Gut microbiota carcinogen metabolism causes distal tissue tumours.

Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development1,2. Similar to drug molecules, pollutants are typically metabolized in the body, which can change their carcinogenic potential and affect tissue distribution through altered toxicokinetics3. Although recent studies demonstrated that human-associated microorganisms can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites4,5, the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota affects the toxicokinetics of nitrosamines, which markedly reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice6,7. We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine carcinogens. Altogether, these results indicate that gut microbiota carcinogen metabolism may be a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer.

An Atlas of Dietary Intakes and Medication Uses on Risk of Bladder Cancer: A Wide-Angle Mendelian Randomization Analysis.

BACKGROUND: Observational studies suggests that diets and medications affect bladder cancer (BC) development, which are subject to confounding and difficult to make causal inference. Here we aimed to investigate whether those observational associations are causal and determining the potential directions and pathways. METHODS: We used 2-sample Mendelian randomization (MR) analysis to assess associations of dietary intakes, medication uses and molecules with BC risk. Genetic summary data were derived from participants of predominantly European ancestry with rigorous instruments selection, where univariable MR, mediation MR and multivariable MR were performed. RESULTS: The results of univariable MR showed 4 dietary intakes and 4 medication uses having a protective effect on BC, while 4 circulating metabolites, 440 circulating proteins and 2 gut microbes were observed to be causally associated with BC risk. Through mediation MR, we found 572 analytes showing consistent mediating effects between dietary intakes or medication uses and BC risk. Furthermore, 9 out of 16 diet-medication pairs showed significant interactions and alterations on BC when consumed jointly. CONCLUSION: In summary, the findings obtained from the current study have important implications for informing prevention strategies that point to potential lifestyle interventions or medication prescriptions to reduce the risk of developing BC.HighlightsThe current study extends observational literature in showing the importance of diets and medications on bladder cancer prevention.The associations of diets and medications on bladder cancer prevention might be through circulating metabolites, circulating proteins and gut microbiotaOur results provide a new understanding of interactions in certain diet-medication pairs which should be taken into account by both physicians and patients during the development of a treatment strategy.

Fruits and vegetables intake and bladder cancer risk: a pooled analysis from 11 case-control studies in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) consortium.

PURPOSE: High consumption of fruits and vegetables decrease the risk of bladder cancer (BC). The evidence of specific fruits and vegetables and the BC risk is still limited. METHODS: Fruit and vegetable consumptions in relation to BC risk was examined by pooling individual participant data from case-control studies. Unconditional logistic regression was used to estimate study-specific odds ratio's (ORs) with 95% confidence intervals (CIs) and combined using a random-effects model for intakes of total fruits, total vegetables, and subgroups of fruits and vegetables. RESULTS: A total of 11 case-control studies were included, comprising 5637 BC cases and 10,504 controls. Overall, participants with the highest intakes versus the lowest intakes of fruits in total (OR 0.79; 95% CI 0.68-0.91), citrus fruits (OR 0.81; 95% CI 0.65-0.98), pome fruits (OR 0.76; 95% CI 0.65-0.87), and tropical fruits (OR 0.84; 95% CI 0.73-0.94) reduced the BC risk. Greater consumption of vegetables in total, and specifically shoot vegetables, was associated with decreased BC risk (OR 0.82; 95% CI 0.68-0.96 and OR 0.87; 95% CI 0.78-0.96, respectively). Substantial heterogeneity was observed for the associations between citrus fruits and total vegetables and BC risk. CONCLUSION: This comprehensive study provides compelling evidence that the consumption of fruits overall, citrus fruits, pome fruits and tropical fruits reduce the BC risk. Besides, evidence was found for an inverse association between total vegetables and shoot vegetables intake.

Development and preliminary evaluation of a novel procedure for creation of an ileal conduit stoma aimed at preventing parastomal hernia.

OBJECTIVES: Our previous study suggested that the operative procedure is critical for the development of parastomal hernia. We developed a novel procedure for the creation of an ileal conduit stoma to prevent parastomal hernia. Herein we evaluate the efficacy and safety of the procedure. METHODS: A total of 113 Japanese patients underwent radical cystectomy and ileal conduit diversion for bladder cancer from January 2017 through December 2021 at our institution. After excluding those with incomplete data, 103 patients consisting of 46 (44.7%) with the conventional procedure and 57 (55.3%) with the novel procedure were consecutively enrolled. The main points of the novel procedure are as follows: (1) the passage of the ileal conduit is ≤2.4 cm in diameter in principle; (2) the posterior rectus sheath and peritoneum are vertically incised 2 cm laterally from the middle of the stoma site to make an oblique passage for the ileal conduit; and (3) the anterior rectus sheath and posterior rectus sheath with peritoneum are fixed to the ileal conduit separately. RESULTS: Radiography-based parastomal hernia was observed in 11 patients (10.7%) with a median follow-up of 22.0 months. The incidences of parastomal hernia were 3.5% and 19.6% in the novel and the conventional procedure groups, respectively (p = 0.011). The former had a significantly lower cumulative incidence of parastomal hernia (p = 0.008, log-rank test). No specific complications associated with the procedure were observed. CONCLUSIONS: The results of the preliminary cohort study suggest that the novel procedure is safe and effective for the prevention of parastomal hernia.

Long-term prevention of bladder cancer progression by alpha1-oleate alone or in combination with chemotherapy.

Bladder cancer is common and one of the most costly cancer forms, due to a lack of curative therapies. Recently, clinical safety and efficacy of the alpha1-oleate complex was demonstrated in a placebo-controlled study of nonmuscle invasive bladder cancer. Our study investigated if long-term therapeutic efficacy is improved by repeated treatment cycles and by combining alpha1-oleate with low-dose chemotherapy. Rapidly growing bladder tumors were treated by intravesical instillation of alpha1-oleate, Epirubicin or Mitomycin C alone or in combination. One treatment cycle arrested tumor growth, with a protective effect lasting at least 4 weeks in mice receiving 8.5 mM of alpha1-oleate alone or 1.7 mM of alpha-oleate combined with Epirubicin or Mitomycin C. Repeated treatment cycles extended protection, defined by a lack of bladder pathology and a virtual absence of bladder cancer-specific gene expression. Synergy with Epirubicin was detected at the lower alpha1-oleate concentration and in vitro, alpha1-oleate was shown to enhance the uptake and nuclear translocation of Epirubicin, by tumor cells. Effects at the chromatin level affecting cell proliferation were further suggested by reduced BrdU incorporation. In addition, alpha1-oleate triggered DNA fragmentation, defined by the TUNEL assay. The results suggest that bladder cancer development may be prevented long-term in the murine model, by alpha1-oleate alone or in combination with low-dose Epirubicin. In addition, the combination of alpha1-oleate and Epirubicin reduced the size of established tumors. Exploring these potent preventive and therapeutic effects will be of immediate interest in patients with bladder cancer.

Genetic factors, adherence to healthy lifestyle behaviors, and risk of bladder cancer.

BACKGROUND: Genetic and lifestyle factors both contribute to the pathogenesis of bladder cancer, but the extent to which the increased genetic risk can be mitigated by adhering to a healthy lifestyle remains unclear. We aimed to investigate the association of combined lifestyle factors with bladder cancer risk within genetic risk groups. METHODS: We conducted a prospective study of 375 998 unrelated participants of European ancestry with genotype and lifestyle data and free of cancer from the UK biobank. We generated a polygenic risk score (PRS) using 16 single nucleotide polymorphisms and a healthy lifestyle score based on body weight, smoking status, physical activity, and diet. Cox models were fitted to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of genetic and lifestyle factors on bladder cancer. RESULTS: During a median follow-up of 11.8 years, 880 participants developed bladder cancer. Compared with those with low PRS, participants with intermediate and high PRS had a higher risk of bladder cancer (HR 1.29, 95% CI 1.07-1.56; HR 1.63, 95% CI 1.32-2.02, respectively). An optimal lifestyle was associated with an approximately 50% lower risk of bladder cancer than a poor lifestyle across all genetic strata. Participants with a high genetic risk and a poor lifestyle had 3.6-fold elevated risk of bladder cancer compared with those with a low genetic risk and an optimal lifestyle (HR 3.63, 95% CI 2.23 -5.91). CONCLUSIONS: Adhering to a healthy lifestyle could substantially reduce the bladder cancer risk across all genetic strata, even for high-genetic risk individuals. For all populations, adopting an intermediate lifestyle is more beneficial than a poor one, and adhering to an optimal lifestyle is the ideal effective strategy for bladder cancer prevention.

Adherence to Mediterranean-Style Dietary Pattern and Risk of Bladder Cancer: A Case-Control Study in Iran.

Few dietary patterns are related to reduce the Bladder Cancer (BC) risk. One of the well-known dietary patterns is the Mediterranean diet (MD). This case-control study investigated the association between MD and the odds of BC among Iranian population. The present case-control study was performed on 103 eligible cases and 200 controls age 45 to 92 years. Diet of participants was assessed by a validated 168-item food frequency questionnaire (FFQ). Adherence to MD was measured by Mediterranean-Style Dietary Pattern Score (MSDPS). Multivariate logistic regression was used to estimate the relationship between MSDPS and risk of BC. After controlling for potential confounders, a negative association was observed between MSDPS and risk of BC (OR = 0.22; 95%CI = 0.09-0.52; p trend = 0.001). Furthermore, significant negative associations were observed for dairy, fish and other seafood, whole-grain, bread intake and risk of BC (p for trend < 0.05). In contrast, the risk of BC increased for high intake of poultry (OR = 1.09; 95%CI = 1.03-1.15; p trend = 0.003), sweets (OR = 1.24; 95%CI = 1.03-1.48; p trend = 0.018) and egg (p for trend = 0.01). Our results suggested that dietary habit in concordance with the principles of the Mediterranean dietary pattern may protect against BC.

Vegetable and fruit intake and the risk of bladder cancer: Japan Public Health Center-based prospective study.

BACKGROUND: Vegetable and fruit consumption may have a protective effect against several types of cancer. However, evidence suggesting that increased intake of vegetables and fruits, their subtypes, or the antioxidant nutrients they contain in abundance decreases the risk of bladder cancer is limited. METHODS: This study included 80,952 participants from the Japan Public Health Center-based Prospective Study, who responded to a food frequency questionnaire in a 5-year follow-up survey in 1995-1998 and were followed up until December 2015 to investigate the associations between intake of vegetables and fruits, their subtypes, or the antioxidant nutrients and bladder cancer risk using Cox proportional hazards regression models. RESULTS: Within 1,287,514 person-years of follow-up, 401 bladder cancer cases (307 men and 94 women) were diagnosed. No association was found between intake of total vegetable and fruit, total vegetable, total fruit, subtypes of vegetables and fruits, or antioxidant nutrients and bladder cancer risk in both men and women, even in the analyses conducted among men stratified by smoking status. CONCLUSIONS: In this population, the consumption of vegetables and fruits was not associated with the risk of bladder cancer.

Folate Intake and Risk of Urothelial Carcinoma: A Systematic Review and Meta-Analysis of Epidemiological Studies.

We aimed to investigate the association between folate intake and the risk of urothelial carcinoma (UC). A systematic literature search using Pubmed and EMBASE databases was performed to find prospective cohort studies, population-based case-control study or hospital-based case-control study investigating the association of folate intake and the risk of UC. A total of 19 studies involving 11,175 cases and 656,161 individuals were included. High intake of folate was associated with a decreased risk of UC, with a pooled OR of 0.78 (95% CI: 0.66-0.93, P = 0.006) for the highest category of intake vs. the lowest. The data suggested that folate may contribute to the prevention of urothelial cancer. However, the association was observed only in case-control studies (OR = 0.56, 95% CI: 0.39-0.79, P = 0.001), but not in cohort studies (RR = 0.97, 95% CI: 0.87-1.09, P = 0.638). Dose-response meta-analysis showed that an increment of folate intake (100 µg/day) corresponded to an 8% deceased risk of invasive UC (RR = 0.92, 95% CI: 0.87-0.98, P = 0.004). High folate intake might be inversely associated with risk of UC particularly invasive UC, which needs to be confirmed.

Chemopreventive Potential of Myrtenal against Nitrosamine-Initiated, Radiation-Promoted Rat Bladder Carcinogenesis.

The present study was undertaken to evaluate the chemopreventive activity of myrtenal, a natural monoterpene, against bladder carcinoma in rats induced with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) and promoted with γ-ionizing radiation (γ-IRR) as well as to assess the involvement of inflammation, apoptosis and oxidative damage in tumor development. Histopathological examination of rat bladder revealed the presence of noninvasive papillary transitional cell carcinoma (Grade 2) in sections from BBN group indicating the credibility of the applied carcinogenesis model. Myrtenal treatment caused improvement in urinary bladder mucosa with cells more likely in Grade 1. Administration of myrtenal to BBN-treated rats exhibited downregulation in the expressions of COX-2, NF-kB and STAT-3 associated with suppression of inflammatory cytokines levels of TNF-α and IL-6 as well as biomarkers of oxidative damage (MDA & NO). In addition, myrtenal treatment caused a significant increase in caspase-3 activity and Bax/Bcl-2 ratio. Data obtained suggested that the anti-inflammatory effect and the induction of apoptosis contributed largely to the beneficial antitumor effects of myrtenal in rats with BBN/γ-IRR-induced bladder carcinoma. Present findings, in addition to benefits described in other pathologies, indicated myrtenal as a potential adjuvant natural compound for the prevention of tumor progression of bladder cancer.

Drug instillation in the management of urinary tract urothelial carcinoma.

PURPOSE OF REVIEW: This article aimed to investigate the efficacy of drug instillation therapy in preventing the recurrence of postsurgical upper urinary tract urothelial carcinoma (UTUC) by reviewing recently published research articles. RECENT FINDINGS: Several clinical trials have shown new potential forms of postsurgical intracavitary and intravesical drug instillation methodologies with better efficacy and less toxicity for use in UTUC. With the improvement of endoscopic imaging techniques and laser sciences, diverse attempts in drug instillation have shown an improved recurrence rate after kidney-sparing surgery in low-grade, low-tumor burden cancers in the upper urinary tract. A gel-form type of mitomycin-C in intracavitary instillation further reduced recurrence rates in UTUC. Other studies have compared different drug instillation methodologies with varying initiation times and timed instillation. They have shown that early instillation with multiple rounds resulted in better protective effects for recurrence rates before, during, and after surgery. SUMMARY: A new gel-form of intracavitary instillation of mitomycin-C, the timing of drug instillation, and refining techniques can result in better recurrence-free survival of patients with UTUC after surgery. Further large-scale prospective clinical trials are needed to validate these new forms of drugs and methodologies to change the therapeutic guidelines of UTUC.

Omega-3 polyunsaturated fatty acids: a modified approach for chemo-prevention of bladder cancer in a rat model and molecular studies of antineoplastic mechanisms.

OBJECTIVES: To test the chemo-preventative effects of omega-3 against bladder cancer (BC) induction in a rat model and its potential antineoplastic mechanisms. MATERIAL AND METHODS: Ninety male Fisher rats were divided into three groups during a 22-week protocol: group 1 (control), group 2 (Placebo + N-butyl-N-4- hydroxybutyl nitrosamine (BBN) for induction of BC and group 3 received omega-3 (1200 mg/kg/day) + BBN. At the end, blood samples and bladder tissues were collected and checked for the presence of malignancy, markers of angiogenesis (VEGF relative gene expression), inflammation (IL-6), proliferation (KI-67 expressions), oxidative stress (serum MDA and serum SOD) and epigenetic control (miRNA-145 level). RESULTS: At the end of the study, 60% and 86.6% rats survived in group 2 and 3 with significant weight loss among rats in group 2 when compared with other groups. In group 2, all rats developed visible bladder lesions of which five and 13 developed squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC). In omega3-treated group, only one developed low grade SCC and one developed high grade non- invasive TCC. Bladders from omega-3-treated rats showed lower expression ofKI-67 (p < 0.05), VEGF (p < 0.001) and IL-6 (p < 0.001) and significant higher expression of mi-RNA (p < 0.001). Also, omega-3-treated group showed statistically significant lower MDA level (p < 0.001). CONCLUSION: Omega-3 inhibits bladder tumor growth in the BBN-induced BC rat model, due to anti-inflammatory, antioxidant, anti-proliferative, and anti-angiogenic properties together with epigenetic control.

Dietary B group vitamin intake and the bladder cancer risk: a pooled analysis of prospective cohort studies.

PURPOSE: Diet may play an essential role in the aetiology of bladder cancer (BC). The B group complex vitamins involve diverse biological functions that could be influential in cancer prevention. The aim of the present study was to investigate the association between various components of the B group vitamin complex and BC risk. METHODS: Dietary data were pooled from four cohort studies. Food item intake was converted to daily intakes of B group vitamins and pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using Cox-regression models. Dose-response relationships were examined using a nonparametric test for trend. RESULTS: In total, 2915 BC cases and 530,012 non-cases were included in the analyses. The present study showed an increased BC risk for moderate intake of vitamin B1 (HRB1: 1.13, 95% CI: 1.00-1.20). In men, moderate intake of the vitamins B1, B2, energy-related vitamins and high intake of vitamin B1 were associated with an increased BC risk (HR (95% CI): 1.13 (1.02-1.26), 1.14 (1.02-1.26), 1.13 (1.02-1.26; 1.13 (1.02-1.26), respectively). In women, high intake of all vitamins and vitamin combinations, except for the entire complex, showed an inverse association (HR (95% CI): 0.80 (0.67-0.97), 0.83 (0.70-1.00); 0.77 (0.63-0.93), 0.73 (0.61-0.88), 0.82 (0.68-0.99), 0.79 (0.66-0.95), 0.80 (0.66-0.96), 0.74 (0.62-0.89), 0.76 (0.63-0.92), respectively). Dose-response analyses showed an increased BC risk for higher intake of vitamin B1 and B12. CONCLUSION: Our findings highlight the importance of future research on the food sources of B group vitamins in the context of the overall and sex-stratified diet.

Association of Dietary Approaches to Stop Hypertension diet and risk of bladder cancer: A case-control study.

OBJECTIVE: The Dietary Approaches to Stop Hypertension (DASH) diet is rich in recommended foods that are inversely associated with bladder cancer (BC) risk. The main objective of this study was to investigate the association between adherence to DASH diet and the risk of BC among Iranian adults. METHOD: This study included 103 BC cases and 200 controls. The controls were patients who were hospitalised for acute non-neoplastic diseases. DASH scores were computed from dietary intake assessed by a previously validated food frequency questionnaire. RESULTS: After controlling for potential confounders, participants in the highest quintile of DASH (compared to the lowest quintile) had 84% lower BC risk (OR = 0.16; 95%CI: 0.05-0.45; p trend = 0.001). Among the DASH components, significant negative associations were observed between low fat dairy and whole grains intake with BC (p value < 0.05). A positive relation was observed for sodium, nuts and legumes, and sweetened beverages (p value < 0.05). CONCLUSION: The results of this study suggested that adherence to DASH might be associated with reduced risk of BC. These findings could be used to develop evidence-based recommendations for the prevention of BC.

Finasteride Use and Risk of Bladder Cancer in a Multiethnic Population.

PURPOSE: Finasteride use has been associated with a reduced incidence of bladder cancer. However, the majority of studies have been conducted primarily in East Asian or White populations. Given differences in the incidence of bladder cancer among racial/ethnic groups, it is important to determine whether the effect of finasteride use on bladder cancer varies by race/ethnicity. MATERIALS AND METHODS: We identified all patients with a diagnosis of benign prostatic hyperplasia between 2000 and 2016 at our academic health center in Bronx, New York via an electronic medical record database. We then identified patients who were prescribed finasteride, and those who developed bladder cancer during followup. We used competing risk analysis to examine associations of finasteride use with risk of bladder cancer, adjusting for age, smoking and race/ethnicity. RESULTS: We identified 42,406 patients with benign prostatic hyperplasia (average±SD age 67±12.9 years), of whom 27.7% were Black and 14.8% were Hispanic. Finasteride was prescribed in 5,698 patients (13.4%). Bladder cancer was diagnosed in 84 of 5,698 finasteride users (1.5%), compared to 762 of 36,708 nonusers (2.1%, log-rank p=0.003). Finasteride was associated with a 36% reduction in risk of bladder cancer (HR: 0.64, 95% CI: 0.51-0.80; p <0.0001) among all patients. When data were stratified by race/ethnicity, finasteride use was associated with a reduction in risk of bladder cancer in White men (HR: 0.61, 95% CI: 0.43-0.86; p=0.005) and Hispanic men (HR: 0.44, 95% CI: 0.21-0.90; p=0.026), but there was no association among Black men (HR: 1.01, 95% CI: 0.67-1.51; p=0.964). CONCLUSIONS: Our study corroborates previous findings that men who are on finasteride have a lower bladder cancer incidence. However, the reduction in risk was seen only in White and Hispanic men, but not among Black men. Therefore, race/ethnicity represents an important stratification factor for future larger studies on finasteride as chemoprevention for bladder cancer.

The role of exosomal miR-375-3p: A potential suppressor in bladder cancer via the Wnt/ß-catenin pathway.

miR-375-3p is a significantly downregulated miRNA in bladder cancer (BC). However, its role in BC regulation is still unclear. In this study, we reported that miR-375-3p overexpression inhibited proliferation and migration and promoted apoptosis in BC cells. Frizzled-8 (FZD8) gene is identified as the direct miR-375-3p targeting gene. miR-375-3p blocks the Wnt/ß-catenin pathway and downstream molecules Cyclin D1 and c-Myc by inhibiting the expression of FZD8 directly, it could increase caspase 1 and caspase 3 expression and promote T24 cell apoptosis as well. miR-375-3p also showed a significant inhibitory effect in vivo in bladder tumor-bearing nude mice, as demonstrated by the reduced tumor volume and Ki67 proliferation index in tumor tissue. Collectively, miR-375-3p is a suppressor of BC that inhibits proliferation and metastasis, and promotes apoptosis in BC cells as well as suppresses tumor growth in a T24 xenograft mouse model, which could be used as a potential therapeutic approach for BC in future.

Intravesical gemcitabine for non-muscle invasive bladder cancer.

BACKGROUND: It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or recurrent setting following transurethral resection of a bladder tumor. This is an update of a Cochrane Review first published in 2012. Since that time, several randomized controlled trials (RCTs) have been reported, making this update relevant.  OBJECTIVES: To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for NMIBC. SEARCH METHODS: We performed a comprehensive literature search of the Cochrane Library, MEDLINE, Embase, four other databases, trial registries, and conference proceedings to 11 September 2020, with no restrictions on the language or status of publication. SELECTION CRITERIA: We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: time to recurrence, time to progression, grade III to V adverse events determined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), and the secondary outcomes: time to death from bladder cancer, time to death from any cause, grade I or II adverse events determined by the CTCAE v5.0 and disease-specific quality of life. We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE. MAIN RESULTS: We included seven studies with 1222 participants with NMIBC across five comparisons. This abstract focuses on the primary outcomes of the three most clinically relevant comparisons. 1. Gemcitabine versus saline: based on two years' to four years' follow-up, gemcitabine may reduce the risk of recurrence over time compared to saline (39% versus 47% recurrence rate, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54 to 1.09; studies = 2, participants = 734; I2 = 49%; low-certainty evidence), but the CI included the possibility of no effect.  Gemcitabine may result in little to no difference in the risk of progression over time compared to saline (4.6% versus 4.8% progression rate, HR 0.96, 95% CI 0.19 to 4.71; studies = 2, participants = 654; I2 = 53%; low-certainty evidence).  Gemcitabine may result in little to no difference in the CTCAE grade III to V adverse events compared to saline (5.9% versus 4.7% adverse events rate, risk ratio [RR] 1.26, 95% CI 0.58 to 2.75; studies = 2, participants = 668; I2 = 24%; low-certainty evidence).  2. Gemcitabine versus mitomycin: based on three years' follow-up (studies = 1, participants = 109), gemcitabine may reduce the risk of recurrence over time compared to mitomycin (17% versus 40% recurrence rate, HR 0.36, 95% CI 0.19 to 0.69; low-certainty evidence). Gemcitabine may reduce the risk of progression over time compared to mitomycin (11% versus  18% progression rate, HR 0.57, 95% CI 0.32 to 1.01; low-certainty evidence), but the CI included the possibility of no effect.  We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to mitomycin (RR 0.51, 95% CI 0.13 to 1.93; very low-certainty evidence). The analysis was only based on recurrent NMIBC. 3. Gemcitabine versus Bacillus Calmette-Guérin (BCG) for recurrent (one-course BCG failure) high-risk NMIBC: based on 6 months' to 22 months' follow-up (studies = 1, participants = 80), gemcitabine may reduce the risk of recurrence compared to BCG (41% versus 97% recurrence rate, HR 0.15, 95% CI 0.09 to 0.26; low-certainty evidence) and progression over time (16% versus 33% progression rate, HR 0.45, 95% CI 0.27 to 0.76; low-certainty evidence). We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to BCG (RR 1.00, 95% CI 0.21 to 4.66; very low-certainty evidence).  In addition, the review provides information on  the comparison of gemcitabine versus BCG and gemcitabine versus one-third dose BCG.  AUTHORS' CONCLUSIONS: Based on findings of this review, gemcitabine may have a more favorable impact on recurrence and progression-free survival than mitomycin but we are very uncertain as to how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high risk disease who have previously failed BCG. The underlying low- to very low-certainty evidence indicates that our confidence in these results is limited; the true effects may be substantially different from these findings; therefore, better quality studies are needed.

Vitamin A and Retinoids in Bladder Cancer Chemoprevention and Treatment: A Narrative Review of Current Evidence, Challenges and Future Prospects.

Bladder cancer (BC) is the tenth most common cancer worldwide with a high recurrence rate, morbidity and mortality. Therefore, chemoprevention and improved treatment of BC are of paramount importance. Epidemiological studies suggest that adequate vitamin A intake may be associated with reduced BC risk. In addition, retinoids, natural and synthetic derivatives of vitamin A, are intensively studied in cancer research due to their antioxidant properties and their ability to regulate cell growth, differentiation, and apoptosis. Findings from in vivo and in vitro models of BC show great potential for the use of retinoids in the chemoprevention and treatment of BC. However, translation to the clinical practice is limited. In this narrative review we discuss: (i) vitamin A and retinoid metabolism and retinoic acid signalling, (ii) the pathobiology of BC and the need for chemoprevention, (iii) the epidemiological evidence for the role of dietary vitamin A in BC, (iv) mechanistic insights obtained from in vivo and in vitro models, (v) clinical trials of retinoids and the limitations of retinoid use, (vi) novel systems of retinoid delivery, and (vii) components of retinoid signalling pathways as potential novel therapeutic targets.

The future burden of kidney and bladder cancers preventable by behavior modification in Australia: A pooled cohort study.

Substantial changes in the prevalence of the principal kidney and bladder cancer risk factors, smoking (both cancers) and body fatness (kidney cancer), have occurred but the contemporary cancer burden attributable to these factors has not been evaluated. We quantified the kidney and bladder cancer burden attributable to individual and joint exposures and assessed whether these burdens differ between population subgroups. We linked pooled data from seven Australian cohorts (N = 367,058) to national cancer and death registries and estimated the strength of the associations between exposures and cancer using adjusted proportional hazards models. We estimated exposure prevalence from representative contemporaneous health surveys. We combined these estimates to calculate population attributable fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death, and compared PAFs for population subgroups. During the first 10-year follow-up, 550 kidney and 530 bladder cancers were diagnosed and over 21,000 people died from any cause. Current levels of overweight and obesity explain 28.8% (CI = 17.3-38.7%), current or past smoking 15.5% (CI = 6.0-24.1%) and these exposures jointly 39.6% (CI = 27.5-49.7%) of the kidney cancer burden. Current or past smoking explains 44.4% (CI = 35.4-52.1%) of the bladder cancer burden, with 24.4% attributable to current smoking. Ever smoking explains more than half (53.4%) of the bladder cancer burden in men, and the burden potentially preventable by quitting smoking is highest in men (30.4%), those aged <65 years (28.0%) and those consuming >2 standard alcoholic drinks/day (41.2%). In conclusion, large fractions of kidney and bladder cancers in Australia are preventable by behavior change.

The global burden of urinary bladder cancer: an update.

Bladder cancer is among the top ten most common cancer types in the world, with approximately 550,000 new cases annually. The highest burden of bladder cancer is currently falling on most developed communities across the globe. But with an anticipated shift in world demographics with growing and aging populations mainly on the African continent, and important shifts in exposure to different risk factors across the world, this is likely to change over the next decades. In this review, we provide an overview of the current incidence, mortality, prevalence, survival, risk factors and costs of bladder cancer worldwide.