Liver transplantation is proposed as the best therapy for early hepatocellular carcinoma in cirrhotic patients. However, the confrontation with the results obtained by surgical resection has never been done on an intention-to-treat basis. Between 1989 and 1997, 164 out of 1,265 patients with hepatocellular carcinoma were evaluated for surgery. Seventyseven (48 men, mean 61 years of age, 74 Child-Pugh class A, size 33 ؎ 18 mm) were resected (first line option) and 87 (65 men, mean 55 years of age, 50 Child-Pugh class B/C, size 24 ؎ 14 mm) were selected for transplantation. The 1-, 3-, and 5-year ''intention-to-treat'' survival was 85%, 62%, and 51% for resection and 84%, 69%, and 69% for transplantation (8 drop-outs on waiting list). Bilirubin and clinically relevant portal hypertension were independent survival predictors after resection. Thereby, the 5-year survival of the best candidates (absence of clinically relevant portal hypertension, n ‫؍‬ 35) was 74%, whereas it was 25% for the worst candidates (portal hypertension and bilirubin H1 mg/dL, n ‫؍‬ 27) (P F .00001). The variable ''drop-out on waiting list'' was the sole survival predictor after transplantation. The 2-year survival rate of patients evaluated for transplantation was 84% in the 1989 to 1995 period (mean waiting time, 62 days; no drop-outs) and 54% during 1996 to 1997 (mean waiting time, 162 days; 8 drop-outs)(P F .003). This outcome was significantly lower than that of the best candidates for resection (P ‫؍‬ .002). In conclusion, a proper selection of candidates for resection promotes better results than transplantation, in which the results are significantly hampered by the growing incidence of drop-outs because of the increasing waiting time. (HEPATOLOGY 1999;30:1434-1440.)There are no randomized controlled clinical trials (RCTs) comparing orthotopic liver transplantation (OLT) versus surgical resection for early hepatocellular carcinoma (HCC) in cirrhotic patients. By now, such an RCT should be considered largely unfeasible because it would require a very large sample size, thus involving several centers sharing the same selection criteria and therapeutic skills. Thus, the debate regarding which should be the preferred treatment option is based on the comparison between the outcomes of independent cohorts of patients. This approach suggests that OLT offers better life expectancy, 1-7 but this assumption is misleading. There are no intention-to-treat studies, and this is of paramount importance because a noteworthy proportion of patients will be excluded from the transplantation program because of tumor growth or development of contraindications while waiting for a donor. Spain has the highest liver donation rate throughout the world (20 liver donors/10 6 inhabitants), 8 and the proportion of drop-outs (because of death or appearance of contraindications) is nowadays around 15%. 9 Furthermore, although the encouraging survival data described for HCC patients effectively transplanted (75% at 5 years) are due both to a restrictive selection p...

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.