Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC. METHODS: The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (n = 323) were randomly assigned to sorafenib-pravastatin combination (n = 162) or sorafenib alone (n = 161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life. RESULTS: After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35 months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7 months vs. 10.5 months; hazard ratio = 1.00; p = 0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported. CONCLUSION: Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC. LAY SUMMARY: Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555.

Hepatocellular carcinoma is diagnosed at a later stage in alcoholic patients: Results of a prospective, nationwide study.

BACKGROUND: Recent data suggest that alcohol-related hepatocellular carcinoma (HCC) is diagnosed at a later stage. The aim of this study was to compare HCC characteristics and outcomes in an alcohol-related group (group A) and a non-alcohol-related group (group NA). METHODS: A total of 1207 patients with newly diagnosed HCC were prospectively included between May 2008 and October 2009. Patients with multiple causes (alcohol plus another cause) were excluded. Patients were followed every year for 5 years. Recorded variables, including etiologies were tested as prognostic factors of survival in a multivariate Cox model after adjustments for a lead-time bias. RESULTS: In all, 894 patients were analyzed: 582 (65.1%) were in group A, and 312 (34.9%) were in group NA. Alcohol-related HCC was more likely to be diffuse and detected in patients with a worse performance status and worse liver function. After adjustments for a lead-time bias, the median overall survival (OS) was 9.7 and 5.7 months in groups NA and A, respectively (P = .0002), and 5.8 and 5.0 months in alcohol-abstinent and alcohol non-abstinent groups, respectively (P = .09). The prognostic role of alcohol disappeared when survival was assessed at each Barcelona Clinic Liver Cancer (BCLC) stage. Patients with HCC detected during a cirrhosis follow-up program (n = 199 [22.3% of the whole cohort]) had increased lead time-adjusted median OS in comparison with patients with HCC diagnosed incidentally (11.7 vs 5.4 months; P < .0001). CONCLUSIONS: In comparison with patients with non-alcohol-related HCC, patients with alcohol-related HCC have reduced OS, mainly because of worse liver function and tumor characteristics at diagnosis, as attested by similar survival within each BCLC stage. Cancer 2018;124:1964-72. © 2018 American Cancer Society.

Correlations between event-related potentials and NK cells, B and T lymphocytes.

BACKGROUND: The links between psychiatry and immune dysfunctions are well known. By contrast, there are few studies that evaluate the link between neuroelectrophysiology and immune system disturbances. SUBJECTS AND METHODS: We retrospectively included 31 patients hospitalized between 2011 and 2012. They completed a sociodemographic questionnaire and were assessed using DSM IV TR on Axis 1. Event-related potentials were performed. Lymphocyte subtypes were quantified using flow cytometry. RESULTS: In terms of P300 latency, there are correlations with the absolute value of leukocytes: for P3a component, we find a correlation in frontal derivation Fz (r=0.405*), in central derivation Cz (r=0.438*), in parietal derivation Pz (r=0.403*) and for P3b component, there is a correlation in Fz (r=0.414*), in Cz (r=0.402*) and in Pz (r=0.425*). In terms of P300 amplitude, for P3b component, there are correlations with CD3 lymphocytes percentage in all derivations (Fz (r=-0.621**); Cz (r=-0.567**); Pz (r=-0.499**)) and with CD19 lymphocytes percentage in all derivations (Fz (r=0.469*); Cz (r=0.466*); Pz (r=0.430*)). For P3a, it is correlated with CD3 percentage (in Fz (r=-0.539**); Cz (r=-0.406*)) and with CD19 percentage (Fz (r=0.364*); Pz (r=0.357*)). With respect to the relationship between mismatch negativity (MMN) amplitude and natural killer (NK) cells percentage, there are correlations in left temporal derivation T3 (r=-0.426*), in Cz (r=-0.401*) and in right temporal derivation T4 (r=-0.427*). A correlation is found between the contingent negative variation (CNV) amplitude and the lymphocytes percentage in Fz (r=-0.471**). CONCLUSIONS: There is a link between lymphocyte-related immunity and electrophysiological disturbances in psychiatric patients. Further studies would be needed to evaluate this relationship more specifically, particularly prospectively and by pathology.

Albumin Use in Patients With Cirrhosis in France: Results of the "ALBU-LIVE" Survey: A Case for Better EASL Guidelines Diffusion and/or Revision.

INTRODUCTION: The use of human albumin for the management of cirrhosis has increased. Recommendations have been published for therapeutic paracentesis (TP), spontaneous bacterial peritonitis (SBP), and type 1 hepatorenal syndrome (HRS). The goal of this survey was to assess the prescription practices of French hepatogastroenterologists. METHODS: All hepatogastroenterologists were contacted. The questionnaire evaluated (1) the use of albumin in validated indications and (2) the prescription of albumin for nonvalidated clinical situations. RESULTS: Responses were analyzed from 451 (50.1%) practitioners. The mean age was 40 years (range, 24 to 67 y). Physicians practiced in a university hospital (47.7%) or a general hospital (45.8%). There were 56.7% senior practitioners. Overall 99.6% of the practitioners compensated for TP. Albumin was used by 87.8% of the physicians, with a fixed dose being used by 84.6%. For SBP, 94% of the physicians used albumin concomitantly with antibiotics. The recommended protocol was followed by 56.2% of the practitioners: more often by senior university hospital practitioners than by senior general hospital practitioners (P=0.015). About 66.5% used albumin infusion for the diagnosis of HRS: used more often by senior university hospital practitioners (P=0.0006). Albumin was used concomitantly with vasopressor treatment by 84%; the dose and the duration varied considerably. About 23.5% used albumin for severe bacterial infection, 47.9% for severe hyponatremia, 43.9% for severe hypoalbuminemia, and 65.9% for hydrothorax. CONCLUSIONS: In this large French survey, albumin is only prescribed in accordance with recommendations for TP. The schedule for SBP is followed by only 56% of the practitioners. The use of albumin for HRS is not adapted to recommendations, which are not well known, suggesting that they should be more diffused.

Validation of the Sarcoidosis Diagnostic Score in a Multicontinental Study.

Rationale: The Sarcoidosis Diagnostic Score (SDS) has been established to quantitate the clinical features consistent with sarcoidosis in a monocentric study. Objectives: We aimed to confirm the diagnostic value of SDS in a large, multicontinental study and to assess the utility of SDS in differentiating sarcoidosis from alternative diagnoses, including infectious and noninfectious granulomatous diseases. Methods: We included patients with biopsy-confirmed sarcoidosis at nine centers across the world. Patients without sarcoidosis seen at the same sites served as control patients. Using a modified World Association of Sarcoidosis and Other Granulomatous Disorders organ assessment instrument, we scored all patients for the presence of granuloma on biopsy, highly probable symptoms, and least probable symptoms for each area. Two sarcoidosis scores were generated: SDS Biopsy (with biopsy) and SDS Clinical (without biopsy). SDS Clinical and Biopsy were calculated for all patients. We calculated and compared the area under the curve (AUC) for SDS Clinical and Biopsy according to different diagnosis scenarios. Results: A total of 1,041 patients with sarcoidosis and 1,035 without sarcoidosis were included. The results for SDS Clinical (AUC, 0.888; 95% confidence interval [CI], 0.874-0.902) and SDS Biopsy (AUC, 0.979; 95% CI, 0.973-0.985) according to AUC were good to excellent for differentiating sarcoidosis from alternative diagnosis. SDS Clinical was less discriminatory in males (P = 0.01) and in high tuberculosis prevalence centers (P < 0.001). However, SDS Clinical (AUC, 0.684; 95% CI, 0.602-0.766) and SDS Biopsy (AUC, 0.754; 95% CI, 0.673-0.835) were not sufficiently discriminative for noninfectious granulomatous diseases, but both SDSs could differentiate sarcoidosis from infectious granulomatous diseases. Algorithms were proposed for the SDS Clinical and SDS Biopsy to assist the clinician in the diagnostic process, and cutoff values were proposed for the SDS Clinical and SDS Biopsy, allowing the diagnosis of sarcoidosis to be safely confirmed or rejected in most cases except for noninfectious granulomatous disease. Conclusions: This multicontinental study confirms that both SDS Clinical and SDS Biopsy have good to excellent performance in discriminating sarcoidosis from alternative diagnoses. Differences in the AUC were seen for high tuberculosis prevalence versus low tuberculosis prevalence centers and for males versus females. Both SDSs had good discriminatory function for infectious granulomatous disease but failed in cases of noninfectious granulomatous disease such as berylliosis.

A survey of patterns of practice and perception of NAFLD in a large sample of practicing gastroenterologists in France.

BACKGROUND & AIMS: Most studies on non-alcoholic fatty liver disease (NAFLD) originate from tertiary care centers with an academic interest. How this emerging entity is accepted and managed by a wider body of gastroenterologists is unknown, despite significant implications for the diagnosis of at-risk subjects and the utilization of healthcare resources. METHODS: We conducted a survey among 352 French, board-certified gastroenterologists from a large variety of practices to understand the clinical burden, perceived severity, and management patterns of NAFLD. RESULTS: Half of participants saw >30 new cases (equal to HCV) of NAFLD and 40% >5 new cases of NASH-cirrhosis yearly. Only 20% of patients were referred by endocrinologists; conversely, gastroenterologists overwhelmingly referred NAFLD patients for assessment of metabolic co-morbidities. In patients with metabolic risk factors, a majority of physicians considered the diagnosis of NAFLD, even if other liver diseases co-existed. The diagnosis heavily relies on aminotransferases, hence patients with normal ALT are usually not diagnosed. Liver biopsy is performed for fibrosis staging but not for the diagnosis/grading of steatohepatitis, and mainly decided based on non-invasive fibrosis procedures. Pharmacological treatment is used despite a lack of clear evidence of efficacy. Physicians monitor patients themselves, usually twice a year. CONCLUSIONS: NAFLD is recognized and accepted as a disease in itself with potentially severe outcomes. Most at-risk patients are currently missed because of non-referral by endocrinologists and no exploration of those with normal aminotransferases. The medical need for the diagnosis and treatment of NAFLD is real in the community of gastroenterologists at large.

Severe liver failure rather than cirrhosis is associated with mortality in patients with infectious endocarditis: a retrospective case-control study.

BACKGROUND: Data on infectious endocarditis (IE) in patients with liver cirrhosis (LC) are sparse. We aimed to describe the characteristics and predictors of mortality from IE in patients with LC. PATIENTS AND METHODS: Overall, 101 patients with LC and 101 controls with IE matched for sex, age, date of IE, and diabetes were retrospectively selected in 23 liver units between 2000 and 2013. RESULTS: Mean age was 60.8±10.5 and 60.6±11.5 years in LC and controls, respectively. Causes of cirrhosis (Child-Pugh A/B/C: 10.4%/41.7%/47.9%, MELD score: 17±7.8) were excess alcohol intake (79.6%), viral hepatitis (17.3%), and metabolic syndrome (14.3%). Previous history of cardiopathy was found in 24.8% of LC (prosthetic valve 8.9%) and 37.6% of controls (P=0.07). The most frequent bacteria involved were gram-positive cocci. LC had significantly fewer aminoglycosides (P=0.0007), rifamycin (P=0.03), and valve surgery (P=0.02) than controls. The proportion of patients who died following cardiac surgery was similar between the two groups (9.7% for LC vs. 8.7% for controls, P=1). In-hospital mortality for Child-Pugh C patients was significantly higher than controls (61.4 vs. 23%, P<0.001), but not for Child-Pugh A (33.3%) or B patients (25.0%). A Child-Pugh score of above C10 was the best predictor of in-hospital mortality. In LC, Child-Pugh score (odds ratio=1.5; 95% confidence interval: 1.2-2.0; P=0.002) and history of decompensation (odds ratio=3.1; 95% confidence interval: 1.1-9.0; P=0.003) were independent predictive factors for in-hospital mortality. CONCLUSION: Severe liver failure but not cirrhosis is the strongest predictive factor of mortality related to IE in LC. Use of aminosides and rifamycin should be reassessed in LC, and cardiac surgery should be considered for selected patients.

[Chronic hepatitis C: management of side effects of treatment]. / Hépatite chronique C: gestion des effets indésirables du traitement.

The treatment of chronic hepatitis C, now well codified with the association of a pegylated interferon alpha and ribavirine, allows to obtain a prolonged virological response in more than half of the cases. The results are even better and reach about 70% of success when the treatment is optimized. In spite of these therapeutic advances, a substantial percentage are non responders or relapsers, mainly because of adverse effects of the treatment which lead to dose reductions or premature discontinuation. The main side effects involved in treatment modification are fatigue, muscular and articular pains, disturbance the humor, insomnia, depression, anaemia and leucopenia. These adverse effects can modify the quality of life of the patients considerably. Thus it is important to take care of them quickly after their appearance or even to try to anticipate them. It is also essential to provide a well adapted therapeutic education to get an optimal compliance to the treatment and thereby a better chance of success.

Hepatogastroenterologists' knowledge of inactive carriers and immunotolerant hepatitis B virus patients in France: results of a practice survey.

BACKGROUND: Before the 2012 revision of the EASL guidelines for the management of hepatitis B virus infection, we conducted a survey to determine how French nonacademic hepatogastroenterologists defined inactive hepatitis B virus carriers and immunotolerant patients. METHODS: We asked 680 hepatogastroenterologists to complete a simple survey consisting of 11 multiple-choice questions. RESULTS: The participation rate was 32%. HBeAg positivity was not identified as a key criterion for the diagnosis of immunotolerance by 61.9% of the respondents. A total of 82.5 and 75.9% of the respondents identified repeatedly normal alanine transaminase levels and repeatedly low viremia (<2000 IU/ml), respectively, as relevant criteria for the HBsAg inactive carrier state. The question on the biological monitoring of inactive carriers and immunotolerant patients was answered by 78% of the respondents, 97% of whom considered determinations of α-fetoprotein concentration and viremia every 6 (n=58, 35%) or 12 months (n=105, 63%) to be useful. Overall, 19% of the respondents declared never having treated an immunotolerant patient; 81% reported that they had treated such patients under some circumstances: 73% before immunosuppression or chemotherapy, 54% treated pregnant women in their third trimester when viremia was greater than 7 log IU/ml, 49% treated health professionals to prevent contamination, and 31% before medically assisted procreation. CONCLUSION: The definition of 'inactive carrier state' seems to have been well assimilated, but immunotolerance remains poorly understood. Biological monitoring was frequently carried out for inactive carriers and immunotolerant patients, but the diversity of the responses obtained highlights the lack of clear recommendations for the follow-up of these populations.

Renal dysfunction associated with telaprevir-containing triple therapy for chronic hepatitis C: is early prediction possible?

INTRODUCTION: Renal dysfunction has recently been described as a potential complication of tritherapy with telaprevir (TVR) in patients with chronic hepatitis C. This study aimed to identify predictive factors for and consequences of TVR-associated renal dysfunction. PATIENTS AND METHODS: A retrospective-prospective study was carried out in 96 patients with chronic hepatitis C, genotype 1, treated with TVR-based tritherapy in 2012-2013, in whom regular serum creatinine measurements were performed during the first 12 weeks of treatment. The patients received standard doses of peginterferon, ribavirin and TVR (2250 mg/day). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula. RESULTS: eGFR decreased significantly from baseline at weeks 4, 8 and 12, the mean maximum decrease being 22.0±23.6 ml/min, with a significant correlation between baseline and minimum eGFR (r=0.58, P<10), stronger between week 2 and minimum eGFR in the subgroup of 62 patients in whom creatinine measurement was performed at week 2. Thirteen patients had an eGFR below 60 ml/min during treatment. Age and baseline eGFR were independent predictors of eGFR below 60 ml/min in the entire population, and only week 2 eGFR when available. The decrease in haemoglobin was significantly correlated with the decrease in eGFR. Age, baseline haemoglobin and the maximum variation in eGFR were independent predictors for minimum haemoglobin. The patients with decreased eGFR had more severe anaemia, and received more blood transfusions and erythropoietin. Renal dysfunction regressed in all patients after stopping TVR. CONCLUSION: The reversible decrease in eGFR in patients receiving TVR-containing tritherapy can be predicted early, possibly allowing measures aimed at preventing anaemia.

Epidemiology and adherence to guidelines on the management of bleeding peptic ulcer: a prospective multicenter observational study in 1140 patients.

BACKGROUND AND OBJECTIVE: Mortality of upper gastrointestinal bleeding seems declining. Whether practice guidelines for the management of peptic ulcer bleeding are followed is unknown. We aimed to update epidemiology of peptic ulcer bleeding and to assess the adherence to guidelines in the French community. METHODS: Between March, 2005 and February, 2006, a prospective multicenter study was conducted including all patients with communautary upper gastrointestinal bleeding. Data from patients with peptic ulcer bleeding were extracted and analyzed. RESULTS: Out of 3203 analyzable patients included, 1140 (35.6%) had a peptic ulcer bleeding and 965 of them a duodenal and/or gastric ulcer. Seven hundred and thirty-five were male (64.5%) and mean age was 66.4 years (±18.8). Overall, 699 patients (61.3%) were taking medication inducing upper gastrointestinal bleeding. Two-hundred and sixty-eight (23.5%) patients had endoscopic therapy, 190 (70.9%) of whom had epinephrine injection alone. Among the 349 patients with high risk stigmata on endoscopy (Forrest IA, IB, IIA), 209 (59.9%) underwent endoscopic therapy. One thousand one hundred and seven patients (97.1%) were given proton-pump inhibitors. One hundred and thirty-four patients (11.8%) experienced haemorrhagic recurrence. Forty-eight patients (4.2%) underwent surgery and 61 (5.4%) died. CONCLUSIONS: Consistently with previous studies, mortality of upper gastrointestinal bleeding seems declining. Further progress lies above all in prevention but also probably in better adherence to therapeutic guidelines and management of comorbidities.

Treatment of chronic hepatitis C with pegylated interferon and ribavirin in treatment-naive patients in 'true life': a plea in favor of independent postmarketing evaluations.

BACKGROUND: Results of treatments for chronic hepatitis C virus are only estimated and disclosed from pivotal trials. AIM: To report the 'true life' results of pegylated interferon and ribavirin in treatment-naive patients. METHODS: A prospective, multicenter observatory in 22 general hospitals. RESULTS: Five-hundred and one patients were included, with 309 men (62%), aged 46 ± 11 years, weighting 70 ± 13 kg, infected with the following hepatitis C virus genotypes: 1 (50%), 2 (12%), 3 (28%), 4 (7.5%), 5 (0.6%). Liver biopsy, available in 436 patients showed stage F3 fibrosis in 24% and F4 in 13%. Two-hundred and seven patients had a comorbid condition. Treatment consisted of interferon alpha 2b in 340 patients and interferon alpha 2a in 161 patients. Dose reductions were necessary in 145 patients (29%). Treatment was prematurely interrupted in 145 patients (29%) owing to lack of efficacy (n =72) or side-effects (n =73). Sustained virological response (SVR) rates were 50% for all patients, and 37.1, 70.5, and 71% for patients with genotype 1, 2 and 3, respectively. At multivariate analysis, age, genotype, and fibrosis severity were the only independent factors of SVR. CONCLUSION: In true life, patients are older and more severe, and SVR is about 10% lower than in pivotal trials.

Acute cholestatic hepatitis revealing Mycoplasma pneumoniae infection without lung involvement in an adult patient.

Liver involvement is an unusual manifestation of Mycoplasma pneumoniae infection. Cases of cholestatic hepatitis without pulmonary involvement have been described in children with M. pneumoniae infection but only two cases of cytolytic hepatitis have been reported in adults. We report here the case of an 18-year-old woman who presented with febrile epigastric pain of short duration associated with an elevation of gamma-glutamyl transpeptidase and alkaline phosphatase levels and with a mononuclear syndrome. Serological tests for M. pneumoniae were positive for IgG and IgM. Clinical symptoms and blood test perturbations completely resolved after treatment with macrolide.

A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C.

UNLABELLED: We conducted a national retrospective survey on hospital practitioners to evaluate the magnitude of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF) prescriptions in patients treated for chronic hepatitis C. Four hundred seventy-one questionnaires were sent, and 274 practitioners (58.2%) responded. Forty-six percent of practitioners used EPO, and 31% used G-CSF. The total number of HCV-infected patients receiving antiviral therapy per year was estimated at 6,630 patients, of whom 8.8% and 4% received EPO and G-CSF, respectively. EPO-beta was the main EPO molecule prescribed at a median dose of 30,000 IU/wk (range: 2,000-80,000). The indications for prescribing EPO varied greatly, including "fragile patients" (34%), "low" Hb level (8-11 g/dL) (19%), "rapid decline" in Hb level (2-5 g/dL during the first month of therapy) (12%), and symptomatic anemic patients (7%). G-CSF was mainly prescribed for a "low" level of neutrophils ranging from 400 to 750 neutrophils/mm3. In multivariate analysis, independent predictors of EPO and G-CSF prescription were age of practitioner less than 45 years (EPO: OR = 1.96, P = 0.03; G-CSF: OR = 2.27, P = 0.004), practice in university hospital (EPO: OR = 5.89, P < 0.0001; G-CSF: OR = 2.39, P = 0.003), and the high number of CHC treated/year (EPO: OR = 6.18, P < 0.0001; G-CSF: OR = 2.58, P = 0.002). CONCLUSION: Our survey reveals an important rate of EPO and G-CSF prescriptions but with considerable disparity in the schedule of injections, the molecules used, and above all the indications. The suitable role of EPO and G-CSF as complements to HCV therapy urgently needs to be clarified.

Prolonged cholestasis and ductopenia following gold salt therapy.

Hepatotoxicity, predominantly cholestatic, is a rare adverse effect of gold salt therapy, which usually completely resolves within a few months. We report the case of a female patient treated for rheumatoid arthritis, who had gold salt overdose, and in whom acute cholestatic hepatitis occurred three weeks after beginning of therapy. Evolution of gold concentration was followed in plasma and urine, as well as in cutaneous and liver dry tissue. Liver biopsy showed marked inflammatory changes of interlobular bile ducts that evolved towards ductopenia, which was responsible for prolonged cholestasis still present 15 months later. In addition, sialadenitis with sicca syndrome was noted six months after onset of the disease. The mechanism of hepatotoxicity was probably immunoallergic since liver lesions were associated with hypersensitivity syndrome including dermatitis and blood and tissue eosinophilia. This is the first report of gold salt hepatotoxicity with histological demonstration of cholangitis followed by ductopenia.