Interferon-gamma inducible protein 10 (IP10) induced cisplatin resistance of HCC after liver transplantation through ER stress signaling pathway.

Tumor recurrence remains an obstacle after liver surgery, especially in living donor liver transplantation (LDLT) for patients with hepatocellular carcinoma (HCC). The acute-phase liver graft injury might potentially induce poor response to chemotherapy in recurrent HCC after liver transplantation. We here intended to explore the mechanism and to identify a therapeutic target to overcome such chemoresistance. The associations among graft injury, overexpression of IP10 and multidrug resistant genes were investigated in a rat liver transplantation model, and further validated in clinical cohort. The role of IP10 on HCC cell proliferation and tumor growth under chemotherapy was studied both in vitro and in vivo. The underlying mechanism was revealed by detecting the activation of endoplasmic reticulum (ER) stress signaling pathways. Moreover, the effect of IP10 neutralizing antibody sensitizing cisplatin treatment was further explored. In rat liver transplantation model, significant up-regulation of IP10 associated with multidrug resistant genes was found in small-for-size liver graft. Clinically, high expression of circulating IP10 was significant correlated with tumor recurrence in HCC patients underwent LDLT. Overexpression of IP10 promoted HCC cell proliferation and tumor growth under cisplatin treatment by activation of ATF6/Grp78 signaling. IP10 neutralizing antibody sensitized cisplatin treatment in nude mice. The overexpression of IP10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway. IP10 neutralizing antibody could be a potential adjuvant therapy to sensitize cisplatin treatment

High-intensity focused ultrasound as a treatment for colorectal liver metastasis in difficult position

published_or_final_versionSpringer Open Choice, 21 Feb 201

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

The Role of Proline Rich Tyrosine Kinase 2 (Pyk2) on Cisplatin Resistance in Hepatocellular Carcinoma

Aims: We previously demonstrated Proline rich tyrosine kinase 2 (Pyk2) plays important roles in regulating tumor progression, migration and invasion in hepatocellular carcinoma (HCC). In this study, we aimed to examine the role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC and to explore its underlying molecular mechanism. Methodology/Principal Findings: Stable transfectants either overexpressing or suppressing Pyk2 were established in different HCC cell lines. MTT, colony formation and Annexin-V assays were employed to examine their in vitro responses to cisplatin. Xenograft ectopic and orthotopic nude mice models were generated to investigate the in vivo responses of them to cisplatin treatment. cDNA microarray was performed to identify Pyk2-induced genes which were further validated by quantitative real-time RT-PCR using clinical HCC samples. In vitro functional study demonstrated that Pyk2-overexpressing HCC transfectants exhibited relatively lower cytotoxicity, higher colony-forming ability and lower apoptosis to cisplatin compared with the control transfectants. Moreover, Pyk2 overexpressing HCC transfectants had a higher survival rate under cisplatin treatment by up-regulation of AKT phosphorylation. In vivo xenograft nude mice model demonstrated that Pyk2-overexpressing transfectants developed higher tolerance to cisplatin treatment together with less tumor necrosis and apoptosis. cDNA microarray analysis revealed that there were more than 4,000 genes differentially expressed upon overexpression of Pyk2. Several upregulated genes were found to be involved in drug resistance and invasion in cancers. Among them, the expression profiles of MDR1, GAGE1, STAT1 and MAP7 were significantly associated with the expression of Pyk2 in clinical HCC samples. Conclusions: Our results may suggest a new evidence of Pyk2 on promoting cisplatin resistance of HCC cells through preventing cell apoptosis, activation of AKT pathway and upregulation of drug resistant genes. © 2011 Geng et al.published_or_final_versio

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

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