HBV感染相关肝癌肝移植术后复发的预测模型

摘要/Abstract

摘要：目的探讨乙型肝炎病毒(HBV)感染相关肝细胞癌(HCC)患者行肝移植术后复发的危险因素,并进一步构建预测模型。方法回顾性分析2015年1月至2020年5月河北北方学院附属第一医院诊治的106例行肝移植HCC患者的临床资料。采用χ²检验进行HCC复发影响因素的单因素分析,logistic回归分析进行HCC复发影响因素的多因素分析,根据筛选的危险因素构建HCC复发的预测模型,并采用受试者工作特征(ROC)曲线对预测模型进行评价。结果106例肝移植HCC患者复发23例,复发率为21.70%;死亡20例。肿瘤分化程度(χ²=6.066,P=0.014)、肿瘤最大径(χ²=4.916,P=0.027)、有无包膜侵犯(χ²=5.543,P=0.019)、术前甲胎蛋白(AFP)(χ²=5.458,P=0.019)、HBV-DNA(χ²=5.446,P=0.020)、中性粒细胞淋巴细胞比值(NLR)(χ²=12.161,P<0.001)、miR-424(χ²=4.400,P=0.036)、染色质域解旋酶DNA结合蛋白8(CHD8)(χ²=10.561,P=0.001)、T-钙黏蛋白(T-cad)(χ²=48.723,P<0.001)、层粘连蛋白(LN)(χ²=18.506,P<0.001)、肝细胞生长因子(HGF)表达(χ²=11.178,P=0.001)与HCC复发有关。多因素logistic回归分析显示,肿瘤最大径≥6.5 cm(OR=1.69,95%CI为1.25~3.17,P=0.002)、术前AFP>400 ng/ml(OR=1.38,95%CI为1.09~1.92,P=0.038)、CHD8阳性(OR=0.77,95%CI为0.52~0.89,P=0.021)、T-cad阳性(OR=0.84,95%CI为0.68~0.92,P=0.006)、LN阳性(OR=1.22,95%CI为1.03~1.50,P=0.013)是HCC复发的危险因素。根据logistic回归分析结果构建函数模型logit(P)=0.262+0.523X₁+0.326X₂-0.259X₃-0.286X₄+0.203X₅,其中X₁、X₂、X₃、X₄、X₅分别为肿瘤最大径、AFP、CHD8、T-cad、LN。ROC曲线分析显示,其预测HCC复发的曲线下面积为0.849(95%CI为0.763~0.894,P<0.001),准确率为83.02%,敏感性为86.96%,特异性为81.93%,临界值为0.736。由logit(P)函数模型可知,P=1/(1+e^-^Y),其中Y=0.262+0.523X₁+0.326X₂-0.259X₃-0.286X₄+0.203X₅。随机抽取1例患者,根据其临床资料,经计算P=0.564,小于临界值0.736,可认为在准确率为83.02%的情况下,该患者不会出现HCC复发。结论肿瘤最大径、术前AFP、CHD8、T-cad、LN表达状况与肝移植后HCC复发有关,据此构建的预测模型可有效预测HCC复发的风险。

关键词:癌,肝细胞,肝移植术,甲胎蛋白,肿瘤直径

Abstract:ObjectiveTo investigate the risk factors for recurrence after liver transplantation in patients with hepatitis B virus (HBV) infection-related hepatocellular carcinoma (HCC), and to further construct a predictive model.MethodsThe clinical data of 106 patients with HCC undergoing liver transplantation in the First Affiliated Hospital of Hebei North University from January 2015 to May 2020 were retrospec-tively analyzed. Theχ²test was used to analyze the factors influencing HCC recurrence, and multivariate logistic regression was used to analyze the influencing factors of HCC recurrence. According to the selected risk factors, the predictive model of HCC recurrence was constructed, and the receiver operating characteristic (ROC) curve was used to evaluate the predictive model.ResultsOf the 106 HCC patients, 23 had recurrence, with a recurrence rate of 21.70%, and 20 died. Tumor differentiation (χ²=6.066,P=0.014), maximum tumor diameter (χ²=4.916,P=0.027), with or without envelope invasion (χ²=5.543,P=0.019), preoperative alpha fetoprotein (AFP) (χ²=5.458,P=0.019), HBV-DNA (χ²=5.446,P=0.020), neutrophil lymphocyte ratio (NLR) (χ²=12.161,P<0.001), the expressions of miR-424 (χ²=4.400,P=0.036), chromodomain helicase DNA-binding protein 8 (CHD8) (χ²=10.561,P=0.001), T-cadherin (T-cad) (χ²=48.723,P<0.001), laminin (LN) (χ²=18.506,P<0.001) and hepatocyte growth factor (HGF) (χ²=11.178,P=0.001) were related to the recurrence of HCC. Multivariate logistic regression analysis showed that the maximum tumor diameter≥6.5 cm (OR=1.69, 95%CI: 1.25-3.17,P=0.002), preoperative AFP>400 ng/ml (OR=1.38, 95%CI: 1.09-1.92,P=0.038), positive CHD8 (OR=0.77, 95%CI: 0.52-0.89,P=0.021), positive T-cad (OR=0.84, 95%CI: 0.68-0.92, P=0.006), positive LN (OR=1.22, 95%CI: 1.03-1.50,P=0.013) were the risk factors of HCC recurrence. According to the results of logistic analysis, the regression equation logit(P)=0.262+0.523X₁+0.326X₂-0.259X₃-0.286X₄+0.203X₅was constructed, whereX₁,X₂,X₃,X₄,X₅were the maximum tumor diameter, AFP, CHD8, T-cad and LN. ROC curve analysis showed that the area under the curve for predicting HCC recurrence was 0.849 (95%CI: 0.763-0.894,P<0.001), the accuracy rate was 83.02%, the sensitivity was 86.96%, the specificity was 81.93%, and the cut-off value was 0.736. According to the logit(P) function model,P=1/(1+e^-^Y), whereY=0.262+0.523X₁+0.326X₂-0.259X₃-0.286X₄+0.203X₅. One patient was randomly selected. According to his clinical data,P=0.564, which was less than the cut-off value (0.736). It could be considered that this patient would not have HCC recurrence with an accuracy rate of 83.02%.ConclusionTumor maximum diameter, preoperative AFP, CHD8, T-cad, LN expression are related to the recurrence of HCC after liver transplantation. The prediction model constructed based on this can effectively predict the risk of HCC recurrence.

Key words:Carcinoma,hepatocellular,Liver transplantation,Alpha-fetoprotein,Tumor diameter

白雪, 孟庆庆, 陈勇, 李静. HBV感染相关肝癌肝移植术后复发的预测模型[J]. 国际肿瘤学杂志, 2021, 48(12): 723-728.

Bai Xue, Meng Qingqing, Chen Yong1, Li Jing. Prediction model of HBV infection-related liver cancer recurrence after liver transplantation[J]. Journal of International Oncology, 2021, 48(12): 723-728.

图/表4

表1

复发与未复发肝移植HCC患者一般临床资料比较(例)"

变量	例数	未复发 (n=83)	复发 (n=23)	χ²值	P值	变量	例数	未复发 (n=83)	复发 (n=23)	χ²值	P值
年龄(岁)						术后化疗
<60	58	48	10	1.497	0.221	是	89	72	17	1.353	0.245
≥60	48	35	13			否	17	11	6
性别						分化程度
男	94	75	19	0.444	0.505	低分化	33	21	12	6.066	0.014
女	12	8	4			中高分化	73	62	11
BMI(kg/m²)						肿瘤数目(个)
<24	80	63	17	0.039	0.844	<3	48	39	9	0.449	0.503
≥24	26	20	6			≥3	58	44	14
术前降期治疗						肿瘤最大径(cm)
是	56	44	12	0.005	0.943	<6.5	67	57	10	4.916	0.027
否	50	39	11			≥6.5	39	26	13
Child-Pugh分级						包膜侵犯
A	51	40	11			有	64	55	9	5.543	0.019
B	42	34	8	0.804	0.669	无	42	28	14
C	13	9	4

表1

表2

复发与未复发肝移植HCC患者血清指标及免疫组织化学指标比较(例)"

变量	例数	未复发 (n=83)	复发 (n=23)	χ²值	P值	变量	例数	未复发 (n=83)	复发 (n=23)	χ²值	P值
术前AFP(ng/ml)						miR-424
>400	38	25	13	5.458	0.019	阳性	78	65	13	4.400	0.036
≤400	68	58	10			阴性	28	18	10
HBV-DNA(U/ml)						CHD8
<500	72	61	11	5.446	0.020	阳性	75	65	10	10.561	0.001
≥500	34	22	12			阴性	31	18	13
TBiL(mmol/L)						T-cad
<25	64	49	15	0.288	0.592	阳性	81	76	5	48.723	<0.001
≥25	42	34	8			阴性	25	7	18
PT(s)						LN
<14	69	53	16	0.258	0.611	阳性	38	21	17	18.506	<0.001
≥14	37	30	7			阴性	68	62	6
INR						HGF
<1.2	66	53	13	0.412	0.521	阳性	34	20	14	11.178	0.001
≥1.2	40	30	10			阴性	72	63	9
NLR						TGF-β
<3.5	57	52	5	12.161	<0.001	阳性	39	27	12	2.988	0.084
≥3.5	49	31	18			阴性	67	56	11

表2

表3

23例肝移植HCC患者复发的多因素logistic回归分析"

变量	β值	Wald 值	OR值(95%CI)	P值
常量	0.262	4.589	1.30(1.06~1.67)	0.008
分化程度低分化	0.132	3.573	1.14(0.52~1.63)	0.085
肿瘤最大径≥6.5 cm	0.523	4.769	1.69(1.25~3.17)	0.002
有包膜侵犯	0.235	2.833	1.26(0.73~1.84)	0.178
术前AFP>400 ng/ml	0.326	4.028	1.38(1.09~1.92)	0.038
HBV-DNA≥500 U/ml	0.141	2.892	1.15(0.59~1.76)	0.177
NLR≥3.5	0.158	3.665	1.17(0.61~2.08)	0.083
miR-424阳性	-0.184	2.306	0.83(0.77~1.59)	0.238
CHD8阳性	-0.259	4.323	0.77(0.52~0.89)	0.021
T-cad阳性	-0.286	4.602	0.84(0.68~0.92)	0.006
LN阳性	0.203	4.538	1.22(1.03~1.50)	0.013
HGF阳性	0.169	3.135	1.18(0.62~1.72)	0.126

表3

图1

参考文献20

[1]	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021,71(3):209-249. DOI: 10.3322/caac.21660.
[2]	Chen JG, Zhang SW. Liver cancer epidemic in China: past, present and future[J]. Semin Cancer Biol, 2011,21(1):59-69. DOI: 10.1016/j.semcancer.2010.11.002.
[3]	Halazun KJ, Najjar M, Abdelmessih RM, et al. Recurrence after liver transplantation for hepatocellular carcinoma: a new moral to the story[J]. Anna Surg, 2017,265(3):557-564. DOI: 10.1097/SLA.0000000000001966.
[4]	王妙婵, 徐爱芳, 包剑锋 . 生物标志物在肝癌术后复发预警中的作用研究进展[J]. 中国卫生检验杂志, 2019,29(13):1661-1663.
[5]	章文燕, 郑树森 . 肝癌移植术后复发相关标志物的研究进展[J]. 临床医学进展, 2019,9(3):310-318. DOI: 10.12677/acm.2019.93047.
[6]	Liver transplantation for hepatocellular carcinoma: Hangzhou experiences: retraction[J]. Transplantation, 2019,103(8):1736. DOI: 10.1097/TP.0000000000002822.
[7]	Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis[J]. N Engl J Med, 1996,334(11):693-699. DOI: 10.1056/NEJM199603143341104.
[8]	Kim JH, Sinn DH, Gwak GY, et al. Factors determining long-term outcomes of hepatocellular carcinoma within the milan criteria: liver transplantation versus locoregional therapy: a retrospective cohort study[J]. Medicine (Baltimore), 2016,95(35):e4735. DOI: 10.1097/MD.0000000000004735.
[9]	Chen J, Xu X, Wu J, et al. The stratifying value of Hangzhou criteria in liver transplantation for hepatocellular carcinoma[J]. PLoS One, 2014,9(3):e93128. DOI: 10.1371/journal.pone.0093128.
[10]	张志强, 刘玉珍, 刘邦 , 等. T-钙黏蛋白与肝癌肝移植术后肿瘤复发转移的相关性研究[J]. 药物评价研究, 2019,42(6):1146-1150. DOI: 10.7501/j.issn.1674-6376.2019.06.016.
[11]	Toso C, Asthana S, Bigam DL, et al. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the scientific registry of transplant recipients database[J]. Hepatology, 2009,49(3):832-838. DOI: 10.1002/hep.22693.
[12]	Thean LF, Low YS, Lo M, et al. Genome-wide association study identified copy number variants associated with sporadic colorectal cancer risk[J]. J Med Genet, 2018,55(3):181-188. DOI: 10.1136/jmedgenet-2017-104913.
[13]	李照, 毛雨鸽, 禹琛 , 等. 乙型肝炎相关性肝癌患者肝移植术后肿瘤复发的危险因素分析[J]. 中华肝脏病杂志, 2018,26(2):98-101. DOI: 10.3760/cma.j.issn.1007-3418.2018.02.005.
[14]	陈慧娟, 王培晓, 黄丽虹 , 等. CHD8蛋白与乙肝相关性肝癌肝移植术后肿瘤复发的相关性分析[J]. 实用器官移植电子杂志, 2018,6(6):444-447. DOI: 10.3969/j.issn.2095-5332.2018.06.008.
[15]	陈凯, 杨洪吉, 邓小凡 , 等. 肝癌根治性切除术后早期复发危险因素分析及预测模型构建[J]. 中华肿瘤防治杂志, 2018,25(5):344-348. DOI: 10.16.73/j.cnki.cjcpt.2018.05.008.
[16]	李东良, 张志强, 陈少华 , 等. T-cadherin在肝细胞癌中的表达及其与肿瘤复发转移的关系[J]. 解放军医学杂志, 2015,40(4):315-318. DOI: 10.11855/j.issn.0577-7402.2015.04.12.
[17]	Yang J, Lu Y, Lin YY, et al. Vascular mimicry formation is promoted by paracrine TGF-β and SDF1 of cancer-associated fibroblasts and inhibited by miR-101 in hepatocellular carcinoma[J]. Cancer Lett, 2016,383(1):18-27. DOI: 10.1016/j.canlet.2016.09.012.
[18]	冯超, 黄丽虹, 王培晓 , 等. 层粘连蛋白预测HBV感染相关性肝癌肝移植术后肿瘤复发的临床意义[J]. 中华器官移植杂志, 2019,40(5):298-302. DOI: 10.3760/cma.j.issn.0254-1785.2019.05.010.
[19]	董骏峰, 滕飞, 李培磊 , 等. 基于up-to-seven标准肝细胞癌肝移植术后生存预测模型的建立和验证[J]. 第二军医大学学报, 2018,39(7):745-752. DOI: 10.16781/j.0258-879x.2018.07.0745.
[20]	曾凯宁, 汪国营, 杨卿 , 等. 基于纤维蛋白原浓度的肝癌肝移植复发预测模型[J]. 实用器官移植电子杂志, 2019,7(1):35-39. DOI: 10.3969/j.issn.2095-5332.2019.01.010.