Both Secreted Protein Acidic and Rich in Cysteine (SPARC) and Hevin are multifunctional matricellular glycoproteins. Recent experimental studies suggested that Hevin and SPARC together diminish angiogenesis, but their significance in hepatocellular carcinoma (HCC) remains unclear. This study aimed to correlate SPARC and Hevin expression with angiogenesis and clinicopathological features in HCC. SPARC and Hevin protein and mRNA expression in HCC specimens were assessed by immunostaining, immunoblotting, and quantitative reverse transcriptase-polymerase chain reaction. Tumour microvessel density (MVD) was assessed by CD34 immunostaining. The role of SPARC and Hevin in HCC was further assessed in an in vivo nude mice xenograft model. Both SPARC and Hevin mRNA levels were significantly higher in tumours than in non-tumourous livers. A significant correlation between tumour SPARC and Hevin mRNA levels was found. Moreover, SPARC protein localized in the tumour sinusoidal area correlated significantly with Hevin protein localized in HCC cells. Truncated forms of SPARC and Hevin proteins were detected in clinical samples. Truncated SPARC protein localized in the tumour sinusoidal area correlated significantly with tumour MVD. On the other hand, overexpression of full-length SPARC in tumour xenografts in athymic nude mice significantly delayed tumour growth, and this delay was related to a decrease in tumour angiogenesis. Expression of Hevin protein within HCC cells was related to the presence of tumour encapsulation and the absence of hepatitis B surface antigen in clinical samples. Overexpression of Hevin in tumour xenografts also significantly delayed tumour growth. In conclusion, this study has shown that SPARC and Hevin are upregulated in HCC compared with non-tumourous liver, and that they are inter-related at both mRNA and protein levels. Moreover, both SPARC and Hevin were related to HCC angiogenesis and tumour progression.

C. P.Y. Lau;R. T.P. Poon;S. T. Cheung;W. C. Yu;上达 范

Journal of Pathology

2006-12

Purpose: Hepatocellular carcinoma (HCC) patients with the same clinicopathologic features can have remarkably different disease outcomes after curative hepatectomy. To address this issue, we evaluated the cDNA microarray gene expression profiles of HCCs and identified claudin-10 expression level was associated with disease recurrence. The aim of the current study is to validate the microarray data by an alternative research method applicable for routine practice. Experimental Design: Quantitative reverse transcription-PCR (RT-PCR) was used to validate the microarray data on claudin-10 expression level. The assay was repeated on a separate HCC sample set to consolidate the prognostic significance of claudin-10. Results: Claudin-10 expression level by quantitative RT-PCR and by microarray measurement showed a high concordance (r = 0.602, P < 0.001). Quantitative RT-PCR was repeated on a separate HCC sample set and the association of claudin-10 expression with recurrence was again confirmed (hazard ratio, 1.2; 95% confidence interval, 1.0-1.4; P= 0.011). By multivariable Cox regression analysis, claudin-10 expression and pathologic tumor-node-metastasis stage were independent factors for prediction of disease recurrence. Conclusion: Claudin-10 expression of HCC can be used as a molecular marker for disease recurrence after curative hepatectomy.

Siu Tim Cheung;Ka Ling Leung;Ying Chi Ip;Xin Chen;Daniel Y. Fong;Irene O. Ng;上达 范;Samuel So

Clinical Cancer Research

2005-1-15

Definitive surgical procedures were performed on 46 patients with strictures of the major bile ducts: dilatation of strictures was undertaken in 6 patients, hepatotomy and plastic repair in 2, biliary‐enteric anastomosis in 18, and liver resection with or without drainage for the rest of the biliary tree in 20 patients. The overall operative morbidity was 21·7 percent. Two patients died within 30 days of operation. One patient died of septicaemia after emergency dilatation of stricture while another died of sepsis from a leakage after hepatotomy and plastic repair. The median follow‐up for the 44 patients who survived the operation was 43 months. All strictures reformed after dilatation within 2 months. Acute cholangitis occurred in six patients, two after dilatation of strictures (with documented recurrent stone formation in one), two after biliary‐enteric anastomosis and two after liver resection. Thus, good clinical results were obtained in 38 out of 44 patients (86·4 percent).

W. Y. Lau;上达 范;W. C. Yip;K. K. Wong

British Journal of Surgery

1987-12

Background: Somatostatin is a potent inhibitor of pancreatic secretion and has been studied for its prophylactic effect on post-ERCP pancreatitis. However, results of previous trials have been inconclusive. Methods: A prospective double-blind controlled study was performed to evaluate the effectiveness of somatostatin in preventing post-ERCP pancreatitis. Post- ERCP enzyme elevation, abdominal pain and pancreatitis were evaluated and compared between 109 patients randomized to receive somatostatin infusion and 111 patients randomized to receive normal saline infusion (placebo); both started 30 minutes before ERCP and continued for 12 hours. Results: Post- ERCP elevation of serum amylase and lipase levels at 6 and 24 hours after ERCP was less frequent in the group given somatostatin but not statistically significant. There was a tendency toward lower mean serum amylase and lipase levels at 24 hours in patients given somatostatin, although the difference was not statistically significant either. Eight patients given somatostatin (7%) and 18 patients given placebo (16%) had significant abdominal pain after ERCP requiring analgesia (p = 0.04). The frequency of clinical pancreatitis was significantly lower in patients given somatostatin (3%) than in those given placebo (10%) (p = 0.03). Conclusions: Prophylactic treatment with somatostatin reduced the frequency of post-ERCP pancreatitis.

R. T.P. Poon;C. Yeung;C. M. Lo;W. K. Yuen;C. L. Liu;上达 范

Gastrointestinal Endoscopy

1999

Of the 208 Chinese patients with histologically proven hepatocellular carcinoma (HCC) seen during a 5-year period, 191 patients presented with symptomatic HCC and 17 patients with asymptomatic HCC (subclinical HCC, SCHCC) being picked up by α-fetoprotein (AFP) screening. Compared with the patients with symptomatic HCC, patients with SCHCC had a better performance status (p < 0.01), higher serum albumin levels (p < 0.05) and lower alkaline phosphatase levels (p < 0.01). In those patients with symptomatic HCC, 4.7% were operable and only 2 patients had a tumour diameter of less than 5 cm. In contrast, patients with SCHCC had a higher operability rate (76.5%, p < 0.0001) and all had a tumour of less than 5 cm in diameter (p < 0.0001). Patients with SCHCC, most of whom had their tumour resected, had a better long-term survival (p < 0.0001). We conclude that patients with SCHCC picked up by AFP serosurveillance have a better performance status, higher operability and better prognosis.

C. Lai;Johnson Y.N. Lau;P. C. Wu;W. M. Hui;Edward C.S. Lai;上达 范;H. Ngan;H. J. Lin

Oncology

1992

Liver cancer has a very poor prognosis and lacks effective therapy. We have previously demonstrated that intraportal injection of adeno-associated-viral (AAV) particles that express angiostatin lead to long-term expression of angiostatin capable of suppressing the outgrowth of EL-4 tumors in the liver. Here we combine AAV-mediated angiostatin therapy with immunotherapy by employing an AAV vector encoding the T-cell costimulator B7.1. Incubation of EL-4 cells with AAV-B7.1 viruses resulted in the rapid expression of B7.1 on the surface of 80% of EL-4 cells. Mice that were vaccinated with B7.1-engineered tumor cells rejected the tumor cells and resisted a secondary challenge with unmodified parental cells. Splenocytes from the vaccinated mice were highly cytotoxic towards parental EL-4 cells in vitro. However, the vaccinated mice failed to resist the challenge of a heavy burden of EL-4 cells. Intraportal injection of AAV particles that express angiostatin into mice that had been vaccinated 1 month earlier with B7.1-engineered tumor cells protected mice against the challenge of a heavy burden of EL-4 cells and eradicated tumors that had disseminated to the liver. The combinational therapy increased the survival rate of mice with advanced liver cancer. These encouraging results warrant investigation of the employment of anti-angiogenic therapy subsequent to cancer immunotherapy for targeting unresectable disseminated liver metastases.

Xueying Sun;Geoffrey W. Krissansen;Peter W.C. Fung;Sue Xu;Juan Shi;Kwan Man;上达 范;Ruian Xu

International Journal of Cancer

2005-2-10

Background. The extension of living donor liver transplantation to adult recipients is limited by the adequacy of the size of the graft. We evaluate the effect of the graft size on the survival of the recipient in order to establish a clinical guide for the minimum requirement. Methods. The clinical records of 14 adults and 11 children (body weight 6.1-100 kg) who underwent living donor liver transplantation for chronic or acute liver failure were reviewed. The effect of the graft weight ratio (graft weight divided by standard liver weight of recipient) on graft function and survival was studied. Results. The graft weight ratio ranged from 31 to 203%. The overall graft and patient survival rates were 84% at a median follow-up of 29 months. The survival rate was 95% for recipients with a graft weight ratio >40%, and 40% only for those with a ratio ≤40% (P=0.016). It was 88% (7/8) when the ratio was >100%, 100% (5/5) when the ratio was 71 to 100%, 100% (7/7) when the ratio was 41 to 70%, and 40% (2/5) only when the ratio was ≤40%. When the graft weight ratio was ≤40%, early graft dysfunction was evident and contributed to the causes of death in three patients. Conclusions. Preoperative computed tomographic measurement of liver size of a living donor is essential. A graft that represented 40% or less of the recipient's standard liver weight should be regarded as a marginal graft with a lower success rate.

Chung Mau Lo;上达 范;Chi Leung Liu;John K. Chan;Banny K. Lam;George K. Lau;William I. Wei;John Wong

Transplantation

1999-10-27

Objective: To review the experience of donor selection and right lobe hepatectomy in adult-to-adult live donor liver transplantation. Methods: From May 1996 to December 2001, 89 live donor liver transplants using right lobe grafts were performed at Queen Mary Hospital, Hong Kong. All donors had received psychological counseling before donor operations. They were screened by laboratory tests including complete blood cell count, liver and renal biochemistry, and viral serology studies. Computed tomography (CT), CT volumetry and hepatic arteriography were routinely performed. All donors underwent the operations using the method designed by us. Results: The median duration of the operations was 8.8 hours. The median blood loss recorded 466 ml. The median intensive care unit and hospital stays were 2 and 10 days, respectively. There was no donor mortality. Complications of donor operations included wound infection, urinary tract infection, biliary stricture, cholestasis, subphrenic collection, bowel obstruction and incision hernia, etc. All donors have recovered and returned to their previous occupations. Conclusions: Live donation of right lobe grafts for adult-to-adult liver transplantation is safe, provided that donor selection is strict and utmost care is exercised during the operation.

上达 范;Chung Mau Lo;Chi Leung Liu

Hepatobiliary and Pancreatic Diseases International

2002-5

Intraoperative iatrogenic rupture of hepatocellular carcinoma (HCC), which can occur during hepatic resection when large tumors are being mobilized, may adversely affect the operative outcome. Little information is available in the literature on this serious intraoperative complication. The aim of the present study is to document iatrogenic rupture of HCC as a serious complication during hepatic resection and its effects on the operative and long-term outcomes of patients with this complication. A retrospective study was performed on all patients with intraoperative iatrogenic rupture of HCC during hepatic resection from 1989 to 1997, and the operative and long-term survival outcomes were compared with those of patients without the complication. Among 194 patients who underwent hepatic resection for a large HCC (≥ 5 em) during the study period, 8 (4.1%) had intraoperative iatrogenic rupture of the tumor. When compared with 186 patients with similar clinical parameters but without intraoperative rupture, patients with intraoperative rupture had significantly more intraoperative blood loss (median 5.7 vs. 2.0 L; p = 0.01) and blood transfusion requirement (median 3.1 vs 0.9 L; p = 0.02). On follow-up, patients in the intraoperative rupture group had a significantly higher intraperitoneal extrahepatic recurrence rate (33.3% vs. 2.9%; p = 0.02) and significantly shorter survival (median 11.5 vs. 37.9 months, p = 0.04) when compared with patients without the complication. Intraoperative iatrogenic rupture is a serious complication of hepatic resection for HCC because it is associated with increased intraoperative blood loss, increased incidence of intraperitoneal extrahepatic recurrence, and short survival. Extreme care should be taken during mobilization of the tumor, and an alternative operative approach in the presence of a difficult hepatic resection of a large HCC may be required to avoid the complication.

Chi Leung Liu;上达 范;Chung Mau Lo;Irene Oi Lin Ng;Ronnie Tung Ping Poon;John Wong

World Journal of Surgery

2002-3

Biliary complications after hepatectomy may lead to sepsis, liver failure, and death. Measures to detect biliary injury after liver transection may reduce such morbidity. The aim of this study was to investigate the trend of biliary complications after hepatectomy during the last 10 years and assess the efficacy of intraoperative measures (methylene blue test, cholangiography, fibrin glue application) for reducing postoperative biliary complications. This is a retrospective study of 616 consecutive patients who underwent hepatectomy in our institution from January 1989 to September 1998. The study period was divided into the first 5 years and the second 5 years for comparison. The hospital mortality rate was 6%. It was significantly reduced during the second 5-year period (3.3% vs. 10.6%; p = 0.0002). The postoperative biliary leakage rate was 5.5% and was also reduced during the second 5-year period (3.5% vs. 9.8%; p = 0.004). Postresection methylene blue tests were performed more frequently during the second 5-year period than the first (63% vs. 28%; p = 0.0001). The postoperative biliary leakage rate was reduced by the methylene blue test (3.6% vs. 7.3%; p < 0.05) but not by application of fibrin glue (7.2% vs. 4.2%) or postresection cholangiography. However, among the 60 patients with a positive methylene blue test, postoperative biliary leakage still occurred in 10% of them after the leakage sites were sutured. In conclusion, the biliary complication rate is decreasing. Only the postresection methylene blue test, but not postresection cholangiography or application of fibrin glue, helps to reduce the postoperative biliary leakage rate.

Chi Ming Lam;Chung Mau Lo;Chi Leung Liu;上达 范

World Journal of Surgery

2001