新型腫瘤標志物(PIVKA-II) 臨床應(yīng)用進展及評價

新型腫瘤標志物（PIVKA-II)臨床應(yīng)用進展及評價第二軍醫(yī)大學東方肝膽外科醫(yī)院高春芳2013.10.12

武漢healthyliverChronichepatitisCirrhosisCancer(HCC)慢性炎癥以及逐漸加深的肝臟損傷典型的乙型肝炎病程ViralmarkerFibrosismarkerTumormarker現(xiàn)有肝癌相關(guān)腫瘤標志物

AFP及其異質(zhì)體AFP-L3

GP73DCP*

α-L-Fucosidase(AFU)CA19-9CA125CEA……

CandidateHCCSerumMarkersGlypican-3(GPC3)TransformingGrowthFactor-1(TGF-1)Insulin-LikeGrowthFactor(IGF)Interleukin(IL)-6andIL-10γ-GlutamylTransferase(GGT)Tumorspecificgrowthfactor(TSGF)Vascularendothelialgrowthfactor(VEGF)HumanCervicalCancerOncogene(HCCR)Tumor-DerivedAutoantibody(TAA)Etc.

MarkersReferencesCutoffvalueSensitivitySpecificitySpecimenGPC3Hippoetal.(2004)2.0ng/ml51%90%serumGP73Marreroetal.(2005)10relativeunits69%75%serumTGF-β1Songetal.(2002)800pg/ml68%>95%plasmaTsaietal.(1997)32mg/gcreatinine67.4%91.0%urinaryIGF-IITsaietal.(2003)4.9mg/gprealbumin31%100%serumIL-6Hsiaetal.(2007)NA46%95%plasmaIL-10Hsiaetal.(2007)NA50%96%plasmaGGTCuietal.(2003)40mAUml-174.2%(43.8%forsmallHCC)82.2%serumHCCRYoonetal.(2004)15μg/ml78.2%95.7%serumClinicaChimicaActa395(2008)19–26維生素K缺乏誘導蛋白ProteinInducedbyVitaminK

Absenceorantagonist-IIabnormalprothrombinproteinPIVKA-II簡介Des-gamma-carboxyprothrombin,DCP（又名脫γ羧基凝血酶原）

T1/260H(2.5days)在以下患者的血清中出現(xiàn)

-維生素K缺乏的患者-使用華法林治療的患者HCC患者1984年首次被描述為腫瘤標志物

原發(fā)性肝癌的一種血清標志物—脫-γ-羧基(異常)凝血酶原

LiebmanHA，etal.NEnglJMed1984;310:1427–31在經(jīng)活檢確實為肝細胞癌的76個患者中，我們發(fā)現(xiàn)有69個患者(91%)的血清含有脫-γ-羧基凝血酶原，平均水平為900ng/ml)。相反，在慢性活動性肝炎患者(平均水平10ng/ml)或轉(zhuǎn)移性肝癌患者(平均水平42ng/ml)中，異常凝血酶原的水平很低，且在正常人中檢測不到。

在5個使用維生素K治療的患者中，異常凝血酶原含量沒有降低，說明它的出現(xiàn)并不是因為維生素K缺乏導致。行腫瘤手術(shù)切除術(shù)的2名患者和1名使用化療的患者，其血清異常凝血酶原濃度顯著降低，而在疾病復(fù)發(fā)后又隨之增加。血清甲胎蛋白的含量與異常凝血酶原水平基本不具相關(guān)性。Researchdesign:

1.largephase2biomarkercase-controlstudyin7academicmedicalcentersintheUnitedStates2.ControlswerepatientswithcompensatedcirrhosisandcaseswerepatientswithHCC3.AFP,DCP,AFP-L3levelsweremeasuredblindedtoclinicaldatainacentralreferencelab.

HCCdiagnosis:DCP0.85(95%CI0.80-0.86)AFP0.77(95%CI0.73-0.81)combineAFP+DCP0.88(95%CI0.85-0.90)EarlyHCCdiagnosis:DCP0.84(95%CI0.81-0.87)AFP0.68(95%CI0.64-0.72)combineAFP+DCP0.83(95%CI0.79-0.86)SMMC7721HepG2外源性DCP促進肝癌細胞的生長，且存在量效關(guān)系HepG2SMMC7721A:VEGFB:TGFαC:FGFEGFRVEGF本實驗室數(shù)據(jù)大樣本臨床case-control驗證HCC313膽管癌83轉(zhuǎn)移性肝癌29

肝血管瘤31肝硬化75健康對照194合計725

非HCC陽性陰性陽性率(%)合計肝硬化21542875肝血管瘤031031繼發(fā)性肝癌32610.3429膽系腫瘤305336.1483健康人群61881.54194合計6035217.04412DCP陽性陰性陽性率(%)合計HCC2555881.46313非HCC6035217.04412合計315410725DCP

總體陽性分布情況TheSensitivityandSpecificityofAFP,DCP,andDCP&AFP

MarkerCutoffSensitivitySpecificityYIDCP4081.0%85.9%0.669(mAU/mL)46.580.2%87.9%0.681AFP2088.4%78.1%0.665(ng/mL)780.5%87.1%0.676DCP+AFP40+20OR97.8%67.1%0.649AND71.6%96.9%0.685AFP&DCPROCAreaUndertheCurveTestResultVariable(s)AreaStd.ErroraAsymptoticSig.bAsymptotic95%ConfidenceIntervalLowerBoundUpperBoundAFP.886.013.000.861.912DCP.868.015.000.840.897Thetestresultvariable(s):AFP,DCPhasatleastonetiebetweenthepositiveactualstategroupandthenegativeactualstategroup.Statisticsmaybebiased.a.Underthenonparametricassumptionb.Nullhypothesis:truearea=0.5AUCCutoffSensitivitySpecificity95%CIAFPDCP0.8860.8686.946.580.8%80.2%87.4%87.9%0.861-0.9120.840-0.897

AFPDCPHCCNon-HCC小計HCC182133315Non-HCC50360410小計232493725DCP與AFP診斷效率一致性比較Kappa值：0.47Intra-assayandinter-assayCV

Intra-assayMean±SDCV(%)inter-assayMean±SDCV(%)LMH47.33±1.15553.33±5.516406±35.032.4