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.

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 upper tract urothelial carcinomas: From bench to clinics.

Urothelial carcinoma in the upper tract is rare and often discussed separately. Many established risk factors were identified for the disease, including genetic and external risk factors. Radiographic survey, endoscopic examination and urine cytology remained the most important diagnostic modalities. In localized upper tract urothelial carcinomas, radical nephroureterectomy with bladder cuff excision are the gold standard for large, high-grade and suspected invasive tumors of the renal pelvis and proximal ureter, whereas kidney-sparing surgeries should be considered in patients with low-risk disease. Advances in technology have given endoscopic surgery an important role, not only in diagnosis, but also in treatment. Although platinum-based combination chemotherapy is efficacious in advanced or metastatic disease, current established chemotherapy regimens are toxic and lack a sustained response. Immune checkpoint inhibitors have led to a new era of treatment for advanced or metastatic urothelial carcinomas. The remarkable results achieved thus far show that immunotherapy will likely be the future treatment paradigm. The combination of immune checkpoint inhibitors and other agents is another inspiring avenue to explore that could benefit even more patients. With respect to the high incidence rate and different clinical appearance of upper tract urothelial carcinomas in Taiwan, a possible correlation exists between exposure to certain external risk factors, such as arsenic in drinking water and aristolochic acid in Chinese herbal medicine. As more gene sequencing differences between upper tract urothelial carcinomas and various disease causes are detailed, this has warranted the era of individualized screening and treatment for the disease.

What do patients with urothelial cancer know about the association of their tumor disease with smoking habits? Results of a German survey study.

Purpose: Smoking represents a primary risk factor for the development of urothelial carcinoma (UC) and a relevant factor impacting UC-specific prognosis. Data on the accordant knowledge of UC-patients in this regard and the significance of physicians in the education of UC-patients is limited. Materials and Methods: Eighty-eight UC-patients were enrolled in a 23-items-survey-study aimed to analyse patient knowledge and awareness of their tumor disease with smoking along with physician smoking cessation counselling. Results: The median age of the study patients was 69 years; 26.1% (n=23), 46.6% (n=41), and 27.3% (n=24), respectively, were non-smokers, previous, and active smokers. Exactly 50% of active smokers reported a previous communication with a physician about the association of smoking and their tumor disease; however, only 25.0% were aware of smoking as main risk factor for UC development. Merely 33% of the active smokers had been prompted directly by their physicians to quit smoking. About 42% of active smokers had received the information that maintaining smoking could result in a tumor-specific impairment of their prognosis. Closely 29% of active and about 5% of previous smokers (during the time-period of active smoking) had been offered support from physicians for smoking cessation. No association was found between smoking anamnesis (p=0.574) and pack-years (p=0.912), respectively, and tumor stage of UC. Conclusions: The results of this study suggest that the medical conversation of physicians with UC-patients about the adverse significance of smoking is limited. Implementation of structured educational programs for smoking cessation may be an opportunity to further enhance comprehensive cancer care.

Role of Checkpoint Inhibition in Localized Bladder Cancer.

CONTEXT: Checkpoint inhibitors (CPIs) are established as a standard therapy option for metastatic bladder cancer; however, their role in earlier-stage disease remains undefined. OBJECTIVE: To summarize the preclinical and clinical evidence forming the rationale for multiple ongoing investigations of CPIs in patients with localized bladder cancer defined by non-muscle-invasive or muscle-invasive stages. EVIDENCE ACQUISITION: A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, transitional cell, localized, muscle-invasive, non-muscle-invasive, superficial, PD-1, PD-L1, CTLA-4, and checkpoint inhibitor, both alone and in combination. The search was limited to publications between January 2000 and December 2017. Publicly available relevant abstracts from recent meetings were also included. EVIDENCE SYNTHESIS: Preclinical immunocompetent murine, rodent, and canine models have each demonstrated proof-of-concept support for CPI therapy approaches in localized urothelial carcinoma (UC). Retrospective analysis of localized UC tumor samples confirms the presence of PD-1, PD-L1, or CTLA-4 in a proportion of patients. Prospective pilot trials of CPI therapy in localized UC demonstrated enhanced adaptive immune response measures. Improved whole-transcriptome platforms may further refine patient selection for CPI therapy. Multiple clinical trials of CPI therapy in localized UC are under way with significant practice-changing potential. CONCLUSIONS: Evidence from preclinical models and retrospective data for patients with localized UC and metastatic UC sufficiently justifies the investigation of CPI approaches in the context of prospective clinical trials. PATIENT SUMMARY: Checkpoint inhibitor (CPI) therapy has provided durable tumor control in a small portion of patients with metastatic urothelial carcinoma (UC). Investigating the potential for similar sustained tumor control in localized UC is logical. Ongoing prospective clinical trials will define whether or not CPI therapy should be extended to patients with curable localized UC in whom standards for successful clinical outcomes are higher and acceptance rates of severe treatment-related toxicity are lower.

Association between levels of urinary heavy metals and increased risk of urothelial carcinoma.

OBJECTIVES: To evaluate possible sources of exposure to heavy metals in the general population, and to determine the association between urinary heavy metals and urothelial carcinoma risk. METHODS: We recruited 205 patients with urothelial carcinoma and 406 control participants for a case-control study between June 2011 and December 2013. The control participants were frequency-matched with cases according to sex and age. We measured the urinary levels of arsenic, cadmium, chromium, nickel and lead by using inductively coupled plasma mass spectrometry. We collected environmental exposure-related information through questionnaires. Multivariate logistic regression and 95% confidence intervals were applied to estimate the urothelial carcinoma risk and potential effects of urothelial carcinoma-related risk factors on the levels of urinary heavy metals. RESULTS: Patients with urothelial carcinoma showed higher urinary levels of arsenic, cadmium, chromium, nickel and lead than the controls. After considering other potential risk factors, a significantly increased risk for urothelial carcinoma was observed in patients with increased urinary levels of cadmium, chromium, nickel and lead. Smokers showed a high urinary cadmium level. In addition to cadmium, a high urinary lead level was associated with cumulative cigarette smoking and herbal medicine use. CONCLUSION: Environmental factors might contribute to higher urinary levels of heavy metals and ultimately result in urothelial carcinoma carcinogenesis. These findings can promote proper environmental surveillance of exposure to heavy metals in the general population.

Results of Intravesical Chemo-Hyperthermia in High-risk Non-muscle Invasive Bladder Cancer.

PURPOSE: To examine the effectiveness of mitomycin-C and chemo-hyperthermia in combination for patients with high-risk non-muscle-invasive bladder cancer. MATERIALS AND METHODS: Between November 2011-September 2013, 43 patients with high-risk non-muscle-invasive bladder cancer undergoing adjuvant chemo-hyperthermia in two centers were evaluated retrospectively. Treatment consisted of 6 weekly sessions, followed by 6 sessions. Recurrence and progression rate, recurrence-free interval and side effects were examined. Analyzed factors included age, gender, smoking status, AB0 blood group, body mass index, T stage and grade, concominant CIS assets. The associations between predictors and recurrence were assessed using multivariate Cox proportional hazard analyses. RESULTS: A total of 40 patients completed induction therapy. Thirteen (32.5%) were diagnosed with tumor recurrence. Median follow-up was 30 months (range 9-39). Median recurrence-free survival was 23 months (range 6-36). The Kaplan-Meier-estimated recurrence-free rates for the entire group at 12 and 24 months were 82% and 61%. There was no statistically significant difference between patient subgroups. Cox hazard analyses showed that an A blood type (OR=6.23, p=0.031) was an independent predictor of recurrence- free. Adverse effects were seen in 53% of patients and these were frequently grades 1 and 2. CONCLUSIONS: Intravesical therapy with combination of mitomycin-C and chemohyperthermia seems to be appropriate in high-risk patients with non-muscle-invasive bladder cancer who cannot tolerate or have contraindications for standard BCG therapy.

Risk stratification for locoregional recurrence after radical cystectomy for urothelial carcinoma of the bladder.

PURPOSE: To externally validate the Christodouleas risk model incorporating pathological tumor stage, lymph node (LN) count and soft tissue surgical margin (STSM) and stratifying patients who develop locoregional recurrence (LR) after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). In addition, we aimed to generate a new model including established clinicopathological features that were absent in the Christodouleas risk model. METHODS: Prospectively assessed multicenter data from 565 patients undergoing RC for UCB in 2011 qualified for final analysis. For the purpose of external validation, risk group stratification according to Christodouleas was performed. Competing-risk models were calculated to compare the cumulative incidences of LR after RC. RESULTS: After a median follow-up of 25 months (interquartile range 19-29), the LR-rate was 11.5 %. The Christodouleas model showed a predictive accuracy of 83.2 % in our cohort. In multivariable competing-risk analysis, tumor stage ≥pT3 (HR 4.32, p < 0.001), positive STSM (HR 2.93, p = 0.005), lymphovascular invasion (HR 3.41, p < 0.001), the number of removed LNs <10 (HR 2.62, p < 0.001) and the administration of adjuvant chemotherapy (HR 0.40, p = 0.008) independently predicted the LR-rate. The resulting risk groups revealed significant differences in LR-rates after 24 months with 4.8 % for low-risk patients, 14.7 % for intermediate-risk patients and 38.9 % for high-risk patients (p < 0.001 for all), with a predictive accuracy of 85.6 %, respectively. CONCLUSIONS: The Christodouleas risk model has been successfully externally validated in the present prospective series. However, this analysis finds that overall model performance may be improved by incorporating lymphovascular invasion. After external validation of the newly proposed risk model, it may be used to identify patients who benefit from an adjuvant therapy and suit for inclusion in clinical trials.

A retrospective review of patients with urothelial cancer in 3,370 recipients after renal transplantation: a single-center experience.

OBJECTIVE: To summarize the diagnosis, surgical intervention and postoperative management of patients with urothelial cancer (UC) after renal transplants (RTx). METHODS: In our retrospective review of 3,370 RTx recipients in our transplant center from 1974 to 2012, all recipients underwent routine checkups and follow-up. Imaging was performed in all patients suspected of having malignancies, and the histological cell type of the specimen slices was reappraised by pathologists. The data of all recipients with malignancies were retrospectively reviewed to determine clinical characteristics after RTx. RESULTS: A total of 169 patients of the cohort of 3,370 had malignancies after RTx. Of 180 tumors, 106 tumors were confirmed as UC. Fifty-two patients had taken drugs containing aristolochic acid. The median time to neoplasia after RTx in the group taking aristolochic acid (30 months) was significantly less than in those not taking aristolochic acid (60.3 months). We recommended surgical intervention for RTx recipients with UC, transurethral resection of bladder tumors for patients with solitary or concomitant superficial UC, and radical cystectomy for high-risk bladder UC. We performed simultaneous bilateral or unilateral nephroureterectomy in patients with upper urinary tract UC. CONCLUSION: Our results suggest that UC is the predominant tumor in Chinese RTx recipients and that regular urinalysis and imaging are needed in all recipients after RTx, especially women with a history of taking aristolochic acid. Surgical interventions did not increase the risk beyond that in UC patients without RTx.

Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes.

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.

Occupational exposure to herbs containing aristolochic acids increases the risk of urothelial carcinoma in Chinese herbalists.

PURPOSE: Aristolochic acid can cause urothelial carcinoma. Herbal remedies containing aristolochic acids were previously categorized as proven group 1 human carcinogens by the WHO cancer agency, the International Agency for Research on Cancer. However, the health effect on workers exposed to aristolochic acid is unclear. Fangchi, a representative herb containing aristolochic acid, is commonly used in the Chinese herbal medicine industry. We determined whether workers exposed to fangchi are at increased risk for urothelial carcinoma. MATERIALS AND METHODS: We designed a case-control study based in a national representative cohort of Chinese herbalists. This study analyzed 6,564 Chinese herbalists employed between 1985 and 1998. All incident cases of urothelial carcinoma that occurred between 1988 and 2001 were defined as the case group. Controls were selected from the baseline cohort in a randomized manner. A total of 24 cases and 140 controls were included in analysis. Information about fangchi exposure was obtained in a questionnaire survey administered in 2002. RESULTS: Processing, selling or dispensing herbs containing fangchi significantly increased the risk of urothelial carcinoma (HR 2.4, 95% CI 1.1-5.3, p = 0.03). This relationship was independent of cigarette smoking or potential arsenic exposure from drinking water from deep wells. CONCLUSIONS: Exposure to the Chinese herbal drug fangchi increases the risk of urothelial carcinoma in herbalists. Appropriate medical monitoring is warranted for workers who have similar exposure.

Aristolochic acid-associated urothelial cancer in Taiwan.

Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of (5')AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.

Epidemiologic status of bladder cancer in Shiraz, southern Iran.

BACKGROUND: Bladder cancer is the second most common malignancy of the genitourinary tract worldwide after prostate cancer. However, in Iran it is the most common cancer of the genitourinary system and the third most common cancer in males. The increasing trend in bladder cancer incidence in recent decades, along with the lack of research on this malignancy in Iran, make epidemiologic research important in light of its preventability through early recognition and limiting exposure to risk factors. The present study aimed to assess the epidemiology of bladder cancer in Shiraz, a large city in southern Iran, during a 2-year period. METHODS: The data for this study were obtained from the population-based cancer registry of the Vice-Chancellery for Health Affairs of Shiraz University of Medical Sciences and Shiraz hospitals between March 1, 2007 and March 1, 2009. Demographic, clinical and pathological aspects of 216 patients with bladder cancer were investigated through careful review of their medical records. Statistical analyses were performed with SPSS software. P values less than 0.05 were considered statistically significant. RESULTS: We analyzed data for 179 (82.9%) men and 37 (17.1%) women (mean age of 65.1∓12.7 years). Tobacco and opium use were found in 109 (65.3%) and 44 (34.1%) patients, respectively. Cigarette smokers and water pipe smokers were mostly men (P=0.001 and P=0.04, respectively). The most common type of tumor was transitional cell carcinoma (95.7%) and most tumors were of low malignant potential grade (39.7%). Nearly half of the patients suffered recurrence. CONCLUSION: Comparisons with previous studies showed that bladder cancer tends to appear slightly more often in the elderly and that the tumors tend to have a higher grade of malignancy in our region. There is a need for more epidemiologic studies on the trends in the incidence and other epidemiologic indices.

Increased risks of upper tract urothelial carcinoma in male and female chinese herbalists.

BACKGROUND/PURPOSE: It has been shown that herbs that contain aristolochic acid induce urological cancer. Chinese herbalists have easy access to such herbs. Our previous mortality study has shown a significantly increased risk of urological cancer in female but not male herbalists. To re-examine this risk in male herbalists, the incidence of urological cancer was analyzed. METHODS: We enrolled all 6550 Chinese herbalists in Taiwan registered during 1985-2000, and we retrospectively followed the development of cancer until 2001 by analysis of data collected from the Taiwan Cancer Registry. Standardized incidence ratios (SIRs) were calculated for urological cancers in herbalists and compared with those for the general population in Taiwan. RESULTS: There were 30 newly diagnosed cases of urological cancer and most of them were transitional cell carcinoma (93.1%). The mean age at diagnosis for urothelial carcinoma was 51.6 years, and 51.9% were in the upper urinary tract. After adjustment for age and sex, the SIR for all urological cancers was 3.51 [(95% confidence interval (CI): 2.37-5.01]. When stratified by location, the SIRs for kidney and upper urinary tract cancers and bladder cancer were 4.24 (95% CI: 2.47-6.80) and 2.86 (95% CI: 1.52-4.89), respectively. When analyzed by sex, the SIRs for all urological cancers, kidney and upper urinary tract cancers, and bladder cancer were also significantly increased in male herbalists. CONCLUSION: The significant risk of urothelial carcinoma noted in male herbalists increases our suspicion that this is an occupational disease that renders regular health assessment of herbalists an urgent necessity.

Consumption of animal products, olive oil and dietary fat and results from the Belgian case-control study on bladder cancer risk.

AIM: The Western diet typically consists of high levels of saturated fat from animal products and has been associated with an increased risk of bladder cancer. Whilst olive oil, the predominant fat in the Mediterranean diet, has been associated with many health benefits its role in bladder cancer aetiology is still unknown. Therefore, we investigated the effect of intake of animal products, olive oil and other major dietary fats on bladder cancer risk. METHODS: Dietary data were collected from 200 cases and 386 controls participating in a Belgian case-control study on bladder cancer. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) by comparing the highest with the lowest tertiles of intake between cases and controls using unconditional logistic regression. Adjustment was made for age, sex, smoking characteristics, occupational exposures and calorie intake. RESULTS: There was a statistically significant inverse association between olive oil intake and bladder cancer consistent with a linear dose-response relationship: middle versus the lowest tertile (OR: 0.62; 95% CI: 0.39-0.99) and the highest versus the lowest tertile (OR: 0.47; 95% CI: 0.28-0.78; p-trend = 0.002). We also observed borderline statistically significant increased odds of bladder cancer for the highest versus the lowest intake of cheese (OR: 1.53; 95% CI: 0.95-2.46; p-trend = 0.08). No potential associations were detected for any other source or type of dietary fat. CONCLUSION: We observed evidence for a protective effect by olive oil and a possible increased risk of bladder cancer associated with a high intake of cheese. Our results require further investigation and confirmation by other studies.

Opium consumption and risk of bladder cancer: A case-control analysis.

OBJECTIVE: We evaluated the relationship between opium consumption and bladder cancer (BC) in a case-control study of an Iranian population. MATERIALS AND METHODS: In a hospital-based case-control study of 179 patients with BC and 179 cancer-free controls frequency-matched by age, sex, and smoking status, we investigated the relationship between opium consumption and BC. A comprehensive epidemiologic interview was conducted on all participants to collect personal information, such as demographics and smoking status. RESULTS: Overall, we found significant age, sex, cigarette smoking adjusted association between BC risk and opium consumption, [odds ratio (OR) = 4.60; 95% confidence interval (CI) = 3.53-6.28]. The elevated risk was more evident in older individuals (OR = 5.42; 95% CI, 4.12-7.28) than younger individuals (OR = 3.65; 95% CI, 2.76-4.76) (P = 0.01). Heavy smokers with the opium consumption exhibited a 6-fold elevated risk for BC (OR = 6.16; 95% CI, 3.34-8.32) (P = 0.0001). When stratified according to different grades of BC, a 3.4-fold increased risk was associated with the opium consumption in grade III with an OR of 3.44 (95% CI, 2.82-8.28) (P = 0.001). A similar but slightly higher risk was also seen in case of grade IV tumors (OR = 3.86; 95% CI, 2.14-10.16) (P = 0.001). Invasive bladder tumors were more common among the opiates users (OR = 2.6; 95% CI, 1.44-5.42) (P = 0.01). Cumulative risk of BC in women with opium consumption (OR = 4.10 95% CI, 3.54-5.88) (P = 0.001) was slightly less than in men (OR = 5.10 95% CI, 3.54-5.88) (P = 0.0001). Based on Pearson correlations, the risk of BC significantly correlated with opium dependence duration (r = 0.74, P = 0.001), type of opiate used (r = 0.65, P = 0.001), and simultaneous cigarette smoking (r = 0.74, P = 0.0001). CONCLUSION: The results indicated that there is about 5-fold increase in risk of developing this cancer in the presence of opium consumption. Further research is needed to investigate the functional implications of the opium consumption in BC.

Expression of VEGF in urinary bladder transitional cell carcinoma in an Iraqi population subjected to depleted uranium: an immunohistochemical study.

The present study aimed to assess the correlation between vascular endothelial growth factor (VEGF) overexpression and the grade, size, and recurrence of transitional cell carcinoma (TCC) in the south of Iraq, which includes regions that have been exposed to high levels of depleted uranium. The study also sought to evaluate whether there is any biomarker in the expression that could be correlated with the increased incidence of this type of cancer in the exposed areas. Samples of formalin-fixed and paraffin-embedded tissue from 54 patients (41 males and 13 females) with TCC and from 32 patients with benign bladder lesions (cystitis) used as controls were included in this study. The avidin-biotin complex method was used for immunohistochemical detection of VEGF. VEGF immunoexpression was positive in 77.77% of TCC but was not found in benign bladder lesions (cystitis) (P<0.05). VEGF immunostaining was positively correlated with grade, stage, and recurrence of TCC but the findings were not statistically significant (P>0.05). These findings support the role of VEGF in the carcinogenesis of TCC regarding evolution, behavior, and aggressiveness. Hence, VEGF could be considered as a poor prognostic parameter in bladder cancer. No positive correlation between immunohistochemical expression and the high incidence of TCC was detected (R=<0.3). The study further concludes that immunohistochemical expression of the VEGF gene in TCC bladder cancer does not differ from similar cancers found in other parts of the world where there has been no known exposure to depleted uranium.

Dietary patterns and risk of bladder cancer: a factor analysis in Uruguay.

OBJECTIVE: To determine the major dietary patterns associated with bladder cancer risk, we conducted a principal components analysis (PCA) in a case-control study from Uruguay. METHODS: A total of 255 newly diagnosed and microscopically confirmed cases of transitional cell carcinoma of the bladder and 501 hospitalized controls were included in the study. Both series were drawn from the four major public hospitals in Montevideo, Uruguay. Cases and controls were frequency matched on age and sex. Controls were submitted to factor (principal components) analysis. RESULTS: We retained three factors that explained 25.1% of the total variance (including error variance). The first factor was labeled as the sweet beverages pattern. This factor was characterized by high loadings of coffee, tea, and added sugar and was strongly associated with risk of bladder cancer (OR 3.27, 95% CI 1.96-5.45). The second factor was labeled as the Western pattern and displayed high loadings of red meat, fried eggs, potatoes, and red wine. This pattern was directly associated with risk of bladder cancer (OR 2.35, 95% CI 1.42-3.89). Finally, the third factor was labeled as the prudent pattern and showed high loadings of fresh vegetables, cooked vegetables, and fruits. This pattern was not associated with risk of bladder cancer. CONCLUSIONS: According to our study, non-alcoholic beverages were the strongest risk factor for bladder cancer, whereas the Western pattern was also associated with a significant increase in risk of bladder cancer.