Objectives:To investigate the effect of the expression of low-density lipoprotein receptor associated protein (LDLR) on the vascular abnormalities in hepatocellular carcinoma (HCC) and its mechanisms.Methods:Based on the information of Oncomine Cancer GeneChip database, we analyzed the correlation between the expression level of LDLR and the expression level of carcinoembryonic antigen (CEA) and CD31 in hepatocellular carcinoma tissues. Lentiviral transfection of short hairpin RNA target genes was used to construct LDLR-knockdown MHCC-97H and HLE hepatocellular carcinoma cells. The differential genes and their expression level changes in LDLR-knockdown hepatocellular carcinoma cells were detected by transcriptome sequencing, real-time fluorescence quantitative polymerase chain reaction, and protein immunoblotting. The gene-related signaling pathways that involve LDLR were clarified by enrichment analysis. The effect of LDLR on CEA was assessed by the detection of CEA content in conditioned medium of hepatocellular carcinoma cells. Angiogenesis assay was used to detect the effect of LDLR on the angiogenic capacity of human umbilical vein endothelial cells, as well as the role of CEA in the regulation of angiogenesis by LDLR. Immunohistochemical staining was used to detect the expression levels of LDLR in 176 hepatocellular carcinoma tissues, and CEA and CD31 in 146 hepatocellular carcinoma tissues, and analyze the correlations between the expression levels of LDLR, CEA, and CD31 in the tissues, serum CEA, and alanine transaminase (ALT).Results:Oncomine database analysis showed that the expressions of LDLR and CEA in the tissues of hepatocellular carcinoma patients with portal vein metastasis were negatively correlated ( r=-0.64, P=0.001), whereas the expressions of CEA and CD31 in these tissues were positively correlated ( r=0.46, P=0.010). The transcriptome sequencing results showed that there were a total of 1 032 differentially expressed genes in the LDLR-knockdown group and the control group of MHCC-97H cells, of which 517 genes were up-regulated and 515 genes were down-regulated. The transcript expression level of CEACAM5 was significantly up-regulated in the cells of the LDLR-knockdown group. The Gene Ontology (GO) function enrichment analysis showed that the differential genes were most obviously enriched in the angiogenesis function. The Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis showed that the relevant pathways involved mainly included the cellular adhesion patch, the extracellular matrix receptor interactions, and the interactions with the extracellular matrix receptors. The CEA content in the conditioned medium of the LDLR-knockdown group was 43.75±8.43, which was higher than that of the control group (1.15±0.14, P＜0.001). The results of angiogenesis experiments showed that at 5 h, the number of main junctions, the number of main segments, and the total area of the lattice formed by HUVEC cells cultured with the conditioned medium of MHCC-97H cells in the LDLR-knockdown group were 295.3±26.4, 552.5±63.8, and 2 239 781.0±13 8211.9 square pixels, which were higher than those of the control group (113.3±23.5, 194.8±36.5, and 660 621.0±280 328.3 square pixels, respectively, all P＜0.01).The number of vascular major junctions, the number of major segments, and the total area of the lattice formed by HUVEC cells cultured in conditioned medium with HLE cells in the LDLR-knockdown group were 245.3±42.4, 257.5±20.4, and 2 535 754.5±249 094.2 square pixels, respectively, which were all higher than those of the control group (113.3±23.5, 114.3±12.2, and 1 565 456.5±219 259.7 square pixels, respectively, all P＜0.01). In the conditioned medium for the control group of MHCC-97H cells,the number of main junctions, the number of main segments, and the total area of the lattice formed by the addition of CEA to cultured HUVEC cells were 178.9±12.0, 286.9±12.3, and 1 966 990.0±126 249.5 spixels, which were higher than those in the control group (119.7±22.1, 202.7±33.7, and 1 421 191.0±189 837.8 square pixels, respectively). The expression of LDLR in hepatocellular carcinoma tissues was not correlated with the expression of CEA, but was negatively correlated with the expression of CD31 ( r=-0.167, P=0.044), the level of serum CEA ( r=-0.061, P=0.032), and the level of serum ALT (r=-0.147, P=0.05). The expression of CEA in hepatocellular carcinoma tissues was positively correlated with the expression of CD31 ( r=0.192, P=0.020). The level of serum CEA was positively correlated with the level of serum ALT ( r=0.164, P=0.029). Conclusion:Knocking down LDLR can promote vascular abnormalities in HCC by releasing CEA.

Objectives:To investigate the effect of the expression of low-density lipoprotein receptor associated protein (LDLR) on the vascular abnormalities in hepatocellular carcinoma (HCC) and its mechanisms.Methods:Based on the information of Oncomine Cancer GeneChip database, we analyzed the correlation between the expression level of LDLR and the expression level of carcinoembryonic antigen (CEA) and CD31 in hepatocellular carcinoma tissues. Lentiviral transfection of short hairpin RNA target genes was used to construct LDLR-knockdown MHCC-97H and HLE hepatocellular carcinoma cells. The differential genes and their expression level changes in LDLR-knockdown hepatocellular carcinoma cells were detected by transcriptome sequencing, real-time fluorescence quantitative polymerase chain reaction, and protein immunoblotting. The gene-related signaling pathways that involve LDLR were clarified by enrichment analysis. The effect of LDLR on CEA was assessed by the detection of CEA content in conditioned medium of hepatocellular carcinoma cells. Angiogenesis assay was used to detect the effect of LDLR on the angiogenic capacity of human umbilical vein endothelial cells, as well as the role of CEA in the regulation of angiogenesis by LDLR. Immunohistochemical staining was used to detect the expression levels of LDLR in 176 hepatocellular carcinoma tissues, and CEA and CD31 in 146 hepatocellular carcinoma tissues, and analyze the correlations between the expression levels of LDLR, CEA, and CD31 in the tissues, serum CEA, and alanine transaminase (ALT).Results:Oncomine database analysis showed that the expressions of LDLR and CEA in the tissues of hepatocellular carcinoma patients with portal vein metastasis were negatively correlated ( r=-0.64, P=0.001), whereas the expressions of CEA and CD31 in these tissues were positively correlated ( r=0.46, P=0.010). The transcriptome sequencing results showed that there were a total of 1 032 differentially expressed genes in the LDLR-knockdown group and the control group of MHCC-97H cells, of which 517 genes were up-regulated and 515 genes were down-regulated. The transcript expression level of CEACAM5 was significantly up-regulated in the cells of the LDLR-knockdown group. The Gene Ontology (GO) function enrichment analysis showed that the differential genes were most obviously enriched in the angiogenesis function. The Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis showed that the relevant pathways involved mainly included the cellular adhesion patch, the extracellular matrix receptor interactions, and the interactions with the extracellular matrix receptors. The CEA content in the conditioned medium of the LDLR-knockdown group was 43.75±8.43, which was higher than that of the control group (1.15±0.14, P＜0.001). The results of angiogenesis experiments showed that at 5 h, the number of main junctions, the number of main segments, and the total area of the lattice formed by HUVEC cells cultured with the conditioned medium of MHCC-97H cells in the LDLR-knockdown group were 295.3±26.4, 552.5±63.8, and 2 239 781.0±13 8211.9 square pixels, which were higher than those of the control group (113.3±23.5, 194.8±36.5, and 660 621.0±280 328.3 square pixels, respectively, all P＜0.01).The number of vascular major junctions, the number of major segments, and the total area of the lattice formed by HUVEC cells cultured in conditioned medium with HLE cells in the LDLR-knockdown group were 245.3±42.4, 257.5±20.4, and 2 535 754.5±249 094.2 square pixels, respectively, which were all higher than those of the control group (113.3±23.5, 114.3±12.2, and 1 565 456.5±219 259.7 square pixels, respectively, all P＜0.01). In the conditioned medium for the control group of MHCC-97H cells,the number of main junctions, the number of main segments, and the total area of the lattice formed by the addition of CEA to cultured HUVEC cells were 178.9±12.0, 286.9±12.3, and 1 966 990.0±126 249.5 spixels, which were higher than those in the control group (119.7±22.1, 202.7±33.7, and 1 421 191.0±189 837.8 square pixels, respectively). The expression of LDLR in hepatocellular carcinoma tissues was not correlated with the expression of CEA, but was negatively correlated with the expression of CD31 ( r=-0.167, P=0.044), the level of serum CEA ( r=-0.061, P=0.032), and the level of serum ALT (r=-0.147, P=0.05). The expression of CEA in hepatocellular carcinoma tissues was positively correlated with the expression of CD31 ( r=0.192, P=0.020). The level of serum CEA was positively correlated with the level of serum ALT ( r=0.164, P=0.029). Conclusion:Knocking down LDLR can promote vascular abnormalities in HCC by releasing CEA.

Objective:To study the expression level of programmed death ligand 1 (PD-L1) in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and its correlation with the clinical characteristics and prognosis.Methods:The clinical data of 75 patients with cHCC-CCA undergoing surgery in Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2019, including 61 males and 14 females, with a median age of 55 years (36 to 77). Immunohistochemistry was conducted to determine the PD-L1 expression in tumor. The status of PD-L1 expression, clinicopathological data and prognosis of patients were analyzed.Results:In low-differentiated cHCC-CCA tissues, the proportion of PD-L1 expression (21.1%, 8/38) was higher than that in moderately to well-differentiated cHCC-CCA tissues (2.70%, 1/37, χ2=4.366, P=0.037). The median disease-free survival (DFS) and overall survival (OS)of PD-L1 positive patients were 12.3 and 15.1 months, respectively, lower than those of PD-L1 negative patients (14.4 and 23.3 months). The difference of DFS was statistically significant ( χ2=4.052, P=0.044). In multivariate analysis, major vascular invasion (DFS: HR=1.965, 95% CI: 1.119-3.450, P=0.019; OS: HR=1.781, 95% CI: 1.022-3.105, P=0.042) and lymph node metastasis (DFS: HR=2.451, 95% CI: 1.1033-5.814, P=0.042; OS: HR=2.652, 95% CI: 1.120-6.279, P=0.027) were identified as independent prognostic factors affecting DFS and OS. Conclusions:The proportion of PD-L1 positive is higher inthe low-differentiated cHCC-CCA tissue compared to that in moderately to well-differentiated cHCC-CCA. The major vascular invasion and lymph node metastasis are independent factors affecting the prognosis of patients with cHCC-CCA.

Liver is the most common metastatic organ in patients with advanced colorectal cancer. Once colorectal cancer liver metastasis (CRLM) occurs, the prognosis will be poor. Therefore early detection of CRLM has a great clinical significance for improving the prognosis of CRLM patients. Surgical resection of primary and metastatic lesion is the only possible curable option for CRLM, translational therapy, interventional therapy and multidisciplinary team also provide more treatment ideas. Long non-coding RNA, cancer stem cells and phosphatidylinositide-3-kinases/protein kinase B signaling pathway reveal the main mechanism of CRLM from different aspects. This article reviews the recent advances in the early diagnosis, treatments and main mechanisms of CRLM.

Objective:To examine a survival prognostic model applicable for patients with intrahepatic cholangiocarcinoma (ICC) based on Bayesian network.Methods:The clinical and pathological data of ICC patients who underwent curative intent resection in ten Chinese hepatobiliary surgery centers from January 2010 to December 2018 were collected.A total of 516 patients were included in the study. There were 266 males and 250 females.The median age( M( Q R)) was 58(14) years.One hundred and sixteen cases (22.5%) with intrahepatic bile duct stones,and 143 cases (27.7%) with chronic viral hepatitis.The Kaplan-Meier method was used for survival analysis.The univariate and multivariate analysis were implemented respectively using the Log-rank test and Cox proportional hazard model.One-year survival prediction models based on tree augmented naive Bayesian (TAN) and na?ve Bayesian algorithm were established by Bayesialab software according to different variables,a nomogram model was also developed based on the independent predictors.The receiver operating characteristic curve and the area under curve (AUC) were used to evaluate the prediction effect of the models. Results:The overall median survival time was 25.0 months,and the 1-,3-and 5-year cumulative survival rates was 76.6%,37.9%,and 21.0%,respectively.Univariate analysis showed that gender,preoperative jaundice,pathological differentiation,vascular invasion,microvascular invasion,liver capsule invasion,T staging,N staging,margin,intrahepatic bile duct stones,carcinoembryonic antigen,and CA19-9 affected the prognosis(χ 2=5.858-54.974, all P<0.05).The Cox multivariate model showed that gender,pathological differentiation,liver capsule invasion, T stage,N stage,intrahepatic bile duct stones,and CA19-9 were the independent predictive factors(all P<0.05). The AUC of the TAN model based on all 19 clinicopathological factors was 74.5%,and the AUC of the TAN model based on the 12 prognostic factors derived from univariate analysis was 74.0%,the AUC of the na?ve Bayesian model based on 7 independent prognostic risk factors was 79.5%,the AUC and C-index of the nomogram survival prediction model based on 7 independent prognostic risk factors were 78.8% and 0.73,respectively. Conclusion:The Bayesian network model may provide a relatively accurate prognostic prediction for ICC patients after curative intent resection and performed superior to the nomogram model.

Hepatocellular carcinoma(HCC) is a common malignant tumor with high morbidity and mortality in China and even in the world.Due to its tumor heterogeneity and dissemination and distant metastasis,prognosis of patients with HCC is often poor.Surgical treatment such as radical hepatectomy is still the first choice for patients with HCC in the current clinical practice.However,the high recurrence and metastasis rate after surgery still hinder the survival and prognosis of these patients.In the era of target and immunotherapy,changes of surgical treatment strategy for HCC is particularly critical.This review focuses on the definition,the feasibility and the evaluation criteria of neoadjuvant therapy for HCC,to provide a new perspective on surgical treatment for HCC.

Objective:To examine a survival prognostic model applicable for patients with intrahepatic cholangiocarcinoma (ICC) based on Bayesian network.Methods:The clinical and pathological data of ICC patients who underwent curative intent resection in ten Chinese hepatobiliary surgery centers from January 2010 to December 2018 were collected.A total of 516 patients were included in the study. There were 266 males and 250 females.The median age( M( Q R)) was 58(14) years.One hundred and sixteen cases (22.5%) with intrahepatic bile duct stones,and 143 cases (27.7%) with chronic viral hepatitis.The Kaplan-Meier method was used for survival analysis.The univariate and multivariate analysis were implemented respectively using the Log-rank test and Cox proportional hazard model.One-year survival prediction models based on tree augmented naive Bayesian (TAN) and na?ve Bayesian algorithm were established by Bayesialab software according to different variables,a nomogram model was also developed based on the independent predictors.The receiver operating characteristic curve and the area under curve (AUC) were used to evaluate the prediction effect of the models. Results:The overall median survival time was 25.0 months,and the 1-,3-and 5-year cumulative survival rates was 76.6%,37.9%,and 21.0%,respectively.Univariate analysis showed that gender,preoperative jaundice,pathological differentiation,vascular invasion,microvascular invasion,liver capsule invasion,T staging,N staging,margin,intrahepatic bile duct stones,carcinoembryonic antigen,and CA19-9 affected the prognosis(χ 2=5.858-54.974, all P<0.05).The Cox multivariate model showed that gender,pathological differentiation,liver capsule invasion, T stage,N stage,intrahepatic bile duct stones,and CA19-9 were the independent predictive factors(all P<0.05). The AUC of the TAN model based on all 19 clinicopathological factors was 74.5%,and the AUC of the TAN model based on the 12 prognostic factors derived from univariate analysis was 74.0%,the AUC of the na?ve Bayesian model based on 7 independent prognostic risk factors was 79.5%,the AUC and C-index of the nomogram survival prediction model based on 7 independent prognostic risk factors were 78.8% and 0.73,respectively. Conclusion:The Bayesian network model may provide a relatively accurate prognostic prediction for ICC patients after curative intent resection and performed superior to the nomogram model.

Hepatocellular carcinoma(HCC) is a common malignant tumor with high morbidity and mortality in China and even in the world.Due to its tumor heterogeneity and dissemination and distant metastasis,prognosis of patients with HCC is often poor.Surgical treatment such as radical hepatectomy is still the first choice for patients with HCC in the current clinical practice.However,the high recurrence and metastasis rate after surgery still hinder the survival and prognosis of these patients.In the era of target and immunotherapy,changes of surgical treatment strategy for HCC is particularly critical.This review focuses on the definition,the feasibility and the evaluation criteria of neoadjuvant therapy for HCC,to provide a new perspective on surgical treatment for HCC.

Objective:To study the survival outcomes in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) treated with sorafenib combined with transcatheter arterial chemoembolization (TACE) versus sorafenib alone.Methods:The data of 92 patients with BCLC stage C HCC at Tianjin Medical University Cancer Institute& Hospital from January 2008 to December 2015 were retrospectively studied. There were 82 males and 10 females. The average age was 56.3 years. Classified according to whether there were vascular invasion and/or distant metastasis, patients were divided into the vascular invasion group ( n=24), the metastasis group ( n=48), and the vascular invasion combined with metastasis group ( n=20). All patients were treated with sorafenib, but some patients received combined treatment with TACE. The survival data of these patients on follow-up was collected. The Kaplan-Meier method was used for survival analysis, and the survival rates were compared by the log-rank test. Univariate and multivariate Cox analyses were used to determine the prognostic factors of patients’ survival. Results:There were no significant differences in the baseline clinical data among the three groups (all P>0.05). Multivariate Cox regression analysis showed that pre-treatment alpha fetal protein >20 μg/L ( HR=1.90, 95% CI: 1.13-3.12), alkaline phosphatase >125 U/L ( HR=1.60, 95% CI: 1.03-2.49) and sorafenib alone ( HR=2.11, 95% CI: 1.23-3.54) were independent risk factors of survival for these patients. There were no significant differences in the cumulative survival rates among the three groups ( P>0.05). In the vascular invasion group, the cumulative survival rates of patients treated with combined sorafenib and TACE ( n=4) were significantly higher than those treated with sorafenib alone ( n=20) ( P<0.05). Conclusion:Compared with sorafenib alone, sorafenib combined with TACE resulted in better prognosis for patients with BCLC stage C HCC. Subgroup analysis showed that patients with vascular invasion had significantly better survival treated with combined sorafenib and TACE than sorafenib alone.

Synchronous colorectal liver metastases refers to the liver metastases being founded before or after the diagnosis of colorectal cancer. Compared with heterochronous liver metastases, the survival of patients with synchronous liver metastases is poor. At the same time, the primary and metastatic lesion need to be considered for the synchronous colorectal liver metastases, so the treatment options and operative turn are diverse. And in order to extend the survival of patients, reasonable choice is crucial. Therefore, this article reviewed the definition of synchronous liver metastases from colorectal cancer, the strategy selection of different lesion states, the selection of surgical sequence, the progress of the latest surgical techniques and we also shared the treatment experience of the center.