0007 and n = 34, P = 0.0054) and in normal bladder samples (n = 35, P = 0.0155), but rs2978974 was not associated with PSCA expression. SNP rs2978974 is located 10 Kb upstream of rs2294008, within an alternative untranslated first exon of PSCA. The non-risk allele G of rs2978974 showed strong interaction with nuclear proteins from five cell lines tested, implying a regulatory function. In conclusion, a joint effect of two PSCA SNPs, rs2294008 and rs2978974, suggests that both variants may be important for bladder cancer susceptibility, possibly through different mechanisms that influence the control of mRNA expression and interaction with regulatory factors. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are involved in post-transcriptional regulation of gene expression through binding to messenger RNAs (mRNA) thereby promoting mRNA degradation or altered translation. A single-nucleotide polymorphism (SNP) located within a miRNA-binding site could thus alter mRNA translation and influence cancer risk and treatment response. The common SNPs located within the 3′-untranslated regions of 20 DNA repair genes were analysed for putative miRNA-binding sites using bioinformatics algorithms, calculating the difference in Gibbs free binding energy (ΔΔG) for each wild-type versus variant allele. Seven SNPs were selected to be genotyped in germ line DNAs both from a bladder cancer case–control series (752 cases and 704 controls) and 202 muscle-invasive bladder cancer radiotherapy cases. The PARP-1 SNP rs8679 was also genotyped in a breast cancer case–control series (257 cases and 512 controls). Without adjustment for multiple testing, multivariate analysis demonstrated an association with increased bladder cancer risk with PARP1 rs8679 (Ptrend = 0.05) while variant homozygotes of PARP1 rs8679 were also noted to have an increased breast cancer risk (P = 0.03). In the radiotherapy cases, carriers of the RAD51 rs7180135 minor allele had improved cancer-specific survival (hazard ratio 0.52, 95% confidence interval 0.31–0.87, P = 0.01). This is the first report of associations between DNA repair gene miRNA-binding site SNPs with bladder and breast cancer risk and radiotherapy outcomes. If validated, these findings may give further insight into the biology of bladder carcinogenesis, allow testing of the RAD51 SNP as a potential predictive biomarker and also reveal potential targets for new cancer treatments. [ABSTRACT FROM AUTHOR]

This article reviews human observations on pioglitazone and bladder cancer risk. The PROspective pioglitAzone Clinical Trial In macroVascular Events trial showed an imbalance in bladder cancer between users of pioglitazone and placebo (14 versus six cases, p = 0.069). However, after excluding bladder cancer probably ascribed to other etiology, a blind assessment concluded that the imbalance might not be related to pioglitazone. Epidemiologic studies conducted in the United States and France using insurance databases independently suggested that pioglitazone use for >2 years might confer a 20%–40% higher risk. Another study evaluating bladder cancer risk in diabetic patients using the National Health Insurance in Taiwan did not find any incident bladder cancer case among 422 pioglitazone users for a follow-up of up to 3 years. Because observational studies may suffer from selection and information bias, and inadequate adjustment for confounders may inflate the estimated risk, causal inference from these studies should be interpreted with caution. While investigating cancer risk associated with a medication, indication bias should also be attended, especially when the medication is used at a late stage of the disease. Because pioglitazone is usually a second or third line antidiabetic agent, the users are always characterized by older age, longer diabetes duration, poorer glycemic control, and higher rates of complications and comorbidities. Biased estimates will also result if these differences are not appropriately addressed in the analyses. Current evidence neither concludes nor excludes a causal role of pioglitazone on bladder cancer. Clinical trials aiming at evaluating the risk of cancer associated with a medication is not ethical and may not be expected to provide an answer on the issue of pioglitazone-related bladder cancer. However, a meta-analysis using all available clinical trials to compare the bladder cancer risk between pioglitazone and comparators will be helpful. Well-conducted epidemiologic observational studies are probably other options. Because bladder cancer incidence and their risk factors may differ significantly among different ethnicities, a clarification of such a link in different ethnicities is needed, better by using long-term databases with large and representative sample size and appropriate adjustment for confounders. Furthermore, the interactions with other comorbidities and concomitant medications should be addressed. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population. [ABSTRACT FROM AUTHOR]

Background: Tea consumption has been reported to be associated with an decreased risk of several types of cancers. However, the results based on epidemiological studies on the association of tea consumption with bladder cancer were inconsistent. This meta-analysis was undertaken to evaluate the relationship between tea consumption and bladder cancer risk. Methods: Eligible studies were retrieved via both computer searches and review of references. The summary relative risk (RR) with 95% confidence interval (CI) was calculated. Results: Twenty three studies met the inclusion criteria of the meta-analysis. No association with bladder cancer was observed in either overall tea consumption group (OR =0.94, 95% CI 0.85-1.04) or subgroups stratified by sex, study design, geographical region or tea types. Conclusions: Our findings did not support that tea consumption was related to the decreased risk of bladder cancer. [ABSTRACT FROM AUTHOR]

Objective: In some but not all studies, hOGG1 Ser326Cys polymorphism has been reported to contribute to the risk of bladder cancer. To determine whether there is a significant association of hOGG1 Ser326Cys polymorphism with the susceptibility for bladder cancer, we performed a comprehensive meta-analysis. Methods: The electronic PubMed, Medline and Springer databases were searched for publications on the association between hOGG1 Ser326Cys polymorphism and bladder cancer through to May 20, 2011. Seven case-control studies were identified, including 2,474 cases and 2,408 controls. From these identified publications, crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association using fixed- or random-effects models. Two investigators each extracted data and conducted the analysis independently. Results: Overall, no significant associations were found between hOGG1 Ser326Cys polymorphism and bladder cancer in codominant models (GG vs. CC: OR 1.11, 95% CI 0.74-1.66, p = 0.63; GC vs. CC: OR 1.07, 95% CI 0.80-1.41, p = 0.65). Similarly, no significant associations with bladder cancer were observed in the recessive model (GG vs. GC+CC: OR 1.05, 95% CI 0.65-1.70, p = 0.85), dominant model (GG+GC vs. CC: OR 1.07, 95% CI 0.87-1.32, p = 0.53) and allele model (G vs. C: OR 1.06, 95% CI 0.90-1.26, p = 0.49). In the stratified analyses by ethnicity, control sources, pathology, Hardy-Weinberg equilibrium, significant associations were still not observed. Conclusions: The overall current literature on hOGG1 Ser326Cys polymorphism and the risk of bladder cancer suggests no statistically significant association between the two. Additional primary studies may be necessary to provide evidence of any significant association between this specific polymorphism and bladder cancer. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Context: Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non–muscle-invasive bladder cancer; however, no markers are available to predict BCG response. Objective: To review the contemporary literature on markers predicting BCG response, to discuss the key issues concerning the identification of predictive markers, and to provide recommendations for further research studies. Evidence acquisition: We performed a systematic review of the literature using PubMed and Embase databases in the period 1996–2010. The free-text search was extended by adding the following keywords: recurrence, progression, survival, molecular marker, prognosis, TP53, Ki-67, RB, fibronectin, immunotherapy, cytokine, interleukin, natural killer, macrophage, PMN, polymorphism, SNP, single nucleotide polymorphism, and gene signature. Evidence synthesis: If thresholds for the detection of urinary interleukin (IL)-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels are standardised, measurement of these cytokines holds promise in the assessment of BCG therapy outcome. Studies on immunohistochemical markers (ie, TP53, Ki-67, and retinoblastoma) display contradictory results, probably because of the small patient groups that were used and seem unsuitable to predict BCG response. Exploring combinations of protein levels might prove to be more helpful to establish the effect of BCG therapy. Single nucleotide polymorphisms, either in cytokines or in genes involved in DNA repair, need to be investigated in different ethnicities before their clinical relevance can be determined. Measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed. Conclusions: IL-2 levels are currently the most promising predictive markers of BCG response. For future studies focusing on new biomarkers, it is essential to make more use of new biomedical techniques such as microRNA profiling and genomewide sequencing. [Copyright &y& Elsevier]

Objective: To explore potential relations between the intake of milk or dairy products and the risk of bladder cancer. Methods: Eligible studies published up to May 2011 were retrieved via both computer searches and manual review of references. Random-effects models were used to calculate summary relative risk estimates (SRRE) based on high-contrast to low-intake values. Sensitivity and influence analyses were conducted, and heterogeneity among study results was explored through stratified analyses by study design, gender, geographic region, year of publication, or whether or not adjustment for several confounders (ie, age, gender, body mass index, smoking, and total energy intake). Results: We extracted data from 14 studies on milk (involving 4879 cases) and 6 studies on dairy products (3087 cases). The total study population was up to 324,241 individuals. Overall, there was no significant association between milk intake and bladder cancer (SRRE 0.89, 95% CI 0.77-1.02). However, an inverse association was found in the United States (SRRE 0.88, 95% CI .79-.99). In addition, no significant association was observed between consumption of dairy products and risk of bladder cancer (SRRE 0.95, 95% CI .71-1.27), though an inverse association was detected in the Japanese population (SRRE 0.56, 95% CI .40-.80). Conclusion: There appears to be enough evidence to support the null hypothesis. The overall result was not statistically significant. The findings of this meta-analysis are not supportive of an independent relationship between the intake of milk or dairy products and the risk of bladder cancer. However, these findings are based on limited research. Further efforts should be made to confirm these findings. [Copyright &y& Elsevier]

Abstract: Nitric oxide (NO) is an important biological messenger known to influence several types of human cancers. NO formation is catalyzed by three different nitric oxide synthase (NOS) enzymes. In this study we analyzed if the NOS3 promoter polymorphism −786T>C (rs2070744) and the NOS3 Glu298Asp polymorphism in exon 7 (rs1799983) influence risk and pathogenesis of urinary-bladder cancer. Allelic discrimination and DNA sequencing were used to determine the −786T>C and the Glu298Asp NOS3 genotypes in 359 urinary-bladder cancer patients, from a population-based patient material, and 164 population controls. Patient genotypes were combined with information on tumor stage, grade, stage and grade progression and cancer-specific death, using a 5-year clinical follow-up. A threefold increased odds ratio for bladder cancer was found in homozygous carriers of the C allele of the −786T>C promoter polymorphism (p =0.017). No increased bladder cancer risk was found for the Glu298Asp polymorphism, but there was an association between the Glu298Asp and tumor grade (p =0.040). Our results suggest that the NOS3 promoter polymorphism −786T>C may influence bladder cancer risk. [Copyright &y& Elsevier]

The role of dietary fat in bladder cancer aetiology is currently unclear due to few studies, equivocal findings and a lack of information on important dietary fatty acids. The aim of the present study was to investigate the association between the intake of major dietary fats and fatty acids and the risk of bladder cancer. A case–control study was conducted in New Hampshire, USA. Dietary data were collected from 322 cases and 239 controls, and OR and 95 % CI were calculated using unconditional logistic regression. Adjustment was made for potential confounders: sex, age, smoking status, pack-years smoked, cholesterol and energy intake. Statistically significant reduced odds of bladder cancer were observed for high intakes (highest quartile v. lowest quartile) of α-linolenic acid (ALA) (OR 0·26, 95 % CI 0·10, 0·65; P for trend = 0·01) and vegetable fat (OR 0·39, 95 % CI 0·18, 0·86; P for trend = 0·03). Borderline statistically significant reduced odds were detected for polyunsaturated fat (OR 0·43, 95 % CI 0·19, 0·98; P for trend = 0·07) and linoleic acid (OR 0·43, 95 % CI 0·19, 0·96; P for trend = 0·06). These fats and fatty acids were highly correlated and following adjustment for each other, the only potential inverse association to remain was for ALA. The present findings suggest that ALA may have a protective role against developing bladder cancer; however, further investigation and replication in other epidemiological studies are required. Future research should focus on the type, source and quantities of different dietary fatty acids consumed. [ABSTRACT FROM PUBLISHER]

p53 is the most frequently mutated gene in all forms of human cancer. It responds to diverse stresses including UVR-induced DNA damage and regulates many downstream genes to initiate cell-cycle arrest, DNA repair or apoptosis. p53 gene variants at codon 11, Pro47Ser and codon 248 (exon 7) were evaluated for bladder cancer (BC) risk in North Indians. In the present study, the above encoding regions in p53 genes were analyzed in a hospital based study in 200 BC and 200 healthy controls age and gender matched and of similar ethnicity. The genotyping was assessed by the polymerase chain reaction restriction fragment length polymorphism technique and statistically evaluated using SPSS software ver. 15.0. A significant association was found with p53 codon 248 polymorphism and BC risk whereas p53 codon 11 and p53 Pro47Ser polymorphism showed no association with BC risk. The individuals carrying the heterozygous genotype (Arg/Trp-Arg/Gln) in the p53 codon 248 polymorphism showed high BC risk (p < 0.001). Combinations with heterozygous and variant genotypes also showed a high risk for BC (p < 0.001). The minor allele (Trp/Gln) carriers of the p53 codon 248 demonstrated a 1.7-fold risk for BC. Furthermore, haplotype analysis revealed that the Glu-Pro-Trp/Gln haplotype is associated with a 1.9-fold risk for BC. A protective role was observed with tumor stage/grade of BC patients with p53 codon 248 (p = 0.003; OR = 0.32). Thus, it is evident from our study that of all the 3 single nucleotide polymorphisms evaluated, only p53 codon 248 (exon7) gene polymorphism has an implication for risk in BC in the North Indian population. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Perturbed apoptosis due to missense alterations in candidate tumor suppressor gene Death receptor 4 (DR4) and in caspases (Casp) lead to deregulated cell proliferation and cancer predisposition. Some data indicate that normal variations within the sequence of apoptotic genes may lead to suboptimal apoptotic capacity and therefore increased cancer risk. To test our proposal we examined whether six single nucleotide polymorphisms (SNPs) of the DR4 and Casp3, 5 genes contrive the risk of bladder cancer (BC) in a North Indian population. Materials and methods: Genotyping was performed in 200 BC patients and 225 controls by Allele-specific PCR and by polymerase chain reaction-restriction fragment length polymorphism. Results: In DR4 Arg141His, BC patients having AA genotype (p = 0.036; OR = 2.51. In Casp5Leu13Phe G > C, significant association was observed with GC (p = 0.025; OR = 1.78) and also in GC + CC (p = 0.026; OR = 1.68). C allele carriers in Casp5Ala90Thr T > C showed low risk of BC (p = 0.036; OR = 0.83). While in Casp3 G > A, AG (p = 0.003; OR = 2.11), GG (p = 0.050; OR = 2.18), G allele (p < 0.001; OR = 1.85) and its carrier AG + GG (p = 0.001; OR = 2.12) have shown significant BC risk. Significant association between DR4 Ala228Glu polymorphism and smoking was observed in BC risk. Haplotype analysis demonstrated that DR4 (Thr209Arg–Arg141His–Ala228Glu) C-G-C is associated with 1.8 folds (OR = 1.85; p = 0.033) risk. GG genotype of Casp3 G > A polymorphism showed increased risk of recurrence (p = 0.009; HR = 5.20). Conclusion: This study provided new support for the association of DR4 and Casp3, 5 in BC development, the tumorigenic effect of which was observed to be more enhanced in case of smoking exposure. [Copyright &y& Elsevier]