新型腫瘤標(biāo)志物(PIVKA-II) 臨床應(yīng)用進(jìn)展及評(píng)價(jià)課件

1、新型腫瘤標(biāo)志物（PIVKA-II) 臨床應(yīng)用進(jìn)展及評(píng)價(jià)第二軍醫(yī)大學(xué)東方肝膽外科醫(yī)院高春芳 2013.10.12 武漢healthy liverChronic hepatitisCirrhosisCancer (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Viral marker Fibrosis marker Tumor marker現(xiàn)有肝癌相關(guān)腫瘤標(biāo)志物 AFP 及其異質(zhì)體 AFP-L3 GP 73 DCP* - L -Fucosidase (AFU) CA 19-9 CA 125 CEA Candidate HCC Serum Markers Glypican-3 (GPC3)

2、Transforming Growth Factor- 1 (TGF- 1 )Insulin-Like Growth Factor (IGF)Interleukin (IL)-6 and IL-10 -Glutamyl Transferase (GGT)Tumor specific growth factor (TSGF)Vascular endothelial growth factor (VEGF)Human Cervical Cancer Oncogene (HCCR)Tumor-Derived Autoantibody (TAA) Etc.Markers ReferencesCutof

3、f valueSensitivitySpecificitySpecimenGPC3Hippo et al.(2004)2.0 ng/ml51%90%serumGP73Marrero et al. (2005)10 relative units69%75%serumTGF-1Song et al. (2002)800 pg/ml68%95%plasmaTsai et al. (1997)32 mg/g creatinine67.4%91.0%urinaryIGF-IITsai et al. (2003)4.9 mg/g prealbumin31%100%serumIL-6Hsia et al.

4、(2007)NA46%95%plasmaIL-10Hsia et al. (2007)NA50%96%plasmaGGTCui et al.(2003)40mAUml-174.2%(43.8% for small HCC)82.2%serumHCCRYoon et al.(2004)15 g/ml78.2% 95.7%serumClinica Chimica Acta 395 (2008) 1926原發(fā)性肝癌的一種血清標(biāo)志物脫-羧基(異常)凝血酶原Liebman HA， et al . N Engl J Med 1984; 310:142731在經(jīng)活檢確實(shí)為肝細(xì)胞癌的76個(gè)患者中，我們發(fā)現(xiàn)有6

5、9個(gè)患者(91%)的血清含有脫-羧基凝血酶原，平均水平為900ng/ml)。相反，在慢性活動(dòng)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(cè)不到。 在5個(gè)使用維生素K治療的患者中，異常凝血酶原含量沒(méi)有降低，說(shuō)明它的出現(xiàn)并不是因?yàn)榫S生素K缺乏導(dǎo)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。Research design: 1. large phase 2 biomarker case-control st

6、udy in 7 academic medical centers in the United States2. Controls were patients with compensated cirrhosis and cases were patients with HCC3. AFP, DCP, AFP-L3 levels were measured blinded to clinical data in a central reference lab. HCC diagnosis: DCP 0.85 (95% CI 0.80-0.86) AFP 0.77 (95% CI 0.73-0.

7、81) combine AFP+DCP 0.88 (95% CI 0.85-0.90) Early HCC diagnosis: DCP 0.84 (95% CI 0.81-0.87) AFP 0.68 (95% CI 0.64-0.72) combine AFP+DCP 0.83 (95% CI 0.79-0.86) SMMC 7721HepG2外源性DCP促進(jìn)肝癌細(xì)胞的生長(zhǎng)，且存在量效關(guān)系EGFRVEGF本實(shí)驗(yàn)室數(shù)據(jù)大樣本 臨床case-control 驗(yàn)證HCC 313膽管癌 83轉(zhuǎn)移性肝癌 29 肝血管瘤 31肝硬化 75健康對(duì)照 194合計(jì) 725 非HCC陽(yáng)性陰性陽(yáng)性率(%)合計(jì)肝

8、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(jì)6035217.04412DCP陽(yáng)性陰性陽(yáng)性率(%)合計(jì)HCC2555881.46313非HCC6035217.04412合計(jì)315410725DCP 總體陽(yáng)性分布情況The Sensitivity and Specificity of AFP, DCP, and DCP& AFPMarkerCutoff SensitivitySpecificityYIDCP4081.0%85.9%0.669(mAU/mL)46.580.2%87.9%0.681AFP2088.

9、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&DCP ROCArea Under the CurveTest Result Variable(s)AreaStd. ErroraAsymptotic Sig.bAsymptotic 95% Confidence IntervalLower BoundUpper BoundAFP.886.013.000.861.912DCP.868.015.000.840.897The test result variable(s): AF

10、P, DCP has at least one tie between the positive actual state group and the negative actual state group. Statistics may be biased.a. Under the nonparametric assumptionb. Null hypothesis: true area = 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(jì)HCC182133315Non-HCC50360410小計(jì)232493725DCP 與AFP 診斷效率一致性比較Kappa 值： 0.47Intra-assay and inter-assay CVIntra-assayMeanSDCV (%)inter-assayMeanSDCV (%)LMH47.331.15553.335.51640635.032.441.000.5547.331.2255.3899.56649