RESUMO
This study was conducted to clarify the role of cytoglobin (Cygb), a globin expressed in hepatic stellate cells (HSCs), in the development of liver fibrosis and cancer in nonalcoholic steatohepatitis (NASH). Cygb expression was assessed in patients with NASH and hepatocellular carcinoma. Mouse NASH model was generated in Cygb-deficient (Cygb(-/-)) or wild-type (WT) mice by giving a choline-deficient amino acid-defined diet and, in some of them, macrophage deletion and N-acetyl cysteine treatment were used. Primary-cultured mouse HSCs isolated from WT (HSCs(Cygb-wild)) or Cygb(-/-) (HSCs(Cygb-null)) mice were characterized. As results, the expression of CYGB was reduced in patients with NASH and hepatocellular carcinoma. Choline-deficient amino acid treatment for 8 weeks induced prominent inflammation and fibrosis in Cygb(-/-) mice, which was inhibited by macrophage deletion. Surprisingly, at 32 weeks, despite no tumor formation in the WT mice, all Cygb(-/-) mice developed liver cancer, which was ameliorated by N-acetyl cysteine treatment. Altered expression of 31 genes involved in the metabolism of reactive oxygen species was notable in Cygb(-/-) mice. Both HSCs(Cygb-null) and Cygb siRNA-transfected-HSCs(Cygb-wild) exhibited the preactivation condition. Our findings provide important insights into the role that Cygb, expressed in HSCs during liver fibrosis, plays in cancer development with NASH.
Assuntos
Globinas/deficiência , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estresse Oxidativo , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Acetilcisteína/administração & dosagem , Acetilcisteína/farmacologia , Animais , Antioxidantes/metabolismo , Citoglobina , Dieta , Globinas/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
An 87-year-old man with hepatocellular carcinoma (HCC) presented with right-sided chest pain. Computed tomography revealed right bloody pleural effusion and an extravasation from an arterially enhanced mass in the right seventh posterior intercostal space. These findings indicated hemothorax from a rupture of HCC metastasis to the chest wall. Angiography of the intercostal arteries confirmed a hypervascular tumor, and transcatheter arterial embolization resulted in hemostasis. He was discharged with palliative care and remains alive after 9 months. Although hemothorax represents an unusual, life-threatening complication of HCC, our case suggests that transcatheter treatment can achieve hemostasis and a favorable survival even in elderly patients.
Assuntos
Carcinoma Hepatocelular , Embolização Terapêutica , Neoplasias Hepáticas , Parede Torácica , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/terapia , Hemotórax/diagnóstico por imagem , Hemotórax/etiologia , Hemotórax/terapia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/terapia , Masculino , Ruptura EspontâneaRESUMO
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Assuntos
Carcinoma Hepatocelular , Úlcera Duodenal , Icterícia Obstrutiva , Neoplasias Hepáticas , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/tratamento farmacológico , Úlcera Duodenal/induzido quimicamente , Úlcera Duodenal/diagnóstico , Humanos , Icterícia Obstrutiva/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Compostos de Fenilureia , QuinolinasRESUMO
Hypothyroidism is a common adverse event of lenvatinib therapy for hepatocellular carcinoma (HCC), whereas thyrotoxicosis has rarely been reported in clinical trials. A 74-year-old man complaining of abdominal pain was found to have liver tumors and paraaortic lymphadenopathy. The intrahepatic lesions were diagnosed as HCC by angiography and treated with transcatheter arterial chemoembolization. Although localized prostate cancer was discovered incidentally, the etiology of paraaortic lymphadenopathy was assumed to be metastatic HCC. Lenvatinib 12 mg/day was started when his thyroid function tests were almost normal but was interrupted because of thyrotoxicosis. The patient was negative for tested thyroid autoantibodies. Color Doppler ultrasonography detected reduced thyroid blood flow, suggesting destructive thyroiditis. Although he resumed lenvatinib at 8 mg/day once his serum level of free thyroxine normalized, thyrotoxicosis recurred. Subsequently, he suffered hypothyroidism, which exacerbated despite levothyroxine replacement. Lenvatinib was discontinued as it was ineffective against the paraaortic lymph node metastasis, and external-beam radiotherapy was performed. After the completion of radiotherapy, the thyroid dysfunction significantly improved. In summary, lenvatinib for HCC can induce transient thyrotoxicosis followed by hypothyroidism, which is compatible with destructive thyroiditis. During lenvatinib therapy, close monitoring of thyroid function and appropriate management of thyrotoxicosis as well as hypothyroidism are essential.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Hipotireoidismo , Neoplasias Hepáticas , Tireoidite , Tireotoxicose , Idoso , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Hipotireoidismo/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Recidiva Local de Neoplasia , Compostos de Fenilureia , Quinolinas , Tireotoxicose/induzido quimicamenteRESUMO
The appropriate management of hepatitis B virus (HBV) infection during pregnancy has not been established in Japan. We herein report five HBV-infected pregnant Japanese women who received tenofovir disoproxil fumarate (TDF). Two of them had been born after the introduction of nationwide immunoprophylaxis and were vertically infected with HBV, highlighting the need to address mother-to-child transmission further. In both entecavir-experienced and nucleoside/nucleotide analog-naïve mothers, TDF suppressed HBV replication without serious adverse events. All five children were free from congenital disorders, growth impairment, and HBV infection. TDF showed safety and efficacy for pregnant woman with chronic hepatitis B and might have helped prevent mother-to-child transmission.
Assuntos
Antivirais/administração & dosagem , Hepatite B Crônica/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Tenofovir/administração & dosagem , Adulto , Criança , Feminino , Guanina/análogos & derivados , Guanina/uso terapêutico , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/imunologia , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Japão , Masculino , Mães , Gravidez , Cuidado Pré-Natal/métodos , Carga ViralRESUMO
Immune checkpoint inhibitors, combined with anti-angiogenic agents or locoregional treatments (e.g., transarterial chemoembolization (TACE)), are expected to become standard-of-care for unresectable hepatocellular carcinoma (HCC). We measured the plasma levels of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays in patients with HCC who underwent lenvatinib (n = 24) or TACE (n = 22) treatment. In lenvatinib-treated patients, plasma levels of sCD27 (soluble cluster of differentiation 27) decreased (p = 0.040) and levels of sCD40 (p = 0.014) and sTIM-3 (p < 0.001) were increased at Week 1, while levels of sCD27 (p < 0.001) were increased significantly at Weeks 2 through 4. At Week 1 of TACE, in addition to sCD27 (p = 0.028), sCD40 (p < 0.001), and sTIM-3 (soluble T-cell immunoglobulin and mucin domain-3) (p < 0.001), levels of sHVEM (soluble herpesvirus entry mediator) (p = 0.003), sTLR-2 (soluble Toll-like receptor 2) (p = 0.009), sCD80 (p = 0.036), sCTLA-4 (soluble cytotoxic T-lymphocyte antigen 4) (p = 0.005), sGITR (soluble glucocorticoid-induced tumor necrosis factor receptor) (p = 0.030), sGITRL (soluble glucocorticoid-induced TNFR-related ligand) (p = 0.090), and sPD-L1 (soluble programmed death-ligand 1) (p = 0.070) also increased. The fold-changes in soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86 and sPD-1 (soluble programmed cell death domain-1) with sPD-L1 were positively correlated in both the lenvatinib and TACE treatment groups. Our results suggest that there are some limited differences in immunomodulatory effects between anti-angiogenic agents and TACE. Further studies from multicenters may help to identify an effective combination therapy.