RESUMEN
Rare but critical bleeding events in primary immune thrombocytopenia (ITP) present life-threatening complications in patients with ITP, which severely affect their prognosis, quality of life, and treatment decisions. Although several studies have investigated the risk factors related to critical bleeding in ITP, large sample size data, consistent definitions, large-scale multicenter findings, and prediction models for critical bleeding events in patients with ITP are unavailable. For the first time, in this study, we applied the newly proposed critical ITP bleeding criteria by the International Society on Thrombosis and Hemostasis for large sample size data and developed the first machine learning (ML)-based online application for predict critical ITP bleeding. In this research, we developed and externally tested an ML-based model for determining the risk of critical bleeding events in patients with ITP using large multicenter data across China. Retrospective data from 8 medical centers across the country were obtained for model development and prospectively tested in 39 medical centers across the country over a year. This system exhibited good predictive capabilities for training, validation, and test datasets. This convenient web-based tool based on a novel algorithm can rapidly identify the bleeding risk profile of patients with ITP and facilitate clinical decision-making and reduce the occurrence of adversities.
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Púrpura Trombocitopénica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopénica Idiopática/complicaciones , Calidad de Vida , Estudios Retrospectivos , Estudios Prospectivos , Hemorragia/diagnóstico , Trombocitopenia/complicacionesRESUMEN
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological emergency. Although therapeutic plasma exchange together with corticosteroids achieve successful outcomes, a considerable number of patients remain refractory to this treatment and require early initiation of intensive therapy. However, a method for the early identification of refractory iTTP is not available. To develop and validate a model for predicting the probability of refractory iTTP, a cohort of 265 consecutive iTTP patients from 17 large medical centres was retrospectively identified. The derivation cohort included 94 patients from 11 medical centres. For the validation cohort, we included 40 patients from the other six medical centres using geographical validation. An easy-to-use risk score system was generated, and its performance was assessed using internal and external validation cohorts. In the multivariable logistic analysis of the derivation cohort, three candidate predictors were entered into the final prediction model: age, haemoglobin and creatinine. The prediction model had an area under the curve of 0.886 (95% CI: 0.679-0.974) in the internal validation cohort and 0.862 (95% CI: 0.625-0.999) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. In conclusion, we developed and validated a highly accurate prediction model for the early identification of refractory iTTP. It has the potential to guide tailored therapy and is a step towards more personalized medicine.
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Creatinina/sangre , Bases de Datos Factuales , Hemoglobinas/metabolismo , Modelos Biológicos , Púrpura Trombocitopénica Trombótica/sangre , Adulto , Factores de Edad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
OBJECTIVE@#To compare the assessment results of the Children Neuropsychological and Behavioral Scale-Revision 2016 (CNBS-R2016) between young children with autism spectrum disorder (ASD) and global developmental delay (GDD, without ASD) and to explore whether CNBS-R2016 could be helpful to early identification of ASD.@*METHODS@#A total of 260 ASD and 371 GDD children aged 18-30 months were enrolled to finish the assessment of CNBS-R2016. The development quotients (DQs) of the five domains of CNBS-R2016 including gross motor, fine motor, adaptability, language and social behavior were compared between the two groups. The receiver operating characteristic (ROC) curve was used to evaluate the value of the autism-predicted domain in identifying ASD and GDD.@*RESULTS@#The DQs of all the five domains in the ASD group were lower than those in the GDD group (P<0.05). The language DQ and total DQ of the ASD group had a negative correlation with the score of the autism-predicted domain (r=-0.566, -0.552 respectively, P<0.01). When the cut-off value of the autism-predicted domain was 10.5, the largest area under the ROC curve was 0.835, and the sensitivity and specificity for the diagnosis of ASD were 0.750 and 0.798 respectively.@*CONCLUSIONS@#The development of ASD children aged 18-30 months is worse than that of GDD children. CNBS-R2016 may be helpful to distinguish ASD from children with developmental delay.
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Preescolar , Humanos , Lactante , Trastorno del Espectro Autista , Discapacidades del Desarrollo , Curva ROC , Conducta SocialRESUMEN
BACKGROUND: Prospective randomized trials have not been used to evaluate the efficacy of adjuvant therapies after intrahepatic cholangiocarcinoma (ICC) resection. METHODS: We analyzed data from the Taiwan Cancer Registry database of ICC patients receiving resection. To compare outcomes, patients with ICC were enrolled and categorized into the following adjuvant treatment modality groups: group 1, concurrent chemoradiotherapy (CCRT); group 2, sequential chemotherapy (CT) and radiotherapy (RT); and group 3, CT alone. RESULTS: We enrolled 599 patients with resectable ICC who received surgery without distant metastasis. Of these patients, 174 received adjuvant CCRT (group 1), 146 received adjuvant sequential CT and RT (group 2), and 279 received adjuvant CT alone (group 3). Multivariate Cox regression analysis indicated that pathologic stage and positive margin were significantly poor independent predictors. After adjustment for confounders, adjusted hazard ratios (95% confidence intervals) for overall mortality at advanced pathologic stages III and IV were 0.55 (0.41-0.74) and 0.92 (0.70-1.33) in groups 1 and 2, respectively, compared with group 3. CONCLUSIONS: Adjuvant CCRT improved survival in resected ICC with advanced pathologic stages or a positive margin in early pathologic stages compared with adjuvant CT alone or adjuvant sequential CT and RT.
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Neoplasias de los Conductos Biliares/terapia , Quimioradioterapia , Colangiocarcinoma/terapia , Adulto , Anciano , Neoplasias de los Conductos Biliares/mortalidad , Colangiocarcinoma/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Primary immune thrombocytopenia (ITP) is a bleeding disorder commonly encountered in clinical practice. The International Working Group (IWG) on ITP has published several landmark papers on terminology, definitions, outcome criteria, bleeding assessment, diagnosis, and management of ITP. The Chinese consensus reports for diagnosis and management of adult ITP have been updated to the 4th edition. Based on current consensus positions and new emerging clinical evidence, the thrombosis and hemostasis group of the Chinese Society of Hematology issued Chinese guidelines for management of adult ITP, which aim to provide evidence-based recommendations for clinical decision making.
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Medicina Basada en la Evidencia , Hematología/organización & administración , Guías de Práctica Clínica como Asunto , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Sociedades Médicas/organización & administración , Anciano , China , Femenino , Humanos , Masculino , Índice de Severidad de la EnfermedadRESUMEN
Nucleoside triphosphate diphosphohydrolase-1 (ENTPD1/CD39) is the rate-limiting enzyme in a cascade leading to the generation of immunosuppressive adenosine and plays an important role in tumor progression. This study aimed to evaluate the expression of CD39 and CD39Foxp3 regulatory T cells (Tregs) and to determine their prognostic role in patients with hepatocellular carcinoma (HCC) after radical resection.Immunohistochemistry (IHC) and double IHC were used to analyze CD39 expression or the expression of CD39 and Foxp3 in a cohort of 324 HCC patients who underwent curative resection. The quantification of CD39 expression levels was determined using a computerized image analysis system and was evaluated by mean optical density (MOD), which corresponded to the positive staining intensity of CD39. The number of positive Foxp3 cells and both CD39 and Foxp3 positive cells in each 1-mm-diameter cylinder were counted under high-power magnification (×400). The "minimum P value" approach was used to obtain the optimal cutoff value for the best separation between groups of patients in relation to time to recurrence (TTR) or overall survival (OS). The expression of CD39 in HCC cell lines with stepwise metastatic potential and in human umbilical vein endothelial cells was determined by reverse transcription-polymerase chain reaction, Western blotting, and immunofluorescence. The SPSS 17.0 statistical package was used for statistics.CD39 was principally expressed on vascular endothelial cells, macrophagocytes, Tregs, and tumor cells in HCC. Compared with paired peritumoral tissues, tumoral tissues had a significantly higher expression level of CD39 (Pâ<â0.0001). Overexpression of tumoral CD39 was related to increased tumor recurrence and shortened overall survival. Furthermore, the expression level of peritumoral CD39 showed a prognostic role in TTR and OS. Double IHC showed that tumoral tissues had significantly higher Foxp3Tregs and CD39Foxp3Tregs count per 1 mm core (14.1659 vs 4.9877, Pâ=â0.001; 11.5254 vs 3.3930, Pâ<â0.001) and a higher CD39Foxp3/Foxp3 ratio compared with paired peritumoral tissues. CD39Foxp3Tregs were a better prognosticator than CD39Tregs for TTR.Overexpression of CD39 protein in HCC was an independent predictor of poor outcome after radical resection. The CD39Foxp3Tregs count added prognostic power to Foxp3Tregs, providing a potential target for tumor immunotherapy.
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Antígenos CD/biosíntesis , Apirasa/biosíntesis , Carcinoma Hepatocelular/fisiopatología , Factores de Transcripción Forkhead/biosíntesis , Neoplasias Hepáticas/fisiopatología , Linfocitos T Reguladores/metabolismo , Biomarcadores de Tumor , Carcinoma Hepatocelular/cirugía , Femenino , Hepatectomía/métodos , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , PronósticoRESUMEN
There is increasing and consistent evidence concerning the association of systemic inflammation and poor outcome in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify a superior inflammation-based prognostic scoring system for patients with HCC undergoing hepatectomy.We analyzed two independent cohorts of a total of 723 patients with HCC who underwent radical surgery between 2010 and 2012. The prognostic value of the inflammation scores, including the Glasgow Prognostic Score (GPS), modified GPS (mGPS), neutrophil-to-lymphocyte ratio, platelet lymphocyte ratio, prognostic index, and prognostic nutritional index, as well as the Barcelona Clinic Liver Cancer and Cancer of the Liver Italian Program staging systems was analyzed in a test cohort of 367 patients and validated in a validation cohort of 356 patients.A high score with the mGPS was associated with large tumor size, vascular invasion, and advanced clinical stage. Multivariate analysis showed that the mGPS was independently associated with overall survival and disease-free survival, and had a higher area under the curve value in comparison with other inflammation-based scores.The results of this study demonstrated that the mGPS is an independent marker of poor prognosis in patients with resectable HCC and is superior to other inflammation-based scores.
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Hepatectomía/estadística & datos numéricos , Invasividad Neoplásica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , China/epidemiología , Femenino , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Evaluación de Resultado en la Atención de Salud/métodos , Gravedad del Paciente , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Proyectos de Investigación , Estudios Retrospectivos , Análisis de Supervivencia , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Carga TumoralRESUMEN
BACKGROUND: Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically. METHODS: The correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB). RESULTS: IHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis. CONCLUSIONS: Down-regulation of intratumoral and peritumoral Sirt3 were both associated with poor outcome in HCC, moreover, intratumoral Sirt3 was a favorable prognostic predictor in early stage patients.
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Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Pronóstico , Sirtuina 3/biosíntesis , Adolescente , Adulto , Anciano , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Niño , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Sirtuina 3/genética , Tasa de SupervivenciaRESUMEN
OBJECTIVES: TCR- gamma-delta + T cells (γδ T cells) are non-conventional T lymphocytes that can recognize and eradicate tumor cells. Our previous studies showed that infiltration and function of γδT cells were substantially attenuated in hepatocellular carcinoma (HCC). However, their prognostic value was not clarified. METHODS: The association between γδ T cells and the clinical outcomes was determined by immunohistochemistry (IHC) in a HCC patient cohort (n = 342). RESULTS: Immunohistochemistry showed decreased infiltration of γδ T cells in tumoral tissues compared with paired peritumoral tissues. The counts of γδ T cells in peritumoral tissues were negatively correlated with tumor size (P = 0.005). Survival analysis showed that the levels of peritumoral γδ T cells were related to both time to recurrence (TTR) and overall survival (OS) (P = 0.010 and P = 0.036, respectively) in univariate analysis, and related to TTR in multivariate analysis (P = 0.014, H.R. [95% CI] = 0.682 [0.502-0.927]). Furthermore, the level of peritumoral γδ T cells showed independent prognostic value for TTR in Barcelona Clinic Liver Cancer (BCLC) stage A patients (P = 0.038, H.R. [95% CI] = 0.727 [0.537-0.984]). However, tumoral γδ T cells did not show independent prognostic value for either TTR or OS in HCC patients. CONCLUSIONS: Low counts of γδ T cells in peritumoral liver tissue are related to a higher incidence of recurrence in HCC and can predict postoperative recurrence, especially in those with early-stage HCC.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Hígado/patología , Recurrencia Local de Neoplasia/epidemiología , Complicaciones Posoperatorias/epidemiología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/inmunología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , China/epidemiología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Hepatectomía , Humanos , Hígado/inmunología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Linfocitos T/metabolismoRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) combined with glucocorticoid in treatment of severe newly diagnosed primary immune thrombocytopenia (ITP). METHODS: From June 2009 to December 2012, 24 male patients and 38 female patients with the diagnosis of severe primary ITP in our hospital were randomized into trial group (31 cases) or control group (31 cases), the median age was 50 years (range: 21-84 years). Trial group was treated with rhTPO combined with glucocorticoid, and control group was treated with glucocorticoid only. RESULTS: At the day 3, 7 and 14 from the beginning of treatment, the average platelet count (APC) in trial group[(35.5±24.9)×109/L, (135.2±94.9)×109/L and (192.0±109.1)×109/L]were significantly higher than that in control group[(24.5±15.6)×109/L, (78.2±121.9)×109/L and (95.8±60.5)×109/L, P=0.022, 0.009 and 0.001, respectively]. There was no significant difference in APC between the two groups at day 28 and 90 after treatment[(147.8±59.1)×109/L vs (105.1±56.9)×109/L, P=0.243; (137.4±52.3)×109/L vs (104.3±59.8)×109/L, P=0.568, respectively]. At the day 7, 14 and 28, the complete response rates in trial group were 61.3%, 87.1% and 80.6%, which were also significantly higher than that in control group (16.1%, 29.0% and 48.3%, P=0.000, 0.000 and 0.004, respectively). The median time to response in trial group was 3 days while in the control group was 5 days; the median duration of complete response in trial group was 76 days while in the control group was 54 days. In trial group, there were 4 cases treated with platelet transfusion, while in control group there were 11 cases, respectively. CONCLUSION: For patients with severe primary ITP, rhTPO combined with glucocorticoid could rapidly increase the platelet count, significantly improve the complete response rate and prolonged the effect with a low incidence of tolerable adverse events compared to single use of glucocorticoid. rhTPO combined with glucocorticoid could be a new therapeutic choice to those patients.
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Glucocorticoides/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Trombopoyetina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Transfusión de Plaquetas , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Peritumoral activated hepatic stellate cells (HSCs) are versatile myofibroblast-like cells closely related with hepatocellular carcinoma (HCC) progression. So far, comprehensive comparison of gene expression of human HSCs during hepatocarcinogenesis is scanty. Therefore, we identified the phenotypic and genomic characteristics of peritumoral HSCs to explore the valuable information on the prognosis and therapeutic targets of HBV related HCC. METHODS: A tissue microarray containing 224 HBV related HCC patients was used to evaluate the expression of phenotype markers of HSCs including α-SMA, glial fibrillary acidic protein (GFAP), desmin, vinculin and vimentin. HSCs and cancer associated myofibroblasts (CAMFs) were isolated from normal, peritumoral human livers and cancer tissues, respectively. Flow cytometry and gene microarray analysis were performed to evaluate the phenotypic changes and gene expression in HCC, respectively. RESULTS: Peritumoral α-SMA positive HSCs showed the prognostic value in time to recurrence (TTR) and overall survival (OS) of HCC patients, especially in early recurrence and AFP-normal HCC patients. Expression of GFAP positive HSCs cell lines LX-2 was significantly decreased after stimulation with tumor conditioned medium. Compared with quiescent HSCs, peritumoral HSCs and intratumoral CAMFs expressed considerable up- and down-regulated genes associated with biological process, cellular component, molecular function and signaling pathways involved in fibrogenesis, inflammation and progress of cancer. CONCLUSIONS: Peritumoral activated HSCs displayed prognostic value in HBV related-HCC, and their genomic characteristics could present rational biomarkers for HCC risk and promising therapeutic targets.
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Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Células Estrelladas Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Adulto , Anciano , Biomarcadores/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/virología , Línea Celular Tumoral , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica , Hepatitis B/complicaciones , Virus de la Hepatitis B , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Anotación de Secuencia Molecular , Miofibroblastos/metabolismo , Fenotipo , Pronóstico , Recurrencia , Reproducibilidad de los Resultados , Transducción de SeñalRESUMEN
BACKGROUND AND AIM: Regulatory T cells (Treg) play a vital role in immunosuppressive crosstalk; however, Tregs from different locations lead to different clinical outcomes. Our aim was, therefore, to compare the prevalences and suppressive phenotypes of Tregs in the peripheral blood, peritumor, and intratumor of patients with hepatocellular carcinoma (HCC). METHODS : The frequencies and phenotypes of CD4(+) CD25(+) CD127(low/-) CD49d(-) Tregs in the periphery, peritumor, and intratumor of 78 HCC patients and 12 healthy controls were evaluated by flow cytometry. Treg-cell suppressive activity was determined using an in vitroâ CD154 expression assay. Tregs from tumor and paired peritumor were then hybridized using an Agilent whole genome oligo microarray, and selected genes were validated by real-time polymerase chain reaction. Functional analysis of the microarray data was performed using Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses. RESULTS : Intratumoral Tregs exhibited higher frequencies and more suppressive phenotypic functions than those in peritumor and periphery, whereas there was no difference between the latter two. Functional analysis showed that complement cascades, p53, and glycosylphosphatidylinositol-anchor biosynthesis pathways were significantly upregulated in intratumoral Tregs; the salivary secretion pathway was significantly downregulated in intratumoral Tregs, and immune cells and tumor-immuno-related Gene Ontology terms were significantly affected. CONCLUSIONS : Tregs in different locations exhibited different functional statuses. A higher prevalence and more suppressive phenotype suggested a critical role for intratumoral Tregs in the formation of multicellular immunosuppressive networks. HCC immunotherapy may be improved, therefore, by specific locational Tregs elimination or suppression.
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Carcinoma Hepatocelular/inmunología , Tolerancia Inmunológica/inmunología , Neoplasias Hepáticas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Antígenos de Superficie/análisis , Subgrupos de Linfocitos B/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunofenotipificación , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Escape del Tumor/inmunologíaRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is a typical malignancy in a background of chronic inflammation. Th17 cells (a major source of IL-17) constitute crucial components of infiltrating inflammatory/immune cells in HCC and can amplify inflammatory response via binding to interleukin-17 receptor (IL-17R). Thus, we investigated the expression and clinical significance of IL-17 and IL-17 receptor family cytokines in HCC. METHODS: The expression and prognostic value of IL-17 and IL-17R (A-E) were examined in 300 HCC patients after resection. Six Th17 associated cytokines in serum (n = 111) were quantified using enzyme-linked immunosorbent assays. Phenotypic features of IL-17+ CD4+ T cells were determined by flow cytometry analysis. RESULTS: High expression of intratumoral IL-17 and IL1-7RE were significantly associated with poorer survival (p = 0.016 and <0.001, respectively) and increased recurrence (both P < 0.001) of HCC patients. Moreover, intratumoral IL-17, individually or synergistically with IL-17RE, could predict HCC early recurrence and late recurrence. Also, peritumoral IL-17RE showed the prognostic ability in HCC (P < 0.001 for OS/TTR). Furthermore, expression levels of Th17 associated cytokines including IL-6, -22, -17R and TNF-α were increased in serum of HCC patients compared to haemangioma patients. Importantly, activated human hepatic stellate cells induced in vitro expansion of IL-17+ CD4+ T cells. CONCLUSIONS: High expression of IL-17 and IL-17RE were promising predictors for poor outcome of HCC patients. The protumor power of IL-17 producing CD4+ T cells was probably involved in the crosstalk with different types of inflammatory/immune cells in HCC.
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Carcinoma Hepatocelular/inmunología , Interleucina-17/biosíntesis , Neoplasias Hepáticas/inmunología , Receptores de Interleucina-17/biosíntesis , Carcinoma Hepatocelular/patología , Femenino , Células Estrelladas Hepáticas/inmunología , Células Estrelladas Hepáticas/patología , Humanos , Inmunohistoquímica , Interleucina-17/inmunología , Neoplasias Hepáticas/patología , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Pronóstico , Receptores de Interleucina-17/inmunología , Células Th17/inmunologíaRESUMEN
BACKGROUND & AIMS: The immunosuppressive network within the tumor microenvironment is one of the major obstacles to the success of cancer immunotherapy. γδ T cells are attractive effectors for cancer immunotherapy. Nevertheless, the promising anti-tumor effect in vitro is partially if not totally mitigated in vivo. Thus, understanding the immune status of tumor-infiltrating γδ T cells is essential for orchestrating effective immunotherapy strategies. In this study, we have investigated the immunophenotype and function of γδ T cells in hepatocellular carcinoma (HCC) patients. METHODS: The phenotype of γδ T cells in peripheral blood, and peritumoral and tumoral tissues of HCC patients (n=61) was characterized by flow cytometry. Functional analysis of the HCC-infiltrating γδ T cells was conducted directly after γδ T cell isolation. RESULTS: The infiltration of γδ T cells in tumoral tissues was significantly reduced compared to paired peritumoral tissues. Impairment in degranulation of the granule pathway and downregulation of IFN-γ secretion were also demonstrated in HCC-infiltrating γδ T cells, which was in agreement with the results of gene microarray analysis, and further strengthened by the compromised specific cytotoxicity and IFN-γ secretion in vitro. Moreover, isolated HCC-infiltrating CD4(+)CD25(+) regulatory T cells (Treg cells) directly suppressed the cytotoxic function and IFN-γ secretion of γδ T cells in a TGFß- and IL-10-dependent manner. CONCLUSIONS: The effector function of γδ T cells was substantially impaired in HCC, which is partially mediated by Treg cells. We propose a new mechanism by which immune privilege develops within the tumor milieu.
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Carcinoma Hepatocelular/fisiopatología , Interleucina-10/fisiología , Neoplasias Hepáticas/fisiopatología , Receptores de Antígenos de Linfocitos T gamma-delta/fisiología , Linfocitos T Reguladores/fisiología , Linfocitos T/fisiología , Factor de Crecimiento Transformador beta/fisiología , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Movimiento Celular/fisiología , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Inmunoterapia , Técnicas In Vitro , Interferón gamma/fisiología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Linfocitos T/patología , Linfocitos T Reguladores/patologíaRESUMEN
BACKGROUND: Interferon regulatory factor (IRF)-1 and IRF-2 are transcriptional factors that mediate interferons functions; the loss of IRF-1 expression and gain of IRF-2 expression were associated with malignant phenotype in multiple cancers. However, their roles in the progression of hepatocellular carcinoma (HCC) remain poorly described. METHODS: Immunohistochemistry was used to analyze the nuclear expression of IRF-1/2 in a cohort of 332 HCC patients. The expression of IRF-1/2 in HCC cell lines with stepwise metastasis potential was determined by immunoblotting. Downregulation of IRF-1 or IRF-2 expression was mediated by shRNAs; a series of experiments were conducted to determine the changes of invasion ability and downstream molecular events. RESULTS: High expression of IRF-1 was associated with good outcome (p<.001 for OS/TTR), while high expression of IRF-2 was relevant to increased recurrence probability (p=.049) in HCC patients. The combination of the 2 IRFs showed better predictive power than either factor alone. Immunoblotting analysis revealed that IRF-2/IRF-1 ratio was positively correlated with the metastatic potential in human HCC cell lines. Downregulation of IRF-2 led to sharply attenuated invasion ability, paralleled with a decreased expression of STAT3, p-STAT3(Ser727), and MMP9. While downregulation of IRF-1 caused a concurrent decrease in IRF-2, little or no change was displayed in IRF-2/IRF-1 ratio, invasion ability, and MMP9 expression. CONCLUSIONS: IRF-1 and IRF-2 expression were associated with prognosis of HCC patients with opposite predictive power. IRF-2/IRF-1 ratio was associated with tumor invasion, probably through modulation of MMP9 expression mediated by STAT3.
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Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Factor 1 Regulador del Interferón/metabolismo , Factor 2 Regulador del Interferón/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Línea Celular Tumoral , Núcleo Celular , Regulación hacia Abajo , Femenino , Humanos , Inmunohistoquímica , Factor 1 Regulador del Interferón/genética , Factor 2 Regulador del Interferón/genética , Estimación de Kaplan-Meier , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Pronóstico , Modelos de Riesgos Proporcionales , ARN Interferente Pequeño , Factor de Transcripción STAT3/metabolismo , TransfecciónRESUMEN
OBJECTIVE: To evaluate the efficacy, safety and prognostic impact of rituximab plus CHOP (R-CHOP) regimen on patients with diffuse large B-cell lymphoma (DLBCL), to access the impact of R-CHOP on patients' prognosis and to compare that with CHOP regimen. METHODS: Five hundred and seven newly diagnosed DLBCL patients were enrolled from Jan. 1, 2000 to May 1, 2010. Patients were administered with 6 cycles of CHOP or at least 4 cycles of R-CHOP treatments. Rituximab was administered intravenously on day 1 at a dose of 375 mg/m(2). The typical CHOP regimen include cyclophosphamide (750 mg/m(2), IV), doxorubicin (50 mg/m(2), IV) and vincristine (1.4 mg/m(2), IV, maximum 2 mg) and prednisone (60 - 100 mg, oral, day 3 - 7). The complete response (CR) rates, overall response (OR) rates, and side events of these 2 groups were compared. RESULTS: Of the 411 analyzable patients, 224 received CHOP regimen and 187 received R-CHOP regimen. CR rate for R-CHOP group and CHOP group was 77.01% and 71.43%, respectively. OR rate in R-CHOP group was higher than that in the CHOP group (95.19% vs 87.95%, P = 0.007). The median follow-up time of R-CHOP group was 28.1 months vs that of 35.2 months in CHOP group. There was significant difference in progression free survival (PFS) and overall survival (OS) between 2 groups (P = 0.018 and 0.034, respectively). At the end of follow-up, the estimated median PFS in R-CHOP group had not been reached, while that was 84.8 months in CHOP group. The median OS in both groups had not yet been reached. The adverse events in R-CHOP group were similar with that in CHOP group. CONCLUSIONS: R-CHOP is a safe and effective regimen for management of newly diagnosed DLBCL, with a better remission rate, PFS and OS.
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Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Prednisona/efectos adversos , Prednisona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Rituximab , Tasa de Supervivencia , Resultado del Tratamiento , Vincristina/efectos adversos , Vincristina/uso terapéuticoRESUMEN
Hepatocellular carcinoma (HCC) is a typical inflammation-related malignancy characterized by high postoperative recurrence and metastasis. Although several inflammatory cells and inflammatory signatures have been linked to poor prognosis, the inflammation-associated molecular mechanisms of HCC development and progression are largely unknown. Here we show that triggering receptor expressed in myeloid cells (TREM)-1, a transmembrane receptor expressing in myeloid cells, was also expressed in tumor-activated hepatic stellate cells (HSCs) and associated with the aggressive behavior of HCC cells. Enzyme-linked immunosorbent assay was used to measure the expression levels of soluble TREM-1 (sTREM-1) in activated hepatic stellate cells supernatant and 92 preoperative and postoperative plasmas of patients with malignancy and/or benign liver tumor/disease, respectively. Expression levels of TREM-1 were assessed by immunohistochemistry in tissue microarray from 240 patients with HCC. As a result, increased secretion of sTREM-1 from activated HSCs was observed after co-culture with HCC cell lines (P < 0.001), and conditioned medium collected from activated HSCs/cancer associated myofibroblasts (CAMFs) with or without agonist/inhibitor of TREM-1 significantly changed the migratory ability of HCC cells. The levels of sTREM-1 were significantly higher in patients with HCC than those with benign liver tumors (P < 0.005). Peritumoral density of TREM-1 was shown to be an independent prognosis predictor according to univariate (P < 0.001 for both overall survival and time to recurrence) and multivariate analysis (P = 0.008 for overall survival; P = 0.005 for time to recurrence). Thus, these observations suggest that TREM-1 is related to the aggressive tumor behavior and has potential value as a prognostic factor for HCC.
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Carcinoma Hepatocelular/metabolismo , Células Estrelladas Hepáticas/metabolismo , Hepatitis B/complicaciones , Neoplasias Hepáticas/metabolismo , Glicoproteínas de Membrana/biosíntesis , Receptores Inmunológicos/biosíntesis , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Movimiento Celular , Células Cultivadas , Técnicas de Cocultivo , Medios de Cultivo Condicionados/química , Femenino , Virus de la Hepatitis B , Hepatocitos/metabolismo , Humanos , Inflamación , Interleucina-6/biosíntesis , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Masculino , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/antagonistas & inhibidores , Persona de Mediana Edad , Células Mieloides/inmunología , Células Mieloides/metabolismo , Miofibroblastos/metabolismo , Pronóstico , Receptores Inmunológicos/agonistas , Receptores Inmunológicos/antagonistas & inhibidores , Receptor Activador Expresado en Células Mieloides 1 , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
BACKGROUND AND AIM: The high expression of the galectin-1 predicts poor patient outcome in several tumors. The aim of this study was to investigate its prognostic value in patients with hepatocellular carcinoma (HCC) after resection. METHODS: Galectin-1 and tumor-infiltrating FoxP3(+) regulatory T cells (Tregs) were validated by tissue microarrays from HCC patients (n = 386) and statistically assessed for correlations with the clinical profiles and the prognosis of the patients. RESULTS: We found that galectin-1, which was prevalently upregulated in HCC, was significantly associated with tumor invasive characteristics (such as vascular invasion, incomplete encapsulation, poor differentiation, multiple number, and large tumor size). Patients with high galectin-1 expression had a significantly poorer tumor recurrence (P = 0.025) and overall survival (P = 0.021) than those with low galectin-1 expression. Even in early-stage disease, high galectin-1 expression was also independently associated with shortened survival (P < 0.001) and increased tumor recurrence (P = 0.005). Multivariate Cox proportional hazards analysis showed that galectin-1 was an independent marker for predicting the poor prognosis of HCC. The galectin-1 level was positively related to the number of tumor-infiltrating FoxP3(+) Tregs (r = 0.416, P < 0.001), and their combination served as a better prognosticator. The postoperative tumor recurrence and survival of HCC patients with galectin-1(high) and FoxP3(high) were significantly poorer than the other groups (both P < 0.001). CONCLUSIONS: Galectin-1 might be a new prognostic factor for HCC after resection and could potentially be a high-priority therapeutic target.
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Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/cirugía , Galectina 1/análisis , Hepatectomía , Neoplasias Hepáticas/química , Neoplasias Hepáticas/cirugía , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/secundario , Femenino , Factores de Transcripción Forkhead/análisis , Hepatectomía/efectos adversos , Hepatectomía/mortalidad , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Linfocitos T Reguladores/inmunología , Factores de Tiempo , Análisis de Matrices Tisulares , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
OBJECTIVE: To investigate the number of peripheral blood CD5(+) B cells and their ability of secreting IL-10 in patients with immune thrombocytopenia (ITP). METHODS: Peripheral blood lymphocytes were isolated from 57 pre-treated, 40 post-treated ITP patients and 25 controls using Ficoll-Hypaque density centrifugation and then stained with PE-CD5/FITC-CD19 for flow cytometric analysis. After 24-hour culture, lymphocytes were stained with APC-IL-10 for intracellular cytokine detection. ELISA assay was employed to determine IL-10 concentration in supernatants. RESULTS: The percentage and absolute number of CD5(+) B cells in peripheral blood from pre-treated ITP patients were significantly higher than that from normal controls (3.75 ± 2.37)% vs (2.10 ± 1.08)%, P < 0.01; (6.29 ± 5.77)× 10(7)/L vs (3.06 ± 1.90)× 10(7)/L, P < 0.01. CD5(+) B cells expressed more intracellular IL-10 than other lymphocyte subsets both in ITP patients and normal controls. The percentages of IL-10(+) cells within CD5(+) B cells in pre-treated ITP patients and normal controls were (29.51 ± 20.73)% and(15.90 ± 9.58)%, respectively(P < 0.01). Intracellular mean fluorescence intensity (MFI) of IL-10 in CD5(+) B cells was 27.95 ± 13.99 in pre-treated patients, which was significantly higher than that in controls (P < 0.01). In contrast, IL-10 concentration in supernatants was (173.05 ± 102.50) ng/L in pre-treated ITP group, which was lower than that (230.61 ± 76.96) ng/L in controls. In patients who achieved remission, the number of CD5(+) B cells decreased to level comparable to normal controls. While intracellular IL-10 MFI of CD5(+) B cells in post-treated ITP patients remained as high as in pre-treated ones, the IL-10 concentration in supernatants increased to level similar to controls. CONCLUSION: The significantly increased number of CD5(+) B cells and accumulated IL-10 in CD5(+) B cells suggested impaired IL-10 secretion in ITP patients. The number and the ability of secreting IL-10 of CD5(+) B cells could be restored after effective treatments in patients with ITP.
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Linfocitos B/metabolismo , Interleucina-10/sangre , Púrpura Trombocitopénica Idiopática/sangre , Adulto , Anciano , Linfocitos B/inmunología , Antígenos CD5/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/inmunología , Adulto JovenRESUMEN
Caspase-8 (CASP8) involved in apoptosis plays an important role in mediating the normal regulation of cell proliferation, differentiation, inflammation, and homeostasis of multicellular organisms. Genetic polymorphisms, rs3834129 (-/CTTACT) and rs3769821 (T/C), in the promoter region of different CASP8 transcripts, were reported to be associated with genetic susceptibility of multiple cancers and non-Hodgkin's lymphoma (NHL), respectively. To investigate whether these two genetic variants, together with rs113686495 (-/CTGTCATT) which is 50 bp downstream of rs3769821, were associated with NHL in Chinese patients, we genotyped two cohorts of case and control samples from Kunming (case n = 64, control n = 133) and Shanghai (case n = 75, control n = 107). Luciferase assays were further performed to characterize the potential role of different alleles in the promoter region of the CASP8 gene. In contrast to previous studies, we found no difference regarding the genotypes and haplotypes of rs3834129, rs3769821, and rs113686495 between the case and control samples. Luciferase assays of the promoter regions harboring different alleles of these three variants also showed no difference. Our negative results gave no support for an active role for these genetic variants in conferring NHL in Chinese patients.