RESUMO
BACKGROUND: This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC). METHODS: Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]). CONCLUSIONS: Nintedanib may have similar efficacy to sorafenib in aHCC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Indóis , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Progressão da Doença , Intervalo Livre de Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/farmacocinética , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Sorafenibe/administração & dosagem , Sorafenibe/efeitos adversos , Sorafenibe/farmacocinética , Resultado do TratamentoRESUMO
TNFα has been shown to play a role in hepatitis C virus (HCV)-induced insulin resistance (IR). Polymorphism of the IL28B gene that encodes IFN-lambda 3 may be associated with IR through modulation of TNFα. The aim of this study was to investigate the relationship between IL28B rs12979860 genotype, the level of TNFα activation and the degree of IR in patients with chronic hepatitis C. One hundred and thirty-three nondiabetic genotype 1 HCV-infected patients with biopsy proven noncirrhotic hepatitis C were investigated for IR (using HOMA index), IL28B rs12979860 genotype and fasting circulating levels of soluble receptor 1 of TNFα (sTNFR1) and adipokines: leptin, adiponectin and IL-6. The HOMA-IR was positively correlated with serum levels of leptin (r = 0.35, P < 0.0001) and sTNFR1 (r = 0.35, P < 0.0001) but not with IL-6 or adiponectin. IL28B rs12979860 CC genotype was observed in 35% patients. Genotype CC and nongenotype CC patients were similar in terms of HOMA-IR (means 1.6 ± 0.9 vs 1.7 ± 1.4) and had similar circulating levels of sTNFR1 and adipokines. Independent factors associated with IR were ferritin (OR = 1.002, P = 0.02), leptin (OR = 1.06, P = 0.02) and sTNFR1 (OR = 7.9, P = 0.04). This study suggests that in nondiabetic, noncirrhotic, HCV genotype 1-infected patients, there is no relationship between IL28B rs12979860 genotype and HOMA-IR or sTNFR1 level. HCV-related IR may be mediated through TNFα independent of IL28B genotype.
Assuntos
Hepatite C Crônica/complicações , Resistência à Insulina , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/sangue , Adiponectina/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Hepatite C Crônica/patologia , Humanos , Interferons , Interleucina-6/sangue , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) worldwide. NAFLD-HCC often occurs in noncirrhotic liver raising important surveillance issues. AIM: To determine the temporal trends for prevalence, clinical characteristics and outcomes of NAFLD-HCC in patients undergoing liver resection. METHODS: Consecutive patients with histologically confirmed HCC who underwent liver resection over a 20-year period (1995-2014). NAFLD was diagnosed based on past or present exposure to obesity or diabetes without other causes of chronic liver disease. RESULTS: A total of 323 HCC patients were included, 12% with NAFLD. From 1995-1999 to 2010-2014, the prevalence of NAFLD-HCC increased from 2.6% to 19.5%, respectively, P = .003, and followed the temporal trends in the prevalence of metabolic risk factors (28% vs 52%, P = .017), while hepatitis C-HCC decreased (from 43.6% to 19.5%, P = .003). NAFLD-HCC occurred more frequently in the absence of bridging fibrosis/cirrhosis (63% of cases, P < .001 compared to other aetiologies). Within the NAFLD group, tumour characteristics were similar between F0-F2 and F3-F4 patients, except for a higher proportion of single nodules (95% vs 54%, P < .01). A total of 53% patients had tumour recurrence and 40% died. NAFLD-HCC had similar time to recurrence and survival as HCCs of other aetiologies. Satellite nodules, tumour size, microvascular invasion and male sex but not the aetiology were independently associated with recurrence. CONCLUSION: Non-alcoholic fatty liver disease increased substantially over the past 20 years among resectable HCCs. It is now the leading cause of HCC occuring without/or with only minimal fibrosis. NAFLD patients are older, with larger tumours while survival and recurrence rates are as severe as in other aetiologies.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Idoso , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/cirurgia , Feminino , Hepatectomia , Hepatite C/complicações , Humanos , Fígado/cirurgia , Cirrose Hepática/epidemiologia , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/cirurgia , Prevalência , Fatores de RiscoAssuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Obesity and the metabolic syndrome (MS) are growing epidemics associated with an increased risk for many types of cancer. In the liver, inï¬ammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although rare cases of HCC arising without cirrhosis raise the possibility of a direct carcinogenesis secondary to nonalcoholic fatty liver disease (NAFLD). Moreover, MS and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with MS to improve the screening guidelines and develop prophylactic treatments in this setting.
Assuntos
Carcinoma Hepatocelular/etiologia , Fígado Gorduroso/complicações , Neoplasias Hepáticas/etiologia , Adiponectina/sangue , Complicações do Diabetes , Progressão da Doença , Hepatite C Crônica/complicações , Humanos , Leptina/sangue , Síndrome Metabólica/complicações , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , Fatores de RiscoAssuntos
Nefropatias/terapia , Transplante de Rim , Nefrologia , Diálise Renal , Sociedades Médicas , Injúria Renal Aguda/induzido quimicamente , Morte Encefálica , França , Hepatite Viral Humana/complicações , Humanos , Nefropatias/complicações , Nefropatias/psicologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/psicologia , Falência Renal Crônica/terapia , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Desnutrição/etiologia , Complicações Pós-Operatórias , Qualidade de Vida , Diálise Renal/efeitos adversos , Obtenção de Tecidos e ÓrgãosAssuntos
Diálise Renal/efeitos adversos , Desequilíbrio Hidroeletrolítico/etiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Volume Sanguíneo , Ensaios Clínicos como Assunto , Líquido Extracelular , Humanos , Hipertensão/etiologia , Hipertensão/prevenção & controle , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Hipotensão/etiologia , Hipotensão/prevenção & controle , Guias de Prática Clínica como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sódio/administração & dosagem , Sódio/efeitos adversos , Intoxicação por Água/etiologia , Intoxicação por Água/prevenção & controle , Desequilíbrio Hidroeletrolítico/fisiopatologia , Desequilíbrio Hidroeletrolítico/prevenção & controleAssuntos
Pletismografia de Impedância , Desequilíbrio Hidroeletrolítico/diagnóstico , Anti-Hipertensivos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Hipertensão/etiologia , Hipertensão/prevenção & controle , Hipotensão/etiologia , Hipotensão/prevenção & controle , Diálise Renal/efeitos adversos , Intoxicação por Água/diagnóstico , Intoxicação por Água/etiologia , Desequilíbrio Hidroeletrolítico/etiologiaAssuntos
Pletismografia de Impedância , Diálise Renal/efeitos adversos , Desequilíbrio Hidroeletrolítico/diagnóstico , Pressão Sanguínea , Composição Corporal , Compartimentos de Líquidos Corporais , Água Corporal , Peso Corporal , Edema/etiologia , Humanos , Modelos Biológicos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Desequilíbrio Hidroeletrolítico/etiologia , Desequilíbrio Hidroeletrolítico/fisiopatologiaAssuntos
Determinação do Volume Sanguíneo/métodos , Diálise Renal/efeitos adversos , Termometria/métodos , Desequilíbrio Hidroeletrolítico/sangue , Volume Sanguíneo , Determinação do Volume Sanguíneo/instrumentação , Desenho de Equipamento , Hemodinâmica , Humanos , Hipotensão/etiologia , Hipotensão/prevenção & controle , Pressão Osmótica , Ultrassom , Desequilíbrio Hidroeletrolítico/etiologia , Desequilíbrio Hidroeletrolítico/terapiaAssuntos
Infecções Bacterianas/microbiologia , Translocação Bacteriana , Colchicina/intoxicação , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/etiologia , Infecções Bacterianas/terapia , Colchicina/sangue , Desidratação/terapia , Relação Dose-Resposta a Droga , Hidratação , Humanos , MasculinoAssuntos
Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/metabolismo , Artefatos , Colina/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Adenoma/diagnóstico por imagem , Adenoma/metabolismo , Adulto , Colina/farmacocinética , Diagnóstico Diferencial , Reações Falso-Positivas , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
Advanced biliary tract carcinomas (BTCs) are often diagnosed at an advanced/metastatic stage and have a poor prognosis. The combination of gemcitabine and oxaliplatin (GEMOX) has shown promising activity in this setting. This international phase II study evaluated the efficacy and safety of GEMOX as first-line therapy in patients with advanced BTCs. Eligible patients with previously untreated locally advanced or metastatic BTC received gemcitabine 1000 mg m(-2) (day 1) and oxaliplatin 100 mg m-2 (day 2), every 2 weeks. Seventy patients were enroled; 72.9% had metastatic disease. Sixty-seven patients were treated. There were 10 confirmed partial responses (14.9%; 95% confidence interval (CI), 7.4-25.7%) in the treated population (RECIST). Twenty-four patients (35.8%) had stable disease. The objective response rate was 20.5% in patients with non-gallbladder cancers (9/44 patients) and 4.3% in patients with gallbladder cancers (1/23). Median overall survival for the intent-to-treat population was 8.8 months (95% CI, 6.9-11.1%) and progression-free survival was 3.4 months (95% CI, 2.5-4.6%). Grade 3/4 toxicities included thrombocytopenia (14.9% of patients), alanine aminotransferase elevation (13.4%), anaemia (10.4%), neutropenia (11.9%) and pain (1 1.9%). In this study, GEMOX demonstrated activity in non-gallbladder carcinoma, but poor activity in gallbladder carcinoma. GEMOX is well tolerated in advanced BTCs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Insulin resistance is a frequent feature of chronic hepatitis C. Whether insulin resistance could be the cause or consequence of steatosis and fibrosis is unknown. The ability of HCV genotype 3 to promote steatosis by itself provides an unique opportunity to answer this question. AIMS: The aim of the present study was to assess the relationships between insulin resistance, steatosis, and fibrosis according to genotype in 141 non-diabetic patients with biopsy proven non-cirrhotic chronic hepatitis C. METHODS: All patients had fasting serum glycaemia and insulinaemia measurements. Insulin resistance was evaluated using the homeostasis model assessment (HOMA IR) method. Liver steatosis was determined according to hepatitis C virus genotype (1 or 3). Logistic regression and multivariate regression analysis were used to identify variables independently associated with insulin resistance, fatty liver, and fibrosis. RESULTS: Although steatosis and fibrosis were more severe in genotype 3 patients, median HOMA IR was significantly higher in patients with genotype 1 related steatosis than in those with genotype 3 related steatosis (2.1 v 1; p = 0.001). Independent risk factors for steatosis were insulin resistance in genotype 1 patients (p = 0.001) and viral load in genotype 3 patients (p = 0.003). Among genotype 1 patients, independent parameters associated with insulin resistance were age (p = 0.04) and steatosis (p = 0.004). Steatosis was associated with more severe fibrosis whatever the genotype (p = 0.002). Among genotype 1 patients, although there was a significant relationship between circulating insulin level and fibrosis stage (p = 0.006), only steatosis and inflammatory score were independently associated with fibrosis. CONCLUSION: This study shows that insulin resistance is the cause rather than the consequence of steatosis and fibrosis in genotype 1 patients and that increased circulating insulin is a risk factor for fibrosis through insulin resistance induced steatosis.