FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial.

BACKGROUND: Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS: In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS: A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS: FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER: NCT00268398.

Long-term hepatitis E viral load kinetics in an immunocompromised patient treated with ribavirin.

Hepatitis E virus (HEV) can cause chronic infections in immunocompromised hosts. Viral kinetics in plasma and stools are poorly understood, particularly during antiviral treatment. Prolonged faecal shedding may be a concern for transmission. We describe HEV kinetics in an immunocompromised patient with prolonged faecal shedding despite undetectable viraemia on ribavirin treatment.

[Alcoholic steatohepatitis: what's new in 2012?]. / Stéatohépatite alcoolique: nouveautés 2012.

Alcoholic liver disease is a spectrum of lesions, of which the most severe is alcoholic steatohepatitis (ASH). Recent European guidelines define alcoholic hepatitis as a clinical syndrome: the recent onset of jaundice and/or ascites in a patient with ongoing alcohol misuse. Next to infection, the most frequent aetiology is ASH, a histological diagnosis. In case of severe ASH, as defined by prognostic scores, a biopsy is needed to confirm the diagnosis. Non-severe forms of ASH may improve with interruption of alcohol abuse only; however survival of severe forms of ASH is improved by the association of corticosteroids and N-acetylcysteine. In case of uncontrolled infection, pentoxifylline may be administered. The Lille score, measured at the 7th day of corticosteroid therapy, measures response to therapy and guides the total duration of treatment.

[Coagulation and cirrhosis: new insight]. / Coagulation et cirrhose: un nouveau regard.

The liver plays a key role in coagulation as all clotting factors except for factor VIII are synthetized by hepatocytes. In cirrhotic patients, there is a decrease of clotting factors and a thrombocytopenia. Those parameters usually modify routine coagulation tests and may suggest that cirrhotic patients are at a higher risk of bleeding. However, studies have shown that these patients are rather at risk for thrombosis. The reason is a concomitant decrease of coagulation inhibitors factors that is not detected in routine laboratory coagulation tests. The coagulation system in cirrhotic patient is a balance of pro and anti-coagulants. This balance may be affected by co-factors such as renal failure or infection. Artificial correction of laboratory values by transfusion of blood products may be rather deleterious (e.g. volume overload, TRALI).

A Case of Drug-Induced Hepatitis due to Lenalidomide.

Lenalidomide is a recent thalidomide analog used for the treatment of refractory multiple myeloma. The main toxicity of this drug consists in severe neutropenia and thrombocytopenia. Lenalidomide-associated liver injury is rare, manifesting itself as elevated liver enzymes and hyperbilirubinemia reversible upon weeks after drug withdrawal. We report here in detail the clinical course as well as the biological and histological alterations of an acute lenalidomide-induced liver injury. Findings on liver biopsy allowed us to discriminate acute inflammatory changes due to the drug and minor associated lesions of graft-versus-host disease in this patient with recurrent myeloma after allogeneic bone marrow transplantation.

[Portal hypertension and HIV infection]. / Hypertension portate et infection par le VIH.

In the era of antiretroviral therapies, the outcome of patients with chronic HIV infection has considerably changed and their prolonged survival allows the development of chronic liver diseases as a major cause of mortality. Although viral hepatitis, alcoholic and non alcoholic steatohepatitis account forthe majority of chronic liver damage in these patients, there is a growing number of cases with unexplained liver disease, many of which are associated with clinical manifestations of portal hypertension. Inthissituation, nodularregenerative hyperplasia is a frequent finding, characterized at histology by the presence of a nodular architecture in the absence of significant fibrosis, resulting from progressive obliteration of small portal veins. This article describes the clinical presentation, diagnostic aspects, pathogenic mechanisms, as well as the management of this emergent non cirrhotic liver disease in HIV-infected patients.

Tezosentan normalizes hepatomesenteric perfusion in a porcine model of cardiac tamponade.

BACKGROUND: To investigate endothelin-1 (ET-1)-dependent hepatic and mesenteric vasoconstriction, and oxygen and lactate fluxes in an acute, fixed low cardiac output (CO) state. METHODS: Sixteen anesthetized, mechanically ventilated pigs were studied. Cardiac tamponade was established to reduce portal venous blood flow (Q(PV)) to 2/3 of the baseline value. CO, hepatic artery blood flow (Q(HA)), Q(PV), hepatic laser-Doppler flow (LDF), hepatic venous and portal pressure, and hepatic and mesenteric oxygen and lactate fluxes were measured. Hepatic arterial (R(HA)), portal (R(HP)) and mesenteric (R(mes)) vascular resistances were calculated. The combined ET(A)-ET(B) receptor antagonist tezosentan (RO 61-0612) or normal saline vehicle was infused in the low CO state. Measurements were made at baseline, after 30, 60, 90 min of tamponade, and 30, 60, 90 min following the infusion of tesozentan at 1 mg/kg/h. RESULTS: Tamponade decreased CO, Q(PV), Q(HA), LDF, hepatic and mesenteric oxygen delivery, while hepatic and mesenteric oxygen extraction and lactate release increased. R(HA), R(HP) and R(mes) all increased. Ninety minutes after tesozentan, Q(PV), LDF and hepatic and mesenteric oxygen delivery and extraction increased approaching baseline values, but no effect was seen on CO or Q(HA). Hepatic and mesenteric handling of lactate converted to extraction. R(HA), R(HP) and R(mes) returned to baseline values. No changes were observed in these variables among control animals not receiving tesozentan. CONCLUSION: In a porcine model of acute splanchnic hypoperfusion, unselective ET-1 blockade restored hepatomesenteric perfusion and reversed lactate metabolism. These observations might be relevant when considering liver protection in low CO states.

[Acetaminophen: hepatotoxicity at therapeutic doses and risk factors]. / Paracétamol: toxicité hépatique aux doses thérapeutiques et populations à risque.

Although used widely and recognized as a safe drug at therapeutic dose, acetaminophen has a narrow therapeutic margin. Its hepatotoxic potential differs for each individual and depends essentially on associated risk factors which could lead to a severe hepatotoxicity even at therapeutic doses. A systematic screening of these risk factors is essential for an accurate risk stratification and selection of the most adapted treatment strategy. In this article, we review the principal risk factors and propose an approach to aminotranferase elevation in patients using acetaminophen.

[Cholestasis in adults. 1. Diagnostic procedure approach]. / Cholestase de l'adulte. 1. Démarche diagnostique.

Cholestasis results abnormal biliary excretion, from the hepatocyte to the ampulla of Vater. Diagnosis of the cause of cholestasis is guided by liver ultrasonography, which can be done at the bedside. Management is then dictated by the level of obstruction. In intrahepatic cholestasis (without bile duct dilatation at ultrasonography), the workup will include blood tests for liver disease and liver biopsy will be discussed case by case. In extrahepatic cholestasis (with bile duct dilatation at ultrasonography), a multidisciplinary approach will involve the radiologist, the surgeon, as well as the endoscopist, and delineate the role of magnetic resonance cholangiopancreatography (MRCP), endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP).

[Cholestasis in adults. 2. Clinical signs and symptomatic treatment]. / Cholestase de l'adulte. 2. Signes cliniques et traitement symptomatique.

Cholestasis, a frequent occurrence in clinical practice, can be suspected when confronted to clinical signs (pruritus and jaundice) and/or increased blood level of alkaline phosphatases, gammaglutamyl transpeptidase and/or conjugated bilirubin. This short review will deal with the management of clinical manifestations and extrahepatic complications, whatever the cause of cholestasis. The management according to etiology will be dealt with in a separated chapter.

[Clinical management of a patient with alcoholic cirrhosis]. / Le suivi clinique d'un patient atteint de cirrhose alcoolique.

Prolonged abstinence from alcohol is crucial in the management and prognosis of a patient with alcoholic cirrhosis. It is also important to prevent complications such as variceal bleeding, hepatocellular and extrahepatic cancers, and malnutrition. Liver transplantation should be considered in patients with persistent liver failure in spite of complete cessation of alcohol consumption. We provide some recommendations in commonly encountered clinical situations for compensated and decompensated alcoholic cirrhosis.

[Therapy of chronic hepatitis B]. / Le point sur le traitement antiviral de l'hépatite B chronique.

The aim of chronic hepatitis B therapy is to suppress hepatitis B virus replication, to control disease activity and progression towards cirrhosis. The first-line drug is the pegylated interferon a, which suppresses HBV replication in 40% of cases, albeit burdened with several contraindications and side effects. Lamivudine, a nucleoside analog inhibiting HBV reverse transcriptase, is indicated in case of failure or contraindication to interferon, may however lead to the selection of resistant mutant HBV strains (20% yearly). In that case, adefovir is indicated and has a lower risk of selection of resistant strains (5% yearly). More effective drugs (telbivudine and entecavir) will soon be available in Switzerland. Two inhibitors of HIV (tenofovir and emtricitabine) may also be used to treat hepatitis B in selected cases. Drug combinations, although supported by theoretical considerations, bring no known clinical benefit and are not reimbursed.