Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer.

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.

Is there a promoting role for artificial sweeteners in the evolution of bladder cancer? A meta-analysis of current literature.

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.

Camrelizumab as adjuvant therapy in urothelial carcinomas after radical surgery in people living with HIV.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective strategies for multiple cancers and may be safe in people living with HIV (PLWH). Camrelizumab is a monoclonal antibody against PD-1 activating T cells against tumor cells. Evidence of camrelizumab's safety and activity in PLWH with urothelial carcinoma (UC) is lacking. Here, findings in a cohort of people living with HIV with advanced or metastatic urothelial carcinoma are presented. METHODS: Patients who had locally advanced or metastatic disease after radical surgery were given camrelizumab (200 mg intravenously every 3 weeks). The primary endpoint was objective response per Response Evaluation Criteria in Solid Tumors version 1.1. The second endpoint was adverse events after treatment. RESULTS: In total, nine patients were included in this study with a median follow-up of 6.2 months (4.1-20.5). The objective response rate achieved 55%. Tumor response comprised 2 (22%) complete responses and 3 (33%) partial responses. The median of progression-free survival was 6.2 months (95% CI, 9.83-20.63). Only two grade 3 adverse reactions were reported (no toxic deaths or immune-related deaths). CONCLUSION: Camrelizumab showed potent antitumor activity and acceptable safety in PLWH with advanced or metastatic urothelial carcinoma.

Trends in the incidence of urothelial carcinoma in Taiwan after the ban on aristolochic acid-containing Chinese herbal preparations, 2001-2018: a national population-based cohort study.

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.

Autoimmune disorders caused by intravesical bacillus Calmette-Guerine treatment: A systematic review.

Intravesical bacillus Calmette-Guérin (BCG) is a common and highly effective treatment for non-muscle invasive urothelial carcinoma of the urinary bladder. BCG may cause an autoimmune reaction in some patients. One hundred and fifty-eight papers were analyzed, for a total of hundred and thirty patients with reactive arthritis, sixty patients with ocular manifestations and eighteen patients with other rheumatologic diseases. Among 130 subjects with reactive arthritis, an autoimmune symptom occurred after 5 instillations of intravesical BCG (IQR 4-6), which represents 5 weeks in most cases. Fifty-one patients had concurrent ocular involvement. The resolution of symptoms was achieved in a median of 32.5 days (IQR 14-90). Forty-two men and twenty women had ocular manifestations, most commonly conjunctivitis. Patients with HLA-B27 typing had earlier presentation of ocular symptoms related to the number of instillations (4.5 vs 6 [p < 0.05]. Resolution of symptoms was achieved at a median of 128 days (IQR 21-150). Among patients treated with NSAIDs (either with or without steroids), the duration of the disease was significantly shorter in both the articular and the ocular groups (28 vs. 120 [p < 0.05] and 30 vs.105 [p < 0.05], respectively). Other autoimmune manifestations included general autoimmune diseases, such as vasculitis, psoriasis and myasthenia gravis.

Latency period of aristolochic acid-induced upper urinary tract urothelial carcinoma.

Purpose: Aristolochic acid (AA) is a carcinogen in upper urinary tract urothelial carcinoma (UTUC). This study investigated the latency period between AA exposure and UTUC development. Materials and methods: This population-based cohort study was designed using record linkage of the National Health Insurance Research Database (NHIRD), Taiwan Cancer Registry Dataset, and cause-of-death data in Taiwan. Those aged 40-79 years were enrolled in this study. Patients who died or had renal insufficiency or UTUC before 2005 were excluded. The doses of AA exposure and rates of comorbidities between 2000 and 2005 were obtained. The Cox proportion hazard model was used to estimate the risk of UTUC between 2005 and 2016. In addition, the Cox model with time-varying coefficient of AA was used to measure the latency period of UTUC. Results: Of the 752,232 participants enrolled from the NHIRD, 520,871 (68.29%), 210,447 (27.59%), and 31,415 (4.12%) were exposed to cumulative AA doses of 0-1 mg, 1-150 mg, and >150 mg, respectively. A total of 1,147 (0.15%) patients were diagnosed with UTUC between 2005 and 2016. The latency periods of UTUC in middle-aged (40-59 years old) men with cumulative AA doses of 1-150 mg and middle-aged women with cumulative AA doses of 1-150 mg and >150 mg were 8, 9, and 7 years, respectively. Among the aged (60-79 years) individuals, no time-varying effect was observed, and the latency period could not be measured. Conclusion: A decreased risk of UTUC was observed after the ban on AA in Taiwan, especially in middle-aged women with moderate to high doses of AA exposure and men with moderate doses of AA exposure. The latency period of UTUC varies with age, the dose of AA exposure, and sex.

Selective inhibition of integrin αvß6 leads to rapid induction of urinary bladder tumors in cynomolgus macaques.

Administration of a novel and selective small molecule integrin αvß6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction of epithelial proliferative changes in the urinary bladder of 2 animals, in the absence of test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae of epithelial cells, variable cytologic atypia, and high mitotic rate, without invasion into the tunica muscularis. Morphologic features and patterns of tumor growth were consistent with a diagnosis of early-stage invasive urothelial carcinoma. Ki67 immunohistochemistry demonstrated diffusely increased epithelial proliferation in the urinary bladder of several monkeys, including those with tumors, and αvß6 was expressed in some epithelial tissues, including urinary bladder, in monkeys and humans. Spontaneous urothelial carcinomas are extremely unusual in young healthy monkeys, suggesting a direct link of the finding to the test agent. Inhibition of integrin αvß6 is intended to locally and selectively block transforming growth factor beta (TGF-ß) signaling, which is implicated in epithelial proliferative disorders. Subsequent in vitro studies using a panel of integrin αvß6 inhibitors in human bladder epithelial cells replicated the increased urothelial proliferation observed in monkeys and was reversed through exogenous application of TGF-ß. Moreover, analysis of in vivo models of liver and lung fibrosis revealed evidence of epithelial hyperplasia and cell cycle dysregulation in mice treated with integrin αvß6 or TGF-ß receptor I inhibitors. The cumulative evidence suggests a direct link between integrin αvß6 inhibition and decreased TGF-ß signaling in the local bladder environment, with implications for epithelial proliferation and carcinogenesis.

Aristolochic acid-containing Chinese herbal medicine and upper urinary tract urothelial carcinoma in Taiwan: a narrative review.

PURPOSE: The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of Aristolochia-based herbal medicines. Here we systematically review the molecular epidemiology, clinical presentation and biomarkers associated with AA-induced UTUC. METHODS: This is a narrative review. Medline, Embase, and Web of Science were searched from inception to December 31, 2021. Studies evaluating the association, detection, and clinical characteristics of AA and UTUC were included. RESULTS: A nationwide database revealed 39% of the Taiwanese population had been exposed to AA-containing herbs between 1997 and 2003. Epidemiological reports revealed AA posed a significantly higher hazard for renal failure and UTUC in herbalists and the general population who ingested AA-containing herbs. The presence of aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, located predominantly on the non-transcribed DNA strand, with a strong preference for deoxyadenosine in a consensus sequence (CAG), was observed in many UTUC patients. Clinically, AA-related UTUC patients were characterized by a younger age, female gender, impaired renal function and recurrence of contralateral UTUC. To date, there are no preventive measures, except prophylactic nephrectomy, for subjects at risk of AA nephropathy or AA-related UTUC. CONCLUSION: AA exposure via Aristolochia-based herbal medicines is a problem throughout Taiwan, resulting in a high incidence of UTUC. Aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, can be used as biomarkers to identify AA-related UTUC. AA-related UTUC is associated with a high recurrence rate of contralateral UTUC.

Recent Advances in the Development of Antibody-Drug Conjugates in Urothelial Cancer.

ABSTRACT: Antibody-drug conjugates (ADCs) have joined the armamentarium against urothelial cancer (UC) as an effective therapy option. Since 2019, the US Food and Drug Administration has approved 2 ADCs for advanced previously treated UC: enfortumab vedotin, which targets nectin-4 and sacituzumab govitecan, which targets trophoblast cell-surface antigen 2. These ADCs are now being tested in earlier disease settings and in previously untreated patients. Furthermore, novel ADCs (e.g., anti-HER-2) are being tested in the clinic and show promising clinical benefit. The next frontier is to understand the mechanisms of resistance and response, gaining experience with ADC-related adverse events and learning the best strategy to sequence and combine these agents with existing therapies. Here, we highlight the recent advances in the development of ADCs for treating localized and metastatic UC.

CHD4 plays a critical role in arsenite-induced oxidative damage in human urothelial carcinoma.

Inorganic arsenic (iAs), a known human carcinogen, induces oxidative DNA damage and epigenetic silencing of tumor suppressor genes related to tumor progression. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a chromatin remodeling protein that acts on DNA repair and DNA methylation under oxidative damage in malignancies, but the role of CHD4 in arsenical urothelial carcinoma (UC) is unidentified. Our purpose was to observe CHD4-related repair effects on As-stimulated oxidative damage in human UC. The markers of oxidative DNA damage 8-hydroxy-2'-deoxyguanosine (8-OHdG) and CHD4 were investigated by immunohistochemistry in 45 UC tissues from non-blackfoot disease (BFD) areas and BFD areas respectively. The cellular mechanisms of CHD4 involved in the oxidative DNA repair and DNA methylation were evaluated by immunocytochemistry and western blot. The expressions of CHD4 and 8-OHdG were significantly increased in UC patients from the As-exposed areas. The underlying mechanism of CHD4-mediated DNA repair and DNA methylation involved the activation of zinc finger MYND-type containing 8 (ZMYND8) and DNA methyltransferase (DNMTs) in SV-HUC-1, T24 and BFTC-905 cells. These results highlight the potential clinical significance of CHD4 in UCs from BFD areas. The CHD4-mediated oxidative DNA repair and epigenetic DNA methylation in UC cells stimulated by arsenic was revealed. CHD4 might be used as a prognostic indicator in arsenical UC.

Efficacy and toxicity of antibody-drug conjugates in the treatment of metastatic urothelial cancer: A scoping review.

INTRODUCTION: Metastatic urothelial cancer (mUC) is an aggressive disease with limited overall survival and treatment options. Antibody-drug conjugates (ADCs) were designed with the intent to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells by linking cytotoxins to monoclonal antibodies (mAbs) and have emerged as new treatment options in mUC, mainly in chemotherapy (CT) and immune-checkpoint inhibitors (ICI)-exposed patients. We aimed to perform a scoping review to assess activity, efficacy, treatment-related adverse events (TRAEs), and impact on quality of life of ADCs in mUC. METHODS: A review of the literature was performed in January 2022 using Pubmed and Embase databases according to the recommendations of the Joanna Briggs Institute. The search method involved querying for the terms "bladder carcinoma" or "urothelial carcinoma" with any of the following: "enfortumab vedotin" (EV), "sacituzumab govitecan" (SG), antibody-drug conjugate. Only prospective clinical trials were included. RESULTS: Ultimately, eleven clinical trials with 1417 patients were selected for inclusion, and five drugs were identified: enfortumab vedotin (EV), sacituzumab govitecan (SG), disitamab vedotin (RC48-ADC), ASG-15ME (anti-SLITRK6), and trastuzumab deruxtecan. The different ADCs have been tested mainly in phase 1 or phase 2 trials, as monotherapy or in combination with ICI. Response rate ranged from 27% with SG in previously treated patients to 73.3% with EV plus pembrolizumab in cisplatin-ineligible patients as first-line treatment. The phase 3 trial, EV-301, confirmed EV superiority over investigator-chosen CT after failure to platinum-based CT and ICI, improving overall survival (12.88 vs. 8.97 months; HR 0.70; 95% CI, 0.56-0.89; P=0.001). TRAEs of any grade occurred in more than 90% of patients in phase 2 or 3 trials, with high rates of grade 3 ≥ events ranging from 51.4 to 73.5% in different trials. TRAEs of particular interest related to EV were rash, neuropathy, and hyperglycemia. SG was associated with diarrhea and hematologic toxicity. Data from phase 2 and 3 trials of EV suggest no impact on quality of life but an improvement in pain symptoms compared to the control arm. CONCLUSIONS: ACDs represent a new therapeutic option for the treatment of mUC. Level-1 evidence has already been achieved by EV in the post-CT and post-ICI settings. A high incidence of potential adverse events was observed in phase 2 and 3 trials, including rash, neutropenia, hematologic toxicity, and neuropathy. Clinicians should be aware of possible adverse events and their optimal management.

Metastatic Urothelial Carcinoma: Have We Take the Road to the Personalized Medicine?

Urothelial cancer is a lethal malignancy characterized by a wide diffusion in Western countries due to a larger exposure to known risk factors, such as aromatic amines, tobacco smoke and benzene [...].

Effectiveness of pembrolizumab in patients with urothelial carcinoma receiving proton pump inhibitors.

BACKGROUND: The association of concurrent proton pump inhibitor (PPI) use with treatment outcome of metastatic urothelial carcinoma (UC) remains controversial. MATERIALS AND METHODS: We retrospectively analyzed the records of 227 patients with platinum-treated metastatic UC treated with pembrolizumab. The primary outcome was overall survival (OS). Immune progression-free survival (iPFS) and objective response per immune response evaluation criteria in solid tumors were also compared. Inverse probability of treatment weighting (IPTW)-adjusted multivariable Cox regression models and an IPTW-adjusted multivariable logistic regression model were used to evaluate the oncological outcomes. Furthermore, the heterogeneity of the treatment effect on OS was examined using interaction terms within the IPTW-adjusted univariate Cox regression models. RESULTS: Overall, 86 patients (37.9%) used PPIs. After weighting, no significant differences in patient characteristics were observed between PPI users and non-users. PPI use was significantly associated with a shorter OS (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.28-3.18, P = 0.003) and iPFS (HR: 1.70, 95% CI: 1.23-2.35, P = 0.001). Although not statistically significant, PPI use was associated with objective response as well (OR: 0.61, 95% CI: 0.36-1.02, P = 0.06). The interaction analyses showed that the effect of PPI significantly decreased with age (HR: 0.97, 95% CI: 0.93-1.00, P[interaction] = 0.048) and was increased in males (HR: 2.97, 95% CI: 1.10-8.05, P[interaction] = 0.032). CONCLUSIONS: PPI use was significantly associated with worse survival of patients with metastatic UC treated with pembrolizumab. Furthermore, the results suggested that its effects decreased with age and was increased in males.

[Immunotherapy in urologic oncology : Response and treatment interruptions due to adverse events in a bicentric real-world analysis]. / Immuntherapien in der Uroonkologie : Ansprechen und Therapieunterbrechungen durch Nebenwirkungen in einer bizentrischen Real-world-Analyse.

BACKGROUND: Immune checkpoint inhibitors (ICI) have been approved in uro-oncology for a few years. Real-world experience regarding benefits and risks with novel side effects are rare. MATERIALS AND METHODS: In a retrospective analysis, all patients who received ICI therapy due to metastatic renal cell carcinoma (NCC) or urothelial carcinoma (UCA) were enrolled at two maximum care hospitals in Germany between July 2016 and May 2021. Radiologic response, progression-free survival (PFS), and adverse events leading to treatment interruption were collected. Oncologic response was compared to randomized controlled trials. RESULTS: In all, 1185 ICI cycles were administered to 145 patients (111 men [77%] and 34 women [23%]): 64 (44.1 %) patients with NCC and 81 (55.9%) patients with UCA received ICI therapy. Of 141 patients with radiological follow-up, an objective response was observed in 21.3% (n = 13) of patients with NCC and 20.0% (n = 16) with UCA (median duration of response 14.9 months [3.0-51.3]). Median PFS was 5.3 months in patients with NCC and 4.8 months with UCA. ICI-associated adverse events requiring treatment interruption were observed in 17.2% patients with NCC and 20.9% with UCA. These were most commonly renal (5.5%: nephritis) and gastrointestinal (4.8%: colitis, diarrhea) adverse events. Hospitalization was required for 22 (15.1%) patients. CONCLUSION: This real-world experience may support patient-centered consultation in treatment decision-making. Further studies on prognostic factors are needed. Therapy interruptions are frequent and the spectrum of side effects requires interdisciplinary treatment.

Molecular profiles and urinary biomarkers of upper tract urothelial carcinomas associated with aristolochic acid exposure.

Recurrent upper tract urothelial carcinomas (UTUCs) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). Here we delineated the molecular programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe. We applied an integrative multiomics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative microRNA (miRNA) and messenger ribonucleic acid (mRNA) expression profiling, immunohistochemical analysis by tissue microarrays and exome and transcriptome sequencing were performed in UTUC and nontumor tissues. Urinary miRNAs of cases undergoing surgery were profiled before and after tumor resection. Ribonucleic acid (RNA) and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1,862 target mRNAs, involving deregulation of cell cycle, deoxyribonucleic acid (DNA) damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcripts were confirmed at the protein level. Exome and transcriptome sequencing of UTUCs revealed AA-specific mutational signature SBS22, with 68% to 76% AA-specific, deleterious mutations propagated at the transcript level, a possible basis for neoantigen formation and immunotherapy targeting. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients' urine prior to tumor resection, thereby defining biomarkers of tumor presence. The complex gene regulation programs of AAN-associated UTUC tumors involve regulatory miRNAs prospectively applicable to noninvasive urine-based screening of AAN patients for cancer presence and recurrence.

Coexisting of myasthenia gravis and fulminant myocarditis induced by nivolumab in a patient with ureteral epithelial cancer.

The adverse events of immune checkpoint inhibitors (ICIs) are mostly immune mediated reactions. In this study, we presented a patient who developed coexisting of myasthenia gravis, myocarditis and anemia after treatment with nivolumab only 1 cycle for ureteral epithelial cancer. A 66-year-old woman was admitted to our department with the complaint of recurrent hematuria and backache for 2 months. This patient was diagnosed with stage IV, T4N3M1, urothelial carcinoma of the right kidney. She received immune checkpoint therapy consisting of nivolumab. Then, the physical and neurological examination found the ptosis of eyes especially the right eye and weakness of proximal limb muscles. Patient presented with sub-sternal chest discomfort, shortness of breath, electrocardiograms suggested atrial fibrillation and possible acute myocardial ischemic. One week later, this patient died of ventricular arrhythmia. This patient has increased clinical awareness by indicating that the immune-related adverse events (irAEs) could simultaneously involve multiple systems and progress quickly. Early recognition of aberrant immune activation and complete evaluation upon the occurrence of irAEs are critical.

mRNA translation is a therapeutic vulnerability necessary for bladder epithelial transformation.

Using genetically engineered mouse models, this work demonstrates that protein synthesis is essential for efficient urothelial cancer formation and growth but dispensable for bladder homeostasis. Through a candidate gene analysis for translation regulators implicated in this dependency, we discovered that phosphorylation of the translation initiation factor eIF4E at serine 209 is increased in both murine and human bladder cancer, and this phosphorylation corresponds with an increase in de novo protein synthesis. Employing an eIF4E serine 209 to alanine knock-in mutant mouse model, we show that this single posttranslational modification is critical for bladder cancer initiation and progression, despite having no impact on normal bladder tissue maintenance. Using murine and human models of advanced bladder cancer, we demonstrate that only tumors with high levels of eIF4E phosphorylation are therapeutically vulnerable to eFT508, the first clinical-grade inhibitor of MNK1 and MNK2, the upstream kinases of eIF4E. Our results show that phospho-eIF4E plays an important role in bladder cancer pathogenesis, and targeting its upstream kinases could be an effective therapeutic option for bladder cancer patients with high levels of eIF4E phosphorylation.

Comparative analysis of patients with upper urinary tract urothelial carcinoma in black-foot disease endemic and non-endemic area.

BACKGROUND: A high incidence of upper urinary tract urothelial carcinoma has been reported in the southwestern area of Taiwan, where arsenic water contamination was considered the main cause. However, there is no definite proof to show a correlation between arsenic water contamination and upper urinary tract urothelial carcinoma. To investigate the clinical and epidemiological features of patients with upper urinary tract urothelial carcinoma between arsenic water endemic and non-endemic areas, we analyzed patients in terms of characteristics, stratified overall survival, disease-free survival, and cancer-specific survival. METHODS: The records of a total of 1194 patients diagnosed with upper urinary tract urothelial carcinoma were retrospectively reviewed. Clinical data and current medical status were collected from the medical records. Statistical analyses were performed to determine the clinical variables and stratified survival curves between endemic and non-endemic groups. RESULTS: Female predominance was revealed in both endemic and non-endemic groups (male:female ratio = 1:1.2-1.4). No statistical differences were found in histological types, staging, and tumor size between the two groups. Nonetheless, patients with characteristics of aging and having end-stage renal disease were outnumbered in the non-endemic group, while a higher prevalence of previous bladder tumors and more ureteral tumors were found in the endemic group. Adjusted stratified cumulative survival curves suggested a poorer prognosis in endemic patients, especially in disease-free survival of early stage disease. CONCLUSIONS: A higher mortality rate with more previous bladder cancer history and ureteral tumors was seen in patients with upper urinary tract urothelial carcinoma residing in the arsenic water contamination area. This may be attributed to the long-term carcinogenic effect of arsenic underground water.

Additive Effects of Arsenic and Aristolochic Acid in Chemical Carcinogenesis of Upper Urinary Tract Urothelium.

BACKGROUND: Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC). METHODS: Hospital-based (n = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T TP53 mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases. RESULTS: In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in TP53 were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC. CONCLUSIONS: Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan. IMPACT: This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.

MiADMSA ameliorate arsenic induced urinary bladder carcinogenesis in vivo and in vitro.

BACKGROUND AND PURPOSE: Arsenicosis is a major threat to public health and is a major cause of the development of urinary bladder cancer. Oxidative/ nitrosative stress is one of the key factors for these effects but the involvement of other associated factors is less known. There is a lack of data for the efficacy of chelator against urinary bladder carcinogenesis. The present study demonstrates the early signs of arsenic exposed urinary bladder carcinogenesis and its attenuation by Monoisoamyl dimercaptosuccinic acid (MiADMSA). METHODS: Male rats were exposed to 50 ppm of sodium arsenite and dimethylarsinic acid (DMA) via drinking water for 18 weeks and treated with MiADMSA (50 mg/kg, orally once daily for 5 days) for 3 weeks with a gap one week between the two courses of treatments. We compared in vivo data with in vitro by co-exposing 100 nM of sodium arsenite and DMA to rat (NBT-II) as well as human transitional epithelial carcinoma (T-24) cells with 100 nM of MiADMSA. RESULTS: The data showed that sodium arsenite and DMA exposure significantly increased the tissue arsenic contents, ROS, TBARS levels, catalase, SOD activities and significantly decreased GSH level which might be responsible for an increased 8-OHdG level. These changes might have increased pro-oncogenic biomarkers like MMP-9 and survivin in serum, bladder tissues, NBT-II, and T-24 cells. High cell migration and clonogenic potential in NBT-II and T-24 cells exposed to arsenic suggest pronounced carcinogenic potential. Significant recovery in these biomarkers was noted on treatment with MiADMSA. CONCLUSION: Early signs of urinary bladder carcinogenesis were observed in arsenic and DMA exposed rats which were linked to metal accumulation, oxidative/ nitrosative stress, 8-OHdG, MMP-9 and survivin which were reduced by MiADMSA possibly via its efficient chelation abilities in vivo and in vitro.