PROJECT SUMMARY/ABSTRACT Patients undergoing surgery to treat their bladder cancer experience persisting complications from their surgery. A lower resistance to infection and muscle wasting are common complications from the surgery. The radical cystectomy operation is not only extremely catabolic, but fraught with the highest complication rate of all the urologic oncology surgeries performed. Improve immune function, enhanced healing and reduced infections would offer significant benefit to bladder cancer. The overall goal of this project is to reduce post- operative complications from the surgical treatment of advanced bladder cancer and to better understand how specialized immunonutrition modulates the immune system to reduce infections and skeletal muscle wasting. The objective of this project is to assess the effectiveness of SIM intake before and after RC surgery compared to a calorie- and nitrogen-matched ONS to reduce post-operative complications. The central hypothesis is that SIM will reduce post-operative complications by restraining the expansion of MDSCs from RC surgery, preserving muscle, and reducing infections. This hypothesis has been formulated on the basis of preliminary data produced in the applicants’ laboratories and practice. The rationale is that surgery induces the expansion of immature immune cells called myeloid-derived suppressor cells, which lower the resistance to infection and may contribute to muscle wasting. SIM intake restrains the expansion of these cells, reduces infection rates, and appears to protect against overall complications and muscle wasting. Guided by strong preliminary data, the hypothesis will be tested in three specific aims: 1) To determine the impact of consuming SIM compared to ONS on post-operative complications from RC surgery; 2) To determine the impact of consuming SIM compared to ONS on infections and skeletal muscle wasting from RC surgery; 3) To evaluate the impact of consuming SIM compared to ONS for restraining MDSCs, decreasing inflammation, and modulating the immune landscape, nutrient metabolism, or the microbiome. The project is significant because there is currently no known means to prevent infections and muscle-wasting after RC surgery. This innovative approach could transform clinical practice to reduce post- operative complications, thereby diminishing the burden of bladder cancer surgery.