P Carrai

Conversion to everolimus monotherapy in maintenance liver transplantation: feasibility, safety, and impact on renal function.

We present the 12‐month results of a prospective trial of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) in maintenance liver transplant (LT) recipients. Forty (M:F = 28:12; 54.9 ± 11 years) patients were enrolled at a mean interval of 45.5 ± 31.2 months from transplantation. Conversion was with EVL at a dosage of 0.75 mg b.i.d., withdrawal of antimetabolites, and a 50%‐per‐week reduction of CNI to a complete stop within 4 weeks. The treatment success was conversion to EVL monotherapy at 12 months while failure was presence of CNI, death, and graft loss. Indication to conversion was deteriorating renal function in 36 (90%). At 12 months, patient‐ and graft survival were 100% and the success rate was 75% (30/40). Ten patients (25%) were failures: four (10%) for acute rejection; three hepatitis C virus‐RNA positive patients (7.5%) for hypertransaminasemia; one (2.5%) for acute cholangitis; and two (5%) due to persistent pruritus and oral ulcers. In patients on EVL monotherapy, at 12 months the mean change of calculated creatinine clearance (cCrCl) was 4.03 ± 12.6 mL/min and the only variable correlated with the probability of improvement was baseline cCrCl (P < 0.0001). Conversion from CNI to EVL is feasible in 75% of the cases and associated with improvement in renal function for patients with higher baseline cCrCl.

Modified RECIST to assess tumor response after transarterial chemoembolization of hepatocellular carcinoma: CT–pathologic correlation in 178 liver explants

PURPOSE To retrospectively evaluate agreement between modified RECIST (mRECIST) assessed at Computed Tomography (CT) and pathology in a large series of patients with hepatocellular carcinoma (HCC) who were transplanted after transarterial chemoembolization (TACE). MATERIALS AND METHODS IRB approval was obtained. The study included 178 patients (M/F=155/23; mean age 55.8 ± 6.3 years) with HCC who were transplanted after TACE from January 1996 to December 2010 and with at least one CT examination before liver transplantation (LT). Two blinded independent readers retrospectively reviewed CT examinations, to assess tumor response to TACE according to mRECIST. Patients were classified in responders (complete and partial response) and non-responders (stable and progressive disease). On the explanted livers, percentage of tumor necrosis was classified as 100, >50 and <50%. RESULTS The mean interval between latest CT and LT was 57.4 ± 39.8 days. At latest CT examination, the objective response rate was 78.1% (139/178), with 86 cases (48.3%) of complete response (CR). A good intra- (k=0.75 and 0.86) and inter-observer (k=0.81) agreement was obtained. On a per-patient basis, agreement between mRECIST and pathology was obtained in 120 patients (67.4%), with 19 cases (10.7%) of underestimation and 39 cases (21.9%) of overestimation of tumor response at CT. CT sensitivity and specificity in differentiating between responders and non-responders were 93 and 82.9%, respectively. Out of 302 nodules, sensitivity and specificity of CT in detecting complete necrosis were 87.5 and 68.9%, respectively. CONCLUSIONS CT can overestimate tumor response after TACE. Nonetheless, mRECIST assessed at CT after TACE are reproducible and reliable in differentiating responders and non-responders.

Use of Octogenarian Donors for Liver Transplantation: A Survival Analysis

Use of very old donors in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk for graft dysfunction and worse long‐term results, especially for hepatitis C virus (HCV)‐positive recipients. This was a retrospective, single‐center review of primary, ABO‐compatible LT performed between 2001 and 2010. Recipients were stratified in four groups based on donor age (<60 years; 60–69 years; 70–79 years and ≥80 years) and their outcomes were compared. A total of 842 patients were included: 348 (41.3%) with donors <60 years; 176 (20.9%) with donors 60–69 years; 233 (27.7%) with donors 70–79 years and 85 (10.1%) with donors ≥80 years. There was no difference across groups in terms of early (≤30 days) graft loss, and graft survival at 1 and 5 years was 90.5% and 78.6% for grafts <60 years; 88.6% and 81.3% for grafts 60–69 years; 87.6% and 75.1% for grafts 70–79 years and 84.7% and 77.1% for grafts ≥80 years (p = 0.065). In the group ≥80 years, the 5‐year graft survival was lower for HCV‐positive versus HCV‐negative recipients (62.4% vs. 85.6%, p = 0.034). Based on our experience, grafts from donors ≥80 years may provide favorable results but require appropriate selection and allocation policies.

Efficacy and Safety of Combination Therapy With Everolimus and Sorafenib for Recurrence of Hepatocellular Carcinoma After Liver Transplantation

BACKGROUND Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. METHODS This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. RESULTS Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). CONCLUSIONS Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.

Risk analysis of ischemic‐type biliary lesions after liver transplant using octogenarian donors

The use of octogenarian donors to increase the donor pool in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk of ischemic‐type biliary lesions (ITBL). The aim of this study was to investigate retrospectively the role of a number of different pre‐LT risk factors for ITBL in a selected population of recipients of octogenarian donor grafts. Between January 2003 and December 2013, 123 patients underwent transplantation at our institution with deceased donor grafts from donors of age ≥80 years. Patients were divided into 2 groups based on the presence of ITBL in the posttransplant course. Exclusion criteria were retransplantations, presence of vascular complications, and no availability of procurement liver biopsy. A total of 88 primary LTs were included, 73 (83.0%) with no posttransplant ITBLs and 15 (17.0%) with ITBLs. The median follow‐up after LT was 2.1 years (range, 0.7‐5.4 years). At multivariate analysis, donor hemodynamic instability (hazard ratio [HR], 7.6; P = 0.005), donor diabetes mellitus (HR, 9.5; P = 0.009), and donor age–Model for End‐Stage Liver Disease (HR, 1.0; P = 0.04) were risk factors for ITBL. Transplantation of liver grafts from donors of age ≥80 years is associated with a higher risk for ITBL. However, favorable results can be achieved with accurate donor selection. Donor hemodynamic instability, a donor history of diabetes mellitus, and allocation to higher Model for End‐Stage Liver Disease score recipient all increase the risk of ITBL and are associated with worse graft survival when octogenarian donors are used. Liver Transplantation 22 588‐598 2016 AASLD.

The impact of everolimus on renal function in maintenance liver transplantation

We retrospectively investigated the impact on renal function (RF) of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) monotherapy in orthotopic liver transplant (OLT) recipients. Between January 2006 and July 2007, 70 deceased donor OLT recipients including 51 men and 19 women of overall mean age of 55.9 +/- 11 years were enrolled into a program of conversion to EVL monotherapy at a mean interval of 45 +/- 35.9 months from transplantation (range, 7-192 months). The indication for conversion was deteriorating RF in 64 (91.4%). Efficacy failure was defined as the persistence of CNI, EVL discontinuation, death, graft loss, loss to follow-up, or need for dialysis at 12 months. Twelve months after switching, 53 patients (75.7%) were on EVL monotherapy. Their mean change in creatinine clearance (CrCl) from baseline (day 1 before EVL introduction) to endpoint (12 months) was 5.8 +/- 13.1 mL/min. On univariate and multivariate analyses, the clinical variable correlated with the greatest probability of improvement was the baseline CrCl (P < .0001). Conversion from CNI to EVL monotherapy was successful in 75.7% of cases with improvement in RF correlated with baseline CrCl. These data supported preemptive minimization of CNI in the posttransplant course, seeking to delay the decline in RF.

Transjugular intrahepatic portosystemic shunt for hepatitis C virus-related portal hypertension after liver transplantation.

Ghinolfi D, De Simone P, Catalano G, Petruccelli S, Coletti L, Carrai P, Marti J, Tincani G, Cicorelli A, Cioni R, Filipponi F. Transjugular intrahepatic portosystemic shunt for hepatitis C virus‐related portal hypertension after liver transplantation.

Efficacy, safety, and pharmacokinetics of intramuscular hepatitis B immune globulin, Igantibe, for the prophylaxis of viral B hepatitis after liver transplantation

BACKGROUND Long-term prophylaxis of hepatitis B virus (HBV) positive liver transplanted subjects with intravenous hepatitis B immunoglobulin (HBIG) is effective, however use of intramuscular HBIG could be as effective with fewer adverse events and lower cost. AIM We conducted a prospective, non-randomized, clinical study to assess the efficacy and safety of HBIG from Grifols, Igantibe, for the prophylaxis of HBV reactivation. METHODS Eighteen adult patients submitted to liver transplantation for HBV-related disease more than 18 months earlier were treated with doses of 2000 I.U. intramuscular Igantibe every 14 days for 6 months. RESULTS Mean trough serum HBsAb IgG titers from months 4 to 6 (primary efficacy variable) were protective (>or=150 I.U./L) at each time point. Individual measurements were also protective throughout the study. HBV replication remained negative for all available subjects until study completion. Pharmacokinetic analysis showed a half-life of 27 days and extensive exposure to the study drug. Safety and tolerability of intramuscular Igantibe were good, with only one adverse event. CONCLUSION Standard-dose intramuscular Igantibe administration proved efficacious in post-liver transplantation prophylaxis by attaining protective levels for up to 6 months, was safe and well tolerated. Pharmacokinetic analysis revealed a long half-life and extensive exposure.

Early Introduction of Subcutaneous Hepatitis B Immunoglobulin Following Liver Transplantation for Hepatitis B Virus Infection: A Prospective, Multicenter Study.

Background Subcutaneous administration of hepatitis B immunoglobulin (HBIg) is effective in preventing hepatitis B virus (HBV) recurrence after liver transplantation, but early conversion to subcutaneous administration is undocumented. Methods In a prospective study, patients transplanted for terminal liver disease due to HBV infection who were HBV DNA-negative at transplant were switched by week 3 posttransplantation from intravenous to subcutaneous HBIg (500 or 1000 IU weekly or fortnightly, adjusted according to serum anti-HBs trough level) if they were HBsAg- and HBV-DNA negative at time of switch. All patients concomitantly received nucleos(t)ide analogue antiviral therapy. Primary endpoint was failure rate by month 6, defined as serum anti-HBs of 100 IU/L or less or HBV reinfection despite serum anti-HBs greater than 100 IU/L. Results Of 49 patients treated, 47 (95.9%) continued treatment until month 6. All patients achieved administration by a caregiver or self-injection by week 14. No treatment failures occurred. Mean anti-HBs declined progressively to month 6, plateauing at a protective titer of approximately 290 IU/L. All patients tested for HBV DNA remained negative (45/45). Only 1 adverse event (mild injection site hematoma) was assessed as treatment-related. Conclusions Introduction of subcutaneous HBIg administration by week 3 posttransplantation, combined with HBV virostatic prophylaxis, is effective and convenient for preventing HBV recurrence.

Circulating gamma-glutamyltransferase fractions in cirrhosis

Four gamma‐gultamyltransferases (GGT) fractions (b‐, m‐, s‐, and f‐GGT) have been identified in human plasma and their concentrations and ratios vary in different pathological conditions. To assess the behaviour of fractional GGT in cirrhotic patients evaluated for liver transplantation.