Summary The purpose of this registry study was to provide an overview of trends and results of liver transplantation (LT) in Europe from 1968 to 2016. These data on LT were collected prospectively from 169 centers from 32 countries, in the European Liver Transplant Registry (ELTR) beginning in 1968. This overview provides epidemiological data, as well as information on evolution of techniques, and outcomes in LT in Europe over more than five decades; something that cannot be obtained from only a single center experience.

BackgroundWe investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).MethodsIn a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint.ResultsRecurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874).ConclusionsSirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

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Cholangiocarcinoma (CCA) is characterized by an abundant stromal reaction. Cancer-associated fibroblasts (CAF) are pivotal players in tumor growth and invasiveness and represent a potential therapeutic target. To understand the mechanisms leading to CAF recruitment in CCA, we studied: 1) the expression of epithelial-mesenchymal transition (EMT) in surgical CCA specimens and CCA cells; 2) the lineage tracking of an EGFP-expressing human male CCA cell line (EGI-1) after xenotransplantation into severe-combined-immunodeficient mice; 3) the expression of platelet-derived growth factors (PDGFs) and their receptors in vivo and in vitro; 4) the secretion of PDGFs by CCA cells; 5) the role of PDGF-D in fibroblast recruitment in vitro; 6) the downstream effectors of PDGF-D signaling. CCA cells expressed several EMT biomarkers but not α-SMA. Xenotransplanted CCA masses were surrounded and infiltrated by α-SMA-expressing CAF, which were negative for EGFP and the human Y-probe, but positive for the murine Y-probe. CCA cells were strongly immunoreactive for PDGF-A and -D, whilst CAF expressed PDGFRβ. PDGF-D, a PDGFRβ agonist, was exclusively secreted by cultured CCA cells. Fibroblast migration was potently induced by PDGF-D and CCA conditioned medium, and was significantly inhibited by PDGFRβ blockade with Imatinib and by silencing PDGF-D expression in CCA cells. In fibroblasts, PDGF-D activated the Rac1 and Cdc42 Rho GTPases and JNK. Selective inhibition of Rho GTPases (particularly Rac1) and of JNK strongly reduced PDGF-D-induced fibroblast migration. Conclusion CCA cells express several mesenchymal markers, but do not transdifferentiate into CAF. Instead, CCA cells recruit CAF by secreting PDGF-D, which stimulates fibroblast migration via PDGFRβ and Rho GTPase and JNK activation. Targeting tumor/stroma interactions with inhibitors of PDGF-D pathway may offer a novel therapeutic approach.

Background. Liver transplantation cures hepatocellular carcinoma (HCC) if within conventional selection criteria. Expanded criteria are elusive. Loco-regional treatments pursue tumor downstaging from outside Milan criteria to within criteria. No trial investigated HCC-downstaging strategy to expand transplant eligibility. Methods. This multi-center trial aimed at comparing successfully downstaged HCC followed by transplantation vs. non-transplant therapies. Eligible patients had good liver function (Child-Pugh A-B7), HCC beyond Milan, 5-year estimated post-transplant survival ≥50%, no macrovascular or extrahepatic spread. Only partial-complete responses according to modified-RECIST were randomized 1:1 after 3 months observation period, during which sorafenib was allowed. Co-endpoints were survival and timeto-tumor event. We used Kaplan-Meier method, log-rank test, Cox regression for intention-to-treat analysis. Survival benefit was the difference between groups mean survival time. Organ allocation policy changed over time and limited patients' accrual to 4 years. After 4 additional years conditional power calculation estimated the probability that the final results would be statistically significant in the remaining study, given the data observed. ClinicalTrials.gov NCT01387503. Findings. 74 patients were enrolled between March 2011 to March 2015: 29 dropped-out pre-randomization. Downstaging median duration was 6 months (1-17). Success-rate was 73%. Progression during observation was 17%. 45 patients were randomized: 23 transplanted vs. 22 controls. Median followup was 71 months (IQR 60-85). 5-year overall survival was 77.5% (95%CI 61.9-97.1%) in transplants vs. 31.2% (95%CI: 16.6-58.5%) in controls (Cox hazard ratio [HR] 0.22, 95%CI: 0.08-0.61; p=0.004). 5-year tumor eventfree survival was 76.8 (95%CI: 60.8-96.9%) vs. 18.3% (95%CI: 7.1-47.0%) in controls (HR: 0.14, 95%CI: 0.05-0.38; p<0001). 5-year survival-benefit favored transplantation by 14.5 months (95%CI: 3.6-25.3; p=0.009). The trial retained a conditional power of 98.6%. Interpretation. After effective and sustained downstaging of eligible HCCs beyond Milan criteria, liver transplantation is superior to nontransplant therapies. Post-downstaging tumor response should contribute to HCC transplant criteria expansion. Funding. Italian Ministry of Health