基于纤维蛋白原浓度的肝癌肝移植复发预测模型
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摘要
目的探讨肝癌肝移植术后复发的危险因素,建立多因素的肝癌肝移植复发预测模型,为评估肝癌肝移植患者预后和筛选合适的肝癌肝移植患者提供依据。方法回顾性分析中山大学附属第三医院173例行肝移植术的肝细胞癌患者的临床资料及随访资料,通过单因素分析和多因素Cox回归分析筛选肝癌肝移植术后复发的独立危险因素,将筛选出的危险因素通过Logistic回归建立回归模型。结果经单因素分析和多因素Cox回归分析,发现术前纤维蛋白原浓度、血管受侵、肿瘤总体积>115 cm~3以及甲胎蛋白(alpha fetoprotein,AFP)> 400 ng/ml是肝癌肝移植术后复发的独立危险因素。通过Logistic回归建立复发预测模型:Y=-3.047+0.699×纤维蛋白原+1.568×肿瘤总体积> 115 cm~3 (0=否,1=是)+0.317×血管受侵(0=无,1=有)+1.6×AFP> 400 ng/ml(0=否,1=是)。研究建立的模型对肝癌肝移植术后复发的预测有较高的敏感度(86.6%)、特异性(65.8%),受试者工作特征(receiver operating characteristic,ROC)曲线下面积为0.800,高于米兰标准(0.687)、杭州标准(0.703)。符合Y≤-0.79的患者5年无复发生存率(recurrence free survival,RFS)显著高于Y>-0.79的患者(92.3%比34.1%,P <0.001)。符合米兰标准、杭州标准的患者中,Y≤-0.79和Y>-0.79的患者5年RFS仍存在显著差异(94.9%比40.9%,P <0.001;93.6%比45.7%,P <0.001)。结论术前纤维蛋白原、血管受侵、肿瘤总体积> 115 cm~3以及AFP> 400 ng/ml是肝癌肝移植术后复发的独立危险因素。研究建立的基于纤维蛋白原浓度的预测模型对肝癌肝移植术后复发的预测有较高的敏感度及特异性,能够将可能受益的患者筛选出来。
Objective To analyse the risk factors of hepatocellular carcinoma(HCC)recurrence after liver transplantation and to build a logistic regression model to predict HCC recurrence which helps patient's selection. Methods A total number of 173 patients diagnosed with HCC and received liver transplantation were enrolled in the research. Univariate and multivariate Cox analysis were used to explore the risk factors of HCC recurrence after liver transplantation, logistic regression was used to build a scoring model. Results Univariate and multivariate Cox regression analysis showed that plasma fibrinogen concentration, macrovascular invasion, total tumor volume > 115 cm~3 and alpha fetoprotein(AFP)> 400 ng/ml were independent risk factors of HCC recurrence after liver transplantation. The logistic regression model was, Y = logit(P)=-3.047 + 0.699 × fibrinogen concentration + 1.568× TTV > 115 cm~3(0 = no,1 = yes) + 0.317×macrovascular invasion(0 = no, 1 = yes) + 1.6× AFP >400 ng/ml(0 = no, 1 = yes). The sensitivity and specificity in predicting HCC recurrence were 86.6% and 65.8%. The area under receiver operating characteristic(ROC) curve was 0.800, compared with 0.687 of Milan criteria and 0.703 of Hangzhou criteria. The 5-year RFS of patients with model score Y ≤-0.79 was significantly higher than patients with Y >-0.79(92.3% vs. 34.1%, P < 0.001). Within patients who meet Milan and Hangzhou criteria, the 5-year RFS of patients with Y ≤-0.79 was also significantly higher than patients with Y >-0.79(94.9% vs. 40.9%, P < 0.001;93.6% vs. 45.7%, P < 0.001,respectively). Conclusion Plasma fibrinogen concentration, macrovascular invasion, total tumor volume > 115 cm~3 and AFP > 400 ng/ml were independent risk factors of HCC recurrence after liver transplantation. The logistic regression models we built was sensitive and specific in predicting HCC recurrence after liver transplantation.
Objective To analyse the risk factors of hepatocellular carcinoma(HCC)recurrence after liver transplantation and to build a logistic regression model to predict HCC recurrence which helps patient's selection. Methods A total number of 173 patients diagnosed with HCC and received liver transplantation were enrolled in the research. Univariate and multivariate Cox analysis were used to explore the risk factors of HCC recurrence after liver transplantation, logistic regression was used to build a scoring model. Results Univariate and multivariate Cox regression analysis showed that plasma fibrinogen concentration, macrovascular invasion, total tumor volume > 115 cm~3 and alpha fetoprotein(AFP)> 400 ng/ml were independent risk factors of HCC recurrence after liver transplantation. The logistic regression model was, Y = logit(P)=-3.047 + 0.699 × fibrinogen concentration + 1.568× TTV > 115 cm~3(0 = no,1 = yes) + 0.317×macrovascular invasion(0 = no, 1 = yes) + 1.6× AFP >400 ng/ml(0 = no, 1 = yes). The sensitivity and specificity in predicting HCC recurrence were 86.6% and 65.8%. The area under receiver operating characteristic(ROC) curve was 0.800, compared with 0.687 of Milan criteria and 0.703 of Hangzhou criteria. The 5-year RFS of patients with model score Y ≤-0.79 was significantly higher than patients with Y >-0.79(92.3% vs. 34.1%, P < 0.001). Within patients who meet Milan and Hangzhou criteria, the 5-year RFS of patients with Y ≤-0.79 was also significantly higher than patients with Y >-0.79(94.9% vs. 40.9%, P < 0.001;93.6% vs. 45.7%, P < 0.001,respectively). Conclusion Plasma fibrinogen concentration, macrovascular invasion, total tumor volume > 115 cm~3 and AFP > 400 ng/ml were independent risk factors of HCC recurrence after liver transplantation. The logistic regression models we built was sensitive and specific in predicting HCC recurrence after liver transplantation.
引文
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[16]Tang L,Liu K,Wang J,et al.High preoperative plasma fibrinogen levels are associated with distant metastases and impaired prognosis after curative resection in patients with colorectal cancer[J].J Surg Oncol,2010,102(5):428-432.
[17]Jones JM,Mcgonigle NC,Mcanespie M,et al.Plasma fibrinogen and serum C-reactive protein are associated with non-small cell lung cancer[J].Lung Cancer,2006,53(1):97-101.
[18]Polterauer S,Grimm C,Seebacher V,et al.Plasma fibrinogen levels and prognosis in patients with ovarian cancer:a multicenter study[J].Oncologist,2009,14(10):979-985.
[19]Polterauer S,Seebacher V,Hefler-Frischmuth K,et al.Fibrinogen plasma levels are an independent prognostic parameter in patients with cervical cancer[J].Am J Obstet Gynecol,2009,200(6):164-168.
[20]Seebacher V,Polterauer S,Grimm C,et al.The prognostic value of plasma fibrinogen levels in patients with endometrial cancer:a multi-centre trial[J].Br J Cancer,2010,102(6):952-956.
[21]Zhu WL,Fan BL,Liu DL.Abnormal expression of fibrinogen gamma(FGG)and plasma level of fibrinogen in patients with hepatocellular carcinoma[J].Anticancer Res,2009,29(7):2531-2534.
[22]Kinoshita A,Onoda H,Imai N,et al.Elevated plasma fibrinogen levels are associated with a poor prognosis in patients with hepatocellular carcinoma[J].Oncology,2013,85(5):269-277.
[2]Mazzaferro V,E Regalia,R Doci,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.
[3]Yao FY,Ferrell L,Bass NM,et al.Liver transplantation for hepatocellular carcinoma:expansion of the tumor size limits does not adversely impact survival[J].Hepatology,2001,33(6):1394-1403.
[4]Zheng SS,Xu X,Wu J,et al.Liver transplantation for hepatocellular carcinoma:Hangzhou experiences[J].Transplantation,2008,85(12):1726-1732.
[5]Toso C,Trotter J,Wei A,et al.Total tumor volume predicts risk of recurrence following liver transplantation in patients with hepatocellular carcinoma[J].Liver transplantation,2008,14(8):1107-1115.
[6]Toso C,Asthana S,Bigam D L,et al.Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the scientific registry of transplant recipients database[J].Hepatology(Baltimore,Md.),2009,49(3):832-838.
[7]陈卫中,潘晓平,倪宗瓒.Logistic回归模型在ROC分析中的应用[J].中国卫生统计,2007,24(1):22-24.
[8]Mosesson MW.Fibrinogen and fibrin structure and functions[J].J Thromb Haemost,2005,3(8):1894-1904.
[9]Tennent GA,Brennan SO,Stangou AJ,et al.Human plasma fibrinogen is synthesized in the liver[J].Blood,2007,109(5):1971-1974.
[10]Dvorak HF.Tumors:wounds that do not heal.Similarities between tumor stroma generation and wound healing[J].N Engl J Med,1986,315(26):1650-1659.
[11]Sahni A,Francis CW.Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation[J].Blood,2000,96(12):3772-3778.
[12]Biggerstaff JP,Seth N,Amirkhosravi A,et al.Soluble fibrin augments platelet/tumor cell adherence in vitro and in vivo,and enhances experimental metastasis[J].Clin Exp Metastasis,1999,17(8):723-730.
[13]Takeuchi H,Ikeuchi S,Kitagawa Y,et al.Pretreatment plasma fibrinogen level correlates with tumor progression and metastasis in patients with squamous cell carcinoma of the esophagus[J].J Gastroenterol Hepatol,2007,22(12):2222-2227.
[14]Yamashita H,et al.Hyperfibrinogenemia is associated with lymphatic as well as hematogenous metastasis and worse clinical outcome in T2 gastric cancer[J].BMC Cancer,2006,1(6):147.
[15]Guo Q,Zhang B,Dong X,et al.Elevated levels of plasma fibrinogen in patients with pancreatic cancer:possible role of a distant metastasis predictor[J].Pancreas,2009,38(3):e75-79.
[16]Tang L,Liu K,Wang J,et al.High preoperative plasma fibrinogen levels are associated with distant metastases and impaired prognosis after curative resection in patients with colorectal cancer[J].J Surg Oncol,2010,102(5):428-432.
[17]Jones JM,Mcgonigle NC,Mcanespie M,et al.Plasma fibrinogen and serum C-reactive protein are associated with non-small cell lung cancer[J].Lung Cancer,2006,53(1):97-101.
[18]Polterauer S,Grimm C,Seebacher V,et al.Plasma fibrinogen levels and prognosis in patients with ovarian cancer:a multicenter study[J].Oncologist,2009,14(10):979-985.
[19]Polterauer S,Seebacher V,Hefler-Frischmuth K,et al.Fibrinogen plasma levels are an independent prognostic parameter in patients with cervical cancer[J].Am J Obstet Gynecol,2009,200(6):164-168.
[20]Seebacher V,Polterauer S,Grimm C,et al.The prognostic value of plasma fibrinogen levels in patients with endometrial cancer:a multi-centre trial[J].Br J Cancer,2010,102(6):952-956.
[21]Zhu WL,Fan BL,Liu DL.Abnormal expression of fibrinogen gamma(FGG)and plasma level of fibrinogen in patients with hepatocellular carcinoma[J].Anticancer Res,2009,29(7):2531-2534.
[22]Kinoshita A,Onoda H,Imai N,et al.Elevated plasma fibrinogen levels are associated with a poor prognosis in patients with hepatocellular carcinoma[J].Oncology,2013,85(5):269-277.
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