【作者】 刘凯；

【导师】 任万华；

【作者基本信息】 山东大学 ， 传染病学（专业学位）， 2018， 硕士

【摘要】 研究背景原发性肝癌(Primary hepatic carcinoma,PHC)在恶性肿瘤中发病率位居第五位,在男性群体中,肝癌在肿瘤相关致死率中占据第二位。该病起病隐匿,多数病人出现明显临床症状时已丧失最佳治疗机会。经导管肝动脉化疗栓塞术(TACE)是国际上公认的中、晚期原发性肝癌的首选治疗方案之一,可以减慢病灶生长速度,延长病人生存年限。通过血清学及放射学方法及早发现病情,并进行前期干预能显著改善病人的预后。血清甲胎蛋白(AFP)常用来诊断PHC。然而,由于单一检测时其敏感性和特异性有限,在PHC的诊断评估中存在漏诊、误诊的可能,因此,迫切需要诊断更有价值的肿瘤标志物以辅助诊断。异常凝血酶原(protein induced by vitamin K absence or antagonist-II,PIVKA-II),又称脱-γ-羧基凝血酶原(des-Y-carboxy-prothrombin,DCP),作为肝癌血清学诊断标志物的重要补充,其应用价值还有待进一步探讨。目的研究异常凝血酶原在肝癌诊断以及在评估TACE术治疗效果中的应用价值。方法完善纳入和排除标准后,本研究纳入2016年10月至2017年9月在山东省立医院感染性疾病科住院的49例初诊初治原发性肝癌患者,并纳入同期住院收治的49例肝硬化病人作为对照组,研究AFP、DCP及联合应用在肝癌诊断中的价值。后对纳入的原发性肝癌患者入院后以TACE作为首次治疗方法,1月后行增强影像学检查,肝癌治疗效果以mRECIST标准评估。寻找TACE术后预测短期缓解的因素,比较DCP、AFP是否阳性对短期预后的影响,评估DCP的变化趋势在评价TACE术后治疗效果中的价值。结果1、对纳入患者的基线血清AFP、DCP表达水平与基本临床资料进行相关性分析,结果显示,二者表达水平与性别、年龄、病因学、Child评分、肿瘤个数无统计学意义,DCP的表达水平与BCLC分期(P=0.042)及肿瘤直径(P=0.002)具有相关性。2、AFP对原发性肝癌诊断的ROC曲线下面积为0.788(95%CI:0.699-0.877),约登指数为0.490,对应的最佳截止值为29.8ng/ml,敏感性为63.30%,特异性为 85.7%,DCP 的 AUR0C=0.863(95%CI:0.784-0.941),约登指数为 0.653,对应的最佳截止值为42.87mAU/ml,敏感性为79.6%,特异性为83.7%,两指标联合诊断示ROC曲线下面积为0.845,略差于DCP单项检测,但两者差异无统计学意义(P=0.622)。3、以mRECIST标准对基线时AFP、DCP阳性及阴性患者行首次TACE术后的治疗效果进行评估,AFP及DCP组的短期TACE术后不同预后分组间未见明显差异。4、对性别、癌栓、child分级、肿瘤直径(>5cm)、肿瘤个数(>4个)、AFP水平(>200ng/ml)、DCP水平(>400mIU/ml)与患者影像学变化的关系行单变量因素分析,除肿瘤直径外,余变量无相关性,肿瘤直径是否大于5cm对TACE术后短期治疗预后差异具有统计学意义(OR:3.98,95%CI1.022-15.51,P=0.046)。5、对纳入患者在TACE术后1月行增强影像学及血清学复查,在49例患者中,有36例(占73.4%)患者实现了影像学部分或完全缓解,在这部分病人中,有23例患者(占63.8%)DCP较基线时下降>300%。在6例影像学进展的患者中,5例DCP较前增加>200%(占83.3%),差异有统计学意义(x2= 15.11,P=0.004),DCP变化能较好的反应影像学变化。对于血清AFP,13例患者因基线时浓度超出监测范围不可测量,17例患者纳入时AFP在正常范围,对这部分病人无法准确评估血清AFP变化,剩余19例病人达到影像学缓解14例(占73.6%),其中13例(占92.8%)实现AFP较前下降>30%。结论1.血清DCP水平与巴塞罗那肝癌分期显著相关,与性别、年龄、病因学、Child评分、肿瘤个数无相关性。2.血清DCP水平在肝硬化患者中对肝癌具有良好的诊断价值,优于AFP单一诊断。3.基线血清DCP水平与肝癌TACE术短期治疗效果无显著相关性。4.血清DCP的变化程度可以用于协助评估TACE术的治疗效果。更多还原

【Abstract】 BackgroundPrimary hepatic carcinoma(PHC)is the fifth most common malignant tumor in both sexes worldwide and is the second leading cause of cancer related-death in males.PHC is insidious,and most patients can not undergo operation when they have obvious clinical symptoms.Transcatheter arterial chemotherapy and embolization(TACE)is internationally recognized treatment method for patients with advanced primary liver cancer,which slows tumor growth and prolongs life survival.Early detection of PHC through serological and imaging methods can significantly improve the prognosis of patients.Serum alpha-fetoprotein(AFP)is commonly used to diagnose PHC.However,the sensitivity and specificity of AFP both are not high enough,the misdiagnosis are often inevitable.Thus,a more accurate method for detecting HPC is needed.Protein induced by vitamin K absence or antagonist-II(PIVKA-Ⅱ),also called des-γ-carboxy-prothrombin(DCP),is one of the most important serological markers in PHC.Futher studies about the application value are required.ObjectiveTo evaluate the diagnostic value in DPC and the therapeutic value in TACE for patients with PHC.MethodsWe included 49 patients with primary hepatic carcinoma in department of infectious diseases from Shandong Provincial Hospital from October 2016 to September 2017,and 49 cases of liver cirrhosis patients as control group.To study the value of AFP,DCP and joint application value in the diagnosis of PHC.TACE was used as the initial therapy.One month later,the imaging examination was performed to evaluate the therapeutic effect of liver cancer by mRECIST standard.To find the short-term prognostic factors of liver cancer after TACE and compare the efifect of DCP and AFP on short-term prognosis.To evaluate the value of DCP changes in the treatment outcome after TACE.Results1.Correlation analysis was performed on baseline serum AFP,DCP expression level and basic clinical data.The results showed that there are no relationship between gender,age,etiology,Child-Pugh score,tumor number and the expression level.The expression level of DCP was correlated with BCLC staging(P=0.042)and tumor diameter(P=0.002).2s In our research,sensitivity=0.796,specificity= 0.837,AUC=0.863 for DCP,sensitivity =0.633,specificity=0.857,AUC=0.788 for AFP,The combined monitoring of the two indicators shows that the area under the ROC curve is 0.845,slightly worse than that of DCP,but there is no statistical significance(P=0.622).The diagnostic accuracy of DCP were better than that of AFP.3.MRECIST standard was used to evaluate the efficacy of the first TACE postoperative treatment among AFP,DCP positive and negative patients,and no significant difference was observed between different prognostic groups among AFP and DCP group.4.The relationship between gender,tumor emboli,child,tumor diameter(>5 cm),tumor number(>4),the AFP levels(>200 ng/ml),DCP levels(>400 miu/ml)and imaging changes in patients was analysed with univariate and multivariate analysis of variance,In addition to turmor diameter,there was no correlation between the residual variables.The results showed that among the 49 patients,a complete radiologic remission is achieved in 36 cases and 13 cases achieved radiographic progression.Among the 22 patients with tumor diameter more than 5cm,13 cases(59.1%)improved,36 cases(40.9%)worsened.Among the 27 patients with tumor diameter less than 5cm,23 cases(85.2%)improved,3 cases(14.8%)worsened.In the multivariable analysis,tumor diameter was an independent risk factor(OR:3.98,95%CIl.022-15.51,P=0.046)。5、The imaging and serological reexamination of the patients was performed in the first month after TACE surgery,and 36 of the 49 patients(73.4%)had achieved imaging partial or complete remission.Among these patients,the level of DCP had decreased>30%compared with baseline in 23 patients(63.8%).In the 6 patients with radiographic progression,the level of DCP had increased>20%compared with baseline in 5 patients(83.3%),The difference was statistically significant(χ2= 15.11,P=0.004),the change of DCP can reflect the change of imaging.For serum AFP,13 patients were not able to measure owing to beyond the monitoring scope at baseline.In 17 patients,AFP was in normal range,and the serum AFP changes were not accurately assessed in this part of patients.In the remaining 19 cases,14 patients(73.6%)had achieved imaging partial or complete remission and the level of DCP had decreased>30%compared with baseline in 13 patients(92.8%).Conclusions1.Serum DCP level was significantly correlated with BCLC staging,and was not correlated with gender,age,etiology,Child-Pugh score,and tumor number.2.The serum DCP level has a good diagnostic value for liver cancer in patients with cirrhosis,which is better than that of AFP.3.There was no significant correlation between baseline serum DCP level and short-term therapeutic effect of TACE.4.The changes of serum DCP can be used to assess the therapeutic effect of TACE.更多还原