We aim to investigate the anticancer effect of a novel immunomodulator FTY720 on a rat orthotopic liver tumor model. A buffalo rat orthotopic liver tumor model was established by injection of a buffalo hepatoma cell line MH7777 into the right portal vein. FTY720 was administered by intraperitoneal injection starting at 10 days after tumor cell injection at a dosage of 5 mg/kg/day. FTY720 markedly suppressed tumor growth and inhibited tumor progression by selective induction of apoptosis of tumor cells via down-regulation of phospho-Akt and up-regulation of cleaved caspase-3, together with decrease of focal adhesion kinase. Moreover, the proliferation index of tumor cells was significantly reduced to 15.92±5.03% by FTY720 compared with that of 42.92±4.47% in the control group (p<0.001). In addition, we confirmed that FTY720 caused no effect on infiltrated lymphocyte in tumor tissue. We conclude that FTY720 is an effective anticancer agent for liver tumor in a rat model without affecting the immune system of the host.

Ng Kevin T.    Kwan Man    Joanna Ho    Chris kin wai Sun    Terence kin wah Lee    Zhao Yi    Chung mau Lo    Ronnie Poon    范上达    

International Journal of Oncology

2007

Background: Radiofrequency ablation (RFA) is a recently developed treatment for hepatocellular carcinoma (HCC). Thus far, the prognostic impact of tumor biomarkers has not been evaluated in this treatment. High serum level of vascular endothelial growth factor (VEGF) has been shown to predict microscopic vascular invasion and metastasis in HCC. This study investigated the prognostic significance of pre-treatment serum VEGF level in patients with HCC undergoing RFA treatment. Methods: Serum VEGF levels were measured using enzyme-linked immunosorbent assay in 120 patients with HCC undergoing RFA, and in 15 healthy controls. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The prognostic significance of serum VEGF levels was assessed by univariate and multivariate analyses. Results: The median serum VEGF level in the HCC patients was 240 pg/mL (range 17-1162), significantly higher than that of healthy controls (p = .024). The serum VEGF levels were significantly correlated with platelet counts (r = .487, p < .001) but not other clinicopathological features. Patients with serum VEGF level > 240 pg/mL had worse overall and recurrence-free survival compared with those with serum VEGF level > 240 pg/mL (p = .005 and .002, respectively). By multivariate analysis, serum VEGF level was a significant prognostic factor of both overall and recurrence-free survival. Conclusions: High pre-treatment serum VEGF levels predict poor prognosis after RFA of HCC. This study highlights the importance of tumor biomarker as a prognostic predictor in ablative therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features. © 2007 Society of Surgical Oncology.

Ronnie Poon    Cecilia Lau    Roberta wing cheung Pang    Ng Kelvin K.    Jimmy Yuen    范上达    

Annals of Surgical Oncology

2007

Liver disease afflicts over 10% of the world population. This includes chronic hepatitis, alcoholic steatosis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC), which are the most health-threatening conditions drawing considerable attention from medical professionals and scientists. Patients with alcoholism or viral hepatitis are much more likely to have liver cell damage and cirrhosis, and some may eventually develop HCC, which is unfortunately, and very often, a fatal malignancy without cure. While liver surgery is not suitable in many of the HCC cases, patients are mostly given palliative support cares or transarterial chemoembolization or systemic chemotherapies. However, HCC is well known to be a highly chemoresistant tumour, and the response rate is <10-20%. To this end, alternative medicines are being actively sought from other sources with hopes to halt the disease's progression or even eliminate the tumours. Traditional Chinese herbal medicine has begun to gain popularity worldwide for promoting healthcare as well as disease prevention, and been used as conventional or complementary medicines for both treatable and incurable diseases in Asia and the West. In this article, we discuss the laboratory findings and clinical trial studies of Chinese herbal medicines (particularly small molecule compounds) for the treatment of liver disease ranging from fibrosis to liver cancer. © 2007 Blackwell Munksgaard.

Luk John M.    Wang Xiaoling    Ping Liu    Wong Kwong-Fai    Chan Kwong-Leung    Yao Tong    Hui Chi-Kin    George Lau    范上达    

Liver International

2007

OBJECTIVE: Pancreatic fistula is a leading cause of morbidity and mortality after pancreaticoduodenectomy. External drainage of pancreatic duct with a stent has been shown to reduce pancreatic fistula rate of pancreaticojejunostomy in a few retrospective or prospective nonrandomized studies, but no randomized controlled trial has been reported thus far. This single-center prospective randomized trial compared the results of pancreaticoduodenectomy with external drainage stent versus no stent for pancreaticojejunal anastomosis. METHODS: A total of 120 patients undergoing pancreaticoduodenectomy with end-to-side pancreaticojejunal anastomosis were randomized to have either an external stent inserted across the anastomosis to drain the pancreatic duct (n = 60) or no stent (n = 60). Duct-to-mucosa anastomosis was performed in all cases. RESULTS: The 2 groups were comparable in demographic data, underlying pathologies, pancreatic consistency, and duct diameter. Stented group had a significantly lower pancreatic fistula rate compared with nonstented group (6.7% vs. 20%, P = 0.032). Radiologic or surgical intervention for pancreatic fistula was required in 1 patient in the stented group and 4 patients in the nonstented group. There were no significant differences in overall morbidity (31.7% vs. 38.3%, P = 0.444) and hospital mortality (1.7% vs. 5%, P = 0.309). Two patients in the nonstented group and none in the stented group died of pancreatic fistula. Hospital stay was significantly shorter in the stented group (mean 17 vs. 23 days, P = 0.039). On multivariate analysis, no stenting and pancreatic duct diameter <3 mm were significant risk factors of pancreatic fistula. CONCLUSION: External drainage of pancreatic duct with a stent reduced leakage rate of pancreaticojejunostomy after pancreaticoduodenectomy. © 2007 Lippincott Williams & Wilkins, Inc.

Ronnie Poon    范上达     Chung mau Lo    Ng Kelvin K.    Wai key Yuen    Chun Yeung    John Wong   

Annals of Surgery

2007

Hepatocellular carcinoma (HCC) is a heterogeneous cancer with no promising treatment and remains one of the most prevailing and lethal malignancies in the world. Researchers in many biological areas now routinely identify and characterize protein markers by a mass spectrometry-based proteomic approach, a method that has been commonly used to discover diagnostic biomarkers for cancer detection. The proteomic research platforms span from the classical two-dimensional polyacrylamide gel electrophoresis (2-DE) to the latest Protein Chip or array technology, which are often integrated with the MALDI (matrix-assisted laser-desorption ionization), SELDI (surface-enhanced laser desorption/ionization) or tandem mass spectrometry (MS/MS). New advances on quantitative proteomic analysis (e.g. SILAC, ICAT, and ITRAQ) and multidimensional protein identification technology (MudPIT) have greatly enhanced the capability of proteomic methods to study the expressions, modifications and functions of protein markers. The present article reviews the latest proteomic development and discovery of biomarkers in HCC that may provide insights into the underlying mechanisms of hepatocarcinogenesis and the readiness of biomarkers for clinical uses. © 2007 Blackwell Munksgaard.

Stella Sun    Nikki pui yue Lee    Ronnie Poon    范上达     Qingyu He    George Lau    Luk John M.   

Liver International

2007

Targeting checkpoint kinases has been shown to have a potential chemosensitizing effect in cancer treatment. However, inhibitors of such kinases preferentially abrogate the DNA damage-induced G checkpoint in p53 as opposed to p53 cells. The mechanisms by which p53 (TP53) can prevent abrogation of the G checkpoint are unclear. Using normal human diploid p53 and p53 fibroblasts as model systems, we have compared the effects of three checkpoint inhibitors, caffeine, staurosporine and UCN-01, on γ-radiation-induced G arrest. The G arrest in p53 cells was abrogated by caffeine, but not by staurosporine and UCN-01, whereas the G arrest in p53 cells was sensitive to all three inhibitors. Chk2 (CHEK1) phosphorylation was maintained in the presence of all three inhibitors in both p53 and p53 cells. Chk1 phosphorylation was maintained only in the presence of staurosporine and UCN-01 in p53 cells. In the presence of caffeine Chk1 phosphorylation was inhibited regardless of p53 status. The pathway of Chk1 phosphorylation → Cdc25A degradation → inhibition of cyclin B1/Cdk1 activity → G arrest is accordingly resistant to staurosporine and UCN-01 in p53 cells. Moreover, sustained phosphorylation of Chk1 in the presence of staurosporine and UCN-01 is strongly related to phosphorylation of p53. The present study suggests the unique role of Chk1 in preventing abrogation of the G checkpoint in p53 cells. © 2007 by Radiation Research Society.

Wang Xiao Qi    Stanbridge Eric J.    Lao Xiaoyan    Qi Cai    范上达     Redpath John L.   

Radiation Research

2007

The present study aimed to investigate the therapeutic efficacy of combining vascular endothelial growth factor (VEGF) receptor blockade using tyrosine kinase inhibitor PTK787 with hypoxia for the treatment of hepatocellular carcinoma (HCC). The in vivo effects of the treatments were determined in a rat orthotopic HCC model, in which hypoxia was generated by hepatic artery ligation (HAL). Compared with HAL alone, PTK787 combined with HAL significantly prolonged the animal survival, reduced the tumor size, induced more tumor tissue necrosis and apoptosis, and down-regulated the expression of von Willebrand factor. The mechanism was explored in vitro using murine HCC and endothelial cell lines, respectively. PTK787 combined with hypoxia decreased the expression of VEGF and VEGF receptors in both cell lines and suppressed the cell viability by induction of cell cycle arrest and promotion of apoptosis. Up-regulation of cleaved form caspase-9 and down-regulation of Bcl-2 and cyclin D1 were detected with the combined treatment. Hypoxia sensitized endothelial cells to the inhibitory effect of PTK787 on forming tubular-like structure. The motility of tumor cells was inhibited by hypoxia and the combined approach, with down-regulation of Rac1, Rho, and phosphorylated Akt expression. However, in the endothelial cells, the combined treatment inhibited the hypoxia-enhanced cell motility, with suppressed Rac1, Rho, and phosphorylated Akt expression. In conclusion, PTK787 combined with hypoxia achieved a better therapeutic efficacy than hypoxia alone through enhancing hypoxia-induced antitumor cell effect and preventing the activation of angiogenic proces. Copyright © 2006 American Association for Cancer Research.

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

Molecular Cancer Therapeutics

2006

An unusual case of infarcted duodenal duplication cyst is presented. Our case is the first ever reported. Total excision followed by duodenojejunostomy successfully cured the patient.

上达 范;W. Y. Lau;S. W. Pang

American Journal of Gastroenterology

1985-5

This multicentric, randomized, double-blind trial compared the efficacy and safety of netilmicin, 4·5 mg/kg od and 1·5 mg/kg tid, in patients with intra-abdominal infections. Of 114 patients enrolled, 57 patients (mean age 40·3 years) in the od group and 55 (mean age 36·8 years) in the tid group were evaluated for efficacy; 58 and 56 patients in corresponding groups were evaluated for safety. Among those evaluated for efficacy were 12 od-treated and 11 tid-treated patients with documented septicaemia, and 32 and 30 patients of respective groups with polymicrobial infections. Initially, 86 and 81 netilmicin-susceptible causative microorganisms were isolated in corresponding groups. Of these pathogens, 55% in the od group and 62% in the tid group were Escherichia coli. Daily dosage of netilmicin ranged from 3·70 to 4·71 mg/kg (mean 4·50) for the od group and from 3·06 to 4·76 mg/kg (mean 4·46) for the tid group. Duration of netilmicin therapy ranged from six to 13 days (mean 8·7 days) for od-treated patients and from seven to 16 days (mean 8·8 days) for tid-treated patients. Concomitant metronidazole was administered to 41 patients of the od group and 34 of the tid group; one patient in the tid group received clindamycin. Clinical and bacteriological responses were assessed, and peak and trough serum netilmicin levels were measured periodically during therapy. Laboratory tests, including determinations of serum creatinine and blood urea nitrogen values, were performed throughout the trial. A clinical cure was achieved in 57/57 od-treated patients and 54/55 tid-treated patients; treatment failed in one tid-treated patient (1/55). In od and tid groups, 86/86 and 80/81 netilmicin-susceptible pathogens initially isolated were considered to be eliminated, respectively; one isolate (Esch. coli) persisted in the tid group. Mean peak serum netilmicin concentration in the od group was approximately two-fold greater than that in the tid group; mean trough serum netilmicin concentrations were similar for the two groups. Adverse reactions were limited to mild pain at the site of netilmicin administration in several patients in each treatment group. Netilmicin od and tid (alone or in combination with metronidazole) were similarly efficacious in the treatment of patients with appendicitis and other intra-abdominal infections caused by netilmicin-susceptible pathogens. Both dosage regimens of netilmicin were safe and well tolerated.

L. F. Hollender;J. Bahnini;N. De Manzini;W. Y. Lau;上达 范;K. Hermansyur;P. Benny;A. N. Husni; Sutjipto;R. R. Lorber

Journal of Antimicrobial Chemotherapy

1989-5

上达 范;W. Y. Lau;M. J.R. Lee;K. P. Wong;K. K. Wong

British Journal of Surgery

1985-9