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.

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.

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.

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.

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.

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.

Enucleation of liver hemangiomas: is there a difference in surgical outcomes for centrally or peripherally located lesions?

BACKGROUND: Partial hepatectomy for centrally located liver lesions is technically more challenging than that for peripheral lesions. Enucleation of liver hemangiomas is easier and safer than partial hepatectomy. Whether enucleation gives the same surgical outcomes for both centrally and peripherally located hemangiomas is unknown. This study aimed to evaluate the difference in surgical outcomes of enucleation of centrally and peripherally located liver hemangiomas. METHODS: This study used a prospectively maintained database consisting of a consecutive series of patients who underwent enucleation of liver hemangiomas in a tertiary referral center from January 2004 to December 2006. Surgical variables, length of hospital stay, and postsurgical complications were compared between centrally and peripherally located liver hemangiomas. RESULTS: During the study period, 172 patients underwent enucleation of hepatic hemangiomas. The lesions were centrally located in 76 patients (44.2%) and peripherally located in 96 patients (55.8%). The 2 groups were comparable in demographic data and lesion characteristics. There was no hospital mortality. The major complication rates were low in both groups (2.6% vs. 3.1%; P = .848). Enucleation of centrally located liver hemangiomas required significantly longer vascular inflow occlusion time (P <.001), longer operating time (P <.001), and more blood transfusion (P = .001). This group also had a higher volume of blood loss (P = .004) and longer hospital stay (P = .024) than the group with peripherally located liver hemangiomas. CONCLUSIONS: Enucleation is a safe surgery for hemangiomas in any part of the liver, although it is technically more demanding for centrally than peripherally located hemangiomas.

Factors related to pleural effusion following hepatectomy for primary liver cancer.

BACKGROUND: Pleural effusion frequently complicates hepatectomy and multiple factors contribute to its development following hepatectomy for primary liver cancer. The purpose of this study was to evaluate these factors. METHODS: From March 2003 to May 2005, 228 consecutive patients with primary liver cancer underwent hepatectomy in our department were evaluated retrospectively to identify factors related to postoperative pleural effusion. RESULTS: Among the 228 patients, postoperative pleural effusions arose in 58 (25.4%). Univariate analysis showed significant differences in postoperative ascites, subphrenic collection, Pringle manoeuvre length, drainage amount on postoperative day 1, albumin level on postoperative day 7, alanine aminotransferase (ALT) level on postoperative days 1 and 3, prealbumin level on postoperative days 3 and 7, and tumor size (P<0.05). Ordinal regression analysis revealed that subphrenic collection, drainage on postoperative day 1 and ALT plus prealbumin on postoperative days 1 and 3 were statistically significantly related to postoperative pleural effusion (P<0.05). CONCLUSION: Subphrenic collection and operative injury to the liver appeared to be significantly related to pleural effusion after hepatectomy for primary liver cancer.

Prevention and management of pleural effusion following hepatectomy in primary liver cancer.

BACKGROUND: Postoperative pleural effusion occurs frequently after hepatectomy. The risk factors, prevention and management of postoperative pleural effusion in patients with primary liver cancer (PLC) who have undergone hepatectomy and the value of the argon beam coagulator (ABC) for the prevention of pleural effusion are studied. METHODS: A total of 523 patients with PLC at our institution who had had right hepatectomy from July 2000 to June 2004 were studied retrospectively. Comparative analysis was made to identify the factors contributing to postoperative pleural effusion and the efficacy of various managements. RESULTS: Of the 523 patients whose livers were dissociated using argon beam cutting and/or coagulation, 20(3.8%) developed pleural effusions; whereas in the other 467 patients underwent hepatectomy with suture ligation of the diaphragmatic secondary wound surface during the same period, 49(10.5%) had pleural effusion (P < 0.01). The factors contributing to postoperative pleural effusion included subphrenic collection, postoperative hepatic insufficiency with ascites, duration of hepatic occlusion and underlying cirrhosis. CONCLUSIONS: Dissociation of the liver by argon beam cutting and/or coagulation can save suture ligation of the diaphragmatic secondary wound surface and may also prevent postoperative pleural effusion. Pleural drainage using an indwelling central-venous-catheter (CVC) in the pleural cavity is safe and efficacious.