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Background: Sorafenib and other tyrosine kinase inhibitors are the current standard of care for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT). Sorafenib is sometimes regarded as a scarcely effective treatment in this setting because of some studies showing a short overall survival (OS) indirectly compared with historical series of nontransplanted patients. Additional data from multicenter prospective studies are needed before drawing definite conclusions., Methods: Retrospective analyses of a large prospective multicenter dataset of sorafenib-treated HCC patients to report the characteristics and outcomes of LT recipients (n = 81)., Results: At the baseline, LT patients had key prognostic features (high prevalence of metastatic disease, and low prevalence of macrovascular invasion, α-fetoprotein >400 ng/mL, ALBI grade >1, performance status >0) that differentiated them from the typical populations of non-LT patient reported in clinical trials and observational studies. Moreover, a relevant proportion of LT patients received concurrent locoregional (12.3%) and postprogression systemic treatments (34.2%), resulting in a median OS of 18.7 mo., Conclusions: Multimodal and sequential treatments are relatively frequent in post-LT HCC patients and contribute to a remarkable OS, together with favorable baseline characteristics. Despite the impossibility of matching with non-LT patients, our results indirectly suggest that the metastatic nature of post-LT recurrence and concurrent antirejection regimens should not discourage systemic treatments., Competing Interests: F.T. has served as a consultant for Bayer, Ipsen, and Eisai and an advisory board member for Laforce. M.I.: speaking/teaching, consultant, and the advisory board for Bayer, Gilead Sciences, BMS, Janssen, Ipsen, MSD, BTG-Boston Scientific, AbbVie, Guerbet, and EISAI. M.D.G. received honoraria for serving on advisory boards for Eisai and Bayer. F.T. is an advisor and a consultant for Bayer and an advisory board member for Sirtex, Alfasigma, and Bristol-Myers Squibb. F.P. is a consultant for AstraZeneca, Bayer AG, EISAI, GE, and Tiziana Life Sciences; Speaker bureau honoraria: Bayer AG, Bracco, EISAI, and Laforce; research contract with Esaote. A.G. has served as a consultant for Bayer. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Immunosuppression after liver transplantation (LT) is presently based on use of calcineurin inhibitors (CNI), although they are associated with an increased incidence of renal dysfunction, cardiovascular complications, and de novo and recurrent malignancies. Over the past decade, mammalian target of rapamycin inhibitors have received considerable attention as immunosuppressants because they are associated with a more favorable renal profile versus CNI, as well as antiproliferative activity in clinical studies. Comprehensive guidelines on use of everolimus (EVR) in LT are still lacking. In Italy, a project, named Everolimus: the road to long-term functioning, was initiated to collect the experience on EVR after LT with the aim of providing guidance for transplant clinicians. Herein, recommendations by this national consensus group, based on Delphi methodology, are presented. Consensus was reached on 20 of the 23 statements proposed, and their level of evidence, grade of recommendation, and percent of agreement are reported. Statements are grouped into 4 areas: (A) renal function; (B) time of EVR introduction, CNI reduction and elimination, and risk for graft rejection; (C) antiproliferative effects of EVR; and (D) management of EVR-related adverse events. The high level of consensus shows that there is good agreement on the routine use of EVR in predefined clinical scenarios, especially in light of posttransplant nephrotoxicity and other adverse events associated with long-term administration of CNIs., Competing Interests: P.D.S. has served as advisor and has received speaker’s fees from Novartis. The other authors declare no conflicts of interest.

Objective: To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC)., Summary Background Data: HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate., Methods: Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC., Results: On histologic examination, 38% of the entire group of 48 patients did not meet the "Milan criteria" and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates., Conclusions: The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation.

Background: A more rapid and aggressive course of hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related infection in organ transplant recipients has been described. Interferon alfa is the most accepted drug for treating HBV and HCV chronic infections. However, the use of interferon alfa-N3 has been contraindicated in heart transplant (HTx) recipients because of the hypothesized greater risk of triggering acute cellular rejection. The aim of this clinical pilot study was to evaluate tolerability, safety, and efficacy of natural leukocyte interferon alfa in the treatment of chronic HBV and HCV in HTx recipients., Methods: Seven HTx recipients were enrolled in the study: two with HBV, four with HCV, and one with combined HBV-HCV chronic infection. The patients had a mean follow-up after heart transplantation of 8.5+/-3 years, before starting interferon alfa-N3 treatment at a dose of 6 MU three times per week, intramuscularly for 12 months., Results: All patients completed the treatment with no major side effects. No unexpected episodes of acute cellular rejection were observed during the treatment. Mean aminotransferase serum levels were significantly lower than before transplantation at 3 (P<0.03), 6 (P<0.02), and 12 (P<0.02) months of treatment and at the 12-month follow-up (P<0.02). A complete and sustained response was achieved in all subjects with HBV-related chronic hepatitis, whereas sustained virologic response was observed in one of four HCV patients., Conclusions: The preliminary data emerging from our study indicate that natural leukocyte interferon alfa-N3 can be safely administered in HTx recipients with chronic HBV or HCV viral hepatitis. Further studies with larger numbers of patients are needed to assess the efficacy of interferon alfa-N3 on HCV virologic response.

Graft-versus-host disease (GVHD) and graft rejection are major problems following intestinal transplantation (IT). Natural killer (NK) cells may be important effector cells in both conditions. In this study, Sprague-Dawley (SD) or SD-Brown Norway (BN) F1 rat intestine was transplanted into BN recipients with and without associated graft mesenteric lymphadenectomy (GML). Cyclosporine (15 mg/kg day) was administered to all animals. Pieces of the intestinal graft were examined 4 days posttransplant and again at death. NK activity calculated using intestinal intraepithelial lymphocytes (IL) was determined utilizing an 18-hr cytotoxic assay assessing 51Cr release and the results are reported as lytic units. YAC-1 cells were used as the target. NK activity was reduced 4 days after IT both in native (8.02 +/- 0.64) and in grafted bowel (3.14 +/- 1.51), with histological evidence of rejection as compared with that of control bowel in ungrafted rats (21.1 +/- 2.14). Survival was increased, on mean, a total of 6 days with the addition of GML in both semiallogenic and allogenic transplanted rats. At the time of death, the NK activity in the native bowel had increased (17.1 +/- 3.02) and histologic evidence of GVHD was present. These data suggest that: (1) NK cells are important in GVHD and (2) both semiallogenic and allogenic transplants survive longer if they are combined with GML (P < or = 0.05 and P < or = 0.01, respectively).