PROJECT SUMMARY/ABSTRACT Patients undergoing surgery to treat their bladder cancer face very high rates of complications and mortality. The radical cystectomy operation is fraught with the highest complication rates of all urologic oncology surgeries performed and is also extremely catabolic. As the National Cancer Institute has identified in its provocative questions 2 & 11, variations in immune function and nutritional interventions affect the response to cancer treatment. Radical cystectomy will continue to save lives, but there is a high cost in terms of persistent surgical complications. The long-term goal of this project is to unlock the potential of nutrition interventions to improve outcomes, survival, and quality of life in cancer patients. The objective of this project is to determine the impact of a specialized form of nutritional support on surgical outcomes and to better understand the mechanisms by which it acts. The hypothesis is that perioperative use of a specialized form of nutritional support will have greater efficacy than a standard form of nutritional support to reduce post- operative complications. This hypothesis has been formulated on the basis of published preliminary data produced in the applicants' laboratories and expert guidelines calling for more rigorous study of this approach. The rationale is that Specialized IMmunonutrition (SIM) is fortified with nutrients (L-arginine, omega-3 fatty acids, dietary nucleotides, and vitamin A) that have immediate effects on immune and inflammatory responses, muscle sparing, and wound healing after surgery. Guided by strong preliminary data, the hypothesis will be tested in three specific aims: 1) To determine the impact of perioperative SIM versus an identical Oral Nutrition Support (ONS) lacking the immuno-modulators on post-operative complications from RC; 2) To compare the impact of SIM to ONS on secondary clinical outcomes after RC surgery; 3) To evaluate the impact of consuming SIM compared to ONS for restraining myeloid-derived suppressor cells (MDSCs), decreasing inflammation, and modulating nutrient metabolism. The project is significant because it offers a high yield, low-risk, low-cost strategy to improve the outcome of patients with bladder cancer who undergo RC. Our innovative approach could transform clinical practice to reduce post- operative complications, thereby diminishing the burden of bladder cancer surgery and has the added potential to help many other surgical patients beyond cystectomy.