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1.
Clin Transl Gastroenterol ; 10(9): e00071, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31478957

RESUMO

OBJECTIVES: Data on long-term natural history of microscopic colitis (MC), including collagenous (CC) and lymphocytic colitis (LC), are lacking. METHODS: All new cases of MC diagnosed in the Somme area, France, between January 1, 2005, and December 31, 2007, were prospectively included. Colonic biopsies from all patients were reviewed by a group of 4 gastrointestinal pathologist experts to assess the diagnosis of CC or LC. Demographic and clinical data were retrospectively collected from diagnosis to February 28, 2017. RESULTS: One hundred thirty cases of MC, 87 CC and 43 LC, were included (median age at diagnosis: 70 [interquartile range, 61-77] and 48 [IQR, 40-61] years, respectively). The median follow-up was 9.6 years (7.6; 10.6). By the end of the follow-up, 37 patients (28%) relapsed after a median time of 3.9 years (1.2; 5.0) since diagnosis, without significant difference between CC and LC (30% vs 26%; P = 0.47). Twenty patients (15%) were hospitalized for a disease flare, and 32 patients (25%) presented another autoimmune disease. Budesonide was the most widely used treatment (n = 74, 59%), followed by 5-aminosalicylic acid (n = 31, 25%). The median duration of budesonide treatment was 92 days (70; 168), and no adverse event to budesonide was reported. Sixteen patients (22%) developed steroid dependency and 4 (5%) were corticoresistant. No difference in the risk of digestive and extradigestive cancer was observed compared with the general population. None of the death (n = 25) observed during the follow-up were linked to MC. In multivariate analysis, age at diagnosis (HR, 1.03; 95% confidence interval, 1.00-1.06; P = 0.02) and budesonide exposure (HR, 2.50; 95% confidence interval, 1.11-5.55; P = 0.03) were significantly associated with relapse. DISCUSSION: This population-based study showed that after diagnosis, two-third of the patients with MC observed long-term clinical remission. Age at diagnosis and budesonide exposure were associated with a risk of relapse.

2.
J Hepatol ; 71(3): 516-522, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31125576

RESUMO

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.

3.
Radiology ; 291(3): 801-808, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31038408

RESUMO

Background A prior in vitro study showed that idarubicin was the most cytotoxic agent for hepatocellular carcinoma (HCC) cell lines. Idarubicin-loaded beads for transarterial chemoembolization (TACE) were previously evaluated for the appropriate dose in a phase I dose-escalation study. Purpose To evaluate objective response rate (ORR), safety, and survival after TACE by using idarubicin-loaded beads for unresectable HCC. Materials and Methods This prospective single-arm phase II study was conducted between January 2015 and January 2017. Participants with unresectable HCC were included in the trial and underwent TACE with idarubicin-eluting beads. The primary end point was 6-month ORR assessed with independent central review by using modified Response Evaluation Criteria in Solid Tumors. Secondary end points were best ORR during the first 6 months, overall survival, progression-free survival, time to progression, and safety. A two-stage Fleming statistical design was used. Results Forty-six study participants (mean age, 71.2 years ± 10.2; six women and 40 men) were included; 44 participants underwent at least one TACE session. The 6-month ORR was 52% (23 of 44). The best ORR achieved was 68% (30 of 44). Fourteen of 44 (32%) participants underwent a curative treatment after TACE. Median progression-free survival, time to progression, and overall survival were 6.6 months, 9.5 months, and 18.6 months, respectively. TACE was discontinued for toxicity in four of 44 (9%) participants. The most frequent grade 3-4 adverse events were elevated aspartate aminotransferase (14 of 44, 32%), elevated γ-glutamyl transpeptidase (eight of 44, 18%), hyperbilirubinemia (seven of 44, 16%), elevated alanine aminotransferase (seven of 44, 16%), and pain (seven of 44, 16%). Conclusion Idarubicin-eluting beads showed a good safety profile and promising objective response rate and time to progression when used as part of a transarterial chemoembolization regimen for unresectable hepatocellular carcinoma. © RSNA, 2019 See also the editorial by Padia in this issue.

4.
Lancet Gastroenterol Hepatol ; 4(6): 454-465, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954567

RESUMO

BACKGROUND: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. METHODS: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693. FINDINGS: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. INTERPRETATION: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. FUNDING: Onxeo.

5.
Dig Liver Dis ; 51(4): 484-488, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30686715

RESUMO

INTRODUCTION: Up to 25% of patients treated with infliximab experience hypersensitivity reactions. Prophylactic premedication prior to infliximab infusion, comprising corticosteroids and/or antihistamines, is widely used in clinical practice but its efficacy has recently been called into question due to the lack of pathophysiological rationale and validation by controlled trials. MATERIALS AND METHODS: We conducted a comprehensive literature search of multiple electronic databases from inception to June 2017 to identify studies reporting the impact of corticosteroid and/or antihistamine premedication on the risk of acute (<24 h) hypersensitivity reaction to infliximab in immune-mediated inflammatory diseases (IMIDs). Random-effects meta-analysis was performed. RESULTS: Ten studies, eight observational studies and two randomized control trials, were identified including a total of 3892 patients with IMIDs, and 1,385 patients with IBD. Corticosteroid premedication was not associated with a decreased risk of hypersensitivity reaction in either IMIDs (7 studies; OR, 1.07, 95%CI, 0.64-1.78; I2 = 57.5%) or IBD (3 studies; OR, 1.04, 95% CI, 0.52-2.07; I2 = 57%). Antihistamine premedication was not associated with a decreased risk of hypersensitivity reaction in IMIDs (3 studies: OR, 1.39, 95% CI, 0.70-2.73; I2 = 85%). The combination of corticosteroids and antihistamines did not decrease the risk of acute infliximab infusion reaction in IMIDs (6 studies; OR, 2.12, 95% CI, 0.61-7.35; I2 = 94%), but was associated with an increased risk in IBD (4 studies, OR, 4.17, 95% CI, 1.61-10.78; I2 = 77%). CONCLUSION: Corticosteroid and/or antihistamine premedication is not associated with a decreased risk of acute hypersensitivity reactions to infliximab in patients with IMIDs. We believe that these premedications should no longer be part of standard protocols.


Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/efeitos adversos , Reação no Local da Injeção/prevenção & controle , Pré-Medicação , Corticosteroides/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Infusões Intravenosas/efeitos adversos , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
J Hepatol ; 69(6): 1274-1283, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30092234

RESUMO

BACKGROUND & AIMS: More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC. METHODS: Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS). RESULTS: From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients' inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5-95.4), 80.3% (95% CI 76.9-83.9), and 3.2% (95% CI 1.6-4.8) respectively. CONCLUSION: This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortality rate of up to 7%. LAY SUMMARY: Cirrhosis is a risk factor for primary liver cancer, leading to recommendations for periodic screening. However, for alcohol-related liver disease the rational of periodic screening for hepatocellular carcinoma (HCC) is controversial, as registry and databased studies have suggested a low incidence of HCC in these patients and highly competitive mortality rates. In this study, a large cohort of patients with biopsy-proven alcoholic cirrhosis prospectively screened for HCC demonstrated a high annual incidence of HCC (2.9%) and a high percentage of small cancers theoretically eligible for curative treatment. This suggests that patients with liver disease related to alcohol should not be ruled out of screening.

7.
Lancet Gastroenterol Hepatol ; 3(9): 614-625, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29983372

RESUMO

BACKGROUND: The value of transient elastography for the non-invasive diagnosis of alcohol-related liver fibrosis is subject to debate. We did an individual patient data (IPD) meta-analysis to determine specific diagnostic cutoff values for liver stiffness in alcohol-related fibrosis, and to assess the effect of aminotransferase concentrations, bilirubin concentrations, and presence of asymptomatic and non-severe alcoholic hepatitis on liver stiffness. METHODS: We searched for studies that included patients with alcohol-related liver disease, liver biopsy, and transient elastography, and with a statistical method for determining the diagnostic cutoffs for alcohol-induced liver fibrosis on the basis of the FibroScan results, in PubMed between Jan 1, 2000, and Sept 30, 2017. Native data bases were obtained from corresponding authors in an Excel form. Pooled diagnostic cutoffs for the various fibrosis stages were determined in a two-stage, random-effects meta-analysis. The effects of aspartate aminotransferase (AST) concentrations, bilirubin concentrations, and histological features of asymptomatic and non-severe alcoholic hepatitis on liver stiffness cutoff were assessed in one-stage, random-effects meta-analysis. FINDINGS: Of 188 studies assessed, ten studies comprising 1026 patients were included in the meta-analysis, yielded liver stiffness cutoffs of 7·0 kPa (area under the receiver operating characteristic curve 0·83 [SE 0·02; 95% CI 0·79-0·87]) for F≥1 fibrosis, 9·0 kPa (0·86 [0·02; 0·82-0·90]) for F≥2, 12·1 kPa (0·90 [0·02; 0·86-0·94]) for F≥3, and 18·6 kPa (0·91 [0·04; 0·83-0·99]) for F=4. AST and bilirubin concentrations had a significant effect on liver stiffness, with higher concentrations associated with higher liver stiffness values (p<0·0001), and with significantly higher cutoff values for diagnosis of all fibrosis stages but F≥1. The presence of histological features of asymptomatic and non-severe alcoholic hepatitis was associated with increased liver stiffness (p<0·0001). In a multivariate analysis, AST (p<0·0001) and bilirubin (p=0·0002) concentrations, and prothrombin activity (p=0·01), were independently associated with the presence of histological features of asymptomatic and non-severe alcoholic hepatitis. Lastly, specific liver stiffness cutoffs were determined on the basis of concentrations of AST and bilirubin. Liver stiffness cutoff values increased in patients with increased AST concentrations, bilirubin concentrations, or both. INTERPRETATION: This IPD meta-analysis highlights the link between liver stiffness and the histological features of asymptomatic and non-severe alcoholic hepatitis, reflected by AST and bilirubin concentrations. In alcohol-related liver disease, FibroScan assessments of liver fibrosis should take into account AST and bilirubin concentrations through the use of specifically adjusted liver stiffness cutoffs. FUNDING: None.

8.
Gastroenterology ; 155(5): 1436-1450.e6, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30031138

RESUMO

BACKGROUND & AIMS: Retrospective studies have found an unexpectedly high incidence of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV)-associated cirrhosis who received direct-acting antiviral (DAA) agents. We analyzed data from the ANRS CO12 CirVir cohort to compare the incidence of HCC in patients with cirrhosis who received DAA therapy vs patients treated with interferon (IFN). METHODS: Data were collected from 1270 patients with compensated biopsy-proven HCV-associated cirrhosis recruited from 2006 through 2012 at 35 centers in France. For descriptive purpose, patients were classified as follows: patients who received DAA treatment (DAA group, n = 336), patients who achieved a sustained virologic response (SVR) following an IFN-based regimen (SVR-IFN group, n = 495), or patients who never received DAA treatment and never had an SVR following IFN therapy (non-SVR group, n = 439). The patients were included in HCC surveillance programs based on ultrasound examination every 6 months, and clinical and biological data were recorded. To account for confounding by indication due to differences in patient characteristics at treatment initiation, we constructed a time-dependent Cox regression model weighted by the inverse probability of treatment and censoring (IPTCW) to assess the treatment effects of DAA on time until HCC. RESULTS: Compared with patients in the SVR-IFN group, patients in the DAA group were older, higher proportions had diabetes or portal hypertension, and liver function was more severely impaired. The crude 3-year cumulative incidences of HCC were 5.9% in the DAA group, 3.1% in the SVR-IFN group, and 12.7% in the non-SVR group (overall P < .001; unadjusted hazard ratio [HR] for HCC 2.03; 95% confidence interval [CI] 1.07-3.84; P = .030 for the DAA group vs the SVR-IFN group). HCC characteristics were similar among groups. Among patients with HCC, the DAA group received less-frequent HCC screening than the other 2 groups (P = .002). After Cox analyses weighted by the IPTCW, we found no statistically significant increase in risk of HCC associated with DAA use (HR 0.89; 95% CI 0.46-1.73; P = .73). CONCLUSIONS: Analysis of data from the ANRS CO12 CirVir cohort reveals that the apparent increase in HCC incidence observed in patients with cirrhosis treated with DAAs compared with patients who achieved SVR following an IFN therapy can be explained by patient characteristics (age, diabetes, reduced liver function) and lower screening intensity.

9.
Presse Med ; 47(7-8 Pt 1): 655-666, 2018 Jul - Aug.
Artigo em Francês | MEDLINE | ID: mdl-30032921

RESUMO

All chronic and excessive consumer of alcohol with recent jaundice should be assessed using a Maddrey's score for severe acute alcoholic hepatitis. Corticosteroids are the first line of treatment, associated with an appropriate nutritional support and alcohol abstinence. Corticosteroids plus N-acetylcysteine combination improves short-term survival over corticosteroids alone, and could be proposed as a first line therapy. The response to treatment is evaluated at the 7th day of treatment, with the Lille model≤0.45. Prognostic of non-responders to corticosteroids with Lille model>0.45 is dramatically low with 23% survival at 6 month. Early liver transplantation in a selected group of patients with non-response to corticosteroids significantly improves 6th month and long-term survival.


Assuntos
Doença Aguda , Hepatite Alcoólica , Algoritmos , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/fisiopatologia , Hepatite Alcoólica/terapia , Humanos , Prognóstico , Índice de Gravidade de Doença
12.
N Engl J Med ; 378(23): 2171-2181, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29874528

RESUMO

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).


Assuntos
Bezafibrato/uso terapêutico , Colangite/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Adulto , Bezafibrato/efeitos adversos , Ácidos e Sais Biliares/sangue , Colangite/etiologia , Método Duplo-Cego , Feminino , Humanos , Hipolipemiantes/efeitos adversos , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Placebos/uso terapêutico , Falha de Tratamento , Ácido Ursodesoxicólico/uso terapêutico
13.
Gastroenterology ; 155(2): 431-442.e10, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29729258

RESUMO

BACKGROUND & AIMS: Semi-annual surveillance for hepatocellular carcinoma (HCC) is recommended for patients with cirrhosis. We aimed to determine how compliance with HCC surveillance guidelines affects survival times of patients with hepatitis C virus- or hepatitis B virus-associated compensated cirrhosis who developed HCC. METHODS: We collected data from the prospective ANRS CO12 CirVir study, from March 2006 through June 2012, on 1671 patients with biopsy-proven viral cirrhosis and no previous liver complications who were undergoing surveillance for HCC at 35 centers in France. Only 216 patients who developed HCC during the follow-up period were included in the analysis. Patients were considered to be compliant with surveillance guidelines if the time between their last surveillance image evaluation and diagnosis of HCC were fewer than 7 months and noncompliant if this time was 7 months or longer. RESULTS: HCC was detected in 216 patients, at a median follow-up time of 59.7 months. Of these patients, 140 (80.5%) were Barcelona Clinic Liver Cancer stage 0/A, 135 (69.9%) received first-line curative treatment (15 underwent transplantation, 29 underwent resection, 89 received percutaneous ablation, and 2 received resection and percutaneous ablation), and 129 (60.0%) were compliant with surveillance guidelines. Seventy-nine of the patients with HCC died; 49 deaths were associated with tumor progression. After lead-time adjustment, overall survival (OS) time was longer in patients compliant with surveillance guidelines (median OS time, 53.2 months) than noncompliant patients (median OS time, 25.4 months) (P = .0107); this difference remained significant even when we changed lead time assumptions. In multivariate analysis adjusted for a propensity score, compliance with HCC surveillance guidelines was associated with low tumor burden, allocation of curative treatment, and increased OS time compared with noncompliance (hazard ratio for OS, 2.19; 95% confidence interval, 1.16-4.14; P = .0150). CONCLUSIONS: In an analysis of data from the ANRS CO12 CirVir cohort, we associated compliance with HCC surveillance guidelines (fewer than 7 months between image evaluations) with early diagnosis, allocation of curative treatment, and longer adjusted OS of patients with hepatitis C virus- or hepatitis B virus-associated compensated cirrhosis and a diagnosis of HCC.


Assuntos
Carcinoma Hepatocelular/mortalidade , Detecção Precoce de Câncer/normas , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/mortalidade , Idoso , Antivirais/uso terapêutico , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/virologia , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Seguimentos , França/epidemiologia , Fidelidade a Diretrizes/estatística & dados numéricos , Hepacivirus/isolamento & purificação , Vírus da Hepatite B/isolamento & purificação , Humanos , Estimativa de Kaplan-Meier , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/terapia , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Guias de Prática Clínica como Assunto , Estudos Prospectivos
14.
Kidney Int ; 94(1): 206-213, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29735308

RESUMO

Patients with advanced chronic kidney disease who receive direct-acting antiviral drugs require special consideration regarding comorbid conditions. Here we assessed the efficacy and safety of grazoprevir plus elbasvir in 93 patients infected with HCV genotype 1 or 4 and with advanced chronic kidney disease in a non-randomized, multicenter, nationwide observational survey. Twenty patients with HCV genotype 1a, 51 patients with 1b, four unclassified genotype 1, 17 with genotype 4 and one with genotype 6 received grazoprevir plus elbasvir (100/50 mg) once daily. All patients had severe chronic kidney disease with 70 patients stage G5, including patients on hemodialysis (74.2%), and 23 were stage G4 chronic kidney disease. Severe liver disease (Metavir F3/F4) was found in 33 patients. A sustained virologic response 12 weeks after the end of therapy was achieved in 87 of 90 patients. Two patients had a virologic breakthrough and one had a relapse after treatment withdrawal. Most patients received many concomitant medications (mean 7.7) related to comorbid conditions. Serious adverse events occurred in six patients, including three deaths while on grazoprevir plus elbasvir, not related to this therapy. Thus, once-daily grazoprevir plus elbasvir was highly effective with a low rate of adverse events in this advanced chronic kidney disease difficult-to-treat population with an HCV genotype 1 or 4 infection.

15.
Dig Liver Dis ; 50(9): 931-937, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29803757

RESUMO

INTRODUCTION: Epidemiological data is lacking on primary Budd-Chiari syndrome (BCS) in France. METHODS: Two approaches were used: (1) A nationwide survey in specialized liver units for French adults. (2) A query of the French database of discharge diagnoses screening to identify incident cases in adults. BCS associated with cancer, alcoholic/viral cirrhosis, or occurring after liver transplantation were classified as secondary. RESULTS: Approach (1) 178 primary BCS were identified (prevalence 4.04 per million inhabitants (pmi)), of which 30 were incident (incidence 0.68 pmi). Mean age was 40 ±â€¯14 yrs. Risk factors included myeloproliferative neoplasms (MPN) (48%), oral contraceptives (35%) and factor V Leiden (16%). None were identified in 21% of patients, ≥2 risk factors in 25%. BMI was higher in the group without any risk factor (25.7 kg/m2 vs 23.7 kg/m2, p < 0.001). Approach (2) 110 incident primary BCS were admitted to French hospitals (incidence 2.17 pmi). MPN was less common (30%) and inflammatory local factors predominated (39%). CONCLUSION: The entity of primary BCS as recorded in French liver units is 3 times less common than the entity recorded as nonmalignant hepatic vein obstruction in the hospital discharge database. The former entity is mostly related to MPN whereas the latter with abdominal inflammatory diseases.

16.
Oncotarget ; 9(22): 16248-16262, 2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29662641

RESUMO

Signaling Lymphocytic Activation Molecules (SLAM) family receptors are initially described in immune cells. These receptors recruit both activating and inhibitory SH2 domain containing proteins through their Immunoreceptor Tyrosine based Switch Motifs (ITSMs). Accumulating evidence suggest that the members of this family are intimately involved in different physiological and pathophysiological events such as regulation of immune responses and entry pathways of certain viruses. Recently, other functions of SLAM, principally in the pathophysiology of neoplastic transformations have also been deciphered. These new findings may prompt SLAM to be considered as new tumor markers, diagnostic tools or potential therapeutic targets for controlling the tumor progression. In this review, we summarize the major observations describing the implications and features of SLAM in oncology and discuss the therapeutic potential attributed to these molecules.

17.
Hepatology ; 68(4): 1245-1259, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29663511

RESUMO

Data on extrahepatic cancers (EHCs) in compensated viral cirrhosis are limited. The objective of the prospective multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites virales CO12 CirVir cohort was to assess the occurrence of all clinical events in patients with compensated viral cirrhosis, including all types of cancer. Patients with the following inclusion criteria were enrolled in 35 French centers: (1) biopsy-proven hepatitis B virus (HBV) or hepatitis C virus (HCV) cirrhosis, (2) Child-Pugh A, or (3) absence of previous liver complications including primary liver cancer (PLC). Patients were followed up prospectively every 6 months. The standardized mortality ratio (SMR) was calculated according to age and gender using 5-year periods. The impact of sustained viral response (SVR) in HCV patients and maintained viral suppression in HBV patients were assessed using time-dependent analysis. A total of 1,671 patients were enrolled between 2006 and 2012 (median age, 54.9 years; men, 67.3%; HCV, 1,323; HBV, 317; HCV-HBV, 31). Metabolic features and excessive alcohol and tobacco consumption were recorded in 15.2%, 36.4%, and 56.4% of cases, respectively. After a median follow-up of 59.7 months, 227 PLCs were diagnosed (5-year cumulative incidence [CumI] 13.4%) and 93 patients developed EHC (14 patients with lymphoid or related tissue cancer and 79 with solid tissue cancer; 5-year EHC CumI, 5.9%). Compared to the general French population, patients were younger at cancer diagnosis, with significantly higher risk of EHC in HCV patients (SMR, 1.31; 95 confidence interval [CI], 1.04-1.64; P = 0.017) and after SVR (SMR = 1.57; 95% CI, 1.08-2.22; P = 0.013). EHC was the fourth leading cause of death in the whole cohort and the first in patients with viral control/eradication. CONCLUSION: Compared to the general French population, HCV cirrhosis is associated with a higher risk of EHC and the first cause of death in patients with viral cirrhosis who achieve virological control/eradication. (Hepatology 2018).

18.
J Laparoendosc Adv Surg Tech A ; 28(5): 553-561, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29350570

RESUMO

INTRODUCTION: Liver resection in cirrhotic patients is associated with increased morbidity and mortality. The objective of this study was to compare short-term results of laparoscopic resection (LR) and open surgery (OS) for minor liver resection in patients with hepatocellular carcinoma (HCC) hepatocellularcarcinoma on nontumor cirrhotic liver (HCC/F4) and patients with colorectal cancer liver metastases (CRLMs) colorectal liver metastases on healthy liver (CRLM/F0). MATERIALS AND METHODS: Between January 2005 and December 2014, all patients undergoing liver resection (n = 754) were included in this study. Liver resections for cholangiocarcinoma or benign tumor, major liver resection (≥3 segments), HCC on healthy liver, CRLM on cirrhotic liver, and liver resection with technically difficult accessibility (segments I, VII, and VIII) were excluded. The primary endpoint of the study was a validated composite endpoint (CEP), which included specific liver surgery complications (Clavien ≥III), allowing comparison of the postoperative course after LR versus OR for HCC/F4 patients and CRLM/F0 patients using propensity score (PS) analysis. Secondary endpoints were major postoperative morbidity according to the Clavien-Dindo classification (≥III) and intensive care unit (ICU) length of hospital stay (LOS) and overall LOS. The test group was defined as HCC/F4 patients operated by LR, and the control group was defined as HCC/F4 patients and CRLM/F0 patients operated by OS and CRLM/F0 patient operated by LR. RESULTS: Sixty patients (38.7%) underwent LR and 95 patients (61.3%) underwent OS. Surgery was performed for CRLM in 93 patients (60%) and for HCC in 62 patients (40%). No difference was demonstrated between HCC/F4 patients and CRLM/F0 patients in the LR group in terms of the CEP (7% versus 18.1%; P = .23), while a significant difference for the CEP was observed between HCC/F4 patients and CRLM/F0 patients after OS (50% versus 21%; P = .021). A higher rate of CEP was observed for HCC/F4 patients operated by OS compared to HCC/F4 patients operated by LR (50% versus 7.8%; P = .009). No significant difference in Clavien-Dindo score ≥III was observed between HCC/F4 patients and CRLM/F0 patients operated by LR (10% versus 4.5%; P = .98). A higher postoperative ascites rate was observed for HCC/F4 patients operated by OS compared to CRLM/F0 patients operated by OS (25% versus 2.8%; P = .006). This difference was no longer observed when HCC/F4 patients were compared to CRLM/F0 operated by LR (7.8% versus 2.8%; P = .09). The postoperative mortality rate was 1.8% and was not correlated with nontumor liver or surgical approach. A shorter LOS was observed for HCC/F4 patients operated by LR compared to HCC/F4 patients operated by OS (7.53 versus 17.13; P = .011). CONCLUSION: The laparoscopic approach for malignant liver tumor is associated with a lower specific complication rate. LR for HCC/F4 could eliminate excess morbidity and decrease LOS in patients with cirrhotic liver.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Colorretais/patologia , Hepatectomia/métodos , Laparoscopia , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/etiologia , Idoso , Ascite/etiologia , Carcinoma Hepatocelular/complicações , Feminino , Hepatectomia/efeitos adversos , Humanos , Unidades de Terapia Intensiva , Tempo de Internação , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Taxa de Sobrevida
19.
Antiviral Res ; 146: 153-160, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28890388

RESUMO

Ribavirin has been widely used for antiviral therapy. Unfortunately, ribavirin-induced anemia is often a cause of limiting or interrupting treatment. Our team has observed that dehydroepiandrosterone (DHEA) has a protective effect against in vitro and in vivo ribavirin-induced hemolysis. The aim of this study was to better understand this effect as well as the underlying mechanism(s). DHEA was able to reduce in vitro intraerythrocytic ATP depletion induced by ribavirin. Only 1% of ATP remained after incubation with ribavirin (2 mM) at 37 °C for 24 h vs. 37% if DHEA (200 µM) was added (p < 0.01). DHEA also helped erythrocytes conserve their size, with a shrinkage of only 10% vs 40% at 24 h with ribavirin alone (p < 0.01), and reduced phosphatidylserine exposure at the outer membrane, i.e. 27% vs 40% at 48 h, (p < 0.05). DHEA also inhibits ribavirin-induced hemolysis, i.e. 34% vs 46.5% at 72 h (p < 0.01). DHEA is an inhibitor of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the hexose monophosphate shunt connected to the glycolytic pathway which is the only energy supplier of the red blood cell in the form of ATP. We have confirmed this inhibitory effect in the presence of ribavirin. All these observations suggest that ribavirin-induced hemolysis was initiated by ATP depletion, and that the inhibitory effect of DHEA on G6PD was able to rescue enough ATP to limit this hemolysis. This mechanism could be important for improving the therapeutic management of patients treated with ribavirin.


Assuntos
Anemia/prevenção & controle , Antivirais/efeitos adversos , Desidroepiandrosterona/farmacologia , Eritrócitos/efeitos dos fármacos , Glucosefosfato Desidrogenase/antagonistas & inibidores , Ribavirina/efeitos adversos , Trifosfato de Adenosina/metabolismo , Anemia/induzido quimicamente , Antivirais/administração & dosagem , Eritrócitos/metabolismo , Hemólise/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Humanos , Via de Pentose Fosfato/efeitos dos fármacos , Ribavirina/administração & dosagem
20.
J Clin Gastroenterol ; 51(7): 639-649, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28692443

RESUMO

BACKGROUND AND GOAL: International guidelines suggest combining a blood test and liver stiffness measurement (LSM) to stage liver fibrosis in chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). Therefore, we compared the accuracies of these tests between the main etiologies of chronic liver diseases. STUDY: Overall, 1968 patients were included in 5 etiologies: CHC: 698, chronic hepatitis B: 152, human immunodeficiency virus/CHC: 628, NAFLD: 225, and alcoholic liver disease (ALD): 265. Sixteen tests [13 blood tests, LSM (Fibroscan), 2 combined: FibroMeters] were evaluated. References were Metavir staging and CHC etiology. Accuracy was evaluated mainly with the Obuchowski index (OI) and accessorily with area under the receiver operating characteristics (F≥2, F≥3, cirrhosis). RESULTS: OIs in CHC were: FibroMeters: 0.812, FibroMeters: 0.785 to 0.797, Fibrotest: 0.762, CirrhoMeters: 0.756 to 0.771, LSM: 0.754, Hepascore: 0.752, FibroMeter: 0.750, aspartate aminotransferase platelet ratio index: 0.742, Fib-4: 0.741. In other etiologies, most tests had nonsignificant changes in OIs. In NAFLD, CHC-specific tests were more accurate than NAFLD-specific tests. The combined FibroMeters had significantly higher accuracy than their 2 constitutive tests (FibroMeters and LSM) in at least 1 diagnostic target in all etiologies, except in ALD where LSM had the highest OI, and in 3 diagnostic targets (OIs and 2 area under the receiver operating characteristics) in CHC and NAFLD. CONCLUSIONS: Some tests developed in CHC outperformed other tests in their specific etiologies. Tests combining blood markers and LSM outperformed single tests, validating recent guidelines and extending them to main etiologies. Noninvasive fibrosis evaluation can thus be simplified in the main etiologies by using a unique test: either LSM alone, especially in ALD, or preferably combined to blood markers.


Assuntos
Técnicas de Imagem por Elasticidade/estatística & dados numéricos , Doença Hepática Terminal/diagnóstico , Cirrose Hepática/diagnóstico , Hepatopatias/complicações , Índice de Gravidade de Doença , Adulto , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Doença Hepática Terminal/etiologia , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/etiologia , Hepatopatias/sangue , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos
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