title: Reduced exposure to calcineurin inhibitors early after liver transplantation prevents recurrence of hepatocellular carcinoma.
abstract: OBJECTIVE
  Recurrence of hepatocellular carcinoma (HCC) is a major complication after liver transplantation (LT). The initial immunosuppression protocol may influence HCC recurrence, but the optimal regimen is still unknown.
  
  
  METHODS
  219 HCC consecutive patients under Milan criteria, who received an LT at 2 European centres between 2000 and 2010, were included. Median follow-up was 51 months (IQR 26-93). Demographic characteristics, HCC features, and immunosuppression protocol within the first month after LT were evaluated against HCC recurrence by using Cox regression.
  
  
  RESULTS
  In the explanted liver, 110 patients (50%) had multinodular HCC, and largest nodule diameter was 3±2.1cm. Macrovascular invasion was incidentally detected in 11 patients (5%), and microvascular invasion was present in 41 patients (18.7%). HCC recurrence rates were 13.3% at 3 years and 17.6% at 5 years. HCC recurrence was not influenced by the use/non-use of steroids and antimetabolites (p=0.69 and p=0.70 respectively), and was similar with tacrolimus or cyclosporine (p=0.25). Higher exposure to calcineurin inhibitors within the first month after LT (mean tacrolimus trough concentrations >10ng/ml or cyclosporine trough concentrations >300ng/ml), but not thereafter, was associated with increased risk of HCC recurrence (27.7% vs. 14.7% at 5 years; p=0.007). The independent predictors of HCC recurrence by multivariate analysis were: high exposure to calcineurin inhibitors defined as above (RR=2.82; p=0.005), diameter of the largest nodule (RR=1.31; p<0.001), microvascular invasion (RR=2.98; p=0.003) and macrovascular invasion (RR=4.57; p=0.003).
  
  
  CONCLUSIONS
  Immunosuppression protocols with early CNI minimization should be preferred in LT patients with HCC in order to minimize tumour recurrence.
authors.affiliation: Hepatology and Liver Transplant Unit, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Perálvarez
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tsochatzis
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Naveas
authors.forename: Giulia
authors.initials: G
authors.lastname: Pieri
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Caparrós
authors.forename: James
authors.initials: J
authors.lastname: O'Beirne
authors.forename: Antonio
authors.initials: A
authors.lastname: Poyato-González
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ferrín-Sánchez
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Montero-Álvarez
authors.forename: David
authors.initials: D
authors.lastname: Patch
authors.forename: Douglas
authors.initials: D
authors.lastname: Thorburn
authors.forename: Javier
authors.initials: J
authors.lastname: Briceño
authors.forename: Manuel
authors.initials: M
authors.lastname: De la Mata
authors.forename: Andrew Kenneth
authors.initials: AK
authors.lastname: Burroughs
mesh_terms: D000368:Aged; D065095:Calcineurin Inhibitors; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000601:surgery*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000401:mortality / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D058570:TOR Serine-Threonine Kinases
keywords: CNI; Calcineurin inhibitors; HCC; Hepatocellular carcinoma; Immunosuppression; LT; Liver transplantation; Recurrence; TC; Trough concentrations; calcineurin inhibitors; hepatocellular carcinoma; liver transplantation; trough concentrations