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Background and Aims: HCC is closely associated with inflammation and immune modulation, and combined chemotherapy with other strategies is under extensive investigation to achieve better efficacy. HCC is accompanied by zinc (Zn) deficiency. This study aims to understand how Zn could affect macrophage function and its application for HCC therapy., Approach and Results: Zn 2+ and the Zn transporter 1 (ZNT1, solute carrier family 30 member 1) were markedly reduced in intrahepatic macrophages from patients with HCC and from mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in patients with HCC. Critically, ZNT1 regulated endosomal Zn 2+ levels for endocytosis of toll-like receptor 4 and programmed cell death ligand 1, thereby decreasing macrophage-induced inflammation and immunosuppression to protect from liver tumors. Myeloid-specific deletion of ZNT1 in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. Notably, Zn supplementation could reduce inflammation and surface programmed cell death ligand 1 expression in macrophages with the increased CD8 + T cell cytotoxicity, which synergized the antitumor efficacy of Sorafenib/Lenvatinib., Conclusions: Our study proposes a new concept that ZNT1 and Zn regulate endosome endocytosis to maintain surface receptors, and Zn supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing programmed cell death ligand 1 + myeloid cells., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Hepatic infarction is a rare liver condition. The purpose of this study is to report a case of hepatic infarction caused by thrombus formation following portal vein stent implantation in a patient with hepatocellular carcinoma and portal vein tumor thrombus, and to explore the underlying causes., Case Report: The patient in this study was a 52-year-old male admitted with diffuse hepatocellular carcinoma involving the right lobe and portal vein tumor thrombus. After undergoing portal vein stent implantation and 125 I particle strand implantation treatment, the portal vein was patent, and the pressure decreased. However, multiple instances of hepatic artery chemoembolization combined with targeted immunotherapy resulted in gradual reduction in the diameter of the hepatic artery and affecting hepatic arterial blood flow. Two months post-stent implantation, thrombus formation within the stent was noted, and the patient's condition did not improve with anticoagulant therapy, as evidenced by follow-up CT scans showing an increase in thrombi. Six months later, the patient suffered from gastrointestinal bleeding and, despite emergency esophagogastric variceal ligation and hemostatic treatment, developed hepatic parenchymal infarction and liver function failure., Conclusions: We reveal the underlying cause is that (1) thrombus formation within the portal vein stent, leading to portal vein embolism and obstructed blood flow due to exacerbate portal hypertension after various treatments; and (2) the effect of hepatic artery chemoembolization, immunotherapy, and targeted therapy on tumor angiogenesis, causing reduced hepatic artery diameter and impaired arterial blood flow. These factors disrupt the liver's dual blood supply system, ultimately contributing to hepatic infarction. To our knowledge, this is the first report of hepatic infarction as a complication following portal vein stent implantation for hepatocellular carcinoma with portal vein tumor thrombus, and it holds significant reference value for guiding the treatment of hepatocellular carcinoma with concurrent portal vein tumor thrombus in a clinical setting., (© 2024. The Author(s).)

Rationale and Objectives: To evaluate the predictive value of tumor and peritumor radiomics in the fatty acid binding protein 4 (FABP4) expression levels and overall survival in patients with hepatocellular carcinoma., Materials and Methods: The genomic data of HCC patients were obtained from The Cancer Genome Atlas. The Dual-area CT images of corresponding patients were downloaded from The Cancer Imaging Archive, for radiomics feature extraction, model construction and prognosis analysis. Simultaneously, using patients from Sichuan Provincial People's Hospital, the prognostic value of the radiomics model in HCC patients was validated., Results: In the TCIA database, the area under the curve (AUC) values of the volumes of interest (VOI) whole model in the training set and internal validation set were 0.812 and 0.754, respectively, and the AUC value of VOI whole+periphery in the training set and internal validation set were 0.866 and 0.779, respectively. In the VOI whole and the VOI whole+periphery model of the independent cohort, there were significant differences in OS between the high and low rad-score groups (P = 0.009, P = 0.021, respectively). Significant positive correlations can be observed between FABP4 expression and correlations with rad-score of VOI whole model (r = 0.691) and VOI whole+periphery model (r = 0.732) in the independent cohort., Conclusion: Radiomics models of tumor and peritumor Dual-area CT images could predict stably the expression levels of FABP4 and may be helping in personalized treatment strategies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8 + T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8 + T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy., Competing Interests: Declaration of competing interest The authors declare that there are no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Aberrant sialylation is closely associated with the tumorigenesis, progression, and metastasis, and may be of importance for disease diagnosis. However, the analysis of altered expression of sialylated glycans (SGs) in blood is particularly challenging due to the low content and poor ionization efficiency of sialylated glycans in mass spectrometry., Methods: An analytical strategy based on enrichment of SGs, liquid chromatography-high resolution mass spectrometric detection, and automatic glycan annotation was developed to profile the sialylated N-glycome in serum. The enrichment of sialylated glycans was accomplished using cationic cotton via electrostatic and hydrogen interaction. Using partial least squares-discriminant analysis (PLS-DA), the approach was applied for nontarget screening and profiling of aberrant sialylated N-glycans in hepatocellular carcinoma (HCC)., Results: 55 SGs were identified in human serum, and three important SGs (SG35, SG45, and SG46) were screened to have good diagnostic specificity for HCC. Their areas under the receiver operating characteristic (ROC) curve (AUC) were higher than α-fetoprotein (AFP)'s (AUC = 0.85), at 0.88, 0.87, and 0.91, respectively. When three SGs are combined, the diagnostic specificity for HCC may increase to 94 %. The fact that SGs biomarkers are sensitive to AFP-Negative HCC is very noteworthy., Conclusions: The method significantly advanced the search for sialylated glycan-based cancer biomarkers. In comparison to traditional indicators like AFP and imaging tools, SGs showed a higher diagnostic sensitivity for HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

The liver is a major organ in metabolism, and alterations in serum lipids are associated with liver disorders. Here, a rapid, easy, and reliable screening technique based on lipidomic profiling was developed using machine learning and surface-assisted laser desorption ionization mass spectrometry (SALDI MS) for liver cancer diagnosis. A graphitized carbon matrix (GCM) was created for serum lipid profiling in SALDI MS and demonstrated a better performance for neutral lipids analysis than conventional organic matrices. The fingerprint of serum lipids, including triacylglycerols (TGs), diacylglycerols (DGs), cholesteryl esters (CEs), glycerophospholipids (GPs), and other components, could be directly obtained by GCM-assisted LDI MS without extraction. Five machine learning methods were applied to distinguish liver cancer (LC) patients from healthy controls (HC) and chronic hepatitis B (CHB) patients. The best diagnostic performance was attained by linear discriminant analysis (LDA), which has a confusion matrix accuracy of 98.3 %. The receiver operating characteristic (ROC) curve for liver cancer exhibited an area under the curve (AUC) of 0.99, indicating a high degree of prediction accuracy. One-way ANOVA analysis revealed that numerous TGs were down-regulated in LC group. The results demonstrated the viability of GCM-assisted LDI MS as a valuable diagnostic tool for liver cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Liver metastasis is a common cause of death in progressive colorectal cancer patients, but the molecular mechanisms remain unclear. Here, it is reported that a conserved and oxidative pentose phosphate pathway-associated circular RNA, circNOLC1, plays a crucial role in colorectal cancer liver metastasis. It is found that circNOLC1 silencing reduces the oxidative pentose phosphate pathway-related intermediate metabolites and elevates NADP + /NADPH ratio and intracellular ROS levels, thereby attenuating colorectal cancer cell proliferation, migration, and liver metastasis. circNOLC1 interacting with AZGP1 to activate mTOR/SREBP1 signaling, or sponging miR-212-5p to upregulate c-Met expression, both of which can further induce G6PD to activate oxidative pentose phosphate pathway in colorectal cancer liver metastasis. Moreover, circNOLC1 is regulated by the transcription factor YY1 and specifically stabilized HuR induces its parental gene mRNA expression. The associations between circNOLC1 and these signaling molecules are validated in primary CRC and corresponding liver metastasis tissues. These findings reveal that circNOLC1 interacting with AZGP1 and circNOLC1/miR-212-5p/c-Met axis plays a key role in oxidative pentose phosphate pathway-mediated colorectal cancer liver metastasis, which may provide a novel target for precision medicine of colorectal cancer., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Liver metastasis is the leading cause of death in colorectal cancer. Immunotherapy using immune checkpoint blockade (ICB) is ineffective due to its immunological cold tumor nature. Herein, we prepared a nanodrug (NCG) encapsulating the transforming growth factor-β receptor inhibitor galunisertib (Gal) and the sonosensitizer chlorin e6 (Ce6), which was aimed to turn this type of cold tumor into a hot one to promote the ICB-based immunotherapy against it. After delivery to the tumor, NCG under ultrasonic irradiation generated reactive oxygen species causing tumor immunogenic cell death and releasing immunostimulatory signals such as calreticulin and HMGB1, which increased tumor immunogenicity and activated the innate T lymphocyte immune response. Moreover, NCG responded to the acidic microenvironment and released Gal, inhibiting phosphorylation and inducing immunosuppressive Smad2/3 signaling. Consequently, the differentiation of MDSCs was inhibited, M1-like polarization of tumor-associated macrophages was induced, and the immunosuppressive barrier of tumor-associated fibroblasts was destroyed to increase the infiltration of effector T cells, which reversed the immunosuppression of the tumor microenvironment and improved the therapeutic efficacy of anti-PD-L1 antibodies. Notably, in the liver metastasis mouse model, combination therapy using NCG (+) and aPD-L1 inhibited the growth of colon cancer liver metastasis, manifesting potential in treating this popular yet intractable malignancy. STATEMENT OF SIGNIFICANCE: Only a limited number of patients with colorectal cancer and liver metastasis can benefit from immune checkpoint blockade therapy, as most of them are microsatellite stable, immunologically cold tumors. Interestingly, there is compelling evidence that sonodynamic therapy (SDT) can convert immunosuppressed cold tumors into hot ones, trigger tumor immunogenic cell death non-invasively, and boost cytotoxic T cells infiltration. However, its therapeutic efficacy is constrained by the abundance of transforming growth factor-β (TGF-β) cytokines in the tumor microenvironment. Here, we reported a TGF-β-targeted inhibitory nanodrug that improved SDT in colon cancer and liver metastasis, reversed the immunosuppressive tumor microenvironment and boosted the immune response to anti-PD-L1 therapy in this cancer. It demonstrated the potential to cure this prevalent but incurable malignancy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: Long non-coding RNAs (lncRNAs) have been shown to be associated with the pathogenesis of different kinds of diseases and play important roles in various biological processes. Although numerous lncRNAs have been found, the functions of most lncRNAs and physiological/pathological significance are still in its infancy. Meanwhile, their expression patterns and regulation mechanisms are also far from being fully understood., Methods: In order to reveal functional lncRNAs and identify the key lncRNAs, we develop a new sparse independence component analysis (ICA) method to identify lncRNA-mRNA-miRNA expression co-modules based on the competitive endogenous RNA (ceRNA) theory using the sample-matched lncRNA, mRNA and miRNA expression profiles. The expression data of the three RNA combined together is approximated sparsely to obtain the corresponding sparsity coefficient, and then it is decomposed by using ICA constraint optimization to obtain the common basis and modules. Subsequently, affine propagation clustering is used to perform cluster analysis on the common basis under multiple running conditions to obtain the co-modules for the selection of different RNA elements., Results: We applied sparse ICA to Liver Hepatocellular Carcinoma (LIHC) dataset and the experiment results demonstrate that the proposed sparse ICA method can effectively discover biologically functional expression common modules., Conclusion: It may provide insights into the function of lncRNAs and molecular mechanism of LIHC. Clinical and Translational Impact Statement-The results on LIHC dataset demonstrate that the proposed sparse ICA method can effectively discover biologically functional expression common modules, which may provide insights into the function of IncRNAs and molecular mechanism of LIHC., (This work is licensed under a Creative Commons Attribution 4.0 License. For more information, see https://creativecommons.org/licenses/by/4.0/.)

The poor prognosis and limited therapeutic options for human hepatocellular carcinoma (HCC), the most common form of liver cancer, highlight the urgent need to identify novel therapeutic modalities. Here, we describe the antitumor activity and underlying molecular mechanisms of a novel Na+/K+-ATPase inhibitor RX108 in human HCC cells and its xenograft model. RX108 dose-dependently inhibited HCC cell proliferation in vitro and tumor growth in a xenograft mouse model, and that the inhibition was associated with induction of apoptosis. Mechanistically, RX108 significantly downregulated alanine serine cysteine transporter 2 (ASCT2) protein expression and reduced glutamine and glutamate concentration in HCC cells and tumors. In addition, RX108 exposure led to a significant decrease in cell energy metabolism in Huh7 and Hep3B cells, including decreased levels of glutathione, NADH, NADPH, and mitochondrial respiration oxygen consumption rate. Furthermore, HCC cells exhibited evidence of glutamine addiction; the antiproliferative effect of RX108 was dependent on glutamine transport. Clinically, elevated ASCT2 mRNA expression in HCCs was associated with unfavorable survival. Taken together, these findings reveal a novel approach to target glutamine metabolism through inhibiting Na+/K+-ATPase and provide a rationale for using RX108 to treat HCC in patients whose tumors express ASCT2 at high levels. RX108 is currently under clinical development., (©2023 American Association for Cancer Research.)

Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, a PPARα/γ target gene involved in tumor progression and chemoresistance, was significantly downregulated. Clinical analysis demonstrated a strong correlation between the protein levels of CES1 and SCD in HCC. Interference with lipid signaling by targeting the CES1-PPARα/γ-SCD axis sensitized HCC cells to cisplatin treatment. As a result, the growth of HCC xenograft tumors in NU/J mice was potently slowed by coadministration of cisplatin and CES1 inhibition. Our results, thus, suggest that CES1 is a promising therapeutic target for HCC treatment.

Background: Upregulation of Stathmin 1 (STMN1), a cytoplasmic phosphoprotein that controls the dynamics of cellular microtubules, is linked to malignant behavior and poor prognosis in a range of malignancies. However, little research has been done on STMN1's potential role in HCC as a single factor in DNA methylation, m 6 A, or immunological modulation., Results: STMN1 is overexpressed in hepatocellular carcinoma, where it is related to clinicopathological parameters and affects the prognosis of HCC patients. STMN1 overexpression plays an important role in the diagnosis and prognosis of hepatocellular carcinoma. Meanwhile, methylation of 7 CpG sites of STMN1 in HCC was correlated with prognosis, and STMN1 expression was closely related to m 6 A modification. In addition, STMN1 expression is associated with immune cell infiltration, immune molecules, and immune checkpoints in HCC., Conclusion: STMN1 has a significant role in hepatocellular carcinoma diagnosis and prediction. STMN1 is implicated not just in the onset and course but also in the immunological modulation of the disease. DNA methylation and m 6 A are both linked to STMN1. Therefore, STMN1 could be used as a diagnostic and prognostic biomarker for HCC, as well as a target for immunotherapy., (© 2022. The Author(s).)

Objective: We investigated three-dimensional (3 D) reconstruction for the assessment of the tumor margin microstructure of hepatoblastoma (HB). Methods: Eleven surgical resections of childhood hepatoblastomas obtained between September 2018 and December 2019 were formalin-fixed, paraffin-embedded, serially sectioned at 4 μm, stained with hematoxylin and eosin (every 19th and 20th section stained with alpha-fetoprotein and glypican 3), and the digital images of all sections were acquired at 100× followed by image registration using the B-spline based method with modified residual complexity. Reconstruction was performed using 3 D Slicer software. Results: The reconstructed orthogonal 3 D images clearly presented the internal microstructure of the tumor margin. The rendered 3 D image could be rotated at any angle. Conclusions: Microstructure 3 D reconstruction is feasible for observing the pathological structure of the HB tumor margin.

Hepatocellular carcinoma (HCC) remains a significant health problem with a substantial genetic predisposition. The liver harbors the largest proportion of macrophages among all the solid organs. There is considerable controversy regarding the relationship between the macrophage receptor with collagenous structure (MARCO) and tumor development and progression. Accordingly, we performed this case-control study to determine whether associations exist between the MARCO single nucleotide polymorphism rs6761637 and HCC susceptibility and clinical characteristics. We successfully genotyped 586 HCC cases and 647 controls using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The overall genotype distribution of rs6761637 was similar in the HCC and control groups (P = 0.143). However, the CT + CC genotypes of rs6761637 were slightly more common in the HCC group among female (P = 0.021), overweight (body mass index ≥ 24 kg/m 2 , P = 0.003), and nonsmoking (P = 0.022) individuals. The minor C allele carriers had a 1.47-fold increased risk of developing large tumor nodules (P = 0.041). rs6761637 did not affect the recurrence-free or overall survival rate of patients with HCC (P = 0.247 and 0.304, respectively). In conclusion, this is the first report of the association between MARCO genetic variations and HCC risk. These results suggest that the MARCO rs6761637 polymorphism may play a regulatory role in HCC carcinogenesis, but it does not seem to predict prognosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatocellular carcinoma (HCC) is one of the most common digestive system cancers (DSCs) with a poor prognosis. Zinc-regulated transporter (ZRT)/iron-regulated transporter (IRT) like protein transporters ( ZIPs ) encode membrane transport proteins, which are responsible for the absorption of zinc and play important roles in the pathogenesis of various human cancers. Tumor-associated macrophages (TAMs) are important participants in the regulation of tumor microenvironment and the development of HCC. Individual role of each ZIP involved in hepatocarcinogenesis remains elusive. In this study, the transcription patterns of ZIPs in the DSCs were screened firstly through GEPIA2 database. Interestingly, the analysis of the DSCs data showed the distinct mRNA levels of ZIPs between DSCs tissues and healthy controls. Notably, the transcription levels of ZIP2 , ZIP5 , ZIP8 , ZIP9 and ZIP14 were decreased significantly in the tissues of human liver cancer compared to paracarcinoma liver tissues. To further confirm the mRNA transcriptional changes of Zips in HCC, N-Nitrosodiethylamine (DEN) combined with carbon tetrachloride (CCl 4 ) inducing mouse model of HCC were established. Consistently, the mRNA levels of Zip2 , Zip9 , and Zip14 in liver tissues of HCC induced mice were also decreased compared with the healthy controls. In addition, mouse peritoneal elucidated macrophages (PEMs)-derived M1/M2 macrophages in vitro , as well as human patients of HCC-derived TAMs, were used to examine the transcription levels of ZIPs . Our results showed that both Zip2 and Zip9 were up-regulated in M2-polarized macrophages. Zip2 transcript was also up-regulated M1-polarized macrophages, but Zip9 was slightly down-regulated. TAMs generated from human liver cancer tissues also displayed a decrease in ZIP9 transcription compared to paracarcinoma tissues. To further explore the role of Zip9 in M1/M2 polarization, the siRNA knockdown results revealed that Zip9 , but not Zip2 , could promote M2 macrophage polarization and impair M1 macrophage polarization. Mechanistically, Zip9 enhances phosphorylated STAT6 to promote M2 macrophage polarization but suppresses the phosphorylation of IκBα/β to inhibit M1 macrophage polarization. Together, our results indicate that ZIP9 may involve in macrophages polarity in HCC development and may be a potent new biomarker for the diagnosis of HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gou, Yang, Tian, Zhu, Zhang, Ren, Tu, Luo, Miao, Zhao, Wang and Wei.)

Hepatoblastoma (HB) is the most common liver cancer in children, this study aims at analyzing the prognostic factors affecting the survival rates and summarizing the treatment experience. In this study, we reviewed patients with primary HB under the age of 14 years who underwent complete tumor resection from June 1997 to March 2019. The data of 72 patients were collected. Survival analysis was performed by Kaplan-Meier, multivariate Cox proportional hazards regression and linear mixed model for repeated measures (LMMRM). The 5-year and the 10-year event-free survival (EFS) of all patients were 78.2% and 73%, respectively. Both the 5-year and 10-year overall survival (OS) were 85.7%. Kaplan-Meier survival analysis showed that patients with tumor capsule infiltration (TCI) and patients with surgical margin less than 1 cm may also have a good prognosis. The Cox proportional hazards regression model analysis results were similar to the Kaplan-Meier analysis results. LMMRM analysis showed that there were significant differences in platelet, alpha-fetoprotein, C-reactive protein and hemoglobin values after surgery in the metastasis group ( P  < 0.05). This study suggests that patients with TCI or narrow surgical margin (<1 cm) may also have a good prognosis, and the risk stratification of HB can be used as the latest grading standard to evaluate the prognosis of patients.

The triggering receptor expressed on myeloid cells-1 (TREM-1) signal is related to the continuous amplification of inflammatory pathway. However, it is not clear whether and how HBV can regulated the expression of TREM-1 on monocyte participated in the progression of liver disease. Here, we showed that the expression of TREM-1 on monocyte subsets were increased significantly in HBV related liver cirrhosis group compared with chronic infected group and healthy control group. HBsAg and HBeAg could up-regulated TREM-1 on monocyte by NF-KB pathway, and at least last for 72 h. Increased TREM-1 on monocyte might associated with high level of inflammatory cytokine (TNF-a, IL-1β and IL-6) and the activation of LX-2 cells. Bioinformatics analysis showed that the high expression of TREM-1 was related to the poor prognosis of hepatocellular carcinoma (HCC). The level of TREM-1 might help to predict the progression of HBV infected liver disease and treat target to prevent fibrosis progression., (Copyright © 2020. Published by Elsevier Inc.)

Background and Aims: Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present., Methods: 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG., Results: The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS., Conclusions: SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.

Objective: The objective of this study is to determine the frequency of no residual cancer tissue in the chemotherapy regression area (CRA) of hepatoblastoma after preoperative chemotherapy and to measure the distance between the tumor capsule and the residual cancer nests. Methods: All the tissues in the CRAs of the resected specimens were excised. HE staining and immunohistochemical staining were performed to determine the frequency of residual cancer tissue in the CRA, and the distances between the residual cancer nests and the tumor capsule were measured. Results: A total of 30 patients were included in the study. The tumor volume decreased after chemotherapy by an average of 619 ml. Of the 30 patients, the CRAs of 18 still had residual cancer nests. The longest distance between the residual cancer nest and tumor capsule was 11.2 mm. Conclusions: After chemotherapy, 60% of patients still had residual cancer nests in CRAs, the furthest distance was 11.2 mm.

Minichromosome maintenance complex component 6 (MCM6) is involved in tumorigenesis of hepatocellular carcinoma (HCC). Because its effect on different populations remains unclear, this study investigated the impact of MCM6 on HCC in Southern Chinese Zhuang population. In addition to assessing the global mRNA levels of MCM6 based on The Cancer Genome Atlas database (TCGA) and The Gene Expression Omnibus database (GEO), associations between MCM6 mRNA levels and clinicopathological features were analyzed. High MCM6 levels were associated with high alpha-fetoprotein (AFP) (>20 ng/mL in serum) (P < 0.0001) and advanced clinical stage (III + IV) (P < 0.001). Higher MCM6 was associated with poorer outcomes (P < 0.01) in these databases. Furthermore, the mRNA and protein expression of MCM6 in the Guangxi Zhuang population was detected by quantitative polymerase chain reaction (qPCR), western blot, and immunohistochemistry (IHC). The results showed that MCM6 levels were up-regulated in the Zhuang population with HCC. Higher MCM6 protein levels were correlated with larger tumor size (>5 cm) (P = 0.038) and advanced clinical stage (III + IV) (p = 0.023). Bioinformatic enrichment analysis of MCM6 and its interacting proteins (CDT1,WEE1,TRIM28 and MKI67) suggested that in addition to being involved in the cell cycle process, these complexes could also be involved in protein binding, pre-replication complex assemble, and nucleus metabolism. Based on the protein-protein interaction (PPI) network with module screen, the interactions between MCM6 and its potential interacting proteins were further studied through protein docking with hot spot analysis. Additionally, the results of the algorithms combining the ROC of MCM6 and its interacting proteins showed that combination biomarker analysis has better HCC diagnosis ability than the single MCM6 test. The combination of MCM6 and TRIM28 was more suitable for the Guangxi Zhuang population. Overall, our study suggests that MCM6 plays an important role in the growth of HCC. MCM6 could be an optimal biomarker for diagnosing HCC and a potential molecular target for HCC therapy in the Zhuang population., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background & Aims: The effect of hepatocellular carcinoma (HCC) on the response to interferon-free direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C (CHC) infection remains unclear. Using a systematic review and meta-analysis approach, we aimed to investigate the effect of DAA therapy on sustained virologic response (SVR) among patients with CHC and either active, inactive or no HCC., Methods: PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from 1/1/2013 to 9/24/2018. The pooled SVR rates were computed using DerSimonian-Laird random-effects models., Results: We included 49 studies from 15 countries, comprised of 3,341 patients with HCC and 35,701 without HCC. Overall, the pooled SVR was lower in patients with HCC than in those without HCC (89.6%, 95% CI 86.8-92.1%, I 2  = 79.1% vs. 93.3%, 95% CI 91.9-94.7%, I 2  = 95.0%, p = 0.0012), translating to a 4.8% (95% CI 0.2-7.4%) SVR reduction by meta-regression analysis. The largest SVR reduction (18.8%) occurred in patients with active/residual HCC vs. inactive/ablated HCC (SVR 73.1% vs. 92.6%, p = 0.002). Meanwhile, patients with HCC who received a prior liver transplant had higher SVR rates than those who did not (p <0.001). Regarding specific DAA regimens, patients with HCC treated with ledipasvir/sofosbuvir had lower SVR rates than patients without HCC (92.6%, n = 884 vs. 97.8%, n = 13,141, p = 0.026), but heterogeneity was high (I 2  = 84.7%, p <0.001). The SVR rate was similar in patients with/without HCC who were treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (n = 101) (97.2% vs. 94.8%, p = 0.79), or daclatasvir/asunaprevir (91.7% vs. 89.8%, p = 0.66)., Conclusion: Overall, SVR rates were lower in patients with HCC, especially with active HCC, compared to those without HCC, though heterogeneity was high. Continued efforts are needed to aggressively screen, diagnose, and treat HCC to ensure higher CHC cure rates., Lay Summary: There are now medications (direct-acting antivirals or "DAAs") that can "cure" hepatitis C virus, but patients with hepatitis C and liver cancer may be less likely to achieve cure than those without liver cancer. However, patients with liver cancer are also more likely to have advanced liver disease and risk factors that can decrease cure rates, so better controlled studies are needed to confirm these findings., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Biomarkers for hepatocellular carcinoma (HCC) following curative resection are not currently sufficient for prognostic indication of overall survival (OS) and disease-free survival (DFS). The aim of this study was to investigate the prognostic performance of osteopontin (OPN), matrix metalloproteinase 7 (MMP7), and pregnancy specific glycoprotein 9 (PSG9) in patients with HCC. A total of 179 prospective patients with HCC provided plasma before hepatectomy. Plasma OPN, MMP7, and PSG9 levels were determined by enzyme-linked immunosorbent assay. Correlations between plasma levels, clinical parameters, and outcomes (OS and DFS) were overall analyzed. High OPN ( ⩾ 149.97 ng/mL), MMP7 ( ⩾ 2.28 ng/mL), and PSG9 ( ⩾ 45.59 ng/mL) were prognostic indicators of reduced OS (P < 0.001, P < 0.001, and P = 0.007, respectively). Plasma PSG9 protein level was an independent factor in predicting OS (P = 0.008) and DFS (P = 0.038). Plasma OPN + MMP7 + PSG9 elevation in combination was a prognostic factor for OS (P < 0.001). OPN was demonstrated to be a risk factorassociated OS in stage I patients with HCC and patients with low α-fetoprotein levels ( < 20 ng/mL). These findings suggested that OPN, MMP7, PSG9 and their combined panels may be useful for aiding in tumor recurrence and mortality risk prediction of patients with HCC, particularly in the early stage of HCC carcinogenesis.

Background: Plant homeodomain finger protein 8 (PHF8) serves an activator of epithelial-mesenchymal transition (EMT) and is implicated in various tumors. However, little is known about PHF8 roles in hepatocellular carcinoma (HCC) and regulating E-cadherin expression., Methods: PHF8 expression pattern was investigated by informatic analysis and verified by RT-qPCR and immunochemistry in HCC tissues and cell lines. CCK8, xenograft tumor model, transwell assay, and tandem mCherry-GFP-LC3 fusion protein assay were utilized to assess the effects of PHF8 on proliferation, metastasis and autophagy of HCC cells in vitro and in vivo. ChIP, immunoblot analysis, rescue experiments and inhibitor treatment were used to clarify the mechanism by which PHF8 facilitated EMT, metastasis and autophagy., Results: PHF8 upregulation was quite prevalent in HCC tissues and closely correlated with worse overall survival and disease-relapse free survival. Furthermore, PHF8-knockdown dramatically suppressed cell growth, migration, invasion and autophagy, and the expression of SNAI1, VIM, N-cadherin and FIP200, and increased E-cadherin level, while PHF8-overexpression led to the opposite results. Additionally, FIP200 augmentation reversed the inhibited effects of PHF8-siliencing on tumor migration, invasion and autophagy. Mechanistically, PHF8 was involved in transcriptionally regulating the expression of SNAI1, VIM and FIP200, rather than N-cadherin and E-cadherin. Noticeably, E-cadherin degradation could be accelerated by PHF8-mediated FIP200-dependent autophagy, a crucial pathway complementary to transcriptional repression of E-cadherin by SNAI1 activation., Conclusion: These findings suggested that PHF8 played an oncogenic role in facilitating FIP200-dependent autophagic degradation of E-cadherin, EMT and metastasis in HCC. PHF8 might be a promising target for prevention, treatment and prognostic prediction of HCC.

As a calcium-dependent phospholipid binding annexin protein, annexin A5 (Anxa5) links to the progression, metastasis, survival, and prognosis of a variety of cancers. Current work showed ANXA5 overexpression was positively correlated with the upregulations of CRKI/II and RAC1 in hepatocarcinoma (HCC) patients' tissues, which potentially enhanced the clinical progression and lymphatic metastasis of HCC. The role and action mechanism of ANXA5 in hepatocarcinoma was then investigated using a hepatocarcinoma Hca-P cell line, an ideal and well-established murine cell model with 100% inducible tumorigenicity of implanted mice with low (~25%) lymph node metastatic (LNM) rate. In vitro evidences indicated ANXA5 stable knockdown resulted in decreased proliferation, migration, invasion and adhesion to lymph node (LN), and increased intercellular cohesion behaviors of hepatocarcinoma Hca-P cells. Consistently, stable ANXA5 knockdown led to reduced in vivo tumorigenicity and malignancy, LNM rate and level potentials of Hca-P- transplanted mice via inhibiting CD34 and VEGF3. The levels of CRKI/II and RAC1 were reduced in tumor tissues from mice transplanted with Hca-P cells with stable ANXA5 knockdown. Molecular action investigation further showed ANXA5 downregulation apparently suppressed the expressions of molecules CRKI/II, DOCK180, RAC1 in integrin pathway, p-MEK, p-ERK, c-Myc, and MMP-9 in MEK- ERK pathway together with VIMINTIN in Hca-P cells in appropriate to knockdown extent. Collectively, Anxa5 was able to mediate HCC carcinogenesis via integrin and MEK-ERK pathways. It is of potential use in the research and treatment of HCC.

Background: As minimally invasive techniques advances, minimally invasive surgery (MIS) has emerged as an alternative modality for advanced gastric cancer. In this study, we compared the short- and long-term surgical outcomes of MIS and conventional open surgery for gastric cancer liver metastasis (GCLM) in terms of safety, feasibility, and efficacy., Methods: This retrospective study used data from a prospective database at the Chinese People's Liberation Army General Hospital. From January 2006 to June 2016, 53 gastric cancer patients with synchronous liver metastasis accepted radical gastrectomy combined with either or both hepatectomy and radiofrequency ablation for liver metastases. The 53 patients enrolled in the study were divided into two groups: a conventional open surgery group (n = 42) and an MIS group (n = 11). Propensity score matching (PSM) analysis was performed to overcome possible bias., Results: With PSM performed at a 1:3 ratio, 11 patients who received MIS were compared with 33 open surgery cases. Mean operation time was significantly longer for the MIS group compared with the open surgery group (301 vs. 236 min, P = 0.032), while the open surgery group had a larger estimated blood loss than the MIS group (421 vs. 196 ml, P = 0.019). Time to first flatus and postoperative complications, including Clavien-Dindo classification, were similar in the two groups. However, patients undergoing MIS had a significantly shorter time to first sips of water (P = 0.020) and soft diet (P = 0.020) compared with open surgery counterparts. Long-term outcomes were comparable between groups (P = 0.090) after adjustment by PSM analysis., Conclusions: MIS achieved superior short-term outcomes and comparable long-term outcomes compared with open surgery in GCLM patients. For experienced surgeons, both laparoscopic and robotic methods of MIS are reasonable approaches for the management of highly selected GCLM patients.

Recurrence of hepatocellular carcinoma (HCC) after transarterial chemoembolisation (TACE) is common due to neoangiogenesis. Cyclooxygenase-2 inhibitors and somatostatin analogues were reported to inhibit tumour angiogenesis. The pilot randomized controlled trial was aimed to prospectively evaluate the protocol of TACE combined with celecoxib and lanreotide (TACE+C+L) in patients with unresectable and advanced HCC. A total of 71 patients with HCC were enrolled and randomly assigned to either TACE (n=35) or TACE+C+L (n=36) group. Overall survival, disease control rate (DCR), and adverse events were assessed during a 3-year follow-up period. The median overall survival of the TACE+C+L group (15.0 months) was doubled compared to that of TACE group (7.5 months), p = 0.012. DCR of the TACE+C+L group was significantly higher than that of the TACE group either at 6 months (72.2% vs 42.9%, p = 0.012) or at 12 months (61.1% vs 28.6%, p = 0.006). The median overall survivals (13 months vs 4.5 months, p = 0.013) and DCR at 12 months (50% vs 13.6%, p = 0.008) of patients with advanced HCC in TACE+C+L groups were significantly higher than those in TACE group. No significant difference of adverse events was observed between the two groups. The occurrence of post-embolisation syndrome in TACE+C+L group was significantly lower than that in TACE group (16.7% vs 60.0%, p = 0.001). In conclusion, the regimen of TACE+C+L prolonged overall survival, enhanced tumour response, reduced post-embolisation syndrome and was well-tolerable in the patients with unresectable HCC. It may be more beneficial for advanced HCC.

Objective: MiR-183 acts as an oncomiR and is usually upregulated in hepatocellular cancer (HCC). This study aims to study the association between miR-183 dysregulation and multi-drug resistance (MDR). Also, how it is dysregulated in HCC cells was investigated., Materials and Methods: The association between miR-183 and HIF-1α in HCC cell line BEL-7402 and the multidrug-resistant variant BEL-7402/5-fluorouracil (BEL-7402/5-FU) were studied using qRT-PCR and Western blot analysis. The mediators involved in feedback regulation between miR-183 and HIF-1α were further studied. Then, the effect of the miR-183-SOCS6 axis on IC50 of BEL-7402/5-FU cells to 5-FU were investigated by MTT assay., Results: The expression of miR-183 and HIF-1α are positively correlated in BEL-7402 and BEL-7402/5-FU cells. IDH2 knockdown resulted in significantly increased HIF-1α expression in both BEL-7402 and BEL-7402/5-FU cells. Knockdown of SOCS6 had similar but stronger effect as miR-183 in promoting MRP2, P-gp, p-STAT3 and HIF-1α expression in BEL-7402 cells, while SOCS6 overexpression also showed similar but stronger effect as miR-183 inhibition in reducing MRP2, P-gp, p-STAT3 and HIF-1α levels in BEL-7402/5-FU cells. Both SOCS6 overexpression and miR-183 knockdown significantly increased the sensitivity of BEL-7402/5-FU cells to 5-FU. MiR-183 overexpression partly abrogated the effect of SOCS6 in enhancing 5-FU sensitivity., Conclusions: Both HIF-1α-miR-183-IDH2-HIF-1α and HIF-1α-miR-183-SOCS6-p-STAT3-HIF-1α feedback loops are involved in miR-183 upregulation in HCC cells. MiR-183 can modulate MDR of HCC cells at least partly through suppressing SOCS6.

Hepatocellular carcinoma (HCC) is frequently associated with pathogen infection-induced chronic inflammation. Large numbers of innate immune cells are present in HCCs and can influence disease outcome. Here, we demonstrated that the tumor suppressor serine/threonine-protein kinase 4 (STK4) differentially regulates TLR3/4/9-mediated inflammatory responses in macrophages and thereby is protective against chronic inflammation-associated HCC. STK4 dampened TLR4/9-induced proinflammatory cytokine secretion but enhanced TLR3/4-triggered IFN-β production via binding to and phosphorylating IL-1 receptor-associated kinase 1 (IRAK1), leading to IRAK1 degradation. Notably, macrophage-specific Stk4 deletion resulted in chronic inflammation, liver fibrosis, and HCC in mice treated with a combination of diethylnitrosamine (DEN) and CCl4, along with either LPS or E. coli infection. STK4 expression was markedly reduced in macrophages isolated from human HCC patients and was inversely associated with the levels of IRAK1, IL-6, and phospho-p65 or phospho-STAT3. Moreover, serum STK4 levels were specifically decreased in HCC patients with high levels of IL-6. In STK4-deficient mice, treatment with an IRAK1/4 inhibitor after DEN administration reduced serum IL-6 levels and liver tumor numbers to levels similar to those observed in the control mice. Together, our results suggest that STK4 has potential as a diagnostic biomarker and therapeutic target for inflammation-induced HCC.

Our previous study has demonstrated that RNF43 could regulate the cell cycle in a p53-dependent manner in HCC. In this study, we aimed to access whether RNF43 could interact with cell cycle proteins involved in p53 pathway, including pRB, Cyclin D1 and MDM2. Totally, 123 paired HCC tissues and corresponding noncancerous tissues from HCC patients were included, and the expression of Cyclin D1, pRB and MDM2 was analyzed using tissue microarray. Our results showed the expression level of RNF43 in HCC was positively correlated with that of MDM2, Cyclin D1 and pRB-S780. There was no significant correlation between the expression of RNF43 and pRB-S807/S811. Indicating that RNF43 effected cell cycling by regulating the expression of pRB, Cyclin D1 and MDM2 proteins, and pRB-S780 but not pRB-S807/S811, was participated in RNF43 regulated cell cycling.

Hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in China. It is important to understand the genetic mechanisms underlying the development and progression of HBV-related HCC and to identify new biomarkers for clinical treatment. The important role of fibroblast growth factor receptors (FGFRs) has been widely recognized in many types of cancers, but the association between FGFR polymorphisms and HCC carcinogenesis has been rarely reported. In this study, 199 patients with HBV-associated cirrhosis, 203 with HBV-associated HCC, and 184 healthy controls with no liver diseases were enrolled as participants. Using SNaPshot assays, five SNPs (rs13317, rs7825208, rs1047057, rs1047111, and rs1966265) of growth factor receptor genes were genotyped. Our results showed that the G/A and G/G genotypes at rs7825208 of FGFR1 were negatively correlated with HBV-related HCC (odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.22-0.93, P = 0.027). However, after Bonferroni correction, these significant differences no longer existed (P > 0.05). Our results indicated that these five polymorphisms of fibroblast growth factor receptor genes do not play any independent roles in the tumorigenesis and progression of HBV-related HCC in Han Chinese patients.

Objective: To investigate the expression difference of somatostatin (SST) , SST receptors (SSTR) and COX-2 in chronic hepatitis, hepatic cirrhosis, precancerous lesion and hepatocellular Carcinoma, and explore the relationship between portal hypertension and SST/SSTR expressions., Methods: A series of human liver tissues were obtained from surgery, including normal liver 4 cases, chronic hepatitis 14 cases, hepatic cirrhosis 40 cases, precancerous lesion 40 cases and HCC tissues 40 cases. Peripheral bloods were collected from 20 patients before and after the operation of transjugular intrahepatic portosystemic shunt (TIPS). SSTR 1-5 subtypes in hepatic tissues were detected by immunohistochemical study and RT-PCR. Levels of SST and COX-2 were quantified by radioimmunoassay and Western blot., Results: 90% of precancerosis expressed high levels of SSTR 2, 5 subtypes, and SSTR mainly distributed surrounding portal vein. At lest 60%o of HCC expressed SSTR 2, 5 subtypes, and there were positive correlations between levels of SSTR 1-5 and SST. Levels of SST in peripheral blood of cirrhotic patients significantly increased after TIPS(P<0. 05). Levels of COX-2 were highest in cirrhosis (about 90%), and decreased in precancerosis (about 80%) and HCC tissues., Conclusions: Precancerosis or early stage of HCC may be the optimum time for synergetic medication of SST analogue and COX-2 inhibitor.

Although the involvement of insulin-like signaling in cancer has been well documented in various types of cancers, the association between the genetic variants in the insulin-like signaling and the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. In this study, a total of 498 individuals including 173 HBV related cirrhosis patients, 171 HBV-related HCC patients, and 154 healthy controls were enrolled. Sixteen single nucleotide polymorphisms (SNPs) in IGF1, IGF2, IGF1R and IGF2R have been genotyped by employing SNaPshot assays. We found A/A genotype at rs3743251 of IGF1R was negatively associated with HBV related HCC [odds ratio (OR) = 0.38, 95% confidence interval (CI) = 0.20-0.72, P = 0.037]; A/G genotype decreased the risk of portal vein thrombosis (OR = 0.38, 95%CI = 0.18-0.82, P = 0.01). These results indicate that rs3743251 polymorphism in IGF1R is associated with the susceptibility of HBV-related HCC., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The objective of this paper was to evaluate the overall accuracy of elastography in the diagnosis of benign and malignant liver lesions by liver biopsy as the gold standard. Literature databases were searched. The studies which were related to evaluate the diagnostic value of elastography for differentiation in benign and malignant liver lesions in English or Chinese were included. The summary receiver operating characteristic (SROC) curve was performed, and the areas under the curve (AUC) were also calculated to present the accuracy of the elastography for the diagnosis of benign and malignant liver lesions. Six studies which included a total of 448 liver lesions in 384 patients were analyzed. The summary sensitivity and specificity of elastography for the differentiation of malignant liver lesions were 85% (95% CI, 80 to 89%) and 84% (95% CI, 80 to 88%), respectively. And the summary diagnostic odds ratio was 46.33 (95% CI, 15.22 to 141.02), and the SROC was 0.9328. Elastography has a high sensitivity and specificity differentiation for benign and malignant liver lesions. As a non-invasive method, it is promising to be applied to clinical practice. To estimate elastography objectively, a large, prospective, international, and multi-center study is still needed.

Objective: To assess the value of gastric and hepatic surgical treatment in gastric cancer patients with liver metastasis and its prognostic implication., Methods: Literature search was performed in pubmed, Embase, Ovid, Springer-Link, Web of Science, CNKI, CBMdisc for clinical research published before March 2013 that compared gastrectomy alone to gastrectomy and hepatectomy. Inclusion criteria and exclusion criteria were performed. Quality assessment was based on NOS scale. Stata12.0 was used for statistical analysis., Results: Nine studies including 431 patients were enrolled for analysis, among whom 189 underwent gastrectomy and hepatectomy and 242 underwent gastrectomy alone. Gastrectomy and hepatectomy group had better survival(HR=0.50, 95%CI:0.34-0.72, z=3.66, P=0.000). There was a subgroup analysis. Gastrectomy with hepatectomy group had significant advantages in prognosis in four foreign studies(HR=0.28, 95%CI:0.18-0.44, z=5.77, P=0.000). There was no significant difference in five domestic studies (HR=0.74, 95%CI:0.55-1.00, z=1.95, P=0.051)., Conclusion: Gastrectomy and hepatectomy in gastric cancer patients with liver metastasis improves long-term survival in select patients.

It has been shown that Ring finger protein 43 (RNF43) is overexpressed in colorectal cancer and mediates cancer cell proliferation; however, its role in hepatocellular carcinoma (HCC) remains unknown. In this study, we found that RNF43 was frequently overexpressed in HCCs, and this overexpression was correlated with positive vascular invasion, poor tumor differentiation, and advanced tumor stage. Functional studies showed that knockdown of RNF43 could induce apoptosis and inhibit proliferation, invasion, colony formation, and xenograft growth of HCCs. Microarray-based gene profiling showed a total of 229 genes differentially expressed after RNF43 knockdown, many of which are involved in oncogenic processes such as cell proliferation, cell adhesion, cell motility, cell death, DNA repair, and so on. These results suggest that RNF43 is involved in tumorigenesis and progression of HCCs and that antagonism of RNF43 may be beneficial for HCC treatment.

Cyclin-dependent kinase inhibitor 3 (CDKN3) belongs to the protein phosphatases family and has a dual function in cell cycling. The function of this gene has been studied in several kinds of cancers, but its role in human hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we found that CDKN3 was frequently overexpressed in both HCC cell lines and clinical samples, and this overexpression was correlated with poor tumor differentiation and advanced tumor stage. Functional studies showed that overexpression of CDKN3 could promote cell proliferation by stimulating G1-S transition but has no impact on cell apoptosis and invasion. Microarray-based co-expression analysis identified a total of 61 genes co-expressed with CDKN3, with most of them involved in cell proliferation, and BIRC5 was located at the center of CDKN3 co-expression network. These results suggest that CDKN3 acts as an oncogene in human hepatocellular carcinoma and antagonism of CDKN3 may be of interest for the treatment of HCC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Intratumoral and circulating regulatory T cells (Tregs) have been shown to be critical in the pathogenesis of hepatocellular carcinoma (HCC). However there is limited knowledge on the alterations of regulatory B cells (Bregs). We here investigated perioperative dynamic alterations of peripheral circulating Tregs and Bregs in HCC patients to reveal the relationship between regulatory lymphocytes and its clinical implications., Methods: 36 patients with HCC, 6 with chronic hepatitis B infection and 10 healthy donors were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before, and after radical surgery. Then, clinical informatics of HCC patients was achieved through Digital Evaluation Score System (DESS) for the assessment of disease severity. Finally, we analysed correlations between digitalized clinical features and kinetics of circulating regulatory lymphocytes., Results: Level of circulating CD4+CD25+CD127- Tregs in HCC patients was significantly lower than that in healthy donors and patients with chronic hepatitis B infection before surgery, but was increased after surgery. Preoperative level of CD19+ IL-10+ Bregs in HCC patients was also significantly lower than the other groups. However it dramatically was elevated right after surgery and remained elevated compared to controls (about 7 days after surgery, P = 0.04). Frequency of circulating Tregs was correlated with circulating leukocytes, ferritin, and clinical features suggesting tumor aggressiveness including portal vein thrombosis, hepatic vein involvement and advanced clinical stages. Frequency of circulating Bregs was associated with Hepatitis B e Antigen (HBeAg) and Hepatitis B virus (HBV) DNA copy number. In addition, DESS was significantly and positively correlated with other staging systems., Conclusion: Frequencies of peripheral Tregs and Bregs in HCC patients increased after surgery. These results suggest that a postoperative combination of therapies against Tregs and Bregs may be beneficial for better outcome of HCC patients after resection.

Background: The prognosis for patients with gastric cancer and synchronous liver metastases is very poor. However, a standard therapeutic strategy has not been well established. The clinical benefit and prognostic factors after hepatic surgical treatment for liver metastases from gastric cancer remain controversial., Methods: Records of 105 patients who underwent gastrectomy regardless of hepatic surgical treatment for gastric cancer with synchronous liver-only metastases in our center between 1995 and 2010 were retrospectively reviewed., Results: The overall survival rate for the 105 patients was 42.1%, 17.2%, and 10.6% at 1, 2, and 3 years, respectively, with a median survival time of 11 months. Multivariate survival analysis revealed that the extent of lymphadenectomy (D) (P < 0.001), lymph node metastases (P < 0.001), extent of liver metastases (H) (P = 0.008), and lymphovascular invasion (P = 0.002) were significant independent prognostic factors for survival. Among patients who underwent D2 lymphadenectomy, those who underwent hepatic surgical treatment had a significantly improved survival compared with those who underwent gastrectomy alone (median survival, 24 vs. 12 months; P < 0.001). However, hepatic surgical treatment was not a prognostic factor for patients who underwent D1 lymphadenectomy (median survival, 8 vs. 8 months; P = 0.495). For the 35 patients who underwent gastrectomy plus hepatic surgical treatment, D2 lymphadenectomy (P < 0.001), lymph node metastases (P = 0.015), and extent of liver metastases (H1 vs. H2 and H3) (P = 0.017) were independent significant prognostic factors for survival., Conclusions: D2 lymphadenectomy plus hepatic surgical treatment may provide hope for long-term survival of judiciously selected patients with hepatic metastases from gastric cancer. Patients with a low degree of lymph node metastases and H1 liver metastases would make the most appropriate candidates. However, if D2 dissection cannot be achieved, hepatic surgical treatment is not recommended.

Aim: To investigate whether the clinicopathologic features of infantile hemangioendothelioma (IHE) of the liver in a Chinese population are similar to the features observed in other races., Methods: The clinical data, radiological findings, histopathological changes and outcome of 12 cases of IHE diagnosed by the Department of Pathology, West China Hospital over the last 10 years were analyzed retrospectively. Immunohistochemical studies were carried out using antibodies against CD31, CD34, Factor VIII, cytokeratin 8 and cytokeratin 18., Results: The 12 patients were aged from fetal to 5 years (three males and nine females). The tumor was presented with different clinical manifestations, mainly as an asymptomatic, palpable, upper abdominal mass, except for the two fetuses who were detected antenatally by ultrasound. In one patient, this presentation was accompanied by an initial severe pneumothorax. No symptoms of congestive heart failure were present and neither congenital abnormalities nor vascular tumors in the skin or other organs were found. Laboratory abnormalities included leukocytosis (40%), anemia (60%), thrombocytosis (60%), hyperbilirubinemia (16.7%), abnormal liver function (50%) and increased α-fetoprotein (80%). Based on radiological findings and gross specimens, the tumor presented as a solitary lesion or a multifocal space-occupying lesion. The tumor size ranged from 5.0 cm × 3.5 cm × 2.0 cm to 13.8 cm × 9.0 cm × 7.7 cm, and the 0.2-1.1 cm nodules were diffusely distributed within the multifocal tumor. Seven cases were surgically resected, three cases underwent biopsy and the two fetuses were aborted. Histologically, nine cases were classified as type I and three as type II, presenting aggressive morphologic features, immature vessels, active mitosis and necrosis. An inflammatory component, predominantly eosinophilic granulocytes, sometimes obscured the nature of the tumor. Ten patients are alive after a follow-up of 1-9 years. Based on immunohistochemistry, the endothelial cells in all cases were positive for CD31, CD34 and polyclonal factor VIII antigen, whereas the scattered hyperplasia bile ducts were positive for cytokeratin 8 and cytokeratin 18., Conclusion: The clinical manifestations of IHE are non-specific. There is no significant correlation between histological type and prognosis. The clinicopathologic features of IHE in Chinese patients may provide a clue to further evidence-based studies.

Background & Objective: Somatostatin analogue (SSTA) has inhibitory effect on the growth of hepatocellular carcinoma (HCC). However, the expression of somatostatin receptor (SSTR) in HCC is still unclear and its correlation to serum alpha-fetoprotein (AFP) has not yet been explored. This study was to investigate the expression of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 subtypes in HCC, and explore their correlations to serum AFP concentration., Methods: The mRNA and protein expression of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 subtypes in 40 specimens of HCC and 40 specimens of liver cirrhosis were detected by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC), respectively. AFP levels in liver tissues and peripheral blood of the 40 HCC patients were measured with enzyme-linked immunosorbent assay (ELISA)., Results: The positive rates of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 proteins were 47.5%, 70.0%, 50.0%, 65.0%, and 67.5% in HCC, and 55.0%, 67.5%, 52.5%, 60.0%, and 47.5% in liver cirrhosis tissues, respectively. The protein levels of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 were markedly higher in HCC than in liver cirrhosis tissues. The expression of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 in HCC had curilinear correlations with serum AFP levels (r = 0.882, 0.901, 0.877, 0.854, 0.903, respectively, P < 0.05). Serum AFP levels ranging between 200-800 ng/ml were associated with high expression of SSTRs in HCC; serum AFP levels below or over that range were associated with low expression of SSTRs., Conclusions: About 60% of the HCC tissues express SSTRs; the protein levels of SSTRs are much higher in HCC than in liver cirrhosis tissues. HCC patients with serum AFP level ranging between 200-800 ng/ml may be good candidates for SSTA therapy.

Objective: To investigate the effects of dendritic cells (DCs) infected with adenovirus vector encoding xenogeneic alpha-fetoprotein (AFP) on breaking the immune tolerance and induction of immunity against hepatocellular carcinomas., Methods: Human and mouse alpha-fetoprotein full-length cDNA were cloned from human HepG2 and mouse Hepa 1 - 6 hepatoma cell lines, respectively, using RT-PCR, and then inserted into adenoviral shuttle vectors to construct Ad hAFP and Ad mAFP. Mice were immunized with Ad hAFP-infected DC and in vitro CTL activity against Hepa 1 - 6 cells was examined by standard (51)Cr release assay. Survival was studied of the immunized mice, with or without depletion of CD8+ or CD4+ T cells, inoculated with Hepa 1 - 6 mouse hepatoma cells., Results: The lytic activity of CTL elicited by the Ad hAFP-infected DCs were much stronger than that by Ad mAFP-infected DCs. 80% of the Ad hAFP/DCs-immunized mice of the inoculated with 5 x 10(6) Hepa 1 - 6 hepatoma cells were still alive two months after inoculation. However, the Ad mAFP/DCs-immunized mice inoculated with 1 x 10(6) Hepa 1 - 6 cells were just 20% surviving two months later. Depletion of CD8+ or CD4+ T cells abolished such an antigen-specific immunity elicited by the DCs infected with Ad hAFP., Conclusion: Adenovirus vector-mediated xenogeneic AFP-infected DCs can effectively break the immune tolerance to hepatocellular carcinomas in an animal model and induce strong antigen-specific T cell response, which are dependent on CD8+ and CD4+ T cells.