GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis.

BACKGROUND: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) is a global, prospective, non-interventional study undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice, including Child-Pugh B patients who were excluded from clinical trials. METHODS: Patients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow-up visits. The second interim analysis was undertaken when ~1500 treated patients were followed up for ≥ 4 months. RESULTS: Of the 1571 patients evaluable for safety, 61% had Child-Pugh A status and 23% Child-Pugh B. The majority of patients (74%) received the approved 800 mg initial sorafenib dose, regardless of Child-Pugh status; however, median duration of therapy was shorter in Child-Pugh B patients. The majority of drug-related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug-related AEs were broadly similar across Child-Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population. CONCLUSIONS: Consistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child-Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in > 3000 patients are ongoing.

First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study.

AIMS: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON), a global, non-interventional, surveillance study, aims to evaluate the safety of sorafenib in all patients with unresectable hepatocellular carcinoma (uHCC) under real-life practice conditions, particularly Child-Pugh B patients, who were not well represented in clinical trials. METHODS: Treatment decisions are determined by each physician according to local prescribing guidelines and clinical practice. Patients with uHCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Demographic data and medical and disease history are recorded at entry. Sorafenib dosing and adverse events (AEs) are collected throughout the study. RESULTS: From January 2009 to April 2011, >3000 patients from 39 countries were enrolled. The prespecified first interim analysis was conducted when the initial approximately 500 treated patients had been followed up for ≥4 months; 479 were valid for safety evaluation. Preplanned subgroup analyses indicate differences in patient characteristics, disease aetiology and previous treatments by region. Variation in sorafenib dosing by specialty are also observed; Child-Pugh status did not appear to influence the starting dose of sorafenib. The type and incidence of AEs was consistent with findings from previous clinical studies. AE profiles were comparable between Child-Pugh subgroups. DISCUSSION: The GIDEON study is generating a large, robust database from a broad population of patients with uHCC. First interim analyses have shown global and regional differences in patient characteristics, disease aetiology and practice patterns. Subsequent planned analyses will allow further evaluation of early trends.

Review article: pharmacological treatment of the hepatorenal syndrome in cirrhotic patients.

Renal failure is common in patients who are dying from end-stage cirrhosis, developing in 40-80% of all patients. Where there is no anatomical or pathological cause for the renal failure, it is termed the hepatorenal syndrome. When the hepatorenal syndrome develops, it will only recover when there is some degree of improvement in liver function. Thus for most patients this will occur only after liver transplantation, although the transplantation mortality is increased in this group. Hepatorenal syndrome is a common complication of alcoholic hepatitis, and this group is unusual in that with time and abstinence, significant recovery of liver function may occur. There is therefore a need for supportive therapy to allow time for some recovery of liver function in patients with alcoholic hepatitis and hepatorenal syndrome. Similarly, patients may need support whilst waiting for liver transplantation. This article reviews the pathophysiology and treatment of hepatorenal syndrome.

Variceal bleeding and portal hypertensive gastropathy.

Cirrhosis can be the end stage of any chronic liver disease. At the time of diagnosis of cirrhosis varices are present in about 60% of decompensated and 30% of compensated patients. The risk factors for the first episode of variceal bleeding in cirrhotic patients are the severity of liver dysfunction, large size of varices and the presence of endoscopic red colour signs but only one-third of patients who have variceal haemorrhage have the above risk factors. Recent interest has been directed at identifying haemodynamic factors that may reflect the pathophysiological changes which lead to variceal bleeding, e.g. it has been confirmed that no bleeding occurs if HVPG falls below 12 mmHg and also a hypothesis has been put forward in which bacterial infection is considered a trigger for bleeding. Pharmacological treatment with beta-blockers is safe, effective and is the standard long-term treatment for the prevention of recurrence of variceal bleeding. Combination of beta-blockers with isosorbide-5-mononitrate needs further testing in randomized controlled trials. The use of haemodynamic targets for reduction in HVPG response needs further study, and surrogate markers of pressure response need evaluation. If endoscopic treatment is chosen, variceal ligation is the modality of choice. The combination of simultaneous variceal ligation and sclerotherapy does not offer any benefit. However, the use of additional sclerotherapy for the complete eradication of small varices after variceal ligation needs to be evaluated. The results of current prospective randomized controlled trials comparing variceal ligation with pharmacological treatment are awaited with great interest. Finally, the use of transjugular intrahepatic portosystemic shunt (TIPS) for the secondary prevention of variceal bleeding is not substantiated by current data, as survival is not improved and because of its worse cost-benefit profile compared to other treatments. In contrast, there still is a role for the selective surgical shunts in the modern management of portal hypertension. The ideal patients should be well compensated cirrhotics, who have had troublesome bleeding - either who have failed at least one other modality of therapy (drugs or ligation), have bled from gastric varices despite medical or endoscopic therapy, or live far from suitable medical services. Recently, ligation has been compared to beta-blockers for primary prophylaxis but so far there is no good evidence to recommend banding for primary prophylaxis, if beta-blockers can be given.

Management of oesophageal varices.

Beta-blockers are the treatment of choice to prevent the first episode of variceal bleeding and further rebleeding episodes. In acute bleeding all patients should receive pharmacological treatment with vasoconstrictors and endoscopic treatment. Failure of therapy should lead to consideration of transjugular intrahepatic portosystemic shunting.

[Postpartum hemorrhage by vaginal laseration: new case and improved management]. / Prise en charge de l'hémorragie de la délivrance par plaies cervicovaginales : un cas de nécrose utérine post-embolisation artérielle.

We describe a case of uterine necrosis, following Gelitaspon(®) embolization for postpartum hemorrhage resulting from vaginal laceration. Previous cases published help to improve the safety of this effective method by showing the risk factors, as particles sizes, ultraselective embolization, prevention of infection. Controlling bleeding by surgery is the priority when hemorragy is due to laceration without uterin atony. In case of failure, embolization is an option which should be proposed without delay. Uterine necrosis should be suspected in case of postembolization septic syndrome.

Elevada circulación del genotipo F del virus de la hepatitis B en población infectada urbana no migratoria y migratoria de Venezuela / High circulation of genotype F hepatitis B non-migratory and migratory urban population infected virus Venezuela

Introducción: Se ha demostrado ampliamente que el genotipo F del virus de la hepatitis B (VHB) es dominante en nuestra población Amerindia. Recientemente, nosotros identificamos que en los pacientes infectados por VHB habitantes no migratorios de áreas urbanas venezolanas prevalece también el genotipo F. Objetivo: Determinar los genotipos del VHB en portadores crónicos urbanos migratorios y compararlos con el grupo no migratorio. Material y Métodos: Se investigaron 136 portadores crónicos del VHB, 110 no inmigrantes y 26 inmigrantes de origen asiático. Se evaluaron antígeno eHB y anti-eHB y los genotipos del VHB, este último mediante PCR. Resultados: En los 110 pacientes urbanos venezolanos persistió la elevada frecuencia del genotipo F (95%) con 3 casos coinfectados, 2 por genotipos A+F y 1 caso con genotipos E+F. Interesantemente, 2 casos demostraron genotipo D del VHB. Hepatitis crónica B (HCB) antígeno-e positivo fue diagnosticada en 83 pacientes (80,6%) mientras 20 casos (19,4%) presentaron HCB antígeno-e negativo. En los pacientes asiáticos infectados con un solo genotipo se identificó el C en 11 casos, el B en 4 pacientes, el F en 3 y, en 1 caso, genotipo D. Se demostró coinfección entre estos diferentes genotipos, incluyendo un caso coinfectado con genotipo E. El genotipo F se encontró coinfectando a 4 pacientes, 2 de ellos con genotipo C. Doce casos presentaron HCB antígeno e positivo y 14 pacientes HCB antígeno e negativo. De los pacientes infectados con genotipo C, 7 de ellos (54%), incluyendo los 2 coinfectados con genotipo F, presentaron HCB antígeno-e negativo. Conclusión: Es notoria la elevada circulación del genotipo F del VHB en nuestras áreas urbanas...

Introduction: It has been widely demonstrated that the genotype F of hepatitis B virus (HBV) is dominant in our Amerindian population. Recently, we identified that genotype F is prevalent in HBV non-migratory infected patients living in urban areas. Objective: To determine the genotypes of HBV in migratory chronic carriers compared to non-migratory population. Material and Methods: We investigated 136 chronic HBV carriers, 110 non-immigrants and 26 immigrants of Asian origin. We assessed hepatitis B e-antigen and antibody and HBV genotypes, the latter using PCR. Results: High prevalence (95%) of genotype F persisted among 110 Venezuelan urban patients, with 3 co-infected patients, 2 with genotypes A+F and 1 case with E+F. Interestingly, 2 cases showed HBV genotype D. Chronic hepatitis B (CHB) e-antigen positive was diagnosed in 83 patients (80.6%) while 20 cases (19.4%) showed CHB e-antigen negative. In Asian patients infected with one sole genotype, C was identified in 11 cases, B in 4 patients, F in 3, and in 1 case, genotype D. Co-infection was demonstrated among these different genotypes, including one case co-infected with genotype E. Genotype F was found in 4 co-infected patients, 2 with genotype C. Twelve cases had CHB e-antigen positive and 14 CHB e-antigen negative. From patients infected with genotype C, 7 of them (54%), including 2 co-infected with genotype F, demonstrated CHB e-antigen negative. Conclusion: It is remarkable the high circulation of HBV genotype F in our urban areas. However, given the distinct outcome described in CHB genotype F and the identification of other genotypes rather than F in urban areas, suggests that inclusion of HBV genotypes in Venezuela, should be considered standard in the management of CHB regardless the patient’s geographical origin.

Drug treatment for bleeding oesophageal varices.

At the time of diagnosis of cirrhosis, varices are present in about 60% of decompensated and 30% of compensated patients. The risk factors for the first episode of variceal bleeding in cirrhotic patients are the severity of liver dysfunction, a large size of the varices and the presence of endoscopic red colour signs, but only a third of patients who suffer variceal haemorrhage demonstrate the above risk factors. The only treatment that does not require sophisticated equipment or the skills of a specialist, and is immediately available, is vasoactive drug therapy. Hence, drug therapy should be considered to be the initial treatment of choice and can be administered while the patient is transferred to hospital, as has been done in one recent study. Moreover, drug therapy is no longer considered to be only a 'stop-gap' therapy until definitive endoscopic therapy is performed. Several recent trials have reported an efficacy similar to that of emergency sclerotherapy in the control of variceal bleeding. Furthermore, recent evidence suggests that those patients with high variceal or portal pressure are likely to continue to bleed or re-bleed early, implying that prolonged therapy lowering the portal pressure over several days may be the optimal treatment. Pharmacological treatment with beta-blockers is safe, effective and the standard long-term treatment for the prevention of recurrence of variceal bleeding. The combination of beta-blockers with isosorbide-5-mononitrate needs further testing in randomized controlled trials. The use of haemodynamic targets for the reduction of the HVPG response needs further study, and surrogate markers of the pressure response need evaluation. Ligation has recently been compared with beta-blockers for primary prophylaxis, but there is as yet no good evidence to recommend banding for primary prophylaxis if beta-blockers can be given.

Assessment of therapeutic benefit of antiviral therapy in chronic hepatitis C: is hepatic venous pressure gradient a better end point?

Chronic hepatitis C is a major healthcare problem. The response to antiviral therapy for patients with chronic hepatitis C has previously been defined biochemically and by PCR. However, changes in the hepatic venous pressure gradient (HVPG) may be considered as an adjunctive end point for the therapeutic evaluation of antiviral therapy in chronic hepatitis C. It is a validated technique which is safe, well tolerated, well established, and reproducible. Serial HVPG measurements may be the best way to evaluate response to therapy in chronic hepatitis C.

[Neuromyelitis optica or Devic disease complicating chickenpox (author's transl)]. / Neuromyélite optique ou maladie de Devic, compliquant une varicelle.

In a 8 year-old girl, chickenpox was complicated with opticomyelitis (Devic's disease). In adults, opticomyelitis is often considered as closely related to multiple sclerosis; in children an infectious etiology must be investigated first.