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

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

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.

Single Versus Maintenance Intravesical Chemotherapy for the Prevention of Bladder Recurrence after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Randomized Clinical Trial.

INTRODUCTION: The objective of this study was to determine the efficiency of 1-year maintenance intravesical chemotherapy (MIC) in reducing bladder recurrence (BR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma compared with single intravesical instillation (SIC). PATIENTS AND METHODS: Between January 2015 and May 2017, patients who underwent RNU were randomized to receive SIC (epirubicin 50 mg) or MIC (once weekly for 6 weeks plus once monthly for 1 year). The primary outcome was the rate of histologically proven BR. The secondary outcomes included chemotherapy-related toxicities and disease-specific survival (DSS). Thirty-five patients in each arm were required to achieve a power of 80%. RESULTS: A total of 38 (SIC) and 36 (MIC) patients were analyzed. In SIC, BR developed in 5 (13.2%) over a median follow-up of 3 months (range, 3-6 months) compared with 9 (25%) patients over 12 months (range, 3-28 months) in MIC (P = .08). The 6- and 12-month BR-free survivals were the same (86.8%) in SIC versus 88.9% and 83.3% in MIC, respectively (P = .2). Lymphovascular invasion was significantly associated with BR (P = .04). Post-RNU intravesical chemotherapy regimens did not alter DSS. Blood transfusion and advanced tumor stage were independent predictors for DSS. No significant medication toxicity was reported. CONCLUSIONS: Following RNU, MIC did not change the natural course of BR beyond a single instillation apart from potentially delaying its occurrence. Lymphovascular invasion and blood transfusion were associated with worse BR and DSS outcomes, respectively.

Smoking Cessation and the Risk of Bladder Cancer among Postmenopausal Women.

Smoking is the strongest established risk factor for bladder cancer. Former smokers have a lower risk of bladder cancer compared with current smokers, but findings on the dose-response relationship between years after quitting and the risk of bladder cancer are inconsistent. A total of 143,279 postmenopausal women from the Women's Health Initiative Study were included. Cox proportional hazards regression models were applied for estimating age- and multivariable-adjusted HRs and their 95% confidence intervals (CI). There were 870 bladder cancer cases identified over an average of 14.8 years of follow-up. After adjusting for pack-years of smoking, bladder cancer risk among former smokers declined by 25% within the first 10 years of cessation and continued to decrease as cessation time increased but remained higher than never smokers after 30 years of quitting (HR, 1.92; 95% CI, 1.43-2.58). Smokers who quit smoking had a lower risk of bladder cancer compared with current smokers (HR, 0.61; 95% CI, 0.40-0.94). We conclude that among postmenopausal women, there is a significant reduction in the risk of bladder cancer after quitting smoking. In addition to primary prevention, smoking cessation is critical to prevent the incidence of bladder cancer in older women.

Epidemiology, prevention, screening, diagnosis, and evaluation: update of the ICUD-SIU joint consultation on bladder cancer.

PURPOSE: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics. METHODS: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system. RESULTS: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities. CONCLUSIONS: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.

Assessing the impact of mass media public health campaigns. Be Clear on Cancer 'blood in pee': a case in point.

OBJECTIVES: To assess the impact on suspected cancer referral burden and new cancer diagnosis of Public Health England's recent Be Clear on Cancer 'blood in pee' mass media campaign. METHODS: A retrospective cohort study design was used. For two distinct time periods, August 2012 to May 2013 and August 2013 to May 2014, all referrals of patients deemed to be at risk of urological cancer by the referring primary healthcare physician to Imperial College NHS Healthcare Trust were screened. Data were collected on age and sex and whether the referral was for visible haematuria, non-visible haematuria or other suspected urological cancer. In addition to referral data, hospital episode data for all new renal cell (RCC) and upper and lower tract transitional cell carcinoma (TCC), as well as testicular and prostate cancer diagnoses for the same time periods were obtained. RESULTS: Over the campaign period and the subsequent 3 months, the number of haematuria referrals increased by 92% (P = 0.013) when compared with the same period a year earlier. This increase in referrals was not associated with a significant corresponding rise in cancer diagnosis; instead changes of 26.8% (P = 0.56) and -3.3% (P = 0.84) were seen in RCC and TCC, respectively. CONCLUSIONS: This study has shown that the Be Clear on Cancer 'blood in pee' mass media campaign significantly increased the number of new suspected cancer referrals, but there was no significant change in the diagnosis of target cancers across a large catchment. Mass media campaigns are expensive, require significant planning and appropriate implementation and, while the findings of this study do not challenge their fundamental objective, more work needs to be done to understand why no significant change in target cancers was observed. Further consideration should also be given to the increased referral burden that results from these campaigns, such that pre-emptive strategies, including educational and process mapping, across primary and secondary care can be implemented.

"Lassie," "Toto," and fellow pet dogs: poised to lead the way for advances in cancer prevention.

Cancer causes substantial morbidity and takes the lives of over 8 million people worldwide each year. Advances in cancer prevention research are crucial, and animal models are key to this. There are many valuable experimentally induced cancer models, but these do not fully meet the needs for cancer prevention studies. Pet dogs with risks for naturally occurring cancer can fill important gaps in cancer prevention research. Using invasive urothelial carcinoma (iUC) as an example, the advantages of utilizing pet dogs include: (1) close similarities between dogs and humans in carcinogenesis, molecular and cellular features, invasive and metastatic behavior, and response to treatment, thus providing high relevance for comparative studies, (2) shared environment between dogs and humans to help identify not-yet-known environmental iUC risks, (3) strong breed-associated risk (5- to 21-fold increased risk compared with mixed breeds) that facilitates investigation of gene-environment interactions, screening, and early intervention, (4) large size of dogs (versus rodents) that allows collection of fluids and tissues via cystoscopy, and detailed imaging at multiple time points, and (5) acceptance for studies in which each participating dog can benefit while enjoying life in their family environment, and in which findings will help other dogs and humans. An ongoing 3-year study in Scottish Terriers (comparable to a 15- to 20-year study in humans) is aimed at defining genetic and environmental risk factors for iUC, effective methods for screening/early detection, and a successful secondary cancer prevention approach with very promising results to date. Pet dogs can indeed propel cancer prevention research.

Impacto de la expresión de p53, MIB-1 y PECAM-1 en el pronóstico del carcinoma urotelial de la pelvis renal / Impact of p53, MIB-1 and PECAM-1 expression on the prognosis of urothelial carcinoma of the renal pelvis

Objetivo: Investigar si la sobreexpresión de los niveles proteicos de p53, MIB-1 y PECAM-1 ocupa un lugar de interés en la predicción de pronóstico del carcinoma de células transicionales del tracto urinario superior (CCT-TUS) de asiento primario en la pelvis renal. Material y método: Análisis uni y multivariante para la predicción de pronóstico en una serie de 82 pacientes con CCT-TUS de pelvis renal sin metástasis al diagnóstico (N0/Nx M0) tratados mediante nefroureterectomía exclusivamente. Se evalúan parámetros clínico-patológicos (edad, sexo, grado, extensión tumoral, variedad histológica, patrón de crecimiento, invasión vascular, infiltración del parénquima renal, necrosis tumoral) y expresión inmunohistoquímica (IHQ) de p53, MIB-1 (ki-67) y PECAM-1 (CD31) en secciones realizadas con microarray de tejido (TMA). Resultados: El 47,6% fueron lesiones de alto grado según la clasificación USIP-OMS. El patrón de crecimiento fue plano en 15,85%. La distribución por categoría T fue: 3,7% pTa, 51,2% pT1, 11% pT2, 29,3% pT3 y 4,9% pT4. El seguimiento medio fue 46,8 + 38,5 (rango: 4-172) meses. La mediana de supervivencia se alcanzó a los 57 (IC 95%: 44-63) meses. El análisis univariante reveló que la supervivencia en estos pacientes se asocia a tamaño tumoral (p = 0,028), variedad histológica (p < 0,0001), patrón de crecimiento (p < 0,0001), grado (p < 0,0001), pT (p = 0,01), invasión vascular (p = 0,025), necrosis (p = 0,004) y sobreexpresión de p53 (p = 0,0006), PECAM-1 (p = 0,0036) y MIB-1 (p = 0,0038). El modelo de regresión de Cox mostró que alto grado (HR = 4,2 [IC 95%: 1,28-13,79]; p = 0,018), patrón de crecimiento plano (HR = 2,52 [IC 95%: 1,05-6,03]; p = 0,038) y sobreexpresión de p53 (HR = 2,8 [IC 95%: 1,22-6,44]; p = 0,015) fueron variables predictivas independientes. Conclusión: El grado histológico, el patrón de crecimiento tumoral y la sobreexpresión de p53 se establecen como los principales factores predictivos de pronóstico en CCT-TUS primario de pelvis renal. No se reproduce el valor independiente de MIB-1 objetivado en otros estudios

Objective: Determining whether the overexpression of p53, MIB-1 and PECAM-1 of protein levels is of interest in predicting the prognosis of transitional cell carcinoma of the upper urinary tract (TCC-UUT) with the primary seat in the renal pelvis. Materials and methods: A univariate and multivariate analysis was conducted for prognosis prediction in a series of 82 patients with TCC-UUT of the renal pelvis who had no metastases at diagnosis (N0/Nx M0) and were treated exclusively with nephroureterectomy. We assessed clinicopathological parameters (age, gender, tumor grade and extent, histological variety, growth pattern, vascular invasion, infiltration of the renal parenchyma, and tumor necrosis) and the immunohistochemical expression of p53, MIB-1 (ki-67) and PECAM-1 (CD31) in sections performed with tissue microarray (TMA). Results: A total of 47.6% of the patients had high-grade lesions according to the USIP-WHO classification. The growth pattern was flat in 15.85%. The distribution by T category was: 3.7% pTa, 51.2% pT1, 11% pT2, 29.3% pT3 and 4.9% pT4. The mean follow-up was 46.8 ± 38.5 (range 4-172) months. The median survival was reached at 57 (95% CI 44-63) months. The univariate analysis revealed that survival in these patients is associated with tumor size (p = 0.028), histological variety (p < 0.0001), growth pattern (p < 0.0001), grade (p < 0.0001), pT (p = 0.01), vascular invasion (p = 0.025), necrosis (p = 0.004) and overexpression of p53 (p = 0.0006), PECAM-1 (p = 0.0036) and MIB-1 (p = 0.0038). The Cox regression model showed that high-grade (HR, 4.2; 95% CI 1.28-13.79; p = 0.018), flat-growth pattern (HR, 2.52; 95% CI 1.05-6.03; p = 0.038) and p53 overexpression (HR, 2.8; 95% CI 1.22-6.44; p = 0.015) were independent predictors. Conclusion: Histological grade, tumor growth pattern and p53 over expression were established as the primary predictors of prognosis for primary TCC-UUT of the renal pelvis. The independent value of MIB-1 observed in other studies was not reproduced in this study

A modified single mini-incision complete urinary tract exenteration for urothelial carcinoma in dialysis patients.

OBJECTIVE: To present our experience with single mini-incision complete urinary tract exenteration (CUTE) for female dialysis patients suffering from urothelial carcinoma (UC). PATIENTS AND METHODS: Institutional review board approval was obtained. From 2005 through 2012, 14 female dialysis patients with UC underwent single mini-incision CUTE, in combination with radical hysterectomy and bilateral salpingo-oophorectomy. All were placed in the modified dorsal lithotomy position without repositioning. An infraumbilical midline mini-incision was made. Bilateral nephroureterectomy was first performed entirely extraperitoneally, followed by radical cystectomy with removal of the uterus and ovaries transperitoneally. RESULTS: All procedures were done successfully without major complications. The median operative time was 242.5 minutes, and estimated blood loss was 500 mL. The median time to oral intake was 2 postoperative days; the median hospital stay was 11 days. Ten patients remained cancer-free at a median follow-up of 46.5 months; six patients were confirmed as having preoperatively undetectable UC or renal cell carcinoma, even after reviewing preoperative computed tomography. CONCLUSIONS: This modified technique provides a time-saving complete urinary tract extirpation to eliminate preoperatively undetectable malignancy, reduce metachronous recurrences, and avert perioperative complications associated with pneumoperitoneum and repositioning. Good cancer control and early convalescence can mutually be achieved in experienced hands.

Efficacy of immediate instillation combined with regular instillations of pirarubicin for Ta and T1 transitional cell bladder cancer after transurethral resection: a prospective, randomized, multicenter study.

BACKGROUND: Immediate intravesical instillation of chemotherapeutic agents after transurethral resection (TUR) of nonmuscle invasive transitional cell bladder cancer has recently been suggested and has been proven to decrease the tumor recurrence rate significantly. This study is to evaluate the efficacy and safety of immediate intravesical instillation combined with regular instillations of Pirarubicin (THP(®)) as prophylaxis compared to regular instillations only after TUR operation. METHODS: This was a prospective, randomized, multi-center, clinical study. Patients diagnosed with non-muscle invasive bladder cancer (Ta and T1) pathologically and suitable for TUR were enrolled randomly into two groups. In the study group, the patients received intravesical instillation within 24-hour post TURBT, followed by regular intravesical therapy using 30 mg/50 ml of THP(®) once a week for 8 weeks, and then once a month to 1 year postoperatively Among the patients. In the control group, patients received regular instillation only. RESULTS: A total of 403 patients were enrolled into this study from 26 institutions in China. Among the potients, 210 were enrolled into the study group and 193 were enrolled into the control group. At the median follow-up of 18 months, the recurrence rate was 7.8% in the study group, significantly lower than that in the control group (14.3%; P = 0.042). Subgroup analysis showed that the recurrence rate in low and intermediate-risk patients was significantly lower in the study group (6.8%) than in the control group (14.0%; P = 0.047), although no significant differences were found in high-risk patients. CONCLUSION: One immediate dose of THP(®) 30 mg after TURBT followed by regular intravesical therapy appears well tolerated and more effective than regular intravesical therapy for preventing tumor recurrence, especially in low and intermediate-risk patients.

p53-stabilizing agent CP-31398 prevents growth and invasion of urothelial cancer of the bladder in transgenic UPII-SV40T mice.

The high prevalence of bladder cancer and its recurrence make it an important target for chemoprevention. About half of invasive urothelial tumors have mutations in p53. We determined the chemopreventive efficacy of a p53-stabilizing agent, CP-31398, in a transgenic UPII-SV40T mouse model of bladder transitional cell carcinoma (TCC) that strongly resembles human TCC. After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm of CP-31398 for 34 weeks. Progression of bladder cancer growth was monitored by magnetic resonance imaging. At 40 weeks of age, all mice were killed; urinary bladders were collected to determine weights, tumor incidence, and histopathology. There was a significant increase in bladder weights of transgenic versus wild-type mice (male: 140.2 mg vs 27.3 mg, P < .0001; female: 34.2 mg vs 14.8 mg, P < .0001). A significant decrease in the bladder tumor weights (by 68.6-80.2%, P < .0001 in males and by 36.9-55.3%, P < .0001 in females) was observed in CP-31398-treated mice. Invasive papillary TCC incidence was 100% in transgenic mice fed control diet. Both male and female mice exposed to CP-31398 showed inhibition of invasive TCC. CP-31398 (300 ppm) completely blocked invasion in female mice. Molecular analysis of the bladder tumors showed an increase in apoptosis markers (p53, p21, Bax, and Annexin V) with a decrease in vascular endothelial growth factor in transgenic mice fed CP-31398. These results suggest that p53-modulating agents can serve as potential chemopreventive agents for bladder TCC.

Long-term NSAID use and incident urothelial cell carcinoma in the VITamins and Lifestyle (VITAL) study.

PURPOSE: Literature on the chemopreventive role of nonsteroidal anti-inflammatory drugs (NSAIDs) in urothelial carcinoma of the bladder (UC) is conflicting. A recent pooled analysis of 3 cohorts reported regular use of nonaspirin NSAIDs was associated with reduced risk of urothelial carcinoma (UC) among nonsmokers only; however, nonsmokers are a group with a low risk of UC. We examine the association between NSAID use and UC risk. MATERIALS AND METHODS: Study participants were members of the VITamins and Lifestyle (VITAL) cohort of 77,048 Washington State residents aged 50-76 years who completed a baseline questionnaire in 2000-2002 on NSAID use and cancer risk factors. Ten-year use of aspirin and other NSAIDs was categorized as none, low-use (1-3 d/wk or <4 years), or high-use (≥ 4 d/wk and ≥ 4 years). Incident UC cases were prospectively identified via linkage to a local cancer registry. Hazard ratios (HR) were estimated by multivariate Cox regression. RESULTS: A total of 385 incident cases of UC were diagnosed over a mean follow-up of 7 years. There was no association with NSAID use and risk of UC. However, the association of use of nonaspirin NSAIDs with UC risk differed by smoking status (P for interaction = 0.02). Specifically, among long-term former smokers (quit ≥ 10 years), nonaspirin NSAID use was associated with a 31% reduction in risk of UC in low-users (HR 0.69, 95% CI 0.46-1.04), and 48% reduction in risk for high-users (HR 0.52, 95% CI 0.24-1.11, P for trend = 0.02). CONCLUSIONS: Our results show a risk reduction with nonaspirin NSAID use among long-term quitters, a group with significant risk of UC.

Bladder cancer patterns of pelvic failure: implications for adjuvant radiation therapy.

PURPOSE: Local-regional failures (LFs) after cystectomy with or without chemotherapy are common in locally advanced disease. Adjuvant radiation therapy (RT) could reduce LFs, but toxicity has discouraged its use. Modern RT techniques with improved normal tissue sparing have rekindled interest but require knowledge of pelvic failure patterns to design treatment volumes. METHODS AND MATERIALS: Five-year LF rates after radical cystectomy plus pelvic node dissection with or without chemotherapy were determined for 8 pelvic sites among 442 urothelial bladder carcinoma patients. The impact of pathologic stage, margin status, nodal involvement, and extent of node dissection on failure patterns was assessed using competing risk analysis. We calculated the percentage of patients whose sites of LF would have been completely encompassed within various hypothetical clinical target volumes (CTVs) for postoperative radiation. RESULTS: Compared with stage ≤pT2, stage ≥pT3 patients had higher 5-year LF rates in virtually all pelvic sites. Among stage ≥pT3 patients, margin status significantly altered the failure pattern whereas extent of node dissection and nodal positivity did not. In stage ≥pT3 patients with negative margins, failure occurred predominantly in the iliac/obturator nodes and uncommonly in the cystectomy bed and/or presacral nodes. Of these patients in whom failure subsequently occurred, 76% would have had all LF sites encompassed within CTVs covering only the iliac/obturator nodes. In stage ≥pT3 with positive margins, cystectomy bed and/or presacral nodal failures increased significantly. Only 57% of such patients had all LF sites within CTVs limited to the iliac/obturator nodes, but including the cystectomy bed and presacral nodes in the CTV when margins were positive increased the percentage of LFs encompassed to 91%. CONCLUSIONS: Patterns of failure within the pelvis are summarized to facilitate design of adjuvant RT protocols. These data suggest that RT should target at least the iliac/obturator nodes in stage ≥pT3 with negative margins; coverage of the presacral nodes and cystectomy bed may be necessary for stage ≥pT3 with positive margins.

Plasma carotenoids and vitamin C concentrations and risk of urothelial cell carcinoma in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Published associations between dietary carotenoids and vitamin C and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. OBJECTIVE: We investigated the association between plasma carotenoids and vitamin C and risk of urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. DESIGN: A total of 856 patients with newly diagnosed UCC were matched with 856 cohort members by sex, age at baseline, study center, date and time of blood collection, and fasting status. Plasma carotenoids (α- and ß-carotene, ß-cryptoxanthin, lycopene, lutein, and zeaxanthin) were measured by using reverse-phase HPLC, and plasma vitamin C was measured by using a colorimetric assay. Incidence rate ratios (IRRs) were estimated by using conditional logistic regression with adjustment for smoking status, duration, and intensity. RESULTS: UCC risk decreased with higher concentrations of the sum of plasma carotenoids (IRR for the highest compared with the lowest quartile: 0.64; 95% CI: 0.44, 0.93; P-trend = 0.04). Plasma ß-carotene was inversely associated with aggressive UCC (IRR: 0.51; 95% CI: 0.30, 0.88; P-trend = 0.02). Plasma lutein was inversely associated with risk of nonaggressive UCC (IRR: 0.56; 95% CI: 0.32, 0.98; P-trend = 0.05). No association was observed between plasma vitamin C and risk of UCC. CONCLUSIONS: Although residual confounding by smoking or other factors cannot be excluded, higher concentrations of plasma carotenoids may reduce risk of UCC, in particular aggressive UCC. Plasma lutein may reduce risk of nonaggressive UCC.

Inhibition of mouse urinary bladder carcinogenesis by açai fruit (Euterpe oleraceae Martius) intake.

Açai, fruit from Euterpe oleraceae Martius, is consumed in natura and in a variety of beverages and food preparations and possesses several potential antioxidant compounds. In a first study for anticarcinogenicity screening, male Swiss mice (n = 20/per group) were chemically-induced to urothelial bladder carcinogenesis for 10 weeks and received a standard diet or a standard diet containing 2.5 and 5 % spray-dried açai pulp (AP) for 10 weeks. At week 20, the incidence of simple and nodular hyperplasia and the incidence and multiplicity of transitional cell carcinoma (TCC) were evaluated. In a second study for antigenotoxicity screening, male Swiss mice (n = 6/per group) were fed standard diet or standard diet containing 5 % AP for three weeks. Urothelial cell suspensions were obtained and challenged with H(2)O(2) for induction of DNA damage and analyzed by comet assay. Overall, dietary 5 % AP reduced TCC incidence and multiplicity (p = 0.019 and p = 0.015, respectively) and tumor cell proliferation and p63 expression (p = 0.02 and p = 0.007, respectively), Furthermore, the group fed the 5 % AP presented a significant reduction (p < 0.01) in DNA damage induced by H(2)O(2), a notable oxidant agent. The results suggest that the spray-dried açai pulp used here inhibits the TCC development in male Swiss mice, probably due to its potential antioxidant action.

Overweight in adolescence is related to increased risk of future urothelial cancer.

Obesity has been linked to various malignancies, but a clear relation of overweight with urothelial cancer has not been established. We assessed the association between adolescent obesity and future risk for urothelial cancer. Medical data on 1,110,835 Israeli adolescents examined for fitness for military duty between 1967 and 2005 were linked to the National Cancer Registry in this nationwide population-based cohort study. We used Cox proportional hazards modeling to estimate the covariate-adjusted hazard ratio (HR) for urothelial cancer associated with BMI measured at age 17. The mean follow-up of 17.6 ± 10.8 years reflected 19,576,635 person years, during which 661 examinees developed urothelial cancer of the bladder, ureter, or renal pelvis. BMI ≥ 85 th standard percentile in adolescence significantly predicted increased risk of urothelial cancer with a HR (adjusted for year of birth, education and religiosity) of 1.42 (95% confidence interval (CI), 1.13-1.77, P = 0.002). Similar results were observed using the ≥ 25 kg/m(2) definition of overweight (HR = 1.36 (95% CI, 1.08-1.72), P = 0.008). Incidence of urothelial cancer was significantly lower in the more educated and among those who attended religious schools. Overweight in adolescence is related to increased risk of future urothelial cancer. In view of the growing incidence of both urothelial cancer and adolescent obesity, our study suggests an avenue for possible prevention of urothelial cancer.

RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration.

Half of patients with muscle-invasive bladder cancer develop metastatic disease, and this is responsible for most of the deaths from this cancer. Low expression of RhoGTP dissociation inhibitor 2 (RhoGDI2; also known as ARHGDIB and Ly-GDI) is associated with metastatic disease in patients with muscle-invasive bladder cancer. Moreover, a reduction in metastasis is observed upon reexpression of RhoGDI2 in xenograft models of metastatic cancer. Here, we show that RhoGDI2 suppresses lung metastasis in mouse models by reducing the expression of isoforms V1 and V3 of the proteoglycan versican (VCAN; also known as chondroitin sulfate proteoglycan 2 [CSPG2]). In addition, we found that high versican levels portended poor prognosis in patients with bladder cancer. The functional importance of tumor expression of versican in promoting metastasis was established in in vitro and in vivo studies in mice that implicated a role for the chemokine CCL2 (also known as MCP1) and macrophages. Further analysis indicated that RhoGDI2 suppressed metastasis by altering inflammation in the tumor microenvironment. In summary, we demonstrate what we believe to be a new mechanism of metastasis suppression that works by reducing host responses that promote metastatic colonization of the lung. Therapeutic targeting of these interactions may provide a novel adjuvant strategy for delaying the appearance of clinical metastasis in patients.