Immune Regulatory Networks and Therapy of γδ T Cells in Liver Cancer: Recent Trends and Advancements.

The roles of γδ T cells in liver cancer, especially in the potential function of immunotherapy due to their direct cytotoxic effects on tumor cells and secretion of important cytokines and chemokines, have aroused research interest. This review briefly describes the basic characteristics of γδ T cells, focusing on their diverse effects on liver cancer. In particular, different subtypes of γδ T cells have diverse or even opposite effects on liver cancer. We provide a detailed description of the immune regulatory network of γδ T cells in liver cancer from two aspects: immune components and nonimmune components. The interactions between various components in this immune regulatory network are dynamic and pluralistic, ultimately determining the biological effects of γδ T cells in liver cancer. We also integrate the current knowledge of γδ T-cell immunotherapy for liver cancer treatment, emphasizing the potential of these cells in liver cancer immunotherapy.

Update on the Diagnosis and Treatment of Combined Hepatocellular Cholangiocarcinoma.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a unique type of liver tumor that contains both hepatocellular carcinoma and cholangiocarcinoma components within a single tumor. The fifth edition of the World Health Organization classification provides a definition and diagnostic criteria for cHCC-CCA. However, the heterogeneous histomorphology and presentation resulting from variation of the proportion of each component poses challenges for clinical diagnosis and treatment. A diagnosis of cHCC-CCA may be suggested by the synchronous elevation of serum tumor markers for hepatocellular carcinoma and cholangiocarcinoma, a mixed enhancement pattern on imaging, and a discrepancy between the elevation of tumor marker and the imaging enhancement pattern. Histopathological examination using hematoxylin and eosin staining is considered the gold standard for diagnosing cHCC-CCA, and comprehensive examination of resection or biopsy specimens is crucial for an accurate diagnosis. Currently, there is no standard treatment for cHCC-CCA, and surgery is the mainstay. Anatomic hepatectomy with lymphadenectomy is among the recommended surgical procedures. The role of liver transplantation in the management of cHCC-CCA is still uncertain. Transarterial chemoembolization may be effective for unresectable cHCC-CCA, particularly for hypervascular tumors. However, the available evidence does not support systemic therapy for advanced cHCC-CCA. The prognosis of cHCC-CCA is generally poor, and there is no established staging system. Further research is needed to better understand the histogenesis and clinical management of cHCC-CCA. This review provides an overview of the current literature on cHCC-CCA with a focus on its clinical characteristics, pathological diagnosis, and management.

Updated information regarding management of hepatic epithelioid hemangioendothelioma.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare hepatic vascular tumor with a borderline biological behavior between hemangioma and hemangiosarcoma. It tends to be multiple or diffuse subcapsular lesions across the liver but has no characteristic clinical manifestations or imaging findings. On computed tomography and magnetic resonance imaging, these lesions usually have a hypodense appearance with heterogeneous enhancement and a "halo sign" or "lollipop sign" may be evident in some cases. HEHE is diagnosed mainly based on a pathological examination along with differential immunohistochemical markers such as CAMTA1, CD31, CD34, CD10, vimentin, and factor VIII antigen. Currently, there are no standardized treatment guidelines for HEHE, and surgery (curative resection and liver transplantation) remains the mainstay of treatment. Studies have indicated that extra-hepatic metastasis might not be a contraindication for resection or transplantation. Systemic chemotherapeutic agents including doxorubicin, vincristine, interferon-a, 5-fluorouracil, and thalidomide, as well as VEGF-related agents are being investigated, but no agents have been approved for the treatment of HEHE.

Retraction Notice to: Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis.

[This retracts the article DOI: 10.1016/j.omtn.2020.05.032.].

Development and validation of a nomogram to predict overall survival in patients with incidental gallbladder cancer: A retrospective cohort study.

Objective: The aim of this study was to develop and validate a nomogram to predict the overall survival of incidental gallbladder cancer. Methods: A total of 383 eligible patients with incidental gallbladder cancer diagnosed in Shanghai Eastern Hepatobiliary Surgery Hospital from 2011 to 2021 were retrospectively included. They were randomly divided into a training cohort (70%) and a validation cohort (30%). Univariate and multivariate analyses and the Akaike information criterion were used to identify variables independently associated with overall survival. A Cox proportional hazards model was used to construct the nomogram. The C-index, area under time-dependent receiver operating characteristic curves and calibration curves were used to evaluate the discrimination and calibration of the nomogram. Results: T stage, N metastasis, peritoneal metastasis, reresection and histology were independent prognostic factors for overall survival. Based on these predictors, a nomogram was successfully established. The C-index of the nomogram in the training cohort and validation cohort was 0.76 and 0.814, respectively. The AUCs of the nomogram in the training cohort were 0.8, 0.819 and 0.815 for predicting OS at 1, 3 and 5 years, respectively, while the AUCs of the nomogram in the validation cohort were 0.846, 0.845 and 0.902 for predicting OS at 1, 3 and 5 years, respectively. Compared with the 8th AJCC staging system, the AUCs of the nomogram in the present study showed a better discriminative ability. Calibration curves for the training and validation cohorts showed excellent agreement between the predicted and observed outcomes at 1, 3 and 5 years. Conclusions: The nomogram in this study showed excellent discrimination and calibration in predicting overall survival in patients with incidental gallbladder cancer. It is useful for physicians to obtain accurate long-term survival information and to help them make optimal treatment and follow-up decisions.

Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4.

Hepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy vs. cytoreductive surgery alone for intrahepatic cholangiocarcinoma with peritoneal metastases: A retrospective cohort study.

BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has survival benefits in patients with intraperitoneal malignant lesions, but there is no study specific to intrahepatic cholangiocarcinoma (ICC). PURPOSE: To compare the prognosis of patients with advanced ICC undergoing CRS + HIPEC compared with CRS alone. METHODS: This study was a retrospective cohort study of patients with advanced ICC treated at the Shanghai Eastern Hepatobiliary Surgery Hospital between 01/2014 and 12/2018. The patients were divided into either CRS + HIPEC or CRS group based on the treatment they received. Overall survival (OS), complications, hospital stay, biochemical indicators, tumor markers, and number of HIPEC were examined. RESULTS: There were 51 and 61 patients in the CRS + HIPEC and CRS groups, respectively. There were no differences between the groups regarding preoperative CA19-9 levels (421 ± 381 vs. 523 ± 543 U/mL, P = 0.208). The hospital stay was longer in the CRS + HIPEC group (22.2 ± 10.0 vs. 18.6 ± 7.6 days, P = 0.033). The occurrence of overall complications was similar in the two groups (37.2% vs. 34.4%, P = 0.756). The postoperative CA19-9 levels were lower in the CRS + HIPEC group compared with the CRS group (196 ± 320 vs. 337 ± 396 U/mL, P = 0.044). The median OS was longer in the CRS + HIPEC group than in the CRS group (25.53 vs. 11.17 months, P < 0.001). Compared with the CRS group, the CRS + HIPEC group showed a higher occurrence of leukopenia (7.8% vs. 0, P = 0.040) but a lower occurrence of total bilirubin elevation (15.7% vs. 37.7%, P = 0.032). CONCLUSION: CRS + HIPEC could be a treatment option for patients with advanced ICC, with improved OS and similar complications and adverse events compared with CRS alone.

Paving the way for small-molecule drug discovery.

Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins, which have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. As commonly used medications, small-molecule drugs can be taken orally, which enter cells to act on intracellular targets. These characteristics make small-molecule drugs promising candidates for drug development, and they are increasingly favored in the pharmaceutical market. Despite the advancements in molecular genetics and effective new processes in drug development, the drugs currently used in clinical practice are inadequate due to their poor efficacy or severe side effects. Therefore, developing new safe and efficient drugs is a top priority for disease control and curing.

Establishment and characterization of 38 novel patient-derived primary cancer cell lines using multi-region sampling revealing intra-tumor heterogeneity of gallbladder carcinoma.

Gallbladder carcinoma (GBC) is a lethal biliary tract malignant neoplasm. Patient-derived primary cancer cell lines (PDPCs) are appropriate models to explore biological characteristics and potential therapeutics; however, there is a lack of PDPCs in GBC. In this study, we aimed to establish and characterize the GBC PDPCs, and further investigated the intra-tumor heterogeneity (ITH). Multi-region sampling (3-9 regions) of the operable tumor tissue samples was used to establish PDPCs. Short tandem repeat genotyping for cell authentication and karyotyping was performed, followed by whole-exome sequencing and RNA sequencing to assess the ITH at the genetic and transcriptional levels, respectively. Thirty-eight PDPCs were successfully established from seven GBC patients and characterized. ITH was observed with a median of 38.3% mutations being heterogeneous (range, 26.6-59.4%) across all patients. Similar with other tumor types, TP53 mutations were always truncal. In addition, there were three genes, KMT2C, CDKN2A, and ARID1A, with truncal mutations in at least two patients. A median of 370 differentially expressed genes (DEGs) was identified per patient. Distinct expression patterns were observed between major histocompatibility complex (MHC) class I and II genes. We found the expression of MHC class II genes in the PDPC samples was closely regulated by CIITA, while that of MHC class I genes were not correlated with CIITA expression. The PDPCs established from GBC patients can serve as novel in vitro models to identify the ITH, which may pave a crucial molecular foundation for enhanced understanding of tumorigenesis and progression.

Whole-Transcriptome Sequencing Identifies Key Differentially Expressed mRNAs, miRNAs, lncRNAs, and circRNAs Associated with CHOL.

To systematically evaluate the whole-transcriptome sequencing data of cholangiocarcinoma (CHOL) to gain more insights into the transcriptomic landscape and molecular mechanism of this cancer, we performed whole-transcriptome sequencing based on the tumorous (C) and their corresponding non-tumorous adjacent to the tumors (CP) from eight CHOL patients. Subsequently, differential expression analysis was performed on the C and CP groups, followed by functional interaction prediction analysis to investigate gene-regulatory circuits in CHOL. In addition, The Cancer Genome Atlas (TCGA) for CHOL data was used to validate the results. In total, 2,895 differentially expressed messenger RNAs (dif-mRNAs), 56 differentially expressed microRNAs (dif-miRNAs), 151 differentially expressed long non-coding RNAs (dif-lncRNAs), and 110 differentially expressed circular RNAs (dif-circRNAs) were found in CHOL samples compared with controls. Enrichment analysis on those differentially expressed genes (DEGs) related to miRNA, lncRNA, and circRNA also identified the function of spliceosome. The downregulated hsa-miR-144-3p were significantly enriched in the competing endogenous RNA (ceRNA) complex network, which also included 7 upregulated and 13 downregulated circRNAs, 7 upregulated lncRNAs, and 90 upregulated and 40 downregulated mRNAs. Moreover, most of the DEGs and a few of the miRNAs (such as hsa-miR-144-3p) were successfully validated by TCGA data. The genes involved in RNA splicing and protein degradation processes and miR-144-3p may play fundamental roles in the pathogenesis of CHOL.

Long Noncoding RNA OIP5-AS1 Promotes the Progression of Liver Hepatocellular Carcinoma via Regulating the hsa-miR-26a-3p/EPHA2 Axis.

Numerous studies have suggested that dysregulated long noncoding RNAs (lncRNAs) contributed to the development and progression of many cancers. lncRNA OIP5 antisense RNA 1 (OIP5-AS1) has been reported to be increased in several cancers. However, the roles of OIP5-AS1 in liver hepatocellular carcinoma (LIHC) remain to be investigated. In this study, we demonstrated that OIP5-AS1 was upregulated in LIHC tissue specimens and its overexpression was associated with the poor survival of patients with LIHC. Furthermore, loss-of function experiments indicated that OIP5-AS1 promoted cell proliferation and inhibited cell apoptosis both in vitro and in vivo. Moreover, binding sites between OIP5-AS1 and hsa-miR-26a-3p as well as between hsa-miR-26a-3p and EPHA2 were confirmed by luciferase assays. Finally, a rescue assay was performed to prove the effect of the OIP5-AS1/hsa-miR-26a-3p/EPHA2 axis on LIHC cell biological behaviors. Based on all of the above findings, our results suggested that OIP5-AS1 promoted LIHC cell proliferation and invasion via regulating the hsa-miR-26a-3p/EPHA2 axis.

Prognosis for intrahepatic cholangiocarcinoma patients treated with postoperative adjuvant transcatheter hepatic artery chemoembolization.

OBJECTIVE: We used meta-analysis to evaluate the efficacy of transcatheter hepatic arterial chemoembolization (TACE) for the treatment of intrahepatic cholangiocarcinoma (ICC). METHODS: We performed the meta-analysis using the R 3.12 software and the quality evaluation of data using the Newcastle-Ottawa Scale. The main outcomes were recorded as 1-year overall survival (OS), 3-year OS, 5-year OS, and hazard ratio (HR) of TACE treatment or non-TACE treatment. The heterogeneity test was performed using the Q-test based on chi-square and I2 statistics. Egger's test was used to test the publication bias. The odds ratio or HR and 95% confidence interval (CI) were used to represent the effect index. RESULTS: Nine controlled clinical trials involving 1724 participants were included in this study; patients came mainly from China, Italy, South Korea, and Germany. In the OS meta-analysis, the 1-year and 3-year OS showed significant heterogeneity, but not the 5-year OS. TACE increased the 1-year OS (odds ratio = 2.66, 95% CI: 1.10-6.46) of the patients with ICC, but the 3- and 5-year OS rates were not significantly increased. The results had no publication bias, but the stability was weak. The HR had significant heterogeneity (I2 = 0%, P= 0.54). TACE significantly decreased the HR of ICC patients (HR = 0.59, 95% CI: 0.48-0.73). The results had no publication bias, and the stability was good. CONCLUSIONS: Treatment with TACE is effective for patients with ICC. Regular updating and further research and analysis still need to be carried out.

Long Stress Induced Non-Coding Transcripts 5 (LSINCT5) Promotes Hepatocellular Carcinoma Progression Through Interaction with High-Mobility Group AT-hook 2 and MiR-4516.

BACKGROUND Long non-coding RNAs (lncRNAs) have been implicated in various human cancer types. However, the underlying mechanisms involved in hepatocellular carcinoma (HCC) progression remain poorly understood. MATERIAL AND METHODS In this study, lncRNA array was used to identify HCC related lncRNAs. RNA immunoprecipitation (RIP) followed mass spectrometry was used to explore lncRNA binding proteins. Western blot, quantitative PCR, tumor sphere formation, migration and viability assay were performed to evaluate the oncogenic role of lncRNAs. RESULTS We identified a novel lncRNA named long stress induced non-coding transcripts 5 (LSINCT5) which facilitates HCC progression. LSINCT5 was significantly upregulated in both HCC specimens and cell lines and correlates with poor survival. In vitro experiments showed that LSINCT5 promoted migration and viability of HepG2 and Huh7 cells. The in vivo xenograft mouse model also confirmed an oncogenic role for LSINCT5. RIP in combination with mass spectrometry identified HMGA2 as the LSINCT5 binding partner. LSINCT5 could bind to HMGA2 and decrease proteasome-mediated HMGA2 degradation leading to EMT activation. LSINCT5 also served as a competing endogenous RNA (ceRNA) for miR-4516, resulting in increased STAT3/BclxL expression and attenuated apoptosis. CONCLUSIONS Our data have collectively established a lncRNA LSINCT5 mediated process during HCC carcinogenesis and might have provided novel insight into therapeutic targeting.

Comparison of clinicopathological characteristics between cirrhotic and non-cirrhotic patients with intrahepatic cholangiocarcinoma: A large-scale retrospective study.

The effect of cirrhosis on the characteristics of intrahepatic cholangiocarcinoma (ICC) has not been fully elucidated. The purpose of this study was to investigate how cirrhosis affects the clinicopathological characteristics and survival of surgically treated ICC patients. A total of 1,312 ICC patients surgically treated between January 2007 and December 2011 at a single institution were retrospectively reviewed and the clinicopathological data were compared between cirrhotic and non-cirrhotic patients. Univariate and multivariate analyses were performed to identify significant and independent prognostic factors in this cohort. A total of 302 patients (23.0%) were cirrhotic. Compared with cirrhotic patients, the tumors in non-cirrhotic patients were usually larger, less differentiated, and more likely to have lymphatic metastasis, vascular and perineural invasion. Following resection, cirrhotic patients achieved a longer survival compared with non-cirrhotic patients (16.0 vs. 13.0 months, respectively; P<0.038). Multivariate analysis demonstrated that hepatitis B virus infection and cirrhosis were independent favorable prognostic factors, while the presence of cholelithiasis, elevated carbohydrate antigen 19-9 and carcinoembryonic antigen levels, multiple tumors, lymphatic metastasis, vascular invasion and positive surgical margin status were independent unfavorable prognostic factors. Overall, the clinicopathological characteristics of ICC patients with and without cirrhosis differed significantly. Compared with cirrhotic patients, in whom the biological behavior of ICC was similar to that of HCC, non-cirrhotic patients exhibited higher-risk pathological characteristics, lower curative resection rate and worse survival.

Low expression of DCXR protein indicates a poor prognosis for hepatocellular carcinoma patients.

The aim of this study was to investigate the prognostic value of dicarbonyl/L-xylulose reductase (DCXR) in human hepatocellular carcinoma (HCC). Immunohistochemistry and tissue microarrays were used to evaluate DCXR protein expression levels. Image-Pro Plus was used to calculate the integral optic density (IOD) in each tissue sample, which represented the expression level of DCXR. DCXR proteins were found to be significantly lower in HCC tumor tissues (P < 0.0001) according to immunohistochemical analysis of DCXR protein levels in 74 paired HCC tissue and peritumoral non-cancer tissues. The prognostic value of DCXR in HCC was assessed in 290 cases of the training cohort and 74 cases of the validation cohort. Shorter overall survival (OS) time and shorter time to recurrence (TTR) in both the training and validation set were found to be associated with lower expression levels of DCXR. In the training set, the expression level of DCXR in HCC was an independent prognostic factor for OS according to univariate and multivariate analyses. In conclusion, DCXR expression is an independent prognostic factor for OS and TTR of post-operative HCC patients, and low expression levels of DCXR in HCC may indicate poor outcome of HCC patients after surgical resection.

NEDD4 Depletion Inhibits Hepatocellular Carcinoma Growth via Targeting PTEN.

BACKGROUND/AIMS: Neural precursor cell-expressed developmentally down-regulated gene 4 (NEDD4) plays an important role in tumor cell growth, yet its role in hepatocellular carcinoma (HCC) remains unclear. This study is to establish NEDD4 as a prognostic biomarker by which the survival of HCC patients can be predicted and to reveal the role of NEDD4 in hepatocellular carcinoma cell growth. METHODS: The expression of NEDD4 in 219 HCC specimens was assessed by immunohistochemistry. Postoperative overall survival and time to recurrence were evaluated by univariate and multivariate analyses. The roles of NEDD4 in hepatocellular carcinoma cell proliferation and invasion were determined. RESULTS: The patients with low NEDD4 expression tumors had an average cumulative survival of 64.9 ± 6.5 months during follow-up while the patients with high NEDD4 expression tumors had an average cumulative survival of 20.3 ± 15.8 months. NEDD4 silencing inhibited Huh7 cell proliferation and altered cell cytoskeletal assembly, and NEDD4 depletion furthermore seemed to suppress cell migration and invasion. A possible molecular mechanism for the observed effects might be that NEDD4 silence led to an increase in PTEN (phosphatase and tensin homologue) expression, which in turn resulted in the inactivation of STAT3, AKT, and ERK1/2. CONCLUSION: Our findings indicate that NEDD4 may participate in the HCC progression and may therefore be a potential target for HCC therapy.

Hepatitis B virus-related combined hepatocellular-cholangiocarcinoma: clinicopathological and prognostic analysis of 390 cases.

BACKGROUND: The reported treatment outcomes of combined hepatocellular-cholangiocarcinoma (HCC-CC) are inconsistent and the clinicopathological factors influencing treatment outcome remain to be defined. PATIENTS AND METHODS: Patients with hepatitis B virus (HBV)-related HCC-CC undergoing surgical treatment at our institution between January 1997 and September 2010 were retrospectively analyzed. Univariate and multivariate analyses were carried out to identify independent clinicopathological factors affecting surgical outcome. RESULTS: A total of 390 patients with HBV-related HCC-CC were included in this study; there were 328 men and 62 women, with a median age of 49 years (range 21-77 years). Among these patients, 74.4% had underlying liver cirrhosis. The median tumor size was 6.5 cm (range 1.3-33 cm) with 68.7% microvascular invasion and 12.3% lymphatic metastasis. The median survival after surgical resection was 1.68 years and the cumulative survival at 1, 2, 5, and 10 years was 62.1, 46.4, 32, and 25.5%, respectively. The disease-free survival at 1, 2, 5, and 10 years was 36.1, 22.3, 15, and 11.3%, respectively. Independent predictors for decreased survival were male sex, tumor number (≥2), major thrombus, microvascular thrombus, γ-glutamyl transpeptidase (GGT) over 60 U/l, and carbohydrate antigen 19-9 level. Independent negative factors affecting disease-free survival included tumor size (>5 cm), major thrombus, and GGT over 60 U/l. CONCLUSION: Long-term surgical survival of HBV-related HCC-CC seemed to be influenced by sex, tumor-related factors (tumor number, major thrombus, and microvascular thrombus), serum GGT, and carbohydrate antigen 19-9 level. Tumor size, major thrombus, and serum GGT level tended to be associated with disease-free survival.

MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma.

BACKGROUND & AIMS: Portal vein tumor thrombus (PVTT) has previously been demonstrated to correlate with poor prognosis of hepatocellular carcinoma. Approximately 50-80% of HCC is accompanied by portal or hepatic vein invasion. The underlying mechanisms of PVTT development remain unclear. This study aimed to elucidate the role of miR-135a in PVTT tumorigenesis. METHODS: In the present study, we investigated the expression of microRNAs and mRNAs in PVTT tissues using advanced microRNA and cDNA microarray techniques. MicroRNA (miR)-135a was noted to be highly over-expressed in PVTT and the cell line CSQT-2 and was selected for further study. We characterized the function of miR-135a in vitro and in vivo. We also analyzed the clinical relevance of miR-135a in relation to the prognosis and survival of HCC patients with PVTT. RESULTS: Our analyses found that the miRNA and mRNA expression profiles of PVTT were distinct from the parenchyma tumor. Overexpression of miR-135a favors invasive and metastatic behavior in vitro. Furthermore, in a CSQT-2 orthotopic transplantation nude mouse model, blockade of miR-135a significantly reduced PVTT incidence. We also found that miR-135a was transcribed by forkhead box M1 (FOXM1), and metastasis suppressor 1 (MTSS1) was identified as the direct and functional target of miR-135a. Additionally, the cohort analysis revealed the relevance of miR-135a with respect to the prognosis and survival of HCC patients with PVTT. CONCLUSIONS: Our data suggest an important role for miR-135a in promoting PVTT tumorigenesis and indicate the potential application of miR-135a in PVTT therapy.

The hepatoprotective effect of hypothermic perfusion of normal saline in period of inflow occlusion of liver in rats.

BACKGROUND: Liver damage in hepatic surgery from warm ischemia and reperfusion (I/R), especially in patients with underlying chronic liver disease, is still challenging. We propose a new method of perfusion of the liver by catheterizing the umbilical vein in the period of hepatic inflow occlusion, and evaluate the influence of transfusion of normal saline (NS) on liver injury in a modified I/R rat model. METHODS: Twenty-eight rats were randomized into four groups (n=7): group I (sham-operated group): no I/R or transfusion; group II (I/R group): I/R + no transfusion; group III (37°C NS group): I/R + transfusion of 37°C NS ; group IV(24°C NS group): I/R + transfusion of 24°C NS. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as lactate dehydrogenase (LDH) were measured in rat serum. Light and electron microscopic examinations were performed on the liver tissues. RESULTS: Perfusion of 24°C NS in the period of inflow occlusion resulted in significant reductions of liver enzymes levels compared to the I/R alone group and 37°C NS group (P<0.001 and P<0.001, respectively). Histologic evaluation revealed the injury grade to be relatively lower in group IV compared to group II and III (P<0.001 and P<0.001, respectively). CONCLUSION: This new hypothermic perfusion technique may be very useful in preserving the hepatocytes in hepatic surgery; it is an inexpensive and easy method, which makes it possible to increase its application.

Vitamin analogues in chemoprevention of hepatocellular carcinoma after resection or ablation--a systematic review and meta-analysis.

OBJECTIVE: While hepatic resection or local ablative therapy may provide a potentially curative treatment for hepatocellular carcinoma (HCC), more than half of these patients develop recurrent HCC within 5 years after treatment. Thus identification of any therapy which can decrease or delay the incidence of recurrence will improve the results of treatment. However, no chemopreventive agent has been approved for HCC. METHODS: A MEDLINE database, Embase, Cancerlit (National Cancer Institute), and CBM (Chinese Biomedical Database) search from 1990 to 2009 was performed to identify relevant articles using the keywords "hepatocellular carcinoma," "vitamin analogue," and "chemoprevention." Additional papers were identified by a manual search of the references from the key articles. The fixed effect model was used for a meta-analysis. RESULTS: Oral administration of acyclic retinoids (vitamin A analogue), and menatetrenone (vitamin K2 analogue) have been tested as chemopreventive agents after hepatic resection or local ablative therapy for HCC. There were one and four randomised, controlled trials (RCTs) which evaluated the efficacy of polyprenoic acid and menatetrenone, respectively. All studies were conducted in Japan. One RCT showed the preventive effect of polyprenoic acid in lowering the incidence of HCC recurrence after hepatic resection or percutaneous ethanol injection, and this effect lasted up to 199 weeks after randomization (or 151 weeks after completion of retinoid administration). Four RCTs evaluated the preventive efficacy of menatetrenone on HCC recurrence after hepatic resection or local ablative therapy. The results of three studies, as well as the meta-analysis of all four studies, showed significantly better tumour recurrence-free survival. The beneficial effect on the overall survival was less definite. CONCLUSION: There is evidence to suggest that chemopreventive therapy after partial hepatectomy or local ablative therapy is beneficial in prolonging disease-free survival, but the evidence is less for an effect on the overall survival. To confirm the beneficial role of vitamin A or K analogues in the chemoprevention of HCC further and larger randomised trials are now required.