Background: As a promising biomarker of hepatocellular carcinoma(HCC), protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ) has been studied extensively. However, its diagnostic capability varies across HCC...Background: As a promising biomarker of hepatocellular carcinoma(HCC), protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ) has been studied extensively. However, its diagnostic capability varies across HCC studies. This study aimed to compare the performance of PIVKA-Ⅱ with alpha-fetoprotein(AFP) in the diagnosis of HCC. Data sources: A systematic literature search was conducted to identify the studies from MEDLINE, Embase and Cochrane Library Databases, which were published up to December 20, 2017 to compare the diagnostic capability of PIVKA-Ⅱ and AFP for HCC. The data were pooled using random effects model. Pooled sensitivity and specificity were calculated. Summary receiver operating characteristic curve(ROC) was employed to evaluate the diagnostic accuracy of each marker. Results: Thirty-one studies were included. The pooled sensitivity(95% CI) of PIVKA-Ⅱ and AFP was 0.66(0.65–0.68) and 0.66(0.65–0.67), respectively in diagnosis of HCC; and the corresponding pooled specificity(95% CI) was 0.89(0.88–0.90) and 0.84(0.83–0.85), respectively. The area under the ROC curve(AUC) of PIVKA-Ⅱ and AFP was 0.856(0.817–0.895) and 0.770(0.728–0.811), respectively. Subgroup analysis showed that PIVKA-Ⅱ was superior to AFP in terms of the AUC for both small HCC( < 3 cm) [0.863(0.825–0.901) vs 0.717(0.658–0.776)] and large HCC( ≥ 3 cm) [0.854(0.811–0.897) vs 0.729(0.682–0.776)]; for American [0.926(0.897–0.955) vs 0.698(0.594–0.662)], European [0.772(0.743–0.801) vs 0.628(0.594–0.662)], Asian [0.838(0.812–0.864) vs 0.785(0.764–0.806)] and African [0.812(0.794–0.840) vs 0.721(0.675–0.767)] HCC patients; and for HBV-related [0.909(0.866–0.951) vs 0.714(0.673–0.755)] and mixed-etiology [0.847(0.821–0.873) vs 0.794(0.772–0.816)] HCC. Conclusion: This meta-analysis indicates that PIVKA-Ⅱ is better than AFP in terms of the accuracy for diagnosing HCC, regardless of tumor size, patient ethnic group, or HCC etiology.展开更多
Protein induced by vitamin K absence or antagonist Ⅱ(PIVKA-Ⅱ) is a putative specific marker of hepatocellular carcinoma(HCC),but it may also be produced by asmall number of gastric cancers.To date,16 cases of PIVKA-...Protein induced by vitamin K absence or antagonist Ⅱ(PIVKA-Ⅱ) is a putative specific marker of hepatocellular carcinoma(HCC),but it may also be produced by asmall number of gastric cancers.To date,16 cases of PIVKA-Ⅱ-producing gastric cancer have been reported,2 of which were reported by us and all of which were identified in Japan.There are no symptoms specific to PIVKA-Ⅱ-producing gastric cancer,and the representative clinical symptoms are general fatigue,appetite loss,and upper abdominal pain.Serum alpha-feto-protein(AFP)levels are also increased in almost allcases.Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is ob-served in approximately 20% of cases.Differential diagnosis between metastatic liver tumor and HCC is often difficult.Grossly,almost all cases appear as advanced gastric cancer.Histologically,a hepatoid pattern is observed in many cases,in addition to a moderately to poorly differentiated adenocarcinoma component.The production of PIVKA-Ⅱ and AFP is usually confirmed using immunohistochemical staining.Treatment and prognosis largely depends on the existence of liver meta-stasis,and the prognosis of patients with liver metas-tasis is very poor.PIVKA-Ⅱ may be produced during the hepatocellular metaplasia of the tumor cells.展开更多
目的:探讨血清生物标志物甲胎蛋白(AFP)、维生素K缺失或拮抗剂Ⅱ诱导的蛋白质(PIVKA-Ⅱ)和磷脂酰肌醇蛋白聚糖3(GPC-3)单独或联合用于肝细胞癌(以下简称肝癌)诊断的价值。方法:检索PubMed、Web of Science、Embase三个数据库,收集2002...目的:探讨血清生物标志物甲胎蛋白(AFP)、维生素K缺失或拮抗剂Ⅱ诱导的蛋白质(PIVKA-Ⅱ)和磷脂酰肌醇蛋白聚糖3(GPC-3)单独或联合用于肝细胞癌(以下简称肝癌)诊断的价值。方法:检索PubMed、Web of Science、Embase三个数据库,收集2002年以来发表的AFP、PIVKA-Ⅱ和GPC-3单独或联合用于诊断肝癌的文献。根据纳入和排除标准筛选文献并提取相关数据。利用诊断准确性研究的质量评价(QUADAS)检查表对纳入的文献进行质量评价,并采用Meta DiSc软件、Review Manager 5.4软件和Stata 15.1软件对AFP、PIVKA-Ⅱ和GPC-3单用和联合使用诊断肝癌的受试者工作特征曲线下面积(AUC)、敏感度、特异度等指标进行数据分析。结果:共纳入32篇文献。Meta分析结果显示,单个标志物用于诊断肝癌时,PIVKA-Ⅱ的AUC值最高,为0.88(95%CI:0.85~0.91),其次是GPC-3和AFP;多个标志物联合用于诊断肝癌的AUC均高于单个标志物,其中PIVKA-Ⅱ联合GPC-3诊断的AUC值最高,为0.90(95%CI:0.87~0.92)。单个标志物用于诊断肝癌时,PIVKA-Ⅱ和GPC-3的敏感度相对较高(分别为0.75和0.76),但GPC-3的特异度不如PIVKA-Ⅱ和AFP(AFP、PIVKA-Ⅱ和GPC-3分别为0.87、0.88和0.81);多个标志物联合用于诊断肝癌的敏感度较单个标志物诊断时有所提高,但特异度无明显提高。单个标志物用于诊断肝癌时,PIVKA-Ⅱ的诊断比值比(DOR)最高,为22(95%CI:13~36),其次是GPC-3和AFP;两个标志物联合用于诊断肝癌的DOR均高于单个标志物,其中AFP联合GPC-3诊断的DOR最高,为25(95%CI:9~67);三个标志物联合用于诊断肝癌时的DOR明显降低,为10(95%CI:7~45)。结论:单个标志物用于肝癌诊断时,PIVKA-Ⅱ的诊断价值更高。两种标志物联合能显著提高肝癌诊断的敏感度,三种标志物联合未能进一步提高诊断价值。结合临床实际,推荐AFP联合PIVKA-Ⅱ用于肝癌的诊断。展开更多
目的:评价化学发光微粒子免疫法(CMIA)与化学发光酶免疫法(CLEIA)检测异常凝血酶原(Protein Induced by Vitamin K Absence or Antagonist-Ⅱ, PlVKA-Ⅱ),通过ROC曲线计算用于诊断肝癌的临界值,并对该临界值灵敏度和特异性进行评价.方法...目的:评价化学发光微粒子免疫法(CMIA)与化学发光酶免疫法(CLEIA)检测异常凝血酶原(Protein Induced by Vitamin K Absence or Antagonist-Ⅱ, PlVKA-Ⅱ),通过ROC曲线计算用于诊断肝癌的临界值,并对该临界值灵敏度和特异性进行评价.方法:选取我院118例肝癌患者及80例肝硬化患者的血清样本,在肝癌组中依照美国临床实验室标准化协会指南比对标准文件EP9-A2,对两种检测方法之间的偏倚进行评估;比较两组病例中PlVKA-Ⅱ检测水平,以临界值(CUT OFF) 40mAU/mL为参考线,分析两种检测对肝癌的诊断特异性.结果:两种方法检测PlVKA-Ⅱ相关性良好, r =0.9993,直线回归方程为Y=0.42667+0.99694X ,在PIVKA-Ⅱ阳性参考限40 mAU/mL,其预期的偏倚值95%可信区间为37.959-42.649mAU/mL,两种方法在肝癌组阳性率分别为88.14%与87.29%,差异均有统计学意义(P<0.05),对肝癌诊断的ROC曲线下面积分别为0.884和0.880.提示两种检测方法对PlVKA-Ⅱ肝癌诊断有均有较高的特异性.结论: CMIA与CLEIA两种方法均能有效检测PlVKA-Ⅱ,且相关性良好,基于PIVKA对肝细胞癌灵敏度的临界值40mAU/mL来诊断肝癌,均有较高的特异性,能够满足临床需要.展开更多
为探究血清PIVKA-Ⅱ与AFP检测在原发性肝细胞癌诊断中的优劣性,对237例患者的血清PIVKA-Ⅱ与AFP进行检测,其中乙肝病毒相关性原发性肝细胞癌(hepatocellular carcinoma, HCC)患者115例、乙肝携带者(asymptomatic carrier, As C) 55例、...为探究血清PIVKA-Ⅱ与AFP检测在原发性肝细胞癌诊断中的优劣性,对237例患者的血清PIVKA-Ⅱ与AFP进行检测,其中乙肝病毒相关性原发性肝细胞癌(hepatocellular carcinoma, HCC)患者115例、乙肝携带者(asymptomatic carrier, As C) 55例、乙肝病毒相关肝硬化(liver cirrhosis, LC)患者47例、非肝癌肿瘤患者20例。检测结果显示:肝癌组PIVKA-Ⅱ的中位表达量高于非肝癌组(包括As C组、LC组、非肝癌肿瘤组), P均小于0.05;使用AFP、PIVKA-Ⅱ和AFP+PIVKA-Ⅱ诊断肝癌的灵敏度分别为67.8%、81.7%和90.4%,对应的ROC曲线下面积为0.881、0.945和0.962, PIVKA-Ⅱ检测肝癌的cut-off值为32 m AU/m L。已有研究报道以40 m AU/m L为PIVKA-Ⅱ的cut-off值,本研究根据PIVKA-Ⅱ是否≥40 m AU/m L将HCC组分为PIVKA-Ⅱ≥40组、PIVKA-Ⅱ<40组,对两组患者的性别、年龄、病毒载量、肿瘤分期、癌结节数目、肿块直径和是否抗病毒治疗进行比较,采用logistic回归分析两组患者的差异性指标,结果显示病毒载量[OR=1.150, 95%CI (1.022, 1.295), P=0.02]为PIVKA-Ⅱ检测肝癌的独立影响因素。相关分析表明PIVKA-Ⅱ与肝癌肿块直径呈正相关。此外, AFP、PIVKA-Ⅱ的cut-off值分组结果表明, PIVKA-Ⅱ≥32且AFP<20组的肝癌肿块直径大于PIVKA-Ⅱ<32且AFP≥20组(P=0.035)。因此, PIVKA-Ⅱ是优于AFP筛查肝细胞癌的血清学肿瘤标志物,其表达量与肿瘤肿块直径呈正相关。展开更多
AIM:To evaluate diagnostic value ofα-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-Ⅱ(PIVKA-Ⅱ)in hepatocellular carcinoma(HCC). METHODS:One hundred and sixty-eight patients during routine HCC sur...AIM:To evaluate diagnostic value ofα-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-Ⅱ(PIVKA-Ⅱ)in hepatocellular carcinoma(HCC). METHODS:One hundred and sixty-eight patients during routine HCC surveillance were included in this study.Of the 168 patients,90(53.6%)had HCC including newly developed HCC(n=82)or recurrent HCC after treatment(n=8).Sera were obtained during their first evaluation for HCC development and at the time of HCC diagnosis before commencing HCC treatment.HCC was diagnosed by histological examination,appropriate imaging characteristics-computed tomography or magnetic resonance imaging.Control sera were collected from 78 patients with benign liver disease(BLD),which were obtained during routine surveillance with a suspicion of HCC.AFP,AFP-L3 and PIVKA-Ⅱwere measured in the same serum by microchip capillary electrophoresis and liquid-phase binding assay on a micro-total analysis system Wako i30 auto analyzer.The performance characteristics of three tests and combined tests for the diagnosis of HCC were obtained using receiver operating characteristic curves in all populations and subgroups with AFP<20 ng/mL. RESULTS:Of 90 HCC patients,38(42.2%)patients had AFP<20 ng/mL,20(22.2%)patients had AFP 20-200 ng/mL and 32(35.6%)patients had AFP>200 ng/mL.Of the 78 BLD patients,74(94.9%)patients had AFP<20 ng/mL.After adjustment for age and HBV infection status,AFP-L3 levels were higher in HCC than in BLD among patients with low AFP levels(<20 ng/mL)(P<0.001).In a total of 168 patients,areas under the curve(AUC)for HCC were 0.879,0.887,0.801 and 0.939 for AFP,AFP-L3,PIVKA-Ⅱand the combined markers,respectively.The combined AUC for three markers showed higher value than the AUCs of individual marker(P<0.05).AFP-L3 had higher AUC value than PIVKA-Ⅱfor HCC detection in entire patients(P =0.043).With combination of AFP-L3(cut-off>5%) and PIVKA-Ⅱ(cut-off>40 AU/L),the sensitivity were 94.4%and specificity were 75.6%in all patients.In 112 patients with low AFP levels(<20 ng/mL),AUCs of AFP-L3,PIVKA-Ⅱand combine AFP-L3 and PIVKA-Ⅱtests were 0.824,0.774 and 0.939,respectively. AFP-L3 with a cut-off value of 5%showed sensitivity of 71.1%and specificity of 83.8%,and PIVKA-Ⅱwith a cut-off value of 40 AU/L had sensitivity of 57.9%and specificity of 95.9%in patients with low AFP levels. The combination of AFP-L3 and PIVKA-Ⅱincreased the sensitivity and specificity up to 92.1%and 79.7%, respectively,in low AFP group.Combined markers detected 81.8%of early stage HCC(Union for Inter-national Cancer Control stageⅠ),86.7%of small sized tumor(<2 cm)and 91.7%of single tumor of HCC in the low AFP group.In multivariate analysis,AFP-L3 was correlated with AFP and tumor size,and PIVKA-Ⅱwas correlated with laboratory tests including serum aspartate aminotransferase,total bilirubin,platelets and albumin levels.PIVKA-Ⅱhad no correlation with AFP,AFP-L3 or tumor characteristics. CONCLUSION:Combined determination of AFP-L3 and PIVKA-Ⅱcould improve the diagnostic value for HCC detection in patients with or without increased AFP levels.展开更多
基金supported in part by the National Natural Sci-ence Foundation of China(81472284 and 81672699)Shanghai Pujiang Program(16PJD004)
文摘Background: As a promising biomarker of hepatocellular carcinoma(HCC), protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ) has been studied extensively. However, its diagnostic capability varies across HCC studies. This study aimed to compare the performance of PIVKA-Ⅱ with alpha-fetoprotein(AFP) in the diagnosis of HCC. Data sources: A systematic literature search was conducted to identify the studies from MEDLINE, Embase and Cochrane Library Databases, which were published up to December 20, 2017 to compare the diagnostic capability of PIVKA-Ⅱ and AFP for HCC. The data were pooled using random effects model. Pooled sensitivity and specificity were calculated. Summary receiver operating characteristic curve(ROC) was employed to evaluate the diagnostic accuracy of each marker. Results: Thirty-one studies were included. The pooled sensitivity(95% CI) of PIVKA-Ⅱ and AFP was 0.66(0.65–0.68) and 0.66(0.65–0.67), respectively in diagnosis of HCC; and the corresponding pooled specificity(95% CI) was 0.89(0.88–0.90) and 0.84(0.83–0.85), respectively. The area under the ROC curve(AUC) of PIVKA-Ⅱ and AFP was 0.856(0.817–0.895) and 0.770(0.728–0.811), respectively. Subgroup analysis showed that PIVKA-Ⅱ was superior to AFP in terms of the AUC for both small HCC( < 3 cm) [0.863(0.825–0.901) vs 0.717(0.658–0.776)] and large HCC( ≥ 3 cm) [0.854(0.811–0.897) vs 0.729(0.682–0.776)]; for American [0.926(0.897–0.955) vs 0.698(0.594–0.662)], European [0.772(0.743–0.801) vs 0.628(0.594–0.662)], Asian [0.838(0.812–0.864) vs 0.785(0.764–0.806)] and African [0.812(0.794–0.840) vs 0.721(0.675–0.767)] HCC patients; and for HBV-related [0.909(0.866–0.951) vs 0.714(0.673–0.755)] and mixed-etiology [0.847(0.821–0.873) vs 0.794(0.772–0.816)] HCC. Conclusion: This meta-analysis indicates that PIVKA-Ⅱ is better than AFP in terms of the accuracy for diagnosing HCC, regardless of tumor size, patient ethnic group, or HCC etiology.
文摘Protein induced by vitamin K absence or antagonist Ⅱ(PIVKA-Ⅱ) is a putative specific marker of hepatocellular carcinoma(HCC),but it may also be produced by asmall number of gastric cancers.To date,16 cases of PIVKA-Ⅱ-producing gastric cancer have been reported,2 of which were reported by us and all of which were identified in Japan.There are no symptoms specific to PIVKA-Ⅱ-producing gastric cancer,and the representative clinical symptoms are general fatigue,appetite loss,and upper abdominal pain.Serum alpha-feto-protein(AFP)levels are also increased in almost allcases.Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is ob-served in approximately 20% of cases.Differential diagnosis between metastatic liver tumor and HCC is often difficult.Grossly,almost all cases appear as advanced gastric cancer.Histologically,a hepatoid pattern is observed in many cases,in addition to a moderately to poorly differentiated adenocarcinoma component.The production of PIVKA-Ⅱ and AFP is usually confirmed using immunohistochemical staining.Treatment and prognosis largely depends on the existence of liver meta-stasis,and the prognosis of patients with liver metas-tasis is very poor.PIVKA-Ⅱ may be produced during the hepatocellular metaplasia of the tumor cells.
文摘目的:评价化学发光微粒子免疫法(CMIA)与化学发光酶免疫法(CLEIA)检测异常凝血酶原(Protein Induced by Vitamin K Absence or Antagonist-Ⅱ, PlVKA-Ⅱ),通过ROC曲线计算用于诊断肝癌的临界值,并对该临界值灵敏度和特异性进行评价.方法:选取我院118例肝癌患者及80例肝硬化患者的血清样本,在肝癌组中依照美国临床实验室标准化协会指南比对标准文件EP9-A2,对两种检测方法之间的偏倚进行评估;比较两组病例中PlVKA-Ⅱ检测水平,以临界值(CUT OFF) 40mAU/mL为参考线,分析两种检测对肝癌的诊断特异性.结果:两种方法检测PlVKA-Ⅱ相关性良好, r =0.9993,直线回归方程为Y=0.42667+0.99694X ,在PIVKA-Ⅱ阳性参考限40 mAU/mL,其预期的偏倚值95%可信区间为37.959-42.649mAU/mL,两种方法在肝癌组阳性率分别为88.14%与87.29%,差异均有统计学意义(P<0.05),对肝癌诊断的ROC曲线下面积分别为0.884和0.880.提示两种检测方法对PlVKA-Ⅱ肝癌诊断有均有较高的特异性.结论: CMIA与CLEIA两种方法均能有效检测PlVKA-Ⅱ,且相关性良好,基于PIVKA对肝细胞癌灵敏度的临界值40mAU/mL来诊断肝癌,均有较高的特异性,能够满足临床需要.
基金Supported by The Industrial Core Technology Development Program funded by the Ministry of Knowledge Economy,No.10033183
文摘AIM:To evaluate diagnostic value ofα-fetoprotein (AFP)-L3 and prothrombin induced by vitamin K absence-Ⅱ(PIVKA-Ⅱ)in hepatocellular carcinoma(HCC). METHODS:One hundred and sixty-eight patients during routine HCC surveillance were included in this study.Of the 168 patients,90(53.6%)had HCC including newly developed HCC(n=82)or recurrent HCC after treatment(n=8).Sera were obtained during their first evaluation for HCC development and at the time of HCC diagnosis before commencing HCC treatment.HCC was diagnosed by histological examination,appropriate imaging characteristics-computed tomography or magnetic resonance imaging.Control sera were collected from 78 patients with benign liver disease(BLD),which were obtained during routine surveillance with a suspicion of HCC.AFP,AFP-L3 and PIVKA-Ⅱwere measured in the same serum by microchip capillary electrophoresis and liquid-phase binding assay on a micro-total analysis system Wako i30 auto analyzer.The performance characteristics of three tests and combined tests for the diagnosis of HCC were obtained using receiver operating characteristic curves in all populations and subgroups with AFP<20 ng/mL. RESULTS:Of 90 HCC patients,38(42.2%)patients had AFP<20 ng/mL,20(22.2%)patients had AFP 20-200 ng/mL and 32(35.6%)patients had AFP>200 ng/mL.Of the 78 BLD patients,74(94.9%)patients had AFP<20 ng/mL.After adjustment for age and HBV infection status,AFP-L3 levels were higher in HCC than in BLD among patients with low AFP levels(<20 ng/mL)(P<0.001).In a total of 168 patients,areas under the curve(AUC)for HCC were 0.879,0.887,0.801 and 0.939 for AFP,AFP-L3,PIVKA-Ⅱand the combined markers,respectively.The combined AUC for three markers showed higher value than the AUCs of individual marker(P<0.05).AFP-L3 had higher AUC value than PIVKA-Ⅱfor HCC detection in entire patients(P =0.043).With combination of AFP-L3(cut-off>5%) and PIVKA-Ⅱ(cut-off>40 AU/L),the sensitivity were 94.4%and specificity were 75.6%in all patients.In 112 patients with low AFP levels(<20 ng/mL),AUCs of AFP-L3,PIVKA-Ⅱand combine AFP-L3 and PIVKA-Ⅱtests were 0.824,0.774 and 0.939,respectively. AFP-L3 with a cut-off value of 5%showed sensitivity of 71.1%and specificity of 83.8%,and PIVKA-Ⅱwith a cut-off value of 40 AU/L had sensitivity of 57.9%and specificity of 95.9%in patients with low AFP levels. The combination of AFP-L3 and PIVKA-Ⅱincreased the sensitivity and specificity up to 92.1%and 79.7%, respectively,in low AFP group.Combined markers detected 81.8%of early stage HCC(Union for Inter-national Cancer Control stageⅠ),86.7%of small sized tumor(<2 cm)and 91.7%of single tumor of HCC in the low AFP group.In multivariate analysis,AFP-L3 was correlated with AFP and tumor size,and PIVKA-Ⅱwas correlated with laboratory tests including serum aspartate aminotransferase,total bilirubin,platelets and albumin levels.PIVKA-Ⅱhad no correlation with AFP,AFP-L3 or tumor characteristics. CONCLUSION:Combined determination of AFP-L3 and PIVKA-Ⅱcould improve the diagnostic value for HCC detection in patients with or without increased AFP levels.
