Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: A multicenter study of 412 patients

AIM： To assess pre-orthotopic liver transplantation （OLT） factors that could be evaluated pre-operatively or controlled post-operatively associated with hepatocellular carcinoma （HCC） recurrence and disease-free survival after liver transplantation （LT）.METHODS： Four hundred and twelve patients transplanted for HCC between 1988 and 1998 in 14 French centers, who survived the postoperative period were studied. Kaplan Meier estimates were calculated for 24 variables potentially associated with recurrence of HCC. Uni- and multivariate analyses were conducted to identify independent predictors of recurrence. RESULTS： Overall 5-year disease-free survival was 57.1%. By univariate analysis, variables associated with disease-free survival were： presence of cirrhosis （P = 0.001）, etiology of liver disease （P = 0.03）, α fetoprotein level （〈 200, 200 to 2000, or 〉 2000; P 〈 0.0001）, y-GT activity （N, N to 2N or 〉 2N; P = 0.02）, the number of nodules （1, 2-3 or ≥ 4; P = 0.02）, maximal diameter of the largest nodule （〈 3 cm, 3 to 5 cm or 〉 5 cm; P 〈 0.0001）, the sum of the diameter of the nodules （〈 3 cm, 3 to 5 cm, 5 to 10 cm or 〉10 cm; P 〈 0.0001）, bilobar location （P = 0.01）, preoperative portal thrombosis （P 〈 0.0001）, peri-operative treatment of the tumor （P = 0.002） and chemoembolization （P = 0.03）, tumor differentiation （P = 0.01）, initial type of calcineurin inhibitor （P = 0.003）, the use of antilymphocyte antibodies （P = 0.02）, rejection episodes （P = 0.003） and period of LT （P 〈 0.0001）. By multivariate analysis, 6 variables were independently associated with HCC recurrence： maximal diameter of the largest nodule （P 〈 0.0001）, time of LT （P 〈 0.0001）, tumor differentiation （P 〈 0.0001）, use of anti-lymphocyte antibody （ATG） or anti-CD3 antibody （OKT3） （P = 0.005）, preoperative portal thrombosis （P = 0.06） and the number of nodules （P = 0.06）. CONCLUSION： This study identifies immunosuppression, through the use of ATG or OKT3, as a predictive factor of tumor recurrence, and confirms the prognostic value of tumor differentiation.

Orthotopic liver transplantation as a rescue operation for recurrent hepatocellular carcinoma after partial hepatectomy

AIM: To compare post-orthotopic liver transplantation (OLT) survival between patients with recurrent hepatocellular carcinoma (HCC) after partial hepatectomy and those who received de novo OLT for HCC and to assess the risk factors associated with post-OLT mortality. METHODS: From July 2003 to August 2005, 77 consecutive HCC patients underwent OLT, including 15 patients with recurrent HCC after partial hepatectomy for tumor resection (the rescue OLT group) and 62 patients with de novo OLT for HCC (the de novo OLT group). Thirty-three demographic, clinical, histological, laboratory, intra-operative and post-operative variables were analyzed. Survival was calculated by the Kaplan- Meier method. Univariable and multivariable analyses were also performed. RESULTS: The median age of the patients was 49.0 years. The median follow-up was 20 mo. Three patients (20.0%) in the rescue OLT group and 15 patients (24.2%) in the de novo OLT group died during the follow-up period (P = 0.73). The 30-day mortality of OLT was 6.7% for the rescue OLT group vs 1.6% for the de novo OLT group (P = 0.27). Cox proportional hazards model showed that pre-OLT hyperbilirubinemia, the requirement of post-OLT transfusion, the size of the tumor, and family history of HCC were significantly associated with a higher hazard for mortality. CONCLUSION: There are no significant differences in survival/mortality rates between OLT as de novo therapy and OLT as a rescue therapy for patients with hcc. Pre-OLT hyperbilirubinemia, post-OLT requirement of transfusion, large tumor size and family history of HCC are associated with a poor survival outcome.

Veno occlusive disease: Update on clinical management

Hepatic veno-occlusive disease is a clinical syndrome characterized by hepatomegaly, ascites, weight gain and jaundice, due to sinusoidal congestion which can be caused by alkaloid ingestion, but the most frequent cause is haematopoietic stem cell transplantation （STC） and is also seen after solid organ transplantation. The incidence of veno occlusive disease （VOD） after STC ranges from 0 to 70%, but is decreasing. Survival is good when VOD is a mild form, but when it is severe and associated with an increase of hepatic venous pressure gradient 〉 20 mmHg, and mortality is about 90%. Prevention remains the best therapeutic strategy, by using non-myeloablative conditioning regimens before STC. Prophylactic administration of ursodeoxycholic add, being an antioxidant and antiapoptotic agent, can have some benefit in reducing overall mortality. Defibrotide, which has pro-fibrinolytic and antithrombotic properties, is the most effective therapy; decompression of the sinusoids by a b-ansjugular intrahepatic portosystemic shunt （TIPS） can be tried, especially to treat VOD after liver transplantation and when multiorgan failure （HOF） is not present. Liver transplantation can be the last option, but can not be considered a standard rescue therapy, because usually the concomitant presence of multiorgan failure contraindicates this procedure.

Xenogeneic hepatic progenitor cell transplantation ameliorate CCl_4 /partial hepatectomy-induced rat acute liver failure

Objective： Hepatic progenitor cell transplantation has shed light on the treatment of liver failure. The present study was designed to evaluate whether xenogeneic liver epithelial progenitor cells （LEPCs） transplantation could promote liver recovery in a rat model of acute liver failure. The engraftment and hepatocytic differentiation of transplanted hepatic progenitor cells in the rat spleen was also investigated. Methods： LEPCs were propagated in vitro for long and transduced with lentiviral vector carrying mCherry gene. Intraperitoneal injection of CC14 followed by 2/3 partial hepatectomy three days later were used to establish rat models of acute liver failure. Rats were intrasplenically injected with mCherry modified LEPCs （n=20, 1× 107 cells/0.5 mL） or the same volume of medium （n=20）. Serum liver enzymes （ALT, AST） and liver histology were evaluated for 21 days after transplantation. The engraftment of transplanted LEPCs in the spleens was tested by polymerase chain reaction （PCR） amplification targeting mCherry gene. The differentiation into hepatocytic lineage of transplanted LEPCs was investigated usingimmunohistochemistry staining against Alb. Results： LEPCs were effectively transduced with lentiviral vector showing a transduction efficiency of 90%. Compared with control, cell-injected group displayed significantly lower levels of ALT and AST （P〈0.05） and better histological features including less swelling change and hepatocyte death. PCR amplification of mCherry sequences confirmed the engraftment of LEPCs in the spleens. Alb-positive cells first appeared 5 days after cell transplantation and the number of Alb-positive cells increased substantially （P〈0.05）, which revealed the hepatocytic differentiation process Conclusion： Xenogeneic hepatic progenitor cells can engraft and differentiate into hepatocytes in the splenic parenchyma. Intrasplenic delivery of hepatic progenitor cells ameliorates CCh/partial hepatectomy-induced liver injury in rats

Portal vein thrombosis in patients with cirrhosis

Portal vein thrombosis(PVT)is frequent in patients with liver cirrhosis and possible severe complications such as mesenteric ischemia are rare,but can be life-threatening.However,different aspects of clinical relevance,diagnosis and management of PVT are still areas of uncertainty and investigation in international guidelines.In this article,we elaborate on PVT classification,geographical differences in clinical presentation and standards of diagnosis,and briefly on the current pathophysiological understanding and risk factors.This review considers and highlights the pitfalls of the various treatment approaches and prophylactic treatments.Finally,we review the controversial issue of clinical impact of PVT on prognosis,especially considering liver transplantation and future perspectives.

Variceal bleeding in cirrhotic patients

Variceal bleeding is one of the major causes of death in cirrhotic patients.The management during the acute phase and the secondary prophylaxis is well defined.Recent recommendations(2015 Baveno VI expert consensus)are available and should be followed for an optimal management,which must be performed as an emergency in a liver or general intensive-care unit.It is based on the early administration of a vasoactive drug(before endoscopy),an antibiotic prophylaxis and a restrictive transfusion strategy(hemoglobin target of 7 g/dL).The endoscopic treatment is based on band ligations.Sclerotherapy should be abandoned.In the most severe patients(Child Pugh C or B with active bleeding during initial endoscopy),transjugular intrahepatic portosystemic shunt(TIPS)should be performed within 72 hours after admission to minimize the risk of rebleeding.Secondary prophylaxis is based on the association of non-selective beta-blockers(NSBBs)and repeated band ligations.TIPS should be considered when bleeding reoccurs in spite of a well-conducted secondary prophylaxis or when NSBBs are poorly tolerated.It should also be considered when bleeding is refractory.Liver transplantation should be discussed when bleeding is not controlled after TIPS insertion and in all cases when liver function is deteriorated.