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

doi:10.3969/j.issn.1001-5256.2022.04.019

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

张炜琪¹,
谢炎^{1, 2},
陈池义²,
贺健^{1, 2},
谭玉莹¹,
黄亚北¹,
张骊²,
蒋文涛^2, , ,

1.
天津医科大学一中心临床学院, 天津 300070
2.
天津市第一中心医院肝移植科, 天津 300192

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

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出版历程
- 收稿日期: 2021-08-10
- 录用日期: 2021-09-11
- 出版日期: 2022-04-20

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

Weiqi ZHANG¹,
Yan XIE^{1, 2},
Chiyi CHEN²,
Jian HE^{1, 2},
Yuying TAN¹,
Yabei HUANG¹,
Li ZHANG²,
Wentao JIANG^{2
, ,
,}

1.
Tianjin Medical University First Center Clinical College, Tianjin 300070, China
2.
Department of Liver Transplantation, Tianjin First Central Hospital, Tianjin 300192, China

Research funding:

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

Tianjin Natural Science Foundation (19JCQNJC10300)

More Information

Corresponding author: JIANG Wentao, dr_JWT001@163.com (ORCID: 0000-0002-0805-3436)

摘要

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。
- 癌, 肝细胞 /
- 肝移植 /
- 复发 /
- 模型, 理论
Abstract: Objective To develop a new model for predicting recurrence after liver transplantation for hepatocellular carcinoma (HCC) beyond Milan criteria based on related preoperative and postoperative indicators. Methods A retrospective analysis was performed for the clinical data of the patients with HCC beyond Milan criteria who underwent orthotopic liver transplantation for the first time in Tianjin First Central Hospital from August 2014 to July 2018, and according to the presence or absence of recurrence during follow-up, the patients were divided into recurrence group and no-recurrence group. The t-test or the Mann-Whitney U test was used for comparison of continuous data between groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to plot survival curves, and the log-rank test was used for comparison of survival curves. Univariate and multivariate Cox proportional hazards regression analyses were used to identify the risk factors for recurrence-free survival after surgery. A new model was developed for recurrence after liver transplantation in the patients with HCC beyond Milan criteria based on the risk factors identified. The area under the receiver operating characteristic curve (AUC) was used to evaluate predictive performance, and the Hosmer-Lemeshow test was used to assess the goodness of fit of the model. Results A total of 117 patients with HCC beyond Milan criteria were enrolled in this study, with a median follow-up time of 24 (1-74) months. A total of 53 patients (45.3%) experienced recurrence after surgery, among whom 52 (98.1%) had recurrence within 3 years after surgery, with a median time to recurrence of 6 (1-52) months. The Cox proportional hazards regression analysis showed that preoperative serum alpha-fetoprotein (AFP) >769 ng/mL, neutrophil-lymphocyte ratio (NLR) >3.75, and ki67 index >0.25 were independent risk factors for recurrence-free survival after liver transplantation. The model established based on these three risk factors had an AUC of 0.843, with good sensitivity (88.7%) and specificity (70.3%). The optimal cut-off value was selected according to the maximization of Youden index, and then the patients were divided into low-risk group (0-1 point) and high-risk group (1.5-4 points). The log-rank test showed that the low-risk group had significantly higher 3-and 5-year recurrence-free survival rates than the high-risk group (84.1%/72.0% vs 10.9%/10.9%, χ²=29.425, P < 0.001). Conclusion Liver transplantation for HCC beyond Milan criteria should be performed with caution, and the predictive model established based on preoperative AFP, NLR, and ki67 index can accurately assess the indication for liver transplantation in such patients.
- Carcinoma, Hepatocellular /
- Liver Transplantation /
- Recurrence /
- Models, Theoretical

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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

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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

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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

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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值
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
变量	HR(95%CI)	P值	HR(95%CI)	P值
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。

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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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