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Ingested arsenic is carcinogenic to the human urinary tract, but uncertainties remain regarding the dose-response relationship. To assess dose-response relationships between arsenic ingestion and urinary cancers, we evaluated the associations between the arsenic level in drinking water and mortality of cancers of the bladder, kidney, and prostate in Taiwan. We utilized the 1971-2000 Taiwan death registry data and calculated the age-standardized mortality rates (ASMRs) using the 1976 world standard population as the reference group. We used the data from a 1974-1976 census survey of wells on the arsenic levels in drinking water conducted by the government to assess exposure levels, which had been divided into three categories: below 0.05 ppm, 0.05-0.35 ppm, and above 0.35 ppm. The data were analyzed using multiple linear regression models and geographical information system. We found no increase in ASMR for all, or any, of the urinary cancers at exposure levels of 0.05-0.35 ppm arsenic, but at exposure levels > 0.35 ppm arsenic was associated with increased ASMR in both males and females for bladder cancer, kidney cancer, and all urinary cancers combined. There was no increased ASMR associated with prostate cancer observed for either exposure category., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: The correlation between spironolactone usage and cancer risk has sparked interest. The objective of this study is to examine the association between spironolactone use and the incidence of urinary tract cancer in the general population., Methods: We conducted a matched population-based cohort study. The study population was obtained from the Taiwan National Health Insurance Research Database (TNHIRD) during the period from 2000 to 2016. The multivariate Cox proportional hazard model was performed to examine the impact of spironolactone use on the risk of urinary tract cancer. A total of 8,608 individuals exposed to spironolactone were exact matched by 1:1 ratio with unexposed controls on factors including age, gender, comorbidities, CCI scores and socioeconomic status. The incidences of urinary tract cancer, including prostate, renal and bladder cancer, were estimated in both spironolactone exposed and non-exposed cohorts., Results: After adjusting for confounding variables, the multivariate Cox regression analysis showed no significant association between spironolactone exposure and urinary tract cancer incidence, including bladder (adjusted hazard ratio [aHR] = 1.19, 95% confidence interval [CI] = 0.72-1.96, p = 0.50), renal (aHR = 1.75, 95% CI = 0.99-3.07, p = 0.053), and prostate cancer (aHR = 0.67, 95% CI = 0.43-1.04, p = 0.07). When the population was stratified into low (cumulative dose < = 29,300 mg) and high (cumulative dose >29,300 mg) dose of spironolactone, only high dose of spironolactone use was significantly associated with a reduced risk of prostate cancer (aHR = 0.45, 95% CI = 0.23-0.89, p = 0.02), while being associated with an elevated risk of renal cancer (aHR = 2.09, 95% CI = 1.07-4.08, p = 0.03). However, no clear cumulative dose-response relationship was observed in theses associations., Conclusions: High cumulative dose of spironolactone may be potentially associated with a decreased incidence of prostate cancer and an increased incidence of renal cancer, while no significant association was observed with bladder cancer incidence. However, given the lack of support from the dose-response pattern, the available evidence is inconclusive to establish a definitive association between spironolactone use and urinary tract cancer., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens., Competing Interests: Declaration of interests M.D.G. has received grants or contracts from Bristol Myers Squibb, Novartis, Dendreon, AstraZeneca, and Merck; and has received consulting fees from Bristol Myers Squibb, Merck, Genentech Inc., AstraZeneca, Pfizer, EMD Serono, Seagen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, RapptaTherapeutics, Alligator, Silverback, Fujifilm, and Curis. X.G., D.R., A.S.R., H.M.S., R.B., K.Y., E.V., R.H., C.-J.H., Y.L., D.V., P.W., I.M., S.S., R.J., and S.M. are employees of Genentech Inc., and hold stocks or stock options in Roche/Genentech Inc. H.L. is an employee of Hoffmann-La Roche Ltd, Canada. L.W., J.Z., and H.Y. are employees of Sema4. E.H. was employed at Immunai during study conduct. R.H.H. and E. Kiner are employees of Immunai. A.B. has served as a consultant or advisor to Roche, Bristol Myers Squibb, MSD, and Pfizer; has received honoraria from Bristol Myers Squibb, MSD, and Pfizer; and has received educational and research grants from Pfizer, Pierre-Fabre, and Bristol Myers Squibb. M.D.S. has received consulting fees from AAA, Accord, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, Bristol Myers Squibb, Eisai, Ferring, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, and Seagen; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AAA, Accord, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, Bristol Myers Squibb, Eisai, Ferring, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, and Seagen; has received support for attending meetings and/or travel from AAA, Accord, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, Bristol Myers Squibb, Eisai, Ferring, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, Sanofi, and Seagen; has participated in a Data Safety Monitoring Board or Advisory Board for Roche, Orion, and CR-UK; and has other financial or non-financial interests by having worked on the ESMO guidelines on bladder cancer and the German S3 Leitlinie Blasenkarzinom. I.D.D. has participated in a Data Safety Monitoring Board or Advisory Board for Roche/Genentech Inc. (WO30070 [IMvigor130] international steering committee; unpaid) and Merck/Pfizer (APAC GU Advisory Board; unpaid: honoraria are invoiced by and paid directly to ANZUP Cancer Trials Group); and has a leadership or fiduciary role in the ANZUP Cancer Trials Group (as a Director and Board Chair; unpaid). J.A.A. has received third-party service as collaboration in the selection, and management of administrative requirements for the participation of SOGUG centers in the study from SOGUG during the conduct of the study; speaking or consulting fees from Bristol Myers Squibb, MSD, Roche, Astellas, Janssen Cilag, Pfizer, Novartis, and Bayer outside the submitted work; travel support from Bristol Myers Squibb, MSD, Roche, and Janssen Cilag outside the submitted work; research funding (from SOGUG) outside the submitted work from Bristol Myers Squibb, Novartis, and Pierre Fabre; and has participated in industry-sponsored clinical trials for Bristol Myers Squibb, MSD, Roche, Astellas, Janssen Cilag, Pfizer, and Novartis outside the submitted work. E. Kikuchi has received grants or contracts (through his institution) from Takeda, Nippon Kayaku, and Taiho; has received consulting fees from Chugai, Nippon Kayaku, MSD, Takeda, Pfizer, Astellas, Bristol Myers Squibb, and Yansen; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, Nippon Kayaku, and Taiho; and has received consulting fees from Chugai, Nippon Kayaku, MSD, Takeda, Taiho, AstraZeneca, Pfizer, Astellas, Bristol Myers Squibb, and Yansen. S.B. is an employee of Roche Products Ltd, UK, holds stocks or stock options in Roche, and has other financial or non-financial interests in Roche. C.L. is an employee of Roche Products Ltd, UK, holds stocks or stock options in Roche, and has other financial or non-financial interests in Roche. P.C.B. has participated in advisory boards for Janssen, Merck, Roche/Genentech Inc., Bristol Myers Squibb, Urogen, EMD Serono, Bayer, Astellas, AbbVie, AstraZeneca, Ferring, H3-Biomedicine, Sanofi, Pfizer, Prokarium, Protara Therapeutics, Stimit, and Verity; has received payment or honoraria as a speaker from Janssen, Bayer, Ferring, H3-Biomedicine, and Pfizer; has participated in clinical trials for Roche/Genentech Inc., Bristol Myers Squibb, and AstraZeneca; and has received non-financial support (scientific collaboration on bladder cancer genomics/transcriptomics) from Decipher Biosciences/Veracyte. E.G. has received grants or contracts from Astellas, AstraZeneca, Ipsen, Merck KGaA, and Pfizer; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Esteve, Ipsen, Janssen, Lilly, Merck KGaA, MSD, Pfizer, Raffo, and Roche; and has received support for attending meetings and/or travel from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, and Merck KGaA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Urinary bladder cancer is a frequent neoplasia in the urogenital system. Ageing and smoking are the two main risk factors, however, some chemical agents such as artificial sweeteners could act as initiators or promoters., Evidence Acquisition: After identifying trends in scientific literature, we conducted a wide search in PubMed database and a meta-analysis was performed on extracted data to determine the role of artificial sweeteners in the development of urinary bladder cancer., Evidence Synthesis: Twenty-one full reports were enrolled from screening of PubMed database into final analysis involving 116,568 subjects in comparisons. Overall, 13,682 and 102,886 cases were identified for bladder cancer patients and healthy controls, respectively. Among artificial sweetener users, 12.5% was the incidence of bladder cancer. In the control group, 11.2% of cases suffered from urothelial carcinoma of the bladder. About 40.7% of the patients suffering from urinary neoplasms and 37.8% of the healthy cases were artificial sweetener users, respectively. There were only minor differences in overall descriptive data. The incidence of urinary bladder cancer among artificial sweetener users and control cases showed no risk difference (RD: 0.00, CI: -0.06 to 0.06). The frequency of artificial sweetener use among patients suffering from urinary bladder neoplasms and healthy subjects was compared which showed equal occurrences (OR: 0.96, CI: 0.79 to 1.17)., Conclusions: According to our results, the carcinogenic risk of artificial sweeteners is not proven. Saccharin should not be kept as a promoter in urothelial malignant transformation.

Purpose: Urothelial carcinoma (UC) of the bladder (BUC) and the upper urinary tract (UTUC) are the two most common UCs. The incidence of UTUC in Taiwan is the highest worldwide. Aristolochic acid (AA) was identified as the main cause of UTUC in Taiwan. To explore trends in the incidence of UC in Taiwan after the ban on Chinese herbal preparations containing AA in 2003., Methods: We used data from the Taiwanese National Health Insurance Research Database-linked Taiwanese National Cancer Registry for 2001-2018. UC was defined in accordance with the International Classification of Disease for Oncology. The age-standardized incidence was calculated on the basis of the World Health Organization standard population. Trends in the incidence were calculated as the annual percent change (APC) by using the Joinpoint regression program., Results: Over the investigated period, the incidence of UC decreased at an average annual percent change (AAPC) of - 1.19% (95% CI - 1.47 ~ - 0.91, P < 0.001). However, the incidence in UTUC significantly increased, with the AAPC being 1.47% (95% CI 1.03 ~ 1.90, P < 0.001). In contrast, the incidence of BUC significantly decreased, with the overall AAPC being - 1.92% (95% CI - 2.3 ~ - 1.54, P < 0. 001). From 2001 to 2018, the overall incidence of UCs and BUC decreased in Taiwan, but the incidence of UTUC significantly increased., Conclusion: We suggest to apply the same review standards of new drug development process to herbal preparations and incorporate them into the adverse drug reaction or poison surveillance system. Most importantly, raise public awareness of the potential toxicity of phytotherapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Postoperative opioid prescriptions are associated with delayed recovery, perioperative complications, opioid use disorder, and diversion of overprescribed opioids, which places the community at risk of opioid misuse or addiction., Objective: To assess a protocol for eliminating postdischarge opioid prescriptions after major urologic cancer surgery., Design, Setting, and Participants: This cohort study of the no opioid prescriptions at discharge after surgery (NOPIOIDS) protocol was conducted between May 2017 and June 2021 at a tertiary referral center. Patients undergoing open or minimally invasive radical cystectomy, radical or partial nephrectomy, and radical prostatectomy were sorted into the control group (usual opioids), the lead-in group (reduced opioids), and the NOPIOIDS group (no opioid prescriptions)., Interventions: The NOPIOIDS group received a preadmission educational handout, postdischarge instructions for using nonopioid analgesics, and no routine opioid prescriptions. The lead-in group received a postdischarge instruction sheet and reduced opioid prescriptions at prescribers' discretion. The control group received opioid prescriptions at prescribers' discretion., Main Outcomes and Measures: Primary outcome measures included rate and dose of opioid prescriptions at discharge and for 30 days postdischarge. Additional outcome measures included patient-reported pain and satisfaction level, unplanned health care utilization, and postoperative complications., Results: Of 647 opioid-naive patients (mean [SD] age, 63.6 [10.0] years; 478 [73.9%] male; 586 [90.6%] White), the rate of opioid prescriptions at discharge for the control, the lead-in, and the NOPIOIDS groups was 80.9% (157 of 194), 57.9% (55 of 95), and 2.2% (8 of 358) (Kruskal-Wallis test of medians: P < .001), and the overall median (IQR) tablets prescribed was 14 (10-20), 4 (0-5.3), and 0 (0-0) per patient in the control, lead-in, and NOPIOIDS groups, respectively (Kruskal-Wallis test of medians: P < .001). In the NOPIOIDS group, median and mean opioid dose was 0 tablets for all procedure types, with the exception of kidney procedures (mean [SD], 0.5 [1.7] tablets). Patient-reported pain surveys were received from 358 patients (72.6%) in the NOPIOIDS group, demonstrating low pain scores (mean [SD], 2.5 [0.86]) and high satisfaction scores (mean [SD], 86.6 [3.8]). There was no increase in postoperative complications in the group with no opioid prescriptions., Conclusions and Relevance: This perioperative protocol, with emphasis on nonopioid alternatives and patient instructions, may be safe and effective in nearly eliminating the need for opioid prescriptions after major abdominopelvic cancer surgery without adversely affecting pain control, complications, or recovery.

Objectives: Haematuria is a common indication for a urology evaluation. In many cases, its cause is not determined unequivocally, but it does not pose any threat to the patient. However, it can represent the first symptom of urinary tract cancer., Background: The present study aimed to compare the risk of urological malignancies in patients with haematuria who received antiplatelet or anticoagulant therapy versus those who did not., Methods: This prospective study included 562 patients with haematuria during the period of 2018‒2021. Among these, 129 patients had macroscopic haematuria. All patients underwent a urinary tract ultrasound, CT with urography, and cystoscopy. Patients with suspected malignancy underwent an appropriate surgical procedure with a pathology examination. Data were analysed with univariate and multiple logistic regression., Results: The incidence rates of malignancies were 21.5 % overall, and 44.2 % and 14.8 % among patients with macroscopic and microscopic haematuria, respectively. Univariate regression showed that the odds of malignancy was significantly higher among patients with antiplatelet therapy compared to patients without antiplatelet therapy (OR: 1.88, 95% CI: 1.14‒3.05). In contrast, anticoagulation therapy did not significantly increase the odds of malignancy compared to no anticoagulation therapy (OR: 1.45, 95% CI: 0.74‒2.69). However, a multiple logistic regression model that included other known risk factors (e.g., sex or age) showed similar odds of malignancy among these patient groups., Conclusions: Malignancy risk for patients who received anticoagulant or antiplatelet therapy was similar to the risk observed in the general population. Antiplatelet and anticoagulant therapy were not significant risk factors of urological malignancy in patients with haematuria. The results from the present study will be used in a power analysis for an upcoming multicentre study (Tab. 4, Ref. 17). Text in PDF www.elis.sk Keywords: anticoagulation therapy, antiplatelet therapy, cancer, haematuria, risk factor.

Urological cancers include bladder, prostate and renal cancers that can cause death in males and females. Patients with urological cancers are mainly diagnosed at an advanced disease stage when they also develop resistance to therapy or poor response. The use of natural products in the treatment of urological cancers has shown a significant increase. Curcumin has been widely used in cancer treatment due to its ability to trigger cell death and suppress metastasis. The beneficial effects of curcumin in the treatment of urological cancers is the focus of current review. Curcumin can induce apoptosis in the three types of urological cancers limiting their proliferative potential. Furthermore, curcumin can suppress invasion of urological cancers through EMT inhibition. Notably, curcumin decreases the expression of MMPs, therefore interfering with urological cancer metastasis. When used in combination with chemotherapy agents, curcumin displays synergistic effects in suppressing cancer progression. It can also be used as a chemosensitizer. Based on pre-clinical studies, curcumin administration is beneficial in the treatment of urological cancers and future clinical applications might be considered upon solving problems related to the poor bioavailability of the compound. To improve the bioavailability of curcumin and increase its therapeutic index in urological cancer suppression, nanostructures have been developed to favor targeted delivery., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Aims: Patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs) have an increased risk of bleeding including haematuria. In the general population, gross haematuria is associated with urinary tract cancer. Consequently, we aimed to investigate the potential association between gross haematuria and urinary tract cancer in anticoagulated patients with AF., Methods and Results: Using Danish nationwide registers, we included Danish AF patients treated with OACs between 2001 and 2015. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risk of urinary tract cancer in patients with and without gross haematuria. We included 125 063 AF patients with a median age of 74 years (interquartile range 65-80) and a majority of males (57%). The absolute risk of gross haematuria 12 months after treatment initiation increased with age ranging from 0.37% [95% confidence interval (CI) 0.31-0.42] to 0.85% (95% CI 0.75-0.96) in the youngest and oldest age groups of ≤70 and >80 years of age, respectively. The 1-year risk of urinary tract cancer after haematuria ranged from 4.2% (95% CI 2.6-6.6) to 6.5% (95% CI 4.6-9.0) for patients in age group >80 and 71-80 years, respectively. Gross haematuria conferred large risk ratios of urinary tract cancer when comparing patients with and without haematuria across all age groups., Conclusion: Gross haematuria was associated with clinically relevant risks of urinary tract cancer in anticoagulated patients with AF. These findings underline the importance of meticulously examining anticoagulated patients with haematuria., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

Introduction: We evaluated the incidence and risk factors for antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in prostate and kidney cancer patients., Materials and Methods: We retrospectively reviewed the clinical data of 547 patients from 13 hospitals. Prostate and kidney cancer patients with bone metastases who were treated with a bone-modifying agent (BMA) between January 2012 and February 2019 were enrolled. Exclusion criteria were BMA use for hypercalcemia, a lack of clinical data, a follow-up period of less than 28 days and a lack of evaluation by dentists before BMA administration. The diagnosis and staging of ARONJ were done by dentists., Results: Two-hundred eighteen patients were finally enrolled in the study, including 168 prostate cancer patients and 50 kidney cancer patients. Of them, 49 (29%) prostate cancer patients and 18 (36%) kidney cancer patients needed tooth extraction prior to BMA initiation. The mean follow-up period after BMA initiation was 552.9 ± 424.7 days (mean ± SD). In the cohort, 23% of the patients were diagnosed with ARONJ in the follow-up period. The 1-year cumulative incidences of ARONJ were 9.4% and 15.4% in prostate and kidney cancer patients, respectively. Multivariate analysis indicated that kidney cancer, tooth extraction before BMA and a body mass index (BMI) ≥ 25 kg/m 2 were significant predictors for ARONJ., Conclusion: ARONJ is not a rare adverse event in urological malignancies. Especially, kidney cancer, high BMI patients and who needed tooth extraction before BMA were high risk for developing ARONJ.

Purpose of Review: To acquaint urologists with aristolochic acid nephropathy, an iatrogenic disease that poses a distinct threat to global public health. In China alone, 100 million people may currently be at risk. We illustrate the power of molecular epidemiology in establishing the cause of this disease., Recent Findings: Molecular epidemiologic approaches and novel mechanistic information established a causative linkage between exposure to aristolochic acid and urothelial carcinomas of the bladder and upper urinary tract. Noninvasive tests are available that detect urothelial cancers through the genetic analysis of urinary DNA. Combined with cytology, some of these tests can detect 95% of patients at risk of developing bladder and/or upper urothelial tract cancer. Robust biomarkers, including DNA-adduct and mutational signature analysis, unequivocally identify aristolochic acid-induced tumours. The high mutational load associated with aristolochic acid-induced tumours renders them candidates for immune-checkpoint therapy., Summary: Guided by recent developments that facilitate early detection of urothelial cancers, the morbidity and mortality associated with aristolochic acid-induced bladder and upper tract urothelial carcinomas may be substantially reduced. The molecular epidemiology tools that define aristolochic acid-induced tumours may be applicable to other studies assessing potential environmental carcinogens.

Purpose: The aim of the study was to assess upper tract urothelial carcinoma (UTUC) health care needs and specific mortality rates in an arsenic-exposed region in Northern Chile and compare them to those of the rest of the country., Material and Methods: Arsenic levels of drinking water were correlated with UTUC hospital discharges and cancer-specific mortality rates. Mortality and hospital admission rate ratios were estimated using a Poisson regression model., Results: There were 257 UTUC-specific deaths in Chile between 1990 and 2016; 81 (34%) of them occurred in Antofagasta, where only 3.5% of the population lives. The peak mortality rate observed in Antofagasta was 2.15/100,000 compared to 0.07/100,000 in the rest of the country. Mortality in the exposed region was significantly higher when compared to the rest of the country (MRR 17.6; 95%CI: 13.5-22.9). The same trend was observed for UTUC hospital discharges (RR 14.8; 95%CI: 11.5-19.1)., Conclusion: Even stronger than for bladder cancer, exposure to arsenic is related to a significant need for UTUC health care and high mortality rates, even 25 years after having controlled arsenic levels in drinking-water. Awareness of this ecologic factor in these affected regions is therefore mandatory., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background : Arsenic is a toxic metalloid element widely distributed throughout the environment. Arsenic contaminated water has become an ongoing public health issue affecting hundred million people worldwide. The aim of this paper was to summarize the evidence in the association between arsenic metabolites and urinary tract cancer risk. Methods : A systematic review was conducted searching for observational studies that evaluated the association of arsenic metabolites and urinary tract cancer. Risk estimates from individual studies were pooled by using random effects models. Results : All the metabolites considered in this study resulted to be significantly associated to urothelial cancer, respectively: IA% 3.51 (1.21-5.82) ( p = 0.003), MMA with WMD = 2.77 (1.67-3.87) ( p < 0.001) and DMA with WMD = -4.56 (-7.91-1.22) ( p = 0.008). Conclusions : Arsenic metabolites are significantly associated to urothelial cancer. Future studies will help to verify the independent association(s) between arsenic metabolites and urothelial cancer.

Rationale : Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. Methods : We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. Results : Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. Conclusion : The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cancer is a public health problem worldwide. Taiwan has a higher incidence rate of urological cancers than many Asian countries do. Aristolochic acid has been considered a potent carcinogen. In this study, we examined whether the cessation of the sales and preparation of aristolochic acid-containing Chinese herbal products (AA-CHPs) in Taiwan contributed to a decline in the incidence rates of bladder cancer, carcinomas of the renal pelvis and other urinary organs, and kidney cancer. We conducted an interrupted time-series analysis of long-term trends in the incidence rates of the aforementioned cancers between 1995 and 2013 in Taiwan. The incidence rates of bladder cancer and carcinomas of the renal pelvis and other urinary organs decreased considerably after 2008 and 2011, respectively. Notably, these change-of-slope time points occurred after the year 2003, when a ban on AA-CHPs was imposed in Taiwan. The ban on AA-CHPs in Taiwan was possibly associated with the reduction in the incidence of bladder cancer and carcinomas of the renal pelvis and other urinary organs.

Arsenic exposure is an environmental risk factor for urothelial carcinoma (UC). The natural history of upper tract urothelial carcinoma (UTUC) differs from that of bladder cancer (BC). However, the risk factors of BC and UTUC are not exactly the same and should be discussed separately. The aims of this study were to evaluate 1) the association between arsenic methylation capacity and UTUC and/or BC, separately, and 2) the association between polymorphisms of the arsenic metabolism-related genes AS3MT, GSTOs, and PNP against BC and/or UTUC, separately. We conducted a hospital-based study and collected 216 BC and 212 UTUC cases, and 813 healthy controls, from September 2007 to October 2011. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generator-atomic absorption spectrometry. The polymorphisms of AS3MT, GSTO, and PNP were identified using the Sequenom MassARRAY platform with iPLEX Gold chemistry. We found that inefficient arsenic methylation capacity was associated with BC in a significant dose-response relationship, but only found that high urinary total arsenic concentration was related to the risk of UTUC, also in a significant dose-response manner. Those with a total urinary arsenic level of > 30.28 μg/L compared to ≤ 9.78 μg/L, had a odds ratio (OR), and 95% confidence interval (CI) of UTUC, of 4.80 (2.22-10.39). The polymorphisms of AS3MT rs11191438, AS3MT rs10748835, and AS3MT rs1046778 were related to the risk of BC and UTUC, while the polymorphisms of AS3MT rs3740393, AS3MT rs11191453, and AS3MT rs11191454 were associated with arsenic methylation capacity. The AS3MT gene polymorphisms and arsenic methylation capacity appear to independently affect the risk of BC and UTUC., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to determine the impact of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), statin, and cyclooxygenase 2 (COX-2) inhibitor on the development of kidney, prostate, and urothelial cancers by analyzing the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC) database., Materials and Methods: Among a representative sample cohort of 1,025,340 participants in NHIS-NSC database in 2002, we extracted data of 799,850 individuals who visited the hospital more than once, and finally included 321,122 individuals aged 40 and older. Following a 1-year washout period between 2002 and 2003, we analyzed 143,870 (male), 320,861 and 320,613 individuals for evaluating the risk of prostate cancer, kidney cancer and urothelial cancer developments, respectively, during 10-year follow-up periods between 2004 and 2013. The medication group consisted of patients prescribed these drugs more than 60% of the time in 2003. To adjustfor various parameters of the patients, a multivariate Cox regression model was adopted., Results: During 10-year follow-up periods between 2004 and 2013, 9,627 (6.7%), 1,107 (0.4%), and 2,121 (0.7%) patients were diagnosed with prostate cancer, kidney cancer, and urothelial cancer, respectively. Notably, multivariate analyses revealed that NSAIDs significantly increased the risk of prostate cancer (hazard ratio [HR], 1.35). Also, it was found that aspirin (HR, 1.28) and statin (HR, 1.55) elevated the risk of kidney cancer. No drugs were associated with the risk of urothelial cancer., Conclusion: In sum, our study provides the valuable information for the impact of aspirin, NSAID, statin, and COX-2 inhibitor on the risk of prostate, kidney, and urothelial cancer development and its survival outcomes.

Recent case series describe detection of BK polyomavirus (BKV) in urinary tract cancers in kidney transplant recipients, suggesting that BKV could contribute to the development of these cancers. We assessed risk for urinary tract cancers in kidney recipients with or without treatment for presumed BKV nephropathy (tBKVN) using data from the United States Transplant Cancer Match Study (2003-2013). Among 55 697 included recipients, 2015 (3.6%) were reported with tBKVN. Relative to the general population, incidence was similarly elevated (approximately 4.5-fold) for kidney cancer in recipients with or without tBKVN, and incidence was not increased in either group for prostate cancer. In contrast, for invasive bladder cancer, incidence was more strongly elevated in recipients with versus without tBKVN (standardized incidence ratios 4.5 vs. 1.7; N = 48 cases), corresponding to an incidence rate ratio (IRR) of 2.9 (95% confidence interval [CI] 1.0-8.2), adjusted for sex, age, transplant year, and use of polyclonal antibody induction. As a result, recipients with tBKVN had borderline increased incidence for all urothelial cancers combined (renal pelvis, ureter, and bladder cancers: adjusted IRR 2.2, 95% CI 0.9-5.4; N = 89 cases). Together with reports describing BKV detection in tumor tissues, these results support an association between BKV and urothelial carcinogenesis among kidney transplant recipients., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The Aristolochic Acid (AA)-specific mutational pattern was recently characterized in urothelial carcinoma (UC) from Belgian AA Nephropathy (AAN) patients (n=5). Besides the A>T transversion hallmark, a specific AA-mutational pattern was found in the TP53 hotspot region in p53-positive immunohistochemistry (IHC) areas and consisted of poly- or multiclonal TP53 alterations and an unusual high prevalence of G>T transversion. In the current study, these data were complemented using the same validated methodology for assessing the complete coding sequence of the TP53 gene in tumor areas stratified according to the percentage of p53-stained cells (i.e., [+], ≥60%; [+/-], 1-59%, [-], no staining). Results were compared to existing data (i.e., other series of AA-associated UC and IARC TP53 database). Aside of the TP53 hotspot region (exons 5-8), multiple mutations were also found in exons 4 and 10. A unique TP53 mutational pattern was characterized by a large spectrum of mutations among which A>T and C>T have the highest prevalence. Most A>T mutations were characterized by the 5'Py-A-Pu sequence. Interestingly, the majority of p53-negative areas were dysplastic (low grade intra-urothelial neoplasia) and disclosed TP53 mutations among which a majority of A>T transversions. Beside nonsense p53-negative mutations, several missense mutations are also known to affect p53 DNA- or zinc-binding domains, hence probably impairing the antigen binding site and/or masking the antigenic epitope. These uncommon histologic, immunopathologic and genetic features in Belgian AAN patients probably result from the unique pattern of duration and extent of AA exposure which led to a cumulative toxic dose ingested over a short period of time. Consequenlty, current results bring additional and valuable evidence unravelling the molecular pathogenesis of AA-induced carcinogenesis and the origin of related high-grade UCs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The melamine contaminated milk powder contamination scandal occurred in China in 2008. Its main consequences so far have been urinary stone formation in children with associated renal damage and increased child mortality. Eight years have passed, but food safety issues still remain of concern in the daily lives of millions of Chinese. Vigilance is required to ensure no recurrence of such food safety problems. Ongoing studies focus on the early detection of food industry malpractice, mechanisms whereby these toxic substances induce disease and how its advent may be prevented and better managed. Melamine undergoes renal excretion, but is metabolized slowly and excreted largely unchanged in the urine. Urinary melamine measurement may provide a rapid and inexpensive way to identify exposure to melamine adulterated food items. Although most patients with melaminerelated urinary stones (MUS) have been responsive to conservative treatment, longer time follow-up is needed to assess chronic effects. Aside from MUS, melamine is a recognized carcinogen and can induce urinary tract tumours. Very little is known about the effects of excessive exposure to melamine contaminated milk powder in infants on growth, adolescent and adult health, although short-term effects have become apparent during the scandal.

Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3-7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long., Competing Interests: The authors declare no conflict of interest.

Arsenic causes oxidative stress in cultured animal and human cells, and it is a well-documented human carcinogen. We conducted a hospital-based case-control study including 167 cases of urothelial carcinoma (UC) and 334 age- and gender-matched healthy controls to evaluate the relationships between urinary arsenic profiles, urinary 8-hydroxydeoxyguanosine (8-OHdG) levels, and human 8-oxoguanine DNA glycosylase (hOGG1) genotypes and UC. The urinary arsenic species were analyzed by high-performance liquid chromatography and hydride generator-atomic absorption spectrometry. Genotyping for hOGG1 (Ser326Cys) and hOGG1 (-15C>G) was performed using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Urinary 8-OHdG was measured with high-sensitivity enzyme-linked immunosorbent assay kits. The results indicated that the hOGG1 326 Cys/Cys genotype and the hOGG1 -15C>G G/G genotype were associated with an increased risk of UC (OR [95 % CI] 1.57 [1.04-2.35] and 1.57 [1.04-2.35], respectively). Participants with high urinary total arsenic, regardless of the haplotype of hOGG1 Ser326Cys and the -15C>G polymorphism, had significantly higher urinary 8-OHdG compared to participants with low urinary total arsenic. This is the first study to investigate the joint effects of high urinary total arsenic or inefficient arsenic methylation capacity indices, and the high-risk G-G haplotype of hOGG1 on the risk of UC. The findings are especially meaningful for participants with risk factors such as high urinary total arsenic, inefficient arsenic methylation indices, high urinary 8-OHdG, and the high-risk G-G haplotype of hOGG1 which are all associated with an increased UC risk.

Mutational signatures associated with specific forms of DNA damage have been identified in several forms of human cancer. Such signatures provide information regarding mechanisms of tumor induction which, in turn, can reduce exposure to carcinogens by shaping public health policy. Using a molecular epidemiologic approach that takes advantage of recent advances in genome sequencing while applying sensitive and specific analytical methods to characterize DNA damage, it has become increasingly possible to establish causative linkages between certain environmental mutagens and disease risk. In this perspective, we use aristolochic acid, a human carcinogen and nephrotoxin found in Aristolochia herbs, to illustrate the power and effectiveness of this multidisciplinary approach. The genome-wide mutational signature for this toxin, detected initially in cancers of the upper urinary tract, has subsequently been associated with cancers of the liver and kidney. These findings have significant implications for global public health, especially in China, where millions of individuals have used Aristolochia herbal remedies as part of traditional Chinese medicine and, thus, are at risk of developing aristolochic acid nephropathy and/or upper urinary tract carcinomas. The studies reported here set the stage for research into prevention and early detection, both of which will be required to manage a potentially devastating global disease., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aristolochic acid nephropathy is a renal disease of toxic origin characterized by a progressive interstitial fibrosis and frequently associated with urinary tract cancer. It was initially reported in Belgium after the intake of slimming pills containing root extracts of a Chinese herb, Aristolochia fangchi. In the following decades, numerous cases have been reported worldwide, particularly in Asian countries. Several experimental models of aristolochic acid nephropathy (AAN) have been designed. They confirm the causal link between AA exposure and the onset of acute and chronic renal toxicity, as well as urinary tract cancer. These experimental models offer the opportunity to study the mechanisms of renal interstitial fibrosis and carcinogenesis. In terms of public health, the history of this nephropathy demonstrates that it is mandatory to submit all "natural medicinal products" to the same controls of efficacy, toxicity and conformity applied to the classical drugs derived from the pharmaceutical producers. Any unusual observation of renal failure and/or cancer of the urinary tract should lead to a questioning about any prior exposure to AA. The confirmation of the ingestion of AA containing compounds by phytochemical analysis is not always feasible. However, the renal biopsy remains a crucial diagnostic point through the demonstration of a hypocellular interstitial fibrosis with a decreasing corticomedullary gradient, mostly in advanced cases of kidney disease. Moreover, the detection of AA-related DNA adducts within a renal or urothelial tissue sample could confirm the prior AA exposure. The persistence of these specific DNA adducts in renal tissue is very long (up to 20 years). Finally, considering the highly carcinogenic properties of AA, a systematic endo-urological screening is absolutely necessary., (Copyright © 2015 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.)

Aristolochic acid (AA) is a carcinogenic, mutagenic and nephrotoxic compound commonly isolated from members of the plant family of Aristolochiaceae (such as Aristolochia and Asarum) and used in Chinese herbal medicine. Use of AA and AA‑containing plants causes chronic kidney disease (CKD) and upper urinary tract carcinoma (UUC); however, the underlying mechanism remains to be defined. miRNAs regulate a number of biological processes, including cell proliferation, differentiation and metabolism. This study explored differentially expressed miRNAs between AA‑induced upper urothelial tract cancer (AAN‑UUC) and non‑AAN‑UUC tissues. Patients with AAN‑UUC and non‑AAN‑UUC (n=20/group) were recruited in the present study. Five tissue samples from each group were used for miRNA microarray profiling and the rest of the tissue samples were subjected to reverse transcription-quantitative polymerase chain reaction analysis including seven selected miRNAs for confirmation. A total of 29 miRNAs were differentially expressed between AAN‑UUC and non‑AAN‑UUC tissues (P<0.05). TargenScan and Gene ontology analyses predicted the functions and targeted genes of these differentially expressed miRNAs, i.e. Akt3, FGFR3, PSEN1, VEGFa and AR. Subsequently, expression of the selected differentially expressed miRNAs (Hsa‑miR‑4795‑5p, Hsa‑miR‑488, Hsa‑miR‑4784, Hsa‑miR‑330, Hsa‑miR‑3916, Hsa‑miR‑4274 and Hsa‑miR‑181c) was validated in another set of tissue samples. A total of 29 miRNAs were identified to be differentially expressed between AAN‑UUC and non‑AAN‑UUC tissues and these miRNA target genes in FGFR3 and Akt pathways, which regulate cell growth and tumor progression, respectively.

Micronucleus (MN) assay was performed on the exfoliated urothelial cells to detect the genotoxic effects of the anti-hyperglycemic drugs, metformin and glimepiride in T2DM patients and to use it as a biomarker for DNA damage by assessing the frequency of micronuclei in the exfoliated urothelial cells. A total of 201 subjects (147 T2DM patients & 54 Normal cases) were selected from diverse age groups (25-75 years) and the mean MN frequency was examined per 1000 cells in all the subjects. Relative to the control group (5.02 ± 1.01), an increased MN frequency was observed in females (26.15 ± 2.15) when compared to males (23.08 ± 2.09) in T2DM patients. Further analysis showed that there was a profound increase in the number of MN in the patients using metformin alone (23.02 ± 4.44), or combination of metformin & glimepiride (24.98 ± 2.87) than to the subjects using glimepiride alone (17.52 ± 3.28). It has been proven by this simple, reliable and non-invasive method that metformin has a potential role in causing genotoxicity and that the MN observed in exfoliated urothelial cells could be used as a reliable biomarker in monitoring the genotoxic risk of the anti-hyperglycemic drugs., (Copyright © 2015. Published by Elsevier Ltd.)

Bladder cancer is estimated to be the ninth most common malignancy with a high rate of recurrence and progression despite therapy, early diagnosis being crucial for timely intervention. Using a well-established animal model of urothelial carcinoma, we performed a comprehensive analysis of urine proteome profile from healthy animals and animals with urothelial carcinoma at two time-points of disease pathogenesis. GeLC-MS/MS, followed by bioinformatics analysis of unique proteins and the ones present in significantly distinct levels among groups, highlighted the biological processes involved in disease pathogenesis such as, for instance, response to selenium and to drugs, neutral lipid metabolism at earlier stages of disease, and inflammation, immune response and wound healing at advanced stages. Proteins from up-regulated biological processes might be seen as putative disease biomarkers. These include, for example, cadherins, lipoproteins, and glysosyltransferases, which may be included in multimarker strategies. Taken together, the data support the application of urine proteomics for the identification of the biological processes modulated by bladder cancer in an integrative perspective. The present exploratory urinary proteomic analysis might be seen as an important starting point for studies targeting urinary proteins in human, aiming at the implementation of novel laboratory approaches for the detection and successful management of urothelial carcinoma.

In the Balkan and Taiwan, the relationship between exposure to aristolochic acid and risk of urothelial neoplasms was inferred from the A>T genetic hallmark in TP53 gene from malignant cells. This study aimed to characterize the TP53 mutational spectrum in urothelial cancers consecutive to Aristolochic Acid Nephropathy in Belgium. Serial frozen tumor sections from female patients (n=5) exposed to aristolochic acid during weight-loss regimen were alternatively used either for p53 immunostaining or laser microdissection. Tissue areas with at least 60% p53-positive nuclei were selected for microdissecting sections according to p53-positive matching areas. All areas appeared to be carcinoma in situ. After DNA extraction, mutations in the TP53 hot spot region (exons 5-8) were identified using nested-PCR and sequencing. False-negative controls consisted in microdissecting fresh-frozen tumor tissues both from a patient with a Li-Fraumeni syndrome who carried a p53 constitutional mutation, and from KRas mutated adenocarcinomas. To rule out false-positive results potentially generated by microdissection and nested-PCR, a phenacetin-associated urothelial carcinoma and normal fresh ureteral tissues (n=4) were processed with high laser power. No unexpected results being identified, molecular analysis was pursued on malignant tissues, showing at least one mutation in all (six different mutations in two) patients, with 13/16 exonic (nonsense, 2; missense, 11) and 3/16 intronic (one splice site) mutations. They were distributed as transitions (n=7) or transversions (n=9), with an equal prevalence of A>T and G>T (3/16 each). While current results are in line with A>T prevalence previously reported in Balkan and Taiwan studies, they also demonstrate that multiple mutations in the TP53 hot spot region and a high frequency of G>T transversion appear as a complementary signature reflecting the toxicity of a cumulative dose of aristolochic acid ingested over a short period of time.

Introduction: Both end-stage renal disease (ESRD) and urothelial cancer (UC) are associated with the consumption of Chinese herbal products containing aristolochic acid (AA) by the general population. The objective of this study was to determine the risk of UC associated with AA-related Chinese herbal products among ESRD patients., Methods: We conducted a cohort study using the National Health Insurance reimbursement database to enroll all ESRD patients in Taiwan from 1998-2002. Cox regression models were constructed and hazard ratios and confidence intervals were estimated after controlling for potential confounders, including age, sex, residence in region with endemic black foot disease, urinary tract infection, and use of non-steroidal anti-inflammatory drugs and acetaminophen., Results: A total of 38,995 ESRD patients were included in the final analysis, and 320 patients developed UC after ESRD. Having been prescribed Mu Tong that was adulterated with Guan Mu Tong (Aristolochia manshuriensis) before 2004, or an estimated consumption of more than 1-100 mg of aristolochic acid, were both associated with an increased risk of UC in the multivariable analyses. Analgesic consumption of more than 150 pills was also associated with an increased risk of UC, although there was little correlation between the two risk factors., Conclusion: Consumption of aristolochic acid-related Chinese herbal products was associated with an increased risk of developing UC in ESRD patients. Regular follow-up screening for UC in ESRD patients who have consumed Chinese herbal products is thus necessary.

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with an excess risk of respiratory tract and bladder cancers in several industries, but the issue requires further quantification. We updated a previous systematic review by reviewing in details cohort studies on workers employed in selected industries with potential PAH exposure published between 2006 and 2014, and we summarized through a meta-analytic approach the main results of all available cohort studies published between 1958 and 2014 investigating cancers of the respiratory and urinary tracts. Thirteen papers on cohort studies investigating cancer risk in workers exposed to PAHs were retrieved through the literature search. These included workers from aluminum production industries (seven studies), iron and steel foundries (two studies), asphalt workers (two studies), and carbon black production (two studies). In the meta-analysis, an excess risk of respiratory tract cancers (mainly lung cancer) was found in iron and steel foundries [pooled relative risk (RR) 1.31, 95 % confidence interval (CI) 1.08-1.59 from 14 studies], while a weak excess risk (pooled RR 1.08, 95 % CI 0.95-1.23 from 11 studies) emerged for aluminum production. A borderline increase risk was also observed for cancer of the bladder in the aluminum production (pooled RR 1.28, 95 % CI 0.98-1.68 from 10 studies) and in iron and steel foundries (pooled RR 1.38, 95 % CI 1.00-1.91 from 9 studies). This updated review and meta-analysis confirm the increased risk from respiratory tract and bladder cancers in selected PAH-related occupations. It cannot be ruled out whether such excesses are due, at least in part, to possible bias or residual confounding.

Objective: To explore the risk factors and treatment outcomes of contralateral new upper tract urothelial carcinoma (UTUC) after nephroureterectomy in a large single-center cohort of UTUC patients., Methods: A retrospective analysis of the clinicopathological data of 509 consecutive patients treated by nephroureterectomy from 2000 to 2010 at a high-volume center in China was conducted., Results: Thirty-five patients (6.9%) were found to develop contralateral UTUC. Gross hematuria was a common symptom, and aristolochic acid (AA) containing Chinese herbs was identified as an underlying cause. In multivariate analysis, renal transplant recipients (HR = 16.507) and preoperative renal insufficiency (HR = 2.523) were independent risk factors. No correlation was found in the clinical and pathological characteristics of primary and subsequent contralateral UTUC. A second round of nephroureterectomy should be performed on renal transplant patients, whereas patients who are older, exhibit relatively better renal function, and have tumors that are single, located in the ureter and small size could be treated with nephron-sparing surgery. No survival difference was detected between the two treatment groups, and developing contralateral UTUC was not associated with worse survival., Conclusion: Contralateral UTUC is comparatively rare, and gross hematuria is a common symptom. Renal transplant history and renal insufficiency are independent risk factors, and prophylactic contralateral nephroureterectomy is considered for uremic UTUC patients with proper renal replacement treatment or renal transplant recipients. These features are likely related to the mechanisms of multifocality of UTUC, and the potential correlation with AA remains to be elucidated. Tumor characteristics and renal function are informative for the decisions concerning surgical options for contralateral UTUC.

Ecological studies in Taiwan, Chile, Argentina, Bangladesh, and Mexico have confirmed significant dose-dependent associations between ingestion of arsenic-contaminated drinking water and the risk of various human malignancies. The FHIT and WWOX genes are active in common fragile sites FRA3B and FRA16D, respectively. Reduced expression of FHIT or WWOX is known to be an early indicator of carcinogen-induced cancers. However, the effect of arsenite on the expressions and molecular mechanisms of these markers is still unclear. The aims of this study were (i) to observe the expression of ATR, WWOX and FHIT proteins in urothelial carcinoma (UC) between endemic and non-endemic areas of blackfoot disease (BFD) by immunohistochemical analyses; (ii) to compare expression of these genes between arsenite-treated SV-HUC-1 human epithelial cells and rat uroepithelial cells; and (iii) to determine the role of DNMT and MEK inhibitors on expressions of WWOX and FHIT in response to arsenite in SV-HUC-1. The experiments revealed that expressions of ATR, WWOX and FHIT in UC significantly differed between BFD areas and non-BFD areas (p=0.003, 0.009 and 0.021, respectively). In fact, the results for the arsenite-treated groups showed that ATR, WWOX and FHIT are downregulated by arsenite in SV-HUC-1. However, the inhibitors suppressed the effects of arsenite on WWOX and FHIT proteins and mRNA expression. In conclusion, arsenite decreased expressions of ATR, WWOX and FHIT via ERK1/2 activation in SV-HUC-1 cells. These findings confirm that dysregulations of these markers may contribute to arsenite-induced carcinogenesis., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aristolochic acid (AA), a component of all Aristolochia-based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA-induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam-DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T-to-T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam-DNA adducts and A:T-to-T:A transversions in TP53 were defined as AA-UUC, whereas patients lacking both of these biomarkers were classified as non-AA-UUC. Cases with either biomarker were classified as possible-AA-UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA-UUC, possible-AA-UUC and non-AA-UUC, respectively. AA-UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end-stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible-AA-UUC and non-AA-UUC patients. All 14 patients who developed contralateral UUC had aristolactam-DNA adducts; ten of these also had signature mutations. The contralateral UUC-free survival period was shorter in AA-UUC compared to possible- or non-AA-UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA-UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC., (Copyright © 2013 UICC.)

Genetic alterations in cancer tissues may reflect the mutational fingerprint of environmental carcinogens. Here we review the pieces of evidence that support the role of aristolochic acid (AA) in inducing a mutational fingerprint in the tumor suppressor gene TP53 in urothelial carcinomas of the upper urinary tract (UUT). Exposure to AA, a nitrophenathrene carboxylic acid present in certain herbal remedies and in flour prepared from wheat grain contaminated with seeds of Aristolochia clematitis, has been linked to chronic nephropathy and UUT. TP53 mutations in UUT of individuals exposed to AA reveal a unique pattern of mutations characterized by A to T transversions on the non-transcribed strand, which cluster at hotspots rarely mutated in other cancers. This unusual pattern, originally discovered in UUTs from two different populations, one in Taiwan, and one in the Balkans, has been reproduced experimentally by treating mouse cells that harbor human TP53 sequences with AA. The convergence of molecular epidemiological and experimental data establishes a clear causal association between exposure to the human carcinogen AA and UUT. Despite bans on the sale of herbs containing AA, their use continues, raising global public health concern and an urgent need to identify populations at risk., (Copyright © 2013 Elsevier B.V. All rights reserved.)

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.

Agent Orange, an herbicide widely used during the Vietnam War, has been linked to various health risks, including urologic malignancy. Exposed veterans are at risk for prostate cancer and may be entitled to compensation if diagnosed with prostate cancer. Current research studies are aimed at mitigating prostate dysplasia and prostate cancer

Strong indications have been presented that dietary poisoning with aristolochic acids (AA) is responsible for Endemic Nephropathy (EN) and AA associated cancer of the upper urinary tract (UUTC). Our recent investigation showed drastic urinary proteome changes in AA treated mice. This study was designed to identify proteome changes associated with AA nephrotoxicity in experimental animal model. The DBA and C57BL mice, which differ in AA sensitivity, were exposed to AA for 4 days. The strategy for urinary, plasma and kidney tissue proteome study of AA exposed and control mice integrated gel-based and in-solution tryptic digestion combined with LC-ESI-MS/MS. To maximize proteome coverage, plasma fractionation scheme was developed and MS compatible sequential tissue extraction procedure was established. Proteomic analyses of urinary, plasma and kidney tissue tryptic digests resulted in identification of several cytoskeletal proteins, as well as proteins involved in kidney development and inflammatory response, that are differentially expressed in both AA exposed and control mice. These proteins are consistent with renal pathogenesis of endotoxicity and cancer. This proteomic strategy could be effectively translated for unbiased discovery of potential biomarkers for EN and associated UUTC in humans. At the same time, these results highlight the significance of AA exposure with EN. This article is part of a Special Issue entitled: Integrated omics., (Published by Elsevier B.V.)

Neuron specific enolase (ENO2, γ-enolase) is a biomarker used to help identify neuroendocrine differentiation in tumors. This laboratory has shown that ENO2 might be a biomarker for exposure to cadmium and arsenite. In this study these observations are extended to the urothelial cell, where environmental exposures are strongly linked to urothelial cancer. The UROtsa urothelial cell line and its Cd²⁺- and As³⁺-transformed counterparts were used as the model. Acute exposure of the UROtsa cells to both As³⁺- and Cd²⁺-caused significant increases in ENO2 expression. Treatment with the histone deacetlyase inhibitor was also shown to significantly increase the expression of ENO2 mRNA. The expression of ENO2 was significantly elevated in the Cd²⁺- and As³⁺-transformed UROtsa cells and tumor transplants. In contrast, ENO1, was unaffected by exposure to As³⁺ or Cd²⁺. Immunofluorescence showed ENO2 associated with both the nucleus and cytoplasm and cytoplasmic ENO2 co-localized with ENO1. The findings extend the evidence suggesting a link between As³⁺ and Cd²⁺ exposure and neuroendocrine differentiation in tumors. The results suggest that ENO2 might be a biomarker of human exposure to Cd²⁺ and As³⁺ that operates through histone modification., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Endemic (Balkan) nephropathy is a chronic tubulointerstitial disease frequently accompanied by urothelial cell carcinomas of the upper urinary tract. This disorder has recently been linked to exposure to aristolochic acid, a powerful nephrotoxin and human carcinogen. Following metabolic activation, aristolochic acid reacts with genomic DNA to form aristolactam-DNA adducts that generate a unique TP53 mutational spectrum in the urothelium. The aristolactam-DNA adducts are concentrated in the renal cortex, thus serving as biomarkers of internal exposure to aristolochic acid. Here, we present molecular epidemiologic evidence relating carcinomas of the upper urinary tract to dietary exposure to aristolochic acid. DNA was extracted from the renal cortex and urothelial tumor tissue of 67 patients that underwent nephroureterectomy for carcinomas of the upper urinary tract and resided in regions of known endemic nephropathy. Ten patients from nonendemic regions with carcinomas of the upper urinary tract served as controls. Aristolactam-DNA adducts were quantified by (32)P-postlabeling, the adduct was confirmed by mass spectrometry, and TP53 mutations in tumor tissues were identified by chip sequencing. Adducts were present in 70% of the endemic cohort and in 94% of patients with specific A:T to T:A mutations in TP53. In contrast, neither aristolactam-DNA adducts nor specific mutations were detected in tissues of patients residing in nonendemic regions. Thus, in genetically susceptible individuals, dietary exposure to aristolochic acid is causally related to endemic nephropathy and carcinomas of the upper urinary tract.

Chinese herbs nephropathy (CHN) and Balkan endemic nephropathy (BEN) are chronic tubulointerstitial renal diseases associated with urothelial carcinoma. The clinical expression and pathological lesions observed at different stages of CHN and BEN are strikingly similar. Both have been linked to exposure to aristolochic acid (AA), a powerful nephrotoxin and human carcinogen. Jelaković et al. present molecular epidemiological evidence relating urothelial carcinoma in patients with BEN to dietary exposure to AA. It is time to abandon the terms 'CHN' and 'BEN' and introduce 'aristolochic acid nephropathy' to cover both clinical conditions.

Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. Individual susceptibility to AA-induced disease likely reflects individual differences in enzymes that metabolize AA. Herein, we evaluated AAI metabolism by human cytochrome P450 (CYP) 1A1 and 1A2 in two CYP1A-humanized mouse lines that carry functional human CYP1A1 and CYP1A2 genes in the absence of the mouse Cyp1a1/1a2 orthologs. Human and mouse hepatic microsomes and human CYPs were also studied. Human CYP1A1 and 1A2 were found to be principally responsible for reductive activation of AAI to form AAI-DNA adducts and for oxidative detoxication to 8-hydroxyaristolochic acid (AAIa), both in the intact mouse and in microsomes. Overall, AAI-DNA adduct levels were higher in CYP1A-humanized mice relative to wild-type mice, indicating that expression of human CYP1A1 and 1A2 in mice leads to higher AAI bioactivation than in mice containing the mouse CYP1A1 and 1A2 orthologs. Furthermore, an exclusive role of human CYP1A1 and 1A2 in AAI oxidation to AAIa was observed in human liver microsomes under the aerobic (i.e., oxidative) conditions. Because CYP1A2 levels in human liver are at least 100-fold greater than those of CYP1A1 and there exists a > 60-fold genetic variation in CYP1A2 levels in human populations, the role of CYP1A2 in AAI metabolism is clinically relevant. The results suggest that, in addition to CYP1A1 and 1A2 expression levels, in vivo oxygen concentration in specific tissues might affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity.

Urinary tract tumors are tenth in frequency, and many environmental carcinogens are excreted by urine. Interplay between chronic inflammatory urolithiasis and urothelial carcinogenesis is not well understood. Experimental evidences show that dietary melamine induce these events even at low concentrations. This is important because thousands of children were exposed to melamine through intentionally contaminated milk formula worldwide. We propose that an increased risk for urinary tumors in adult life may occur and screenings for early urinary signs may be necessary. Therefore, urothelial biology, melamine carcinogenic potential, and related epidemiology are discussed, recommending a preventive dietary polyunsaturated fatty acid-based supplementation, since they modulate such interplay in rodents.

Objective: We sought to investigate the association between urothelial carcinoma (UC) after kidney transplantation and aristolochic acid (AA) exposure, and to explore the potential role of AA in HRas and TP53 gene mutations., Materials and Methods: UC was confirmed in 100 of 3790 patients who underwent kidney transplantation between January 1974 and May 2011. We retrospectively analyzed clinical data for these patients. Malignancies were identified in 136 patients (15 males and 85 females, of age range 27-71 years mean, 53.2±6.3). UC was the most common diagnosis (100/136; 73.5%). The median time from transplantation to the first confirmed diagnosis of a tumor was 34.5 months (range, 2-273). Polymerase chain reaction-based resequencing methods were used to detect mutations in the target regions of exons 2 and 3 of the HRas gene and exons 5, 6, 7, and 8 of the TP53 gene in 90 of 100 samples., Results: UC was identified in 53 of 380 patients exposed to AA and 47 of 3410 patients not exposed to AA (P<0.05). Pathologic examination of the UC specimens from AA-exposed patients identified heterozygous HRas changes in 3 cases, and deletion or replacement mutations in the TP53 gene in 4. No genetic mutations were observed among the control group., Conclusion: UC after kidney transplantation significantly correlated with AA exposure; however, there seemed to be no significant difference in mutations in exons 2 and 3 of the HRas gene and those in exons 5, 6, 7, and 8 of the TP53 gene in terms of tumor development, a result that is inconsistent with previous studies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers., Methods: To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped., Results: The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) ≥ 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE ≥ 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively., Conclusions: The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.

Objectives: To extend follow-up of cause-specific mortality in workers at seven beryllium processing plants and to estimate associations between mortality risk and beryllium exposure., Methods: 9199 workers were followed for mortality from 1940 through 2005. Standardised mortality ratios (SMRs) were estimated based on US population comparisons for lung, nervous system and urinary tract cancers, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and categories containing chronic beryllium disease (CBD) and cor pulmonale. Associations with maximum and cumulative exposure were calculated for a subset of the workers., Results: Overall mortality in the cohort compared with the US population was elevated for lung cancer (SMR 1.17; 95% CI 1.08 to 1.28), COPD (SMR 1.23; 95% CI 1.13 to 1.32), and the categories containing CBD (SMR 7.80; 95% CI 6.26 to 9.60) and cor pulmonale (SMR 1.17; 95% CI 1.08 to 1.26). Mortality rates for most diseases of interest increased with time-since-hire. For the category including CBD, rates were substantially elevated compared to the US population across all exposure groups. Workers whose maximum beryllium exposure was ≥ 10 μg/m(3) had higher rates of lung cancer, urinary tract cancer, COPD and the category containing cor pulmonale than workers with lower exposure. Significant positive trends with cumulative exposure were observed for nervous system cancers (p = 0.0006) and, when short-term workers were excluded, lung cancer (p = 0.01), urinary tract cancer (p = 0.003) and COPD (p < 0.0001)., Conclusion: These findings reaffirm that lung cancer and CBD, and suggest that COPD and nervous system and urinary tract cancers, are related to beryllium exposure. Cigarette smoking and exposure to other lung carcinogens are unlikely to explain these elevations.

Arsenic compounds are well-known toxic and carcinogenic agents, and they are widely distributed throughout the earth's crust. These compounds are associated with various human malignancies. It has been reported that there is an elevated risk of bladder cancer in an area highly contaminated with arsenic on the southwest coast of Taiwan. However, the underlying mechanisms of arsenic-associated carcinogenesis are still unclear. The cell cycle regulatory proteins are important indicators in control of cell cycle progression. Moreover, the high expression of Cyclin-D1 and loss of p16 has been associated with a worse prognosis in a variety of human cancers. Therefore, we investigated the effect of arsenic on Cyclin-D1 and p16 expression and evaluated the role of the ERK signaling pathway and DNA methylation in arsenic carcinogenesis. Our study results showed that Cyclin-D1 high expression was found in 56.3% (9/16) of urothelial carcinomas (UC) from a blackfoot disease (BFD) area and 6.3% (1/16) of UC from a non-BFD area (p=0.002). The p16 low expression in 81.2% (13/16) of UC from BFD areas was significantly lower than in non-BFD areas (25.0%; 4/16) (p=0.001). In addition, the Cyclin-D1 increased expression but decreased p16 expression in arsenite-treated SV-HUC-1 cells. However, when cells were pretreated with inhibitors (5-aza-CdR or U0126), the effects of arsenite on Cyclin-D1 and p16 expression were suppressed. Finally, these results indicated that Cyclin-D1 and p16 both might play important roles in carcinogenesis as a result of arsenic., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: No optimal, well designed and reproducible animal model for upper urothelial carcinogenesis exists. This study characterized the histopathological features on top of immunolocalization of alpha-dystroglycans (alpha-DG) and matrix metalloproteinase (MMP-9) and cell turn-over in the upper urinary tract using a novel experimental model., Methods: Seventy-five female Fischer 344 rats were divided into three groups: the control group received a 0.30-ml dose of 0.9% physiological saline; the MNU group (chemical carcinogen N-methyl-N-nitrosourea) received 0.30 ml of MNU; and the MNU-citrate group received 0.30 ml of MNU plus sodium citrate, every one intravesically every other week for a total of 4 doses. After 15 weeks, bladder, ureters and renal pelvis were collected for morphological and molecular analysis., Results: Associated management with MNU and sodium citrate was able to lead to 100% of both urinary bladder and upper urinary tract tumors, being the high-grade noninvasive papillary urothelial carcinoma the most frequent lesion. The upper urothelium showed reduced alpha-DG and increased MMP-9 and Ki-67 immunoreactivities in the MNU-citrate group in relation to the other groups. MNU group presented no upper urothelium tumor and 100% bladder tumor., Conclusions: This is a relevant evolution on experimental animal model for upper urinary tract carcinogenesis field. MMP-dependent disruption of the DG complex plays an important role in urothelial tumor carcinogenesis and showed the model applicability and significance. MNU-citrate model could contribute to a better understanding of human upper urothelial cancer development as well as to its local treatment strategies in a near future.