Novel serum microRNAs panel on the diagnostic and prognostic implications of hepatocellular carcinoma.

AIM: To determine a panel of serum microRNAs (miRNAs) that could be used as novel biomarkers for diagnosis of hepatocellular carcinoma (HCC). METHODS: We initially screened 9 out of 754 serum miRNAs by TaqMan Low Density Array in two pooled samples respectively from 35 HCC and 35 normal controls, and then validated individually by RT-qPCR in another 114 patients and 114 controls arranged in two phases. The changes of the selected miRNAs after operation and their prognostic value were examined. RESULTS: miR-375, miR-10a, miR-122 and miR-423 were found to be significantly higher in HCC than in controls (P < 0.0001), and the area under the receiver-operating-characteristic curve for the 4-miRNA panel was 0.995 (95%CI: 0.985-1). All the four miRNAs were significantly reduced after surgical removal of the tumors (P < 0.0001), while still higher than normal controls (at least P < 0.05). CONCLUSION: The four serum miRNAs (miR-375, miR-10a, miR-122 and miR-423) could potentially serve as novel biomarkers for the diagnostic and prognostic of HCC.

Transforming growth factor-ß and peripheral regulatory cells are negatively correlated with the overall survival of hepatocellular carcinoma.

AIM: To understand the cellular and molecular changes in peripheral blood that can lead to the development of hepatocellular carcinoma (HCC) and provide new methods for its diagnosis and treatment. METHODS: Peripheral blood mononuclear cells were isolated from the peripheral blood of HCC patients and normal controls and then analyzed by flow cytometry. The percentage of transforming growth factor-ß (TGF-ß)+ regulatory cells (Tregs) in the peripheral blood was measured, and the expression of TGF-ß was also determined. Then, the relationship between the changes and the 5-year survival of patients was analyzed. In addition, recombinant human TGF-ß (rhTGF-ß) and recombinant human interleukin-6 were added to stimulate the cultured cells, and their effects on HCC were evaluated. RESULTS: The expression of TGF-ß and the percentage of TGF-ß+ Tregs in the peripheral blood of HCC patients increased significantly compared with normal controls. Compared with the low TGF-ß expression group, the high TGF-ß expression group had a significantly lower 5-year survival rate, and the same result was found in the two TGF-ß+ Treg groups, suggesting that TGF-ß and TGF-ß+ Tregs were negatively correlated with the overall survival of the patients. In addition, rhTGF-ß promoted the growth of tumor cells and induced high expression levels of IL-6, which further promoted tumor proliferation. CONCLUSION: The results showed that TGF-ß may promote tumor growth and proliferation by inducing the production of IL-6, and TGF-ß and TGF-ß+ Tregs may serve as new markers for predicting a poor prognosis in HCC.

Methylation-Mediated Silencing of GATA5 Gene Suppresses Cholangiocarcinoma Cell Proliferation and Metastasis.

Cholangiocarcinoma (CCA) is one of the most common hepatic and biliary malignancies, accounting for about 3% of all gastrointestinal tumors. GATA5 is a transcription factor capable of suppressing the development of various human cancer types. Transcriptional inactivation and CpG island (CGI) methylation of GATA3 and GATA5, two members of the GATA family of transcription factors, have been observed in some human cancers. But whether high-density CGI methylation of GATA5 is associated with the clinical course of CCA patients has not been clarified. Herein, we observed reduced expression of GATA5 in CCA tissues compared with noncancerous tissues. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored GATA5 expression in CCA cell lines. Furthermore, GATA5 expression was downregulated after treatment with IL-6 in human intrahepatic biliary epithelial cells. Upregulated GATA5 inhibited CCA cell growth and metastasis. Mechanistically, GATA5 suppressed CCA cell growth and metastasis via Wnt/ß-catenin pathway. Specific ß-catenin inhibitor or siRNA abolished the discrepancy of the proliferation and metastasis capacity between GATA5-overexpression CCA cells and their control cells, which further confirmed that Wnt/ß-catenin was required in GATA5-inhibited CCA cell growth and metastasis.

Percutaneous biliary stenting combined with radiotherapy as a treatment for unresectable hilar cholangiocarcinoma.

Hilar cholangiocarcinoma is often unresectable at the time of the initial diagnosis, and the provision of a definite palliative benefit is important in patients with unresectable hilar cholangiocarcinoma. The aim of the present study was to evaluate the safety of percutaneous biliary stenting and to analyze whether percutaneous biliary stenting combined with radiotherapy (RT) prolonged the stent patency and survival time of patients. In total, the cases of 38 patients with unresectable hilar cholangiocarcinoma that underwent percutaneous biliary stenting at the Navy General Hospital were retrospectively reviewed in the present study. Uncovered metallic stenting (UMS) combined with RT was administered to 25 patients, and UMS alone was administered to 13 patients. The records of early complications subsequent to percutaneous biliary stenting were collected, and the stent patency and survival times of patients were analyzed and compared between the two groups. The technical success rate of the procedure was 100% and the successful drainage rate was 86.8%. The overall early complication rate was 15.8% and the procedure-associated mortality rate was 2.6%. The median stent patency was 326 days in the UMS+RT group and 196 days in the UMS group (P=0.022). The UMS+RT group (median, 367 days) demonstrated a longer survival time compared with the UMS group (median, 267 days; P=0.025). Percutaneous biliary stenting offers a safe and effective method for the palliative treatment of patients with unresectable hilar cholangiocarcinoma, and percutaneous biliary stenting combined with RT may prolong stent patency and patient survival time.

Choice of approach for hepatectomy for hepatocellular carcinoma located in the caudate lobe: isolated or combined lobectomy?

AIM: To investigate the significance of the surgical approaches in the prognosis of hepatocellular carcinoma (HCC) located in the caudate lobe with a multivariate regression analysis using a Cox proportional hazard model. METHODS: Thirty-six patients with HCC underwent caudate lobectomy at a single tertiary referral center between January 1995 and June 2010. In this series, left-sided, right-sided and bilateral approaches were used. The outcomes of patients who underwent isolated caudate lobectomy or caudate lobectomy combined with an additional partial hepatectomy were compared. The survival curves of the isolated and combined resection groups were generated by the Kaplan-Meier method and compared by a log-rank test. RESULTS: Sixteen (44.4%) of 36 patients underwent isolated total or partial caudate lobectomy whereas 20 (55.6%) received a total or partial caudate lobectomy combined with an additional partial hepatectomy. The median diameter of the tumor was 6.7 cm (range, 2.1-15.8 cm). Patients who underwent an isolated caudate lobectomy had significantly longer operative time (240 min vs 170 min), longer length of hospital stay (18 d vs 13 d) and more blood loss (780 mL vs 270 mL) than patients who underwent a combined caudate lobectomy (P < 0.05). There were no perioperative deaths in both groups of patients. The complication rate was higher in the patients who underwent an isolated caudate lobectomy than in those who underwent combined caudate lobectomy (31.3% vs 10.0%, P < 0.05). The 1-, 3- and 5-year disease-free survival rates for the isolated caudate lobectomy and the combined caudate lobectomy groups were 54.5%, 6.5% and 0% and 85.8%, 37.6% and 0%, respectively (P < 0.05). The corresponding overall survival rates were 73.8%, 18.5% and 0% and 93.1%, 43.6% and 6.7% (P < 0.05). CONCLUSION: The caudate lobectomy combined with an additional partial hepatectomy is preferred because this approach is technically less demanding and offers an adequate surgical margin.