| Part one:Explore the feasibility of minimally invasive therapy for intrahepatic cholangiocarcinomaObjective:Intrahepatic cholangiocarcinoma(ICC)is a rare malignant disease.Few studies on the treatment of minimally invasive surgery(i.e laparoscopic surgery)for ICC exist and these focus mainly on small solitary tumors.The main concerns of minimally invasive surgery for large(≥5 cm)or multiple(≥2)ICCs are potential risks of inadequate resection margin,tumor rupture,uncontrollable bleeding,tumor seeding,and inadequate lymph node sampling.In this part of study we aimed to determine the safety,feasibility and oncological efficacy of minimally invasive surgery for large(≥5 cm)or multiple(≥2)ICCs.Methods:Among 50 patients receiving liver resection for ICC between May 2004 and January 2016,12 patients who had undergone minimally invasive surgery for large or multiple ICCs(Group A,n=12)were compared with 18 patients who had undergone minimally invasive surgery for small solitary ICCs(Group B,n=18);were also compared with 20 patients who had undergone open liver resection for large or multiple ICCs(Group C,n=20).Perioperative and long-term outcomes were analyzed.Results:Compared with Group B,Group A had fewer patients with T1 tumors(58.3%vs.100%;P=0.006),and a longer hospital stay(14 vs.9 days;P=0.039);operating time,blood loss,surgical margin,cases receiving lymph node dissection,conversion rates,and morbidity were comparable.There were no life-threatening complications,and no mortality.No tumor rupture or dissemination occurred,nor did port-site recurrence follow surgery.After a median follow-up of 22 months,no difference was noted in 3-year overall survival(56.3%vs.59.5%;P>0.05)and recurrence-free survival(43.8%vs.50%;P>0.05)between the two groups;Similarly,perioperative and long-term outcomes were comparable between Group A and Group C.Conclusion:Our experience demonstrated that minimally invasive surgery for large or multiple ICCs is technically safe,feasible,and oncologically effective in select patients.Future larger-scale studies and well-designed randomized trials are warranted to evaluate this issue.Part two:Explore the mechanisms underlying biliary-driven liver regenerationObjective:During normal liver regeneration,the newly generated hepatocytes originate from pre-existing hepatocytes.However,if hepatocyte proliferation is impaired,biliary epithelial cells(BECs)dedifferentiate into liver progenitor cells(LPCs),which subsequently differentiate into either hepatocytes or BECs and recover the liver mass,which is called biliary-driven regeneration.Currently,the mechanisms underlying biliary-driven regeneration remain largely unknown.By using a zebrafish biliary-driven liver regeneration model in which BECs greatly contribute to hepatocytes,we performed a genetic screen and a chemical screen to identify critical factors that regulate biliary-driven liver regeneration,.Methods:By using Tg(fabpl0a:CFP-NTR)background zebrafish,we screened 9 candidate genes which were identified from RNA-seq analyses of the regenerating livers and were upregulated during the regeneration process in biliary-driven liver regeneration.The genes include baspl,egfra,erbb2,dusp5,hbegfa,hbegfb,pprcl,tfe3a and TWEAK.Meanwhile,we also tested 4 selected compounds on biliary-driven liver regeneration.Tg(Tp1:H2B-mCherry)and Tg(Tpl:VenusPEST)lines were used to reveal BECs.Liver size was assessed by fabp10a:CFP expression;liver marker expression was analyzed by immunostaining and in situ hybridization.Results:The mutants of the 9 genes did not exhibit any defects in biliary-driven liver regeneration.Intriguingly,a PI3K inhibitor,LY294002,impaired the regeneration process.Conclusion:The zebrafish biliary-driven liver regeneration model can be used to screen candidate genes and compounds.The PI3K inhibitor may inhibit biliary-driven liver regeneration.More future studies are warranted to evaluate more mechanisms by which PI3K/Akt signaling regulates biliary-driven liver regeneration. |
