The Study Of Indicator Makers For Prognosis Of Advanced HCC Patients Received Radiofrequency Ablation And Therapeutic Strategies To Enhance The Efficiency Of Radiofrequency Ablation On HCC Cells

High proportion of hepatitis viruses(HBV,hepatitis B virus or HCV,hepatitis C virus)infection makes China a heavily afflicted country of hepatocellular carcinomas(HCCs);effective HCC treatment approaches will relieve this urgent medical burden.Patients suffering from HBV or HCV related chronic hepatitis would finally progress into hepatocellular carcinoma(HCC),even with efficient antiviral treatment.Normally HCC cannot be diagnosed until developed into advanced-stage which is not suitable for liver transplantation or surgical resection.Unfortunately,systemic chemotherapeutic therapies have not been used routinely since advanced HCC contains a multi-drug resistance(MDR)feature to cytotoxic chemo-agents,e.g.paclitaxel etoposide or camptothecin.Recent application of an oral molecular targeted agent,sorafenib,improves advanced HCC patients' survival,the antitumor effect of Sorafenib is not widely observed or satisfactorily.There are only 27.7%-43.6% proportion of patients are sensitive to sorafenib treatment;whereas even those sensitive patients may become resistance to sorafenib during sorafenib treatment.Therefore,there are limited treatment options available for advanced HCC patients,current HCC treatments have poor clinical outcomes and poor prognosis.Radiofrequency ablation(RFA),an in situ ablative therapy which selectively destroys HCC tissues,is a promising treatment for advanced-stage HCC patients with cirrhosis and compromised liver function.However,rapid or aggressive recurrence of HCCs after RFA treatment is a major obstacle.It is urgent to study the mechanisms of the recurrence of HCCs after RFA treatment and identify predictive prognosis marker of HCC patients.In the presence work,1.We firstly performed a systematic review and network meta-analysis to reveal what is the best combination treatment with interventional therapies of unresectable hepatocellular carcinoma.To assess the comparative efficacy and safety of combination treatment with transarterial chemoembolization(TACE)for patients with unresectable hepatocellular carcinoma(HCC)through a systematic review and network meta analysis and to identify what is the best combination treatment with TACE.A network meta-analysis was used to identify evidence from relevant randomized controlled trials.We searched databases for publications up to June 2017.The prespecified primary efficacy outcomes were treatment response and 6-month to3-year overall survival(OS),while the secondary efficacy outcomes were 1-and2-year disease-free survival(DFS);safety outcomes were advance effects of combination treatment.We conducted pairwise meta-analyses using a random effects model and then performed random-effects network meta-analyses.A total of 48 trials were eligible(50 analyses),involving 5627 patients and 19 treatment arms:(1)RFA,(2)DEB-TACE;(3)TACE+sorafenib;(4)TACE+stereotactic body radiation therapy(TACE+SBRT);(5)TACE+PMCT;(6)TAI;(7)TACE+Licartin;(8)selective internal radiotherapy(SIRT);(9)TACE+RFA);(10)TACE;(11)TACE+brivanib;(12)TACE+3DCRT;(13)TACE+amiodarone;(14)TACE+interferon-?(TACE+IFN);(15)TACE+PEI;(16)TACE+radiotherapy therapy(TACE+RT);(17)TACE+PAI;(18)percutaneous acetic acid injection(PAI);(19)high-dose hepatic arterial infusion chemotherapy(HAIC).In comparison with other types of combination therapy arms,network meta-analysis disclosed that combination of TACE with RFA would be better than TACE or RFA single usage.And the adverse effects of TACE+sorafenib were serious.2.Then,we revealed the roles of MESI-1 in RFA for unresectable HCC.Radiofrequency ablation(RFA)is a local-ablative therapy for unresectable hepatocellular carcinoma(HCC).At present,there is no predictive marker for RFA treatment outcomes.This work aimed to valuate myeloid ecotropic viral integration site 1(MEIS-1)in predicting post-RFA treatment outcomes of unresectable HCC patients.The time to progression(TTP)and overall survival(OS)of 81 HCC patients who received RFA treatment were measured.The protein level of MEIS-1 in tumor specimens was measured by western blot.The role of MEIS-1 in RFA-treating HCC in vivo growth nude mouse model was examined via PET/CT imaging.Higher level of MEIS-1 in tumor tissue is associated with better RFA treatment outcomes.The median TTP was 9.0(95% confidence interval [CI]: 6.8-11.3)months in patients with high MEIS-1 expression(n = 43)versus 6.0(95% CI: 4.6-7.4)months in patients with low MEIS-1 expression(n=38).Moreover,in rodent HCC model we found overexpression of MEIS-1 enhanced the anti-tumor effect of RFA treatment.We conclude that high level of MEIS-1 expression predicts better RFA treatment outcome in HCC.3.Thirdly,we developed a novel strategy for combination of Apatinib and RFA in HCC.Radiofrequency ablation(RFA)is one of the foremost choices of advanced hepatocellular carcinoma(HCC),however,rapid and aggressive HCC recurrence often occurs after RFA due to the epithelial-mesenchymal transition(EMT).Although combination of RFA with Sorafenib could attenuate the recurrence of HCCs,application of this molecular targeted agent creates a heavily medical burden and oral administration of Sorafenib also brings severe side-effects.In this study,we prepared a Apatinib-microcrystalline formula(Apa-MS)which sustainably releases Apatinib,a novel molecular targeted agent.Based on this,we injected Apatinib solution(Apa-Sol)or Apa-MS into subcutaneous HCC tumors and found Apa-MS could slow down the Apatinib releasing in vivo and in turn inhibited the EMT of HCC cells for extended time.Moreover,in rodent HCC model Apa-MS enhanced the anti-tumor effect of RFA treatment.Based on these we conclude that the slow-releasing system of Apatinib allows Apatinib to keep effective in tumor tissues for a long time and could enhance the antitumor effect of RFA on HCC.