Claire Vanlemmens

Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.

BACKGROUND & AIMS The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). METHODS Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. RESULTS α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P < .001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. CONCLUSIONS Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.

Risk Factors for New-Onset Diabetes Mellitus Following Liver Transplantation and Impact of Hepatitis C Infection : An Observational Multicenter Study

New‐onset diabetes mellitus (NODM) remains a common complication of liver transplantation (LT). We studied incidence and risk factors in 211 French patients who had undergone a primary LT between 6 and 24 months previously. This is a cross‐sectional and retrospective multicenter study. Data were collected on consecutive patients at a single routine post‐LT consultation. Demographic details, immunosuppressive regimens, familial and personal histories, hepatitis status, and cardiovascular risk were analyzed to compare those who developed NODM (American Diabetes Association/World Health Organization criteria) with the others. The overall incidence of NODM was 22.7%: 24% in tacrolimus (Tac)‐treated patients (n = 175; 82.9%) and 16.7% in cyclosporine‐treated patients (n = 36; 17.1%). A total of 81% of the cases were diagnosed within 3 months of LT (M3). Among hepatitis C virus (HCV)‐infected (HCV(+)) patients, NODM incidence was 41.7% whereas among those patients negative for this virus (HCV(−)), the incidence was only 18.9% (P = 0.008). In Tac‐treated patients, the incidence of NODM in the HCV(+) patients was significantly higher than in the HCV(−) patients (46.7% and 19.3%, respectively, P = 0.0014). Only 1 of 6 (16.7%) of the HCV(+) patients developed NODM on cyclosporine. Other independent pretransplantation risk factors for NODM included impaired fasting glucose (IFG) and a maximum lifetime body‐mass index (BMI) over 25 kg/m2. In conclusion, emergence of NODM after LT is related to risk factors that can be detected prior to the graft, like maximum lifetime BMI, IFG, and HCV status. Tac induced a significantly higher incidence of NODM in the HCV(+) compared to the HCV(−) patients. The treatment should therefore be tailored to the patients risk especially in case of HCV infection. Liver Transpl 13:136–144, 2007.

Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation

The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI‐related renal dysfunction was defined by an increase in serum creatinine with values >140 μmol/L and <300 μmol/L. Patients were randomized in 2 groups. Study group: combination of MMF (2 to 3 g/day) and reduced dose of CNI ≥50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty‐six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 ± 24.2 μmol/L at day 0 to 143.4 ± 19 μmol/L at month 12 and a significant increase in creatinine clearance, from 42.6 ± 10.9 mL/min to 51.7 ± 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 ± 23.4 μmol/L at day 0 to 181.6 ± 63 μmol/L at month 12, and in creatinine clearance, from 42.8 ± 12.8 mL/min to 44.8 ± 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects. Liver Transpl 12:1755–1760, 2006.

Immediate Listing for Liver Transplantation Versus Standard Care for Child–Pugh Stage B Alcoholic Cirrhosis: A Randomized Trial

BACKGROUND Liver transplantation improves survival of patients with end-stage (Child-Pugh stage C) alcoholic cirrhosis, but its benefit for patients with stage B disease is uncertain. OBJECTIVE To compare the outcomes of patients with Child-Pugh stage B alcoholic cirrhosis who are immediately listed for liver transplantation with those of patients assigned to standard treatment with delay of transplantation until progression to stage C disease. DESIGN Randomized, controlled trial. SETTING 13 liver transplantation programs in France. PATIENTS 120 patients with Child-Pugh stage B alcoholic cirrhosis and no viral hepatitis, cancer, or contraindication to transplantation. INTERVENTIONS Patients were randomly assigned to immediate listing for liver transplantation (60 patients) or standard care (60 patients). MEASUREMENTS Overall and cancer-free survival over 5 years. RESULTS Sixty-eight percent of patients assigned to immediate listing for liver transplantation and 25% of those assigned to standard care received a liver transplant. All-cause death and cirrhosis-related death did not statistically differ between the 2 groups: 5-year survival was 58% (95% CI, 43% to 70%) for those assigned to immediate listing versus 69% (CI, 54% to 80%) for those assigned to standard care. In multivariate analysis, independent predictors of long-term survival were absence of ongoing alcohol consumption (hazard ratio, 7.604 [CI, 2.395 to 24.154]), recovery from Child-Pugh stage C (hazard ratio, 7.633 [CI, 2.392 to 24.390]), and baseline Child-Pugh score less than 8 (hazard ratio, 2.664 [CI, 1.052 to 6.746]). Immediate listing for transplantation was associated with an increased risk for extrahepatic cancer: The 5-year cancer-free survival rate was 63% (CI, 43% to 77%) for patients who were immediately listed and 94% (CI, 81% to 98%) for those who received standard care. LIMITATION Restriction of the study sample to alcoholic patients may limit the generalizability of results to other settings. CONCLUSION Immediate listing for liver transplantation did not show a survival benefit compared with standard care for Child-Pugh stage B alcoholic cirrhosis. In addition, immediate listing for transplantation increased the risk for extrahepatic cancer. FUNDING The French National Program for Clinical Research.

Predictive factors of alcohol relapse after orthotopic liver transplantation for alcoholic liver disease

OBJECTIVES The objective of this prospective study was to determine whether sociological and/or alcohol-related behavioral factors could be predictive of relapse after orthotopic liver transplantation for alcoholic liver disease. METHODS Fifty-five liver-transplanted patients out of a series of 120 alcoholic cirrhotic patients were enrolled in a randomized prospective study. This study was initially designed to compare the 2 year survival in intent-to-transplant patients versus in-intent-to-use conventional treatment patients. For all patients, an identical questionnaire was completed at inclusion, and every 3 months for 5 years to collect data on alcohol-related behavior factors. RESULTS Fifty-one patients fulfilled the criteria for the study. The mean follow-up was 35.7 months (range: 1-86). Rate of alcohol relapse was 11% at one year and 30% at 2 years. Alcohol intake above 140 g a week was declared by 11% and 22% of patients at one and 2 years, respectively. The only variable leading to a significantly lower rate of relapse was abstinence for 6 months or more before liver transplantation (23% vs 79%, P=0.0003). This variable was also significant for patients whose alcohol intake was greater than 140 g per week (P=0.003) (adjusted relative risk=5.5; 95%CI=1.3-24.5; P=0.02). Multivariate analysis (Cox model) showed that abstinence for 6 months or more before liver transplantation was the unique predictive variable. CONCLUSION In this prospective study of 51 patients transplanted for alcoholic liver disease, abstinence before liver transplantation was the only predictive factor of alcohol relapse after liver transplantation.

Steroid withdrawal at day 14 after liver transplantation: A double‐blind, placebo‐controlled study

Some clinical studies in liver transplantation have recently reported safety advantages and similar acute rejection rates with early steroid withdrawal. The aim of this study was to evaluate the efficacy and safety of an immunosuppressive regimen with steroid withdrawal at day 14. A multicenter, 1‐year, comparative, double blind, placebo‐controlled study was performed. Patients undergoing a first cadaveric liver transplantation were recruited and all received basiliximab + cyclosporine + intravenous methylprednisolone. Patients without severe postoperative complications were randomized at day 7 to receive a maintenance regimen with Neoral (cyclosporine) + prednisolone (group 1) or without steroids (Neoral + placebo; group 2), after a 7‐day blinded oral steroid tapering period. A total of 174 patients were randomized at day 7 (group 1: n = 90; group 2: n = 84). The incidence of biopsy‐confirmed and treated acute rejection at 6 months was 38.1% in group 2 vs. 24.4% in group 1 (P = .03) with a trend for a higher incidence of Grade II / III acute rejection (28.6% vs. 18.9%; P = .12). Changes from baseline were similar with regard to metabolic parameters (glycemia, total cholesterol, and triglycerides). A trend toward a better glucose tolerance was observed, as fewer patients received an antidiabetic treatment in the placebo group (2 vs. 10). In conclusion, this first double‐blind, placebo‐controlled study of steroid withdrawal at day 14 showed a higher incidence of acute rejection, only balanced by a trend of a lower need of antidiabetic treatment. (Liver Transpl 2004;10:1454–1460.)

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 Wilsons 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.

Assessment of adrenal function in cirrhotic patients using concentration of serum-free and salivary cortisol

Objective: Because over 90% of serum cortisol is bound to albumin and corticosteroid‐binding globulin (CBG), changes in these proteins can affect measures of serum total cortisol levels in cirrhotics without altering serum‐free and salivary cortisol concentrations.

Comparison of two techniques of transarterial chemoembolization before liver transplantation for hepatocellular carcinoma : A case-control study

Supraselective transarterial chemoembolization (STACE) more efficiently targets chemotherapy delivered via the feeding arterial branches of the tumor than does conventional transarterial chemoembolization (TACE). However, the hypothesis of its greater efficacy compared with the latter is subject to controversy. The aim of the present study was to compare STACE to conventional TACE in a controlled study of candidates for liver transplantation (LT) for hepatocellular carcinoma (HCC). Patients were matched for factors associated with HCC recurrence and survival. Sixty patients were included: 30 who were treated with STACE and 30 treated with conventional TACE. The 2 groups were similar in terms of matched criteria. In the overall population (uni‐ and multinodular HCC), there was no marked difference between the 2 groups in 5‐year disease‐free survival: 76.8% vs. 74.8%. In sensitivity analysis of patients considered to be the best candidates for TACE (uninodular HCC ≤5 cm), there was a trend toward significance between STACE and TACE in 5‐year disease‐free survival: 87% vs. 64% (P = 0.09). The only factor associated with complete tumor necrosis was STACE in the overall population (30.8% vs. 6.9%, P = 0.02), with a similar trend in the subgroup of patients with a single nodule (33.3% vs. 6.7%, P = 0.06), whereas the mean number of procedures was similar in the 2 groups (mean, 1.3 procedures; range 1‐5 procedures; P = NS). STACE is more efficient at inducing complete tumor necrosis in the liver. This study observed trends toward improvement in the disease‐free survival of patients with uninodular HCC ≤5 cm. Future studies focusing on such patients are warranted. Liver Transpl, 2007.

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 &mgr;mol/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 &mgr;mmol/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&mgr;mol/L or >100 &mgr;mol/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 &mgr;mol/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.