RESUMEN
BACKGROUND: This study aims to determine the impact of intracellular hepatitis B virus (HBV) DNA, covalently closed circular DNA (cccDNA) and viral replicative activity in both tumour and non-neoplastic liver on prognosis and to determine the relationship of viral replicative activity and Ishak fibrosis in predicting outcome following resection. METHODS: A total of 99 prospectively enrolled patients treated with primary liver resection for HBV-HCC are included. Intracellular HBV DNA and cccDNA were quantitated by real-time PCR. The RNA-sequencing (RNA-seq) was performed in a subset of 21 patients who had either minimal liver fibrosis (Ishak stages 0-2) or end-stage fibrosis (Ishak stage 6). RESULTS: Tumour tissue contained a lower cccDNA copy number compared with paired non-neoplastic liver, and larger tumours (>3 cm) had less cccDNA compared with small tumours (⩽3 cm). High viral replicative activity in non-neoplastic liver was associated with higher HCC recurrence rate independent of Ishak fibrosis stage. Genes correlated with viral replicative activity in non-neoplastic liver (620 genes) were distinct from those associated with end-stage fibrosis (1226 genes). Genes associated with viral replicative activity were preferentially distributed in regions on chr3, chr16 and chr19. CONCLUSIONS: Viral replicative activity in non-neoplastic liver is associated with HCC recurrence through mechanisms that are distinct from and independent of Ishak fibrosis stage.
Asunto(s)
Carcinoma Hepatocelular/virología , ADN Viral/análisis , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/virología , Neoplasias Hepáticas/virología , Hígado/virología , Replicación Viral , Anciano , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , ADN Circular/análisis , Femenino , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Genotipo , Hepatectomía , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/aislamiento & purificación , Humanos , Estimación de Kaplan-Meier , Hígado/patología , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Recurrencia , Carga Tumoral , Carga ViralRESUMEN
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.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Carcinoma Hepatocelular/terapia , Inmunoterapia Activa/métodos , Neoplasias Hepáticas/terapia , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/inmunología , Animales , Antígenos CD4/metabolismo , Vacunas contra el Cáncer/inmunología , Carcinoma Hepatocelular/inmunología , Línea Celular Tumoral , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/metabolismo , Neoplasias Hepáticas/inmunología , Ratones , Ratones Endogámicos , Fosforilación , Factor de Transcripción STAT3/metabolismo , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Quantitation of hepatitis B surface antigen (HBsAg) in hepatitis B-associated hepatocellular carcinoma (HBV-HCC) remains to be clearly defined. This study aims to determine the association of HBsAg quantity with intrahepatic HBV viral load and activity in both tumor and non-neoplastic liver of HBV-HCC patients. Data were obtained from 89 prospectively enrolled patients treated with primary liver resection for HBV-HCC at a single Western institution (2008-2013). Circulating HBsAg was quantitated using ELISA. HBV DNA, covalently closed circular (cccDNA) and precore-pregenomic RNA (preC-pgRNA) in both tumor and non-neoplastic liver were quantitated by real-time PCR from fresh liver resection specimens. Circulating HBsAg was detectable in all 89 patients. HBsAg negatively correlated with age, and positively correlated with pre-operative serum AFP and ALT levels. HBsAg correlated with HBV cccDNA copy number in tumor or non-neoplastic liver tissue. It also correlated with preC-pgRNA copy number in non-neoplastic liver tissue. HBsAg did not correlate with serum HBV DNA, total intrahepatic HBV DNA, viral replicative activity or transcriptional activity. In HBV-HCC patients, HBsAg levels correlated with cccDNA copy number in tumor or non-neoplastic liver tissue, suggesting that a greater pool of cccDNA is associated with a higher rate of HBsAg production.
Asunto(s)
Carcinoma Hepatocelular/virología , ADN Circular/aislamiento & purificación , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/complicaciones , Neoplasias Hepáticas/virología , Adulto , Anciano , ADN Circular/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Humanos , Hígado/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Suero/virología , Carga ViralRESUMEN
This study aims to evaluate localized expression of CD4, interleukin (IL)-17, Foxp3, and CD8 in hepatitis B-associated hepatocellular carcinoma (HBV-HCC) and to explore their potential effects on outcome following surgical resection. This prospective study includes 66 HBV-HCC surgical resection patients enrolled from 2008 to 2013. CD4, IL-17, Foxp3, and CD8 mRNA in 4 regions of the resection specimens (center of the tumor, periphery of the tumor, non-neoplastic liver bordering tumor, non-neoplastic liver distant from tumor) was quantitated using real-time polymerase chain reaction. The tumoral regions had lower CD4 and CD8 expression as compared with paired non-neoplastic regions, whereas the expression of IL-17 and Foxp3 did not differ. High Foxp3 in all regions except non-neoplastic liver distant from tumor was associated with poor overall survival, whereas low CD8 expression in distant non-neoplastic liver may be associated with high HCC recurrence rate. Although the expression of almost all molecules did not differ between small (≤3 cm) and large HCC (>3 cm), high IL-17 in periphery of tumor, high CD8 in center of tumor, or low CD8 in distant non-neoplastic liver was associated with high HCC recurrence rate in patients with small HCC, but not in those with large HCC. The effect of immune cells on HCC progression therefore depends on the expression level, localization, and tumor size, and an imbalance toward regulatory T cells is associated with poor outcome.
Asunto(s)
Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/mortalidad , Hepatitis B/complicaciones , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/mortalidad , Linfocitos Infiltrantes de Tumor/inmunología , Adulto , Anciano , Antígenos de Superficie/metabolismo , Biomarcadores , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Fenotipo , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Carga TumoralRESUMEN
BACKGROUND: This study was designed to evaluate the prognostic value of three systemic inflammation markers, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and prognostic nutritional index (PNI), for hepatocellular carcinoma (HCC) associated with hepatitis B (HBV). METHODS: This analysis included 234 HBV-HCC patients who underwent primary surgical resection at the Mount Sinai Medical Center between 1988 and 2013. Serum albumin and circulating neutrophil, lymphocyte, and platelet counts immediately before surgery were obtained to calculate NLR, PLR, and PNI. RESULTS: Patients with larger tumor size (>3 cm) had higher NLR, higher PLR, and lower PNI. Stratified analysis showed that the impact of three markers on outcome depends on the severity of liver fibrosis. High NLR, high PLR, or low PNI was associated with poor outcome only in patients without end-stage fibrosis (Ishak stage 0-5) and not in those with cirrhosis (Ishak stage 6). Multivariate analysis in Ishak stage 0-5 patients showed that only high NLR was associated with poor outcome independent of tumor size. Of the three markers, only NLR correlated with PD-L1 expression in center of tumor, but not in nonneoplastic liver. CONCLUSIONS: The prognostic value of these three markers following surgery was only significant for HBV-HCC patients without end-stage fibrosis, and among the three markers, only NLR remained a significant prognostic indicator independent of tumor size. The correlation of NLR with intratumoral PD-L1 expression raises a hypothesis for shared pathways leading to PD-L1-mediated local tolerance within tumor and systemic inflammatory responses represented by elevated NLR in HBV-HCC.
Asunto(s)
Carcinoma Hepatocelular/patología , Hepatitis B/patología , Inflamación/patología , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Índice de Severidad de la Enfermedad , Biomarcadores de Tumor/análisis , Plaquetas/patología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/virología , Femenino , Estudios de Seguimiento , Hepatitis B/inmunología , Hepatitis B/virología , Virus de la Hepatitis B , Humanos , Inflamación/inmunología , Inflamación/virología , Cirrosis Hepática/inmunología , Cirrosis Hepática/virología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/virología , Linfocitos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neutrófilos/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: The aims of this study were to create a model of peritoneal carcinomatosis in patients with gastric cancer and to evaluates outcomes in patients with gastric cancer treated using surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A single-institution cohort of patients with gastric cancer was analyzed according to the development of gastric cancer with peritoneal carcinomatosis (GCPC). Variables were evaluated using regression analysis. Kaplan-Meier analysis was used to evaluate outcomes after surgical resection, cytoreductive surgery, and HIPEC. RESULTS: Age ≤60 years and local tumor stage (T3/T4) were significantly associated with GCPC (odds ratio, 3.95 and 3.94, respectively). Thirty-six-month survival was 57% for patients without peritoneal disease and 39% for patients with GCPC. There was no significant trend of improved survival after surgical management or HIPEC. CONCLUSIONS: Age ≤60 years and T3/T4 tumor stage are risk factors for GCPC. Intermediate-term survival of patients with GCPC treated with surgical resection or cytoreductive surgery and HIPEC was not improved, though future research should address the possible benefits of aggressive approaches to the treatment of GCRC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia del Cáncer por Perfusión Regional , Hipertermia Inducida , Neoplasias Peritoneales/terapia , Neoplasias Gástricas/patología , Adulto , Anciano , Quimioterapia Adyuvante , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Registros Médicos , Persona de Mediana Edad , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/cirugía , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Hepatitis B (HBV)-associated hepatocellular carcinoma (HCC) is often associated with alpha-fetoprotein (AFP) production. Although serum AFP has been demonstrated to be a prognostic factor for patient survival, optimal cutoff levels remain unclear. METHODS: Patients with HBV-associated HCC treated by primary liver resection were prospectively followed at a single institution between 1995 and 2008. AFP level was categorized into quintiles for KaplanMeier analysis and multivariable Cox proportional hazards regression models. RESULTS: Best 5-year survival after surgery was observed for patients with AFP in the first quintile (1.4-4.1 ng/mL), with progressively worse outcomes for patients in each increasing quintile. AFP was associated with overall survival (HR = 1.61; 95 % CI 1.30-1.98), disease-free survival (HR = 1.26; 95 % CI 1.10-1.44), and 2-year recurrence (HR = 1.30; 95 % CI 1.07-1.57) in multivariate analysis. Noncirrhotic patients (Ishak 1-5) with AFP in quintile 1 had 94 % 5-year survival, compared with 0 % survival for patients with AFP in quintile 5 (2,332.7-327,560.0 ng/mL) and Ishak stage 6 cirrhosis. CONCLUSIONS: Preoperative serum AFP is an independent predictor of prognosis among HBV-HCC patients following surgical resection. Categorizing AFP into quintiles creates the opportunity to observe differences in outcomes even at low serum levels within the normal range. Additionally, combining AFP quintiles and fibrosis staging provides a predictive model of prognosis for HCC. Thus, even small differences in AFP within the normal range may impact prognosis and disease progression for HBV-HCC.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/sangre , Hepatitis B/sangre , Neoplasias Hepáticas/sangre , Recurrencia Local de Neoplasia/sangre , alfa-Fetoproteínas/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/virología , Femenino , Estudios de Seguimiento , Hepatectomía , Hepatitis B/mortalidad , Hepatitis B/virología , Virus de la Hepatitis B/patogenicidad , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/virología , Estadificación de Neoplasias , Cuidados Preoperatorios , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
Recognizing hepatocellular nodules that cannot be classified as typical for hepatocellular carcinoma, hepatocellular adenoma, or focal nodular hyperplasia is important, especially in a patient with high risk for hepatocellular carcinoma. The authors report a case of a 53-year-old man with chronic hepatitis B, who was referred to the hospital with a liver mass found on routine imaging follow-up. Abdominal ultrasound revealed a 2.4-cm hypoechoic lesion. Contrast computed tomography showed homogeneous arterial enhancement and mild hyperdensity on portal venous phase images. Due to the high risk for hepatocellular carcinoma, the patient underwent laparoscopic left lateral segmentectomy that revealed a 2.2-cm poorly defined red-brown lesion. The nodule was diagnosed as a hypervascular/telangiectatic hyperplastic hepatocellular nodule based on histopathologic findings and immunostaining profile with negative glutamine synthetase, diffuse positive CD34 highlighting hyperplastic endothelial cells along the telangiectatic sinusoids and dilated vascular channels, and CK7 and CK19 reactive normal bile ducts within the lesion.
Asunto(s)
Hiperplasia Nodular Focal/diagnóstico , Hepatitis B Crónica/diagnóstico , Telangiectasia/diagnóstico , Malformaciones Vasculares/diagnóstico , Biomarcadores/análisis , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/virología , Diagnóstico Diferencial , Hiperplasia Nodular Focal/metabolismo , Hiperplasia Nodular Focal/cirugía , Hepatectomía , Hepatitis B Crónica/complicaciones , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Tomografía Computarizada Multidetector , Valor Predictivo de las Pruebas , Telangiectasia/metabolismo , Telangiectasia/cirugía , Ultrasonografía Doppler en Color , Malformaciones Vasculares/metabolismo , Malformaciones Vasculares/cirugíaRESUMEN
BACKGROUND: Chronic hepatitis B virus (HBV) infection induces persistent but ineffective immune activation that contributes to necroinflammation, fibrosis, and risk of hepatocellular carcinoma (HCC). This study aims to determine the relationship of intrahepatic total HBV (ih HBV) DNA and covalently closed circular DNA (cccDNA) with necroinflammation and fibrosis, and their impact on prognosis after resection in HBV HCC patients. METHODS: Data are from 111 patients treated with primary liver resection for HBV HCC at Mount Sinai, New York (1991-2008). ih HBV DNA and cccDNA were quantitated by real-time PCR. Necroinflammation was graded according to histologic activity index (HAI), and liver fibrosis was staged by the modified Ishak method. RESULTS: A total of 106 (95%) and 89 patients (80%) had detectable ih HBV DNA and cccDNA, respectively, while 43% had detectable serum HBV DNA. cccDNA made up a small proportion of ih HBV DNA (median cccDNA/ih HBV DNA ratio = 0.022). Higher levels of ih HBV DNA were associated with higher HAI and serum alanine aminotransferase (ALT), while a lower ratio of cccDNA/ih HBV DNA was associated with higher HAI, ALT, and Ishak fibrosis stage. ih HBV and cccDNA were not associated with survival, but the lowest quintile of cccDNA/ih HBV DNA ratio (<0.0024) was independently associated with poor overall survival. CONCLUSIONS: A lower cccDNA/ih HBV DNA ratio was associated with greater necroinflammation and liver fibrosis, and was independently associated with poor overall survival. Thus, intracellular virus loads and relative proportions of virus DNA reflect histologic damage in the liver and influence the clinical outcome of HBV HCC patients.