Non-muscle invasive bladder cancer risk stratification

Introduction: Non-muscle invasive bladder cancer (NMIBC) comprises about 70% of all newly diagnosed bladder cancer, and includes tumors with stage Ta, T1 and carcinoma in situ (CIS.) Since, NMIBC patients with progression to muscle-invasive disease tend to have worse prognosis than with patients with primary muscle-invasive disease, there is a need to significantly improve risk stratification and earlier definitive treatment for high-risk NMIBC. Materials and Methods: A detailed Medline search was performed to identify all publications on the topic of prognostic factors and risk predictions for superficial bladder cancer/NMIBC. The manuscripts were reviewed to identify variables that could predict recurrence and progression. Results: The most important prognostic factor for progression is grade of tumor. T category, tumor size, number of tumors, concurrent CIS, intravesical therapy, response to bacillus Calmette–Guerin at 3- or 6-month follow-up, prior recurrence rate, age, gender, lymphovascular invasion and depth of lamina propria invasion are other important clinical and pathological parameters to predict recurrence and progression in patients with NMIBC. The European Organization for Research and Treatment of Cancer (EORTC) and the Spanish Club UrológicoEspañol de Tratamiento Oncológico (CUETO) risk tables are the two best-established predictive models for recurrence and progression risk calculation, although they tend to overestimate risk and have poor discrimination for prognostic outcomes in external validation. Molecular biomarkers such as Ki-67, FGFR3 and p53 appear to be promising in predicting recurrence and progression but need further validation prior to using them in clinical practice. Conclusion: EORTC and CUETO risk tables are the two best-established models to predict recurrence and progression in patients with NMIBC though they tend to overestimate risk and have poor discrimination for prognostic outcomes in external validation. Future research should focus on enhancing the predictive accuracy of risk assessment tools by incorporating additional prognostic factors such as depth of lamina propria invasion and molecular biomarkers after rigorous validation in multi-institutional cohorts

South Asian diets and insulin resistance

A role of dietary nutrients in relation to insulin resistance has been suggested but conclusive evidence in human beings is lacking. Asian Indians and South Asians are prone to develop insulin resistance and the metabolic syndrome. In the present paper, data pertaining to nutrient intake, insulin resistance and cardiovascular risk factors in Asian Indians and South Asians have been reviewed. In these populations, several dietary imbalances have been reported: low intake of MUFA, n-3 PUFA and fibre, and high intake of fats, saturated fats, carbohydrates and transfatty acids (mostly related to the widespread use of Vanaspati, a hydrogenated oil). Some data suggest that these nutrient imbalances are associated with insulin resistance, dyslipidaemia and subclinical inflammation in South Asians. Specifically, in children and young individuals, a high intake of n-6 PUFA is correlated with fasting hyperinsulinaemia, and in adults, high-carbohydrate meal consumption was reported to cause hyperinsulinaemia, postprandial hyperglycaemia and hypertriacylglycerolaemia. Dietary supplementation with n-3 PUFA leads to an improved lipid profile but not insulin sensitivity. Inadequate maternal nutrition in pregnancy, low birth weight and childhood 'catch-up' obesity may be important for the development of the metabolic syndrome and diabetes. Even in rural populations, who usually consume traditional frugal diets, there is an increasing prevalence of cardiovascular risk factors and the metabolic syndrome due to changes in diets and lifestyle. Nationwide community intervention programmes aimed at creating awareness about the consequences of unhealthy food choices and replacing them by healthy food choices are urgently needed in urban and rural populations in India, other countries in South Asia and in migrant South Asians

Abstract LB-017: Minnelide reduces castration-resistant and enzalutamide-resistant prostate cancer via downregulation of androgen receptor-mediated signaling

Abstract Prostate cancer is the second leading cause of cancer death in men in western countries. Advanced prostate cancer is often resistant to hormonal treatment and systemic chemotherapy has limited efficacy. Androgen receptor (AR), a ligand dependent transcription factor plays pivotal role in the development and progression of prostate cancer. While majority of prostate cancers are initially androgen dependent and respond to androgen ablation therapy, most patients eventually recur with more aggressive castration-resistant prostate cancer (CRPC) where AR signaling is reactivated even in the absence of androgen stimulation. Therefore developing novel chemotherapeutic agents for castrate resistant prostate cancer (CRPC) treatment is critical to improve survival in men with CRPC. Triptolide, a diterpene triepoxide isolated from a chinese herb, is extremely effective against several cancers like pancreatic cancer, colorectal cancer and liver cancer both in vivo and in vitro. The water-soluble pro-drug of triptolide, Minnelide, downregulates HSP70 via inhibition of the activity of transcription factor Sp1. Since both Sp1 and HSP70 have been reported to be critical in functionality of AR, we assessed therapeutic potential of Minnelide on androgen dependent, CRPC in vitro and in vivo. Triptolide treatment resulted in dose- and time-dependent cell death in an androgen dependent cell line LNCaP, CRPC cell line C4-2 and enzalutamide resistant CRPC tumor cell line 22RV1. Triptolide treatment decreased expression of AR full length, AR splice variants and its downstream targets (PSA, NKX3.1) at the mRNA and protein levels. Further, reporter assay with AR responsive elements showed that triptolide decreased transcriptional activity of AR. Expression levels of Sp1 and HSP70 were also reduced following treatment with triptolide these cell lines. To test the efficacy of Minnelide in vivo, male athymic nude mice were castrated 7 days prior to implantation of enzalutamide resistant CRPC (22RV1) cells subcutaneously. The animals received daily intraperitoneal injection of Minnelide and tumor volume was measured weekly until tumor size reached 2cm3.Mice receiving daily injection of Minnelide had significantly smaller tumors than controls as early as two week of treatment (p = 0.008). Triptolide therapy inhibited enzalutamide resistant CRPC growth both in vitro and in vivo. Further, our studies for the first time showed that triptolide induces prostate tumor cell death by reducing expression of both full length AR and AR splice variants in a similar manner. Citation Format: Sumit Isharwal, Shrey Modi, Usman Barlass, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee, Badrinath Konety. Minnelide reduces castration-resistant and enzalutamide-resistant prostate cancer via downregulation of androgen receptor-mediated signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-017. doi:10.1158/1538-7445.AM2015-LB-017</jats:p