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超米兰标准肝细胞癌肝移植术后复发预测模型的建立

张炜琪 谢炎 陈池义 贺健 谭玉莹 黄亚北 张骊 蒋文涛

引用本文:
Citation:

超米兰标准肝细胞癌肝移植术后复发预测模型的建立

DOI: 10.3969/j.issn.1001-5256.2022.04.019
基金项目: 

国家自然科学基金面上项目 (81870444)

天津市自然科学基金 (19JCQNJC10300)

伦理学声明:本研究于2021年8月17日经天津市第一中心医院医学伦理委员会批准,批号:2021N071KY。
利益冲突声明:本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明:张炜琪负责资料收集,数据分析及文章撰写;蒋文涛负责课题设计,研究指导,审校并最终定稿;谢炎、陈池义、贺健、谭玉莹、黄亚北、张骊参与数据收集和分析。
详细信息
    通信作者:

    蒋文涛, dr_JWT001@163.com

Development of a new model for predicting recurrence after liver transplantation for hepatocellular carcinoma beyond Milan criteria

Research funding: 

General Project of National Natural Science Foundation of China (81870444);

Tianjin Natural Science Foundation (19JCQNJC10300)

More Information
  • 摘要:   目的  根据患者术前和术后相关指标建立一个预测超米兰标准肝细胞癌(HCC)患者肝移植术后复发的模型。  方法  回顾性分析2014年8月-2018年7月在天津市第一中心医院接受首次原位肝移植的超米兰标准HCC患者的临床资料。根据随访期间肿瘤是否复发, 将患者分为复发组和未复发组。计量资料组间比较采用t检验或Mann-Whitney U检验, 计数资料组间比较使用χ2检验或Fisher精确检验。生存曲线采用Kaplan-Meier法构建, 曲线间差异采用log-rank检验。使用单因素和多因素Cox比例风险回归筛选影响术后无复发生存的危险因素。根据筛选得出的危险因素建立预测超米兰标准HCC患者肝移植术后复发的模型, 使用受试者工作特征曲线(ROC曲线)下面积来判断预测效能, Hosmer-Lemeshow检验用于评估模型的拟合优度。  结果  共纳入117例超米兰标准HCC患者, 中位随访时间24(1~74)个月。共53例(45.3%)患者术后复发, 其中52例(98.1%)于术后3年内复发, 中位复发时间为6(1~52)个月。Cox风险回归分析显示患者术前血清甲胎蛋白(AFP)>769 ng/mL, 中性粒细胞与淋巴细胞比值(NLR)>3.75以及ki67指数>0.25是患者肝移植术后无复发生存的独立危险因素(P值均 < 0.05)。根据这3个危险因素建立的评分模型ROC曲线下面积为0.843, 并且具有良好的灵敏度(88.7%)及特异度(70.3%)。根据约登指数最大化标准选取最佳截断值, 将患者分为低危组(0~1分)和高危组(1.5~4分), log-rank检验显示低危组患者术后3年、5年无复发生存率(84.1%、72.0%)明显高于高危组(10.9%、10.9%)(χ2=29.425, P < 0.001)。  结论  超米兰标准肝癌肝移植要慎重进行, 本研究根据患者术前AFP、NLR以及ki67指数建立的预测模型有助于更精准地把握此类患者的肝移植指征。

     

  • 图  1  各连续变量预测复发的能力

    注:a,术前血清AFP;b,年龄;c,肿瘤最大直径;d,KLI;e,MELD评分;f,NLR。

    Figure  1.  The performance of continuous variables for predicting recurrence

    图  2  新HCC复发预测模型的预测能力

    Figure  2.  The performance of the new model for predicting HCC recurrence

    图  3  两组患者的无复发生存率与总体生存率比较

    Figure  3.  The comparison of recurrence-free survival and overall survival between the two groups

    表  1  117例患者的一般资料

    Table  1.   The general data of 117 patients

    项目 复发组(n=53) 未复发组(n=64) 统计值 P
    年龄(岁) 52.02±8.28 56.16±10.11 t=2.388 0.019
    男/女(例) 45/8 59/5 χ2=1.556 0.212
    肝硬化(有/无,例) 47/6 61/3 0.296
    病因(乙型肝炎/非乙型肝炎,例) 48/5 54/10 χ2=0.994 0.319
    术前局部区域治疗(有/无,例) 34/19 41/23 χ2=0.001 1.000
    卫星灶(有/无,例) 15/38 9/55 χ2=3.605 0.058
    门静脉癌栓(有/无,例) 23/30 17/47 χ2=3.651 0.056
    肿瘤个数(单个/多个,例) 12/41 16/48 χ2=0.089 0.766
    肿瘤最大直径(≤5 cm/>5 cm,例) 21/32 48/16 χ2=14.997 <0.001
    微血管侵犯(有/无,例) 12/41 32/32 χ2=9.248 0.002
    肿瘤分化程度(高/中/低,例) 1/39/13 0/54/10 χ2=2.801 0.246
    术前AFP(>769 ng/mL/≤769 ng/mL,例) 31/22 14/50 χ2=16.422 <0.001
    MELD评分 7.80(6.05~18.39) 8.36(6.09~14.16) Z=-0.134 0.893
    NLR(>3.75/≤3.75,例) 28/25 8/56 χ2=22.137 <0.001
    免疫组化
      AFP(-/+,例) 31/22 47/17 χ2=2.915 0.088
      CK19(-/+,例) 45/8 59/5 χ2=1.556 0.212
      CK(-/+,例) 5/48 9/55 χ2=0.590 0.443
      P53(-/+,例) 25/28 32/32 χ2=0.093 0.760
      GS(-/+,例) 6/47 12/52 χ2=1.229 0.268
      VEGF(-/+,例) 12/41 14/50 χ2=0.010 0.921
      EGFR(-/+,例) 9/44 9/55 χ2=0.190 0.663
      GPC3(-/+,例) 5/48 13/51 χ2=2.636 0.104
      KLI(>0.25/≤0.25,例) 35/18 18/46 χ2=16.817 <0.001
    注:MELD,终末期肝病模型;CK, 角蛋白;GS,谷氨酰胺酶;VEGF,血管内皮生长因子;EGFR,表皮生长因子受体;GPC3,磷脂酰肌醇蛋白聚糖3;KLI,ki67指数。
    下载: 导出CSV

    表  2  单因素及多因素Cox回归分析结果

    Table  2.   The results of univariate and multivariate Cox regression analysis

    变量 单因素分析 多因素分析
    HR(95%CI) P HR(95%CI) P
    年龄(>54岁) 0.738(0.410~1.328) 0.311
    性别(男性) 0.750(0.353~1.593) 0.454
    肝硬化 0.900(0.384~2.109) 0.809
    病因(乙型肝炎) 1.095(0.428~2.804) 0.850
    术前局部区域治疗 0.948(0.540~1.667) 0.854
    卫星灶 1.879(1.030~3.428) 0.040 1.625(0.833~3.171) 0.285
    门静脉癌栓 2.107(1.214~3.659) 0.008 0.707(0.360~1.389) 0.931
    肿瘤个数(多个) 1.176(0.617~2.242) 0.623
    肿瘤最大直径(>5 cm) 3.202(1.800~5.700) <0.001 1.508(0.744~3.053) 0.306
    微血管侵犯 2.845(1.485~5.448) 0.002 1.468(0.713~3.022) 0.272
    肿瘤分化程度
      低分化 0.710(0.092~5.471) 0.743
      中分化 0.384(0.052~2.834) 0.348
    AFP>769 ng/mL 3.687(2.097~6.481) <0.001 4.429(2.438~8.045) <0.001
    NLR>3.75 3.901(2.246~6.774) <0.001 3.877(2.119~7.097) <0.001
    免疫组化
      KLI>0.25 4.351(2.375~7.974) <0.001 2.655(1.356~5.200) 0.004
      AFP(+) 1.774(1.024~3.072) 0.041 0.720(0.348~1.490) 0.247
      CK19(+) 2.641(1.227~5.681) 0.013 2.157(0.911~5.106) 0.075
      CK(+) 1.599(0.635~4.027) 0.319
      P53(+) 1.288(0.750~2.212) 0.358
      GS(+) 0.940(0.624~1.416) 0.768
      VEGF(+) 0.658(0.345~1.257) 0.205
      EGFR(+) 0.783(0.382~1.605) 0.504
      GPC3(+) 1.974(0.785~4.965) 0.149
    注:HR,风险比。
    下载: 导出CSV

    表  3  基于多因素Cox回归分析β系数的模型得分

    Table  3.   The score of the model based on β coefficient of multivariate Cox regression analysis

    变量 β系数 得分
    AFP>769 ng/mL 1.488 1.5
    NLR>3.75 1.355 1.5
    KLI>0.25 0.977 1.0
    下载: 导出CSV
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