Abstract
目的
胃癌是全球第5大常见癌症和第3大癌症死亡原因，严重危害人类健康，对胃癌根治术后患者的总体生存的预测一直备受关注。研究表明，胃癌患者术前的营养及炎症状态与其预后相关。本研究旨在评估第三腰椎骨骼肌指数(the skeletal muscle index at the third lumbar vertebra，L3-SMI)作为三分类变量时的预测价值，并比较常见的营养及炎症相关指标在预测胃癌患者术后生存方面的性能。
方法
回顾性分析2011至2018年中南大学湘雅医院胃肠外科未行新辅助化疗并接受胃癌根治术治疗的胃癌患者的临床资料，随访患者生存状态。通过术前CT计算患者的L3-SMI值，术前最后1次实验室检查结果计算8项营养及炎症相关指标[中性粒细胞与淋巴细胞比值(neutrophil-to-lymphocyte ratio，NLR)、血小板与淋巴细胞比值(platelet-to-lymphocyte ratio，PLR)、淋巴细胞与单核细胞比值(lymphocyte-to-monocyte ratio，LMR)、全身免疫-炎性指数(systemic immune-inflammation index，SII)、全身炎症反应指数(systemic inflammation response index，SIRI)、泛免疫炎症值(pan-immune-inflammation value，PIV)、白蛋白与球蛋白比值(albumin-globulin ratio，AGR)和预后营养指数(prognostic nutritional index，PNI)]。使用X-tiler软件对L3-SMI进行三分类。通过受试者操作特征(receiver operating characteristic，ROC)曲线定义8项营养及炎症相关指标的最佳截断值。采用Kaplan-Meier生存曲线分析总生存期(overall survival，OS)，采用单因素和多因素Cox比例风险模型分析各指标与生存的关系，计算C指数评估各指标的预测性能，并使用亚组分析探究同一指标在不同亚组中的一致性。
结果
共纳入546例患者，最短随访时间为36个月。Kaplan-Meier生存曲线及单因素分析结果显示L3-SMI和8项营养及炎症相关指标与患者的OS均相关(均P<0.01)。在调整年龄、性别、肿瘤位置、分化程度、pTNM分期、胃癌根治术类型、贫血状态、CEA和AFP后，多因素Cox分析结果显示L3-SMI(HR=0.676，95% CI 0.523~0.872)、AGR(HR=0.611，95% CI 0.452~0.827)和PNI(HR=0.590，95% CI 0.418~0.833)是胃癌根治术后患者生存的独立影响因素，然后将L3-SMI和8个营养及炎症相关指标及其他影响因素同时纳入Cox回归模型进行分析也验证L3-SMI、AGR、PNI的独立效应。C指数分析结果显示，在预测1年OS方面，PNI的C指数(0.632，95% CI 0.568~0.695)最高，在预测3年和5年OS时，AGR的C指数(3年为0.584，95% CI 0.548~0.622；5年为0.578，95% CI 0.542~0.613)最高。在亚组分析中，较高的AGR、PNI和L3-SMI与年龄<65岁、低位胃癌、低分化胃癌、pTNM Ⅲ期、接受胃次全切除手术亚组患者较低的死亡风险相关。
结论
与其他指标相比，术前营养相关指标(包括L3-SMI、AGR、PNI)对胃癌患者总体生存预后有较好的预测作用。通过对营养相关指标的评估，可识别出存在不良预后风险的胃癌根治术患者，为此类患者制订合理的营养治疗方案，将有利于延长患者的生存时间。
Keywords: 胃癌根治术, 预后, 总生存期, 第三腰椎骨骼肌指数, 白蛋白与球蛋白比值, 预后营养指数
Abstract
Objective
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide, posing a serious threat to public health. Prognostication of overall survival (OS) in patients undergoing radical gastrectomy remains a clinical priority. Evidence suggests that preoperative nutritional and inflammatory status correlated with postoperative outcomes. This study aims to evaluate the prognostic value of the skeletal muscle index at the third lumbar vertebra (L3-SMI) as a trichotomous variable and to compare the performance of commonly used nutritional and inflammation-related indicators in predicting postoperative survival in GC patients.
Methods
This retrospective study analyzed clinical data of patients who underwent radical gastrectomy with neoadjuvant chemotherapy between 2011 and 2018 at the Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University. L3-SMI was measured by preoperative CT, and 8 preoperative nutritional/inflammatory indices were calculated from the latest laboratory tests before surgery: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), pan-immune-inflammation value (PIV), albumin-globulin ratio (AGR), and prognostic nutritional index (PNI). L3-SMI was categorized into 3 groups using X-tiler software. ROC curves were used to determine optimal cut-off values for the other eight indices. Kaplan-Meier curves and univariate/multivariate Cox proportional hazards models were used to analyze the association between variables and OS. Concordance index (C-index) and subgroup analysis assessed predictive performance and consistency across patient subgroups.
Results
A total of 546 patients were included, with a minimum follow-up time of 36 months. Kaplan-Meier and univariate analysis showed that L3-SMI and the 8 indicators were significantly associated with OS (all P<0.01). After adjusting for age, gender, tumor site, differentiation, pTNM stage, type of surgery, anemia, CEA, and AFP, multifactorial Cox analysis revealed that L3-SMI (HR=0.676, 95% CI 0.523 to 0.872), AGR (HR=0.611, 95% CI 0.452 to 0.827), and PNI (HR=0.590, 95% CI 0.418 to 0.833) were independent predictors of OS. The full model confirmed the independent prognostic roles of L3-SMI, AGR, and PNI. Among all indicators, PNI had the highest C-index for 1-year OS prediction (0.632, 95% CI 0.568 to 0.695), while AGR showed the best performance at 3 years (0.585, 95% CI 0.548 to 0.622) and 5 years (0.578, 95% CI 0.542 to 0.613). Subgroup analysis indicated that higher L3-SMI, AGR, and PNI were associated with lower mortality risk in patients aged<65 years, with lower gastric tumors, poor differentiation, stage III pTNM, or who underwent subtotal gastrectomy.
Conclusion
Compared with other indicators, preoperative nutritional markers such as L3-SMI, AGR, and PNI demonstrated superior prognostic value for OS in gastric cancer patients undergoing radical gastrectomy. Assessing these indices can help identify patients at high risk of poor prognosis, thereby guiding targeted nutritional interventions and potentially improving survival outcomes.
Keywords: radical gastrectomy, prognosis factors, overall survival, skeletal muscle index at the third lumbar vertebra, albumin-to-globulin ratio, prognostic nutritional index
胃癌是全球第5大常见癌症，也是第3大癌症死亡原因，严重危害人类健康[1]。迄今为止，手术切除依然是可治愈性胃癌最有效的治疗方式。如何准确预测胃癌患者的术后生存情况一直是研究焦点。美国癌症联合委员会(American Joint Committee on Cancer，AJCC)胃癌分期系统可用于预测胃癌患者的总生存期(overall survival，OS)[2]，而一些临床检验指标，如癌胚抗原(carcinoembryonic antigen，CEA)[3]、甲胎蛋白(alpha fetoprotein，AFP)[4]和预后营养指数(prognostic nutritional index，PNI)等[5]，也被证明与胃癌患者的预后相关。
在笔者之前的研究[6-7]中，第三腰椎骨骼肌指数(the skeletal muscle index at the third lumbar vertebra，L3-SMI)是胃癌根治术后患者生存的预测指标之一，低L3-SMI可能与胃癌患者的OS、无病生存期(disease-free survival，DFS)和无进展生存期(progression free survival，PFS)缩短有关。在亚洲肌少症工作组(Asian Working Group for Sarcopenia，AWGS)发布的指南共识[8-9]中，目前尚无L3-SMI诊断肌少症的标准，只提供了部分相关研究。有研究[10]显示L3-SMI与体重指数(body mass index，BMI)有较高的相关性，且目前尚无证据表明L3-SMI值越高的胃癌患者OS越好，因此笔者推测L3-SMI可能与BMI一样有一个正常参考值范围。
术前的营养及炎症相关指标可有效预测胃癌患者预后。炎症反应标志物，如中性粒细胞与淋巴细胞比值(neutrophil-to-lymphocyte ratio，NLR)[11-12]、血小板与淋巴细胞比值(platelet-to-lymphocyte ratio，PLR)[13-14]、淋巴细胞与单核细胞比值(lymphocyte-to-monocyte ratio，LMR)[15]、全身免疫炎症指数(systemic immune-inflammation index，SII)[16]、全身炎症反应指数(systemic inflammation response index，SIRI)[17]，已被证明可预测胃癌的进展和预后。泛免疫炎症值(pan-immune-inflammation value，PIV)是一种新的结直肠癌预后预测指标[18]，也可能对胃癌预后具有预测作用。白蛋白与球蛋白比值(albumin-globulin ratio，AGR)[19]和PNI[20]等营养相关指标偏低则被认为是胃癌根治术患者不良预后的独立影响因素。
L3-SMI、营养及炎症相关指标对胃癌患者的生存均具有预测价值。然而，有必要确认哪些指标是建立胃癌根治术后患者生存预测模型的最佳预测因子。在本研究中，笔者对L3-SMI进行三分类，以验证它在胃癌根治术后患者生存中的预测作用，同时还评估和比较8个营养/炎症指标对胃癌根治术后患者总生存期的预测作用和性能。
1. 对象与方法
1.1. 伦理声明
本研究严格遵循《赫尔辛基宣言》的伦理原则，并经中南大学湘雅医院医学伦理委员会批准(审批号：2024060662)，所有纳入的患者均知情同意。
1.2. 对象
研究对象为中南大学湘雅医院胃肠外科2011至2018年收治的胃癌患者。纳入标准：1)病理检查证实为胃腺癌；2)年龄≥18岁；3)行胃癌根治术；4)非急诊手术。排除标准：1)临床资料不完整；2)远处转移(M1)；3)术前曾接受化疗；4)合并有血液疾病、传染病、免疫系统疾病或其他严重合并症[21]。
1.3. 数据的收集
通过住院电子病历系统获取研究对象的临床资料。1)患者的年龄、性别；2)肿瘤的位置、组织分化程度、病理TNM(pathological TNM，pTNM)分期；3)术前最后一次实验室检查结果(CEA、AFP、血红蛋白、总蛋白、白蛋白、球蛋白、白细胞计数、淋巴细胞计数、中性粒细胞计数、单核细胞计数、血小板计数)；4)8个营养及炎症相关指标(NLR、PLR、LMR、SII、SIRI、PIV、AGR和PNI)，各指标的计算方法见附表1(https://doi.org/10.57760/sciencedb.22598)。
表1.
纳入患者的临床资料(n=546)
Table 1 Clinical data of patients included in this study (n=546)
| Variables | Values | Variables | Values |
|---|---|---|---|
| Age distribution/[No.(%)] | AFP/[No.(%)] | ||
| <65 years | 450(82.4) | ≤20 ng·mL-1 | 541(99.1) |
| ≥65 years | 96(17.6) | >20 ng·mL-1 | 5(0.9) |
| Gender/[No.(%)] | Total protein/(g·L-1) | 67.450(63.000, 71.730) | |
| Male | 345(63.2) | Albumin/(g·L-1) | 40.900(37.800, 43.900) |
| Female | 201(36.8) | Globulin/(g·L-1) | 26.300(23.700, 29.130) |
| Tumor location/[No.(%)] | WBC/(×109·L-1) | 5.600(4.680, 6.900) | |
| Upper | 13(2.4) | Anemia*/[No.(%)] | 215(39.4) |
| Middle | 153(28.0) | Platelet/(×109·L-1) | 221.000(180.000, 268.250) |
| Low | 380(69.6) | Neutrocyte/(×109·L-1) | 3.300(2.400, 4.200) |
| Degree of differentiation/[No.(%)] | Lymphocyte/(×109·L-1) | 1.700(1.300, 2.000) | |
| Poor | 452(82.8) | Monocytes/(×109·L-1) | 0.400(0.300, 0.600) |
| Medium | 82(15.0) | L3-SMI/(cm2·m-2) | 40.960(35.350, 46.640) |
| High | 12(2.2) | NLR | 1.940(1.390, 2.720) |
| pTNM/[No.(%)] | PLR | 133.490(101.440, 178.240) | |
| Ⅰ | 153(28.0) | LMR | 4.000(3.000, 5.000) |
| Ⅱ | 138(25.3) | SII | 428.500(292.460, 636.390) |
| Ⅲ | 255(46.7) | SIRI | 0.830(0.540, 1.300) |
| Type of gastrectomy/[No.(%)] | PIV | 184.120(112.210, 298.980) | |
| Subtotal | 409(74.9) | AGR | 1.530(1.360, 1.720) |
| Total | 137(25.1) | PNI | 49.450(45.380, 53.420) |
| CEA/[No.(%)] | |||
| <5 ng·mL-1 | 516(94.5) | ||
| ≥5 ng·mL-1 | 30(5.5) |
Non-normally distributed continuous variables are represented by the median (1st quartile, 3rd quartile). *Hemoglobin<130 g/L for female, and <115 g/L for male. pTNM: Pathological TNM; L3-SMI: Skeletal muscle index at the third lumbar vertebra; CEA: Carcinoembryonic antigen; AFP: Aalpha fetoprotein; WBC: White blood cell count; Hb: Hemoglobin; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; PIV: Pan-immune-inflammation value; AGR: Albumin-globulin ratio; PNI: Prognostic nutritional index.
1.4. L3-SMI的评估
由2位影像学专家使用GE AW4.6(GE Healthcare)的X-SECTION功能分析术前最后一次CT检查的第三腰椎(L3)图像，测定L3横截面的骨骼肌总面积，包括腰大肌、竖脊肌、腰方肌、腹横肌、腹外斜肌、腹内斜肌。通过腰椎L1~L5高度对第三腰椎横截面的骨骼肌总面积进行标准化，计算L3-SMI(单位为cm2/m2)[6]。为了减小评估结果的偏差，评估过程采用盲法控制，取2位专家评估数据的平均值作为最终结果，若2位专家的评估数据差异>10%，则重新组织评估。
1.5. 终点指标
主要终点指标是OS，定义为从患者接受胃癌根治术到死亡的时间。对患者进行电话随访，本研究最后的随访时间是2021年12月，最短随访时间为36个月，最长随访时间为110个月。
1.6. 统计学处理
使用SPSS 26.0和GraphPad Prism 9.5.0进行数据分析。使用Kolmogorov-Smirnov法对数据进行正态性检验，符合正态分布连续变量以均数±标准差表示，非正态分布的连续变量以中位数(第1四分位数，第3四分位数)表示，分类变量以频数和百分比表示。使用X-tile程序对L3-SMI值进行分析，并根据L3-SMI值的高低将研究对象分为3组(Low、Normal和High组)[22]。通过受试者操作特征(receiver operating characteristic，ROC)曲线定义NLR、PLR、LMR、SII、SIRI、PIV、AGR、PNI的最佳截断值。采用单因素和多因素Cox分析L3-SMI和8个营养/炎症相关指标对胃癌患者术后OS的影响。采用Kaplan-Meier生存曲线分析OS，并使用双侧Log-rank检验进行分析。将L3-SMI和8个营养及炎症相关指标及其他影响因素纳入Cox回归模型进行分析，确定胃癌患者总体生存的独立影响因素，并建立列线图。C指数用于评估营养及炎症相关指标的预测性能，范围从0.5(完全不一致)到1.0(完全一致)。为确定同一指标是否适用于不同亚组，研究进一步对年龄、性别，肿瘤的位置、分化程度、pTNM分期，以及胃癌根治术类型进行亚组分析。χ 2检验用于比较独立样本中的比例，Mann-Whitney U检验用于对2个独立样本进行分析，Kruskal-Wallis H检验用于比较多个独立样本之间的分布。双侧检验P<0.05被认为差异具有统计学意义，多重比较的P值使用Bonferroni方法进行调整。
2. 结 果
2.1. 患者一般资料
共纳入546例胃癌患者(图1)，患者的年龄为(55.60±10.70)岁，65岁以下的患者有450例(82.4%)，且以男性患者居多(345/546，63.2%)。452例(82.8%)为低分化胃癌，255例(46.7%)pTNM分期为Ⅲ期，137例(25.1%)为全胃切除术。患者的CEA、AFP、Hb分别为1.250(0.740, 2.230) ng/mL、1.130(0.600, 2.010) ng/mL、128.000(112.000, 141.000) g/L，CEA阳性(≥5 ng/mL)30例(5.5%)，AFP阳性(>20 ng/mL)5例(0.9%)。患者的中位随访时间为66.14个月，截至2021年12月，234例(42.8%)患者死亡。患者1年、3年和5年生存率分别为89.3%、68.3%和65.4%。纳入患者的临床资料见表1。
图1.
患者纳入流程图
Figure 1 Flow diagram participants included in the study *Missing CT image data and L3 skeletal muscle data
2.2. L3-SMI和8个营养及炎症相关指标的最佳截断值
L3-SMI值的性别特异性X-tile三分类结果见附图1和附表2(https://doi.org/10.57760/sciencedb.22598)。女性Low、Normal和High组的L3-SMI的截断值分别 为<28.7 cm2/m2、28.7~40.9 cm2/m2、>40.9 cm2/m2，男性分别为<36.7 cm2/m2、36.7~50.7 cm2/m2、>50.7 cm2/m2。
表2.
L3-SMI和8个营养及炎症相关指标对胃癌患者术后OS的影响单因素及多因素Cox分析
Table 2 Univariate and multivariate Cox analysis of impact of L3-SMI and 8 nutrition/inflammation related indicators on postoperative overall survival in gastric cancer patients
| Indicators | Model 0 | Model 1 | Model 2 | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
| L3-SMI stage | 0.608(0.472-0.783) | <0.001 | 0.679(0.528-0.874) | 0.003 | 0.676(0.523-0.872) | 0.003 |
| NLR | ||||||
| ≤2.660 | Reference | Reference | Reference | |||
| >2.660 | 1.595(1.176-2.164) | 0.003 | 1.283(0.933-1.765) | 0.126 | 1.215(0.876-1.687) | 0.244 |
| PLR | ||||||
| ≤151.715 | Reference | Reference | Reference | |||
| >151.715 | 1.765(1.325-2.350) | <0.001 | 1.239(0.919-1.671) | 0.160 | 1.205(0.882-1.646) | 0.242 |
| LMR | ||||||
| ≤3.270 | Reference | Reference | Reference | |||
| >3.270 | 0.605(0.453-0.807) | 0.001 | 0.723(0.538-0.972) | 0.032 | 0.775(0.570-1.055) | 0.106 |
| SII | ||||||
| ≤720.80 | Reference | Reference | Reference | |||
| >720.80 | 1.742(1.258-2.412) | 0.001 | 1.318(0.945-1.839) | 0.104 | 1.240(0.876-1.754) | 0.225 |
| SIRI | ||||||
| ≤1.245 | Reference | Reference | Reference | |||
| >1.245 | 1.762(1.306-2.377) | <0.001 | 1.413(1.036-1.928) | 0.029 | 1.348(0.981-1.851) | 0.065 |
| PIV | ||||||
| ≤173.935 | Reference | Reference | Reference | |||
| >173.935 | 1.522(1.138-2.036) | 0.005 | 1.108(0.823-1.491) | 0.501 | 1.064(0.786-1.440) | 0.690 |
| AGR | ||||||
| ≤1.455 | Reference | Reference | Reference | |||
| >1.455 | 0.550(0.413-0.732) | <0.001 | 0.601(0.445-0.811) | 0.001 | 0.611(0.452-0.827) | 0.001 |
| PNI | ||||||
| ≤45.350 | Reference | Reference | Reference | |||
| >45.350 | 0.501(0.371-0.676) | <0.001 | 0.610(0.441-0.843) | 0.003 | 0.590(0.418-0.833) | 0.003 |
Model 0: Unadjusted model; Model 1: Adjusted by age, gender, tumor location, degree of differentiation, pTNM stage, and type of gastrectomy; Model 2: Adjusted by age, gender, tumor location, degree of differentiation, pTNM stage, type of gastrectomy, anemia status, CEA, and AFP. HR: Hazard ratio; 95% CI: 95% confidence interval; OS: Overall survival.
ROC曲线分析结果显示：NLR、PLR、LMR、SII、SIRI、PIV、AGR、PNI最佳截断值分别为2.660、151.715、3.270、720.800、1.245、173.935、1.455、45.350(附表3，https://doi.org/10.57760/sciencedb. 22598)。
表3.
8个营养及炎症相关指标预测胃癌患者胃癌根治术后OS的C指数
Table 3 C-index of 8 nutrition/inflammation related indicators predicting postoperative OS in patients with gastric cancer undergoing radical gastrectomy
| Indicators | C-index (95% CI) | ||
|---|---|---|---|
| One-year survival | Three-year survival | Five-year survival | |
| AGR | 0.582(0.518~0.646) | 0.585(0.548~0.622) | 0.578(0.542~0.613) |
| PNI | 0.632(0.568~0.695) | 0.577(0.543~0.613) | 0.576(0.542~0.610) |
| NLR | 0.626(0.563~0.690) | 0.564(0.528~0.599) | 0.557(0.522~0.591) |
| PLR | 0.569(0.505~0.633) | 0.561(0.524~0.598) | 0.570(0.534~0.605) |
| LMR | 0.611(0.547~0.675) | 0.561(0.524~0.597) | 0.563(0.528~0.598) |
| SII | 0.597(0.536~0.658) | 0.558(0.525~0.591) | 0.554(0.522~0.586) |
| SIRI | 0.621(0.557~0.685) | 0.569(0.534~0.605) | 0.568(0.533~0.602) |
| PIV | 0.601(0.543~0.659) | 0.566(0.530~0.602) | 0.560(0.525~0.595) |
2.3. L3-SMI对胃癌患者术后OS的影响
在调整年龄、性别、肿瘤位置、分化程度、pTNM分期、胃癌根治术类型、贫血状态、CEA和AFP后，多因素Cox分析结果显示L3-SMI是胃癌根治术后患者OS的独立影响因素(表2)。
Kaplan-Meier曲线(图2)显示L3-SMI值高的胃癌患者OS更好。值得注意的是，对于L3-SMI值而言，High组与Normal组患者的OS在1年(P=0.225 0)和 3年(P=0.126 8)时差异无统计学意义，而在5年时，High组的OS显著优于Normal组，差异有统计学意义(P=0.013 9，经Bonferroni方法调整后的P值为0.016 7)。
图2.
胃癌患者胃癌根治术后的生存曲线
Figure 2 Survival curve of gastric cancer patients after radical gastrectomy A-C: One-year (A), 3-year (B), and 5-year (C) survival curve of patients with high, normal, and low L3-SMI; D-F: One-year (D), 3-year (E), and 5-year (F) survival curve of patients with high and low AGR; G-I: One-year (G), 3-year (H), and 5-year (I) survival curve of patients with high and low PNI.
L3-SMI的Low、Normal和High组患者的年龄、pTNM分期、L3-SMI、总蛋白、白蛋白等指标差异均有统计学意义(均P<0.05；附表4，https://doi.org/10. 57760/sciencedb.22598)。
2.4. 8个营养及炎症相关指标对胃癌患者术后OS的影响
在调整年龄、性别、肿瘤位置、分化程度、pTNM分期、胃癌根治术类型、贫血状态、CEA和AFP后，多因素Cox分析结果显示AGR和PNI是胃癌根治术后患者OS的独立影响因素(表2)。
Kaplan-Meier曲线分析结果显示：对AGR和PNI高水平组胃癌患者的1年、3年和5年OS均优于低水平组(均P<0.05，图2)；对于NLR、PLR、SII、SIRI、PIV而言，高水平组胃癌患者的1年、3年和5年OS均优于低水平组(均P<0.05；附图2，https://doi.org/10. 57760/sciencedb.22598)。
比较不同等级的AGR组和PNI组患者的资料发现，患者的年龄、pTNM分期、总蛋白、白蛋白等指标存在显著差异，低AGR或PNI组的患者伴随更差的基础状态(附表5、6，https://doi.org/10.57760/sciencedb. 22598)。
2.5. 胃癌根治术后患者OS的独立影响因素的Cox回归分析
将L3-SMI和8个营养及炎症相关指标及其他影响因素纳入Cox回归模型进行分析，结果显示：组织分化程度、pTNM分期、胃癌根治术类型、AFP、L3-SMI、AGR、PNI是胃癌根治术后患者OS的独立影响因素(附表7，https://doi.org/10.57760/sciencedb. 22598)。纳入上述独立影响因素建立列线图(附图3，https://doi.org/10.57760/sciencedb.22598)。
图3.
L3-SMI、AGR、PNI在胃癌根治术患者中的亚组分析结果
Figure 3 Subgroup analysis of L3-SMI, AGR, and PNI in patients with gastric cancer undergoing radical gastrectomy
pTNM: Pathological TNM; HR: Hazard ratio; 95% CI: 95% confidence interval. *P for interaction
2.6. L3-SMI和8个营养及炎症相关指标的C指数
在预测胃癌患者1年、3年和5年的OS方面，L3-SMI的C指数并不理想，分别为0.587(95% CI 0.524~0.649)、0.551(95% CI 0.515~0.586)和0.569(95% CI 0.535~0.602)；8个营养/炎症相关指标均未在胃癌根治术后患者生存(1年、3年和5年)预测中表现出令人满意的性能；PNI在预测1年的生存中表现出最高的C指数(0.632，95% CI 0.568~0.695)，AGR在预测3年、5年的生存中表现出最高的C指数(表3)。
AGR、PNI和L3-SMI可显著增加pTNM分期对胃癌根治术后患者生存(1年、3年和5年)的预测作用(附表8，https://doi.org/10.57760/sciencedb.22598)。
2.7. 亚组分析
在调整年龄、性别、肿瘤部位、分化程度、pTNM分期、贫血、CEA、AFP因素后，森林图(图3)显示较高的AGR、PNI和L3-SMI与年龄<65岁、低位胃癌、低分化胃癌、pTNM Ⅲ期、接受胃次全切除手术亚组患者较低的死亡风险相关。这提示，术前高AGR、PNI和L3-SMI是患者术后生存的保护因素。
3. 讨 论
术前营养及炎症相关指标可预测胃癌根治术后患者的预后。本研究对L3-SMI作为三分类变量对胃癌根治术后患者生存的预测价值进行评估，同时比较8个营养、炎症相关指标对胃癌根治术后患者生存的预测价值。本研究结果表明术前营养相关指标，特别是L3-SMI、AGR和PNI，在预测胃癌根治术后患者生存方面具有优越性。
欧洲老年人肌肉减少工作小组(European Working Group on Sarcopenia in Older People，EWGSOP)将L3-SMI作为评价肌肉质量的金标准[23]。L3-SMI在评估整体肌肉质量、全面分析身体成分以及评估疾病风险方面具有重要意义。在先前的研究[7]中，笔者发现不同研究的L3-SMI截断值存在差异，且这些值主要通过二元分类方法确定。因此，本研究探索定义L3-SMI类似于BMI分类的正常参考值范围。本研究首先使用X-tile程序建立三分类界限，并进一步通过生存曲线比较L3-SMI各组间OS的差异。结果发现：L3-SMI High与Normal组间在1年、3年OS方面差异均无统计学意义，但在5年OS方面，High与Normal组间的差异有统计学意义；L3-SMI Low组的1年、3年、5年OS均最低，与其他2组之间的差异均有统计学意义。多因素分析结果显示L3-SMI是胃癌根治术后患者预后的独立影响因素，与以往研究[24]结果相符。以上结果均表明高L3-SMI与胃癌患者的长期预后存在相关性，保持或增加骨骼肌质量可能延长胃癌根治术后患者的生存期。癌症可能直接影响肌肉组织的代谢和生长[25]，胃癌患者的运动量通常会减少，且伴随异常的营养代谢[7]。这可能是胃癌患者L3-SMI较低，并影响其长期生存的原因之一。
本研究结果发现营养及炎症相关指标与胃癌患者术后生存率之间存在关联。高炎症指标和低营养指标均与较差的生存结果相关。这些发现与先前研究[12, 16-17, 19, 26-28]的结论一致。但通过多因素分析发现只有AGR、PNI和L3-SMI是独立的影响因素，这与其他研究的结果不同，有待进一步验证。在C指数分析中，本研究发现营养指标AGR、PNI预测3年和 5年OS时表现出更好的性能。低AGR组和低PNI组的总蛋白、白蛋白、血红蛋白和L3-SMI较低，表明患者处于营养不良状态。在被诊断为胃癌后，患者经常会遇到营养摄入不足的问题，这种不足往往因患者及其家属缺乏营养知识而加剧，因此，胃癌患者的营养不良患病率高[29]。术前营养指标降低可能源于胃癌导致的营养摄入障碍和患者错误的饮食习惯与观念。因此，营养支持和营养知识的宣教在胃癌患者综合护理中具有重要意义，营养疗法已成为癌症综合治疗不可或缺的一部分[30]。实施有效的营养干预措施可以改善患者的营养状况，保持骨骼肌质量，增强对化疗的耐受性，对其生活质量产生积极影响[31]，甚至有望延长患者的生存期。值得注意的是，炎症标志物(包括NLR、LMR、SIRI和PIV)对1年OS表现出良好的预测性能。炎症被认为是癌症的十大标志性特征之一[32]，术前炎症标志物水平可能与癌症的严重程度相关，并可预测患者生存时间[33]。此外，营养不良患者的炎症指标也往往较高，这些发现值得进一步在前瞻性试验中验证。
本研究发现术前较高的L3-SMI、AGR和PNI是胃癌根治术患者生存的独立保护因素。在亚组分析中，这3个指标仅在特定亚组中表现出保护作用。这可能归因于某些亚组中的患者数量有限，同时相关亚组病例少也可能是导致PNI与肿瘤位置、胃切除术类型之间存在交互效应的原因。AFP是胃癌根治术后患者OS的独立危险因素，产生AFP的胃癌是一种罕见且侵袭性的胃癌亚型，其血管内皮生长因子C(vascular endothelial growth factor C，VEGF-C)表达较高，预后较差[34-35]。以后有必要进行样本量更大的前瞻性研究，并补充其他与胃癌根治术患者生存期相关的基线特征，如转移性淋巴结数量[36]及淋巴管侵犯[37]等。
本研究的局限性：首先，现有研究已经证明L3-SMI对胃癌患者的独立预后价值，即使在调整BMI后依然成立[10]。遗憾的是，由于本研究缺乏BMI数据，无法评估L3-SMI三分类时的预测作用是否仍然独立。其次，由于部分病例临床数据缺失，样本量有限，不足以进行全面的分析，有些指标被遗漏，比如老年营养风险指数(geriatric nutritional risk index，GNRI)需要体重和身高[38]，控制营养状况评分(controlling nutritional status，CONUT)需要血脂检测结果[39]。最后，本研究未能获得患者疾病特异性生存数据，总体生存期可能受到后续治疗和非癌症相关死亡的影响，未来需要进一步的队列研究，以更深入地评估患者预后并建立更稳健的预测模型。
综上所述，与其他指标相比，术前营养相关指标L3-SMI、AGR、PNI对胃癌患者总体生存有较好的预测作用。通过对营养相关指标的评估，可以识别存在不良预后风险的胃癌根治术患者，为此类患者制订合理的营养治疗方案，有利于延长胃癌患者的生存时间。
基金资助
国家自然科学基金(81803233)；中国博士后科学基金(2021M693561)；2024年中国药学会-施维雅青年医院药学创新资助项目(CPA-B04-ZC-2024-001)；湖南省自然科学基金(2023JJ30938)；长沙市自然科学基金(kq2208387)。This work was supported by the National Natural Science Foundation (81803233), the Fellowship of China Postdoctoral Science Foundation (2021M693561), the Hospital Pharmacy Innovation Project for the Youth Established by Chinese Pharmaceutical Association and Servier (CPA-B04-ZC-2024-001), the Natural Science Foundation of Hunan Province (2023JJ30938), and the Natural Science Foundation of Changsha City (kq2208387), China.开放获取(Open access)：本文遵循知识共享许可协议，允许第三方用户按照署名-非商业性使用-禁止演绎4.0(CC BY-NC-ND 4.0)的方式，在任何媒介以任何形式复制、传播本作品(https://creativecommons.org/licenses/by-nc-nd/4.0/)。
利益冲突声明
作者声称无任何利益冲突。
作者贡献
谢凯强 研究构思与实施，数据采集与分析，论文撰写与修改；冯绾、刘竹贤、雷昊 数据采集，论文修改，对文章的知识性内容作批评性审阅；刘合利 研究构思，论文修改，对文章的知识性内容作批评性审阅；唐密密 研究构思与指导，论文修改，对文章的知识性内容作批评性审阅，研究经费的获取。所有作者阅读并同意最终的文本。
Footnotes
http://dx.chinadoi.cn/10.11817/j.issn.1672-7347.2025.240521
原文网址
http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/202502204.pdf
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