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.

Multidisciplinary meetings specific to hepatocellular carcinoma: How to proceed?

The French "cancer plan" has created a framework for good practice in the course of care for cancer patients. Decisions must be made in a multidisciplinary team meeting (MDM) and an individualized care plan (ICP) is to be established for each patient. Hepatocellular carcinoma (HCC) is a common cancer with complex treatments that warrant a dedicated meeting. Cancer coordination centers (3C) ensure the organization and the functioning of MDMs. Multidisciplinary, standardized and systematic assessment of HCC patients allows for personalized management and orients them toward treatment that is either curative (transplantation, surgical resection, ablathermy) or palliative (chemoembolization, radiotherapy, systemic treatment, supportive care). MDMs bring together all the professionals treating the disease, and who are tasked with producing an enforceable document effective that justifies decisions and is often an essential step towardinclusion of patients in a clinical trial. It must be carried out according to a systematic schema in an approach applied from initial diagnosis to treatment outset and throughout the treatment. Numerous advances in HCC treatments have rendered their management complex, with the possibility of liver transplantation, twhose access is regulated by the Biomedicine Agency requiring the submission of MDM reports. MDMs must meet specific quality criteria to ensure effective management based on general guidelines and yet specifically tailored to each patient.

Liver Transplantation With Old Grafts: A Ten-Year Experience.

BACKGROUND: The persistent scarcity of donors has prompted liver transplantation teams to find solutions for increasing graft availability. We report our experience of liver transplantations performed with grafts from older donors, specifically over 70 and 80 years old. PATIENTS AND METHODS: We analyzed our prospectively maintained single-center database from January 1, 2005, to December 31, 2014, with 380 liver transplantations performed in 354 patients. Six groups were composed according to donor age: <40 (n = 84), 40 to 49 (n = 67), from 50 to 59 (n = 62), from 60 to 69 (n = 76), from 70 to 79 (n = 64), and ≥80 years (n = 27). RESULTS: Donors <40 years of age had a lower body mass index, died more often from trauma, and more often had cardiac arrest and high transaminase levels. In contrast, older donors (≥70 years of age) died more often from stroke. Recipients of grafts from donors <50 years of age were more frequently infected by hepatitis C virus; recipients of oldest grafts more often had hepatocellular carcinoma. Cold ischemia time was the shortest in donors >80 years of age. Patient survival was not significantly different between the groups. In multivariate analysis, factors predicting graft loss were transaminase peak, retransplantation and cold ischemia time but not donor age. CONCLUSIONS: Older donors >70 and >80 years of age could provide excellent liver grafts.

Serum levels of a negative regulator of cell proliferation (AcSDKP) are increased in certain human haemopathies.

One of the first known effects of the endogenous peptide N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) is to inhibit entry into DNA synthesis of pluripotent haematopoietic stem cells (CFU-S) in mice. A specific anti-AcSDKP polyclonal antibody allows the level of the tetrapeptide by to be determined by enzyme immunoassay with good sensitivity and specificity. We present results demonstrating the presence of AcSDKP in humans: serum levels of 34 healthy controls were found to be between 0.7 and 2.5 pm/ml, regardless of age and sex. High levels were found in 44% of asymptomatic controls but only in 8% of AIDS patients out of a total of 37 patients with HIV. Subsequently, studies of serum levels were performed before treatment in 121 subjects with disorders of the nonlymphoid and the lymphoid lineages. Our results did not demonstrate any decrease in serum levels, however a moderate or marked increase was noted in one-third of the subjects, which was greater in disorders of the non-lymphoid lineages (48% of 72 patients) than the lymphoid lineage (21% of 50 patients). The most significant differences were observed between controls versus patients with myeloproliferative disorders (MPD, 24 patients: p < 0.001), controls versus patients with acute myelogenous leukaemia (AML, 15 patients: p < 0.02), as well as patients with AML versus patients with primary myelodysplastic syndromes (PMDS, 10 patients: p < 0.05). The pathophysiology of these abnormalities is discussed.

[Heat stroke and fulminans hepatitis: is MARS system relevant?]. / Coup de chaleur d'exercice avec hépatite fulminante: intérêt du système MARS?

Exertional heat stroke (EHS) is a life-threatening condition caused by an extreme elevation in core body temperature. Acute liver failure has been reported during EHS justifying liver transplantation in some cases. The Molecular Adsorbent Recirculating System (MARS) could be indicated in such situations. We report a case of a 58-year old patient who suffered acute liver failure occurring after EHS. The patient was referred for liver transplantation and benefited of MARS therapy. After three sessions of MARS, liver function improved progressively and the transplantation was not necessary. The patient completely recovered.

Production and characterization of monoclonal antibodies against the leukemia inhibitory factor low affinity receptor, gp190.

Leukemia inhibitory factor (LIF), oncostatin-M (OSM), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT1) act through transmembrane receptors which share the gp190 glycoprotein chain. The understanding of its involvement in the biology of these cytokines is of importance since these systems have recently been shown to participate in major inflammatory and neoplastic processes such as myelomatosis (Rose-John, S., Heinrich, P.C., 1994. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem. J. 300, 281). In addition, this family of receptors also shares the gp130 transducing chain, with the IL6 and IL11 receptors. Because IL6 and gp130 were the first members to be discovered, most of the available reagents are directed at them. In this respect, monoclonal antibodies have played a major role in elucidating these receptor/ligand interactions and exploring the pathophysiological aspects of their biology. So far, no such reagents have been described for the gp190. We now report the production and characterization of 16 monoclonal antibodies directed against human gp190. They were obtained using recombinant chimeric or truncated proteins produced in a eukaryotic CHO cell line. One was able to block the biological activity of LIF. Because gp190 comprises two hematopoietin binding domains, crude epitope mapping was possible using the same reagents. While more of these antibodies are required, the present set validate the technological approach used for their preparation and should improve our understanding of this class of cytokines.

Outcome of liver transplantation in Wilson's disease: A demonstrative case.

A Wilson's disease (WD) patient developed a progressive liver cirrhosis and a disabling 'rubral' tremor, despite decoppering therapy, and subsequently underwent orthotopic liver transplantation (OLT). This case illustrates the outcome of OLT in WD, by demonstrating: (a) correction of the metabolic syndrome without further deposition of copper in the transplanted liver, (b) improvement of the neurological condition, (c) concomitant mobilization of copper deposits, as suggested by the fading of the Kayser-Fleischer corneal rings, (d) fading of brain MRI signal abnormalities on T2 weighted images. This case illustrates that OLT can be considered in WD, but only with caution because of the significant morbidity of the procedure.

[Autoimmune thyroid diseases and Horton disease]. / Thyréopathies autoimmunes et maladie de Horton.

In a retrospective study of 115 patients with giant cell arteritis, 5 clinically patent autoimmune diseases were recorded; including 2 patients (1.8%) with Grave's disease and 1 with hypothyroidism. Among these patients, 46 had systematic assays of blood thyroid hormones and 39 were systematically investigated for anti-thyroid antibodies (ATAb):3 (6.5%) had biological hypothyroidism and 4 (10.3%) had ATAb. These findings were not significantly different from those of a control group of 39 age and sex matched patients.

[Death in Horton disease. Prognostic factors]. / Les décès dans la maladie de Horton. Facteurs de pronostic.

The authors reported causes of death and searched for prognosis factors in Giant Cell Arteritis (GCA). The diagnosis was confirmed by temporal biopsy in all cases. Fourteen patients died during treatment; thirty-six patients had completely recovered (follow up > 6 months after withdrawal of steroid therapy). The commonest causes of death were cardiovascular (n = 7) and digestive (n = 4); they occurred after an average of 195 days of treatment, half of them during the first three months. One death was due to GCA (autopsy) and five deaths were attributed to the treatment with corticosteroids. The prognosis factors were searched for by comparing age, sex, clinical signs, laboratory data before treatment, past medical history in the both series; further more initial dose of Prednisone and the dose after 180 days of steroid therapy were compared in the two groups. The adverse prognosis factors revealed by this study were: advanced age (p < 0.01), previous ischaemic heart disease (p < 0.05) and higher dose of corticosteroids administered at 6 months of treatment (< 0.01).

[Severe acute hepatic failure and haemophagocytic syndrome: cause or consequence?]. / Insuffisance hépatique aiguë sévère et syndrome d'activation macrophagique: cause ou conséquence?

Haemophagocytic syndrome corresponds to an unconnected macrophagic activity with haemophagocytosis. We report the case of a haemophagocytic syndrome in a 49-year-old woman with initially a severe acute hepatic failure. This syndrome is probably underestimated in ICU patients. Haemophagocytic syndrome should be suspected in patients with fever and jaundice without infection.

Concurrent temporal arteritis and Churg-Strauss syndrome.

We describe the case of a 41-year-old man who presented with clinical and histopathologic evidence of temporal artery lesions associated with the Churg-Strauss syndrome. Pathological examination of the temporal artery showed panarteritis without giant cell formation or fibrinoid necrosis. We review the world literature concerning the vasculitides with features that overlap giant cell arteritis (GCA) and polyarteritis nodosa (PAN) and classify into 2 sub-groups PAN with unusual temporal artery localization and GCA with variably disseminated arterial injuries. These cases emphasize the fact that not all arteritis involving the temporal arteries is GCA. Only 3 cases with temporal artery involvement and concurrent Churg-Strauss syndrome have been published.

[Agranulocytosis caused by dapsone. Apropos of 3 cases. Review of the literature]. / Agranulocytoses à la dapsone. A propos de 3 observations--revue de la littérature.

Authors describe three cases of agranulocytosis in patients with giant cell (temporal) arterities treated with Dapsone and corticosteroids. The culture in vitro of CFU.GM. cells of two patients, four healthy subject and two patients treated with Dapsone with out granulopenia, demonstrates no any toxic effect of Dapsone. A review of the literature finds 59 cases of agranulocytosis in patients treated with Dapsone alone or in combination with other drugs. Doses of Dapsone ranged from 25 mg to 300 mg a day. Agranulocytosis occurred between the 4th and the 12th week, more often near the 8th week. Agranulocytosis occurred suddenly without previous granulocytopenia. These facts argue for immunoallergic mechanism. This Dapsone side effect requires to restrict its use and to reserve it to serious diseases or failures of other therapeutic drugs. It needs too to keep a close eye on the patients between the 6th and 12th week.

Heterozygous protein C deficiency and dysfibrinogenemia acquired by liver transplantation.

Orthotopic liver transplantation is now a successful treatment for end-stage liver diseases. Since most components of the coagulation system are synthesized by liver parenchymal cells, there is always a risk of genetic defects of hemostasis being transmitting by liver transplantation. Some coagulation factor defects, such as protein C deficiency, do not induce abnormalities in routine coagulation tests and, thus, go undetected before organ procurement. We report the first case, to our knowledge, of the transmission of heterozygous protein C deficiency, an autosomal recessive genetic defect, associated with dysfibrinogenemia, an autosomal dominant trait, by liver transplantation. Both the recipient and the donor presented with severe thrombotic complications. This case shows that potentially morbid genetic defects can be transmitted by organ transplantation, and it emphasizes the difficulty associated with organ procurement criteria, particularly for liver transplantation, in which routine blood tests appear insufficient for determining whether or not organs can or should be procured from a given donor.

Progression from idiopathic portal hypertension to incomplete septal cirrhosis with liver failure requiring liver transplantation.

We report the case of a 30-year-old male patient suffering from what was initially thought to be end-stage cryptogenic cirrhosis with portal hypertension and liver failure, who underwent liver transplantation. Histological examination of the surgical specimen showed incomplete septal cirrhosis. At the age of 17 this patient had presented pancytopenia and splenomegaly, which were treated by splenectomy. The surgeon discovered portal hypertension. Re-examination of the wedge liver biopsy taken at this time revealed features of idiopathic portal hypertension. This case clearly shows that incomplete septal cirrhosis may be a late manifestation of idiopathic portal hypertension. The presence of sinusoidal dilatation and peliosis as well as early evidence of fibrosis which are already visible on the initial biopsy and are still present on the late specimen, are indirect evidence of a continuous process which ultimately led to incomplete cirrhosis with liver failure.

Recurrence and accelerated progression of hepatitis C following liver transplantation.

The patient described had recurrent hepatitis C following OLT. This hepatitis appeared early postOLT and progressed to fibrosing cholestatic hepatitis, a severe form of HCV recurrence. Factors such as genotype 1, high viral load and severe damage on the first postOLT biopsy may indicate a more severe outcome. We have hypothesized that, in parallel to what is known for hepatitis B, this rare form of recurrence was linked to a high expression of virus C proteins in the liver graft. Severe form of hepatitis C recurrence should be treated early with the best currently available treatment which is a combination of IFN and ribavirin. Large series of patients with comparable virological, histological and immunological inclusions criteria are necessary to evaluate the efficacy of this treatment.