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1.
Ann Surg Oncol ; 23(Suppl 5): 574-582, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26786094

RESUMO

The immune status of the tumor microenvironment influences tumor progression, and hepatocellular carcinoma (HCC) with an immunosuppressive signature often is associated with a poor prognosis. This study examined the impact of a bone marrow-derived dendritic cell (DC) vaccine loaded with autologous tumor cell lysate on tumor progression and the tumor microenvironment using an orthotopic murine HCC model. An orthotopic murine HCC was established by implantation of Hepa1-6 cells in the liver. The impact of DC vaccine loaded with Hepa1-6 cell lysate on tumor progression, survival, and tumor-infiltrating lymphocytes and cytokines was examined. Treating mice with DC vaccine loaded with Hepa1-6 cell lysate inhibited the progression of murine HCC generated through orthotopic implantation of Hepa1-6 cells and resulted in a 90 % survival rate by day 60 compared with a survival rate lower than 5 % for untreated mice. This anti-tumor response was associated with inhibition of STAT3 phosphorylation within the tumor. The DC vaccine reduced accumulation of Foxp3+CD4+ regulatory T cells within the tumor microenvironment and prevented TGF-ß production from the tumor tissue. Tumor cell lysate-loaded DC vaccine prevented HCC progression in a clinically relevant orthotopic murine HCC model. The effect of DC vaccine on the accumulation of Foxp3+CD4+ regulatory T cells within the tumor microenvironment and on the production of TGF-ß suggests that tumor regression by DC vaccination may be associated with an altered immunosuppressive tumor microenvironment.


Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma Hepatocelular/terapia , Imunoterapia Ativa/métodos , Neoplasias Hepáticas/terapia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Animais , Antígenos CD4/metabolismo , Vacinas Anticâncer/imunologia , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Hepáticas/imunologia , Camundongos , Camundongos Endogâmicos , Fosforilação , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/biossíntese
4.
Am J Surg Pathol ; 31(4): 607-14, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17414109

RESUMO

Hepatoportal sclerosis (HPS) is one of the causes of noncirrhotic portal hypertension. In general, hepatic synthetic function is preserved and treatment is aimed at relief of the portal hypertension. In this study, we present the clinical and pathologic features of HPS cases who underwent liver transplantation (LT). LT cases with confirmed gross and microscopic diagnosis of HPS are included. Weight of the explanted liver, presence of thrombi in the main blood vessels, and gross and microscopic characteristics were assessed. Clinical information was gathered from chart review. From 1995 to 2004, 8 LT patients were diagnosed with HPS. Cirrhosis resulting from alcohol (2), autoimmune hepatitis (2), and hepatitis B (1), or cryptogenic cirrhosis (3) was the presumed diagnoses pre-LT. Seven patients presented with bleeding varices and 5 had concomitant ascites. At the time of LT, mean values were: prothrombin time of 15.2 seconds, serum albumin 3.2 g/dL, serum bilirubin 3.5 mg/dL, alkaline phosphatase 140 IU/L, aspartate aminotransferase 39.4 IU/L, and alanine aminotransferase 34.7 IU/L. Explanted livers were shrunken, with weights ranging from 715 to 1199 g (mean 934). Nonocclusive portal vein thrombosis was present in 2 patients. On histologic examination, there was dense portal fibrosis, marked phlebosclerosis, and presence of variable degrees of megasinusoid formation. Four livers also had features of incomplete septal cirrhosis. None showed histologic features of the presumed underlying liver disease. In conclusion, HPS can cause hepatic synthetic dysfunction that may necessitate LT. Small liver volume, significant portal fibrosis, and phlebosclerosis may contribute to hepatic parenchymal loss and subsequent synthetic compromise.


Assuntos
Falência Hepática/etiologia , Falência Hepática/patologia , Falência Hepática/cirurgia , Transplante de Fígado , Fígado/patologia , Adulto , Idoso , Feminino , Humanos , Hipertensão Portal/etiologia , Fígado/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Sistema Porta/patologia , Esclerose
7.
Hepatol Int ; 5(1): 597-602, 2010 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-21442058

RESUMO

Hemophagocytic syndrome is a potentially fatal complication that rarely occurs after liver transplantation. We present a 25-year-old man with a history of Still's disease who presented with fever, arthralgia, and elevated serum ferritin levels 6 months after undergoing liver transplantation for fulminant hepatic failure due to autoimmune hepatitis potentially triggered by infliximab therapy. Liver biopsy demonstrated features consistent with hemophagocytic syndrome. The patient was successfully treated with a course of high dose steroids and had complete resolution of his symptoms and normalization of liver chemistry test abnormalities. Patients with Still's disease may rarely complicate with fulminant hepatic failure with infliximab therapy. Hemophagocytic syndrome a rare potentially life threatening condition may occur in such patients following liver transplantation.

8.
Liver Int ; 24(3): 198-203, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15189269

RESUMO

AIMS: Hepatocyte proliferation (HP) is an adaptive response to liver injury. The relationships between HP and necroinflammation, fibrosis, and serum alpha-fetoprotein (AFP) levels in chronic hepatitis C virus (HCV) infection, however, are not well understood. METHODS: Proliferative hepatocytes (Ki-67+) were identified using immunohistochemical staining in formalin-fixed, paraffin-embedded liver tissue from 156 HCV RNA-positive patients with different degrees of liver histopathology. Twenty high-power fields (HPFs) in lobular areas were counted in each specimen. RESULTS: HP increased by 1.22 +/- 0.25 cells/HPF per increase in necroinflammation from grade 0 (median: 0.13; range: [0.1-0.5] cells/HPF) through grade 3 (median: 1.80; range: [0.0-25.2] cells/HPF; P=0.002). HP increased by 0.81 +/- 0.20 cells/HPF per increase in fibrosis from stage 0 (median: 0.33; range: [0.0-1.3] cells/HPF) through stage 3 (median: 1.70; range: [0.0-25.2] cells/HPF) and then decreased in stage 4 (to median: 0.90; range: [0.0-5.3] cells/HPF). HP also increased with advancing age (P=0.03). Among patients with advanced liver disease, HP was no higher in patients with elevated serum AFP levels (median: 1.68; range: [0.1-5.3] cells/HPF) than in those with normal serum AFP levels (median: 1.70; range: [0.0-25.2] cells/HPF; P=0.26). CONCLUSIONS: In patients with chronic HCV infection, HP increases with histologic progression of liver disease, but is impaired in cirrhosis. HP was not increased in patients with elevated serum AFP levels.


Assuntos
Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Hepatócitos/patologia , Hepatopatias/etiologia , alfa-Fetoproteínas/análise , Adulto , Envelhecimento , Divisão Celular , Progressão da Doença , Feminino , Hepatite C Crônica/sangue , Humanos , Imuno-Histoquímica , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade , Necrose , Índice de Gravidade de Doença
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