BACKGROUND: The indocyanine green (ICG) retention test is the most popular liver function test for selecting patients for major hepatectomy. Traditionally, it is done using spectrophotometry with serial blood sampling. The newly-developed pulse spectrophotometry is a faster alternative, but its accuracy on Child-Pugh A cirrhotic patients undergoing hepatectomy for hepatocellular carcinoma has not been well documented. This study aimed to assess the accuracy of the LiMON®, one of the pulse spectrophotometry systems, in measuring preoperative ICG retention in these patients and to devise an easy formula for conversion of the results so that they can be compared with classical literature records where ICG retention was measured by the traditional method. METHODS: We measured the liver function of 70 Child-Pugh A cirrhotic patients before hepatectomy for hepatocellular carcinoma from September 2008 to January 2009. ICG retention at 15 minutes measured by traditional spectrophotometry (ICGR15) was compared with ICG retention at 15 minutes measured by the LiMON (ICGR15(L)). RESULTS: The median ICGR15 was 14.7% (5.6%-32%) and the median ICGR15(L) was 10.4% (1.2%-28%). The mean difference between them was -4.3606. There was a strong correlation between ICGR15 and ICGR15(L) (correlation coefficient, 0.844; 95% confidence interval, 0.762-0.899). The following formula was devised: ICGR15=1.16×ICGR15(L)+2.73. CONCLUSIONS: The LiMON provides a fast and repeatable way to measure ICG retention at 15 minutes, but with constant underestimation of the real value. Therefore, when comparing results obtained by traditional spectrophotometry and the LiMON, adjustment of results from the latter is necessary, and this can be done with a simple mathematical calculation using the above formula. © 2012, Hepatobiliary Pancreat Dis Int.

Tan to Cheung    See ching Chan    Kenneth siu ho Chok    Albert chi yan Chan    Wanching Yu    Ronnie Poon    Chung mau Lo    范上达    

Hepatobiliary and Pancreatic Diseases International

2012

Background: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. Methods: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. Results: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P =.23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P =.26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P =.002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P =.01), gastrointestinal bleeding (P =.02), and hepatic encephalopathy (P =.02). Conclusions: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed. Cancer 2012. © 2012 American Cancer Society. with Child-Pugh class A and B cirrhosis tolerated sorafenib similarly and derived similar survival benefit. Among patients with Child-Pugh class B disease, most benefits were observed in patients with a score of 7. © 2012 American Cancer Society.

Chiu Joanne    Tang Yuen Fong    Tzy jyun Yao    Wong Ashley    Wong Hilda    Leung Roland    Pierre Chan    Tan to Cheung    Albert chi yan Chan    Roberta wing cheung Pang    范上达     Ronnie Poon    Thomas chung cheung Yau   

Cancer

2012

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.

Siriwardana Rohan Chaminda    Chung mau Lo    See ching Chan    范上达    

World Journal of Surgery

2012

Background: The platelet count varies considerably between individuals, but within an individual the platelet count is remarkably stable over time. Mechanisms controlling the platelet count are not yet established. Objective: In the present study, we tested the hypothesis that the liver is important in controlling the circulating platelet count, as the liver is the main producer of thrombopoietin. Methods: We compared the platelet count prior to and after liver transplantation in >250 patients transplanted for familial amyloidotic polyneuropathy (FAP). In contrast to most patients undergoing liver transplantation, patients with FAP have normal liver function before transplantation. Furthermore, we compared platelet counts in 89 living liver donors with the platelet count in the recipients of these grafts. Finally we compared platelet counts in donor-recipient pairs of hematopoietic stem cells. Results and conclusions: The platelet count prior to transplantation correlated with the platelet count at 3 or 12months after transplantation in patients with FAP (r=0.48, P<0.0001 at 3months, r=0.39, P<0.0001 at 12months), whereas the platelet count in a living liver donor did not correlate with the platelet count in the recipient at 3 or 12months after transplantation (r=0.16, P=0.26 at 3months, r=0.11, P=0.30 at 12months). The platelet count of related donors of hematopoietic stem cells correlated with the platelet count in the recipient after transplantation (r=0.25, P=0.011). Conclusions: These results suggest that the liver, in spite of being the prime producer of thrombopoietin, does not dictate the circulating platelet count, whereas the bone marrow does appear to play a role. © 2012 International Society on Thrombosis and Haemostasis.

Ton Lisman    Pittau    Leite    Marieke De Boer    Meijer Karina    Hanneke Kluin- Nelemans    Huls Gerwin    Te Boome    Jürgen Kuball    Nowak    范上达     Daniel Azoulay    Robert jack Porte   

Journal of Thrombosis and Haemostasis

2012

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.

范上达     Mau Lo Chung    Ronnie Poon    Chun Yeung    Leung Liu Chi    Wai key Yuen    Ming Lam Chi    Ng Kelvin K.    See ching Chan   

Annals of Surgery

2011

Objective: This study aims to evaluate the outcome of patients with hepatocellular carcinoma (HCC) treated by high-intensity focused ultrasound (HIFU) in a single tertiary referral center. Background: HIFU is the latest developed local ablation technique for unresectable HCC. The initial experience on its efficacy is promising, but the survival benefit of patients undergoing HIFU for HCC is poorly defined. Methods: From October 2006 to December 2008, 49 patients received HIFU for unresectable HCC. Each patient underwent a single session of HIFU with a curative intent. Treatment efficacy and survival outcome were evaluated. Clinicopathologic factors affecting the primary technique effectiveness and overall survival rates were investigated by univariate analysis. Results: The median size of the treated tumors was 2.2 cm, ranging from 0.9 to 8 cm. The majority of patients had single tumors (n = 41, 83.6%). Thirty-one patients (63.2%) had artificial right pleural effusion during HIFU treatment to reduce damage to the lung and diaphragm. The hospital mortality rate was 2% (n = 1) and the complication rate was 8.1% (n = 4). The primary technique effectiveness rate was 79.5% (39 of 49 patients). It increased from 66.6% in the initial series to 89.2% in the last 28 patients. Tumor size (3.0 cm) was the significant risk factor affecting the complete ablation rate. The 1- and 3-year overall survival rates were 87.7% and 62.4%, respectively. Child-Pugh liver function grading was the significant prognostic factor influencing the overall survival rate. Conclusions: HIFU is an effective treatment modality for unresectable HCC with a high technique effectiveness rate and favorable survival outcome. © 2011 Lippincott Williams & Wilkins.

Ng Kelvin K.    Ronnie Poon    See ching Chan    Kenneth siu ho Chok    Tan to Cheung    Tung Helen    Chu Ferdinand S. K.    Waikuen Tso    Wanching Yu    Chung mau Lo    范上达    

Annals of Surgery

2011

Purpose: Brain-derived neurotrophic factor (BDNF) has emerged as a novel angiogenic factor, and yet its impact on tumorigenesis is unclear. This study aimed at investigating the roles of BDNF in angiogenesis and tumor development. Experimental Design: BDNF was overexpressed in a mouse endothelial cell (EC) line by stable transfection, and angiogenic properties of the transfectants were assessed. Microarray analysis was employed to explore the molecular pathways. The impact of modulating BDNF levels in two mouse EC lines on tumorigenic potential of a transformed mouse liver cell line was evaluated by an in vivo cotransplantation model. BDNF and tropomyosin receptor kinase B (TrkB) protein levels were determined in 50 pairs of human hepatocellular carcinoma (HCC) tissues by Western blotting and immunohistochemistry. Survival analysis was carried out to determine their clinical significance. Results: Overexpression of BDNF could promote EC proliferation, migration, invasion, and survival. Microarray and molecular studies showed that RhoA, caspase-9, caspase-3, growth arrest specific 6, and VEGF could mediate BDNF/TrkB-induced angiogenesis. The cotransplantation experiment showed that high BDNF-expressing ECs could facilitate tumor angiogenesis and growth, whereas knockdown of BDNF by short hairpin RNAs impaired such effects. Furthermore, examination on human HCC tissues revealed upregulation of BDNF and TrkB protein levels in 46.0% and 33.3% of the cases studied, respectively. Immunohistochemistry disclosed strong BDNF reactivity in both tumor and endothelial cells. High TrkB expression was associated with shorter overall survival. Conclusions: BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC. ©2011 AACR.

Lam Chi Tat    Yang Zhen Fan    Lau Chi Keung    Tam Ka Ho    范上达     Ronnie Poon   

Clinical Cancer Research

2011

OBJECTIVE: To investigate whether circulating cancer stem cells (CSCs) of hepatocellular carcinoma (HCC) can predict its recurrence after hepatectomy. BACKGROUND: HCC recurrence frequently occurs within the first year after hepatectomy, probably due to circulating tumor cells that have been shed from the primary tumor before hepatectomy. Because CSCs are more likely to initiate tumor growth than mature cancer cells, a high level of circulating CSCs may be a hint for HCC recurrence. METHODS: Multicolor flow cytometry was used to detect the number of circulating CSCs (CD45CD90CD44 ) in the peripheral circulation of 82 HCC patients 1 day before hepatectomy. The patients were monitored by CT or MRI for recurrence every 3 months. RESULTS: Forty-one (50%) patients had recurrence after a median follow-up period of 13.2 months (range, 1.3-57.1 months). Patients with recurrence had a higher median level of circulating CSCs than patients without recurrence (0.02% vs. 0.01%; P < 0.0001). Circulating CSCs > 0.01% predicted intrahepatic recurrence (relative risk 3.54; 95% CI, 1.41-8.88; P = 0.007) and extrahepatic recurrence (relative risk 10.15; 95% CI, 3-34.4; P = 0.0002). Patients with >0.01% circulating CSCs had a lower 2-year recurrence-free survival rate (22.7% vs. 64.2%; P < 0.0001) and overall survival rate (58.5% vs. 94.1%; P = 0.0005) than patients with ≤0.01% circulating CSCs. On multivariable analysis, circulating CSCs > 0.01%, tumor stage and tumor size were independent factors predicting recurrence-free survival. CONCLUSIONS: Circulating CSCs predicted posthepatectomy HCC recurrence with high accuracy. They may be the target of eradication in the prevention of posthepatectomy HCC metastasis and recurrence. Copyright © 2011 by Lippincott Williams & Wilkins.

范上达     Yang Zhen Fan    David Ho    Ng Michael N.    Wanching Yu    John Wong   

Annals of Surgery

2011

Microvascular invasion is a poor prognostic indicator of the recurrence of hepatocellular carcinoma (HCC) after surgical treatment. Positron emission tomography (PET) with [ F]fludeoxyglucose ([ F]FDG) as a tracer has been employed to predict the prognosis before surgery for various kinds of tumors, but it has not been found to be sensitive enough for HCC. Thus, [ C]acetate has been adopted as an additional tracer. This study was designed to evaluate the ability of dual-tracer PET ([ F]FDG and [ C]acetate) to predict microvascular invasion before liver resection or transplantation. Fifty-eight HCC patients who were preoperatively examined with whole-body dual-tracer PET were studied. Twenty-five patients were [ F]FDG-positive, and 56 were [ C]acetate-positive. The sensitivity of [ F]FDG in detecting primary HCC was 43%, and the sensitivity of [ C]acetate was 93%. Twenty-nine patients had HCC with microvascular invasion according to the final pathological examination. The sensitivity, specificity, positive predictive value, and negative predictive value of [ F]FDG PET in predicting microvascular invasion were 55.2%, 69%, 64%, and 60.6%, respectively; the corresponding rates for [ C]acetate PET were 93.1%, 0%, 48.2%, and 0%. The factors associated with HCC recurrence, which included multifocal involvement, a large tumor size, microsatellite lesions, poor HCC differentiation, and an advanced stage of disease, were analyzed and compared with positive PET results. A tumor size greater than 5 cm was significantly associated with positive [ F]FDG PET results; [ C]acetate was not associated with poor prognostic indicators. Preoperative [ F]FDG PET may predict microvascular invasion. The addition of [ C]acetate improves the overall sensitivity of PET, but it has no incremental value in predicting microvascular invasion. © 2011 AASLD.

Tan to Cheung    See ching Chan    Chilai Ho    Kenneth siu ho Chok    Albert chi yan Chan    Sharr William Wei    Kelvin kwok chai Ng    Ronnie Poon    Chung mau Lo    范上达    

Liver Transplantation

2011

Background: Despite the potentially severe impact of bile leakage on patients' perioperative and long-term outcome, a commonly used definition of this complication after hepatobiliary and pancreatic operations has not yet been established. The aim of the present article is to propose a uniform definition and severity grading of bile leakage after hepatobiliary and pancreatic operative therapy. Methods: An international study group of hepatobiliary and pancreatic surgeons was convened. A consensus definition of bile leakage after hepatobiliary and pancreatic operative therapy was developed based on the postoperative course of bilirubin concentrations in patients' serum and drain fluid. Results: After evaluation of the postoperative course of bilirubin levels in the drain fluid of patients who underwent hepatobiliary and pancreatic operations, bile leakage was defined as bilirubin concentration in the drain fluid at least 3 times the serum bilirubin concentration on or after postoperative day 3 or as the need for radiologic or operative intervention resulting from biliary collections or bile peritonitis. Using this criterion severity of bile leakage was classified according to its impact on patients' clinical management. Grade A bile leakage causes no change in patients' clinical management. A Grade B bile leakage requires active therapeutic intervention but is manageable without relaparotomy, whereas in Grade C, bile leakage relaparotomy is required. Conclusion: We propose a simple definition and severity grading of bile leakage after hepatobiliary and pancreatic operative therapy. The application of the present proposal will enable a standardized comparison of the results of different clinical trials and may facilitate an objective evaluation of diagnostic and therapeutic modalities in the field of hepatobiliary and pancreatic operative therapy. © 2011 Mosby, Inc.

Moritz Koch    Oliver james Garden    Padbury Robert    Nuh Rahbari    René Adam    Capussotti Lorenzo    范上达     Yokoyama Yukihiro    Crawford Michael    Makuuchi Masatoshi    Christopher Christophi    Banting Simon W.    Brooke-Smith Mark E.    Usatoff Valery    Masato Nagino    Guy Maddern    Hugh Thomas J.    Jean nicolas nicolas Vauthey    Greig    Rees Myrddin    Yuji Nimura    Figueras Joan    Ronald paul DeMatteo.    Markus wolfgang Büchler    Jürgen Weitz   

Surgery

2011