Bernard Ellero

Long‐term survival in post‐transplant lymphoproliferative disorders with a dose‐adjusted ACVBP regimen

Post‐transplant lymphoproliferative disorders (PTLD) are severe complications after solid organ transplantation with no consensus on best treatment practice. Chemotherapy is a therapeutic option with a high response and a significant relapse rate leading to a low long‐term tolerance rate. Currently, most centres use anthracycline‐based drug combinations, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). We assessed the efficacy and safety of a dose‐adjusted ACVBP (doxorubicin reduced to 50 mg/m2, cyclophosphamide adjusted to renal function, vindesine, bleomycin, prednisone) regimen in patients failing to respond to a reduction in immunosuppressive therapy. Favourable responses were observed in 24 (73%) of the 33 treated patients. Fourteen (42%) patients died, mostly from PTLD progression. Actuarial survival was 60% at 5 years and 55% at 10 years. Survival prognostic factors were: number of involved sites (P = 0·007), clinical stage III/IV (P = 0·004), bulky tumour (P < 0·0001), B symptoms (P = 0·03), decreased serum albumin (P = 0·03) and poor performance status (P = 0·06). Both the international and the PTLD prognostic index were predictive for survival (P = 0·001 and P = 0·002, respectively). Overall 128 cycles were given. Grade 3 or 4 neutropenia was recorded after 26 (20%) chemotherapy cycles in 19 (58%) patients. Forty‐one (32%) infections were recorded in 26 (79%) patients. This study demonstrated that an individual dose‐adjustment of ACVBP regimen was manageable in PTLD patients and favourably impacted on long‐term survival.

Early Evolution of Hepatitis C Virus (HCV) Quasispecies after Liver Transplant for HCV-Related Disease

BACKGROUND End-stage liver disease as a result of chronic hepatitis C virus (HCV) infection is the main indication for liver transplant (LT), but allografts are systematically infected with HCV soon after transplant. Viral quasispecies are poorly described during the early posttransplant period. METHODS For 17 patients who received an LT for HCV disease, plasma viral quasispecies evolution was determined by sequence analysis of hypervariable region 1 of the E2 envelope gene before transplant (BT), after 7 days (D7), and after 1 month (M1). T helper (Th)1/Th2 cytokine levels were determined concomitantly. RESULTS HCV quasispecies showed a significant decrease in amino acid diversity at D7 and M1, compared with BT (P<.05). A correlation was observed between low plasma tumor necrosis factor-alpha levels at D7 and decreased quasispecies amino acid complexity at the same date. Nucleic acid diversity was lower for genotype 1 than for genotype 3 infection (P<.05). The complexity and diversity of amino acids were lower in patients with hepatocellular carcinoma (HCC) BT than in those without HCC (P<.05). Conserved amino acid residues within quasispecies were shared by the whole cohort before and after LT. CONCLUSION Viral structural and/or host immunological features could favor the emergence of fitter HCV strains after LT.

Frequent Compartmentalization of Hepatitis C Virus with Leukocyte-Related Amino Acids in the Setting of Liver Transplantation

BACKGROUND Nonrandom distribution of hepatitis C virus (HCV) quasispecies (compartmentalization between blood plasma and leukocytes) suggests the presence of HCV leukotropic variants. HCV compartmentalization in the setting of liver transplantation (LT) is poorly understood. To study HCV leukotropic variants, we investigated the evolution of HCV compartmentalization after immunosuppression in liver transplant recipients. METHODS Plasma and peripheral blood mononuclear cell (PBMC) samples were collected from 5 liver transplant recipients before and after LT. We used clone sequencing to analyze the hypervariable region 1 (HVR1)-E2(384-419) region, which plays a key role in HCV entry and the induction of neutralizing responses, and assessed compartmentalization through phylogenetic analyses and Mantels test. RESULTS Compartmentalization was frequent in the LT setting. HCV quasispecies were more homogeneous after LT in both the plasma and PBMC compartments, with a significant decrease in quasispecies complexity (P = .003) and genetic distances (P = .004) after transplantation. Our analysis identified 8 PBMC-related amino acid residues in HVR1. CONCLUSIONS HCV compartmentalization between plasma and PBMCs and the emergence of leukotropic variants could be potentiated by immunosuppression in liver transplant recipients. The identification of defined leukotropic variants may contribute to the understanding of virus-host interactions after transplantation.

Corticosteroid avoidance in adult kidney transplant recipients under rabbit anti‐T‐lymphocyte globulin, mycophenolate mofetil and delayed cyclosporine microemulsion introduction

We conducted the first prospective, randomized, open‐label multicenter study in low‐immunologic risk adult recipients of primary cadaver kidney transplants receiving rabbit anti‐T‐lymphocyte globulin, mycophenolate mofetil, cyclosporine microemulsion introduced on day 5, with and without corticosteroids. Patients were randomly assigned according to age and cold ischemia time to receive corticosteroids for at least 6 months or no corticosteroids at all. The main efficacy evaluation criterion was acute rejection (including all treated episodes and those biopsy‐confirmed) during the first year following transplantation. For this purpose, this report includes the actual results of the whole 12‐month follow‐up of all randomized patients. For efficacy analysis, 98 patients were evaluated in the Steroid avoidance group and 99 in the Steroid maintenance group. Taken as a whole, 81% of the patients (n = 159) never received anti‐rejection treatment. From the 38 patients who received anti‐rejection treatment, 25 (25.5%) were in the Steroid avoidance group and 13 (13.1%) in the Steroid maintenance group (P < 0.031), experiencing respectively 17 (17.3%) and 7 (7.1%) biopsy‐proven first episodes of acute rejection (P < 0.031). Borderline changes (6 vs. 3) were not considered as biopsy‐proven acute rejections. Onset of first rejection was significantly shorter in the Steroid avoidance group (P < 0.027). First‐line anti‐rejection treatment response, need for any rescue therapy, as well as histologic severity of rejection episodes did not statistically differ between the groups. One‐year post‐transplantation analysis showed no differences in delayed graft function, serum creatinine, creatinine clearance, 24‐h proteinuria, as well as serious adverse events between the groups. De novo diabetes (P < 0.07) or dyslipidemia (P < 0.01) as well as newly diagnosed malignancies (P < 0.059) were however more frequently observed in the Steroid maintenance group. At the end of the first post‐transplant year, 99% of patients in the Steroid avoidance group and 97% of patients in the Steroid maintenance group were respectively alive (P = 0.34), with respectively 95% and 93.2% of functioning kidney grafts (P = 0.62). Our results showed that total avoidance of corticosteroids from the day of transplantation was associated with a significantly increased number of clinically diagnosed and treated, and biopsy‐proven acute rejections during the first year of transplantation. Nevertheless, overall outcome, 1‐year patient and graft survival as well as renal function were similar, and the patients in the Steroid avoidance group exhibited a lower incidence of de novo dyslipidemia, diabetes mellitus and malignancies often associated with steroid treatment (Clinical Trials.gov NCT00200551).

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

Backrounds/purposeHereditary 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 methodsBetween 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.ResultsNo 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.ConclusionsDespite 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.

Candida albicans arteritis transmitted by preservation fluid after liver transplantation.

BACKGROUND Fungal infections remain among the main causes of mortality in the chronically immunosuppressed liver transplant (LT) patient. Bacterial and fungal contamination of preservation fluid (PF), in which grafts are stored, represents a potential source of infection for recipients. CASE REPORT A 54-year-old patient underwent LT for chronic alcoholic cirrhosis. Mycological culture of the liver PF was positive for Candida albicans. The patient received antimycotic prophylaxis for 4 weeks in absence of clinical and serological signs of infection. He was urgently readmitted 4 months later with hemobilia caused by an arterial pseudoaneurysm that was fistulized in the biliary anastomosis. After an unsuccessful embolization, arterial resection and reconstruction and a biliodigestive anastomosis were performed, with an uneventful postoperative course. Pathology found a mycotic arteritis of the graft artery. Mycotic culture of the arterial segment confirmed the presence of the same Candida albicans genotype previously isolated in the PF. CONCLUSIONS Mycotic arteritis is one of the possible complications of yeast contamination of PF. Surgeons and physicians involved in the care of LT patients should be aware of this potentially lethal complication and adopt all the available means for early detection.

Lack of endothelial dysfunction in patients under tacrolimus after orthotopic liver transplantation

Abstract:  Background:  Endothelial dysfunction is a significant cause of vascular and end‐organ damage after solid organ transplantation. The aim of this study was to compare endothelial function in healthy controls and in patients who received tacrolimus for immunosuppression after orthotopic liver transplantation (OLT).

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.

Impact of real-time metabolomics in liver transplantation: Graft evaluation and donor-recipient matching

BACKGROUND & AIMS There is an emerging need to assess the metabolic state of liver allografts especially in the novel setting of machine perfusion preservation and donor in cardiac death (DCD) grafts. High-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS-NMR) could be a useful tool in this setting as it can extemporaneously provide untargeted metabolic profiling. The purpose of this study was to evaluate the potential value of HR-MAS-NMR metabolomic analysis of back-table biopsies for the prediction of early allograft dysfunction (EAD) and donor-recipient matching. METHOD The metabolic profiles of back-table biopsies obtained by HR-MAS-NMR, were compared according to the presence of EAD using partial least squares discriminant analysis. Network analysis was used to identify metabolites which changed significantly. The profiles were compared to native livers to identify metabolites for donor-recipient matching. RESULTS The metabolic profiles were significantly different in grafts that caused EAD compared to those that did not. The constructed model can be used to predict the graft outcome with excellent accuracy. The metabolites showing the most significant differences were lactate level >8.3 mmol/g and phosphocholine content >0.646 mmol/g, which were significantly associated with graft dysfunction with an excellent accuracy (AUROClactates = 0.906; AUROCphosphocholine = 0.816). Native livers from patients with sarcopenia had low lactate and glycerophosphocholine content. In patients with sarcopenia, the risk of EAD was significantly higher when transplanting a graft with a high-risk graft metabolic score. CONCLUSION This study underlines the cost of metabolic adaptation, identifying lactate and choline-derived metabolites as predictors of poor graft function in both native livers and liver grafts. HR-MAS-NMR seems a valid technique to evaluate graft quality and the consequences of cold ischemia on the graft. It could be used to assess the efficiency of graft resuscitation on machine perfusion in future studies. LAY SUMMARY Real-time metabolomic profiles of human grafts during back-table can accurately predict graft dysfunction. High lactate and phosphocholine content are highly predictive of graft dysfunction whereas low lactate and phosphocholine content characterize patients with sarcopenia. In these patients, the cost of metabolic adaptation may explain the poor outcomes.

Cardiac diastolic dysfunction in renal-transplant recipients is associated with increased circulating Adrenomedullin

Abstract:  Background:  Renal transplantation is an excellent therapeutic alternative for end‐stage renal diseases. Nevertheless, the cardiac function is often impaired in renal‐transplant patients (RTR) and importantly determines their prognosis. Adrenomedullin (ADM), a peptide involved in cardiovascular homeostasis, is believed to protect both cardiac and renal functions – by increasing local blood flows, attenuating the progression of vascular damage and remodelling and by reducing glomerular injury – and might be involved in renal‐transplantation physiopathology. This work was performed to investigate whether an increase in circulating ADM might be related to RTR cardiac function.