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.

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.

[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.

[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.

T-lymphocyte populations in hepatitis C and HIV co-infected patients treated with interferon-alfa-2a and ribavirin.

OBJECTIVE: The effects on T-lymphocyte populations of two interferon-alfa-2a (IFN) regimens associated with ribavirin were evaluated in 36 HCV-HIV co-infected patients with chronic hepatitis C, T-CD4 cell count > 250 cells/ micro L and a plasma viral load of < 10 000 HIV RNA copies/mL. METHODS: Patients were given IFN for 48 weeks. Group A (18 patients) received 6 mega units (MU) subcutaneously three times a week for 24 weeks, then 3 MU three times a week for the last 24 weeks. Group B (18 patients) received 9 MU daily for 2 weeks, 3 MU daily for 22 weeks, then 3 MU three times a week for the last 24 weeks. Serum HCV RNA was evaluated at weeks 12 and 72. Ribavirin was added at week 16 for virologic nonresponders at week 12. CD3, CD3 CD4, CD3 CD8, CD3 CD4 human leucocyte antigen (HLA)-DR and CD3 CD8 HLA-DR lymphocyte subsets were evaluated before, during and after treatment by cytofluorometry. Controls were healthy and HCV mono-infected patients. RESULTS: CD3 CD4 and CD3 CD8 T-cells counts were both impaired during anti-HCV therapy, but returned to baseline value after treatment completion. Lymphopenia concerned mainly CD8 T-cells, the percentage of which decreased, whereas that of CD4 increased. Three patients displayed reversible CD4 lymphopenia < 200 cells/ micro L. HIV infection at inclusion was responsible for higher CD3 CD8 HLA-DR T-cell percentages in co-infected patients than in healthy and HCV mono-infected subjects. T-cell sequestration in lymphoid tissues and enhanced apoptosis may account for lymphopenia. CONCLUSION: High-dosed IFN anti-HCV therapy induced only moderate and transient CD4 lymphopenia in HIV co-infected patients.

HLA-DR expression on lymphocyte subsets as a marker of disease activity in patients with systemic lupus erythematosus.

A major problem in the management of SLE patients is to predict a flare or to distinguish between active and quiescent disease. Serological markers are widely used to assess disease activity, but many patients have close to or normal values for these parameters while exhibiting obvious disease-related signs and symptoms. This study aimed to determine which serological parameters, among ESR, ANA and anti-dsDNA antibody titres, CH50 and the HLA-DR expression on circulating T-lymphocyte subsets, best reflected the development of SLE flares. Sixty SLE patients were included, 34 with quiescent disease throughout the entire follow-up period and 26 who experienced an SLE flare defined as having active disease. According to univariate analysis, all parameters were significantly higher for patients with active disease, with the percentage of CD8+DR+ cells being the most significant parameter (P = 10-7). Multivariate logistic regression analysis identified three independent variables enabling the identification of a lupus flare: CH50, the CD8+DR+ and CD4+DR+ cell percentages among total lymphocytes. The CD8+DR+ cell percentage is the biological parameter most significantly associated with a flare (P < 0.001), even more powerful than CH50 (P < 0.01). HLA-DR expression on CD8+ lymphocytes clearly coincided with disease evolution in seven patients enrolled as having quiescent disease, but who experienced one flare during follow-up that subsequently resolved. The percentage of circulating CD8+DR+ lymphocytes appears to be a biological marker which accurately reflects disease activity. A larger prospective study is needed to demonstrate the real efficacy of this marker in predicting an exacerbation in SLE patients.

Low rejection rates with tacrolimus-based dual and triple regimens following liver transplantation.

We studied the outcome of 345 liver transplant patients who received tacrolimus-based immunosuppressive therapy either as a dual regimen (with corticosteroids, n=172) or as a triple regimen (with corticosteroids and azathioprine, n=173) for 3 months after transplantation (3-month cohort). A further analysis was conducted for the first 195 patients randomised (dual n=100, triple n=95) who were followed up for 12 months after transplantation (12-month cohort). For the 3-month cohort, patient survival was 90.7% (dual) and 91.9% (triple), graft survival after 3 months was 88.4% (dual therapy) and 89.6% (triple therapy). Acute rejections were experienced by 67/172, 39.0% of patients on dual therapy and by 60/173, 34.7% of patients on triple therapy; corticosteroid-resistant rejections were reported in 9 patients (5.2%) in either treatment group. The overall safety profile was similar for the two treatment groups. Significant differences, however, were found for thrombocytopenia (dual 13/172, 7.6%, triple 37/173, 21.4%, p<0.001) and leukopenia (dual 4/172, 2.3%, triple 24/173, 13.9%, p<0.001). For the 12-month cohort, patient survival was 85.6% (dual) and 88.4% (triple) after 1 year. Graft survival was 81.7% (dual) and 85.2% (triple) 12 months after transplantation. Acute rejections were reported for 38/100, 38.0% of patients on dual therapy and 36/95, 37.9% of patients on triple therapy, corticosteroid-resistant rejections were 7/100, 7.0% (dual) and 7/95, 7.4% (triple) of patients. In the 12-month cohort, no significant differences in the safety profiles of the treatment groups were found. We conclude that both tacrolimus-based dual and triple drug regimens provide effective and safe immunosuppression following orthotopic liver transplantation.

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.

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.

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.

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.

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.

[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.