D3-creatine dilution to determine skeletal muscle mass in colon cancer patients

摘要 结直肠癌（CRC）是美国第四大最常见的癌症。临床上使用- 获得计算机断层扫描（CT）扫描以测量肌肉横截面积（CSA）、患病率 在非转移性CRC患者中，低肌肉估计为42%。低CT CSA与 化疗毒性风险增加2倍以上，手术并发症风险增加26%， CRC特异性死亡风险增加。然而，使用CT来估计肌肉质量受到限制， CT不是所有癌症的标准治疗，通常仅限于一个解剖区域，无法区分 收缩肌蛋白和肌筋膜中的其他组织之间的关系。替代方法包括双能X射线 吸收测定法（DXA），测量所有瘦体重（LBM），包括纤维化和结缔组织， 水和器官。然而，DXA和CT都不能直接量化全身肌肉质量， 让病人暴露在辐射下安全和非侵入性的方法来评估肌肉质量将有助于我们 了解肌肉损失可能影响癌症后发病率和死亡率的机制， 加强干预措施，如针对癌症患者肌肉质量的身体活动。为此， 首次在癌症患者中，拟议的研究将评估直接和非侵入性的 方法来评估全身肌肉质量与结果。氘代肌酸稀释（d3-肌酸）估计值 使用口服剂量的d3-肌酸并测量d3-肌酸酐， 几天后，在一个单一的现场尿液样本中富集。由于肌酸位于收缩肌内， 肌节的组成部分，D3-肌酸稀释提供了功能性肌肉质量的量度。本研究 将测量90名参与随机对照试验的结肠癌患者的d3-肌酸肌肉质量 化疗期间的阻力训练，其中CT CSA和DXA LBM已经被收集。我们 将测试d3-肌酸肌肉质量是否响应于阻力训练而变化，并检查d3-肌酸肌肉质量是否响应于阻力训练而变化。 肌酸肌肉质量与功能、代谢、炎症和化疗结果相关。在 此外，我们将比较与d3-肌酸肌肉质量结果的关联强度 对于那些患有CT CSA和/或DXA LBM的人。如果癌症患者的d3-肌酸肌肉质量可以预测力量， 功能，化学毒性和癌症相关的生物标志物，那么d3-肌酸稀释将是一个有用的工具， 研究癌症患者肌肉质量和身体活动干预的作用。在未来的日子里， 根据这项研究中产生的证据，简单的d3-肌酸稀释试验可能有一天会被使用。 在临床上鉴定具有低肌肉质量的癌症患者以进行干预以减轻化学毒性， 心脏代谢风险、功能损害和死亡率。

ABSTRACT Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer in the United States. Using clinically- acquired computed tomography (CT) scans to measure muscle cross-sectional area (CSA), the prevalence of low muscle in nonmetastatic CRC patients is estimated to be 42%. Low CT CSA has been associated with a more than 2-fold increased risk of chemotoxicity, a 26% increased risk of surgical complication and a 46% increased risk of CRC-specific death. However, the use of CT to estimate muscle mass is constrained because CT is not the standard of care in all cancers, is often limited to one anatomic region and cannot distinguish between contractile muscle protein and other tissue in muscle fascia. Alternatives include dual energy x-ray absorptiometry (DXA), which measures all lean body mass (LBM), including fibrotic and connective tissue, water, and organs. However, neither DXA nor CT directly quantifies total body muscle mass and both methods expose patients to radiation. Safe and non-invasive methods to assess muscle mass will contribute to our understanding of the mechanisms by which muscle loss may affect morbidity and mortality after cancer and enhance interventions such as physical activity that target muscle mass in cancer patients. To this end, for the first time in cancer patients, the proposed study will evaluate the associations of a direct and non-invasive method to assess total body muscle mass with outcomes. Deuterated creatine dilution (d3-creatine) estimates total creatine pool size, and thus muscle mass, using an oral dose of d3-creatine and measuring d3-creatinine enrichment in a single, spot-urine sample a few days later. Since creatine is located within the contractile components of the sarcomere, d3-creatine dilution provides a measure of functional muscle mass. This study will measure d3-creatine muscle mass in 90 colon cancer patients participating in a randomized controlled trial of resistance training during chemotherapy in which CT CSA and DXA LBM are already being collected. We will test whether d3-creatine muscle mass changes in response to resistance training and examine whether d3- creatine muscle mass is associated functional, metabolic, inflammatory and chemotherapy outcomes. In addition, we will compare the strength of the associations with outcomes found with d3-creatine muscle mass to those with CT CSA and/or DXA LBM. If d3-creatine muscle mass in cancer patients is predictive of strength, function, chemotoxicity and cancer-related biomarkers, then d3-creatine dilution will be a useful tool for research on the role of muscle mass and physical activity interventions in cancer patients. In the future, informed by the evidence generated in this study, the simple d3-creatine dilution test might someday be used clinically to identify cancer patients with low muscle mass for interventions to mitigate chemotoxicity, cardiometabolic risk, functional impairment and mortality.