Wan-Guang 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.

The Role of NF-κB in Hepatitis B Virus X Protein-Mediated Upregulation of VEGF and MMPs

ABSTRACT Hepatitis B virus X protein (HBx) promotes hepatocellular carcinoma (HCC) invasion and metastasis by a poorly understood mechanism. This study investigated the role of NF-κ B in HBx-mediated upregulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). In a stably expressing HBx cell line, NF-κ B level was examined by laser scanning confocal microscopy before and after treatment with pyrrolidine dithiocarbamate (PDTC; an NF-κ B inhibitor). VEGF, MMP2, MMP9, and MMP14 mRNA and protein levels were quantitated by real-time PCR and Western blotting, respectively. HBx stimulated NF-κ B signaling and increased VEGF, MMP2, MMP9, and MMP14 mRNA and protein levels. PDTC treatment blocked HBx-mediated stimulation of NF-κ B signaling and decreased VEGF, MMP9, and MMP14 (but not MMP2) mRNA and protein levels. In vivo studies, PDTC reduced angiogenesis in subcutaneous xenograft of nude mice which injected HepG2-HBx cells. This suggests that NF-κ B is involved in upregulating these genes and in the HBx-mediated invasion and metastasis of HCC.

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.

Relevance of two genes in the multidrug resistance of hepatocellular carcinoma: in vivo and clinical studies

Aims and background A former study evaluated the roles of four multidrug resistance-related proteins, namely multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance-related protein (MRP1), and lung resistance-related protein (LRP), in the MDR mechanism of the multidrug resistant hepatoma HepG2/ADM cell line and proposed that up-regulated MDR1 and BCRP are responsible for the MDR of hepatocellular carcinoma. This work aims to confirm that assumption in vivo and in clinical specimens. Methods First, the chemotherapeutic resistance of subcutaneous HepG2/ADM tumor and hepatocellular carcinoma samples post-transarterial chemoembolization (TACE) was determined by MTT, contrary to subcutaneous HepG2 tumor and hepatocellular carcinoma samples without TACE, respectively. Then, the mRNA and protein differential expression of the four genes between the MDR tissues and drug-sensitive tissues were quantitatively investigated by real-time RT-PCR and enhanced chemiluminescence western blot analysis, respectively. Results 1) mRNA expression of BCRP and MDR1 was respectively amplified 38.3 and 20.1 fold in tumors of HepG2/ADM mice compared to those of HepG2 mice, whereas they were respectively augmented for 14.6 and 9.3 times in TACE samples, contrary to the tumor tissues without TACE. 2) The protein presence of MDR1 and BCRP in MDR tumors was also significantly higher than those in the control group in vivo and in clinical specimens. 3) The mRNA expressions of MDR1 and BCRP were correlated to their protein levels. Conclusions The study showed that MDR1 and BCRP may be the most important factors for drug resistance in hepatocellular carcinoma. Moreover, the positive correlation between their mRNA and protein expression indicates the easy prediction of HCC MDR and possible inhibitive target of drug resistance at multi-levels.

Inhibiting Survivin Expression Enhances TRAIL-Induced Tumoricidal Activity in Human Hepatocellular Carcinoma Via Cell Cycle Arrest

Human Hepatocellular carcinoma (HCC) cell types exhibit a major resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death, and the key determinants of mechanisms accounting for TRAIL susceptibility, still remain controversial. Our previous studies showed that overexpression of survivin reduced sensitivity of HCC cells to TRAIL. The aim of this study is to investigate how tumor cells escape TRAIL-mediated surveillance through survivin expression and how to reverse the resistance of TRAIL-inducing apoptosis. Seven tumor cell lines were treated with or without TRAIL protein and antisense oligodeoxynucleotides (ODNs) against survivin in culture. HepG2 and SMMC7721 cells were treated with mimosine, thymidine or nocodazole to synchronize their cell cycle phases and then used to test their sensitivity to TRAIL. In vivo effects of TRAIL plasmid alone or in combination with survivin antisense ODNs on tumor growth were evaluated in a nude mouse hepatoma model of HepG2 cell grafts. Varied levels of survivin mRNA in various cell lines were evaluated and negatively correlated to TRAIL-induced apoptosis. Hepatoma HepG2 and SMMC7721 cells in G1 or S phase are more sensitive to TRAIL than those in G2 phase. Treatment with survivin antisense ODNs caused S phase arrest and significantly enhanced TRAIL-induced apoptosis. TRAIL protein caused G2/M arrest and resulted in an increase of survivin in HepG2 cells. Combined TRAIL plasmid and survivin antisense ODNs significantly supressed the growth of tumor xenografts as compared to TRAIL plamid or antisense ODNs alone during a 4-week of observation. The findings indicate that survivin may play a role in tumor cell resistance to TRAIL-induced apoptosis, at least in part, through cell cycle regulation. Manipulation of survivin expression levels may sensitizes tumor cells to TRAIL-induced apoptosis.

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.

Synergism of hydroxyapatite nanoparticles and recombinant mutant human tumour necrosis factor-α in chemotherapy of multidrug-resistant hepatocellular carcinoma

Background/Aims: Locoregional chemotherapy continues to be the mainstay for the treatment of unresectable hepatocellular carcinoma (HCC). One of the principal obstacles implicated in its unsuccessful therapy is multidrug resistance (MDR). Former studies have identified the multidrug‐resistant nature and possible mechanisms of hepatoma cells both in vitro and in vivo. This work aimed to develop an effective strategy for the treatment of HCC with MDR.

Surgical Treatment of Giant Liver Hemangioma Larger Than 10 cm: A Single Center's Experience With 86 Patients

AbstractThe ideal surgical treatment of giant liver hemangioma is still controversial. This study aims to compare the outcomes of enucleation with those of resection for liver hemangioma larger than 10 cm in different locations of the liver and establish the preoperative predictors of increased intraoperative blood loss.Eighty-six patients underwent enucleation or liver resection for liver hemangioma larger than 10 cm was retrospectively reviewed. Patient demographic, tumor characteristics, surgical indications, the outcomes of both surgical treatment, and the clinicopathological parameters influencing intraoperative blood loss were analyzed.Forty-six patients received enucleation and 40 patients received liver resection. Mean tumor size was 14.1 cm with a range of 10–35 cm. Blood loss, blood product usage, operative time, hepatic vascular occlusion time and frequency, complications and postsurgical hospital stay were similar between liver resections and enucleation for right-liver and left-liver hemangiomas. There was no surgery-related mortality in either group. Bleeding was more related to adjacency of major vascular structures than the size of hemangioma. Adjacency to major vascular structures and right or bilateral liver hemangiomas were independently associated with blood loss >550 mL (P = 0.000 and 0.042, respectively).Both enucleation and liver resection are safe and effective surgical treatments for liver hemangiomas larger than 10 cm. The risk of intraoperative blood loss is related to adjacency to major vascular structures and the location of hemangioma.