Table_1_Bidirectional association between perioperative skeletal muscle and subcutaneous fat in colorectal cancer patients and their prognostic significance.docx

IntroductionLow skeletal muscle mass and high adipose tissue coexist across the body weight spectrum and independently predict the survival ratio of colorectal cancer (CRC) patients. This combination may lead to a mutually exacerbating vicious cycle. Tumor-associated metabolic conditions primarily affect subcutaneous adipose tissue, but the nature and direction of its relationship with skeletal muscle are unclear. This study aims to examine the bidirectional causal relationship between skeletal muscle index (SMI) and subcutaneous fat index (SFI) during the perioperative period in CRC patients; as well as to validate the association between perioperative SMI, SFI, and CRC prognosis.
MethodsThis population-based retrospective cohort study included patients with stage I-III colorectal cancer who underwent radical resection at the Third Affiliated Hospital of Kunming Medical University between September 2012 and February 2019. Based on inclusion and exclusion criteria, 1,448 patients were analyzed. Preoperative (P1), 2 months postoperative (P2), and 5 months postoperative (P3) CT scans were collected to evaluate the skeletal muscle index (SMI; muscle area at the third lumbar vertebra divided by height squared) and subcutaneous fat index (SFI; subcutaneous fat area at the third lumbar vertebra divided by height squared). A random intercept cross-lagged panel model (RI-CLPM) was used to examine the intra-individual relationship between SMI and SFI, and Cox regression was employed to assess the association between SMI, SFI, recurrence-free survival (RFS), and overall survival (OS).
ResultsThe median age at diagnosis was 59.00 years (IQR: 51.00–66.00), and 587 patients (40.54%) were female. RI-CLPM analysis revealed a negative correlation between SFI and subsequent SMI at the individual level: P1-P2 (β = −0.372, p = 0.038) and P2-P3 (β = −0.363, p = 0.001). SMI and SFI showed a negative correlation during P1-P2 (β = −0.363, p = 0.001) but a positive correlation during P2-P3 (β = 0.357, p = 0.006). No significant correlation was found between the random intercepts of SFI and SMI at the between-person level (r = 0.157, p = 0.603). The Cox proportional hazards multivariate regression model identified that patients with elevated SFI had poorer recurrence-free survival (HR, 1.24; 95% CI: 1.00–1.55). Compared to patients with normal preoperative SMI and SFI, those with low SMI or high SFI had poorer recurrence-free survival (HR, 1.26; 95% CI: 1.03–1.55) and overall survival (HR, 1.39; 95% CI: 1.04–1.87). However, no significant association between SMI and SFI and the prognosis of colorectal cancer patients was observed postoperatively.
ConclusionIn CRC patients, preoperative muscle loss leads to postoperative fat accumulation, exacerbating muscle loss in a feedback loop. Elevated preoperative SFI predicts poorer survival outcomes. Monitoring SMI and SFI is crucial as prognostic indicators, despite non-significant postoperative associations. Further research is needed to improve patient outcomes.

引言
低骨骼肌量与过量脂肪组织可在全体重范围内共存，且二者可独立预测结直肠癌（colorectal cancer, CRC）患者的生存率。这种共存状态可能形成相互恶化的恶性循环。肿瘤相关代谢状态主要影响皮下脂肪组织，但其与骨骼肌之间的关联性质及作用方向尚不明确。本研究旨在探讨结直肠癌患者围手术期骨骼肌指数（skeletal muscle index, SMI）与皮下脂肪指数（subcutaneous fat index, SFI）之间的双向因果关系，并验证围手术期SMI、SFI与结直肠癌预后之间的关联。
方法
本项基于人群的回顾性队列研究纳入了2012年9月至2019年2月期间，于昆明医科大学第三附属医院接受根治性切除术的I~III期结直肠癌患者。根据纳入排除标准，最终共纳入1448例患者进行分析。收集患者术前（P1）、术后2个月（P2）及术后5个月（P3）的CT影像，以评估骨骼肌指数（SMI；第三腰椎骨骼肌面积除以身高平方）与皮下脂肪指数（SFI；第三腰椎皮下脂肪面积除以身高平方）。采用随机截距交叉滞后面板模型（random intercept cross-lagged panel model, RI-CLPM）分析SMI与SFI的个体内关联，并通过Cox回归评估SMI、SFI与无复发生存期（recurrence-free survival, RFS）及总生存期（overall survival, OS）之间的关联。
结果
患者确诊时的中位年龄为59.00岁（四分位间距：51.00~66.00岁），其中女性患者587例，占比40.54%。随机截距交叉滞后面板模型分析显示，个体水平上SFI与后续SMI呈负相关：P1~P2阶段（β=-0.372，p=0.038）及P2~P3阶段（β=-0.363，p=0.001）。P1~P2阶段SMI与SFI呈负相关（β=-0.363，p=0.001），而P2~P3阶段二者则呈正相关（β=0.357，p=0.006）。个体间水平上，SFI与SMI的随机截距项无显著相关性（r=0.157，p=0.603）。Cox比例风险多因素回归模型分析显示，SFI升高的患者无复发生存期更差（风险比HR=1.24，95%置信区间CI：1.00~1.55）。与术前SMI及SFI均正常的患者相比，术前SMI低下或SFI升高的患者无复发生存期（HR=1.26，95%CI：1.03~1.55）及总生存期（HR=1.39，95%CI：1.04~1.87）均更差。但术后SMI、SFI与结直肠癌患者预后未发现显著关联。
结论
在结直肠癌患者中，术前骨骼肌丢失可导致术后脂肪堆积，进而通过反馈环路加重骨骼肌丢失。术前SFI升高可预测不良生存结局。尽管术后SMI、SFI与预后无显著关联，但将SMI与SFI作为预后指标进行监测仍具有重要价值。未来仍需开展进一步研究以改善患者预后。