Bixiang Zhang

Combined hepatocellular cholangiocarcinoma originating from hepatic progenitor cells: immunohistochemical and double-fluorescence immunostaining evidence

Aims:  Combined hepatocellular cholangiocarcinoma (CHC) is a rare form of primary liver cancer, showing a mixture of hepatocellular and biliary features. Data suggest that most CHC arise from hepatic progenitor cells (HPCs). The aim was to investigate the origin of CHC.

Effects of Location and Extension of Portal Vein Tumor Thrombus on Long-Term Outcomes of Surgical Treatment for Hepatocellular Carcinoma

The role of surgical resection and thrombectomy for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is controversial. This study aimed to evaluate the effects of the location and extent of PVTT on the long-term outcomes of surgical treatment for HCC. A total of 438 patients with HCC and PVTT underwent liver resection with or without thrombectomy. These 438 patients were divided into 2 groups: in group A, PVTT was located in the hepatic resection area or protruded into the first branch of the main portal vein beyond the resection line for <1 cm (286 patients), and in group B, PVTT extended into the main portal vein (152 patients). Concomitant thrombectomy was performed in 147 patients (51.4%) of group A and in all patients of group B. PVTT recurrence within 6 months after surgery in group B was significantly higher than that in group A: 76.9% vs. 11.3%. Remnant liver recurrence within 1 year after surgery was 45.0% in group A and 78.8% in group B. The cumulative 1-, 2-, 3-, and 5-year overall survival rates were 58.7%, 39.9%, 22.7%, and 18.1% for group A and 39.5%, 20.4%, 5.7%, and 0% for group B, respectively. The overall survivals were significantly better in group A than group B (P < .02). Liver resection with thrombectomy yielded better outcomes in the HCC patients with PVTT confined to the first or second branch of the main portal vein compared with PVTT extending into the main portal vein.BackgroundThe role of surgical resection and thrombectomy for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is controversial. This study aimed to evaluate the effects of the location and extent of PVTT on the long-term outcomes of surgical treatment for HCC.MethodsA total of 438 patients with HCC and PVTT underwent liver resection with or without thrombectomy. These 438 patients were divided into 2 groups: in group A, PVTT was located in the hepatic resection area or protruded into the first branch of the main portal vein beyond the resection line for <1 cm (286 patients), and in group B, PVTT extended into the main portal vein (152 patients). Concomitant thrombectomy was performed in 147 patients (51.4%) of group A and in all patients of group B.ResultsPVTT recurrence within 6 months after surgery in group B was significantly higher than that in group A: 76.9% vs. 11.3%. Remnant liver recurrence within 1 year after surgery was 45.0% in group A and 78.8% in group B. The cumulative 1-, 2-, 3-, and 5-year overall survival rates were 58.7%, 39.9%, 22.7%, and 18.1% for group A and 39.5%, 20.4%, 5.7%, and 0% for group B, respectively. The overall survivals were significantly better in group A than group B (P < .02).ConclusionsLiver resection with thrombectomy yielded better outcomes in the HCC patients with PVTT confined to the first or second branch of the main portal vein compared with PVTT extending into the main portal vein.

Chinese experience with hepatectomy for huge hepatocellular carcinoma

The risks and outcome of hepatic resection for huge hepatocellular carcinoma (HCC) are controversial.

Transforming growth factor β induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling

Hepatic progenitor cells (HPCs) are activated in the chronic liver injury and are found to participate in the progression of liver fibrosis, while the precise role of HPCs in liver fibrosis remains largely elusive. In this study, by immunostaining of human liver sections, we confirmed that HPCs were activated in the cirrhotic liver and secreted transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF), both of which were important inducers of liver fibrosis. Besides, we used HPC cell lines LE/6 and WB-F344 as in vitro models and found that TGF-β induced secretion of CTGF in HPCs. Moreover, TGF-β signaling was intracrine activated and contributed to autonomous secretion of CTGF in HPCs. Furthermore, we found that TGF-β induced expression of CTGF was not mediated by TGF-β activated Smad signaling but mediated by TGF-β activated Erk, JNK and p38 MAPK signaling. Taken together, our results provide evidence for the role of HPCs in liver fibrosis and suggest that the production of CTGF by TGF-β activated MAPK signaling in HPCs may be a therapeutic target of liver fibrosis.

Modified technique of hepatic vascular exclusion: effect on blood loss during complex mesohepatectomy in hepatocellular carcinoma patients with cirrhosis

BackgroundHepatic veins remain patent during complete inflow occlusion (CIO) and bleeding from them may continue. Occlusion of the inferior vena cava (ICV) during CIO may reduce blood loss from hepatic veins. This study was designed to compare the overall outcomes after application of CIO with or without occlusion of the ICV below the liver in complex mesohepatectomy for hepatocellular carcinoma (HCC) patients with cirrhosis.Materials and methodsOne hundred and eighteen (118) patients were randomly assigned to CIO or a modified technique of hepatic vascular exclusion (MTHVE). Hemodynamic parameters were evaluated and the amount of blood loss, measurement of liver enzymes, and postoperative progress were recorded.ResultsBlood loss during liver transection in CIO groups was significantly greater than that in MTHVE group (P=0.046). Thus, incidence of blood transfusion was significantly greater in patients of the CIO group (P=0.041). There were no significant differences in liver enzyme changes, bilirubin, or morbidity in the postoperative period between the two groups.ConclusionsCIO with occlusion of the ICV below the liver is a safe, effective, and feasible technique during mesohepatectomy in HCC patients with cirrhosis. Excellent results were obtained with minimized bleeding, limited hepatic function damage, and low rate of postoperative complications.

Randomized clinical trial comparing infrahepatic inferior vena cava clamping with low central venous pressure in complex liver resections involving the Pringle manoeuvre.

Control of bleeding remains key to successful hepatic resection. The present randomized clinical trial compared infrahepatic inferior vena cava (IVC) clamping with low central venous pressure (CVP) during complex hepatectomy using portal triad clamping (PTC).

HSCs play a distinct role in different phases of oval cell-mediated liver regeneration

Hepatic stem cell niche plays an important role in hepatic oval cell‐mediated liver regeneration. As a component of hepatic stem cell niche, the role of hepatic stellate cells (HSCs) in oval cell proliferation needs further studies. In the present study, we isolated HSCs from rats at indicated time point after partial hepatectomy (PH) in 2‐acetylaminofluorene/PH oval cell proliferation model. Conditional medium (CM) from HSCs were collected to detect their effects on proliferation and the mitogen‐activated protein kinase pathway activation of two oval cell lines. We found that CM collected from HSCs at early phase of liver regeneration (4 and 9 days group) contained high levels of hepatocyte growth factor (HGF) and stimulated oval cell proliferation via extracellular signal‐regulated kinase and p38 pathway. CM collected from HSCs at terminal phase of liver regeneration (12 and 15 days group) contained high levels of transforming growth factor (TGF)‐β1, which suppressed DNA synthesis of oval cells. The shift between these two distinct effects depended on the balance between HGF and TGF‐β1 secreted by HSCs. Our study demonstrated that HSCs acted as a positive regulator at the early phase and a negative regulator at the terminal phase of the oval cell‐mediated liver regeneration. Copyright

Reduced expression of transcriptional intermediary factor 1 gamma promotes metastasis and indicates poor prognosis of hepatocellular carcinoma

Transcriptional intermediary factor 1 gamma (TIF1γ) may play either a potential tumor‐suppressor or ‐promoter role in cancer. Here we report on a critical role of TIF1γ in the progression of hepatocellular carcinoma (HCC). Reduced expression of TIF1γ was detected in HCC, especially in advanced HCC tissues, compared to adjacent noncancerous tissues. HCC patients with low TIF1γ expression had shorter overall survival times and higher recurrence rates than those with high TIF1γ expression. Reduced TIF1γ expression was an independent and significant risk factor for recurrence and survival after curative resection. In HCC cells, TIF1γ played a dual role: It promoted tumor growth in early‐stage HCC, but not in advanced‐stage HCC, whereas it inhibited invasion and metastasis in both early‐ and advanced‐stage HCC. Mechanistically, we confirmed that TIF1γ inhibited transforming growth factor‐β/ Drosophila mothers against decapentaplegic protein (TGF‐β/Smad) signaling through monoubiquitination of Smad4 and suppressed the formation of Smad2/3/4 complex in HCC cells. TGF‐β‐inducing cytostasis and metastasis were both inhibited by TIF1γ in HCC. We further proved that TIF1γ suppressed cyotstasis‐related TGF‐β/Smad downstream c‐myc down‐regulation, as well as p21/cip1 and p15/ink4b up‐regulation in early‐stage HCC. Meanwhile, TGF‐β inducible epithelial‐mesenchymal transition and TGF‐β/Smad downstream metastatic cascades, including phosphatase and tensin homolog deleted on chromosome ten down‐regulation, chemokine (CXC motif) receptor 4 and matrix metalloproteinase 1 induction, and epidermal growth factor receptor– and protein kinase B–signaling transactivation, were inhibited by TIF1γ. In addition, we found that the down‐regulation of TIF1γ in HCC was caused by hypermethylation of CpG islands in the TIF1γ promoter, and demonstrated that the combination of TIF1γ and phosphorylated Smad2 was a more powerful predictor of poor prognosis. Conclusion: TIF1γ regulates tumor growth and metastasis through inhibition of TGF‐β/Smad signaling and may serve as a novel prognostic biomarker in HCC. (Hepatology 2014;60:1620–1636)

Role of Mesohepatectomy with or without Transcatheter Arterial Chemoembolization for Large Centrally Located Hepatocellular Carcinoma

Background: The role of preoperative transcatheter arterial chemoembolization (TACE) for resectable hepatocellular carcinoma (HCC) was controversial. Methods: 246 patients with large centrally located HCC underwent mesohepatectomy (MH) and were divided into two groups: group A, 89 patients with preoperative TACE; group B, 157 patients without preoperative TACE. The aim was to evaluate the influence of preoperative TACE on postoperative complications and long-term results of patients with large centrally located HCC. Results: In the 89 patients of the TACE-MH group, a total of 123 (mean 1.4 per patient) preoperative TACEs were performed. The differences in postoperative complications (34.8 vs. 24.2%;p = 0.075) and overall hospital mortality (3.4 vs. 0.6%; p = 0.103) between the two groups were not significant. The postoperative recurrence rate in the remnant liver was higher in the MH group than in the TACE-MH group (79.6 vs. 73.0%), while the extrahepatic metastasis rate in the TACE-MH group was higher than that in the MH group (11.1 vs. 7.0%). Overall 1-, 3-, and 5-year survival rates were 87.1, 62.9, and 46.2%, respectively, for the TACE-MH group, and 82.2, 54.4, and 31.7%, respectively, for the MH group (p = 0.001); 1-, 3-, and 5-year disease-free survival rates were 75.0, 46.2, and 31.8%, respectively, for the TACE-MH group, and 69.6, 38.0, and 16.5%, respectively, for the MH group (p = 0.002). Conclusions: Long-term outcomes of patients with preoperative TACE were improved and the pattern of the recurrences after surgery was altered. The patients with large centrally located HCC could benefit more from this neoadjuvant treatment, although there was some influence of preoperative TACE on postoperative complications.

Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells.

BackgroundActivin A, an important member of transforming growth factor-β superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation.ResultsUsing the 2-acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti-proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2-acetylaminofluorene/partial hepatectomy model.ConclusionActivin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells.