RESUMEN
BACKGROUND: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.
Asunto(s)
Hepatitis Autoinmune , Tacrolimus , Humanos , Tacrolimus/efectos adversos , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/tratamiento farmacológico , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento , Inmunosupresores/efectos adversos , Ácido Micofenólico/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite increasing treatment options for this disease, prognosis remains poor. CRIPTO (TDGF1) protein is expressed at high levels in several human tumours and promotes oncogenic phenotype. Its expression has been correlated to poor prognosis in HCC. In this study, we aimed to elucidate the basis for the effects of CRIPTO in HCC. We investigated CRIPTO expression levels in three cohorts of clinical cirrhotic and HCC specimens. We addressed the role of CRIPTO in hepatic tumourigenesis using Cre-loxP-controlled lentiviral vectors expressing CRIPTO in cell line-derived xenografts. Responses to standard treatments (sorafenib, doxorubicin) were assessed directly on xenograft-derived ex vivo tumour slices. CRIPTO-overexpressing patient-derived xenografts were established and used for ex vivo drug response assays. The effects of sorafenib and doxorubicin treatment in combination with a CRIPTO pathway inhibitor were tested in ex vivo cultures of xenograft models and 3D cultures. CRIPTO protein was found highly expressed in human cirrhosis and hepatocellular carcinoma specimens but not in those of healthy participants. Stable overexpression of CRIPTO in human HepG2 cells caused epithelial-to-mesenchymal transition, increased expression of cancer stem cell markers, and enhanced cell proliferation and migration. HepG2-CRIPTO cells formed tumours when injected into immune-compromised mice, whereas HepG2 cells lacking stable CRIPTO overexpression did not. High-level CRIPTO expression in xenograft models was associated with resistance to sorafenib, which could be modulated using a CRIPTO pathway inhibitor in ex vivo tumour slices. Our data suggest that a subgroup of CRIPTO-expressing HCC patients may benefit from a combinatorial treatment scheme and that sorafenib resistance may be circumvented by inhibition of the CRIPTO pathway. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Resistencia a Antineoplásicos , Proteínas Ligadas a GPI/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Sorafenib/farmacología , Anciano , Anciano de 80 o más Años , Animales , Antibióticos Antineoplásicos/farmacología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Chaperón BiP del Retículo Endoplásmico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos NOD , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Péptidos/farmacología , Fenotipo , Transducción de Señal/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Ensayos Antitumor por Modelo de Xenoinjerto , Pez CebraRESUMEN
BACKGROUND AND OBJECTIVE: Deterioration of nutritional status during PEG-interferon containing therapy for chronic hepatitis C can be ameliorated by preventive nutritional support. We aimed to explore whether such support also affects paid labour productivity, physical exercise and performance status. METHODS: In this prospective randomized controlled trial (J Hepatol 2012;57:1069-75), 53 patients with chronic hepatitis C had been allocated to "on demand" support (n=26: nutritional intervention if weight loss>5%) or preventive support (n=27: regular dietary advice plus energy- and protein-rich evening snack) during PEG-interferon-containing therapy. Paid labour productivity, physical exercise and performance status were evaluated at baseline, after 24 and (if applicable) after 48 weeks of treatment. RESULTS: At baseline, 46% of patients performed paid labour and 62% performed some kind of physical exercise. Furthermore, most patients were able to carry out normal activity with only minor symptoms of disease (mean Karnofsky performance score: 94). Decreases of paid labour productivity (-21% vs. -70%, P=0.003), physical exercise activity (-43% vs. -87%, P=0.005) and Karnofsky performance scores (-12% vs. -24%, P<0.001) were less in the preventive than in "on demand" group after 24 weeks of treatment. Effects of preventive nutritional support were even more pronounced after 48 weeks. CONCLUSIONS: Preventive nutritional support markedly ameliorates decreases of paid labour productivity, physical exercise and performance status during PEG-interferon-containing treatment for chronic hepatitis C.
Asunto(s)
Antivirales/uso terapéutico , Eficiencia , Ejercicio Físico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Trastornos Nutricionales/terapia , Apoyo Nutricional , Polietilenglicoles/uso terapéutico , Antivirales/efectos adversos , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Trastornos Nutricionales/inducido químicamente , Polietilenglicoles/efectos adversos , Estudios Prospectivos , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Although antiviral treatment for hepatitis C (HCV) is highly effective, side effects often occur, including weight loss, digestive symptoms, and impaired quality of life. We aimed at exploring the beneficial effects of preventive nutritional support. METHODS: In a randomized controlled trial, 53 HCV patients were allocated to "on demand" support (n=26: nutritional intervention if weight loss >5%) or preventive support (n=27: regular dietary advice plus energy- and protein-rich evening snack). Nutritional state (including validated Jamar Hand Grip Strength), digestive symptoms (visual analog score), and quality of life (SF-36 survey) were evaluated at baseline, and after 24 and 48 weeks of peginterferon α-2b and ribavirin treatment. RESULTS: The primary end point (weight loss at 24 weeks) was reached in 22 patients in both groups. Weight decreased markedly in the "on demand" group (decrease at 24 weeks: 5.4 kg or 6.9%, p<0.001), but not in the preventive group (decrease 0.3 kg or 0.3%, p=n.s.). Jamar Hand Grip Strength deteriorated in the "on demand" group (from 40.3 ± 15.5 kg to 32.0 ± 13.1 kg, p<0.001) but not in the preventive group (from 40.7 ± 10.4 kg to 39.7 ± 8.9 kg, p=n.s.). Intake of energy, proteins, and fat decreased markedly in the "on demand" group but increased in the preventive group. Although digestive symptoms and quality of life deteriorated, impairment was significantly less in the preventive group. CONCLUSIONS: Preventive nutritional advice plus supplementation prevents weight loss and catabolic state during HCV antiviral therapy, with improved digestive symptoms and quality of life.
Asunto(s)
Antivirales/uso terapéutico , Enfermedades del Sistema Digestivo/prevención & control , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Terapia Nutricional , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Anciano , Sistema Digestivo/fisiopatología , Enfermedades del Sistema Digestivo/fisiopatología , Femenino , Fuerza de la Mano/fisiología , Hepatitis C/fisiopatología , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Estado Nutricional/fisiología , Calidad de Vida , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Cirrhotic patients are at considerable risk for bacterial infections, possibly through increased intestinal permeability and bacterial overgrowth. Proton pump inhibitors (PPIs) may increase infection risk. We aimed to explore the potential association between PPI use and bacterial infection risk in cirrhotic patients and potential underlying mechanisms in complementary patient and animal models. MATERIALS AND METHODS: Bacterial overgrowth was determined in jejunum of 30 rats randomly allocated to 6-week PPI treatment, gastrectomy or no treatment. In 84 consecutive cirrhotic patients, bacterial infection risk was prospectively assessed and related to PPI use. Intestinal permeability was determined by polyethylene glycol (PEG) test in nine healthy individuals and 12 cirrhotic patients. RESULTS: Bacterial overgrowth was much more common in jejunum of rats treated with PPI or gastrectomy compared with nontreated rats. Twenty-four patients (29%) developed a bacterial infection during a median follow-up of 28 months. Although PPI users tended to experience infection more often than patients without PPI therapy, PPI use was not an independent predictor of bacterial infection (HR 1·2, 95% CI 0·5-3·0, P = 0·72), after correction for Child-Pugh class (HR 3·6, 95% CI 1·5-8·7, P = 0·004) and age (HR 1·05, 95%CI 1·01-1·09, P = 0·02). In cirrhotic patients, 24-h urinary recovery of PEGs 1500 and 3350 was significantly higher compared with healthy controls. CONCLUSIONS: Although in our animal model PPIs induced intestinal overgrowth, stage of liver disease rather than PPI use was the predominant factor determining infection risk in cirrhotic patients. Increased intestinal permeability may be a factor contributing to infection risk.