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PURPOSE: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown. METHODS: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry. RESULTS: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8. CONCLUSION: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.
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Carcinoma Hepatocelular , Movimiento Celular , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Células Madre Neoplásicas , Transducción de Señal , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Movimiento Celular/genética , Regulación hacia Abajo/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Línea Celular Tumoral , Transducción de Señal/genética , Factor 4 Similar a Kruppel , Masculino , Femenino , Animales , Glutatión Peroxidasa/metabolismo , Glutatión Peroxidasa/genética , Persona de Mediana Edad , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Ratones Endogámicos BALB CRESUMEN
Primary liver cancer (PLC) poses a leading threat to human health, and its treatment options are limited. Meanwhile, the investigation of homogeneity and heterogeneity among PLCs remains challenging. Here, using single-cell RNA sequencing, spatial transcriptomic and bulk multi-omics, we elaborated a molecular architecture of 3 PLC types, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC). Taking a high-resolution perspective, our observations revealed that CHC cells exhibit internally discordant phenotypes, whereas ICC and HCC exhibit distinct tumor-specific features. Specifically, ICC was found to be the primary source of cancer-associated fibroblasts, while HCC exhibited disrupted metabolism and greater individual heterogeneity of T cells. We further revealed a diversity of intermediate-state cells residing in the tumor-peritumor junctional zone, including a congregation of CPE+ intermediate-state endothelial cells (ECs), which harbored the molecular characteristics of tumor-associated ECs and normal ECs. This architecture offers insights into molecular characteristics of PLC microenvironment, and hints that the tumor-peritumor junctional zone could serve as a targeted region for precise therapeutical strategies.
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Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Células Endoteliales/metabolismo , Neoplasias de los Conductos Biliares/genética , Colangiocarcinoma/genética , Conductos Biliares Intrahepáticos , Microambiente Tumoral/genéticaRESUMEN
BACKGROUND AND PURPOSE: Tumor recurrence after liver transplantation (LT) impedes the curative chance for hepatocellular carcinoma (HCC) patients. This study aimed to develop a deep pathomics score (DPS) for predicting tumor recurrence after liver transplantation using deep learning. PATIENTS AND METHODS: Two datasets of 380 HCC patients who underwent LT were enrolled. Residual convolutional neural networks were used to identify six histological structures of HCC. The individual risk score of each structure and DPS were derived by a modified DeepSurv network. Cox regression analysis and Concordance index were used to evaluate the prognostic significance. The cellular exploration of prognostic immune biomarkers was performed by quantitative and spatial proximity analysis according to three panels of 7-color immunofluorescence. RESULTS: The overall classification accuracy of HCC tissue was 97%. At the structural level, immune cells were the most significant tissue category for predicting post-LT recurrence (HR 1.907, 95% CI 1.490-2.440). The C-indices of DPS achieved 0.827 and 0.794 in the training and validation cohorts, respectively. Multivariate analysis for recurrence-free survival (RFS) showed that DPS (HR 4.795, 95% CI 3.017-7.619) was an independent risk factor. Patients in the high-risk subgroup had a shorter RFS, larger tumor diameter and a lower proportion of clear tumor borders. At the cellular level, a higher infiltration of intratumoral NK cells was negatively correlated with recurrence risk. CONCLUSIONS: This study established an effective DPS. Immune cells were the most significant histological structure related to HCC recurrence. DPS performed well in post-LT recurrence prediction and the identification of clinicopathological features.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Pronóstico , Factores de RiesgoRESUMEN
Background: Postoperative recurrence impedes the curability of early-stage hepatocellular carcinoma (E-HCC). We aimed to establish a novel recurrence-related pathological prognosticator with artificial intelligence, and investigate the relationship between pathological features and the local immunological microenvironment. Methods: A total of 576 whole-slide images (WSIs) were collected from 547 patients with E-HCC in the Zhongshan cohort, which was randomly divided into a training cohort and a validation cohort. The external validation cohort comprised 147 Tumor Node Metastasis (TNM) stage I patients from The Cancer Genome Atlas (TCGA) database. Six types of HCC tissues were identified by a weakly supervised convolutional neural network. A recurrence-related histological score (HS) was constructed and validated. The correlation between immune microenvironment and HS was evaluated through extensive immunohistochemical data. Results: The overall classification accuracy of HCC tissues was 94.17%. The C-indexes of HS in the training, validation and TCGA cohorts were 0.804, 0.739 and 0.708, respectively. Multivariate analysis showed that the HS (HR= 4.05, 95% CI: 3.40-4.84) was an independent predictor for recurrence-free survival. Patients in HS high-risk group had elevated preoperative alpha-fetoprotein levels, poorer tumor differentiation and a higher proportion of microvascular invasion. The immunohistochemistry data linked the HS to local immune cell infiltration. HS was positively correlated with the expression level of peritumoral CD14+ cells (p= 0.013), and negatively with the intratumoral CD8+ cells (p< 0.001). Conclusions: The study established a novel histological score that predicted short-term and long-term recurrence for E-HCCs using deep learning, which could facilitate clinical decision making in recurrence prediction and management.
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BACKGROUND: Combination conversion therapies afforded curative surgery chance for initially unresectable hepatocellular carcinoma (uHCC). This study aimed to evaluate the conversion rate and clinical outcomes of a first-line conversion regimen of lenvatinib combined with transarterial chemoembolization (TACE) plus immunotherapy for initial uHCC by interpreting real-world data. METHODS: Conversion therapy data of patients with uHCC from November 2018 to January 2021 were analysed. The regimens included triple combination therapy (t-CT: lenvatinib, TACE, plus toripalimab) and dual combination therapy (d-CT: lenvatinib plus TACE). Another study population diagnosed with hepatocellular carcinoma of macrovascular invasion disease were included as the upfront surgery cohort. Treatment responses and conversion rate were primary outcomes. Survival and adverse events were analysed. RESULTS: Fifty-one patients receiving t-CT (n = 30) and d-CT (n = 21) were enrolled. Higher overall response rates (76.7 per cent versus 47.6 per cent, P = 0.042) and disease control rates (90.0 per cent versus 57.1 per cent, P = 0.042) were observed via t-CT than d-CT. Both median overall survival and event-free survival were not reached in the t-CT cohort. A higher rate of curative conversion resection was achieved through t-CT than d-CT (50.0 per cent versus 19.0 per cent, P = 0.039). The disease-free survival of patients undergoing conversion resection in the t-CT cohort (n = 15) was higher than that in the upfront surgery cohort (n = 68, P = 0.039). Both t-CT and d-CT regimens were tolerable. CONCLUSIONS: Better treatment responses and conversion rate for patients with uHCC were obtained with first-line t-CT. Neoadjuvant t-CT before surgery should be recommended for patients with macrovascular invasion.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/efectos adversos , Humanos , Neoplasias Hepáticas/patología , Compuestos de Fenilurea , Quinolinas , Resultado del TratamientoRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by inflammation and immunopathogenesis. Accumulating evidence has shown that the cystathionine ß-synthase/hydrogen sulfide (CBS/H2S) axis is involved in the regulation of inflammation. However, roles of CBS in HCC development and immune evasion have not been systematically investigated, and their underlying mechanisms remain elusive. Here, we investigated the roles of CBS in tumor cells and tumor microenvironment of HCC. METHODS: 236 HCC samples were collected to detect the expression of CBS, cleaved Caspase-3 and paired related homeobox 2 (PRRX2) and the number of immune cells. HCC cell lines were employed to examine the effects of CBS on cellular viability, apoptosis and signaling in vitro. Cbs heterozygous knockout mice, C57BL/6 mice, nude mice and non-obese diabetic severe combined immunodeficiency mice were used to investigate the in vivo functions of CBS. RESULTS: Downregulation of CBS was observed in HCC, and low expression of CBS predicted poor prognosis in HCC patients. CBS overexpression dramatically promoted cellular apoptosis in vitro and inhibited tumor growth in vivo. Activation of the Cbs/H2S axis also reduced the abundance of tumor-infiltrating Tregs, while Cbs deficiency promoted Tregs-mediated immune evasion and boosted tumor growth in Cbs heterozygous knockout mice. Mechanistically, CBS facilitated the expression cleaved Caspase-3 in tumor cells, and on the other hand, suppressed Foxp3 expression in Tregs via inactivating IL-6/STAT3 pathway. As a transcription factor of IL-6, PRRX2 was reduced by CBS. Additionally, miR-24-3p was proven to be an upstream suppressor of CBS in HCC. CONCLUSIONS: Our results indicate the antitumor function of CBS in HCC by inactivation of the PRRX2/IL-6/STAT3 pathway, which may serve as a potential target for HCC clinical immunotherapy.
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Cistationina betasintasa/inmunología , Proteínas de Homeodominio/inmunología , Interleucina-6/inmunología , Neoplasias Hepáticas/inmunología , Factor de Transcripción STAT3/inmunología , Linfocitos T Reguladores/inmunología , Animales , Apoptosis/fisiología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Cistationina betasintasa/biosíntesis , Cistationina betasintasa/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Sulfuro de Hidrógeno/inmunología , Sulfuro de Hidrógeno/metabolismo , Interleucina-6/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Escape del Tumor , Microambiente TumoralRESUMEN
RhIII-catalyzed sp2 C-H cross-coupling of acrylamides with organoboron reactants has been accomplished using a commercially available N-2,6-difluoroaryl acrylamide auxiliary. A broad range of aryl and vinyl boronates as well as a variety of heterocyclic boronates with strong coordinating ability can serve as the coupling partners. This transformation proceeds under moderate reaction conditions with excellent functional group tolerance and high regioselectivity.
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BACKGROUND: The prognosis of patients with combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (CHC) is usually poor, and effective adjuvant therapy is missing making it important to investigate whether these patients may benefit from adjuvant transarterial chemoembolization (TACE). We aimed to evaluate the efficiency of adjuvant TACE for long-term recurrence and survival after curative resection before and after propensity score matching (PSM) analysis. METHODS: In this retrospective study, of 230 patients who underwent resection for CHC between January 1994 and December 2014, 46 (18.0%) patients received adjuvant TACE. Univariate and multivariate regression analyses were used to identify the independent predictive factors of survival. Cox regression analyses and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS) between patients who did or did not receive adjuvant TACE. RESULTS: A total of 230 patients (mean age 52.2 ± 11.9 years; 172 men) were enrolled, and 46 (mean age 52.7 ± 11.1 years; 38 men) patients received TACE. Before PSM, in multivariate regression analysis, γ-glutamyl transpeptidase (γ-GT), tumour nodularity, macrovascular invasion (MVI), lymphoid metastasis, and extrahepatic metastasis were associated with OS. Alanine aminotransferase (ALT), MVI, lymphoid metastasis, and preventive TACE (HR: 2.763, 95% CI: 1.769-4.314, p < 0.001) were independent prognostic factors for DFS. PSM created 46 pairs of patients. Before PSM, adjuvant preventive TACE was not associated with an increased risk of OS (HR: 0.911, 95% CI: 0.545-1.520, p = 0.720) or DFS (HR: 3.345, 95% CI: 1.686-6.638, p = 0.001). After PSM, the 5-year OS and DFS rates were comparable in the TACE group and the non-TACE group (OS: 22.7% vs 14.9%, respectively, p = 0.75; DFS: 11.2% vs 14.4%, respectively, p = 0.06). CONCLUSIONS: The present study identified that adjuvant preventive TACE did not influence DFS or OS after curative resection of CHC.
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Neoplasias de los Conductos Biliares/mortalidad , Carcinoma Hepatocelular/mortalidad , Quimioembolización Terapéutica/mortalidad , Colangiocarcinoma/mortalidad , Hepatectomía/mortalidad , Neoplasias Hepáticas/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/terapia , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/terapia , Quimioterapia Adyuvante , Colangiocarcinoma/patología , Colangiocarcinoma/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Comorbidity among cancer patients is prevalent and influential to prognosis after operation. Limited data are available on comorbidity evaluations in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to assess the comorbidity distribution in ICC patients and to adapt the Charlson Comorbidity Index (CCI) or the age-adjusted CCI (ACCI) for survival prediction. METHODS: The study cohort included 268 ICC patients treated with curative surgery from January 2000 to December 2007 at the Department of Liver Surgery, Zhongshan Hospital. The association between the comorbidity index and overall survival (OS) or disease-free survival (DFS). was analyzed by the Kaplan-Meier method. Multivariable analysis was established to select the determinant parameters. RESULTS: Major comorbid conditions of ICC patients included liver disease, hypertension, diabetes and ulcer. The median follow-up time was 25.5 months in the whole data set. Among the entire cohort, the 1-, 3- and 5-year OS rates were 55.3%, 26.0% and 15.6%, respectively. In multivariate analysis, the ACCI correlated with OS, and higher scores were associated with poorer prognosis (hazard ratio =1.134, 95% confidence interval: 1.015-1.267 and P value =0.026). CCI was not an independent predictive factor for OS or DFS. CONCLUSIONS: In contrast to CCI, ACCI was a more promising model to accurately predict OS in ICC patients who underwent liver resection. Further research should be focused on the impact of comorbidity therapies.
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BACKGROUND: Immunoscore have shown a promising prognostic value in many cancers. We aimed to establish and validate an immune classifier to predict survival after curative resection of hepatocellular carcinoma (HCC) patients who have undergone curative resection. METHODS: The immunohistochemistry (IHC) classifier assay was performed on 664 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC. A nine-feature-based HCC-IHC classifier was then constructed by the least absolute shrinkage and selection operator method. The associations between the HCC-IHC classifier and patient outcomes were assessed. Herein, a nomogram was generated from the Cox regression coefficients and evaluated by decision curve analysis. RESULTS: We constructed an HCC-IHC classifier based on nine features; significant differences were found between the low-HCC-IHC classifier patients and high-HCC-IHC classifier patients in the training cohort in the 5-year relapse-free survival rates (46.7% vs. 26.7%, respectively; P < 0.001). The HCC-IHC classifier-based nomogram presented better accuracy than traditional staging systems. CONCLUSIONS: In conclusion, the HCC-IHC classifier could effectively predict recurrence in early-stage HCC patients and supplemented the prognostic value of the BCLC staging system. The HCC-IHC classifier may facilitate patient decision-making and individualise the management of postoperative patients with early-stage HCC.
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Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunohistoquímica/métodos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de Supervivencia , Transcriptoma/genéticaRESUMEN
BACKGROUND: Mixed evidence challenges preoperative alpha-fetoprotein (AFP) as an independent prognostic factor for patients with hepatocellular carcinoma (HCC) after hepatectomy. RESULTS: Daily post-operative decrease of AFP by 9% as compared to the preoperative level (A09) were selected as the Cut-off. The Kaplan-Meier curve showed that A09 was significantly different for OS (P=0.043) and RFS (P=0.03). A decrease in risk by 54% was observed for OS and 32% for RFS in the at-risk population (A09>9%). A better concordance was observed after adding A09 into TNM and BCLC staging systems. Moreover, a consistent concordance was observed in the internal (FDZS5:0.63; FDZS3:0.608) and external (FDZS5:0.85; FDZS3:0.762) validation cohorts, suggesting its prognostic value in HCC population with elevated AFP. CONCLUSIONS: Decrease in perioperative serum AFP rather than preoperative AFP is an independent prognostic factor for HCC patients after hepatectomy. Cut-off A09 significantly discriminates overall and recurrence-free survival and could be interpret into TNM and BCLC staging systems to improve the stratification power for HCC patients with elevated AFP. METHODS: Kaplan-Meier curve depicted the differences of overall survival (OS) and recurrence-free survival (RFS). Nomogram and concordance were employed to evaluate the superiority of the current staging system.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , alfa-Fetoproteínas/metabolismo , Anciano , Biomarcadores de Tumor , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Background: Whether microvascular invasion (MVI) adversely influences oncological outcomes for intrahepatic cholangiocarcinoma (ICC) patients remains unclear. The purpose of this study was to determine the impact of MVI on postoperative survival and establish a new predictive model for MVI before surgical intervention in patients with ICC. Methods: In this two-center retrospective study, 556 and 31 consecutive patients who underwent curative liver resection for ICC at ZSH and XJFH were analyzed, respectively. Propensity score matching (PSM) and Cox regression analyses were used to explore the prognostic role of MVI on the OS and DFS. Multivariate logistic regression was used to identify the relative risk factors of MVI, which were incorporated into the nomogram. Results: After PSM, 50 MVI cases matched with 172 non-MVI cases, and no bias was observed between the two groups (propensity score, 0.118 (0.099, 0.203) vs. 0.115 (0.059, 0.174), p=0.251). The multivariate Cox analysis showed that MVI was negatively associated with OS (HR 1.635, 95% CI 1.405-1.993, p=0.04) and DFS (HR 1.596, 95% CI 1.077-2.366, p=0.02). The independent factors associated with MVI were ALT, AFP, tumor maximal diameter, and tumor capsule. The nomogram that incorporated these variables achieved good concordance indexes for predicting MVI. Patients with a cutoff score of 168 were considered to have different risks of the presence of MVI preoperatively. Conclusions: The presence of MVI was an adverse prognostic factor for ICC patients. Using the nomogram model, the risk of an individual patient harboring MVI was determined, which led to a rational therapeutic choice.
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Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with poor prognosis. The evaluation of recurrence risk after liver resection is of great importance for ICCs. We aimed to assess the prognostic value of intra- and peritumoral immune infiltrations and to establish a novel histopathology-related immunoscore (HRI) associated with ICC recurrence. A total of 280 ICC patients who received curative resection between February 2005 and July 2011 were enrolled in our study. Patients were randomly assigned to the derivation cohort (n = 176) or the validation cohort (n = 104). Sixteen immune biomarkers in both intra- and peritumoral tissues were examined by immunohistochemistry. The least absolute shrinkage and selection operator (LASSO) Cox model was used to establish the HRI score. Cox regression analysis was used for multivariate analysis. Nine recurrence-related immune features were identified and integrated into the HRI score. The HRI score was used to categorize patients into low-risk and high-risk groups using the X-tile software. Kaplan-Meier analysis presented that the HRI score showed good stratification between low-risk and high-risk groups in both the derivation cohort (P < 0.001) and the validation cohort (P = 0.014), respectively. Multivariate analysis demonstrated that serum γ-glutamyl transpeptidase, carbohydrate antigen 19-9, lymphoid metastasis, tumor numbers, and the HRI score were independent risk factors associated with recurrence-free survival (RFS). The combination of Shen's model and HRI score provided better performance in recurrence prediction compared with traditional staging systems. The HRI score might serve as a promising RFS predictor for ICC with prognostic values.
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Antígenos de Carbohidratos Asociados a Tumores/metabolismo , Biomarcadores de Tumor/metabolismo , Colangiocarcinoma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Hígado/metabolismo , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , Estudios de Cohortes , Femenino , Hepatectomía , Humanos , Hígado/patología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Pronóstico , Proyectos de Investigación , Análisis de Supervivencia , Carga Tumoral , gamma-Glutamiltransferasa/metabolismoRESUMEN
Purpose: To develop and validate a decision aid to help make individualized estimates of tumor recurrence for patients with resected combined hepatocellular cholangiocarcinoma (CHC). Patients and methods: Risk factors of recurrence were identified in the derivation cohort of 208 patients who underwent liver resection between 1995 and 2014 at Zhongshan Hospital to develop a prediction score. The model was subsequently validated in an external cohort of 101 CHC patients using the C concordance statistic and net reclassification index (NRI). Results: On multivariate analysis, five independent predictors associated with tumor recurrence were identified, including sex, γ-glutamyl transferase, macrovascular invasion, hilar lymphoid metastasis and adjuvant transcatheter arterial chemoembolization. The prediction score was constructed using these 5 variables, with scores ranging from 0 to 5. A patient with a score of 0 had a predicted 1- and 5-year recurrence risk of 11.1% and 22.2%, respectively. In the validation cohort, the NRIs of prediction score vs American Joint Committee on Cancer 7th TNM staging system at 1-year and 5-year were 0.185 (95% CI, 0.090-0.279, P<0.001) and 0.425 (95% CI, 0.044-0.806, P=0.03), respectively. Conclusion: Our developed and validated prediction score might be a simple and reliable method in postoperative CHC patients and help clinicians identify candidates who may benefit from future adjuvant therapies.
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BACKGROUND: Intratumoral immune infiltrates have manifested a robust prognostic signature in patients with hepatocellular carcinoma (HCC). We hypothesized that a novel tissue-related immune signature (TRIS) could improve the prediction of postoperative survival for patients diagnosed with early/intermediate HCC. METHODS: Twenty-eight immune features were immunohistochemically examined on 352 HCC specimens. The LASSO Cox regression model was used to construct a five-feature-based TRIS. The univariate and multivariate Cox analyses were performed. Based on independent predictors, the immune-clinical prognostic index (ICPI) was established. Performance assessment was measured with C-index and compared with seven traditional staging systems. The independent validation cohort (n = 393) was included to validate the model. RESULTS: By using the LASSO method, the TRIS were constructed on the basis of five immune features, CD3intratumoral (T), CD27T, CD68peritumoral (P), CD103T, and PD1T. Multivariate Cox analysis showed that the TRIS was an independent prognostic predictor. In the training cohort, γ-glutamyl transferase, tumor diameter, tumor differentiation, and TRIS were incorporated into the ICPI. The ICPI presented satisfactory discrimination ability, with C-index values of 0.691 and 0.686 in the training and validation cohorts, respectively. Compared with seven conventional staging systems (C-index, training cohort, 0.548-0.597; validation cohort, 0.519-0.610), the ICPI exhibited better performance for early/intermediate-stage HCCs. Further, the patients were categorized into three subgroups with X-tile software, and the stratified ICPI presented a superior corrected Akaike information criterion and homogeneity in both cohorts. CONCLUSIONS: Our ICPI was a useful and reliable prognostic tool which may offer good individualized prediction capability for HCC patients with early/intermediate stage.
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Carcinoma Hepatocelular/diagnóstico , Inmunofenotipificación , Neoplasias Hepáticas/diagnóstico , Linfocitos Infiltrantes de Tumor/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Estudios de Cohortes , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación/métodos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Linfocitos/patología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de Supervivencia , Análisis de Matrices Tisulares , TranscriptomaRESUMEN
Glutathione transferase Mu 1 (GSTM1) induces cancer drug resistance by hydrolyzing cancer chemotherapeutics or activating the anti-apoptosis pathway. However, the chemoresistance-inducing mechanism of GSTM1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, the expression of GSTM1 was examined in three HCC cell lines. Oxaliplatin and sorafenib were selected as chemotherapeutic agents. Small interfering RNA was used to decrease GSTM1 expression. Cell death was measured using MTT and annexin V/propidium iodide assays. Activation of autophagy was evaluated by green fluorescent protein-light chain 3 redistribution and analysis of autophagy-related 5 expression in MHCC97-H and Huh-7 cells. A stepwise increase in GSTM1 expression with increasing metastatic potential of HCC cell lines was revealed. Cell death induced by oxaliplatin and sorafenib was significantly increased following GSTM1-knockdown in MHCC97-H and Huh-7 cells. Activation of autophagy was significantly inhibited by silencing GSTM1 expression. The results of the present study suggest that GSTM1 may protect HCC cells against the effect of oxaliplatin treatment through activating autophagy. The present study provides a novel perspective on HCC drug-resistance.
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Aims: To compare the long-term prognosis of younger and elderly patients with combined hepatocellular-cholangiocarcinoma (CHC) who underwent curative resection between 1993 and 2014 at our center. Methods: Two hundred and thirteen patients who underwent liver resection for CHC were enrolled in our study. The overall survival (OS) and disease-free survival (DFS) of elderly patients (age≥60, n=52) and younger patients (age<60, n=161) were compared by multivariate analysis and propensity score matching (PSM) analysis. Results: Among the 213 CHC patients, the elderly patients had a higher rate of worse Child-Pugh grade (P=0.027), abnormal serum albumin (P<0.001) and lymphoid metastases (P=0.024). The proportion of HBV-positive CHC patients (74.6%, 159/213) was much higher than that observed in healthy cohorts. Younger patients had a higher rate of hepatitis B virus (HBV) infection compared to older patients (83.9% vs 46.2%, P<0.001). OS and DFS of the elderly and younger patients before and after propensity score matching were comparable. Conclusion: Elderly and younger patients who underwent liver resection for CHC have comparable long-term OS and DFS.
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Backgrounds: Regarding the difficulty of CHC diagnosis and potential adverse outcomes or misuse of clinical therapies, an increasing number of patients have undergone liver transplantation, transcatheter arterial chemoembolization (TACE) or other treatments. Objective: To construct a convenient and reliable risk prediction model for identifying high-risk individuals with combined hepatocellular-cholangiocarcinoma (CHC). Methods: 3369 patients who underwent surgical resection for liver cancer at Zhongshan Hospital were enrolled in this study. The epidemiological and clinical characteristics of the patients were collected at the time of tumor diagnosis. Variables (P <0.25 in the univariate analyses) were evaluated using backward stepwise method. A receiver operating characteristic (ROC) curve was used to assess model discrimination. Calibration was performed using the Hosmer-Lemeshow test and a calibration curve. Internal validation was performed using a bootstrapping approach. Results: Among the entire study population, 250 patients (7.42%) were pathologically defined with CHC. Age, HBcAb, red blood cells (RBC), blood urea nitrogen (BUN), AFP, CEA and portal vein tumor thrombus (PVTT) were included in the final risk prediction model (area under the curve, 0.69; 95% confidence interval, 0.51-0.77). Bootstrapping validation presented negligible optimism. When the risk threshold of the prediction model was set at 20%, 2.73% of the patients diagnosed with liver cancer would be diagnosed definitely, which could identify CHC patients with 12.40% sensitivity, 98.04% specificity, and a positive predictive value of 33.70%. Conclusions: Herein, the study established a risk prediction model which incorporates the clinical risk predictors and CT/MRI-presented PVTT status that could be adopted to facilitate the diagnosis of CHC patients preoperatively.
RESUMEN
Peroxisomes account for ~35% of total H2O2 generation in mammalian tissues. Peroxisomal ACOX1 (acyl-CoA oxidase 1) is the first and rate-limiting enzyme in fatty acid ß-oxidation and a major producer of H2O2 ACOX1 dysfunction is linked to peroxisomal disorders and hepatocarcinogenesis. Here, we show that the deacetylase sirtuin 5 (SIRT5) is present in peroxisomes and that ACOX1 is a physiological substrate of SIRT5. Mechanistically, SIRT5-mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation in both cultured cells and mouse livers. Deletion of SIRT5 increases H2O2 production and oxidative DNA damage, which can be alleviated by ACOX1 knockdown. We show that SIRT5 downregulation is associated with increased succinylation and activity of ACOX1 and oxidative DNA damage response in hepatocellular carcinoma (HCC). Our study reveals a novel role of SIRT5 in inhibiting peroxisome-induced oxidative stress, in liver protection, and in suppressing HCC development.
Asunto(s)
Acil-CoA Oxidasa/antagonistas & inhibidores , Acil-CoA Oxidasa/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Estrés Oxidativo , Sirtuinas/metabolismo , Acil-CoA Oxidasa/genética , Animales , Daño del ADN , Regulación hacia Abajo , Femenino , Técnicas de Silenciamiento del Gen , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Peróxido de Hidrógeno , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Oxidación-Reducción , Peroxisomas/química , Pronóstico , Sirtuinas/genéticaRESUMEN
BACKGROUND: Whether perioperative blood transfusions (PBTs) adversely influence oncological outcomes for intrahepatic cholangiocarcinoma (ICC) patients after curative resection remains undetermined. METHODS: Of the 605 patients who underwent curative liver resection for ICC between 2000 and 2012, 93 received PBT. We conducted Cox regression and variable selection logistic regression analyses to identify confounding factors of PBT. Propensity score matching (PSM) and Cox regression analyses were used to compare the overall survival (OS) and disease-free survival (DFS) between the patients with or without PBT. RESULTS: After exclusion, 93 eligible patients (15.4%) received PBT, compared with 512 (84.6%) who did not receive PBT; the groups were highly biased in terms of the propensity score (PS) analysis (0.096 ± 0.104 vs. 0.479 ± 0.372, p < 0.001). PBT was associated with an increased risk of OS (HR: 1.889, 95% CI: 1.446-2.468, p < 0.001) and DFS (HR: 1.589, 95% CI: 1.221-2.067, p < 0.001) in the entire cohort. After propensity score matching (PSM), no bias was observed between the groups (PS,0.136 ± 0.117 VS. 0.193 ± 0.167, p = 0.785). In the multivariate Cox analysis, PBT was not associated with increased risks of OS (HR: 1.172, 95% CI: 0.756-1.816, p = 0.479) and DFS (HR: 0.944, 95% CI: 0.608-1.466, p = 0.799). After propensity score adjustment, PBT was still not associated with OS or DFS after ICC curative resection. CONCLUSIONS: The present study found that PBT did not affect DFS and OS after curative resection of ICC.