| Part Ⅰ In Vivo Evaluation of CalliSpheres Microspheres in the Porcine Renal Artery Embolization ModelObjective The aim of this study was to compare the operational performance,embolization effect,and the loeal and systemie foreign body tissue reactions of CalliSpheres microspheres and Embosphere microspheres in the porcine renal artery embolization model.Methods 24 healthy normal pigs were randomized into CSM group and Embosphere Microspheres(ESM)group equally,and embolized with CSM(300-500 μm)or ESM(300-500 μm)in the lower pole second branch artery and subordinated branch artery of right kidneys,respectively.The occurrence of vascular rapture,the volume of microspheres used,number of embolic vessels,the degree of embolization,non-target embolization and the delivery performance of mcrospheres were recorded during the operation.On Day 2(D2),Day 7(D7)and Day 28(D28)after operation,4 experimental pigs were subjected to angiography to evaluate the vascular recanalization in each group.Blood routine,coagulation function and liver and renal function were examined before and on D2,D7 and D28 after surgery.Then euthanasia was carried out for those pigs,and the euthanized pigs were subjected to renal macroscopic and histopathological examination.Results The embolization was performed successfully in all pigs without obvious adverse events or deaths.No vascular rupture was found in any animal in the CSM group or ESM group.There were no significant difference between test group and control group in the volume of microspheres used,number of embolic vessels,the degree of embolization,non-target embolization,vessel recanalization rate and delivery performance of microspheres(P>0.05).On the laboratory examination parameters,the blood routine,coagulation function,liver function as well as renal function indexes were similar between the two groups at each time point except for activated partial thromboplastin time,which was longer in CSM group compared with ESM group on D28.As for pathology results in the lower pole of right kidney,on D2 and 7,macroscopic fendings were mainly present as renal necrosis,stasis,and exudation of capsule and/or swollen;on D28,macroscopic findings were present as decrescent,firm,andjor uneven surface.These findings were correlated microscopically with necrosis on D 2,inflanuuation on D7 and 28,and thin cortex,fibrosis and/or capsule thickening on D28.There was no difference between CSM group and ESM group in terms of these macroscopic or microscopic manifestations.Conclusion Each result of evaluation parameters of animal experiments demonstrated that CalliSpheres embolic microsphere and Embosphere microspheres are basically substantial equivalent.Both microspheres can effeectively achieve the target vascular embolization and there were no adverse reactions caused by embolism in animals.The tissue reactions of both CalliSpheres and Embosphere was very mild and was essentially the same.CalliSpheres microsphere has the same safeness and effectiveness.Part Ⅱ Serum Pharmacokinetics in Hepatocellular Carcinoma Patients Treated with Transarterial Chemoembolization Using Epirubicin-loaded CalliSpheres MicrospheresObjective The purpose of this study was the pharmacokinetic(PK)profile assessment in the serum of patients affected by hepatocellular carcinoma(HCC)treated with transarterial chemoembolization(TACE)with CalliSpheres drug-eluting beads.Methods This stxudy included 19 patients,10 treated with CalliSpheres and 9 with DC Bead,preloaded with epirubicin.No patient randomization was used for the inclusion in one group or in the other.Peripheral blood samples were taken from all patients immediately after completion of embolic delivery and at 5min,10min,20m,40min,60min,2h,3h,6h,24h,3d5 7d after the procedure.Whole blood was collected into tubes and processed by centrifugation to yield serum.Serum epirubicin levels were measured by HPLC-MS/MS assay procedure.Pharmacokinetic parameters,including peak serum concentration(Cmax),serum half-life time(T1/2),area under the drug-time curve from 0 to t(AUC0-t),area under the drug-time curve from 0 to infinity by extrapolation(AUCO-∞),mean residence time(MRT),volume of distribution(Vd),and clearance(Cl),were assessed.Results The peak serum drug concentration after microsphere injection was observed at 5 minutes and followed by a rapid decrease in the first 2 hours in all 19 patients.There were no significant difference between CalliSpheres group and DC Bead group in the pharmacokinetic parameters Cmax,AUCO0-t,AUC0-∞,T1/2,MRT,Vd,and Cl.Conclusion The preliminary results of this study demonstrates that the pharmacokinetic characteristics of CalliSpheres microspheres and DC Bead microspheres loaded with epirubicin in the embolization treatment of HCC are basically consistent,showing the characteristics of sustained release of drugs and maintaining a low serum drug concentration.Part Ⅲ Comparison of Short-term Efficacy and Safety between Different Drug-eluting Beads and Conventional Lipiodol Emulsion in The Treatment of Hepatocellular CarcinomaObjective To analyze and compare the short-term efficacy and safety of transcatheter arterial chemoembolization with different drug-eluting beads(DEB-TACE)and conventional transcatheter arterial chemoembolization(cTACE)in the treatment of hepatocellular carcinoma(HCC).Methods This retrospective study included all patients receiving TACE therapy for HCC between February 2016 and June 2018 at the First Affiliated Hospital of Soochow University.A total of 162 patients were enrolled in this study,including 85(52.5%)reveived TACE with conventional ethiodized oil emulsion(cTACE group),37(22.8%)received TACE with DC Bead drug-eluting beads(DCB group),and 40(24.7%)received TACE with CalliSpheres drug-eluting beads(CalliSpheres group).The clinical efficacy was assessed 1 month and 3 months after proeedure using the modified response evaluation criteria in solid tumors(mRECIST)and the incidence of complications was recorded.The levels of alpha-fetoprotein(AFP)and prothrombin induced by vitamin K absence-Ⅱ(PIVKA-Ⅱ)were compared before and 1 month after procedure,as well as the level changes of blood routine,liver and renal function before and 3 days,1 week and 1 month after treatment.Results According to the mRECIST standard,the objective response rate(ORR)at 1 month of the 3 groups was 49.4%,62.2%and 67.5%respectively,and the disease control rate(DCR)was 87.1%,94.6%and 92.5%respectively,there were no statistically significant differences between the 3 groups(P>0.05).The ORR at 3 months of the 3 groups was 41.2%,51.4%and 55.0%respectively,and the DCR was 77.6%,86.5%and 87.5%respectively,there were no statistically significant differences between the 3 groups(P>0.05).However,patients with Child-Pugh B,ECOG 1,bilobar disease,and recurrent disease in the DCB group and CalliSpheres group showed a significant increase in ORR compared to cTACE group(P<0.05).The serum levels of AFP and PIVKA-Ⅱ in both groups were significantly lower than those before procedure(P<0.05).The levels of TBIL,ALT and AST in the 3 groups were significantly increased and ALB were significantly decreased on the three days after procedure(P<0.05).One week after the procedure,the liver function began to recover and returned to the normal level at one month after the procedure.There was no significant difference in blood routine,renal function before and after procedure among the three groups(P>0.05).Postembolization syndrome was seen in all 3 groups,but the incidence of nausea and vomiting in the cTACE group was significantly higher than that in the DCB and CalliSpheres groups(P<0.05).Five patients(5.9%)in the cTACE group endured bone marrow function suppressed;and one patient(2.5%)endured liver abscess in the CalliSpheres group.Conclusion The short-term clinical efficacy and safety were equivalent in patients treated with cTACE,DC Bead and CalliSpheres.However,DEB-TACE showed some advantages in patients with Child-Pugh B,ECOG 1,bilobar disease,and recurrent disease compare to cTACE therapy.DEB-TACE can significantly reduce the chemotherapy drugs related complications such as nausea and vomiting and suppression of bone marrow function. |
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