Impact of Body Composition and Related Inflammatory and Immune States on Prognosis of Non-Muscle Invasive Bladder Cancer

摘要 膀胱癌是美国十大最常见的癌症之一，也是治疗费用最高的癌症之一。 大多数病例(75%)是非肌肉浸润性膀胱癌(NMIBC)，复发率高(70%)和 进展(25%)。虽然预后因素在很大程度上尚不清楚，但卡介苗的成功 卡介苗(BCG)，一种膀胱内免疫疗法，作为40多年来治疗NMIBC最有效的疗法， 强调炎症和免疫环境在确定治疗反应和 预后。鉴于被诊断为膀胱癌的年龄中值为73岁，患者通常面临 与年龄相关的肌肉重量减少(肌肉量减少)，脂肪积累增加(肥胖)，或两者兼而有之(肌肉量减少 肥胖)，都以慢性炎症和免疫反应改变为特征。这些身体 成分表型与肿瘤进展和死亡率增加有关。因此，我们假设 确诊时的身体成分可能会影响宿主的炎症和免疫环境，并影响膀胱 癌症预后。这一假说将在《膀胱癌流行病学、健康和生活方式》中得到验证 2015-2019年新诊断的NMIBC患者的研究(BE-WELL；R01 CA172855，MPI：关/唐/库什) 在Kaiser Permanente，NMIBC最大的前瞻性队列研究之一，纳入了1,472名患者 通过丰富的患者、临床和生物医学数据来检查遗传和生活方式因素对预后和 生死存亡。我们建议对身体成分、炎症和免疫力进行全面调查 在膀胱癌的预后中，良好地确定肥胖、肌肉和炎症以及 诊断时的免疫生物标记物可以识别治疗失败和/或治疗失败的高危NMIBC患者 疾病复发和进展。我们的目标是：1)确定计算机与 NMIBC患者的体层摄影术(CT)得出的身体成分表型(骨质疏松症、肥胖症、肌肉瘤病) 复发(首次和多次)和进展；2)确定身体成分与卡介苗的关系 免疫治疗结果，包括不良事件和治疗失败；3)检查 循环炎症和免疫生物标志物与身体成分、卡介苗转归和NMIBC的关系 预后；4)探讨是否增加了身体成分测量以及炎症和免疫生物标记物 改进了当前NMIBC患者风险分层模型的性能。考虑到常见的临床情况 使用CT，身体成分测量可以很容易地纳入当前的临床病理因素- 建立风险分层系统，提高NMIBC的临床护理水平。

Abstract Bladder cancer is one of the top ten most common cancers in the U.S., and one of the most expensive to treat. Most cases (75%) are non-muscle-invasive bladder cancer (NMIBC) with high rates of recurrence (70%) and progression (25%). While prognostic factors remain largely unknown, the success of Bacillus Calmette-Guerin (BCG), an intravesical immunotherapy as the most effective therapy for NMIBC for over four decades, highlights the potential of the inflammatory and immune environments in determining treatment response and prognosis. Given the median age of bladder cancer diagnosis is 73 years, patients are commonly faced with age-related loss of muscle mass (sarcopenia), increase of fat accumulation (obesity), or both (sarcopenic obesity), which are all characterized by chronic inflammation and altered immune responses. These body composition phenotypes are associated with tumor progression and increased mortality. Thus, we hypothesize that body composition at diagnosis may shape the host inflammatory and immune milieu and impact bladder cancer prognosis. This hypothesis will be tested in the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well; R01 CA172855, MPI: Kwan/Tang/Kushi) of newly diagnosed NMIBC patients from 2015-2019 at Kaiser Permanente, one of the largest prospective cohort studies of NMIBC, with 1,472 patients enrolled with rich patient, clinical, and biospecimen data to examine genetic and lifestyle factors in prognosis and survival. We propose to conduct a full investigation of body composition, inflammation, and immunity in bladder cancer outcomes in Be-Well to determine how adiposity, muscle, and inflammatory and immune biomarkers at diagnosis can identify NMIBC patients at high risk for treatment failure and/or disease recurrence and progression. Our aims are: 1) to determine the association of computed tomography (CT)-derived body composition phenotypes (sarcopenia, adiposity, myosteatosis) with NMIBC recurrence (first and multiple) and progression; 2) to determine the association of body composition with BCG immunotherapy outcomes including adverse events and treatment failure; 3) to examine the association of circulating inflammatory and immune biomarkers with body composition and BCG outcomes and NMIBC prognosis; 4) explore if the addition of body composition measures and inflammatory and immune biomarkers improves the performance of current risk stratification models for NMIBC patients. Given the common clinical use of CT, body composition measures could be readily incorporated into the current clinicopathological factor- based risk stratification system to improve the clinical care of NMIBC.