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The value of 18F-fluorodeoxyglucose positron-emission-tomography-computed tomography (FDG-PET/CT) for staging patients with (very) high-risk non-muscle invasive bladder cancer (NMIBC) is unknown. In this study among NMIBC patients referred for RC, FDG-PET/CT detected metastases that were not detected by CT, leading to treatment changes in 10% of patients. However, the use of FDG-PET/CT should be weighed against its disadvantages, including false-positive lesions. Introduction and Objectives: 18F-fluorodeoxyglucose positron-emission tomography-computed tomography (FDGPET/CT) is increasingly used in the preoperative staging of patients with muscle-invasive bladder cancer. The clinical added value of FDG-PET/CT in high-risk non-muscle invasive bladder cancer (NMIBC) is unknown. In this study, the value of FDG-PET/CT in addition to contrast enhanced (CE)-CT was evaluated in high-risk NMIBC before radical cystectomy (RC). Materials and Methods: This is a retrospective analysis of consecutive patients with high risk and very-high risk urothelial NMIBC scheduled for RC in a tertiary referral center between 2011 and 2020. Patients underwent staging with CE-CT (chest and abdomen/pelvis) and FDG-PET/CT. We assessed the clinical disease stage before and after FDG-PET/CT and the treatment recommendation based on the stage before and after FDG-PET/CT. The accuracy of CT and FDG-PET/CT for identifying metastatic disease was defined by the receiver-operating curve using a referencestandard including histopathology/cytology (if available), imaging and follow-up. Results: A total of 92 patients were identified (median age: 71 years). In 14/92 (15%) patients, FDG-PET/CT detected metastasis (12 suspicious lymph nodes and 4 distant metastases). The disease stage changed in 11/92 (12%) patients based on additional FDG-PET/CT findings. FDG-PET/CT led to a different treatment in 9/92 (10%) patients. According to the reference standard, 25/92 (27%) patients had metastases. The sensitivit y, specificit y and accuracy of FDG-PET/CT was 36%, 93% and 77% respectively, versus 12%, 97% and 74% of CE-CT only. The area under the ROC curve was 0.643 for FDG-PET/CT and 0.545 for CT, P = .036. Conclusion: The addition of FDG-PET/CT to CE-CT imaging changed the treatment in 10% of patients and proved to be a valuable diagnostic tool in a selected subgroup of NMIBC patients scheduled for RC. [ABSTRACT FROM AUTHOR]

The best treatment option for high-risk non muscle-invasive bladder cancer is BCG immunotherapy. In this study we looked for potential interaction between drugs with known immunomodulatory effects (angiotensin receptor blockers and ACE-inhibitors) and cancer recurrence in patients treated with BCG. Our results show a benefit in patients treated with angiotensin receptor blockers. Introduction: The gold standard treatment for high-risk NMIBC is BCG immunotherapy. Some studies suggested an immomodulatory effects for commonly used drugs (ie, ACE-I and ARBs). We aimed to determine whether these drugs impact the prognosis of patients with high-risk NMIBC treated with BCG. Materials and Methods: Retrospective analysis on 208 patients from a single academic center with primary high-risk NMIBC treated with transurethral resection followed by 6 weekly instillations of BCG and up to 12 monthly maintenance instillations. ARBs or ACE-I use at the time of treatment initiation was recorded. Inverse probability of treatment weighting (IPTW) was used to adjust for clinical and pathological covariates. IPTW-adjusted Kaplan-Meier curves and weighted Cox proportional hazards regression were used to compare 2-yr failure-free (2-yr FFS), failure-free (FFS), overall recurrence-free (RFS) and progression-free survival (PFS). Results: A total of 68 patients were on ACE-I, and 38 on ARBs and treatment respectively. At a median follow-up of 26 months, ACE-I treatment had no significant impact on cancer-related outcomes. Conversely, patients treated with ARBs experienced significant improvements in 2-yr FFS (HR 0.3; 0.1-0.9, P = .004), FFS (HR 0.4, 0.1-0.9, P = .005), and PFS (HR 0.001; < 0.001-0.001, P < .001). No significant impact was found for ARB use in RFS (HR 0.6; P = .09). Sensitivity analyses confirmed these results. Conclusions: our findings support a potential role of the angiotensin-renin system in bladder cancer development. We identified ARBs as potential beneficial drugs that seems to act in synergy with BCG-immunotherapy. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Ranitidine has been shown to contain the carcinogen N-nitrosodimethylamine and increase urinary N-nitrosodimethylamine in humans. We investigated whether ranitidine use is associated with increased bladder cancer risk. METHODS: A nested case-control study was conducted within the Primary Care Clinical Informatics Unit Research database which contains general practice records from Scotland. Bladder cancer cases, diagnosed between 1999 and 2011, were identified and matched with up to 5 controls (based on age, sex, general practice, and date of registration). Ranitidine, other histamine-2 receptor agonists, and proton pump inhibitors were identified from prescribing records. Odds ratios (ORs) and 95%confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for comorbidities and smoking. RESULTS: There were 3,260 cases and 14,037 controls. There was evidence of an increased risk of bladder cancer in ranitidine users, compared with nonusers (fully adjusted OR51.22;95% CI 1.06-1.40), which was more marked with use for over 3 years of ranitidine (fully adjusted OR 5 1.43; 95% CI 1.05-1.94). By contrast, there was little evidence of any association between proton pump inhibitor use and bladder cancer risk based on any use (fully adjusted OR50.98; 95% CI 0.88-1.11) or over 3 years of use (fully adjusted OR 5 0.98; 95% CI 0.80-1.20). DISCUSSION: In this large population-based study, the use of ranitidine particularly long-term use was associated with an increased risk of bladder cancer. Further studies are necessary to attempt to replicate this finding in other settings. [ABSTRACT FROM AUTHOR]

Bladder cancer is one of the most common malignancies involving the urinary system of about 1.65 million cases worldwide. To attain the 25 by 25 goal set by the World Health Organization (25% reduction in non-communicable diseases between 2015 and 2025), developing strategies to reduce cancer burdens is essential. The data of the study comprised the age-specific bladder cancer cases and total population numbers from age 25 to 85 and above from 1997 to 2016 in Taiwan. An ensemble age–period–cohort model was used to estimate bladder cancer incidence trends and forecast the trends to 2025. For men, the projected age-standardized incidence rates per 100,000 people in 2020 and 2025 are 13.0 and 10.4, respectively, with a 16.1% and 32.9% decrease projected from 2016 to 2020 and 2025, respectively. For women, the projected age-standardized incidence rates per 100,000 people in 2020 and 2025 are 4.7 and 3.7, respectively, with a 16.1% and 33.9% decrease projected from 2016 to 2020 and 2025, respectively. The age-specific bladder cancer incidence rates demonstrated a consistently downward trend after 2003 for all ages and both sexes. This study projects that the incidence rates of bladder cancer in Taiwan will continue to decrease, and more than a 25% reduction can be achieved from 2016 to 2025. [ABSTRACT FROM AUTHOR]

Men are at a higher risk of developing bladder cancer than women. Although the urinary bladder is not regarded as an sex organ, it has the potential to respond to androgen signals. The mechanisms responsible for the gender differences remain unexplained. Androgen receptor (AR) after binding with 5α-dihydrotestosteron (DHT) undergoes a conformational change and translocates to nucleus to induce transcriptional regulation of target genes. However androgen/AR signaling can also be activated by interacting with several signaling molecules and exert its non-genomic function. The aim of present study was to explain whether the progression of bladder cancer in men is dependent on androgen/AR signaling. Studies were carried out on human bladder cancer cell lines: HCV29, T24, HT1376 and HTB9. Bladder cancer cells were treated for 48 h with 10 nM DHT or not, with replacement after 24 h. Expression of cell signaling proteins, was analyzed using Western Blot and RT-PCR. Subcellular localization of protein was studied using the ProteoExtract Subcellular Proteome Extraction Kit and Western blot analysis. We showed that DHT treatment significantly increased AR expression in bladder cell line HCV29. We also observed DHT-mediated activation of Akt/GSK-3β signaling pathway which plays a central role in cancer progression. Presented results also show that androgen/AR signaling is implicated in phosphorylation of eIF4E which can promote epithelial–mesenchymal transition (EMT). We indicate that AR plays an essential role in bladder cancer progression in male patients. Therefore, androgen-activated AR signaling is an attractive regulatory target for the inhibition or prevention of bladder cancer incidence in men. [ABSTRACT FROM AUTHOR]

Abstract Background Vascular endothelial growth factor (VEGF) gene plays a key role in angiogenesis and tumor growth. The relationship between VEGF gene polymorphisms and bladder cancer (BCa) risk was studied extensively in recent years. However, the currently available results are controversial. To ascertain whether VEGF polymorphisms are associated with the susceptibility to BCa, we conducted this systematic review and meta-analysis. Materials and methods Relevant studies were collected systemically from PubMed, Medline, Embase, Web of Science databases and the Cochrane Library. Odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated using random or fixed effects models by Stata statistical software. This systematic review protocol was registered at International prospective register of systematic reviews (PROSPERO) under number CRD42018099279. Results A total of eight articles including twenty case-control studies with 3206 BCa cases and 3645 controls were enrolled for this meta-analysis. By pooling all eligible studies, we found that rs3025039, rs833052 and rs25648 polymorphisms were significantly associated with BCa risk. However, in subgroup analyses by stage, we identified a decreased association between the rs699947 A-allele and Muscle-invasive Bladder Cancer (MIBC) under allele contrast, homozygous and recessive genetic models (A vs C: OR = 0.76; AA vs CC: OR = 0.49, 95%CI = 0.27–0.90, I 2 = 0.0%, P = 0.021; AA vs CA + CC: OR = 0.60, 95%CI = 0.38–0.96, I 2 = 0.0%, P = 0.034). As to ethnicity subgroup analysis, rs699947 and rs3025039 polymorphisms were thought as a risk factor for BCa risk in Asian population, while a decreased association was revealed between rs699947 (C > A) A-allele and BCa risk in African population under dominant, recessive, homozygous, heterozygous and allele contrast genetic models. While for other polymorphisms, null results were found. Conclusion Our meta-analysis suggested that rs3025039 (C > T), rs833052 (C > A) and rs25648 (C > T) polymorphisms of VEGF gene increased susceptibility to BCa risk. And our study also demonstrated homozygous TT genotype in rs3025039, homozygous AA genotype in rs833052 and homozygous TT genotype in rs25648 were significantly relevant to elevated BCa risk. In the meanwhile, it is worth noting that rs699947 (C > A) A-allele should be thought as a protective factor for MIBC. Highlights • Rs3025039, rs833052 and rs25648 polymorphisms increased BCa risk. • Rs699947 A-allele should be a protective factor for MIBC. [ABSTRACT FROM AUTHOR]

Most cases of urogenital parasitosis are registered in Africa. However, migration movements and travellers moving from developed to developing countries are responsible for leading to an increased incidence of genitourinary infections caused by parasites in the western world including Spain having serious economic and health implications. The importance of its early detection and treatment also results from its potential risk for infertility, susceptibility for HIV infection and the development of bladder cancer. The most common presentation symptom is terminal haematuria, and when diagnosed, praziquantel is the treatment of choice. We report a series of 6 cases of urinary schistosomiasis that happened in a single centre in Spain and reminds the importance of having the infection in mind in certain cases of haematuria study. [ABSTRACT FROM AUTHOR]

Purpose: The main risk factor for bladder cancer (BC) is cigarette smoking, but also occupational exposure to carcinogens is relevant, causing about 4-10% of BC. We aimed at investigating the association between BC risk, occupations held in the past and exposure to occupational carcinogens, also assessing whether these associations were influenced by tumour grade.Methods: We pooled data from two Italian case-control studies on male BC, analyzing 893 cases and 978 controls. Occupations were classified using the International Standard Classification of Occupations and exposure to carcinogens was assigned using a validated Job Exposure Matrix. Logistic regression approach was used as well as a semi-Bayesian model, based on a priori information on exposure.Results: A significantly increased BC risk was found for chemical engineering technicians, postmen, and lathe operators, but only, for the latter, the association remained significant after Bayesian control for type I error. Among carcinogens, cadmium and trichloroethylene were associated with BC. When analyzing data by grade, exposure to these carcinogens was associated with low-grade BC only.Conclusions: Our results suggest that monitoring workplaces to prevent exposure to carcinogenic agents is still an important task, which should be still given adequate importance in public health. [ABSTRACT FROM AUTHOR]

Abstract Cisplatin is an important chemotherapeutic agent against metastatic bladder cancer, but resistance often limits its usage. With the recent recognition of lipid metabolic alterations in bladder cancers, we studied the metabolic implications of cisplatin resistance using cisplatin-sensitive (T24S) and resistant (T24R) bladder cancer cells. Real-time live metabolomics revealed that T24R cells consume more glucose, leading to higher production of glucose-derived acetate and fatty acids. Along with the activation of general metabolic regulators, enzymes involved in acetate usage (ACSS2) and fatty acid synthesis (ACC) and a precursor for fatty acid synthesis (acetyl-CoA) were elevated in T24R cells. Consistently, metabolic analysis with 13C isotope revealed that T24R cells preferred glucose to acetate as the exogenous carbon source for the increased fatty acid synthesis, contrary to T24S cells. In addition, ACSS2, rather than the well-established ACLY, was the key enzyme that supplies acetyl-CoA in T24R cells through glucose-derived endogenous acetate. The relevance of ACSS2 in cisplatin resistance was further confirmed by the abrogation of resistance by an ACSS2 inhibitor and, finally, by the higher expression of ACSS2 in the patient tissues with cisplatin resistance. Our results may help improve the treatment options for chemoresistant bladder cancer patients and provide possible vulnerability targets to overcome the resistance. Highlights • New metabolic phenotypes of cisplatin-resistant bladder cancer cells • Glucose-derived acetate for the fatty acid synthesis through ACSS2 • High ACSS2 expression observed in cisplatin-resistant patient tissues [ABSTRACT FROM AUTHOR]

Objective: To assess whether radiotherapy (RT) for prostate cancer (PCa) was a risk factor for secondary bladder cancer (BLCa) through a meta-analysis. Materials and methods: The MEDLINE, Embase, and the Cochrane Library were systematically searched for all studies investigating the risk of BLCa in patients with RT. The association between RT and risk of BLCa was summarized using hazard ratio with a 95%CI. The protocol for this meta-analysis is available from PROSPERO (CRD42018090075). Results: Overall, 619,479 participants (age: 57–79 years) were included from 15 studies, 206,852 of whom were patients who received RT. Synthesis of results indicated that RT was significantly associated with an increased risk of BLCa compared with the risk in those who received radical prostatectomy or non-RT (overall HR=1.6, 95%CI: 1.33–1.92, P<0.001). The results were consistent when restricted to a 5-year lag period (HR=1.84, 95%CI: 1.26–2.69, P=0.002) and multivariable adjustment (HR=1.96, 95%CI: 1.47–2.62, P<0.001), but not for 10-year lag period (HR=1.93, 95%CI: 0.9– 4.16, P=0.093) and brachytherapy subgroup (HR=1.33, 95%CI: 0.87–2.05, P=0.188). The GRADE-profiler revealed that the rate of events of BLCa on average in the RT-patients and the non-RT control was 2,462/183,669 (1.3%) and 4,263/382,761(1.1%), respectively; the overall quality of the evidence was low. Conclusion: Patients who received RT for PCa was associated with higher risks of developing secondary BLCa compared to those unexposed to RT, but the absolute effect was low. [ABSTRACT FROM AUTHOR]

Patient‐reported outcome measures (PROMs) are important tools used to understand patient‐focused outcomes from care. Various PROMs have been developed for patients with bladder cancer (BC), although the disease's heterogeneity makes selection difficult. Accurate measurement of health‐related quality of life (HRQL) can only be achieved if the PROM chosen is 'fit for purpose' (i.e. psychometrically sound). Systematic reviews of psychometric properties are useful for selecting the best PROM for a specific purpose. The COnsensus‐based Standards for the selection of health Measurement INstruments (COSMIN) developed a checklist to improve the selection of health measurement instruments as part of a review process. Our aims were to undertake a systematic review, using the COSMIN criteria, to assess the quality of studies that report the psychometric properties of PROMs used with people with BC and determine the psychometric quality of these PROMs. An electronic search of seven databases including PubMed, MEDLINE and EMBASE (PROSPERO reference CRD42016051974) was undertaken to identify English language publications, published between January 1990 and September 2017 that evaluated psychometric properties of PROMs used in BC research. Two researchers independently screened abstracts and selected full‐text papers. Studies were rated on methodological quality using the COSMIN checklist. Overall, 4663 records were screened and 23 studies, reporting outcomes in 3568 patients, were evaluated using the COSMIN checklist. Most PROMs had limited information reported about their psychometric properties. Studies reporting on the Bladder Cancer Index (BCI) and Functional Assessment of Cancer Therapy Vanderbilt Cystectomy Index (FACT‐VCI) provided the most detail and these PROMs could be evaluated on the most COSMIN properties. Based on the available evidence, no existing PROM stands out as the most appropriate to measure HRQL in BC populations. This is due to two factors; (i) the heterogeneity of BC and its treatments (ii) no PROM was evaluated on all COSMIN measurement properties due to a lack of validation studies. We suggest future evaluation of generic, cancer generic and BC‐specific PROMs to better understand their application with BC populations and propose strategies to help clinicians and researchers. [ABSTRACT FROM AUTHOR]

Halobenzoquinones (HBQs) were reported as disinfection byproducts (DBPs) which had potential risk of bladder cancer. In this paper, a highly selective analytical method for HBQs was developed by HBQs-mediated assembly of amino acid modified Mn-doped ZnS/Quantum Dots (Mn: ZnS QDs). In the presence HBQs, a charge-transfer complex (CTC) was formed between aromatic rings of HBQs and the primary amino groups on the surface of the QDs. The formation of CTC led to the aggregation of QDs, as a result fluorescence decreasing occurred. The decrease was correlated with the concentration of HBQs. Then a fluorescence sensor array for discrimination of three kinds of HBQs including 2,6-Dichloro-1,4-benzoquinone (DCBQ), 2,6-Dibromo-1,4-benzoquinone (DBBQ) and 2,3,6-trichloro-1,4-benzoquinone (TCBQ) was developed. Four kinds of amino acids including cysteine, threonine, tyrosine and tryptophan were embellished on the Mn: ZnS QDs. The different extents of aggregation led to different fluorescence decreasing effect, thus distinct fluorescence patterns were created. It showed that three kinds of HBQs could be discriminated successfully by fluorescence sensor array at a range of concentrations through principal component analysis (PCA). The unknown samples were predicted by with a stepwise linear discriminant analysis (SLDA) using Mahalanobis distance as a selection criterion with accuracy of 100%. Remarkably, the practicability of the proposed sensor array was further validated by identification of three kinds of HBQs at different concentrations in real drinking water samples. Compared to LC/MS/MS, this fluorescent sensor array-based method was proved to be more convenient since the nanoparticles can be prepared flexibly according to the property of the target. [ABSTRACT FROM AUTHOR]

Purpose: Genome-wide association studies (GWAS) have led to the identification of a bladder cancer susceptibility variant (rs710521) in a non-coding intergenic region between the TP63 and LEPREL1 genes on chromosome 3q28, suggesting a role in the transcriptional regulation of these genes. In this study, we aimed to functionally characterize the 3q28 bladder cancer risk locus.Methods: Fine-mapping was performed by focusing on the region surrounding rs710521, and variants were prioritized for further experiments using ENCODE regulatory data. The enhancer activity of the identified region was evaluated using dual-luciferase assays. CRISPR/Cas9-mediated deletion of the enhancer region was performed and the effect of this deletion on cell proliferation and gene expression levels was evaluated using CellTiter-Glo and RT-qPCR, respectively.Results: Fine-mapping of the GWAS signal region led to the identification of twenty SNPs that showed a stronger association with bladder cancer risk than rs710521. Using publicly available data on regulatory elements and sequences, an enhancer region containing the bladder cancer risk variants was identified. Through reporter assays, we found that the presence of the enhancer region significantly increased ΔNTP63 promoter activity in bladder cancer-derived cell lines. CRISPR/Cas9-mediated deletion of the enhancer region reduced the viability of bladder cancer cells by decreasing the expression of ΔNTP63 and p63 target genes.Conclusions: Taken together, our data show that bladder cancer risk-associated variants on chromosome 3q28 are located in an active enhancer region. Further characterization of the allele-specific activity of the identified enhancer and its target genes may lead to the identification of novel signaling pathways involved in bladder carcinogenesis. [ABSTRACT FROM AUTHOR]

Urinary bladder cancer (UBC) is one of the most common malignancies worldwide. The etiology of UBC is multifactorial and includes both exogenous and endogenous factors. Exogenous risk factors include exposure to heavy metals, aromatic amines, and environmental pollutants including pesticides such as organochlorine pesticides (OCPs). Environmental factors alone are incapable of directly producing DNA damage and may require activation by phase I metabolizing enzymes like cytochrome P450 in order to become active carcinogen. The present study is designed to study CYP1A1 gene expression, OCP level in cases of UBC, as well as to explore the plausible role of gene--environment interaction in the etiology of UBC among North Indian population. A total of 60 cases with equal number of controls were enrolled under this study, the OCP levels were estimated using gas chromatography, CYP1A1 mRNA expression was quantified by real-time quantitative polymerase chain reaction, and fold change was calculated using the ΔΔCt method. In the present study, the levels of OCP were found to be significantly higher with the upregulation of CYP1A1 mRNA expression among UBC cases as compared to controls. While putting multiple linear regression, it has been observed that there is a significant interaction between the levels of OCPs and ΔCt value of CYP1A1 gene taken into account hematuria episodes as dependent variable. The study concludes that when there is predisposition of OCPs and upregulation of CYP1A1 gene, then the result will be an increment in hematuria episodes which indicates that gene--environment interaction plays a significant role in the causation of UBC among North Indian population. [ABSTRACT FROM AUTHOR]

Objective: It has been reported that the periodontal disease is linked to a number of malignant tumors such as lung cancer and pancreatic cancer. In this study, we aimed to investigate the association of periodontal disease with risk of bladder cancer by a meta-analysis. Methods: PubMed, Scopus, ScienceDirect, and Chinese National Knowledge Infrastructure (CNKI) were searched for eligible publications up to December 15, 2017. Cohort and nested case-control studies on the association between periodontal disease and risk of bladder cancer were included. After study selection and data extraction, pooled hazard ratios (HRs) and their 95% confidence intervals (95%CIs) were calculated using a fixed-effect inverse-variance model. All analyses were performed using the RevMan 5.3 software. Results: Finally, five cohort studies were identified and included in this meta-analysis, involving 1,104 bladder cancer cases of 298,476 participants. Summary estimates based on adjusted data showed that periodontal disease was not significantly associated with the risk of bladder cancer (HR = 1.09, 95% CI = 0.95–1.25, I2 = 0%). A similar result was also observed after cumulative, subgroup and sensitivity analyses. Conclusions: Current evidence from cohort studies suggests that patients with periodontal disease may not be at an increased risk of developing bladder cancer. [ABSTRACT FROM AUTHOR]

Objective: This meta-analysis of published case-control and cohort studies sought to quantify the magnitude and direction of association between chronic UTI (defined as the infection of the urinary tract that either does not respond to treatment or keeps recurring) and risk of bladder carcinoma (BCa) (i.e., including mainly urothelial carcinoma, squamous cell carcinoma or adenocarcinoma).Methods: A literature search was conducted using Medline, Embase, Ovid, Web of Science, Science Direct and Cochrane Library, which was supplemented with manual search of reference lists of the identified articles. Case-control and cohort studies examining UTI as a predictor of BCa risk published through June 2016 were eligible. Using random-effects models, odds ratios (OR) or relative risks (RR) from eligible studies were combined to synthesize summary effect estimates. The included studies were assessed for methodological quality and potential publication bias. Heterogeneity by study characteristics was examined by sub-group and meta-regression analyses.Results: Eighteen case-control and three cohort studies published between 1963 and 2016 were eligible. Random-effects models showed that UTI was significantly associated with an increased BCa risk both in case-control studies (summary ORRE = 2.33; 95% CI 1.86, 2.92) and cohort studies (summary RRRE = 2.88; 95% CI 1.20, 6.89). The observed relationship of UTI with an increased BCa risk was independent of the study characteristics considered. No significant publication bias was detected.Conclusions: Chronic UTI was significantly and independently associated with an increased BCa risk. However, due to the presence of high between-study heterogeneity and inconsistent patterns of adjusted confounding effects, more data are needed to clarify the role of chronic UTI in causation of BCa and if established, prompt and effective treatment of UTI may minimize a substantial proportion of BCa risk. [ABSTRACT FROM AUTHOR]

Objectives: Few studies discussed the link between benign prostatic hyperplasia (BPH) and bladder cancer. We performed this cohort study to investigate whether there is an association between BPH and subsequent risk of bladder cancer.Methods: We identified 35,092 study subjects including 17546 BPH patients and 17546 comparisons from the National Health Insurance database. The comparison cohort was frequency matched with age and index-year. We measured subsequent bladder cancer rates (per 1000 person-years) in two cohorts. Attributable risks (ARs) was calculated based on the bladder cancer rates in two cohorts. The hazard ratios (HRs) and 95% confidence intervals (CIs) for bladder cancer were estimated via Cox proportional hazard regression.Results: BPH patients had a higher bladder cancer rate than comparisons (AR = 0.81 per 1000 person-years) and exhibited 4.69- and 4.11-fold increases in bladder cancer risk in the crude and adjusted Cox models, respectively (95% CIs = 4.15-6.99 and 2.70-6.26). The AR was highest in patients aged 65-74 years old (AR = 1.33). BPH patients with chronic kidney disease were at an elevated bladder cancer risk. Regarding the association between bladder cancer and transurethral prostatectomy (TURP), BPH patients who underwent TURP were at a higher risk of bladder cancer (AR = 1.69; HR = 6.17, 95% CI = 3.68-10.3) than those who did not (AR = 0.69; HR = 3.73, 95% CI = 2.43-5.74).Conclusions: In this study, BPH patients were found to have an increased risk of subsequent bladder cancer. Based on the limitations of retrospective nature, further studies are needed. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the prognostic impact of size and number of tumors in primary low-grade (LG) Ta bladder urothelial carcinoma (UC), and thus allow accurate risk stratification of low-risk non-muscle invasive bladder cancer (NMIBC). This study was a retrospective analysis of 245 patients with primary LG Ta UC of the urinary bladder who were treated with transurethral resection. Differences in intravesical recurrence-free survival (RFS) according to various cutoff values of tumor size and tumor number were calculated using Cox proportional hazards model. Median maximum size of tumor was 1.4 cm, and 153 patients (62.4%) had solitary tumors. Forty-nine patients experienced intravesical recurrence during a median 34 months of follow-up. Patients with solitary tumors had significantly longer RFS times compared with those with =8 tumors (P=0.003). Patients with larger tumors had significantly shorter RFS times for each cutoff value (P=0.01 for 1.0 cm, P<0.0001 for 1.5 and 2.0 cm, P=0.006 for 3.0 cm). On multivariate analysis, each cutoff value of tumor size was found to be a predictor of RFS; among them, the cutoff of 1.5 cm showed the strongest association (hazard ratio, 4.12; 95% confidence interval, 2.11-8.81; P<0.001). If we consider only lower risk NMIBC patients, such as primary LG Ta, the appropriate cutoff value of tumor size to predict intravesical recurrence might be 1.5 cm, but not 3.0 cm generally adopted in various guidelines. These findings suggest the need for rational risk assessment with consideration of the diversity of patients with NMIBC. [ABSTRACT FROM AUTHOR]

Pioglitazone has been reported to increase the risk of bladder cancer but the conclusions of published clinical studies are confusing. We conducted a systematic review and meta-analysis of all eligible randomized controlled trial (RCT) studies and observational studies, in order to identify a more precise relationship between pioglitazone and risk of bladder cancer. We searched for publications up to January 24, 2018, in PubMed, EMBASE, Scopus, Web of Science, Cochrane register, and Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. Relative risk and 95% confidence interval (CI) were used to assess this correlation. A dose-related meta-analysis was performed as well. Data on RCT studies showed a null association between pioglitazone and bladder cancer. The pooled RR estimates of the 12 included studies illustrated that pioglitazone is associated with a 14% increased risk of bladder cancer (95% CI 1.03–1.26). No evidence of publication bias was detected. In the dose effect analysis, patients who used a higher dose of pioglitazone had an increased risk of bladder cancer. In conclusion, this meta-analysis indicated that pioglitazone is associated with an increased risk of bladder cancer. Further research should be conducted to confirm our findings and reveal the potential biological mechanisms. [ABSTRACT FROM AUTHOR]

N-acetyltransferase 1 (NAT1), a polymorphic Phase II enzyme, plays an essential role in metabolizing heterocyclic and aromatic amines, which are implicated in urinary bladder cancer (BCa). This systematic review investigates a possible association between the different NAT1 genetic polymorphisms and BCa risk. Medline, PubMed, EMBASE, Scopus, Web of Science, OpenGrey, and BASE databases were searched to identify eligible studies. The random-effect model was used to calculate pooled effects estimates. Statistical heterogeneity was tested with Chi-square and I2. Twenty case-control studies, including 5606 cases and 6620 controls, met the inclusion criteria. Pooled odds ratios (OR) analyses showed a statistically significant difference in NAT1*10 versus non-NAT1*10 acetylators in the total sample (OR: 0.87; 95% CI: 0.79-0.96) but was borderline among Caucasians (OR: 0.88 with 95% CI: 0.77-1.01). No statistically significant differences in BCa risk were found for: NAT1*10 versus NAT1*4 wild type (OR: 0.97; 95% CI: 0.78-1.19), NAT1 ‘Fast’ versus ‘Normal’ acetylators (OR: 1.03; 95% CI: 0.84-1.27), and NAT1 ‘Slow’ versus ‘Fast’ (OR: 2.32; 95% CI: 0.93-5.84) or ‘Slow’ versus ‘Normal’ acetylators (OR: 1.84; 95% CI: 0.92-3.68). When stratifying by smoking status, no statistically significant differences in BCa risk were found for NAT1*10 versus non-NAT1*10 acetylators among the different subgroups. Our study suggests a modest protective role for NAT1*10 and a possible risk contributory role for slow acetylation genotypes in BCa risk. Further research is recommended to confirm these associations. [ABSTRACT FROM AUTHOR]

Abstract: Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta‐analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose–response relationship with a generalized least‐squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever‐users of pioglitazone versus never‐users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time‐ (P = 0.003) and dose‐dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose‐ and time‐dependent manner. Patients with long‐term and high‐dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer. [ABSTRACT FROM AUTHOR]

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Halobenzoquinones (HBQs) are a class of emerging disinfection byproducts. Chronic exposure to chlorinated drinking water is potentially associated with an increased risk of human bladder cancer. HBQ-induced cytotoxicity involves depletion of cellular glutathione (GSH), but the underlying mechanism remains unclear. Here we used ultrahigh performance liquid chromatography–high resolution mass spectrometry and electron paramagnetic resonance spectroscopy to study interactions between HBQs and GSH and found that HBQs can directly react with GSH, forming various glutathionyl conjugates (HBQ-SG) in both aqueous solution and HepG2 cells. We found that the formation of HBQ-SG varies with the initial molar ratio of GSH to HBQ in reaction mixtures. Higher molar ratios of GSH to HBQ facilitate the conjugation of more GSH molecules to an HBQ molecule. We deduced the reaction mechanism between GSH and HBQs, which involves redox cycling-induced formation of halosemiquinone (HSQ) free radicals and glutathione disulfide, Michael addition, as well as nucleophilic substitution. The proposed reaction rates are in the following order: formation of HSQ radicals > substitution of bromine by GSH > Michael addition of GSH on the benzoquinone ring > substitution of chlorine by GSH > substitution of the methyl group by GSH. The conjugates identified in HBQ-treated HepG2 cells were the same as those found in aqueous solution containing a 5:1 ratio of GSH:HBQs. [ABSTRACT FROM AUTHOR]

Background Exposure to trihalomethanes (THMs) in drinking water has consistently been associated with an increased risk of bladder cancer, but evidence on other cancers including the breast is very limited. Objectives We assessed long-term exposure to THMs to evaluate the association with female breast cancer (BC) risk. Methods A multi case-control study was conducted in Spain from 2008 to 2013. We included 1003 incident BC cases (women 20–85 years old) recruited from 14 hospitals and 1458 population controls. Subjects were interviewed to ascertain residential histories and major recognized risk factors for BC. Mean residential levels of chloroform, brominated THMs (Br-THMs) and the sum of both as total THM (TTHMs) during the adult-lifetime were calculated. Results Mean adult-lifetime residential levels ranged from 0.8 to 145.7 μg/L for TTHM (median = 30.8), from 0.2 to 62.4 μg/L for chloroform (median = 19.7) and from 0.3 to 126.0 μg/L for Br-THMs (median = 9.7). Adult-lifetime residential chloroform was associated with BC (adjusted OR = 1.47; 95%CI = 1.05, 2.06 for the highest (> 24 μg/L) vs. lowest (< 8 μg/L) quartile; p-trend = 0.024). No association was detected for residential Br-THMs (OR = 0.91; 95%CI = 0.68, 1.23 for > 31 μg/L vs. < 6 μg/L) or TTHMs (OR = 1.14; 95%CI = 0.83, 1.57 for > 48 μg/L vs. < 22 μg/L). Conclusions At common levels in Europe, long-term residential total THMs were not related to female breast cancer. A moderate association with chloroform was suggested at the highest exposure category. This large epidemiological study with extensive exposure assessment overcomes several limitations of previous studies but further studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

While drinking water disinfection has effectively prevented waterborne diseases, an unintended consequence is the generation of disinfection byproducts (DBPs). Epidemiological studies have consistently observed an association between consumption of chlorinated drinking water with an increased risk of bladder cancer. Out of the >600 DBPs identified, regulations focus on a few classes, such as trihalomethanes (THMs), whose concentrations were hypothesized to correlate with the DBPs driving the toxicity of disinfected waters. However, the DBPs responsible for the bladder cancer association remain unclear. Utilities are switching away from a reliance on chlorination of pristine drinking water supplies to the application of new disinfectant combinations to waters impaired by wastewater effluents and algal blooms. In light of these changes in disinfection practice, this article discusses new approaches being taken by analytical chemists, engineers, toxicologists and epidemiologists to characterize the DBP classes driving disinfected water toxicity, and suggests that DBP exposure should be measured using other DBP classes in addition to THMs. [ABSTRACT FROM AUTHOR]

Background and Objectives: Renal transplant recipients (RTRs) have a 2- to 7-fold risk of developing a neoplasm compared to general population. Bladder urothelial neoplasms in this cohort has an incidence of 0.4–2%. Many reports describe a more aggressive behavior. The objective of this study is to describe oncologic characteristics of bladder urothelial neoplasms in RTRs and to evaluate its recurrence, progression, and survival rates. Methods: A retrospective multicentered study was performed evaluating all de novo bladder urothelial neoplasms cases in RTRs from 1988 to 2014. Descriptive statistical analysis and evaluation of recurrence, progression, and survival rates were performed. Results: A total of 28 de novo bladder transitional cell carcinomas (TCCs) were identified (incidence rate 0.64%). Cancer-specific survival rates were 100, 75, and 70% after 1, 5, and 10 years, respectively. Age at diagnosis superior to 60 years was found to be a statistically significant variable for recurrence risk. Progression rate was 14%. Presence of CIS was significantly associated with progression. All cancer-specific deaths were in the high-risk group and all were progressions from non-muscle invasive to muscle invasive bladder cancer. Conclusions: Bladder urothelial neoplasms following renal transplant is associated with a trend toward worst prognosis. Early aggressive treatments, such as early radical cystectomy, might be advisable to reduce cancer-specific deaths. [ABSTRACT FROM AUTHOR]

Arsenic in drinking water impacts health. Highest levels of arsenic have been historically observed in Taiwan and Bangladesh but the contaminant has been affecting the health of people globally. Strong associations have been confirmed between exposure to high-levels of arsenic in drinking water and a wide range of diseases, including cancer. However, at lower levels of exposure, especially near the current World Health Organization regulatory limit (10 μg/L), this association is inconsistent as the effects are mostly extrapolated from high exposure studies. This ecological study used Bayesian inference to model the relative risk of bladder and kidney cancer at these lower concentrations—0–2 μg/L; 2–5 μg/L and; ≥ 5 μg/L of arsenic—in 864 bladder and 525 kidney cancers diagnosed in the study area, Nova Scotia, Canada between 1998 and 2010. The model included proxy measures of lifestyle (e.g. smoking) and accounted for spatial dependencies. Overall, bladder cancer risk was 16% (2–5 μg/L) and 18% (≥ 5 μg/L) greater than that of the referent group (< 2 μg/L), with posterior probabilities of 88% and 93% for these risks being above 1. Effect sizes for kidney cancer were 5% (2–5 μg/L) and 14% (≥ 5 μg/L) above that of the referent group (< 2 μg/L), with probabilities of 61% and 84%. High-risk areas were common in southwestern areas, where higher arsenic-levels are associated with the local geology. The study suggests an increased bladder cancer, and potentially kidney cancer, risk from exposure to drinking water arsenic-levels within the current the World Health Organization maximum acceptable concentration. [ABSTRACT FROM AUTHOR]

Background Swimming in a chlorinated pool results in high exposure levels to disinfection by-products (DBPs), which have been associated with an increased risk of bladder cancer. Objectives By studying molecular responses at the blood transcriptome level we examined the biological processes associated with exposure to these compounds. Methods Whole-genome gene expression and microRNA analysis was performed on blood samples collected from 43 volunteers before and 2 h after 40 min swimming in an indoor chlorinated pool (PISCINAII study). Exposure to THMs was measured in exhaled breath. Heart rate and kcal expenditure were measured as proxies for physical activity. Associations between exposure levels and gene expression were assessed using multivariate normal models (MVN), correcting for age, body mass index and sex. A Bonferroni threshold at 5% was applied. Results MVN-models for the individual exposures identified 1778 genes and 23 microRNAs that were significantly associated with exposure to at least one DBP. Due to co-linearity it was not possible to statistically disentangle responses to DBP exposure from those related to physical activity. However, after eliminating previously reported transcripts associated with physical activity a large number of hits remained associated with DBP exposure. Among those, 9 were linked with bladder and 31 with colon cancer. Concordant microRNA/mRNA expressions were identified in association with DBP exposure for hsa-mir-22-3p and hsa-miR-146a-5p and their targets RCOR1 and TLR4, both related to colon cancer in association with DBP exposure. Conclusions Short-term exposure to low levels of DBPs shows genomics responses that may be indicative of increased cancer risk. [ABSTRACT FROM AUTHOR]

Aim: We performed a meta-analysis of epidemiological studies evaluating exposure to pioglitazone and the risk for bladder cancer and compared these results to the drug's effects on cardiovascular disease (CVD) and non-alcoholic steatohepatitis (NASH).Methods: Pubmed and Embase were searched for cohort and case control studies for all years through 2016.Results: Data from 17 papers were analyzed. In cohort studies, 822 of 357,888 pioglitazone-exposed patients (0.23%) developed bladder cancer while 7691 of 2,898,682 unexposed (0.26%) did. In case control studies, 3219 of 1,146,916 patients (0.28%) developed bladder cancer. A random effects model showed no significant association between ever vs never use or with cumulative doses of pioglitazone. However, there was a significant association with 1-2 years (HR = 1.28 [1.08-1.55]) and >2 years (HR = 1.42 [1.14-1.77]) of exposure. The numbers needed to treat for one additional case of bladder cancer ranged from 899 to 6380 while to benefit CVD and NASH, 4-256 and 2-12, respectively.Conclusions: Given the very small prevalence of bladder cancer in diabetic patients exposed (or not) to pioglitazone (<0.3%) and the much greater beneficial effects of the drug on CVD and NASH, the use of pioglitazone should be resurrected. [ABSTRACT FROM AUTHOR]

Background/Aims: Emerging studies on brain-derived neurotrophic factor (BDNF) have shown that might be novel biomarkers and therapeutic targets for cancer. We explore the role of BDNF in the tumorigenesis of bladder cancer and the underlying molecular mechanism. Methods: 368 patients with diagnosed bladder cancer and 352 healthy controls were enrolled to evaluate the association of BDNF and the miR-146b. Bioinformatics algorithm analysis and luciferase assay were performed to identify the target genes of miR-146b. Real-time PCR and western-blot were carried out to validate the relationship between miR-146b and CRK. MTT assay and FACS were used to evaluated the proliferation and apoptosis of cancer cells. MVs were isolated and transfect into the culture cells to confirm the above observation. Results: The clinical study shows that BDNF Met/Met was significantly associated with the risk of bladder cancer. In addition, comparing with Val/Val and Val/Met, Met/Met has lower miR-146b level. Luciferase assay shows that BDNF Val/Val is apparently enhanced miR-146b promoter-luciferase, but not BDNF Met/Met. Based on luciferase assay, CRK is a direct target gene of miR-146b. MiR-146b mimics significantly inhibited the expression of CRK and activation of AKT level. The expression of CRK and the activation of AKT (p-AKT) were significantly inhibited by MV-BDNF Val/Val-miR-146b or MV-BDNF Val/Met-miR-146b, but not MV-BDNF Met/Met-miR-146b. MV-BDNF Val/Val-miR-146b or Val/Met-miR-146b obviously inhibited cell proliferation, which eliminated by CRK. Meanwhile, with MV-BDNF Met/Met-miR-146b or Met/Met-miR-146b+CRK did not affect the proliferation. MV-BDNF Val/Val-miR-146b or Val/Met-miR-146b enhanced cell apoptosis, which could be eliminated by CRK. Meanwhile, MV-BDNF Met/Met-miR-146b or Met/Met-miR-146b+CRK did not promote apoptosis. Conclusion: BDNF VAL66MET polymorphism is associated with miR-146b and its target gene CRK. MiR-146b and CRK mediated BDNF VAL66MET polymorphism associated proliferation and apoptosis via activation of AKT. Thus, BDNF Val66Met is associated with the risk of bladder cancer, and the BDNF variant could be used a biomarker for the diagnosis of bladder cancer. [ABSTRACT FROM AUTHOR]

The prognostic value of repeat transurethral resection of bladder tumor (TURBT) in patients with diagnosed high-risk, non-muscle-invasive bladder cancer (NMIBC) was investigated. We retrospectively reviewed the medical records of patients treated from October 2004 to December 2013 at Seoul National University who underwent repeated TURBT within 2–6 weeks after an initial resection. The study enrolled patients who had been diagnosed with NMIBC at both the initial and repeat TURBT; patients with muscle-invasive tumors on repeat TURBT were excluded. We used stepwise multivariate Cox regression models stratified by study to assess the independent effects of the predictive factors and estimated hazard ratios (HRs) from the Cox models. We investigated a total of 198 patients who were diagnosed with high-risk NMIBC. In logistic regression analyses, number of bladder tumors (2–7: OR, 2.319; 8≤: OR, 3.353; p<0.05), initially high tumor grade (OR, 2.435; p = 0.040), and presence of carcinoma in situ lesion (OR, 3.639; p = 0.017) correlated with residual tumor in the repeated-TURBT specimen. T1 stage in repeated-TURBT significantly correlated with recurrence (HR, 1.837; p = 0.010) and progression (HR, 2.806; p = 0.029) in multivariate analysis. The high grades of tumors in repeated-TURBT also significantly correlated with progression but not recurrence in the multivariate analysis (HR 2.152; p = 0.008). In this study, the pathologic findings in repeated-TURBT correlated with recurrence and progression in high-risk NMIBC. Repeated-TURBT is valuable because it can predict the recurrence and progression of high-risk NMIBC in addition to obtaining accurate pathologic findings. [ABSTRACT FROM AUTHOR]

Objective: To develop and validate a nomogram assessing cancer and all-cause mortality following radical cystectomy. Given concerns regarding the morbidity associated with surgery, there is a need for incorporation of cancer-specific and competing risks into patient counseling and recommendations.Materials and Methods: A total of 5325 and 1257 diagnosed with clinical stage T2-T4a muscle-invasive bladder cancer from January 1, 2006 to December 31, 2011 from Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare linked data, respectively. Cox proportional hazards models were used and a nomogram was developed to predict 3- and 5-year overall and cancer-specific survival with external validation.Results: Patients who underwent radical cystectomy were mostly younger, male, married, non-Hispanic white and had fewer comorbidities than those who did not undergo radical cystectomy (P < .001). Married patients, in comparison with their unmarried counterparts, had both improved overall (hazard ratio 0.76; 95% confidence interval 0.70-0.83, P < .001) and cancer-specific (hazard ratio 0.76; 95% confidence interval 0.68-0.85, P < .001) survival. A nomogram developed using Surveillance, Epidemiology, and End Results-Medicare data, predicted 3- and 5-year overall and cancer-specific survival rates with concordance indices of 0.65 and 0.66 in the validated Texas Cancer Registry-Medicare cohort, respectively.Conclusion: Older, unmarried patients with increased comorbidities are less likely to undergo radical cystectomy. We developed and validated a generalizable instrument that has been converted into an online tool (Radical Cystectomy Survival Calculator), to provide a benefit-risk assessment for patients considering radical cystectomy. [ABSTRACT FROM AUTHOR]

Only a few nutritional factors have been identified to predict the risk of developing complications after radical cystectomy (RC). This narrative review delineates the current known effects of preoperative nutritional status factors in this context. The report highlights the heterogeneity between study methods and results. We determined that low albuminemia values increase mortality risk and overall complications. In addition, obesity tends to increase the risk of developing venous thromboembolism and adverse events. Additional prospective studies, using standardized methods to both define and report complications, should be conducted to strengthen the connections between preoperative nutritional status factors and post-RC complications. Furthermore, intervention studies testing the impact of strategies to improve nutritional status on the risk of complications after RC are also needed. [ABSTRACT FROM AUTHOR]

Introduction: Partial cystectomy (PC) for urothelial carcinoma (UC) in selected patients may avoid the morbidity of radical cystectomy (RC). We describe use and outcomes of PC for UC in routine clinical practice. Methods: All patients with urothelial carcinoma of the bladder (UCB) undergoing PC or RC in Ontario from 1994-2008 were identified using the Ontario Cancer Registry and linked electronic records. Pathology reports were reviewed. Variables associated with PC use were identified using logistic regression. Cox proportional hazards model identified factors affecting cancer-specific (CSS) and overall survival (OS). Results: A total of 3320 patients underwent PC (n=181; 5%) or RC (n=3139; 95%) from 1994-2008. PC patients were older (36% 80+ years vs. 19%; p<0.001) and more likely to have organ-confined (

Background: Novel theranostic options for high-risk non-muscle invasive bladder cancer are urgently needed. This requires a thorough evaluation of experimental approaches in animal models best possibly reflecting human disease before entering clinical studies. Although several bladder cancer xenograft models were used in the literature, the establishment of an orthotopic bladder cancer model in mice remains challenging.Methods: Luciferase-transduced UM-UC-3LUCK1 bladder cancer cells were instilled transurethrally via 24G permanent venous catheters into athymic NMRI and BALB/c nude mice as well as into SCID-beige mice. Besides the mouse strain, the pretreatment of the bladder wall (trypsin or poly-L-lysine), tumor cell count (0.5 × 106-5.0 × 106) and tumor cell dwell time in the murine bladder (30 min - 2 h) were varied. Tumors were morphologically and functionally visualized using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography (PET).Results: Immunodeficiency of the mouse strains was the most important factor influencing cancer cell engraftment, whereas modifying cell count and instillation time allowed fine-tuning of the BLI signal start and duration - both representing the possible treatment period for the evaluation of new therapeutics. Best orthotopic tumor growth was achieved by transurethral instillation of 1.0 × 106 UM-UC-3LUCK1 bladder cancer cells into SCID-beige mice for 2 h after bladder pretreatment with poly-L-lysine. A pilot PET experiment using 68Ga-cetuximab as transurethrally administered radiotracer revealed functional expression of epidermal growth factor receptor as representative molecular characteristic of engrafted cancer cells in the bladder.Conclusions: With the optimized protocol in SCID-beige mice an applicable and reliable model of high-risk non-muscle invasive bladder cancer for the development of novel theranostic approaches was established. [ABSTRACT FROM AUTHOR]

Purpose We sought to determine whether race, gender and number of bladder cancer risk factors are significant predictors of hematuria evaluation. Materials and Methods We used self-reported data from SCCS (Southern Community Cohort Study) linked to Medicare claims data. Evaluation of subjects diagnosed with incident hematuria was considered complete if imaging and cystoscopy were performed within 180 days of diagnosis. Exposures of interest were race, gender and risk factors for bladder cancer. Results Of the 1,412 patients evaluation was complete in 261 (18%). On our adjusted analyses African American patients were less likely than Caucasian patients to undergo any aspect of evaluation, including urology referral (OR 0.72, 95% CI 0.56–0.93), cystoscopy (OR 0.67, 95% CI 0.50–0.89) and imaging (OR 0.75, 95% CI 0.59–0.95). Women were less likely than men to be referred to a urologist (OR 0.59, 95% CI 0.46–0.76). Also, although all patients with 2 or 3 risk factors had 31% higher odds of urology referral (OR 1.31, 95% CI 1.02–1.69), adjusted analyses indicated that this effect was only apparent among men. Conclusions Only 18% of patients with an incident hematuria diagnosis underwent complete hematuria evaluation. Gender had a substantial effect on referral to urology when controlling for socioeconomic factors but otherwise it had an unclear role on the quality of evaluation. African American patients had markedly lower rates of thorough evaluation than Caucasian patients. Number of risk factors predicted referral to urology among men but it was otherwise a poor predictor of evaluation. There is opportunity for improvement by increasing the completion of hematuria evaluations, particularly in patients at high risk and those who are vulnerable. [ABSTRACT FROM AUTHOR]

Bladder cancer is the sixth most prevalent malignancy in the United States and causes more than 16,000 deaths annually. The most common clinical presentation is asymptomatic hematuria, which should prompt evaluation with cystoscopy, renal function testing, and upper urinary tract imaging in adults 35 years and older and in those with irritative voiding symptoms, risk factors for bladder cancer, or gross hematuria at any age. Transurethral resection of the bladder tumor allows for definitive diagnosis, staging, and primary treatment. Non-muscle-invasive disease is treated with transurethral resection, most often followed by intravesical bacille Calmette-Guérin or intravesical chemotherapy. Bladder cancer that invades the muscle layer is typically treated with radical cystectomy and neoadjuvant chemotherapy because of higher rates of progression and recurrence. No major organization recommends screening asymptomatic adults for bladder cancer, and the U.S. Preventive Services Task Force concluded that current evidence is insufficient to assess the balance of benefits and harms of screening. [ABSTRACT FROM AUTHOR]

Importance: Antithrombotic medications are among the most commonly prescribed medications.Objective: To characterize rates of hematuria-related complications among patients taking antithrombotic medications.Design, Setting, and Participants: Population-based, retrospective cohort study including all citizens in Ontario, Canada, aged 66 years and older between 2002 and 2014. The final follow-up date was December 31, 2014.Exposures: Receipt of an oral anticoagulant or antiplatelet medication.Main Outcomes and Measures: Hematuria-related complications, defined as emergency department visit, hospitalization, or a urologic procedure to investigate or manage gross hematuria.Results: Among 2 518 064 patients, 808 897 (mean [SD] age, 72.1 [6.8] years; 428 531 [53%] women) received at least 1 prescription for an antithrombotic agent over the study period. Over a median follow-up of 7.3 years, the rates of hematuria-related complications were 123.95 events per 1000 person-years among patients actively exposed to antithrombotic agents vs 80.17 events per 1000 person-years among patients not exposed to these drugs (difference, 43.8; 95% CI, 43.0-44.6; P < .001, and incidence rate ratio [IRR], 1.44; 95% CI, 1.42-1.46). The rates of complications among exposed vs unexposed patients (80.17 events/1000 person-years) were 105.78 for urologic procedures (difference, 33.5; 95% CI, 32.8-34.3; P < .001, and IRR, 1.37; 95% CI, 1.36-1.39), 11.12 for hospitalizations (difference, 5.7; 95% CI, 5.5-5.9; P < .001, and IRR, 2.03; 95% CI, 2.00-2.06), and 7.05 for emergency department visits (difference, 4.5; 95% CI, 4.3-4.7; P < .001, and IRR, 2.80; 95% CI, 2.74-2.86). Compared with patients who were unexposed to thrombotic agents, the rates of hematuria-related complications were 191.61 events per 1000 person-years (difference, 117.3; 95% CI, 112.8-121.8) for those exposed to both an anticoagulant and antiplatelet agent (IRR, 10.48; 95% CI, 8.16-13.45), 140.92 (difference, 57.7; 95% CI, 56.9-58.4) for those exposed to anticoagulants (IRR, 1.55; 95% CI, 1.52-1.59), and 110.72 (difference, 26.5; 95% CI, 25.9-27.0) for those exposed to antiplatelet agents (IRR, 1.31; 95% CI, 1.29-1.33). Patients exposed to antithrombotic agents, compared with patients not exposed to these drugs, were more likely to be diagnosed as having bladder cancer within 6 months (0.70% vs 0.38%; odds ratio, 1.85; 95% CI, 1.79-1.92).Conclusions and Relevance: Among older adults in Ontario, Canada, use of antithrombotic medications, compared with nonuse of these medications, was significantly associated with higher rates of hematuria-related complications (including emergency department visits, hospitalizations, and urologic procedures to manage gross hematuria). [ABSTRACT FROM AUTHOR]

Accumulating evidences indicate that long noncoding RNAs (lncRNAs) might play important roles in tumorigenesis and metastasis. EMT (epithelial-to-mesenchymal transition) is considered as a critical step in invasion and metastasis of various tumors including bladder cancer (BC). Recent researches have showed that lncRNA H19 is implicated in metastasis through regulating EMT and the reverse MET (mesenchymal-to-epithelial transition). However, underlying mechanisms remain largely unknown. Here, we screened lncRNA and mRNA expression profiles of BC with microarray assay. We found that H19 and DNMT3B displayed a higher co-expression in BC tissues and cells. Functionally, we demonstrated that H19 could increase proliferation, invasion and migration, regulate EMT as well as rearrange cytoskeleton of BC cells in vitro . Moreover, ectopic expression of H19 promoted tumorigenesis, angiogenesis and pulmonary metastasis in vivo , whereas knockdown of H19 has a contrary role in vivo and in vitro . Mechanistically, we proved that H19 could directly bind to miR-29b-3p (miR-29b) and derepress the expression of target DNMT3B. H19 and miR-29b-3p showed a co-localization. More importantly, up-regulating H19 antagonized miR-29b-3p-mediated proliferation, migration and EMT suppression in BC cells. Furthermore, H19 knockdown partially reversed the function of miR-29b-3p inhibitor on DNMT3B and facilitated miR-29b-3p-induced MET. Taken together, we demonstrated for the first time that H19 might function as ceRNA (competing endogenous RNA) for miR-29b-3p and relieve the suppression for DNMT3B, which led to EMT and metastasis of BC. Our findings highlight a novel mechanism of H19 in progression of BC and provide H19/miR-29b-3p/DNMT3B axis as a promising therapeutic target for BC. [ABSTRACT FROM AUTHOR]

To improve the clinical decision-making regarding further treatment management and follow-up scheduling for patients with muscle-invasive bladder cancer ( MIBC) after radical cystectomy ( RC), a better prediction accuracy of prognosis for these patients is urgently needed. The objective of this study was to evaluate the validity of differentially expressed micro RNAs (mi RNAs) based on a previous study as prognostic markers for overall survival ( OS) after RC in models combined with clinicopathological data. The expression of six mi RNAs (miR-100-5p, miR-130b-3p, miR-141-3p, miR-199a-3p, miR-205-5p, and miR-214-3p) was measured by RT- qPCR in formalin-fixed, paraffin-embedded tissue samples from 156 MIBC patients who received RC in three urological centers. Samples from 2000 to 2013 were used according to their tissue availability, with follow-up until June 2016. The patient cohort was randomly divided into a training ( n = 100) and test set ( n = 56). Seventy-three samples from adjacent normal tissue were used as controls. Kaplan-Meier, univariate and multivariate Cox regression, and decision curve analyses were carried out to assess the association of clinicopathological variables and mi RNAs to OS. Both increased (miR-130b-3p and miR-141-3p) and reduced (miR-100-5p, miR-199a-3p, and miR-214-3p) mi RNA expressions were found in MIBC samples in comparison to nonmalignant tissue samples ( P < 0.0001). miR-199a-3p and miR-214-3p were independent markers of OS in Cox regression models with the significant clinicopathological variables age, tumor status, and lymph node status. The prediction model with the clinicopathological variables was improved by these two mi RNAs in both sets. The predictive benefit was confirmed by decision curve analysis. In conclusion, the inclusion of both mi RNAs into models based on clinical data for the outcome prediction of MIBC patients after RC could be a valuable approach to improve prognostic accuracy. [ABSTRACT FROM AUTHOR]

Purpose PD-L1 is expressed on tumor cells and tumor immune cell infiltrates. In metastatic bladder cancer increased tumor immune cell infiltrate PD-L1 positivity correlated with better overall survival. However, to our knowledge in high grade T1 bladder tumors positivity on tumor cells and tumor immune cell infiltrates, and correlation with outcomes or pathological features remain unknown. Materials and Methods Formalin fixed, paraffin embedded tumor samples from 140 patients with clinically annotated, high grade T1 bladder tumors were retrieved. All patients were initially diagnosed with high grade T1 bladder tumors by transurethral resection, subsequently received bacillus Calmette-Guérin and had a median followup of 7.4 years. PD-L1 positivity on initial transurethral resection was evaluated by immunohistochemistry using a mouse monoclonal antiPD-L1 antibody (405.9A11). Tumor cell PD-L1 positivity was defined as staining of 5% of the tumor cell membrane. Tumor immune cell infiltrate PD-L1 positivity was scored based on the extent of infiltrate and the percent of positive cells. The Fisher exact test was used to assess associations of PD-L1 positivity with disease outcomes, carcinoma in situ presence and the difference between high grade T1 bladder tumors and muscle invasive bladder cancer. Results Among 140 patients with high grade T1 bladder tumors tumor cells and tumor immune cell infiltrate PD-L1 positivity was seen in 6 (4%) and 48 (34.3%), respectively. In a subset of 106 patients with adequate followup PD-L1 positivity did not correlate with disease outcomes on tumor cells (p = 0.3) or on tumor immune cell infiltrates (p = 0.47). PD-L1 positivity also did not correlate with the presence of carcinoma in situ. Tumor cell PD-L1 positivity was significantly less in high grade T1 bladder tumors than in muscle invasive bladder cancer (p <0.001). Conclusions PD-L1 is widely expressed on tumor immune cell infiltrates but not on tumor cells in high grade T1 bladder tumors. We did not find a correlation between PD-L1 positivity and outcomes or carcinoma in situ presence. Tumor cell PD-L1 positivity is significantly lower in high grade T1 bladder tumors than in muscle invasive bladder cancer. [ABSTRACT FROM AUTHOR]

Objective The long noncoding RNA PCAT1 is an important gene involved in urinary tumors. In this study, we aimed to explore the association between polymorphisms in PCAT1 and bladder cancer susceptibility. Methods A two-stage case-control study was conducted to assess the association between four tagging SNPs (i.e., rs4871771, rs1902432, rs16901904 and rs710886) and bladder cancer risk. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated with unconditional univariate and multivariate logistic regression. Results At the first stage of discovery, we identified that SNP rs710886A > G was significantly associated with bladder cancer risk (OR = 0.86, 95% CI = 0.74–0.99, P = 0.046). At the following stage of validation, individuals with GG genotype were found to have a significant reduction in bladder cancer risk compared with those carrying AA genotype (adjusted OR = 0.83, 95% CI = 0.74–0.93, P = 0.001). Furthermore, stratified analyses showed that protective effect of rs710886 was more pronounced in subgroup of age > 60 and never smoking, and had little to do with sex. Besides, rs710886 was identified as an eQTL for PCAT1 . G allele was consistent with lower PCAT1 expression. Conclusion This study indicates that genetic variants in lncRNA PCAT1 were associated with bladder cancer susceptibility and the SNP rs710886 may act as a potential biomarker for bladder cancer risk. [ABSTRACT FROM AUTHOR]

The current study aims to investigate whether MDM2-SNP309 and p53R72P polymorphisms were associated with the risk of bladder cancer in Mongolian populations. These polymorphisms were evaluated in 79 controls and 63 bladder cancer cases using a PCR-restriction fragment length polymorphism assay, followed by analysis using multivariate logistic regression model and the Kaplan-Meier model to determine the odds ratio (OR) and age at onset of bladder cancer, respectively. The results revealed that the homozygous (G/G) genotype of MDM2-SNP309 increased the risk of bladder cancer compared to the wild-type (T/T) genotype [OR=1.629; 95% confidence interval (CI)=0.622-4.266] among Mongolians. On the other hand, the homozygous (P/P) genotype of p53R72P tended to protect the population from bladder cancer compared with the wild-type (R/R) genotype (OR=0.445; 95% CI=0.1727-2.147). It also showed that G/G genotype of MDM2-SNP309 increased the risk of bladder cancer when combined with the R/R genotype of p53R72P (OR=3.355; 95% CI=0.3914-28.766). Stratification by smoking and history of chronic urinary tract diseases tended towards increasing the risk association of the G/G (OR=2.3704; 95% CI=0.4308-3.044) and T/G genotypes (OR=5; 95% CI=0.8442-30.4088) of MDM2-SNP309 with bladder cancer, respectively. The protective role of P/P of p53R72P remained following stratification. MDM2-SNP309 and p53R72P were not involved in early age onset of bladder cancer in Mongolian patients. Taken together, MDM2-SNP309 and p53R72P had no significant association with bladder cancer in Mongolian patients. The two SNPs were also not able to predict early age at onset of bladder cancer. [ABSTRACT FROM AUTHOR]

Epidemiological studies have indicated that ingestion of inorganic arsenic resulted in increased risks of bladder cancer and chronic hyperproliferation could play a direct role in the development of cancer. This study examined the effects of arsenite on JAK2/STAT3 pathway and expressions of proliferation and anti-apoptosis factors. The results showed that long term exposure to low doses arsenite enhanced human uroepithelial cells (SV-HUC-1 cells) proliferation and BrdU positive rate was significant increased. mRNA and protein expressions of proliferation factors, such as cyclin D1, COX-2, and proliferating cell nuclear antigen (PCNA), increased in chronically exposed arsenite SV-HUC-1 cells with exposure time. Furthermore, JAK2/STAT3 signal pathway was activated following exposure to arsenite in SV-HUC-1 cells. Knockdown of STAT3 reduced expressions of cyclin D1, COX-2, PCNA, and BCL2 induced by arsenite. In conclusion, arsenic induced proliferation in human uroepithelial cells after short and long term exposure to arsenite and JAK2/STAT3 signaling pathway might be pivotal in arsenite-induced proliferation by regulating cyclin D1, COX-2, PCNA, and BCL2. [ABSTRACT FROM AUTHOR]

In the 1980s, a case–control epidemiologic study was conducted in Iowa (USA) to analyze the association between exposure to disinfection by-products (DBPs) and bladder cancer risk. Trihalomethanes (THMs), the most commonly measured and dominant class of DBPs in drinking water, served as a primary metric and surrogate for the full DBP mixture. Average THM exposure was calculated, based on rough estimates of past levels in Iowa. To reduce misclassification, a follow-up study was undertaken to improve estimates of past THM levels and to re-evaluate their association with cancer risk. In addition, the risk associated with haloacetic acids, another class of DBPs, was examined. In the original analysis, surface water treatment plants were assigned one of two possible THM levels depending on the point of chlorination. The re-assessment considered each utility treating surface or groundwater on a case-by-case basis. Multiple treatment/disinfection scenarios and water quality parameters were considered with actual DBP measurements to develop estimates of past levels. The highest annual average THM level in the re-analysis was 156 μg/L compared to 74 μg/L for the original analysis. This allowed the analysis of subjects exposed at higher levels (> 96 μg/L). The re-analysis established a new approach, based on case studies and an understanding of the water quality and operational parameters that impact DBP formation, for determining historical exposure. [ABSTRACT FROM AUTHOR]

People with type 2 diabetes are at increased risk of bladder cancer. Pioglitazone is said to increase it further, although published evidence is mixed. We conducted a meta-analysis to determine if any link between the use of pioglitazone and an increased risk of bladder cancer can be found. A comprehensive literature search was conducted through electronic databases as well as registries for data of clinical trials to identify studies that investigate the effect of pioglitazone on bladder cancer in diabetic patients. We used the risk ratio (RR) and the hazard ratio (HR) provided by the studies to illustrate the risk of occurrence of bladder cancer in the experimental group compared to that in the control group. Fourteen studies using RR and 12 studies using HR were included in the analysis. The overall RR was 1.13 with 95% CI (0.96-1.33) with low heterogeneity among the studies using RR, suggesting that no connection exists between use of pioglitazone and the risk of bladder malignancy. The summary HR was 1.07 (0.96-1.18) allowing us to affirm that there is no link between long-term use of pioglitazone and bladder cancer. Our results support the hypothesis of no difference in the incidence of bladder cancer among the pioglitazone group and the nonuser group. Our conclusion is that the explanation of hypothetically increased risk of bladder malignancy should be attributed to other factors. Funding : Tchaikapharma High Quality Medicines Inc. [ABSTRACT FROM AUTHOR]

Objective: The association between opium use and bladder cancer has been investigated in many studies, with varying reporting results reported. This study aims to estimate the total odds ratio for the association between bladder cancer and opium consumption using meta-analysis. Methods: The study was designed according to PRISMA guidelines. Two independent researchers searched for the relevant studies using PubMed, Web of Science, Scopus, OVID, Embase, and Google Scholar. After systematic screening of the studies identified during the first step, Cochrane risk of bias tool was determined for the selected studies. The case-control and the cohort studies were investigated to assess risk of bladder cancer due to opium use. In addition, the cross-sectional studies were analysed separately to assess frequency of opium consumption. These estimates were combined using the inverse variance method. Fixed or random effect models were applied to combine the point odds ratios. The heterogeneity between the primary results was assessed using the Cochran test and I-square index. The suspected factors for heterogeneity were investigated using meta-regression models. An Egger test was conducted to identify any probable publication bias. Forest plots illustrated the point and pooled estimates. All analyses were performed using Stata version 14 software and RevMan version 5.3. Results: We included 17 primary studies (11 case-control, one cohort and five cross-sectional) in the final meta-analysis. The total odds ratios (95% confidence intervals) for developing bladder cancer by opium use alone, and concurrent use of opium and cigarettes were estimated as 3.85 (3.05–4.87) and 5.7 (1.9–16.3) respectively. The odds ratio (95% confidence interval) for opium use with or without cigarette smoking was estimated as 5.3 (3.6–7.7). Conclusion: This meta-analysis showed that opium use similar to cigarette smoking and maybe with similar mechanisms can be a risk factor for bladder cancer. It is therefore expected to be a risk factor for other cancers. [ABSTRACT FROM AUTHOR]

Background. A possible association between the TACC3 rs798766 polymorphism and urinary bladder cancer risk has been indicated in published literature. We performed this meta-analysis as a synthesis of all relevant data to summarize currently available evidence and to provide estimation with increased precision. Methods. EMBASE, PubMed, Google Scholar, and Wanfang Data were searched. “rs798766” and “urinary bladder cancer” were used as the search terms. A total of 6 eligible studies were identified, in which 8194 cases and 50,165 controls were investigated. Meta-analysis was performed using extracted data. Subgroup analysis by ethnicity was also performed. Population attributable risk (PAR) was calculated. Results. We found a significant association between rs798766[T] and increased risk of bladder cancer, allelic[T] OR=1.27, 95%CI=1.20–1.33. Subgroup analysis by ethnicity revealed similar results, allelic[T] OR=1.24, 95%CI=1.17–1.32 in Caucasian subjects and allelic[T] OR=1.33, 95%CI=1.21–1.46 in Asian subjects. PAR based on pooled allelic ORs and the frequency of the risk allele in control subjects was 4.63% in the overall population and 3.92% in Asians and 4.36% in Caucasians. Conclusion. rs798766 is associated with increased risk of bladder cancer, and no ethnic difference was found. [ABSTRACT FROM AUTHOR]

Tobacco smoke (TS) is an important risk factor of bladder cancer. Epithelial‑mesenchymal transition (EMT) is involved in the initiation and development of cancer. The role of extracellular signal‑regulated kinase (ERK) 5 in regulating TS‑induced EMT remains to be elucidated. The aim of the present study was to investigate the regulatory role of ERK5 in TS‑triggered EMT in the bladder of mice. BALB/c mice were used for an in vivo TS exposure model. Mice were treated for 6 h a day for 12 weeks. The results demonstrated that mice exposed to TS had decreased mRNA and protein expression levels of the epithelial markers E‑cadherin and zonula occludens‑1, whereas expression levels of the mesenchymal markers Vimentin and N‑cadherin were increased. Treatment with XMD8‑92, a highly specific ERK5 inhibitor, effectively abrogated TS‑triggered activation of ERK5, activator protein‑1 and EMT alterations in the bladder of BALB/c mice. The data suggested that ERK5 regulates TS‑mediated urocystic EMT. These findings provide insight into the molecular mechanisms of TS‑associated bladder tumorigenesis. [ABSTRACT FROM AUTHOR]