基于炎症相关指标术前预测肝内胆管癌淋巴结转移的列线图模型构建

A nomogram for preoperative prediction of lymph node metastasis in patients with intrahepatic cholangiocarcinoma based on inflammation-related markers

目的构建基于炎症相关指标的预测肝内胆管癌(ICC)淋巴结转移的列线图模型,并进行临床验证。方法回顾性收集2010年1月至2018年12月中国10家三级甲等医院收治的858例行根治性切除术的ICC患者的临床和病理学资料。术中行淋巴结清扫508例,其中207例患者的变量资料完整(男性84例,女性123例;≥60岁109例,<60岁98例;术后病理学诊断淋巴结阳性69例),用于构建列线图模型。绘制受试者工作特征曲线计算术前影像学检查判断淋巴结状态的准确率,通过Log-rank检验比较总体生存时间。使用向后法逐步回归筛选偏回归平方和有统计学意义的术前变量,应用R软件构建列线图模型及其临床决策曲线和临床影响曲线,使用Bootstrap法进行内部验证。另外回顾性收集2019年1月至2021年6月中国9家三级甲等医院收治的107例术中行淋巴结清扫的ICC患者的临床信息对列线图模型的准确率进行外部验证。根据列线图评分将858例ICC患者中未行淋巴结清扫且临床资料完整的80例患者分为淋巴结转移高风险组和低风险组,通过Log-rank检验比较其与病理学诊断淋巴结转移和未转移患者的总体生存情况。结果440例患者记录了术前影像学检查对淋巴结状态的评估结果,曲线下面积为0.615,假阴性率为62.8%(113/180),假阳性率为14.2%(37/260)。207例用于构建列线图模型的患者,术后淋巴结转移阳性和阴性的中位生存时间分别为18.5个月和27.1个月(P<0.05)。通过向后法逐步回归方法筛选出5项与淋巴结转移显著相关的变量,分别为合并结石、中性粒细胞与淋巴细胞比值、白蛋白、肝包膜侵犯和系统性免疫炎症指数,据此构建列线图模型,一致性指数(C-index)为0.737(95%CI:0.667~0.806)。外部验证的C-index为0.674(95%CI:0.569~0.779)。校准预测曲线与参考曲线均吻合良好。临床决策曲线显示,当设置列线图模型中高淋巴结转移风险阈值约为0.32时,能够获得最大净获益0.11,此时付出和获益比为1∶2。临床影响曲线显示,当设置列线图模型中高淋巴结转移风险阈值约为0.6时,预测淋巴结转移的准确率在90%以上。列线图模型评估高淋巴结转移和低淋巴结转移风险患者与病理学检查证实有淋巴结转移或无转移患者的总体生存时间的差异无统计学意义(Log-rank检验:P值分别为0.082和0.510)。结论基于炎症相关指标构建术前预测ICC淋巴结转移的列线图模型预测准确率良好,可作为术前判断淋巴结转移的补充手段,以指导ICC患者淋巴结清扫的个性化决策。

Objectives To construct a nomogram for the prediction of lymph node metastases of intrahepatic cholangiocarcinoma(ICC)based on inflammation-related markers,and to conduct its clinical verification.Methods Clinical and pathological data from 858 ICC patients who underwent radical resection were retrospectively collected from 10 domestic tertiary hospitals in China from January 2010 to December 2018.Among the 508 patients who underwent lymph node dissection,207 cases had complete variable clinical data to construct the nomogram,including 84 males and 123 females,109 patients≥60 years,98 patients<60 years and 69 patients were pathologically diagnosed with positive lymph nodes after surgery.The receiver operating characteristic curve was drawn to calculate the accuracy of preoperative imaging examinations to determine the status of the lymph nodes,and the difference in overall survival time was compared by Log-rank test.Partial regression squares and statistically significant preoperative variables were screened by backward stepwise regression analysis.Software R was applied to construct a nomogram,clinical decision curve,clinical influence curve,and the Bootstrap method was used for internal verification.Additionally,retrospectively collecting clinical information from 107 ICC patients with intraoperative lymph node dissection admitted to 9 tertiary hospitals in China from January 2019 to June 2021 was for external verification to verify the accuracy of the nomogram.Eighty patients with complete clinical data but without lymph node dissection were divided into high-risk lymph node metastasis group and low-risk group according to the nomogram score among the 858 patients.Log-rank test was used to compare the overall survival of patients with or without lymph node metastasis diagnosed by pathology.Results The area under the curve of preoperative imaging examinations for the assessment of lymph node status of 440 patients was 0.615,with a false negative rate of 62.8%(113/180)and a false positive rate of 14.2%(37/260).The median survival time of 207 patients used to construct a nomogram with positive or negative postoperative pathological lymph node metastases was 18.5 months and 27.1 months,respectively(P<0.05).Five variables related to lymph node metastasis were screened by a stepwise backward regression analysis,which were combined calculi,neutrophil/lymphocyte ratio,albumin,invasion of the liver capsule and the systemic immune inflammation index,according to which a nomogram was constructed with concordance index(C-index)of 0.737(95%CI:0.667 to 0.806).The C-index of external verification was 0.674(95%CI:0.569 to 0.779).The calibration prediction curve was in good agreement with the reference curve.The results of the clinical decision curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set at about 0.32,the maximum net benefit could be obtained by 0.11,and the cost/benefit ratio was 1∶2.The results of the clinical influence curve showed that when the risk threshold for high lymph node metastases in the nomogram was set to about 0.6,the probability of correctly predicting lymph node metastasis could reach more than 90%.There were no significant differences in overall survival time between patients with high/low risk of lymph node metastasis assessed by the nomogram and those with pathologically confirmed lymph node metastasis or without lymph node metastasis(Log-rank test:P=0.082 and 0.510,respectively).Conclusion The prediction accuracy of the preoperative nomogram for ICC lymph node metastasis based on inflammation-related markers is satisfactory,which can be used as a supplementary method for the preoperative diagnosis of lymph node metastasis and is helpful for clinicians to make a personalized decision about lymph node dissection for patients with ICC.