| Objective To evaluate the changes of serum protein induced by vitamin K absence or antagonist Ⅱ(PIVKA-Ⅱ),lectin-reactive alpha-fetoprotein(AFP-L3),alpha-fetoprotein(AFP)levels and other indicators before and after transcatheter arterial chemoembolization(TACE)in hepatocellular carcinoma(HCC)patients and their values in efficacy surveillance and recurrence prediction.Methods Laboratory indicators and clinical features before and after TACE of 96 HCC patients who underwent TACE as initial treatment and were followed in a year in the Infection Department of Liaocheng People’s Hospital(February 2018～October 2020)were retrospectively analyzed.Patients with chronic hepatitis(n=132)or cirrhosis(n=117)served as controls respectively.The serum level changes of PIVKA-Ⅱ,AFP and AFP-L3besidesγ-glutamyl transpeptidase(γ-GT),albumin/globulin(A/G),aspartate transaminase/alanine ransaminase(AST/ALT),neutrophil-to-lymphocyte ratio(NLR),monocyte-to-lymphocyte ratio(MLR),platelet-to-lymphocyte ratio(PLR),etc tested before,4-5 weeks and 6-12 months after TACE besides imaging indicators were analyzed.All HCC patients were divided into groups with or without recurrence according to CT or MRI images.The changes of indicators in HCC patients before and after TACE were compared by Wilcoxon signed rank test,and the association between any two indicators were analyzed by Spearman correlation analysis.The univariate analysis of HCC recurrence were conducted by Mann-Whitney U test orχ~2test while the multivariate were by binary Logistic regression analysis.The abilities of indicators to predict HCC recurrence were assessed by the area under the receiver operating characteristic(ROC)curve(AUC)and Z test.The sensitivity and specificity of indicators were compared byχ~2test.The generalized estimating equation model(GEE)model was used to find the statistical significance of a time effect and tumor markers.Results1.Before TACE,Serum PIVKA-Ⅱ,AFP-L3 and AFP levels were significantly higher in HCC patients compared to patients with chronic hepatitis or cirrhosis(PIVKA-Ⅱ:U=1345.50,1674.50;AFP-L3:U=2547.00,2604.00;AFP:U=2756.00,2999.50,all P<0.001).The serum levels of PIVKA-Ⅱ,AFP-L3,AST/ALT,NLR,MLR and PLR were all positively correlated with the tumor sizes(r=0.479,0.448,0.394,0.212,0.228,0.364,all P<0.05).The serum levels of PIVKA-Ⅱ were positively correlated with MLR(r=0.294,P=0.010).The serum levels of PIVKA-Ⅱ were positively correlated with AST/ALT(r=0.227,P=0.038),while other indicators showed no correlation between each other(all P>0.05).2.4-5 weeks after TACE,the serum levels of PIVKA-Ⅱ,AFP-L3,AFP,AST/ALT,Alb,A/G and SCr in all HCC patients were totally lower than those before TACE(Z=-5.91,-4.74,-4.63,-3.53,-2.54,-2.57,-2.46,all P<0.001),and the levels of PIVKA-Ⅱ(Z=-5.95,-2.47,P<0.05),AFP-L3(Z=-2.37,-2.28,P<0.05)and AFP(Z=-2.36,-2.03,P<0.05)in HCC patients of all TNM stages were lower than those before TACE of same stages.The levels of PIVKA-Ⅱ and AFP-L3 decreased more than AFP(P<0.05).6-12 months after TACE,the serum levels of PIVKA-Ⅱ in stage-I and Ⅱ patents were lower than 4-5 weeks after TACE(Z=-1.73,P<0.05),while the levels of PIVKA-Ⅱ and AFP-L3 in stage-ⅡI patients were slightly higher than 4-5 weeks after TACE(Z=-2.34,-1.84,P<0.05).The other indicators remained unchanged(P>0.05).3.In a year-long follow-up based on imaging tests,46 patients experienced HCC recurrence and the recurrence rate in total was 47.9%.The univariate analysis of recurrence showed that tumor sizes,tumor numbers,portal vein tumor thrombus(PVT),Child-Pugh class before TACE as well as the serum levels of PIVKA-Ⅱ,AFP-L3,AFP,Alb,A/G,AST/ALT,MLR before,4-5 weeks and 6-12 months after TACE besidesγ-GT at 6-12 months after TACE were associated with recurrence(all P<0.05).The multivariate analysis showed that the maximum tumor size≥5.8cm(OR=1.14,95%CI:4.32-8.16,P=0.034),AST/ALT≥0.97(OR=2.23,95%CI:1.22-13.76,P=0.008),PIVKA-Ⅱ≥58.3AU/L(OR=6.25,95%CI:3.67-19.68,P<0.001)and AFP-L3≥12%(OR=4.51,95%CI:1.54-17.87,P=0.003)were independent risk factors of HCC recurrence after TACE.4.According to the ROC analysis,before TACE,the ROC-AUC of the tests of serum PIVKA-Ⅱ,AST/SLT and AFP-L3 were all higher than tumor sizes in predicting HCC recurrence(Z=2.14,2.03,1.98,all P<0.05),and the PIVKA-Ⅱ showed the biggest AUC(0.815).The AUC of the combination test of PIVKA-Ⅱ+AST/ALT was higher than PIVKA-Ⅱ or AST/ALT alone(Z=2.05,2.18,P<0.05),while it showed no significant difference with the combination test of PIVKA-Ⅱ+AST/ALT+AFP-L3(Z=1.22,P>0.05).And the combination test of PIVKA-Ⅱ+AST/ALT+AFP-L3 also showed nosignificantdifferencewiththecombinationtestof PIVKA-Ⅱ+AST/ALT+AFP-L3+tumor sizes(Z=1.35,P>0.05).The tests of PIVKA-Ⅱ and AFP-L3 respectively showed the greatest sensitivity and specificity compared to other factors(all P<0.05).The combinations of indicators significantly increased the sensitivity of single indicators(all P<0.05),while they showed no difference on specificity with PIVKA-Ⅱ and AFP-L3(all P>0.05).5.6-12 months after TACE,adding PIVKA-Ⅱ+AFP-L3 to ultrasound(US)increased sensitivity to 84.8%while lowering specificity from 96.0%to 78.0%(P<0.05).6.According to the GEE model,PIVKA-Ⅱ,AFP-L3 and AFP all significantly affected the recurrence outcome(all P<0.05),and the interaction term AFP*time was significant.The utility of AFP as predictors of recurrence weakened over time(r=-0.0006,P<0.05).Conclusions1.Serum PIVKA-Ⅱ,AFP-L3 and AFP levels were significantly higher in HCC patients compared to patients with chronic hepatitis or cirrhosis.2.The serum levels of PIVKA-Ⅱ and AFP-L3 of HCC patients decreased greater than AFP after TACE,which were superior to AFP in TACE efficacy surveillance.3.The serum levels of PIVKA-Ⅱ,AFP-L3,AST/ALT,NLR,MLR and PLR were all positively correlated with the tumor sizes.4.The maximum tumor size and the levels of AST/ALT,PIVKA-Ⅱ and AFP-L3before TACE were independent risk factors of HCC recurrence.The combination tests of factors significantly increased the sensitivity of predicting HCC recurrence but didn’t decreased the specificity. |
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