Background: Venovenous bypass was considered necessary to maintain haemodynamic stability and avoid splanchnic and retroperitoneal congestion during the anhepatic phase of liver transplantation. It was essential for right lobe living donor liver transplantation (LDLT) in which the inferior vena cava needed to be cross-clamped to construct wide and short hepatic vein anastomoses. However, many complications related to venovenous bypass have been reported. This study aimed to determine whether venovenous bypass was necessary for right lobe LDLT. Methods: Between June 1996 and June 2001, 72 patients underwent right lobe LDLT. The outcomes for the first 29 patients who had venovenous bypass during the operation were compared with those of the remaining 43 patients who did not have venovenous bypass. In patients without bypass, blood pressure was maintained during the anhepatic phase by boluses of fluid infusion and vasopressors. Results: Compared with patients undergoing operation without venovenous bypass, patients who had venovenous bypass required significantly more blood, fresh frozen plasma and platelet infusion, and had a lower body temperature; their postoperative hepatic and renal function in the first week was worse than that in patients who did not have a bypass. The time to tracheal extubation was longer and the incidence of reintubation for ventilatory support was higher with venovenous bypass. Six of the 29 patients with venovenous bypass died in hospital, compared with two of the 43 patients without a bypass (P = 0.05). By multivariate analysis, the lowest body temperature during the transplant operation was the most significant factor that determined hospital death. Conclusion: Venovenous bypass is not necessary and is probably harmful to patients undergoing right lobe LDLT, and should therefore be avoided.

上达 范;B. H. Yong;C. M. Lo;C. L. Liu;J. Wong

British Journal of Surgery

2003-1-1

上达 范

2011-1-1

Background: Transarterial chemoembolization (TACE) is widely used for unresectable hepatocellular carcinoma (HCC), but the long-term survival benefit remains unclear. Methods: Pretreatment variables were analysed for factors predictive of actual 5-year survival from a prospective database of patients with inoperable HCC treated by TACE between 1989 and 1996. Results: Complete 5-year follow-up (median 91 months) was obtained for 320 patients who underwent a median of 4 (range 1-41) TACEs. Median tumour size was 9 (range 1-28) cm. There were 25 5-year survivors (8 per cent), including eight with tumours larger than 10 cm in diameter and three with portal vein branch involvement. On univariate analysis, female gender (P = 0.037), absence of ascites (P = 0.028), platelet count below 150 × 10⁹ per litre (P = 0.011), albumin concentration greater than 35 g/l (P = 0.04), α-fetoprotein level below 1000 ng/ml (P = 0.007), unilobar tumour (P = 0.027), fewer than three tumours (P = 0.015), absence of venous invasion (P = 0.011), and tumour diameter less than 8 cm (P = 0.021) were significant predictors of 5-year survival. Albumin concentration greater than 35 g/l (P = 0.011), unilobar tumour (P = 0.012) and α-fetoprotein level below 1000 ng/ml (P = 0.014) were independent prognostic factors on multivariate analysis. Conclusion: Five-year survival is possible with TACE for inoperable HCC, even in some patients with advanced tumours. Unilobar tumours, α-fetoprotein level below 1000 ng/ml and albumin concentration greater than 35 g/l were factors predictive of 5-year survival.

C. B. O'Suilleabhain;R. T.P. Poon;J. L. Yong;G. C. Ooi;W. K. Tso;上达 范

British Journal of Surgery

2003-3-1

Hepatic resection is considered the treatment of choice for HCC; however, the prognosis of patients after resection of HCC varies widely, depending on the clinicopathologic features. The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) tumor-node-metastasis (TNM) staging system is widely used evaluating patients with HCC. The current TNM staging for HCC uses pathologic characteristics of tumors, including size, number and location of tumor nodules, presence of vascular invasion, perforation of visceral peritoneum, and invasion of adjacent organs as criteria for T staging. Recently, a simplified AJCC/UICC staging for HCC has been proposed. In addition, the Liver Cancer Study Group of Japan proposed a new simplified staging system based on number of tumor nodules, size of tumors, and invasion into the portal vein, hepatic vein, or bile duct. This article evaluates the prognostic value of the new AJCC/UICC TNM staging and the new Japanese staging in a large cohort of Chinese patients who underwent hepatectomy for HCC in a single institution.

Ronnie Tung Ping Poon;上达 范

Surgical Oncology Clinics of North America

2003-1

Platelets are an important place for the storage of angiogenic factors, such as vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). The present study aims to investigate the interaction between BDNF-TrkB pathway and platelet activation during tumor development. In an orthotopic hepatocellular carcinoma (HCC) model, increased levels of serum and plasma BDNF were detected with tumor progression. Higher numbers of CD62P⁺ and TrkB⁺ platelets were found in the tumor-bearing rats. In the in vitro setting, tumor-conditioned-medium (TCM) and BDNF recombinant protein stimulated CD62P upregulation and subsequent BDNF release in the freshly isolated platelets, whereas this effect could be inhibited by TrkB blockade. TCM and BDNF culture augmented the expression of heat shock protein 90 (Hsp90) in the platelets, which could be reversed by TrkB blockade. In conclusion, this study suggested the presence of BDNF-TrkB autocrine loop in platelets and its importance in regulating platelet activation during tumor development.

Zhen Fan Yang;David W. Ho;Chi Keung Lau;Ka Ho Tam;Chi Tat Lam;Ronnie T.P. Poon;上达 范

Biochemical and Biophysical Research Communications

2006-8-4

Our previous studies revealed that macrophages played an important role in linking injury, inflammatory and immune response in small-for-size liver transplantation. However, the molecular basis that promoted macrophage activation was not clear. In the present study, we explored the potential role of allograft inflammatory factor-1 (AIF-1) in mediating the survival and pro-inflammatory activity of macrophages in a macrophage cell line. First, the expression of AIF-1 was investigated with the stimulation of pro-inflammatory cytokines and anti-inflammatory treatment. Second, the level of inducible nitric oxide synthase (iNOS) and the survival and migration activity of macrophages were determined with the alterations of AIF-1 expression. Finally, a potential molecule that regulated AIF-1 expression was identified by the proteomic approach. The macrophage cell line expressed a certain level of endogenous AIF-1, which could be enhanced by pro-inflammatory cytokines IL-1β or tumor necrosis factor-α and suppressed by anti-inflammatory drug sodium salicylate. AIF-1 augmentation induced by AIF-1/PCDNA3.1(+) transfection enhanced the levels of iNOS and monocyte chemoattractant protein-1, and promoted the cell migration. On the other hand, suppression of AIF-1 expression by AIF-1/short interference RNA (siRNA) inhibited iNOS production, induced macrophage cell apoptosis and blocked the cell migration. Using two-dimensional electrophoresis, a disintegrin and metalloproteinase domain 3 (ADAM3) was identified after AIF-1/siRNA transfection. Transfection of ADAM3/ PCDNA3.1(+) up-regulated the expression of AIF-1 and iNOS, whereas suppression of ADAM3 expression down-regulated AIF-1 and iNOS expression. In conclusion, AIF-1 played an important role in the survival and pro-inflammatory activity of macrophages, and ADAM3 might be an upstream molecule that regulated AIF-1 expression.

Zhen Fan Yang;David W. Ho;Chi Keung Lau;Chi Tat Lam;Ching Tung Lum;Ronnie T.P. Poon;上达 范

International Immunology

2005-11

Lipopolysaccharide (LPS), a bacterial endotoxin, triggers deleterious systemic inflammatory responses when released into blood circulation, causing organ dysfunction and death. In response to LPS stimulation, CD14 and toll-like receptor (TLR)-4 elicit inflammatory signaling cascades. Although leukocyte integrins (CD11b/CD18 and CD11c/CD18) were reported to bind LPS and induce NF-κB translocation, the evidence on such epitope location remains elusive. The present study aims to delineate the LPS-binding sites on the integrin CD18 antigen and to design peptide(s) as potential prophylactic and/or therapeutic agents to modulate LPS effects in activated Jurkat cells. Epitope mapping analysis using a series of CD18 truncated variants revealed two putative LPS-binding sites within the βA region (216-248 and 266-318 a.a.), which were further confirmed by point mutation studies. Inhibition assay demonstrated that the CD18-βA_266-318 peptide could block LPS binding in a dosedependent manner. Our data also indicated that treatment with the CD18-peptide modulated TNF-α mRNA transcription via the NF-κB signaling pathway in LPS-activated Jurkat cells. In conclusion, we have identified two novel LPS-binding sites located at the CD18 βA domain of leukocyte integrin, and the integrin peptide βA_266-318 is shown to inhibit LPS binding and subsequent inflammatory events, having therapeutic implications to cure Gram-negative endotoxemia.

Kwong Fai Wong;John M. Luk;R. Holland Cheng;Lloyd B. Klickstein;上达 范

FASEB Journal

2007-10

Aim: To test the hypothesis that enhancement of the activity of heme oxygenase can interfere with processes of fibrogenesis associated with recurrent liver injury, we investigated the therapeutic potential of over-expression of heme oxygense-1 in a CCI₄-induced micronodular cirrhosis model. Methods: Recombinant adeno-associated viruses carrying rat HO-1 or GFP gene were generated. 1×10¹² vg of adeno-associated viruses were administered through portal injection at the time of the induction of liver fibrosis. Results: Conditioning the rat liver with over-expression of HO-1 by rAAV/HO-1 significantly increased the HO enzymatic activities in a stable manner. The development of micronodular cirrhosis was significantly inhibited in rAAV/HO-1-transduced animals as compared to controls. Portal hypertension was markedly diminished in rAAV/ HO-1-transduced animals as compared to controls, whereas there are no significant changes in systolic blood pressure. This finding was accompanied with improved liver biochemistry, less infiltrating macrophages and less activated hepatic stellate cells (HSCs) in rAAV/ HO-1-transduced livers. Conclusions: Enhancement of HO activity in the livers suppresses the development of cirrhosis.

Tung Yu Tsui;Chi Keung Lau;Jian Ma;上达 范;Gabriel Glockzin;Aiman Obed;Hans J. Schlitt

World Journal of Gastroenterology

2006-4-7

Background: The aim of the study was to validate the use of Physiological and Operative Severity Score in the enumeration of Mortality and morbidity (POSSUM) and Portsmouth (P) POSSUM scoring systems to predict postoperative mortality in a group of Chinese patients who had a major hepatectomy for hepatocellular carcinoma. Methods: A retrospective analysis was performed on data collected prospectively over a 6-year interval from January 1997 to December 2002. The mortality risks were calculated using both the POSSUM and the P-POSSUM equations. Results: Two hundred and fifty-nine patients underwent major hepatectomy; there were 17 (6-6 per cent) postoperative deaths. Of 32 preoperative and intraoperative variables studied, age, smoking habit, serum creatinine concentration, American Society of Anesthesiologists grade, and physiological and operative severity scores were found to be significant factors predicting mortality. On multivariate analysis only the physiological and operative severity scores were independent variables. The POSSUM system overpredicred mortality risk (14-2 per cent) and there was a significant lack of fit in these patients (X² = 14.1, 3 d.f., P = 0.003). The mortality rate predicted by P-POSSUM was 4.2 per cent and showed no significant lack of fit (x² = 7.6, 3 d.f., P = 0.055), indicating that it predicted outcome effectively. A new logistic equation was derived from the present patient data set that requires testing prospectively. Conclusion: P-POSSUM significantly predicted outcome in Chinese patients who had major hepatectomy for hepatocellular carcinoma. A modified disease-specific equation requires further testing.

C. M. Lam;上达 范;A. W.C. Yuen;W. L. Law;K. Poon

British Journal of Surgery

2004-4

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 (CD45^-CD90⁺CD44 ⁺) 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.

上达 范;Zhen Fan Yang;David W.Y. Ho;Michael N.P. Ng;Wan Ching Yu;John Wong

Annals of Surgery

2011-10