The progress in the development of systemic treatment for advanced pancreatic cancer (APC) has been slow. The main stream treatment remains using chemotherapy including gemcitabine, FOLFIRINOX, and nab-paclitaxel. Erlotinib is the only approved biological therapy with marginal benefit. Studies of agents targeting epidermal growth factor receptor, angiogenesis, and RAS signaling have not been satisfying, and the usefulness of targeted therapy in APC is uncertain. Understanding in molecular processes and tumor biology has opened the door for new treatment strategies such as targeting insulin-like growth factor 1 receptor, transforming growth factor β, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Notch pathway. New directions also include the upcoming immunotherapy and many novel agents that act on the microenvironment. The practice of personalized medicine using predictive biomarkers and pharmacogenomics signatures may also enhance the effectiveness of existing treatment. Future treatment approaches may involve comprehensive genomic assessment of tumor and integrated combinations of multiple agents to overcome treatment resistance.

Joanne W. Chiu;Hilda Wong;Roland Leung;Roberta Pang;Tan To Cheung;上达 范;Ronnie Poon;Thomas Yau

Oncologist

2014

Background: The International Study Group for Liver Surgery (ISGLS) definition of post hepatectomy liver failure (PHLF) was developed to be consistent, widely applicable, and to include severity stratification. This international multicentre collaborative study aimed to prospectively validate the ISGLS definition of PHLF. Methods: 11 HPB centres from 7 countries developed a standardised reporting form. Prospectively acquired anonymised data on liver resections performed between 01 July 2010 and 30 June 2011 was collected. A multivariate analysis was undertaken of clinically important variables. Results: Of the 949 patients included, 86 (9%) met PHLF requirements. On multivariate analyses, age ≥70 years, pre-operative chemotherapy, steatosis, resection of >3 segments, vascular reconstruction and intraoperative blood loss >300 ml significantly increased the risk of PHLF. Receiver operator curve (ROC) analysis of INR and serum bilirubin relationship with PHLF demonstrated post-operative day 3 and 5 INR performed equally in predicting PHLF, and day 5 bilirubin was the strongest predictor of PHLF. Combining ISGLS grades B and C groups resulted in a high sensitivity for predicting mortality compared to the 50-50 rule and Peak bilirubin >7 mg/dl. Conclusions: The ISGLS definition performed well in this prospective validation study, and may be the optimal definition for PHLF in future research to allow for comparability of data.

Asma Sultana;Mark Brooke-Smith;Shahid Ullah;Joan Figueras;Myrddin Rees;Jean Nicolas Vauthey;Claudius Conrad;Thomas J. Hugh;O. James Garden;上达 范;Michael Crawford;Masatoshi Makuuchi;Yukihiro Yokoyama;Markus Büchler;Robert Padbury

HPB

2018-5

Aims: Telomerase activation is known to be a common event in human cancer and may be a useful marker for malignancy. In general, the histological features of pancreatic endocrine tumours cannot be used to determine their malignant potential. The aim of this study was to investigate the role of testing telomerase activity in pancreatic endocrine tumours. Methods: Prospectively collected fresh frozen tissue specimens from 10 patients with pancreatic endocrine tumours (nine insulinomas, one adrenocorticotrophin producing pancreatic endocrine tumour) were examined by a highly sensitive polymerase chain reaction (PCR) based telomerase repeat protocol (TRAP). Results: Of the 10 pancreatic endocrine tumours, three had telomerase activity. The positive cases included two frankly malignant tumours with liver metastases and one pancreatic endocrine tumour occurring in the setting of multiple endocrine neoplasia type 1. The latter had an infiltrative border. Vascular and perineural tumour infiltration was noted. In the two malignant pancreatic endocrine tumours with liver metastases, telomerase activity was noted in the tumour and the adjacent morphologically non-neoplastic pancreas. Conclusion: To our knowledge, this is the first report of the role of telomerase activity in pancreatic endocrine tumours. Telomerase activity might be useful for distinguishing between benign and malignant pancreatic endocrine tumours.

K. Y. Lam;C. Y. Lo;上达 范;J. M. Luk

Journal of Clinical Pathology

2000

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.

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

Liver International

2007-9

Background: Postoperative hepatic failure is the leading cause of hospital mortality following hepatectomy for hepatocellular carcinoma (HCC). This prospective study was performed to identify the best test for assessment of the adequacy of hepatic functional reserve in patients with HCC before hepatectomy. Methods: Between April 1989 and June 1993, 127 patients with HCC underwent hepatectomy. Each patient was evaluated before operation with the indocyanine green (ICG) clearance test, the aminopyrine breath test and the amino acid clearance test. Results: Fourteen patients (11 per cent) died after hepatectomy. ICG retention at 15 min showed significant differences between patients who survived or died. By discriminant analysis, the safety limit of ICG retention at 15 min for major hepatectomy was 14 per cent and the relative risk of hospital mortality was 3. Conclusion: The ICG clearance test, expressed as the percentage of ICG retained at 15 min, is the best discriminating preoperative test for evaluating hepatic functional reserve in patients with HCC before hepatectomy.

H. Lau;K. Man;上达 范;W. C. Yu;C. M. Lo;J. Wong

British Journal of Surgery

1997

OBJECTIVE: To compare the incidence and severity of acute cwellular rejection (ACR) between living donor liver transplantation (LDLT) and cadaveric liver transplantation (CLT). METHODS: 51 patients underwent LDLT among which 30 received the liver of blood-related donors, and 65 patients underwent CLT. Clinical data, such as the cold ischemic time of liver graft, use of immunosuppressive agents, ACR rate, response to steroid therapy, HLA matching between donor and recipient, and survival rates of liver graft and patients were collected and analyzed. RESULTS: The graft survival rate, patient survival rate, ACR rate, ACR multiple incidence rate, and no response rate to steroid therapy in CLT and LDLT groups were 72% vs 78%, 77% vs. 78%, 48% vs. 41%, 20% vs. 10%, and 11% vs. 4% (P > 0.05). The difference of ACR rates between CLT and living blood-related donor liver transplantation was statistically insignificant. There was no significant difference in number of HLA allele mismatching between patients with ACR and those without ACR. The combined immunosuppression therapy rely mainly on FK506 use reduced the occurrence of ACR (P < 0.05). CONCLUSION: There is no marked difference in incidence of ACR between LDLT and CLT. ACR in liver transplantation is correlated to neither HLA matching between donors and recipients nor to cold ischemic time of the liver graft. FK506 avoids ACR better than cyclosporin2 A.

上达 范;Z. Zhang

Zhonghua yi xue za zhi

2001-9-25

We studied the safety of right-lobe donor hepatectomy in living donors with a positive serological test result for antibody against hepatitis B core antigen (anti-HBc). Of 54 right-lobe living liver donors, serum anti-HBc was positive in 29 donors (54%) and negative in 25 donors (46%). None had a history of hepatitis and all had normal liver biochemistry test results before surgery. Surgical data, postoperative liver function, and outcome of donors were compared according to anti-HBc status. Donors positive for anti-HBc were significantly older (median age, 42 v 31 years; P < .001), but there was no difference in other demographics and liver size. Median blood loss was greater in anti-HBc-positive donors (600 v 350 mL; P = .007). Histological examination showed no difference in degree of portal fibrosis or fatty change in liver grafts. There was no significant difference in postoperative serum transaminase levels or prothrombin times; however, anti-HBc-positive donors had greater serum bilirubin levels day 6 (26 v 21 μmol/L; P = .01) and day 7 (22 v 15 μmol/L; P = .004) after surgery. Postoperative complications developed in 10 anti-HBc-positive and 6 anti-HBc-negative donors (P = .4). All donors who developed cholestasis were positive for anti-HBc, aged 45 years or older, and had mild fatty changes of the liver. Hospital stays were similar. All donors had completely normal liver function at a median follow-up of 31 months (range, 21 to 76 months). A positive serological test result for anti-HBc should not be regarded as a contraindication for right-lobe liver donation.

Chung Mau Lo;上达 范;Chi Leung Liu;Boon Hun Yong;Yik Wong;Irene Oi Lin Ng;John Wong

Liver Transplantation

2003-8-1

Background: Extended hepatectomy with resection of more than four segments is a high-risk operation, especially in patients with hepatocellular carcinoma (HCC) associated with chronic liver disease. This study evaluated the risk factors for morbidity and mortality following extended hepatectomy for HCC. Methods: Preoperative and intraoperative variables of 155 patients who underwent extended hepatectomy for HCC were analysed to identify risk factors for postoperative morbidity and mortality. Results: The overall morbidity rate was 55.5 per cent (n = 86). Most morbidity was due to ascites or pleural effusion. Significant life-threatening complications occurred in 20.0 per cent (n = 31). The perioperative mortality rate was 8.4 per cent (n = 13). Multivariate analysis found that portal clamping (P = 0.023) and perioperative blood transfusion (P < 0.001) were risk factors for morbidity, whereas perioperative blood transfusion (P < 0.001) was the only risk factor for significant morbidity. Co-morbid illness (P = 0.019) and perioperative blood transfusion (P = 0.004) were risk factors for perioperative mortality. Conclusion: Meticulous operative techniques to minimize blood loss and transfusion, while avoiding a prolonged Pringle manoeuvre, may help reduce postoperative morbidity. Avoidance of perioperative blood transfusion and careful preoperative selection of patients in terms of overall physiological status are important measures to reduce the postoperative mortality rate.

A. C. Wei;R. Tung Ping Poon;上达 范;J. Wong

British Journal of Surgery

2003-1-1

A prospective study to determine the safety and effectiveness of choledochoscopy in acute cholangitis and acute suppuratie cholangitis due to common bile duct stones was conducted on 70 patients. Common bile duct pressures determined on the first 20 patients showed that choledochoscopy was unlikely to cause cholangiovenous reflux. Laboratory and clinical parameters revealed that choledochoscopy did not cause septicemia, worsen cholangitis, or provoke acute pancreatitis. There was no iatrogenic injury during choledochoscopy, and the choledochoscopic views were minimally affected by cholangitis. Choledochoscopy detected overlooked stones after conventional methods of exploration of common bile ducts in 14.3% of patients and it helped to remove impacted stones in 2.9% of patients. As a result, the incidence of retained stones after choledochoscopy was 1.4%. Time spent in choledochoscopy was short, and the total postoperative septic complication rate was only 10%. There was no operative mortaltiy. it is concluded that choledochoscopy is safe and effective in cholangitis.

W. Y. Lau;K. K. Chong;上达 范;K. W. Chu;W. C. Yip;G. P. Poon;K. K. Wong

Annals of Surgery

1987

Background: Hepatocellular carcinoma (HCC) is highly malignant and metastatic. Currently, there is no effective chemotherapy for patients with advanced HCC leading to an urgent need to seek for novel therapeutic options. We aimed to investigate the effect of a garlic derivative, S-allylcysteine (SAC), on the proliferation and metastasis of HCC. Methodology/Principal Findings: A series of in vitro experiments including MTT, colony-forming, wound-healing, invasion, apoptosis and cell cycle assays were performed to examine the anti-proliferative and anti-metastatic effects of SAC on a metastatic HCC cell line MHCC97L. The therapeutic values of SAC single and combined with cisplatin treatments were examined in an in vivo orthotopic xenograft liver tumor model. The result showed that the proliferation rate and colony-forming abilities of MHCC97L cells were suppressed by SAC together with significant suppression of the expressions of proliferation markers, Ki-67 and proliferating cell nuclear antigen (PCNA). Moreover, SAC hindered the migration and invasion of MHCC97L cells corresponding with up-regulation of E-cadherin and down-regulation of VEGF. Furthermore, SAC significantly induced apoptosis and necrosis of MHCC97L cells through suppressing Bcl-xL and Bcl-2 as well as activating caspase-3 and caspase-9. In addition, SAC could significantly induce the S phase arrest of MHCC97L cells together with down-regulation of cdc25c, cdc2 and cyclin B1. In vivo xenograft liver tumor model demonstrated that SAC single or combined with cisplatin treatment inhibited the progression and metastasis of HCC tumor. Conclusions/Significance: Our data demonstrate the anti-proliferative and anti-metastatic effects of SAC on HCC cells and suggest that SAC may be a potential therapeutic agent for the treatment of HCC patients.

Kevin T.P. Ng;Dong Yong Guo;Qiao Cheng;Wei Geng;Chang Chun Ling;Chang Xian Li;Xiao Bing Liu;Yuen Yuen Ma;Chung Mau Lo;Ronnie T.P. Poon;上达 范;Kwan Man

PLoS ONE

2012-2-28