| BackgroundHepatocellular carcinoma(HCC)is the most common primary liver cancer and is an important medical problem that threatens human health globally.Hepatocellular carcinoma ranks fourth in our country as the most common tumor and the third leading cause of cancer deaths.Because of the occult onset of HCC,Ultrasonography(US)and alpha-fetoprotein(AFP)serological tests were recommended as high-risk groups for high-risk HCC patients according to the 2017 edition of the Chinese Code of Practice for Diagnosis and Treatment of Primary Liver Cancer check.However,the study found that the sensitivity and specificity of US for the diagnosis of early HCC is low,while about 30%of HCC can be negative for AFP.Therefore,early HCC and AFP-negative HCC are not easily detected.When the diagnosis is confirmed,the disease has progressed to the advanced stage and cannot be cured.In addition,HCC is prone to recurrence after treatment,especially for early and AFP-negative HCC patients,currently lack of simple and effective serological indicators to assess interventional efficacy and determine the prognosis of patients.Midkine(MDK)is a heparin-binding growth factor.MDK was found to be underexpressed in the serum of patients with normal liver and liver cirrhosis,but highly expressed in the serum of patients with primary liver cancer.The sensitivity of serum MDK to detect HCC and specificity are better than AFP,may be conducive to the early diagnosis of HCC.However,it has been reported that there is no significant correlation between MDK and tumor diameter,number,tumor stage,and AFP level.Circulating tumor cells(CTC)refers to a variety of types of tumor cells that are present in the peripheral blood of patients.The study found that the presence of CTC tumor cells spontaneously,or because of the diagnosis and treatment operation,tumor cells from the primary lesion or tumor metastasis shedding and into the peripheral blood circulation,the formation of CTCs.CTC is considered to be the primary stage of tumor invasion and metastasis,and its count is used as a prognostic judgment for a variety of tumors.Among them,epithelial-mesenchymal transition(EMT)of CTCs cell subtypes leads to more aggressive cell metastasis and may lead to poor prognosis of patients.At present,there is no literature comparing the results of peripheral blood MDK and CTC counts in the diagnosis of HCC,especially the evaluation of early or AFP-negative HCC and interventional efficacy.ObjectiveIn this study,the peripheral blood AFP,MDK and CTCs were counted and typed before and after interventional treatment in newly diagnosed patients with HCC.The tumor imaging findings in the same period were used as the standard controls to investigate 1)Detection of MDK and CTCs in peripheral blood of patients.Whether MDK and CTCs can be used as useful biomarkers for diagnosis of HCC.2)Compared with AFP,whether peripheral blood MDK and CTCs counts have an advantage over the detection rate of HCC.3)Whether the counts and subtypes of AFP,MDK,and CTCs were related to the clinicopathological parameters of the tumor.4)Whether there is a correlation between the expression of MDK and CTCs in peripheral blood in HCC patients.5)Compared with AFP,the value of peripheral blood MDK and CTCs counts and subtypes analysis to assess the efficacy of HCC patients.6)Whether MDK and CTCs counts in peripheral blood has guiding significance for the prognosis of HCC patients after interventionMethods2016.1-2017.6,totally 84 patients with hepatocellular carcinoma(HCC)and 24 controls were enrolled in this study.Serum AFP,serum MDK,counts of CTCs in peripheral blood and CTCs were analyzed before treatment.Of the 84 patients with hepatocellular carcinoma,27 patients with stage I patients underwent radiofrequency ablation.Twenty-nine patients with stage II received TACE.Twenty-eight patients in stage III received TACE plus sorafenib.Follow-up was performed every 2 months after treatment.All patients with HCC were tested for peripheral blood AFP,MDK,CTCs,and CTCs subtypes.Magnetic Resonance Imaging(MRI)was performed on plain and dynamic enhanced scans of the abdomen and chest electrons.Computed Tomography(CT)scans were performed to evaluate whether interventional treatment was performed again based on ’imaging findings.A total of 18 months of follow-up recorded the Time To Progress(TTP).SPSS 18.0 software was used for statistical analysis.AFP≥20ug/1,MDK≥0.654ng/ml,CTCs count≥3 个/5ml as the positive value.The χ2 test was used to compare the positive detection rate of HCC with count of CTC in serum AFP,MDK and peripheral blood,and to evaluate the relationship between the change of CTC subtypes before and after treatment and the sensitivity of evaluation.The sensitivity,specificity,area under the curve(AUC),and 95%confidence interval(CI)of HCC were evaluated using receiver operating characteristics(ROC)to assess AFP,MDK and CTC counts.Compare the positive rates of MDK and CTC in early HCC or AFP-negative HCC.The data were normal distribution test,rank sum test was used to evaluate AFP,MDK,CTCs count,CTCs subtypes in different clinical parameters of the tumor groups,and the comparison of the changes of tumor markers and efficacy after treatment.Spearman correlation analysis was used to assess the correlation between AFP,MDK,CTCs counts,CTCs subtypes and clinical tumor parameters.The LogRank(Mantel-Cox)method was used for regression analysis to evaluate the significance of MDK and CTC for prognostic evaluation of HCC.All P values were bilateral,P<0.05 was statistically significant.ResultsThe positive rate of HCC counts in peripheral blood AFP,MDK,and CTC counts:Among the 84 HCC patients in this study,the positive detection rates of AFP,MDK,and CTC counts in peripheral blood were 51.2%,95.2%,and 73.8%,respectively.There was a statistically significant difference between the three groups.The sensitivity,specificity,and accuracy of AFP,MDK,and CTC counts in peripheral blood for HCC detection:AFP has a HCC diagnostic sensitivity of 51.2%,a specificity of 100%,and an accuracy of 62.04%.MDK’s HCC diagnostic sensitivity was 95.2%,specificity was 95.8%,and accuracy was 95.37%.The diagnostic sensitivity of HCC for CTCs was 73.8%,specificity was 91.7%,and accuracy was 77.78%.The area under the curve(AUC)of AFP,MDK and CTC counts in peripheral blood was compared:The area under the ROC curves of AFP,MDK,and CTC counts was 0.709,0.995,and 0.829,respectively.Comparing the three results:AFP and MDK,CTC AUC differences were statistically significant;MDK and CTC AUC difference was not statistically significant.The positive rate of detection of MDK and CTC counts in peripheral blood of patients with AFP-negative HCC and early stage HCC was compared:The positive rate of HCC between MDK and CTCs in the AFP-negative group was 95.12%and 65.85%,respectively.The positive rate of MDK and CTCs in the early HCC subgroup was 83.33%,0.00%,respectively.The positive rate of peripheral blood AFP,MDK,and CTC counts in early HCC patients was 55.56%,29.63%for CTC,and 85.19%for MDK.Serum AFP,MDK,CTC count,CTC subtype and tumor clinical parameters of different groups and correlation analysis results:serum AFP and tumor number,tumor size,with or without vascular invasion,clinical stage of liver cancer in each group differences were not statistically significant,and No correlation with the above clinical parameters.Serum MDK and tumor number,tumor size,with or without vascular invasion,the clinical stage of liver cancer in each group differences were statistically significant,and with the number of tumors and clinical stage has a positive correlation.CTC count of peripheral blood and tumor number,tumor size,with or without vascular invasion,liver cancer clinical stage differences were statistically significant,and with the above clinical parameters were positively correlated.CTC classification of peripheral blood and tumor number,with or without vascular invasion,HCC clinical stage differences were statistically significant,and the tumor size was no significant difference.Comparison of the positive rate of AFP,MDK and CTC counts before and after interventional therapy and the sensitivity evaluation of efficacy:This study showed that the positive rate of serum AFP and MDK after interventional treatment of HCC was significantly lower than that of interventional therapy,and there was a statistical difference between AFP and MDK.The significance of learning,CTC differences were not statistically significant.Correlation analysis between serum AFP,MDK and count of CTCs in peripheral blood:There was a positive correlation between serum AFP,MK and CTC count.Results of comparison of CTC counts in interventional efficacy evaluation after treatment:This study showed that the serum AFP,MDK,and CTC counts were significantly lower in the effective group after treatment than in the post-treatment invalid group,with a statistically significant difference.Results of CTC subtype analysis before and after interventional treatment:The positive rate of CTC epithelial subtype before treatment was lower than that after treatment,and the difference was statistically significant.The positive rate of mixed and interstitial subtypes before treatment was higher than that after treatment,and the difference was not statistically significant.The analysis of the prognosis of HCC interventional therapy by peripheral blood MDK and CTC results:Patients with HCC positive for MDK and CTC before intervention were more likely to have disease progression than those with negative HCC.The difference was statistically significant.Conclusions1.Serum MDK,CTCs count of peripheral blood can be used as an effective biomarker to assist diagnosis of HCC.2.For the detection rate of early HCC or AFP-negative HCC,MDK has more advantages than CTC.3.Serum MDK in the number of tumors,tumor size,with or without vascular invasion,clinical stages of HCC were significantly different between groups,serum MDK and tumor number and clinical stage have a positive correlation.4.CTC count in peripheral blood in the number of tumors,tumor size,with or without vascular invasion,clinical staging of liver cancer were significantly different between groups,and CTC count of peripheral blood and the above clinical parameters were positively correlated.CTC subtype of peripheral blood in the number of tumors,with or without vascular invasion,the clinical stage of HCC in each group were significantly different.5.HCC patients with serum MDK detection and CTCs count and classification of peripheral blood in patients after interventional evaluation of efficacy,prognosis analysis of patients with guiding significance.6.HCC patients with serum MDK and CTCs count positive correlation.Peripheral blood MDK and CTC positive HCC are more prone to postoperative tumor progression... |
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