How can a vascular surgeon help in kidney transplantation.

Kidney transplantation is a surgical procedure involving both vascular and ureteric anastomoses. As a matter of fact, it can be performed either by urologists or vascular surgeons. However, vascular surgeon's expertise can be helpful at different times. In the present paper we describe how can vascular surgeons help at the different stages of kidney transplantation process in modern care: 1) before kidney transplantation for recipient preparation in order to allow subsequent graft implantation, either by performing percutaneous embolization of renal arteries in the setting of polycystic kidney disease or treatment of aneurysmal or occlusive lesions that would contra-indicate graft implantation; 2) at the time of surgery graft back table preparation and repair; and 3) after surgery for long-term follow-up, including transplant renal artery stenosis treatment or transplant nephrectomy.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

BACKGROUND: We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). METHODS: In 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. RESULTS: Recurrence-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). CONCLUSIONS: Sirolimus 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.

Patients with acute liver failure listed for superurgent liver transplantation in France: reevaluation of the Clichy-Villejuif criteria.

In France, decisions regarding superurgent (SU) liver transplantation (LT) for patients with acute liver failure (ALF) are principally based on the Clichy-Villejuif (CV) criteria. The aims of the present study were to study the outcomes of patients registered for SU LT and the factors that were predictive of spontaneous improvement and to determine the usefulness of the CV criteria. All patients listed in France for SU LT between 1997 and 2010 who were 15 years old or older with ALF were included. In all, 808 patients were listed for SU transplantation: 22% with paracetamol-induced ALF and 78% with non-paracetamol-induced ALF. Of these 808 patients, 112 improved spontaneously, 587 underwent LT, and 109 died or left the waiting list because of a worsening condition. The 1-year survival rate according to an intention-to-treat analysis and the survival after LT were 66.3% [interquartile range (IQR), 62.7%-69.7%] and 74.2% (IQR, 70.5%-77.6%), respectively. The factors that were predictive of a spontaneous recovery with ALF-related paracetamol hepatotoxicity were as follows: hepatic encephalopathy grade 0, 1, or 2 [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.99-11.6]; creatinine clearance≥60 mL/minute/1.73 m2 (OR, 4.77; 95% CI, 1.96-11.63), a bilirubin level<200 µmol/L (OR, 21.64; 95% CI, 1.76-265.7); and a factor V level>20% (OR, 5.79; 95% CI, 1.66-20.29). For ALF-related nonparacetamol hepatotoxicity, the factor that was predictive of a spontaneous recovery was a bilirubin level<200 µmol/L (OR, 10.38; 95% CI, 4.71-22.86). The sensitivity, specificity, and positive and negative predictive values for the CV criteria were 75%, 56%, 50%, and 79%, respectively, for ALF due to paracetamol and 69%, 50%, 64%, and 55%, respectively, for ALF not related to paracetamol. The performance of current criteria for SU transplantation could be improved if paracetamol-induced ALF and non-paracetamol-induced ALF were split and 2 other items were included in this model: the bilirubin level and creatinine clearance.

Long term results of liver transplantation for Wilson's disease: experience in France.

BACKGROUND & AIMS: Liver transplantation (LT) is the therapeutic option for severe complications of Wilson's disease (WD). We aimed to report on the long-term outcome of WD patients following LT. METHODS: The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5). RESULTS: Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III. CONCLUSIONS: Liver failure associated with WD is a rare indication for LT (<1%), which achieves an excellent long-term outcome, including renal function.

Pathologic response to non-surgical locoregional therapies as potential selection criteria for liver transplantation for hepatocellular carcinoma.

BACKGROUND: Preoperative locoregional treatments (PLT) are performed to avoid progression before liver transplantation for hepatocellular carcinoma (HCC). The objective of this study was to analyze the prognostic factors affecting the outcome in patients who received PLT. MATERIAL AND METHODS: A retrospective analysis of patients who underwent liver transplantation (LT) was performed. All patients who underwent PLT with confirmed pathological diagnosis of HCC were included. The rate of tumor necrosis (TN) was assessed by microscopic histological examination. RESULTS: From January 1997 to December 2010, PLT was performed in 154 patients ROC analysis individuated a TN cut-off value at 40%. Ninety-one patients (59.1%) of the patients presented TN>40%. At multivariate analysis, TN<40% (HR=1.76; p=0.04) and vascular invasion (VI) (HR=2.16; p<0.01) were associated with lower Overall Survival (OS). At multivariate analysis, TN<40% (HR=1.59; p=0.001) and VI (HR=2.51; p=0.001) were significant associated with lower Disease Free Survival (DFS). One, 3 and 5 years OS was 87.9%, 82.0% and 69.1% for patients with TN>40% and 82.5%, 64.2% and 53.2% for those with TN<40% (p=0.02). Tumour size <5 cm (p=0.02); age <55 years (p=0.02); absence of VI (p=0.02) and multiple procedures (p=0.04) were predictive factors for TN>40%. CONCLUSIONS: Response to preoperative locoregional treatment can be used as potential selection criteria for LT.

Liver transplantation for neuroendocrine tumors in Europe-results and trends in patient selection: a 213-case European liver transplant registry study.

OBJECTIVE: The purpose of this study was to assess outcomes and indications in a large cohort of patients who underwent liver transplantation (LT) for liver metastases (LM) from neuroendocrine tumors (NET) over a 27-year period. BACKGROUND: LT for NET remains controversial due to the absence of clear selection criteria and the scarcity and heterogeneity of reported cases. METHODS: This retrospective multicentric study included 213 patients who underwent LT for NET performed in 35 centers in 11 European countries between 1982 and 2009. One hundred seven patients underwent transplantation before 2000 and 106 after 2000. Mean age at the time of LT was 46 years. Half of the patients presented hormone secretion and 55% had hepatomegaly. Before LT, 83% of patients had undergone surgical treatment of the primary tumor and/or LM and 76% had received chemotherapy. The median interval between diagnosis of LM and LT was 25 months (range, 1-149 months). In addition to LT, 24 patients underwent major resection procedures and 30 patients underwent minor resection procedures. RESULTS: Three-month postoperative mortality was 10%. At 5 years after LT, overall survival (OS) was 52% and disease-free survival was 30%. At 5 years from diagnosis of LM, OS was 73%. Multivariate analysis identified 3 predictors of poor outcome, that is, major resection in addition to LT, poor tumor differentiation, and hepatomegaly. Since 2000, 5-year OS has increased to 59% in relation with fewer patients presenting poor prognostic factors. Multivariate analysis of the 106 cases treated since 2000 identified the following predictors of poor outcome: hepatomegaly, age more than 45 years, and any amount of resection concurrent with LT. CONCLUSIONS: LT is an effective treatment of unresectable LM from NET. Patient selection based on the aforementioned predictors can achieve a 5-year OS between 60% and 80%. However, use of overly restrictive criteria may deny LT to some patients who could benefit. Optimal timing for LT in patients with stable versus progressive disease remains unclear.

Treatment of recurrent HCV infection following liver transplantation: results of a multicenter, randomized, versus placebo, trial of ribavirin alone as maintenance therapy after one year of PegIFNα-2a plus ribavirin.

BACKGROUND & AIMS: We aimed at determining the effect of maintenance therapy with ribavirin alone, after a year of combined peginterferon-alfa 2a (PegIFNα-2a) and ribavirin therapy, on viral response and liver histology after liver transplantation (LT). METHODS: Hundred and one patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring), 1-5years after LT, were enrolled. PegIFNα-2a and ribavirin were initiated at 90 µg/wk and 600 mg/d, respectively, then increased or adjusted as a function of tolerance. At 12 months, combination therapy was discontinued and patients were randomized to ribavirin or placebo for a further 12 months. Growth factor use was permitted. RESULTS: At 18 months, a sustained virological response (SVR) was obtained in 47.9% of patients in Per Protocol (PP) analysis, and was higher in patients with genotype 2 or 3 than in patients with genotype 1 or 4, in patients with genotypes 1+4 receiving ciclosporine than in those receiving tacrolimus, in patients with worse renal function, in those having received EPO, in patients with lower weight, and in those with lower viral load at 3 months. Using logistic regression, only the early viral response, recipient weight and renal function were independently associated with better SVR. SVR, viral load, activity, and fibrosis scores were similar, at M18 and M30, in patients randomized to ribavirin, or to placebo. CONCLUSIONS: A PP SVR was achieved in 47.9% of patients with established recurrent hepatitis C after LT. Maintenance therapy with ribavirin alone does not improve the virological response or the histological parameters.

Liver transplantation for unresectable hepatocellular carcinoma in normal livers.

BACKGROUND & AIMS: The role of liver transplantation in the treatment of hepatocellular carcinoma in livers without fibrosis/cirrhosis (NC-HCC) is unclear. We aimed to determine selection criteria for liver transplantation in patients with NC-HCC. METHODS: Using the European Liver Transplant Registry, we identified 105 patients who underwent liver transplantation for unresectable NC-HCC. Detailed information about patient, tumor characteristics, and survival was obtained from the transplant centers. Variables associated with survival were identified using univariate and multivariate statistical analyses. RESULTS: Liver transplantation was primary treatment in 62 patients and rescue therapy for intrahepatic recurrences after liver resection in 43. Median number of tumors was 3 (range 1-7) and median tumor size 8 cm (range 0.5-30). One- and 5-year overall and tumor-free survival rates were 84% and 49% and 76% and 43%, respectively. Macrovascular invasion (HR 2.55, 95% CI 1.34 to 4.86), lymph node involvement (HR 2.60, 95% CI 1.28 to 5.28), and time interval between liver resection and transplantation < 12 months (HR 2.12, 95% CI 0.96 to 4.67) were independently associated with survival. Five-year survival in patients without macrovascular invasion or lymph node involvement was 59% (95% CI 47-70%). Tumor size was not associated with survival. CONCLUSIONS: This is the largest reported series of patients transplanted for NC-HCC. Selection of patients without macrovascular invasion or lymph node involvement, or patients ≥ 12months after previous liver resection, can result in 5-year survival rates of 59%. In contrast to HCC in cirrhosis, tumor size is not a predictor of post-transplant survival in NC-HCC.

Renal function, efficacy and safety postconversion from twice- to once-daily tacrolimus in stable liver recipients: an open-label multicenter study.

This multicenter, open-label, phase III study assessed renal function, safety, and efficacy in stable adult liver transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients received tacrolimus BID for 6weeks before conversion to tacrolimus QD (1:1 [mg:mg] total daily dose basis) for 12weeks. Primary endpoint: change in steady state creatinine clearance (CrCl) between treatment phases. Of 112 patients enrolled, 98 were converted to QD dosing (full analysis set [FAS]). Mean (SD) tacrolimus dose was 3.7 (1.7) mg/day during BID and at conversion, and 3.9 (1.8) mg/day at Week 12. 74.5% of patients required no dose adjustment on conversion (FAS). Mean tacrolimus whole blood trough levels were at the lower end of the recommended range during tacrolimus BID and QD; the difference between mean steady-state trough levels was statistically significant (7.5ng/ml vs. 6.5ng/ml; P<0.0001). Following conversion, mean tacrolimus trough levels were reduced by 15% (about 1ng/ml) without any cases of acute rejection, remained stable during the remainder of the study, and were more consistent, showing reduced between- and within-patient variability in trough levels. Renal function remained stable, demonstrating noninferiority of tacrolimus QD versus BID (relative difference in mean calculated CrCl -0.1% [±6.3%]). Patient and graft survival were 100%. Adverse events incidence was low during both treatment phases.

Efficacy and safety of Celsior preservation fluid in liver transplantation: one-year follow up of a prospective, multicenter, non-randomized study.

The purpose of this prospective, nine-center, non-randomized study was to assess the efficacy and safety of Celsior preservation fluid in liver transplantation using unselected donors. As data comparing allograft outcomes following liver transplantation using Celsior and University of Wisconsin (UW) preservation fluids are limited, we also compared our cohort with matched controls selected from the European Liver Transplant Registry (ELTR) who received total liver grafts preserved with UW solution during the same period. One hundred and forty patients who received livers preserved with Celsior were included. The primary endpoint, graft loss at one-yr post-transplantation, was observed in 24 patients (17.1%) which was not significantly different from the 20.0% pre-defined threshold rate (95% confidence interval [CI] 10.9, 23.4; p=0.398). Predictive factors for graft loss on univariate analysis were moderate-to-severe steatosis on the donor graft (5/22 patients with graft loss vs. 8/107 patients without, p=0.046) and duration of warm ischemia (1.4±1.1 h in patients with graft loss vs. 0.9±0.5 h in patients without, p=0.034). Hepatic artery thrombosis and stenosis occurred in seven (5.0%) and six (4.3%) patients, respectively. The comparison of our patients to 420 ELTR controls showed that one-yr graft survival rates (Celsior: 82.9%, 95% CI 75.8, 88.2; UW: 78.6%, 95% CI 74.4, 82.2) and Kaplan-Meier one-yr graft survival distributions (p=0.285) were similar. Within the cold ischemia time achieved in our study, liver preservation with Celsior appeared efficient and safe. Comparison with ELTR patients suggested that liver allograft survival was similar using Celsior or UW solution for preservation of unselected donor grafts.

Hepatitis C recurrence after liver transplantation: has the human leukocyte antigen mismatching at individual loci a role?

BACKGROUND AND AIM: The objective of this 11-year cohort retrospective study conducted in adult patients with chronic hepatitis C virus (HCV) who underwent liver transplantation (LT) was to identify whether human leukocyte antigen (HLA) mismatching is associated with the recurrence of HCV and with the time to recurrence of HCV. METHODS: Among the 181 patients (74% men; mean age: 54 years, range 25-71) who underwent a LT between 1995 and 2006 in the study center, 163 had relevant data in their medical chart documenting HCV recurrence, and 107 (65.64%) reported a histological evidence of HCV recurrence. RESULTS: Survival was 78% at 5 years. There was no significant relationship between the total score of HLA-mismatches and the recurrence of HCV. Similarly, there was no significant relationship between the total score of HLA mismatches and the time to recurrence of HCV. For the analyses at each individual locus, a significant relationship between the individual scores of HLA-mismatches and the recurrence of HCV were observed. Out of the 40 patients who experienced a rejection, the rate of recurrence was not different according to the severity of the rejection (75% mild, 64% moderate and 64% for severe rejection). CONCLUSIONS: In conclusion, this large study did not demonstrate any relationship between the total score of HLA mismatches and HCV-recurrence. Contrarily a significant relationship between the individual scores of HLA mismatches (HLA-A3, HLA-B35, HLA-DR3, HLA-DR7, HLA-DQ2, HLA-DQ2-0) and the recurrence of HCV were observed.

Robotic liver resection as a bridge to liver transplantation.

BACKGROUND: The surgical robotic system is superior to traditional laparoscopy in regards to 3-dimensional images and better instrumentation. Robotic surgery for hepatic resection has not yet been extensively reported. The aim of this article is to report the first known case of liver resection with the use of a robot in France. METHODS: A 61-year-old male with hepatitis C liver cirrhosis and hepatocellular carcinoma was referred for surgical treatment. Preoperative clinical evaluation and laboratory data disclosed a Child-Pugh class A5 patient. Magnetic resonance imaging showed a 3.4-cm tumor in segment III. Liver size was normal, and there were not signs of portal hypertension. Five trocars were used. RESULTS: Liver transection was achieved with Harmonic scalpel and bipolar forceps without pedicle clamping. Hemostasis of raw surface areas was accomplished with interrupted stitches. Operative time was 180 minutes. Blood loss was minimal, and the patient did not receive transfusion. The recovery was uneventful, and the patient was discharged on the fifth postoperative day without ascites formation. CONCLUSION: The robotic approach may enable liver resection in patients with cirrhosis. The da Vinci robotic system allowed for technical refinements of laparoscopic liver resection due to 3-dimensional visualization of the operative field and instruments with wrist-type end-effectors.

Biliary strictures after liver transplantation: is percutaneous treatment indicated?

BACKGROUND: Biliary complications are common after orthotopic liver transplantation. Our study's aim is to evaluate the efficacy of percutaneous treatment of biliary strictures after orthotopic liver transplantation (OLT). MATERIAL/METHODS: Sixty-five patients with biliary anastomotic strictures received percutaneous transhepatic balloon cholangioplasty (PTBC). Three dilatations were performed with a 2- to 4-week period between the procedures. Primary and secondary patency were evaluated, with a follow-up between 6 months and 6 years. RESULTS: PTBC successfully treated strictures in 52.3% (34/65) of cases. The normalization of clinical and biological features was noted at 2.3 months on average. Neither intercurrent episodes of sepsis nor a worsening of liver function were noted during the treatment; a significant complication was recorded in 8 patients. No patient needed surgery for the treatment of complications after PTBC. Factors related to a successful PTBC included older age at transplantation and single-site stricture. There were 7 recurrent strictures after PTBC, all successfully treated by nonsurgical procedures. The number of dilatations performed affected both the likelihood of success and the long-term risk of stricture recurrence. Of the 31 PTBC failures, 19 underwent subsequent surgical revision, 8 were treated endoscopically, and 4 were re-transplanted. Multifocal stenoses, central hepatic duct involvement, and intrahepatic localization resulted associated with treatment failure. CONCLUSIONS: PTBC should be considered as a first choice option for treatment of biliary strictures after liver transplantation as well as endoscopic treatment. For solitary extrahepatic strictures that fail PTBC and ERCP, surgical revision provides good results.

Impact of tumour differentiation to select patients before liver transplantation for hepatocellular carcinoma.

AIM: To generate a new score with improved accuracy compared with Milan criteria to select patients. PATIENTS: The training cohort comprised 373 patients transplanted for hepatocellular carcinoma (HCC) between 1988 and 1998 (cohort 1). An algorithm was derived from the analysis of patient data by the proportional hazard Cox regression model. The area under the receiver operating characteristic (AUROC) was used to determine a cut-off value. The validation cohort comprised 140 patients transplanted between 1999 and 2001 (cohort 2). RESULTS: Multivariate analysis identified three predictors of 5-year tumour-free survival: tumour differentiation (P=0.02), diameter (P<0.0001) and number of nodules (P=0.04). A cut-off value of 4 was derived from the AUROC of the final score. Five-year tumour-free survival was 60.2 ± 3.1% in patients with as score <4 and 36.4 ± 4.7% in individuals with a score ≥4, P<0.0001. In the validation cohort, 5-year tumour-free survival was 82.8 ± 3.6% (score <4) and 50.0 ± 10.7% (score ≥4), P=0.0003. In patients with a score <4, there was no significant difference in 5-year tumour-free survival between Milan+ and Milan- patients, either in cohort 1 or 2. Five-year tumour-free survival of Milan- patients was significantly better in individuals with a score <4 compared with those with a score ≥4, both in cohort 1 (61.5 ± 9.1 vs 31.4 ± 4.6%, P=0.009) and in cohort 2 (P=0.02). CONCLUSION: A novel score taking into account tumour differentiation shows higher accuracy than Milan criteria in predicting 5-year tumour-free survival following liver transplantation for HCC. Prospective studies should validate these findings.

Successful liver transplantation for Rendu-Weber-Osler disease, a single centre experience.

UNLABELLED: BACKROUNDS/PURPOSE: Hereditary hemorrhagic telangiectasia or Rendu-Weber-Osler is an autosomal dominant inherited disorder characterized by arteriovenous malformations and telangiectasia that may affect the nose, skin, lungs, brain and gastrointestinal tract. Liver involvement of the disease has been described to be responsible of biliary tract necrosis, high cardiac output and portal hypertension, due to intra-hepatic vascular shunts. We aimed to present four cases of successful orthotopic liver transplantations in this indication performing our modified Piggy-back technique. PATIENTS AND METHODS: Between 2002 and 2008, four patients have been diagnosed for Rendu-Weber-Osler disease and underwent liver transplantation. Three of them suffered from high cardiac output with heart failure, two presented HBV infection and one patient suffered from renal failure requiring a liver-kidney transplantation. We performed our modified Piggy-back technique for liver implantation, which consists to clamp selectively the hepatic veins during the hepatectomy, without venous bypass, the retro-hepatic vena cava is preserved. RESULTS: No hemodynamic concerns disturbed the surgery and no massive transfusions were needed. The liver replacement corrected the cardiac insufficiency due to high cardiac output for the three patients. At present, the four patients are getting well. CONCLUSIONS: Despite new advances in immunotherapy for the medical treatment of Rendu-Weber-Osler disease, liver transplantation remains the curative option for hepatic based-hereditary hemorrhagic telangiectasia.

Viral entry and escape from antibody-mediated neutralization influence hepatitis C virus reinfection in liver transplantation.

End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma.

BACKGROUND: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. METHODS/DESIGN: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. DISCUSSION: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. TRIAL REGISTER: Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).

Assessing renal function with daclizumab induction and delayed tacrolimus introduction in liver transplant recipients.

BACKGROUND: Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection. METHODS: This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months. RESULTS: The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time. CONCLUSIONS: Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.