Good outcome of liver transplantation in patients with pre-existing renal cell carcinoma.

The presence of a pre-existing or recent extra-hepatic solid tumor was considered for a long time as an absolute contraindication to liver transplantation, by fear of futility with an unacceptable increase in non-liver-related mortality. However, cancer-related mortality in solid malignancies is heterogeneous, and experts suggest that case-by-case multidisciplinary decisions should be made. Here, we report the cases of 3 patients with favorable oncological and liver outcome in patients with renal cell carcinoma detected during pre-transplant evaluation that nonetheless underwent liver transplantation.

Original Study: Transjugular Intrahepatic Portosystemic Shunt as a Bridge to Abdominal Surgery in Cirrhotic Patients.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) has been suggested to reduce portal hypertension-associated complications in cirrhotic patients undergoing abdominal surgery. The aim of this study was to compare postoperative outcome in cirrhotic patients with and without specific preoperative TIPS placement, following elective extrahepatic abdominal surgery. METHODS: Patients were retrospectively included from 2005 to 2016 in four centers. Patients who underwent preoperative TIPS (n = 66) were compared to cirrhotic control patients without TIPS (n = 68). Postoperative outcome was analyzed using propensity score with inverse probability of treatment weighting analysis. RESULTS: Overall, colorectal surgery accounted for 54% of all surgical procedure. TIPS patients had a higher initial Child-Pugh score (6[5-12] vs. 6[5-9], p = 0.043) and received more beta-blockers (65% vs. 22%, p < 0.001). In TIPS group, 56 (85%) patients managed to undergo planned surgery. Preoperative TIPS was associated with less postoperative ascites (hazard ratio = 0.330 [0.140-0.780]). Severe postoperative complications (Clavien-Dindo > 2) and 90-day mortality were similar between TIPS and no-TIPS groups (18% vs. 23%, p = 0.392, and 7.5% vs. 7.8%, p = 0.644, respectively). CONCLUSIONS: Preoperative TIPS placement yielded an 85% operability rate with satisfying postoperative outcomes. No significant differences were found between TIPS and no-TIPS groups in terms of severe postoperative complications and mortality, although TIPS patients probably had worse initial portal hypertension.

A practical approach to tuberculosis diagnosis and treatment in liver transplant recipients in a low-prevalence area.

Solid organ transplant candidates/recipients are at risk of mycobacterial infections. Although guidelines on the management of latent tuberculosis infection and active tuberculosis are available for solid organ transplant recipients, limited guidance focuses on end-stage liver disease or liver transplant recipients who require management in a referral center. Therapeutic challenges arise from direct antituberculosis drug-related hepatotoxicity, and substantial metabolic interactions between immunosuppressive and antituberculosis drugs. Another issue is the optimal timing of therapy with regards to the time of transplantation. This review focuses on the importance of tuberculosis screening with immunological tests, challenges in the diagnosis, management, and treatment of latent tuberculosis infection and active tuberculosis, as well as risk assessment for active tuberculosis in the critical peri-liver transplantation period. We detail therapeutic adjustments required for the management of antituberculosis drugs in latent tuberculosis infection and active tuberculosis, particularly when concomitantly using rifampicin and immunosuppressive drugs.

Safety of sofosbuvir-based regimens after liver transplantation: longitudinal assessment of renal function in the prospective ANRS CO23 CUPILT study.

BACKGROUND: In liver transplant recipients with hepatitis C virus recurrence, there is concern about renal safety of sofosbuvir-based regimens. Changes in serum creatinine or in the estimated glomerular filtration rate (eGFR) under treatment are used to look for possible renal toxicity. However, serum creatinine and eGFR are highly variable. AIM: To analyse renal function trajectory with numerous assays of serum creatinine over a long period of time. METHODS: In a multicentre cohort of 139 patients, the eGFR was obtained from serum creatinine using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Slopes of eGFR were defined as a change in eGFR during a period divided by time. Pre-treatment, on-treatment and post-treatment periods were 9 months, 3-9 months and 4.5 months. Interactions between eGFR slopes and the pre-treatment eGFR, use of ribavirin or mycophenolate mofetil, and stage of fibrosis were addressed. On-treatment eGFR slopes were separated in tertiles. Pre- and post-treatment eGFR slopes were compared globally and according to tertiles. RESULTS: The post-treatment eGFR slope was significantly better than pre-treatment eGFR slope (+0.18 (IQR -0.76 to +1.32) vs -0.11 (IQR -1.01 to +0.73) mL/min/1.73 m2 /month, P = 0.03) independently of the pre-treatment eGFR (P = 0.99), ribavirin administration (P = 0.26), mycophenolate mofetil administration (P = 0.51) and stage of fibrosis (F3 and F4 vs lower stages, P = 0.18; F4 vs lower stages, P = 0.08; F4 Child-Pugh B and C vs lower stages, P = 0.38). Tertiles of on-treatment eGFR slopes were -1.71 (IQR -2.54 to -1.48), -0.78 (IQR -1.03 to -0.36) and +0.75 (IQR +0.28 to +1.47) mL/min/1.73 m2 /month. Pre- and post-treatment eGFR slopes were not significantly different according to tertiles (respectively, P = 0.34, 0.08, 0.73). CONCLUSION: The eGFR varies during treatment and gives a confusing picture of the renal safety of sofosbuvir-based regimens. In contrast, longitudinal assessment of the eGFR shows a rising trajectory over longer time, meaning that these therapies are safe for the kidneys in our cohort of liver transplant recipients.

Sleep, training load and performance in elite female gymnasts.

Training load (TL) and recovery should be in optimal balance to obtain maximal performance gains. We aimed to study sleep as a recovery technique and its relationship with TL and performance in elite athletes. Twenty-six elite female artistic gymnasts were divided into an under 13 (n = 6), an under 14 (n = 6), a junior (n = 7; 14-15y) and a senior (=World Championship (WC) competitors, n = 7; ≥16y) category. Sleep, through sleep logs, and training parameters, using the session Rate of Perceived Exertion (sRPE) scale, were monitored to calculate total sleep time (TST), sleep efficiency (SE), TL, monotony and strain. Performance of WC competitors was evaluated through coach and WC qualification ranking. For the entire group, TST (effect sizes (ES) = -1.12, confidence intervals (CI) = -60:-47, P < .05) and SE (ES = -0.13, CI = -1.40:-0.10, P = .022) were shorter during week than weekend nights. TST and SE were highest in youngest gymnasts (P < .05). TL was lowest in under 13 and senior gymnasts (P < .05), while TL, monotony and strain were highest in junior gymnasts (P < .05). A negative regression was found between TST and TL the day after, while higher TL also led to lower TST the following night (P < .001). For the WC competitors, TST the night before the qualifications was shorter than the mean TST of the WC period (ES = -0.95, CI = -170:24, P = .030). TST correlated with coach ranking (r = -0.857, P = .014). Higher TL correlated with worse WC (r = 0.829, P = .042) and coach (r = 0.893, P = .007) ranking. This research in elite gymnasts indicated associations between decreased TST, augmented TL and inferior performance. Optimizing sleep and TL may therefore represent strategies to enhance performance.

Te-based chalcogenide materials for selector applications.

The implementation of dense, one-selector one-resistor (1S1R), resistive switching memory arrays, can be achieved with an appropriate selector for correct information storage and retrieval. Ovonic threshold switches (OTS) based on chalcogenide materials are a strong candidate, but their low thermal stability is one of the key factors that prevents rapid adoption by emerging resistive switching memory technologies. A previously developed map for phase change materials is expanded and improved for OTS materials. Selected materials from different areas of the map, belonging to binary Ge-Te and Si-Te systems, are explored. Several routes, including Si doping and reduction of Te amount, are used to increase the crystallization temperature. Selector devices, with areas as small as 55 × 55 nm2, were electrically assessed. Sub-threshold conduction models, based on Poole-Frenkel conduction mechanism, are applied to fresh samples in order to extract as-processed material parameters, such as trap height and density of defects, tailoring of which could be an important element for designing a suitable OTS material. Finally, a glass transition temperature estimation model is applied to Te-based materials in order to predict materials that might have the required thermal stability. A lower average number of p-electrons is correlated with a good thermal stability.

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

Progressive multifocal leukoencephalopathy after liver transplantation can have favorable or unfavorable outcome.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus (JCPyV) in immunocompromised patients, including solid organ transplant recipients. We report 2 cases of PML late after liver transplantation (144 and 204 months) and review the few other published cases. The clinical course of PML is characterized by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. No direct antiviral therapy is available against the JCPyV. The prognosis is therefore extremely poor. Restoration of the immune response achieved by tapering or ending the immunosuppressive therapy is the basis of treatment in transplanted patients. One of our patients is alive 3 years after diagnosis after total withdrawal of immunosuppressive therapy. The other presented severe rejection when tapering immunosuppression and died 26 months after diagnosis.

Shear wave elastography: An accurate technique to stage liver fibrosis in chronic liver diseases.

OBJECTIVES: The goals of this study were to assess the diagnostic accuracy of shear wave elastography (SWE) using the results of histopathological analysis as a standard of reference and compare the results of SWE and those of transient elastography (TE) to the degree of fibrosis as evaluated by histomorphometry. PATIENTS AND METHODS: Adult patients who were scheduled to undergo liver biopsy were prospectively enrolled in the study. The diagnostic performances of SWE were assessed using AUROC curve analysis according to fibrosis thresholds defined by ≥F2 (significant fibrosis), ≥F3 (advanced fibrosis) and F4 (cirrhosis). Additional analyses using the Obuchowski measures for pairwise comparisons of fibrosis stages were performed. In a subgroup of 55 patients, the relationships between stiffness as measured using SWE and TE and the percentage of fibrosis were compared using Spearman's rank coefficient. RESULTS: Among the initially enrolled 170 patients, 148/170 (87%) had successful SWE acquisition and formed the study population. SWE sensitivity and specificity were respectively 85.1% and 82.7% (≥F2), 88.9% and 90.3% (≥F3), 93.3% and 98.3% (F4). The AUROC curves of SWE along with their 95% confidence intervals (CI) were respectively 0.904 (95%CI: 0.845-0.946) for fibrosis ≥F2; 0.958 (95%CI: 0.912-0.984) for fibrosis ≥F3 and 0.988 (95%CI: 0.955-0.999) for fibrosis=F4. The global Obuchowski measure was 0.953±0.007. In the subgroup study, a significant correlation was found between the percentage of fibrosis and stiffness as assessed by SWE (r=0.77; 95%CI: 0.63-0.86; P<0.0001) and by TE (r=0.65; 95%CI: 0.47-0.78; P<0.01). CONCLUSION: SWE is accurate to assess liver fibrosis in patients with chronic liver disease.

Paediatric liver transplanted patients and prevalence of hepatitis E virus.

BACKGROUND: Hepatitis E is an emerging disease in developed countries and is usually asymptomatic, particularly in children. Chronic infection is possible in immunocompromised individuals. In the context of a liver transplant, it can simulate a rejection. In this case, antiviral therapy may be considered, thus highlighting the need to diagnose hepatitis E virus (HEV) infection in this population. OBJECTIVES: Given the lack of data in France, we have studied the the prevalence of antibodies to HEV in the paediatric liver transplant population. STUDY DESIGN: This was a retrospective study, carried out in Lyon between 1st January 2010 and 31 May 2013. HEV serology (anti-HEV IgM &IgG) and HEV PCR were studied in 96 children who had undergone liver transplants (84 isolated liver and 12 combined liver and kidney transplants). RESULTS: Eight patients (8.3%; 62.5% girls; mean age:12.3 years) were HEV seropositive. The mean period since their transplantation was 10 years (range:2-21.8 years). Biliary atresia was the principal indication for transplantation. Seven of these eight children had received liver transplants. There were no differences between the epidemiological and clinical data concerning these patients and the remainder of the study population, particularly with respect to immunosuppression(7/8 tacrolimus; 50% dual immunosuppression). No cases of chronic hepatitis E were found, but 1/8 had chronic cytolysis(EBV&adenovirus infection). In all the patients tested(4/8), seroconversion had occurred after the transplant. There was no significant differences between the age groups in this study. CONCLUSIONS: This study showed that in France, the prevalence of antibodies to HEV in paediatric liver and combined liver and kidney transplant patients is 8.3%, as has been found by other European authors.

Landscape and climatic characteristics associated with human alveolar echinococcosis in France, 1982 to 2007.

Human alveolar echinococcosis (AE) is a severe hepatic disease caused by Echinococcus multilocularis. In France, the definitive and intermediate hosts of E. multilocularis (foxes and rodents, respectively) have a broader geographical distribution than that of human AE. In this two-part study, we describe the link between AE incidence in France between 1982 and 2007 and climatic and landscape characteristics. National-level analysis demonstrated a dramatic increase in AE risk in areas with very cold winters and high annual rainfall levels. Notably, 52% (207/401) of cases resided in French communes (smallest French administrative level) with a mountain climate. The mountain climate communes displayed a 133-fold (95% CI: 95-191) increase in AE risk compared with communes in which the majority of the population resides. A case-control study performed in the most affected areas confirmed the link between AE risk and climatic factors. This arm of the study also revealed that populations residing in forest or pasture areas were at high risk of developing AE. We therefore hypothesised that snow-covered ground may facilitate predators to track their prey, thus increasing E. multilocularis biomass in foxes. Such climatic and landscape conditions could lead to an increased risk of developing AE among humans residing in nearby areas.

[Hepatic involvement in hereditary alpha-1-antitrypsin deficiency]. / Atteinte hépatique du déficit héréditaire en alpha-1-antitrypsine.

Apha-1-antitrypsin deficiency is an autosomal recessive genetic disorder seen in all races. The molecular defect is a specific mutation of the SERPINA1 gene leading to synthesis of an abnormal protein (alpha-1-antitrypsin Z) that cannot be secreted and polymerizes in the endoplasmic reticulum of hepatocytes. The inter-individual variability in the responses to intracellular stress induced by the accumulation of abnormal polymers and the mechanisms allowing their degradation is, without doubt, responsible for the different clinical manifestations of the disease. The disease affects the liver where the abnormal protein is synthesized and the lung, which is its place of action. Liver involvement is well recognized in homozygous infants of the phenotype ZZ. In this situation the disease may present a varying picture from neonatal cholestasis (about 15% of neonatal defects) to cirrhosis. However, evolution towards cirrhosis affects less than 3% of infants with the ZZ phenotype and it is preceded in 80% of cases by neonatal cholestasis. In adolescents or adults the manifestations associated with alpha-1-antitrypsin deficiency are usually limited to biochemical abnormalities but may lead to cirrhosis or hepatocellular carcinoma. The hepatic disorder and its complications are treated symptomatically though the pulmonary involvement may benefit from substitution treatment. More specific treatments targeting the molecular and cellular abnormalities are the subject of research.

Regression of new-onset diabetes mellitus after conversion from tacrolimus to cyclosporine in liver transplant patients: results of a pilot study.

INTRODUCTION: New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. AIM: To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM. METHOD: In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. RESULTS: At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001). CONCLUSIONS: These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.

Transcatheter local thrombolysis in patients with extensive TIPS thrombosis.

BACKGROUND: Transcatheter local thrombolytic therapy in patients with portosplanchnic venous thrombosis has been used in few cases. CASE REPORTS: Here, we present our single-center experience with transcatheter thrombolytic therapy in three patients with extensive refractory portal and transjugular intrahepatic portosystemic shunt (TIPS) thrombosis. Thrombolytic therapy was successful for all three patients. Two patients developed minor procedure-related bleeding. CONCLUSION: Local thrombolysis could be proposed in case of TIPS thrombosis for patients in whom the venous flow cannot be restored by using conventional anticoagulant therapy and stent mechanical revision.

Introduction of mycophenolate mofetil in maintenance liver transplant recipients: what can we expect? Results of a 10-year experience.

BACKGROUND: Mycophenolate mofetil (MMF) is a cornerstone immunosuppressive drug after liver transplantation (OLT). The aim of this study was to evaluate the long term results of the addition of MMF in maintenance OLT recipients. METHODS: From 1996 to 2006, MMF was introduced because of (1) histologic features of rejection or (2) calcineurin inhibitor (CNI) toxicity in order to reduce CNI dosage. RESULTS: The study population included 208 patients (median, age 54 ± 9 years), with a median delay between OLT and MMF introduction of 54 ± 43 months. The median dosage of MMF was 1180 mg/d at the end of follow-up. After a median follow-up of 50 ± 26 months, 26.4% of the patients taking MMF did present ≥1 side effect and MMF discontinuation rate was 13.8% (transient in 3.8%). The main side effects were digestive disorders (45%), pruritus ± rash ± mucitis (12.7%), and myelosuppression (16.4%). MMF was withdrawn because of digestive disorders (17.2%), pruritus ± rash ± mucitis (17.2%), and myelosuppression (24.1%). The mean glomerular filtration rate as calculated by the Cockcroft-Gault formula value significantly increased after the introduction of MMF (58.1 vs 71.4 mL/min; paired t-test; P < .01). Improvement of renal function was significantly associated with initial association with tacrolimus (vs cyclosporine), initial trough level of cyclosporine (not tacrolimus), delay between OLT and MMF introduction, and age of renal impairment. CONCLUSION: Our results suggest that the introduction of MMF in OLT maintenance recipients is efficient and well-tolerated (one quarter of the patients presented significant side effects, leading to treatment discontinuation in 10% of the patients).

Liver transplantation for multiple angiomyolipomas complicating tuberous sclerosis complex.

Tuberous sclerosis complex is a genetic multisystem disorder characterised by widespread hamartomas in several organs, including the brain, heart, skin, eyes, kidney, lung, and liver. Hepatic multiple, bilateral angiomyolipomas are a rare and usually asymptomatic complication in patients with tuberous sclerosis. We report here the case of a patient who needed liver transplantation because of debilitating manifestations and mechanical complications of massive liver involvement by multiple angiomyolipomas (severe malnutrition, anorexia and abdominal pain). Seventeen tumors, from 2 to 16 cm in diameter, were identified at examination of the liver explant. No feature suggestive of malignant behaviour was identified at histological examination. In conclusion, this unusual indication of liver transplantation underlines the interest of this therapeutic approach for benign tumors for which the multiplicity of the lesions and their huge volume prevent any attempt at surgical resection.

Extra-anatomical hepatic artery reconstruction following post-embolization iatrogenic dissection and arterial anastomotic rupture in two liver transplant recipients.

When hepatic artery reconstruction is required during hepatic transplantation, this is generally performed with donor vessels. We describe two cases requiring a prosthesis. The first case was a 58-year-old man transplanted for cirrhosis complicated by hepatocellular carcinoma. During transplantation, dissection of the celiac trunk occurred due to arterial embolization and the use of the patient's vessels was impossible. An extra-anatomical bypass between the infra-renal aorta and the donor hepatic artery was performed via the interposition of a graft tube. The second case was a 52-year-old man transplanted for cirrhosis complicated by hepatocellular carcinoma. On day 16, a ruptured anastomosis was suspected and the patient underwent emergency revision laparotomy. Arterial revascularisation was performed with an aortohepatic bypass using a synthetic GoreTex((R)) graft. Patient follow-up was uneventful.

[Antitumoral effect of proliferation signal inhibitors]. / Effet antitumoral des inhibiteurs du signal de prolifération.

The mammalian target of rapamycin (mTOR) is implicated in cell growth especially during cancer development and progression. Its action is dependent on well known oncogenic pathways that regulate tumor cell growth and cell cycle progression, in response to different stimuli. Sirolimus, temsirolimus and everolimus are specific inhibitors of mTOR that have originally been characterized by their antifungal and immunosuppressive properties, but also significantly inhibit cancer cells'proliferation, invasion, and metastasis, and promote apoptosis. In addition, mTOR inhibitors display potent antiangiogenic properties by the suppression of vascular endothelial growth factor signal transduction. The antitumoral effects of mTOR inhibitors, as a monotherapy or in combination with tyrosine kinase inhibitors or usual cytotoxic agents, have been extensively suggested in preclinical studies, including animal models. In a clinical setting, preliminary reports have demonstrated that mTOR inhibitors use is associated with an acceptable safety profile. Currently, mTOR inhibitors are tested in multiple trials and various cancer types, usually in intermittent schedules to avoid significant immunosuppression. Of particular interest is the use of mTOR inhibitors in the field of organ transplantation, including liver transplantation, in preventive or curative strategies, for the treatment of recurrent hepatocellular carcinoma and de novo post-transplantation malignancies.