Research Profile of the Division of Hepato-biliary and Pancreatic Surgery at the Department of Surge

Paul B.S. Lai  Department of Surgery, Chinese University of Hong Kong, Hong Kong SAR, China

Clinical Research - Use of inflow vascular occlusion in hepatectomy

Bleeding and liver failure are two major obstacles for successful liver resections.  Bleeding not only increases operative morbidity and mortality, excessive bleeding has been shown to increase tumor recurrence and decrease long-term survival.  Thus reducing blood loss and avoiding blood transfusion are important targets in liver resection nowadays.

Use of inflow vascular occlusion (the Pringle maneuver) remains the simplest and most effective way to reduce blood loss during liver resection.  It is widely practiced by many liver surgeons.  However, the potential problem of ischaemic-reperfusion injury to remnant liver remains a concern when the Pringle maneuver is employed.

With the advance in instrumental designs and techniques for liver resection, blood loss during hepatectomy can now be much reduced.  Routine use of the Pringle maneuver is no longer necessary.  Since 2003, our institute had consecutive cases of liver resections carried out without routine Pringle maneuver and these included cases of laparoscopic liver resections.  Open liver resections are performed with CUSA (cavitron ultrasonic surgical aspirator) and TissueLink (saline linked radio-frequency dissecting sealer), while laparoscopic resections are performed with Ligasure (bipolar vessel sealing device) and TissueLink.  About one-third of the liver resections were major hepatectomy (resection of three or more liver segments).  The commonest indication for hepatectomy was hepatocellular carcinoma (about 50%) and thus not surprisingly up to one-third of the liver specimens would have cirrhosis.  The operative mortality was less than 1%.  The median blood loss was about 300ml with a blood transfusion rate of 7%.  The median post-operative hospital stay was 7 days.  From our experience, we noted that low blood loss, low mortality and morbidity rates can be achieved in liver resection without the routine Pringle maneuver.  Furthermore, the avoidance of inflow vascular occlusion may speed up the recovery of liver function and help to cut down postoperative hospital stay.

Building on our experience in liver resection without routine application of the Pringle maneuver, we are currently conducting a prospective randomized trial to compare liver resection with or without routine Pringle maneuver.  The primary end points include operative blood loss and operative time.  The secondary end points are mortality rate, morbidity rate, hospital stay and post-operative recovery of liver function.  Liver function recovery was assessed by serial post-operative serum bilirubin, alanine transferase (ALT), alkaline phosphatase (ALP), the international normalized ratio (INR) for clotting.  Our aim is to determine whether adding the Pringle maneuver to modern hepatectomy technique will further reduce the blood loss and operative time, and to determine the impact of the Pringle maneuver on operative morbidity and mortality especially on incidence of post-operative liver failure.

Basic Research - Towards novel and better treatments for hepatocellular carcinoma

In the past few years, our laboratory has focused on three areas in basic research of hepatocellular carcinoma (HCC).  The first area is Bid and HCC.  We have demonstrated that the level of Bid (a pro-apoptotic protein) is reduced in tumorous liver tissues of HCC patients compared with non-tumorous liver tissues.  In cell culture experiments, we found that the over-expression of Bid or its truncated form tBid significantly enhanced the sensitivity of HCC cells to chemotherapeutic agents such as 5-Fluorouracil and Doxorubicin by promoting apoptosis.  Our results also showed that Bid was localized in both the nucleus and the cytoplasm and that upon a proper stimulus such as DNA damage stress, Bid could be translocated from the nucleus to the mitochondria to execute its pro-apoptotic function.  p53 plays an important role in the translocation of Bid from the nucleus to the cytoplasm.  Based on these data, we proposed that Bid/tBid might be a therapeutic agent for HCC.  In order to make the Bid/tBid specifically target the HCC, we fused human alpha-fetoprotein (AFP) promoter with Bid/tBid to make AFP-Bid/tBid adenoviral DNA.  It was found that this AFP-Bid/tBid adenoviral DNA could specifically target AFP-producing HCC cells in both in vitro cell cultures and in vivo orthotopic hepatic tumor models in mice.  Experiments are currently being conducted in our laboratory to further optimize the anti-tumour effect of AFP-Bid/tBid.

The second area is in ZBP-89 and HCC.  ZBP-89 is a transcription factor and it is known to suppress a number of solid tumors growth.  We found that ZBP-89 could induce the death of HCC cells and the effect of ZBP-89 was associated with the increase in Bak and caspase-6.  Our results have also shown that the ZBP-89 can be used to increase the cytotoxic effects of several chemotherapeutic agents.  It also appears that the anti-proliferative effect of ZBP-89 is more obvious in cells containing wild-type p53 than those with mutant p53.  Our laboratory will continue to explore the mechanisms responsible for the anti-tumor effect of ZBP-89.

The third area is hepatitis B x (HBx) protein and HCC.  We have found the HBx is frequently mutated in both serum and liver tissue samples from local HCC patients.  In order to further explore the relationship between HBx and HCC, we have cloned the HBx mutants and tested the cloned HBx in cell culture models.  We found that different HBx mutants had different effects on the generation of reactive oxygen species (ROS) and some apoptotic molecules such as Bid.  The carboxy-terminus of HBx can significantly enhance the processing of Bid into tBid and thus subject HCC cells more sensitive to apoptotic stimulation.

In conclusion, our researches have opened up some new areas towards HCC treatment.  We hope that further studies in these areas will bring the laboratory results closer to clinical practice.