Continuous improvement of survival outcomes of resection of hepatocellular carcinoma: A 20-year experience

Objective: To investigate the trend of the posthepatectomy survival outcomes of hepatocellular carcinoma (HCC) patients by analysis of a prospective cohort of 1198 patients over a 20-year period. Background: The hospital mortality rate of hepatectomy for HCC has improved but the long-term survival rate remains unsatisfactory. We reported an improvement of survival results 10 years ago. It was not known whether there has been further improvement of results in recent years. Methods: The patients were categorized into two 10-year periods: period 1, before 1999 (group 1, n = 390) and period 2, after 1999 (group 2, n = 808). Patients in group 2 were managed according to a modified protocol and technique established in previous years. Results: The patients in group 2 were older and had a higher incidence of comorbid illness and cirrhosis. They had a lower hospital mortality rate (3.1% vs 6.2%, P = 0.012) and longer 5-year overall survival (54.8% vs 42.1%, P < 0.001) and disease-free survival rates (34.8% vs 24%, P = 0.0024). An improvement in the overall survival rate was observed in patients with cirrhosis, those undergoing major hepatectomy, and those with tumors of tumor-node-metastasis stages II, IIIA, and IVA. A significant increase in the survival rates was also seen in patients whose tumors were considered transplantable by the Milan criteria (72.5% vs 62.7%, P = 0.0237). Multivariate analysis showed a significantly more favorable patient survival for hepatectomy in period 2. Conclusions: A continuous improvement of survival outcomes after hepatectomy for HCC was achieved in the past 20 years even in patients with advanced diseases. Hepatectomy remains the treatment of choice for resectable HCC in a predominantly hepatitis B virus-based Asian population. © 2011 Lippincott Williams & Wilkins.postprin

Survival Analysis of Re-resection Versus Radiofrequency Ablation for Intrahepatic Recurrence After Hepatectomy for Hepatocellular Carcinoma

Ó The Author(s) 2011. This article is published with open access at Springerlink.com Background Tumor recurrence after resection of hepatocellular carcinoma is a common phenomenon. Re-resection and radiofrequency ablation (RFA) are good options for treating recurrent HCC. This study compared the efficacy of these two modalities in the treatment of intrahepatic HCC recurrence after hepatectomy. Methods From January 2001 to December 2008, a total of 179 patients developed intrahepatic HCC recurrence after hepatectomy. To treat the recurrence, 29 patients underwent re-resection and 45 patients had RFA. Patient characteristics, clinicopathologic data, and survival outcomes were reviewed. Results Child-Pugh status, time to develop first recurrence (12.2 vs. 8.7 months), and recurrent tumor size (2.1 vs. 2.1 cm) were comparable for the two groups. Time to develop a second intrahepatic recurrence after re-resection and RFA was 5.9 and 4.0 months respectively. The 1-, 3-, and 5-year disease-free survival rates were 41.4%, 24.2%, and 24.2 % after re-resection and 32.2%, 12.4%, and 9.3% after RFA (p = 0.14). The 1-, 3-, and 5-year overall survival rates were 89.7%, 56.5%, and 35.2 % after re-resection and 83.7%, 43.1%, and 29.1 % after RFA (p = 0.48). For the second recurrence, 33.3 % of patients underwent a second round of RFA and 10.0 % underwent a third resection

Validation of graft and standard liver size predictions in right liver living donor liver transplantation

Purpose: To assess the accuracy of a formula derived from 159 living liver donors to estimate the liver size of a normal subject: standard liver weight (g) = 218 + body weight (kg) × 12.3 + 51 (if male). Standard liver volume (SLV) is attained by a conversion factor of 1.19 mL/g. Methods: The total liver volume (TLV) of each of the subsequent consecutive 126 living liver donors was determined using the right liver graft weight (RGW) on the back table, right/left liver volume ratio on computed tomography, and the conversion factor. The estimated right liver graft weight (ERGW) was determined by the right liver volume on computed tomography (CT) and the conversion factor. SLV and ERGW were compared with TLV and RGW, respectively, by paired sample t test. Results: Donor characteristics of both series were similar. SLV and TLV were 1,099.6 ± 139.6 and 1,108.5 ± 175.2 mL, respectively, (R 2 = 0.476) (p = 0.435). The difference between SLV and TLV was only -8.9 ± 128.2 mL (-1.0 ± 11.7%). ERGW and RGW were 601.5 ± 104.1 and 597.1 ± 102.2 g, respectively (R 2 = 0.781) (p = 0.332). The conversion factor from liver weight to volume for this series was 1.20 mL/g. The difference between ERGW and RGW was 4.3 ± 49.8 g (0.3 ± 8.8%). ERGW was smaller than RGW for over 10% (range 0.21-40.66 g) in 18 of the 126 donors. None had the underestimation of RGW by over 20%. Conclusion: SLV and graft weight estimations were accurate using the formula and conversion factor. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Liver transplantation for acute-on-chronic liver failure

Purpose: To evaluate the outcome of liver transplantation for acute-on-chronic liver failure. Patients and methods: From November 1991 to December 2007, 517 patients underwent liver transplantation at Queen Mary Hospital, Hong Kong. Among them, 149 had acute-on-chronic liver failure as defined in the recent Asian Pacific Association for the Study of Liver Consensus Meeting. Their clinical data were reviewed and their survival outcomes were compared with those of patients who underwent liver transplantation for fulminant hepatic failure and for cirrhosis only in the same period. Results: The patients with acute-on-chronic liver failure included 50 patients having acute exacerbation of chronic hepatitis B and 99 cirrhotic patients with acute deterioration. Their median model for end-stage liver disease scores were 35 and 37, respectively. Preoperative infection (35%), hepatorenal syndrome (38%), and respiratory failure (28.8%) were common. One hundred and three patients received living donor liver grafts and 46 patients received deceased donor liver grafts. The hospital mortality rate was 4.7%. The 5-year survival rates were 93.2% for patients with acute exacerbation of chronic hepatitis B and 90.5% for cirrhotic patients with acute deterioration. The results were similar to those of the patients with fulminant hepatic failure (n = 37) and the patients having cirrhosis only (n = 301). Conclusions: Liver transplantation for acute-on-chronic liver failure is life-saving, and the survival rates it attains are similar to those attained by transplantation for other liver conditions.published_or_final_versionSpringer Open Choice, 21 Feb 201

Role of Portal Vein Embolization in Hepatocellular Carcinoma Management and Its Effect on Recurrence: A Case-control Study

Background Liver regeneration that occurs after portal vein embolization (PVE) may have adverse effects on the microscopic tumor foci in the residual liver mass in patients with hepatocellular carcinoma (HCC). Methods Fifty-four HCC patients with inadequate functional residual liver volume were offered PVE during a seven-year period. Among them, 34 (63%) patients underwent curative resection. They were compared with a matched control group (n = 102) who underwent surgery without PVE. Postoperative complications, pattern of recurrence, and survival were compared between groups. Results In the PVE group, a pre-embolization functional residual liver volume of 23% (12-33.5%) improved to 34% (20-54%) (p = 0.005) at the time of surgery. When the two groups were compared, minor (PVE, 24%; control, 29%; p = 0.651) and major (PVE, 18%; control, 15%; p = 0.784) complications were similar. After a follow-up period of 35 months (standard deviation 25 months), extrahepatic recurrences were detected in 10 PVE patients (29%) and 41 control patients (40%) (p = 0.310). Intrahepatic recurrences were seen in 10 (29%) and 47 (46%) cases (p = 0.109) in the PVE and control groups, respectively. In the PVE group, 41% (n = 14) of the recurrences were detected before one year, compared with 42% (n = 43) in the control group (p = 1). Disease-free survival rates at 1, 3, and 5 years were 57, 29, and 26% in the control group and 60, 42, and 42% in the PVE group (log-rank, p = 0.335). On multivariate analysis, PVE was not a factor affecting survival (p = 0.821). Conclusions Portal vein embolization increases the resectability of initially unresectable HCC due to inadequate functional residual liver volume, and it has no deleterious oncological effect after major resection of HCC. © The Author(s) 2012.published_or_final_versionSpringer Open Choice, 28 May 201

FTY720 Suppresses Liver Tumor Metastasis by Reducing the Population of Circulating Endothelial Progenitor Cells

Background: Surgical procedures such as liver resection and liver transplantation are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor recurrence and metastasis after liver surgery remains a major problem. Recent studies have shown that hepatic ischemia-reperfusion (I/R) injury and endothelial progenitor cells (EPCs) contribute to tumor growth and metastasis. We aim to investigate the mechanism of FTY720, which was originally applied as an immunomodulator, on suppression of liver tumor metastasis after liver resection and partial hepatic I/R injury. Methodology/Principal Findings: An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Two weeks after orthotopic liver tumor implantation, the rats underwent liver resection for tumor-bearing lobe and partial hepatic I/R injury. FTY720 (2 mg/kg) was administered through the inferior caval vein before and after I/R injury. Blood samples were taken at days 0, 1, 3, 7, 14, 21 and 28 for detection of circulating EPCs (CD133+CD34+). Our results showed that intrahepatic and lung metastases were significantly inhibited together with less tumor angiogenesis by FTY720 treatment. The number of circulating EPCs was also significantly decreased by FTY720 treatment from day 7 to day 28. Hepatic gene expressions of CXCL10, VEGF, CXCR3, CXCR4 induced by hepatic I/R injury were down-regulated in the treatment group. Conclusions/Significance: FTY720 suppressed liver tumor metastasis after liver resection marred by hepatic I/R injury in a rat liver tumor model by attenuating hepatic I/R injury and reducing circulating EPCs. © 2012 Li et al.published_or_final_versio

A Garlic Derivative, S-allylcysteine (SAC), Suppresses Proliferation and Metastasis of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is highly malignant and metastatic. Currently, there is no effective chemotherapy for patients with advanced HCC leading to an urgent need to seek for novel therapeutic options. We aimed to investigate the effect of a garlic derivative, S-allylcysteine (SAC), on the proliferation and metastasis of HCC. Methodology/Principal Findings: A series of in vitro experiments including MTT, colony-forming, wound-healing, invasion, apoptosis and cell cycle assays were performed to examine the anti-proliferative and anti-metastatic effects of SAC on a metastatic HCC cell line MHCC97L. The therapeutic values of SAC single and combined with cisplatin treatments were examined in an in vivo orthotopic xenograft liver tumor model. The result showed that the proliferation rate and colony-forming abilities of MHCC97L cells were suppressed by SAC together with significant suppression of the expressions of proliferation markers, Ki-67 and proliferating cell nuclear antigen (PCNA). Moreover, SAC hindered the migration and invasion of MHCC97L cells corresponding with up-regulation of E-cadherin and down-regulation of VEGF. Furthermore, SAC significantly induced apoptosis and necrosis of MHCC97L cells through suppressing Bcl-xL and Bcl-2 as well as activating caspase-3 and caspase-9. In addition, SAC could significantly induce the S phase arrest of MHCC97L cells together with down-regulation of cdc25c, cdc2 and cyclin B1. In vivo xenograft liver tumor model demonstrated that SAC single or combined with cisplatin treatment inhibited the progression and metastasis of HCC tumor. Conclusions/Significance: Our data demonstrate the anti-proliferative and anti-metastatic effects of SAC on HCC cells and suggest that SAC may be a potential therapeutic agent for the treatment of HCC patients. © 2012 Ng et al.published_or_final_versio

Proline-Rich Tyrosine Kinase 2 (Pyk2) Promotes Cell Motility of Hepatocellular Carcinoma through Induction of Epithelial to Mesenchymal Transition

Aims: Proline-rich tyrosine kinase 2 (Pyk2), a non-receptor tyrosine kinase of the focal adhesion kinase (FAK) family, is up-regulated in more than 60% of the tumors of hepatocellular carcinoma (HCC) patients. Forced overexpression of Pyk2 can promote the proliferation and invasion of HCC cells. In this study, we aimed to explore the underlying molecular mechanism of Pyk2-mediated cell migration of HCC cells. Methodology/Principal Findings: We demonstrated that Pyk2 transformed the epithelial HCC cell line Hep3B into a mesenchymal phenotype via the induction of epithelial to mesenchymal transition (EMT), signified by the up-regulation of membrane ruffle formation, activation of Rac/Rho GTPases, down-regulation of epithelial genes E-cadherin and cytokeratin as well as promotion of cell motility in presence of lysophosphatidic acid (LPA). Suppression of Pyk2 by overexpression of dominant negative PRNK domain in the metastatic HCC cell line MHCC97L transformed its fibroblastoid phenotype to an epithelial phenotype with up-regulation of epithelial genes, down-regulation of mesenchymal genes N-cadherin and STAT5b, and reduction of LPA-induced membrane ruffle formation and cell motility. Moreover, overexpression of Pyk2 in Hep3B cells promoted the phosphorylation and localization of mesenchymal gene Hic-5 onto cell membrane while suppression of Pyk2 in MHCC97L cells attenuated its phosphorylation and localization. Conclusion: These data provided new evidence of the underlying mechanism of Pyk2 in controlling cell motility of HCC cells through regulation of genes associated with EMT. © 2011 Sun et al.published_or_final_versio

Combination of RGD Compound and Low-Dose Paclitaxel Induces Apoptosis in Human Glioblastoma Cells

) peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX) pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis. peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells.This study provides a novel concept of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment