1 LIVING-RELATED LIVER TRANSPLANTATION [LRLT] IN EUROPE: REPORT OF THE EUROPEAN LIVER TRANSPLANT REGISTRY [ELTR]

René Adam, Xavier Rogiers, Jan Lerut, Christoph Broelsch, Yves Revillon, Olivier Boillot, John G O'Grady, Peter Neuhaus, Bernard De Hemptinne, European Liver Transplant Association [ELTA], Paul Brousse Hospital, Villejuif, France; University Hospital Eppendorf, Hamburg, Germany; Cliniques Universitaires Saint-Luc, Brussels, Belgium; University Hospital Essen, Essen, Germany; Necker-Enfants Malades Hospital, Paris, France; Edouard Herriot Hospital, Lyon, France; King's College Hospital, London, UK; Charité Campus Virchow Klinikum, Berlin, Germany; Ghent University Hospital, Gent, Belgium

INTRODUCTION: Owing to organ shortage, LRLT is increasingly performed worldwide. Results from individual centers have been reported but multicentric prospective evaluation is still lacking. METHODS: From October 1991 to June 2002, the ELTR cumulated the results of 928 LRLT performed in 52 centers from 15 European countries. Data were prospectively registered, updated every 6 months and controlled by audit visits of contributing centers. The aim of this study was to assess donor and patient outcome and to compare LRLT to cadaveric LT. RESULTS: There were 433 LRLT performed in adults and 495 in children. By the last 2.5 years adult LRLT largely exceeded pediatric LT [358 vs 157]. The graft used was mainly the right liver for adults [94%] and the left liver lobe for children [84%]. Donor operative mortality was 0.4% [4/928] with 4 postoperative deaths related to pulmonary embolism [1], sepsis [2] and cardiac failure [1]. Donor morbidity accounted for 19% early postoperative complications, higher for right liver donation [34%] than for left lobe donation [10%] [p < 0.0001]. As compared with cadaveric LT, there were more cancers [22% vs 10%, p < 0.0001], less acute hepatic failures [4% vs 8%, p=0.05] and less retransplantations [1% vs 10%, p < 0.0001]. Overall 5-year graft survival was 75%, better for children than for adults [80% vs 65% at 3 years, p = 0.0003]. While survival of LRLT was better than cadaveric LT for children [80% vs 70%, p < 0.001], it was similar for adults [65% vs 68% at 3 years]. The size of the graft significantly affected the outcome of adults [2-month graft loss: 28% for right livers, 46% for left livers, 64% for left lobes, p < 0.001]. Overall, graft loss included more primary non-functions [15% vs 9% of all graft loss, p < 0.01] and more technical complications [16% vs 13%, p < 0.05] but less rejection [1% vs 7%, p < 0.05] after LRLT than after cadaveric LT. CONCLUSIONS: In Europe, LRLT includes a mortality risk of 0.4% and an early complication rate of 19% for the donor. Compared with cadaveric LT indications for LRLT differ significantly. Results are better for children but similar for adults. Graft size is a critical factor for outcome.

2 LIVING DONOR LIVER TRANSPLANTATION AS A MODALITY FOR EXPANDING DONOR POOL

Yasuhiko Sugawara and Masatoshi Makuuchi, University of Tokyo, Tokyo, Japan

BACKGROUND: Liver transplantation from a living donor [LDLT] is now widespread as an alternative therapy for end-stage liver diseases. The quick development of LDLT, however, raised serious ethical dilemmas, especially as regards donor safety. To evaluate the feasibility of LDLT, the results in a single institute were retrospectively analysed. MATERIALS AND METHODS: In total 249 LDLT procedures were performed for 245 patients at the University of Tokyo from January 1996 to November 2003. They consisted of 175 adults and 70 pediatric patients. The common indications included biliary atreasia in 73, viral hepatitis and cirrhosis with or without hepatocellualr carcinoma in 67 and cholestatic disease in 62, including primary biliary cirrhosis, autoimmune hepatitis and primary sclerosing cholangitis. Most donors were related to the patients, and consisted of 91 parents, 70 children, 33 siblings, 27 spouses and others in 24. The most common procedure was left liver with or without caudate lobe resection [n= 97] followed by right liver resection [n=77]. RESULTS: The rates of acute rejection and vascular and biliary complications were 31%, 6% and 27%, respectively. Eleven patients died during hospitalisation. The postoperative hospital stay among the surviving patients was 55±28 days. Nine patients experienced late death and the 3-year cumulative survival rate was 88%. Four patients underwent re-transplantation. The most frequent complication in donors was bile juice leakage from the dissection plane of the liver or stump of the bile duct in 13, and six of these donors underwent re-operation for drainage. CONCLUSIONS: The long-term results of the recipients seemed to be satisfactory and no major complications were experienced in the donors. From a technical standpoint, refinement in biliary reconstruction will be necessary. For better long-term outcome, the strategy for hepatitis C virus must be established.

3 FIVE-YEAR SURVIVAL AFTER RESECTION OF HEPATIC METASTASES FROM COLORECTAL CANCER IN PATIENTS SCREENED BY POSITRON EMISSION TOMOGRAPHY WITH F-18 FLUORODEOXYGLUCOSE [FDG-PET]

Steven M Strasberg, Felix Fernandez, Jeffrey A Drebin, David C Linehan, Barry A Siegal and Farrokh Dehdashti, Washington University in St Louis, St Louis, MO, USA

OBJECTIVE: The 5-year overall survival [5yOS] after liver resection for colorectal cancer metastases without preoperative FDG-PET has been established in 19 studies [6070 patients]. The median 5yOS in these studies is 30% [range 12–41%] and has not improved over time. FDG-PET detects unsuspected tumor in 25% of patients considered to have resectable hepatic metastasis by conventional staging. We report the first 5yOS survival results in a cohort of patients evaluated preoperatively by FDG-PET. METHODS: From 3/95 to 6/02, all patients having liver resection for colorectal cancer metastases had preoperative FDG-PET. A prospective database was maintained. RESULTS: We studied 100 patients [56 men, 44 women]. The metastases were synchronous in 57, single in 63, unilateral in 78, and 3 segments] in 74 and resection margins were >1 cm in 52. Median follow-up was 31 mo [0.1–96 mo], with 12 actual >5-year survivors. There was one postoperative death. The actuarial 5yOS was 58% [95% CI 44–72%] [Figure]. In uni- and multivariate analyses, none of the common risk factors for recurrence [size >5 cm, multiple tumors, bilaterality, synchronicity] correlated with survival. CONCLUSIONS: Screening by FDG-PET is associated with excellent post-resection 5yOS for patients with colorectal cancer metastases. The lack of correlation with established risk factors for recurrence suggests that these are surrogates for occult extrahepatic disease, which is often detected by FDG-PET.![An external file that holds a picture, illustration, etc. Object name is MHPB06-001S1.gif][//i0.wp.com/www.ncbi.nlm.nih.gov/pmc/articles/PMC2020689/bin/MHPB06-001S1.gif]

4 RESECTION OF NON-RESECTABLE LIVER METASTASES AFTER CHEMOTHERAPY: PROGNOSTIC FACTORS AND LONG-TERM RESULTS

René Adam, Valerie Delvart, Gérard Pascal, Denis Castaing, Daniel Azoulay, Bernard Paule, Francis Levi, Francis Kunstlinger and Henri Bismuth, Paul Brousse Hospital, HepatoBiliary Center, Villejuif, France

INTRODUCTION: Surgery of primarily non-resectable [NR] colorectal liver metastases [CRLM] after downstaging chemotherapy is still questioned and prognostic factors of outcome are lacking. METHODS: From February 1988 to December 2000, 1400 consecutive patients with CLRM were managed at a single institution. Of these, 295 [21%] were primarily resected from their CRLM and 1105 [79%] initially NR were treated by systemic chemotherapy [oxaliplatin or irinotecan regimens]. They were prospectively reviewed every three courses of chemotherapy by the same multidisciplinary team and surgery was reconsidered in case of documented response to chemotherapy when the operative strategy could remove all the tumoral tissue. In the group of patients resected after chemotherapy, 15 factors assumed to be predictive of survival [size, number and timing of metastases, main cause of initial non-resectability, tumour markers, type and duration of chemotherapy, of the operative procedure and pathology of the resected specimen] were evaluated by uni- and multivariate analysis. RESULTS: In the NR group, 139 ‘good responders’ [13%] were secondarily submitted to hepatic resection after an average of 10 courses of chemotherapy. CRLM were initially NR because they were too large [7%], ill-located [15%], multinodular [55%] or associated with extrahepatic tumour [22%]. One hundred and four procedures [75%] were major hepatectomies [≥3 segments]. Operative mortality within 2 months was 0.7% [1/139]. Tumour recurrence could be treated by repeat hepatectomy in 50 patients [36%] or pulmonary resection in 27 [19%]. After a mean follow up of 5.3±3.2 years, overall 5-year survival was 36% [median 39 months] and disease-free survival was 22%. Sixteen patients [12%] were disease-free >5 years after rescue surgery. Comparatively, 5-year survival of the 295 patients resected at once was 47% [p = 0.02]. At multivariate analysis, four preoperative factors were independently associated with decreased overall survival: a rectal primary, a number of metastases ≥3, a carbohydrate antigen [CA 19-9] level >100 UI/L and the presence of either peritoneal or lymph nodes concomitant metastases. Estimation of 5-year survival according to the presence of 0, 1, 2, 3 or 4 of these factors was respectively 60%, 35%, 15% and 2%. CONCLUSION: Chemotherapy allows 13% of patients with irresectable CRLM to be rescued by liver surgery with a 5-year survival of 36%. Four preoperative factors are able to predict long-term survival.

5 SURGICAL TREATMENT OF PANCREAS DIVISUM CAUSING CHRONIC PANCREATITIS: THE OUTCOME BENEFITS AFTER DUODENUM PRESERVING PANCREATIC HEAD RESECTION

Hans G Beger, University of Ulm, Ulm, Germany

Based on ERCP a pancreas divisum [PD] can be found in 1–6% of patients. The correlation of this abnormality with pancreatic disease is an issue of continuing controversy. Nevertheless, in some patients this abnormality can lead to recurrent acute pancreatitis [rAP] or chronic pancreatitis [CP]. We report of 36 patients [21 male, 15 female, mean age 37.9 years] with pancreas divisum in which the duodenum-preserving resection of the head of the pancreas [DPPHR] was carried out between 5/1982 and 2/2000. According to the classification of pancreas divisum, 10 patients demonstrated a complete PD, 25 a functionally incomplete PD and one a dorsal duct type. Histologically, 30 patients had chronic pancreatitis, 6 patients had recurrent acute pancreatitis without chronic pancreatitis. 97% of the patients suffered from upper abdominal pain. The preoperative pain score [visual analogue scale, VAS, [mean]] was 7.8 [CP] and 6.3 [rAP], respectively. 61% of the patients had endoscopic or surgical intervention prior to the DPPHR. There was no operative related mortality. Complications following DPPHR occurred in 28%, only 1 patient had to be reoperated. Follow-up [mean 39.3 month] was 100%, 4 patients died [1 suicide, 2 cancer of the oesophagus, 1 cardiac arrest]. 50% of the patients were completely pain-free, 31% had a significant reduction of pain with a mean pain score of 2 [VAS] [p < 0.002]. 6 patients [5 CP, 1 rAP] had further attacks of acute pancreatitis with need for hospitalisation [Table]. CONCLUSION: the DPPHR reduce pain and preserved the endocrine function in the majority of the patients with pancreas divisum. Therefore DPPHR should be the procedure of choice instead of other resective or drainage procedures.

CP [n=30]

rAP [n=6]

preop [n=30]postop [n=26]preop [n=6]Postop [n=6]Duration of symptoms [months]47.549.8Pain [VAS] score7.8*1.2*6.35.2Attacks of pancreatitis29pts5 pts6 pts1 pt[7 pt]*[3 pt]*[6 pt][2 pt]No diabetes75%61%75%63%OGTT impaired16%26%25%38%IDDM10%13%0%0%Endoscopic intervention26%62%Surgery *p4 cm in diameter were enrolled in this study. Preoperative cross-sectional imaging in combination with intra-operative ultrasound was used to identify the tumours. Patients were treated with MTA alone [n=4] or MTA with liver resection [n=7]. A total of 67 liver tumours was treated in this group of patients, 53 with MTA and 14 resected. The tumour types included metastases from colorectal cancer [n=6] and parathyroid carcinoma [1], hepatocellular carcinoma [2], adenoma [1] and carcinoid [1]. Two patients were treated laparoscopically, the remainder being treated at open surgery. The largest tumour was 6.5 cm in diameter, necessitating a single treatment of 4 min. Lesions 4–4.5 cm in diameter were treated in 3 min or less. Most ablations were carried out with a single insertion of the applicator. Complications, tumour recurrence and survival were recorded. RESULTS: Mean age was 61.4 years [range 30–79]. The mean tumour size was 5.0 cm [range 4.0–6.5] and the mean MTA treatment time was 4 min [range 2–7]. Six patients were alive at mean follow-up of 10 months [range 1–27, median 8]. There were no complications related to the MTA treatment. Two patients died of preexisting cardiac conditions in the postoperative period. Successful ablation was achieved in all patients, and no obvious tumour recurrence was visible at 3 months on imaging. At 1 year, two patients had hepatic tumour recurrence distant from the original ablation site and one patient developed extrahepatic disease at 27 months. CONCLUSIONS: Successful large volume ablation was achieved in all patients using this novel microwave equipment. This was accomplished using a rapid, single insertion technique comparing favourably with other currently available ablative modalities. It appears safe and effective with minimal complications.

60 RADIOFREQUENCY ABLATION VERSUS SURGICAL RESECTION FOR SINGLE HEPATOCELLULAR CARCINOMA: LONG-TERM OUTCOMES

Makoto Ogihara, Linda L Wong and Junji Machi, Department of Surgery, University of Hawaii School of Medicine, Honolulu, HI, USA

OBJECTIVES: Radiofrequency ablation [RFA] has been increasingly utilized for hepatocellular carcinoma [HCC]. Some believe the results are similar to those of surgical resection; however, no prospective controlled studies have been performed and such a study may be difficult to conduct. We, therefore, retrospectively reviewed patients with single HCC and compared the local control efficacy and long-term outcomes between resection and RFA. METHODS: From 1995 to August 2003, a total of 87 patients underwent resection [n=47] or RFA [n=40]. 36 patients with poor operative risk due to underlying liver dysfunction and 4 patients who refused resection underwent RFA. Each treatment arm was further divided into two subgroups based on tumor size. Group 1, resection, 30%; fibrosis, cirrhosis or non-icteric cholestasis] and 444 [62%] were major resections [≥3 segments]. In all patients serum bilirubin and prothrombin time [PT] were collected respectively on postoperative days [PD] 0, 1, 3, 5, and 7. Patients were classified as at risk of PLF when either serum bilirubin level was ≥50 µmol/L and/or PT ≤ 50%; the subgroup with both criteria was identified as the fifty-fifty criteria group. The mortality was considered during hospital stay. RESULTS: The overall postoperative mortality rate was 3.1%. Overall analysis of postoperative liver function tests showed that PT decreased to a minimum at PD1 and then regularly increased after PD3, while the peak of serum bilirubin level was observed on PD7. Therefore we analysed PLF on PD5 showing that bilirubin ≥50 µmol/L was present in 102 [14.3%] patients and a PT ≤50% in 42 [6%]. The simultaneous presence of bilirubin ≥50 µmol/L and PT ≤50% [fifty-fifty criteria] was observed in 25 cases [3.5%] with a mortality rate of 44%. The mortality rate of patients with only one or none of these criteria was highly significantly lower [p50 µmol/L and PT 10cm], following a right hepatic lobectomy. These were treated by RFA. Immediate post-treatment images showed the RFA bed to be hyperintense on T1-weighted [T1W] images and hypointense on T2W images. In two patients [patients 2 and 4], the post-treatment iMRI findings significantly altered management, as additional applications of RFA were required to completely encompass the target lesions. Our initial experience identified several technical factors that will require development. Specifically, the left and anterior aspects of the liver are suboptimally visualized; large patients are not easily imaged; and digital subtraction images are essential. These ongoing pilot studies have identified the problems with the present technology. Our findings will determine the direction of future development.

68 COMPARING SURVIVAL RATES OF HEPATIC ARTERIAL CHEMO-EMBOLIZATION FOR HEPATOCELLULAR CARCINOMA WITH DIFFERENT EMBOLIC AGENTS: GELFOAM AND POLYVINYL ALCOHOL

Christopher E Fundakowski, Daniel B Brown, Michael D Darcy, Mauricio Lisker-Melman, Thomas K Pilgram, William C Chapman and Jeffrey S Crippen, Washington University, St. Louis, MO, USA

PURPOSE: To compare survival rates of patients who have undergone hepatic artery chemo-embolization [HACE] with either gelfoam powder [GP] or polyvinyl alcohol [PVA] particles and ethiodol for hepatocellular carcinoma. MATERIALS AND METHODS: HACE was performed on 83 patients who underwent HACE using 50 mg cisplatin, 20 mg adriamycin, and 10 mg mitomycin-C with either GP [n=44] or 300–500 mem PVA and ethiodol [n=39]. Length of patient survival was calculated from the patient's first HACE procedure. Transplant recipients were censored at the time of surgery. CTP and MELD scores were calculated for both groups. All patients were categorized as either alive or deceased at time periods of 3, 6, 12, and 24 months. Survival differences were tested for statistical significance with the log rank test. All categorical and patient survival data were analysed using product-limit [Kaplan–Meier] survival analysis. Fisher exact tests were used to test patterns for statistical significance. RESULTS: Mean and median CTP and MELD scores were similar [p=0.35 CTP, p=0.13 MELD] for each group. Overall mean and median patient survival was 23.9 and 17 months. Mean and median survival with GP was 25.4 and 18 months, while with PVA it was 9.8 and 14 months. The difference in mean survival was not significant [log rank test, p=0,27]. Mortality within 30 days occurred in one GP patient [liver failure] and two PVA patients [variceal bleed, sepsis]. A greater percentage of GP patients were alive at 3, 6, 12, and 24 months. The differences in survival between groups approached statistical significance at 6 and 12 months and were significantly greater at 24 months. CONCLUSIONS: Whole group mean and median survival were not significantly different based upon the embolic agent used. Patients who survived past 12 months had a survival advantage when embolized with GP.

Outcomes

Embolic agent3-month survival6-month survival12-month survival24-month survivalGelfoam41/44 [93%]35/42 [83%]25/39 [64%]8/28 [29%]PVA31/39 [79%]21/33 [64%]10/26 [38%]0/17 [6%]Fisher exact testp=0.10p=0.06p=0.07p=0.02

69 A MODIFIED COMBINED PERCUTANEOUS TRANSHEPATIC AND ENDOSCOPIC TRANSPAPILLARY TECHNIQUE FOR DIFFICULT CANNULATION OF BILE DUCT

Wen Li, Enqiang Lighu, Zhiqiang Wang, Fengchu Cai, Xiangdong Wang, Hong Du, Jiangyun Meng, Liufang Cheng and Yunsheng Yang, General Hospital of the Chinese People's Liberation Army, Beijing, China and Department of Gastroenterology, Beijing, China

BACKGROUND: Morbidity and mortality remain high for combined percutaneous and endoscopic procedures to approach the bile duct when endoscopic deep cannulation of the bile duct fails. AIMS: To modify the combined percutaneous and endoscopic procedures in order to decrease the procedure-related morbidity and mortality. PATIENTS AND METHODS: Sixteen consecutive patients with malignant biliary obstruction or benign biliary stenosis with stones underwent attempted endoscopic biliary therapy using a modified combined percutaneous transhepatic and endoscopic transpapillary approach. All patients had had failed endoscopy-alone procedures and had contraindications to surgery. The indication was palliation of malignant biliary obstruction in 15 cases [8 common bile duct, 7 hilar], assistance with sphincterotomy for the removal of common bile duct stones and management of benign biliary stenosis in 1 case. The first procedure was percutaneous transhepatic access to the biliary tree guided under colour Doppler ultrasound. Subsequent attempts were to introduce a guidewire or a cannula through the cannula or the guidewire into the duodenum. A duodenoscope is then positioned in the duodenum immediately after the percutaneous procedures. Lastly the wire or the cannula from the percutaneous transhepatic access guided [‘kiss’] the endoscopic catheter or wire to access the common bile duct. There is no need to grasp and extract the guide wire perorally. RESULTS: The percutaneous transhepatic access to the biliary tree was successful in all cases [100%]. Subsequent attempts via common bile duct and papilla access to the duodenum were successful in all but two cases [88%]. Twelve of the 14 patients [86%] then had successful cannulation and stent placement by the modified combined percutaneous-transhepatic and peroral-endoscopic procedures [kiss technique]. Procedure-related morbidity and mortality were 6% and 0% respectively. CONCLUSION: The modified combined percutaneous and endoscopic procedures [kiss technique] to approach the bile duct showed a very low procedure-related morbidity and mortality.

MeasureLevel3-month survival6-month survival12-month survival24-month survivalCTPHigh [≥7]28/37 [76%]20/33 [61%]10/29 [34%]1/21 [5%]Low [≤6]45/47 [96%]37/43 [86%]26/37 [70%]7/24 [29%]p=0.01p=0.02p=0.01p=0.05Fisher exact test MELDHigh [≥11]31/39 [79%]23/35 [66%]15/32 [47%]3/23 [13%]Low [≤10]42/45 [93%]34/41 [83%]21/34 [62%]5/22 [23%]Fisher exact testp=0.10p=0.11p=0.32p=0.46

70 A PALLIATIVE TREATMENT OPTION FOR UNRESECTABLE CHOLANGIOCARCINOMA – INITIAL EXPERIENCE WITH TRANSCATHETER ARTERIAL CHEMO-EMBOLIZATION [TACE] IN A SINGLE INSTITUTION

Ingrid Burger, Kelvin Hong and Jean-Francois Geshwind, Johns Hopkins Hospital, Baltimore, MD, USA

PURPOSE: Unresectable cholangiocarcinoma carries a dismal prognosis with median survival ranging from 6 to 12 months. Palliative treatment options have been disappointing and have not been shown to significantly prolong survival. Transcatheter arterial chemo-embolization [TACE] has been quite effective in prolonging the life of patients with primary and some secondary liver cancer but has not readily been used against cholangiocarcinoma. Thus, the purpose of our study was to assess the impact of TACE on the survival of patients with unresectable, intrahepatic cholangiocarcinoma. METHODS: Fifteen patients with unresectable cholangiocarcinoma were treated with one or more rounds of TACE between 1995 and 2003 at our institution. Follow-up MR imaging was performed on all patients at 4–6 weeks after each TACE to determine tumor response and need for further treatment. Survival was calculated using the Kaplan–Meier survival curve. RESULTS: The median survival for 15 patients treated with TACE was 20 months [12–28 months, 95% CI]. Follow-up MR imaging demonstrated 25–75% tumor necrosis in a majority of patients. Two patients who were previously determined to have unresectable tumors were actually able to be resected following TACE treatments and tumor shrinkage. Complications immediately following TACE treatment occurred in a minority of patients and included transient nausea, vomiting, diarrhea, hypertension, tachycardia, and right upper quadrant pain. A majority of these complications were managed with conservative therapy alone. CONCLUSIONS: Our results suggest that TACE was effective at prolonging survival of patients with unresectable cholangiocarcinoma. It was also generally well tolerated and, when compared to other therapies, TACE offered the advantage of a minimally invasive approach. TACE may therefore be an appropriate and promising palliative therapeutic option for patients with cholangiocarcinoma.

71 COMPARISON OF MELD AND CTP SCORES TO PREDICT SURVIVAL FOLLOWING CHEMO-EMBOLIZATION FOR HEPATOCELLULAR CARCINOMA

Christopher E Fundakowski, Daniel B Brown, Michael D Darcy, Mauricio Lisker-Melman, Jeffrey S Crippen, Thomas K Pilgram and William C Chapman, Washington University, St Louis, MO, USA

PURPOSE: To compare the value of the Model for End-stage Liver Disease [MELD] and Child-Turcotte Pugh [CTP] scores to predict patient survival rates from hepatic artery chemo-embolization [HACE] for hepatocellular carcinoma [HCC]. MATERIALS AND METHODS: Eighty-seven patients underwent 169 HACE sessions. MELD and CTP values were calculated prior to the initial treatment. MELD and CTP scores were placed in high and low categories about their respective medians, with the low category including the median score. Patient survival was tracked at 3, 6, 12, and 24 months, and log rank tests were used to determine statistical significance within the survival differences. Survival length was tracked from the date of the first HACE. Transplant recipients were censored at the time of surgery. RESULTS: Mean and median survival for all patients was 24 and 17 months. Sixteen patients were censored for transplant at a mean of 12.9 months. MELD and CTP scores correlated well to each other [r = 0.68]. CTP score [r = − 0.35, p = 0.04] correlated more strongly to survival than MELD [r = − 0.26, p = 0.12]. After high/low score category division, a statistically greater survival difference was predicted by CTP [27.2 vs 10.3 months, p = 0.03] than MELD [27.5 vs 15.8 months, p = 0.19]. Survival differences between high and low risk groups at the 3-, 6-, 12-, and 24-month intervals are displayed in the Table above. CTP scoring showed the difference between high and low groups to be statistically significant for all time periods. Statistical significance was not approached for any of the time lengths with the MELD system. CONCLUSIONS: CTP correlates better than MELD to overall patient survival and is a better predictor than MELD of survival at specific time points.

Aetiology1 RFA>1 RFAFall AFPRapid progression 1 yearDied 0.05]. CONCLUSIONS: T1 ampullary cancer had a good prognosis, but relatively high recurrence rate [16.9%] even after pancreatoduodenectomy. Moreover, when the recurrence developed, it had a dismal result. Not a few patients with T1 ampullary cancer had, not confined to ampulla, lymph node metastasis, perineural invasion, and CBD or P-duct involvement, which could not be predicted. Therefore, ampullectomy for T1 ampullary cancer cannot be an alternative operation to pancreatoduodenectomy because of the possibility of high recurrence rate and pancreatoduodenectomy should be preferably performed for adequate radical resection.

94 IMPROVED RESULTS OF RESECTION OF HILAR CHOLANGIOCARCINOMA [KLATSKIN TUMORS]: A SINGLE-CENTER, 15-YEAR EXPERIENCE

Sander Dinant, Michael F Gerhards, Olivier RC Busch, Hugo Obertop, Dirk J Gouma and Thomas M Van Gulik, Academic Medical Center, Amsterdam, The Netherlands

BACKGROUND: Radical resection of hilar cholangiocarcinoma [HC] is difficult due to its proximal infiltration into the biliary tree and its frequent involvement of the bifurcation of the portal vein. In the mid-1990s, several studies showed improved results of more aggressive resection of HC in combination with extended liver resection and portal vein reconstruction. Based on these results, we changed our treatment strategy towards performing more resections in combination with [extended] hemihepatectomy, with particular emphasis on complete excision of segment 1 and with reconstruction of the portal vein when necessary. The aim of this study was to assess the outcome of this changed strategy in terms of postoperative morbidity and mortality, microscopical tumor clearance and patient survival. METHODS: A total of 99 patients underwent surgical resection of HC in a 15-year period [1988–2002]. The patients were divided into 3 groups, according to 5-year intervals: group 1 [1988–1993, n=45, mean age 60.6±1.7 years], group 2 [1993–1998, n=25, mean age 58.1±2.3 years] and group 3 [1998–2003, n=29, mean age 60.7 ±2.1 years]. Proximal infiltration of HC was classified according to the Bismuth-Corlette system [I–IV] on the basis of preoperative imaging studies. Patients routinely received postoperative radiotherapy [55 Gy]. RESULTS: Compared with group 1, there were significantly more patients with type III and IV tumors in groups 2 and 3 [38%, 64% and 72% in group 1, 2 and 3, respectively, p100 ng/ml in the presence of a radiographically malignant stricture. Neoadjuvant therapy included external beam irradiation with radio-sensitizing bolus 5-FU chemotherapy, followed by a transcatheter Iridium-192 brachytherapy boost and either intravenous 5-FU or oral capecitabine therapy. A staging abdominal exploration with biopsy of regional hepatic lymph nodes was performed as close as possible to the time of transplantation, and patients with regional hepatic lymph node meta-stases or extrahepatic disease were excluded from OLT. We compared results after OLT with results for patients who underwent potentially curative conventional resection [extrahepatic bile duct including the bifurcation and hepatic resection] at our institution during the same time period. All resection patients had negative margins and absence of regional lymph node metastases. RESULTS: Seventeen patients were enrolled in the transplant protocol, had negative staging operations, and underwent OLT. 20 patients had negative regional lymph nodes and underwent potentially curative resection. CONCLUSIONS: Neoadjuvant therapy and liver transplantation achieved significantly better survival than resection for patients with hilar CCA. Liver transplantation with neoadjuvant therapy has emerged as an effective treatment for patients with localized, regional lymph node-negative, hilar cholangiocarcinoma.

n1 year3 years5 yearsResection2085±751±1230±12Transplantation survival from beginning of neoadjuvant therapy1794±682±982±9Transplantation survival from transplantation1788±882±982±9

122 OUTCOME AFTER PANCREATODUODENECTOMY FOR TUMOR IN PATIENTS WITH BILE DUCT POSITIVE CULTURE

Alexandre Cortes, Reza Kianmanesh, Alain Sauvanet, Sylvie Janny, Philippe Sockeel, Philippe Ruszniewski and Jacques Belghiti, Beaujon Hospital, Clichy, France

From 2002 to 2003, 79 patients underwent pancreatoduodenectomy [PD] for periampullary tumors. All received i.v. antibioprophylaxis [cefazo-lin + metronidazole] and had routine bacteriological examination of the gallbladder and/or bile duct. Thirty-five patients had infected bile [B+ group] and were compared with 44 patients with sterile bile [B− group]. The 2 groups were comparable for age, ASA, tumor size and pancreas consistency [soft/hard] and the type of tumors except for ampullomas which were more common in B+ [26 vs 2%, p = 0.001]. Preoperative instrumental and non-instrumental biliary endoscopic procedures had been performed in 80% of patients in B+ vs 14% in B− [p < 0.001], including 9 isolated sphincterotomies [20 vs 5%, p < 0.03] and 20 endoprosthesis insertions [57 vs 0%, p < 0.0001]. Serum bilirubin level was lower in B+ [p < 0.05]. Operative time and blood loss were similar in both groups. One patient died postoperatively [B + ]. The rate of pancreatic fistula was similar in both groups. Overall morbidity was increased in B+ [77 vs 59%, p = 0.05]. Postoperative infectious complications [all proven] included superficial wound infections [26 vs 5%, p = 0.005], intraperitoneal infectious collections [23 vs 7%, p = 0.035], and pneumonia [14 vs 2%, p = 0.045]. To treat infectious complications, antibiotics [>7 days] were more often given in B+ [71 vs 43%, p = 0.012]. In bile culture, the 3 most frequent bacteria were Escherichia coli, Enteroccocus faecalis and Klebsiella pneumoniae. Among B+ patients, bile contained at least 2 micro-organisms in 54%, and in 94% micro-organisms were resistant to cefazo-lin + metronidazole. In patients with infectious complications, the same micro-organism was isolated in bile and another sampling in 49%. Microorganisms isolated in bile were susceptible to the combination of piperacillin + tazobactam in 66% of patients. In B−, bile sterility was definitively established after a 48-h culture, except in one patient. In patients undergoing PD, bile infection in 80% of cases is related to previous instrumental biliary endoscopic procedures. Micro-organisms found in bile culture were [i] resistant to cefazolin + metronidazole in 94% of cases [used as antibioprophylaxis], [ii] multiple in 54%, and [iii] responsible for an increased rate of infectious complications [superficial and deep].

123 LAPAROSCOPIC PANCREATIC RESECTION: A SINGLE INSTITUTION EXPERIENCE WITH 30 PATIENTS

Alexandre Rault, Antonio Sa Cunha, Christophe Laurent, Dominique Larroudé, Frederic N Dobo Epoy, Denis Collet and Bernard Masson, CHU Bordeaux, Pessac, France

BACKGROUND: Potential applications of laparoscopy in pancreatic surgery include pancreatic reaction for benign disease: cystic lesions and insulinomas. We report a single institution series of 30 patients who presented pancreatic benign tumor treated by laparoscopy. RESULTS: All presented pancreatic benign turn patients were operated at the Bordeaux University Hospital between 03/ 1999 and 05/2003. The median age was 45 [26–72]. Our conversion rate was 13% [4 cases: one undetectable cephalic insulinoma, one undetectable corporeal insulinoma, bleeding, and the last one for technical problem]. In 26 patients [87%], the entire procedure was performed by laparoscopy. 12 patients had undergone an enucleation [10 insulinomas, 1 serous cystadenoma, 1 mucinous cystadenoma], 3 patients had a distal pancrea-tectomy [2 insulinomas, 1 included spleen] and 7 patients underwent a left pancreatectomy [3 mucinous cyatadenoma, 1 serous cystadenoma, 1 cystic tumor and 1 insulinoma, 1 gastrinoma], 2 patients had a spleno-pancreatectomy [1 malignant insulinoma and 1 mucinous cystadenoma] and one patient had a total duodeno-pancreatectomy [mucinous poly-cystadenomatosis]. One other patient underwent a median pancreatectomy with pancreatico-gastric anastomosis [mucinous cystadenoma]. The median operating time was 140 min [60–80 min] and median intraoperative blood loss was 250 ml. Morbidity rate was represented by 3 pancreatic leakage [10%], a postoperative bleeding [reoperation] and a partial splenic ischemia [no reoperation]. There were no deaths. Mean hospital stay was 12 days. CONCLUSION: Laparoscopic surgery for benign lesions, especially left pancreatectomies, appears to be a safe procedure.

124 REDUCING PANCREATIC DUCT LEAK AND HEMORRHAGE DURING LAPAROSCOPIC DISTAL PANCREATECTOMY AND PARTIAL SPLENECTOMY USING STAPLE LINE REINFORCEMENT WITH AN ABSORBABLE POLYMER MEMBRANE

Esther C Consten, Michel Gagner, Luca Milone and Sergio Bardaro, New York Presbyterian Hospital, Weill Cornell University, New York, NY, USA

BACKGROUND: Laparoscopic distal pancreatectomy is not performed without significant risk. Bleeding may occur in 0.5–36% of patients. Perioperative complications like pancreatic duct leaks and fistula formation are reported in 16–23% of cases. AIM: A new technique of staple line reinforcement with an absorbable polymer membrane was tested in an animal model to investigate a reduction of perioperative hemorrhage and leaks after pancreas resections. MATERIALS AND METHODS: Twenty female 40-kg pigs underwent laparoscopic distal pancreatectomy and partial splenectomy in the present prospective animal survival study. In 10 consecutive animals [group A], a staple line reinforcement technique with an absorbable polymer membrane, which buttresses the resection site, was used for transection. A conventional stapler without buttressing was used to transect the pancreas and spleen in a control group of 10 animals [group B]. Necropsy was performed: pancreas and spleen were sent for histopathology after 6 weeks. RESULTS: Operative data did not differ between the two groups. Operative time was 118 minutes in group A and 116 minutes in group B. Peroperative blood loss after distal pancreatectomy [5±1 ml vs 75±5 ml] was significantly higher in group B [p < 0.04]. Significantly higher bleeding rates were also encountered after partial splenectomy in group B [45±7 ml vs 215±12 ml] [p < 0.01]. Mortality in group B was 10%. There was 1 death in group B [10%] due to extensive postoperative bleeding at the staple line region of the spleen. A retrogastric fluid collection with elevated amylase levels was encountered in 1 animal [10%, group B]. At necropsy, results showed in group A, that reinforcement material was absorbed completely and no local inflammatory reactions or fibrosis in duodenum, stomach or colon could be demonstrated. Minimal adhesions were encountered in both groups. Histopathology results showed fibrotic changes and injury to vessels and pancreatic duct only in group B. Methylene blue test demonstrated a leak of the pancreatic duct at the transection site only in 2 cases of group B. No leaks or damage were encountered in group A. CONCLUSION: The results of the present study show that this staple line reinforcement technique with the absorbable polymer membrane reduces staple line hemorrhage and pancreatic duct leakage after distal pancreatectomies. This study supports future application of absorbable buttress material for pancreatic transection and partial splenectomy in humans. This may result in diminishing perioperative complications such as bleeding and pancreatic leaks.

125 LAPAROSCOPIC RESECTION OF PANCREATIC NEUROENDOCRINE TUMORS

Michael F Daily, Robert E Glasgow, Kathryn F Hatch, Courtney L Scaife and Sean J Mulvihill, University of Utah, Salt Lake City, UT, USA

Pancreatic neuroendocrine tumors are rare neoplasms with variable biologic behavior. Conventional treatment involves open exploration with enucleation or resection. We describe a series of nine consecutive patients with pancreatic neuroendocrine tumors treated laparoscopically at a university hospital between September 2001 and November 2003. Diagnoses include five patients with insulinoma, two with gastrinoma, one each with ampullary carcinoid and non-functioning islet cell tumor. All lesions were successfully localized by surgeon-performed, intraoperative laparoscopic ultrasonography. All patients with insulinoma were treated by enucleation and were cured. One gastrinoma patient underwent successful laparoscopic enucleation with node dissection but recurred, requiring open reoperation. The tumor in a second gastrinoma patient could not be localized, requiring conversion to laparotomy with transduodenal excision. The patient with ampullary carcinoid was successfully treated by laparoscopic transduodenal excision, but recurred 12 months later and required open pancreaticoduodenectomy for cure. The non-functioning islet cell tumor was cured with laparoscopic distal pancreatectomy. Mean [SEM] operating time was 201 [21] minutes. Mean [SEM] length of stay was 7.3 [2.3] days. Major morbidity included pancreatic leak in three of nine patients, all treated successfully with percutaneous drainage. One patient required readmission for bleeding from a Mallory Weiss tear. There were no deaths. Laparoscopic resection of pancreatic neuroendocrine tumors represents a technically challenging, but feasible alternative for treatment of these rare tumors. Success depends on accurate preoperative biochemical diagnosis, use of intraoperative ultrasound for localization, and patient selection. Lesions most suitable for a laparoscopic approach are solitary, benign lesions that are amenable to enucleation or limited pancreatectomy.

nSensitivity [%]Specificity [%]Accuracy [%]Positive predictive value [%]Negative predictive value [%]Angiography1195093893895EUS837086844195

126 COMPARISON OF MESENTERIC ANGIOGRAPHY AND ENDOSCOPIC ULTRASOUND FOR DETECTION OF PORTAL VEIN INVASION IN PATIENTS UNDERGOING PANCREATICODUODENECTOMY

Jonathan F Finks, James P Dolan, Douglas O Faigel, John G Hunter and Brett C Sheppard, Oregon Health & Science University, Portland, OR, USA

METHODS: We performed a retrospective review of the medical records, preoperative studies, operative notes and pathology reports of 152 consecutive patients undergoing pancreaticoduodenectomy from April 1994 through December 2003. In 21 cases, no preoperative studies were available for review, and these patients were excluded from the study. Results of preoperative studies were compared to operative and histo-pathologic findings when available. Criteria for portal vein [PV] invasion on preoperative imaging studies included loss of interface, encasement or intraluminal mass. Operative findings of tumor invasion, or adherence to the PV without a surgical plane, were accepted as invasion unless disputed by pathologic findings. RESULTS : 131 patients were included in this study. Results were available from angiography in 119 and endoscopic ultrasound [EUS] in 83 patients. Six patients underwent PV resection for suspected invasion. In 3 of these cases, an assessment of PV involvement was not included in the pathology report. In 1 case, there was no tumor invasion and in 2 cases, the final diagnosis was pancreatitis. Final pathologic diagnoses were pancreatic cancer [48], ampullary/duodenal cancer [27], cholangiocarcinoma [8], islet cell tumor [6], pancreatitis [13], benign lesion [28], and metastatic cancer [1]. Operative findings indicated PV involvement in 13 cases. Study results are presented in the Table above. When results of angiography and EUS concurred [56 patients, 79%], the positive and negative predictive values for the combined tests improved to 75% and 98%, respectively. CONCLUSIONS : While neither test reliably predicted PV invasion in this group of patients selected to undergo a Whipple procedure, angiography and EUS were both highly effective in ruling out PV involvement. As EUS offers the added benefits of tissue diagnosis and lymph node staging, and can be paired with therapeutic endoscopic intervention, it should remain the study of choice following CT scan. In cases where EUS is equivocal with regard to PV involvement, or when planning PV resection, angiography may provide valuable information.

127 SYSTEMATIC APPRAISAL OF THE EVIDENCE FOR SYNCHRONOUS PORTAL/SUPERIOR MESENTERIC VEIN RESECTION AT PANCREATICODUODENECTOMY

Priyantha Siriwardana and Ajith K Siriwardena, HPB Unit, Department of Surgery, Manchester Royal Infirmary, Manchester, UK

INTRODUCTION: Tumour clearance at pancreaticoduodenectomy [PD] may be enhanced by en bloc resection of the portal/superior mesenteric vein [PV/SMVR]. However, vein resection is associated with increased peri-operative risks. Almost all available data come from cohort series and there is no clear consensus on which patients [if any] benefit from PV/ SMVR and on overall outcome. The aim of this study was to undertake a systematic review of the available evidence on PV/SMVR to obtain an overview of procedure-related complications and outcome from pooled cohort data. METHODS: A computerised search of the MEDLINE database was conducted for the period between 1996 and 2002 using the keywords ‘pancreatic cancer’ and ‘portal vein’. The bibliographies of articles retrieved from this search were manually cross-referenced to identify further articles. For each MEDLINE citation, the title, abstract, authors, institution, journal, major and minor descriptors were downloaded. The search identified 514 abstracts. Non-English, animal studies, reviews and reports were excluded [383]. Of the remaining 131 articles, a further 88 were excluded due to no data on outcome of PVR, leaving 43 articles. When 19 sequential reports/double publications were excluded, there were 24 non-duplicated datasets which comprised the study population. RESULTS: There were 952 PV/SMVR [39%] of 2462 patients undergoing pancreaticoduodenectomy. Overall operative details and outcome data are expressed as median [range] in the Table. In-hospital mortality of PV/SMVR in the pooled cohort was 38 [4%] and, 1-, 2-, 3- and 5-year survival were 38%, 15%, 12% and 7.5%, respectively. CONCLUSION: The results of pooled data suggest that synchronous portal vein resection may be carried out with pancreaticoduodenectomy with a relatively low per-operative morbidity but without convincing evidence of any survival benefit.

MedianRangeNo. of PV/SMVR per series313–172Duration of accrual [months]11548–239Operating time [minutes]517168–955Portal vein occlusion time [minutes]578–302Blood loss/transfusion [ml]2800300–20,000Length of vein resected [cm]40.8–10Hospital stay [days]198–125Morbidity/complications32%12–55%

128 SURVIVAL BENEFIT OF EXTENDED PANCREATICODUODENECTOMY FOR A LIMITED GROUP OF PATIENTS WITH PANCREATIC HEAD CANCER

Sonshin Takao, Hiroyuki Shinchi, Kousei Maemura, Hiroshi Kurahara, Yuukou Mataki and Takashi Aikou, Kagoshima University, Kagoshima, Japan

OBJECTIVES: Whether an extended pancreaticoduodenectomy can bring about a survival benefit for the patient with pancreatic head cancer is still controversial. METHODS: 101 patients underwent a pancreatectomy for pancreatic head cancer between 1980 and 2001. 40 patients in the extended resection [ER] group had an extended lymphadenectomy and neural plexus dissection, while 61 patients in the conventional resection [CR] group did not have these extended procedures. Tumor status, morbidity, mortality, survival, recurrent type, and micrometastasis of the lymph node were retrospectively studied and compared between both groups. RESULTS: Morbidity and mortality were not associated with an extended resection. The incidence of R0 operations in the ER group was higher when compared with that in the CR group [p < 0.01]. The actuarial 5-year survival rate [30.6%] of patients with pStage IIA or IIB in the ER group was significantly higher than that [8.2%] in the CR group [p = 0.04] because local recurrence [47%] in the CR group was higher than that [25%] in the ER group [p=0.02]. In immunohistochemical study of micrometastasis as isolated tumor cells [ITC] according to TNM Classification [6th edn], the survival time of pN0[i − ] patients was significantly better than that of pN0[i + ] or pN1. CONCLUSION: An adequate extended resection might be required for survival benefit of patients with pStage IIA or IIB pancreatic head cancer.

129 PREDICTORS OF PANCREATICOENTERIC ANASTOMOTIC LEAK OR FISTULA AND EFFECT ON PATIENT OUTCOMES FOLLOWING PANCREATICODUODENECTOMY

C Max Schmidt, Emilie Powell, Eric A Wiebke, Thomas J Howard, Constantin T Yiannoutsos, At Nakeeb, Keith D Lillemoe and James A Madura, Departments of Surgery and Departments of Biostatistics, Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

BACKGROUND: Despite advances in the care of patients undergoing pancreaticoduodenectomy [PD], pancreatic fistula [PF] continues to be a common complication. We conducted a retrospective review of a prospectively collected database at an academic, tertiary care hospital to determine predictors of PF following PD and the effect of PF on patient outcomes. 516 consecutive patients underwent PD Between 1980 and 2002. RESULTS: Pancreatic fistula occurred in 46 patients [9%] with a mean age of 57 years. 72% of the patients were male. The frequency of PF by pathology was: 10% periampullary adenocarcinoma [23% duodenal, 17% ampullary, 13% bile duct, 6% pancreatic], 4% pancreatitis, 8% cystic neoplasms, 16% islet cell neoplasms, and 25% trauma. Patients presenting symptoms, signs and preoperative labs were not predictive of PF. Peri-operative factors associated with PF are shown in the Table below. OUTCOME: 45 of 46 PF closed spontaneously and one patient required operative revision of the pancreaticojejunostomy. Perioperative mortality was 0% in patients with PF. Patients developing a PF showed a significantly higher incidence of wound infection [15% vs 4%, p < 0.005] and general septic complications [21% vs 5%, p < 0.005]. Median length of stay [25 vs 12 days] and reoperation rate [15% vs 2%] were also significantly higher in these patients [p < 0.005]. In the periampullary adenocarcinomas there was a trend towards improved patient survival for patients with PF [3-year survival 48% vs 25%, p = NS] in the group and according to specific periampullary adenocarcinoma subtype. Correspondingly, there was no difference in size, differentiation, margin status or node status in patients with or without fistulas. CONCLUSIONS: The development of pancreatic fistula following PD is predicted by pathologic subtype, likely reflecting the texture of the gland. Other predictors of PF include invaginated anastamosis and the use of closed suction drainage. Outcomes in patients with PF are remarkable for longer hospital stay and higher septic complications but no significant difference in survival or mortality.

130 THE UNSOLVED PROBLEM OF PANCREATIC FISTULA AFTER LEFT PANCREATECTOMY

Gianpaolo Balzano, Alessandro Zerbi, Paolo Veronesi, Marco Polese, Marco Cristallo and Valerio Di Carlo, Pancreas Unit, Department of Surgery, San Raffaele Hospital, Milan, Italy

BACKGROUND: Pancreatic fistula is a frequent complication of left pancreatectomy. Its severity is lower than fistula following pancreaticojejunostomy; however, it may prolong postoperative stay and causes discomfort for patients, who need to keep a drain tube for several weeks. In this study we compared the results of different techniques to close the proximal pancreas during left pancreatectomy. DESIGN AND PATIENTS: Retrospective review of prospectively collected data about 122 patients who have undergone left pancreatectomy since 1996 at our Institution. Pancreatic closure was accomplished by a hand-sewn technique [32 pts] or two kinds of mechanical staplers: until 2001 the linear stapler Proximate TL™ [50 pts]; then the Endo GIA II™ stapler [40 pts]. The choice of technique was not randomised. Operative results in these groups were compared. Further factors that were considered in the uni- and multivariate analysis were: identification of the pancreatic duct with separate suture ligation, hand-sewn suture in addition to stapling closure, spleen preservation, use of PTFE pledgets for reinforcing the suture, sex, age, indication for pancreatectomy, associated diseases. Fistula was defined as a drain output >5 ml with amylase level 5 times higher than the serum value after day 5. RESULTS: Overall mortality was 0%, morbidity was 47%, pancreatic fistula rate was 33%, mean±SD postoperative stay was 12±7 days. All fistulas healed spontaneously [mean duration 54 days]. Fistula rate was 34% after hand-sewn closure, 26% after linear stapler closure and 42% after Endo GIA II stapler closure [p = NS]. None of the factors considered in the analysis proved to reduce significantly the onset of fistula. The best result was obtained in 13 patients with pledget suture [fistula rate 15% vs 36%, p = 0.07]. Also spleen preservation [28 patients] seemed to be a protective factor [fistula rate 21% vs 37%, p = 0.12]. Main duct ligation [46 patients] had no significant effect [30% vs 35%, p = 0.5]. At the multivariate analysis no factor significantly influenced fistula onset. CONCLUSION: Pancreatic fistula after left pancreatectomy remains an unsolved problem. Mechanical closure of the pancreas did not reduce the onset of fistula. The use of pledgets to reinforce the suture is advisable.

Operation

Anastamosis

Drains

Bowel prep

Preoperative stent

PPPDClassicDuct–mucosaInvaginatedPenroseSuctionYesNoYesNon2632523455624427222631211304% PF11%7%7%21%3%14%6%19%9%8%p valueNS20% of the samples. A total of 398 genes satisfied these analysis criteria for differential expression between the two groups [200 genes over-expressed and 198 genes under-expressed]. These are principally genes involved in the key processes of cell adhesion, angiogenesis and growth factor-induced tumour proliferation. We have identified a highly significant and consistent gene expression signature of liver metastases detected within 12 months of the primary. These genes are pivotal in biological pathways associated with metastasis and may be responsible for the observed aggressive phenotype. Further work to evaluate the use of these genes as potential molecular markers or therapeutic targets is required.

173 DOES PRE-OPERATIVE CHEMOTHERAPY HAVE AN EFFECT ON HEPATOCYTE METABOLISM?

James C Hewes, Amanda J Woodrooffe, Barry J Fuller and Brian R Davidson, Academic Division of Surgical Specialities, London and Pharmagene Laboratories Ltd, Royston, UK

INTRODUCTION: Whilst it is well established that locoregional chemotherapy directed at colorectal liver metastases causes hepatocyte damage, little is known of the effects of systemic chemotherapy on the normal liver. With the advent of new chemotherapeutic agents such as oxaliplatin and irinotecan which are specifically used in the neoadjuvant setting, it is important that any detrimental effects on hepatocytes are documented. Anecdotal evidence from liver surgeons suggests that there is a change in the parenchyma following systemic chemotherapy. This study was therefore undertaken in an attempt to establish the differential function of isolated hepatocytes taken from resected livers which have either been exposed to preoperative chemotherapy or not. METHODS: 41 patients undergoing hepatectomy for colorectal metastases between 1999 and 2003 were recruited. The patients were arranged into 4 groups according to their preoperative chemotherapy status: neoadjuvant oxaliplatin [n=10]; neoadjuvant 5-fluorouracil [5FU] [n=7]; adjuvant 5FU [n=17] or no chemotherapy [n=7]. Hepatocytes were isolated from sections of normal liver parenchyma taken from the region of the resected mass most distant from the tumour using a modified two-step collagenase perfusion technique. The initial cell viability and cell yield were calculated using trypan blue dye exclusion. The metabolism of 8 different compounds was then calculated using the rate of disappearance of the parent compound and the production of a specific metabolite over a 2-h time course. This reflected the function of individual CYP enzymes. Non-parametric statistical tests were then applied to the data in order to determine significance. RESULTS: When all 4 groups were compared it was seen that there were no significant differences in the initial cell viability and viable cell yield. There was also comparable metabolism of 7-ethoxycoumarin, testosterone, diclofenac, bufuralol, s-mephenytoin, coumarin, chlorzoxa-zone, midazolam and 7-hydroxycoumarin, reflecting the function of CYP 1A2, 3A4, 2C9, 2D6, 2C19, 2A6, 2E1,3A4, UGTand SULT, respectively. CONCLUSION: It is therefore seen that the administration of neoadjuvant systemic chemotherapy has no detrimental effect on the function of normal hepatocytes isolated at the time of surgery. This has implications for both the surgeon and oncologist with respect to treatment regimens, surgical technique and postoperative liver function.

174 CAUDATE HEPATECTOMY FOR CANCER: A SINGLE INSTITUTION EXPERIENCE WITH 146 PATIENTS

William G Hawkins, Michael S Cohen, William R Jarnagin, Yuman Fong, Michael D'Angelica, Ronald P Dematteo and Leslie H Blumgart, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

PURPOSE: Caudate lobe resection is technically demanding with the disparate goals of preserving major vascular and biliary anatomy without compromising tumor clearance. Herein, we assess our results with caudate resection for malignant disease. METHODS: From 1992 to 2003, we performed caudate resection for malignancy in 146 patients. Clinicopathologic correlates were analysed in these patients using chi-square or t-tests. Survival was determined using the method of Kaplan and Meier. RESULTS: Of the 146 patients identified, 20 [14%] underwent an isolated caudate resection ‘Caudate only’ and 126 [86%] underwent caudate resection as part of a more extensive hepatectomy ‘Caudate plus’ [Table]. The most common other liver procedures were right trisegmentectomy [30%], left lobectomy [23%], and left trisegmentectomy [17%]. The most common indication for caudate resection was metastatic colon cancer [45%] followed by cholangiocarcinoma [25%] and primary hepatocellular cancer [10%]. 21 patients also underwent resection of the portal vein [n=16] and/or vena cava [n=13]. The median estimated blood loss was 800 ml with a median transfusion of 2 units. The median length of stay was 9 days. At least one complication was reported in the majority of patients [55%]. Nine patients [6%] died as a result of postoperative complications. Postoperative mortality was significantly higher in patients who underwent a major vascular resection [29 vs 2.5%, p < 0.001]. Median survivals for patients with colorectal metastasis, cholangiocarcinoma, and hepatocellular carcinoma were 36, 28, and 32 months, respectively. CONCLUSION: Caudate resection of the liver can be performed safely but concomitant major vascular resection substantially increases the mortality of the procedure.

HepatectomyCaudate onlyCaudate plusNumber of patients20 [14%]126[86%]Vena cava resection2 [10%]11 [9%]Portal vein resection2 [10%]14 [11%]Median blood loss625 ml800 mlMedian operative time220 min320 minPositive margin5 [25%]36 [29%]Median hospital stay7 days10 daysMortality0 [0%]9 [7%]

175 EXOGENOUS ADENOSINE INCREASES SPHINCTER OF ODDIMOTILITY, ACTING VIA CHOLINERGIC MOTOR NEURONS

Charmaine Michelle Woods, Gino Saccone and James Toouli, Flinders University, Bedford Park, SA, Australia

BACKGROUND: The sphincter of Oddi [SO] is a complex neuromuscular structure, which regulates the flow of bile and pancreatic juice into the duodenum. Purines such as ATP and adenosine modify gastrointestinal motility but their actions in the biliary tree are poorly understood. Recently exogenous ATP was demonstrated to increase SO activity acting via cholinergic and nitrergic pathways. AIM: To determine if exogenous adenosine [1] modulates SO motility in vivo, [2] involves cholinergic neural pathways. METHOD: SO motility was recorded in fasted, anaesthetised, Australian brush-tailed possums [n=17] with a multilumen manometry catheter. Adenosine [10 µl, 1 µM-10 mM] was applied topically to the extraduodenal portion of the SO before and after pretreatment with hexamethonium [HEX; n=6], atropine [ATR; n=4] or the neurotoxin tetrodotoxin [TTX; n=5]. One-minute periods, representing the control period or the peak response, were analysed for area under curve [AUC], contraction amplitude, frequency and basal pressure. The duration of the adenosine-induced response was also determined. Data were analysed using repeated measures ANOVA. RESULTS: Adenosine concentration-dependently increased SO activity for AUC [p < 0.05], amplitude [p < 0.05] and duration of response [p < 0.05], but had no effect on contraction frequency or basal pressure. Adenosine application [10 mM] increased SO activity to 293 + 30% and 305 + 44% of control for AUC and amplitude respectively, lasting 180 + 93 s. Pretreatment with TTX and the muscarinic antagonist ATR blocked the adenosine-induced response [AUC, amplitude and duration: p < 0.05], whereas pretreatment with the nicotinic antagonist HEX had no effect. CONCLUSION: Exogenous adenosine increases SO activity acting via cholinergic motor neurons, suggesting that purines can regulate SO motility. [Supported by NH&MRC of Australia, grant

102133, and the National Parks and Wildlife Service.]

176 ALTERED GLUCOSE METABOLISM IS ASSOCIATED WITH IMPAIRED GALLBLADDER MOTILITY

Attila Nakeeb, Gabriele E Sonnenberg, John Touzios, Anthony G Comuzzie, Ahmed H Kissebah and Henry A Pitt, Indiana University School of Medicine, Indianapolis, IN, Medical College of Wisconsin, Milwaukee, WI and Southwest Foundation for Biomedical Research, San Antonio, TX, USA

BACKGROUND: Obesity, increased age, female gender, hyperlipidemia and diabetes all have been associated with increased risk for cholesterol gallstone formation. Biliary cholesterol hypersecretion, enhanced crystal formation and impaired gallbladder emptying are the key elements in gallstone pathogenesis. However, which risk factors are associated with specific pathogenic elements remains to be elucidated. In addition, data on biliary motility may be confused by existing gallstones. Therefore, the aim of this analysis was to determine which clinical risk factors were associated with impaired gallbladder emptying in humans without gallstones. METHODS: Gallbladder [GB] ultrasound examinations were performed on 180 adult Caucasian non-diabetic volunteers without gallstones. Volunteers had fasting blood drawn and then received a standardized fatty meal. GB volume was measured before and after the meal, and the ejection fraction [EF] was calculated. An EF of 30], and the mean age was 39 years [range 18–78]. 55% were female, and 37% had an elevated cholesterol [XOL]. Only 3% had a fasting blood sugar over 120 mg/dl, but 21% had an abnormal gallbladder EF. Risk factors stratified by EF are shown in the Table. CONCLUSIONS: These data suggest that among volunteers without diabetes or gallstones 1] 21% have impaired gallbladder emptying and 2] the only clinical risk factor associated with this abnormality is increased fasting serum glucose. We conclude that altered glucose metabolism, and not obesity, increased age, female gender or hyperlipidemia, is associated with impaired gallbladder motility.

BMIAgeFemaleXOLGlucoseEF < 25%31.738.755%19296.6*EF > 25%29.938.956%19480.7

*p 25%.

177 POSTOPERATIVE ERCP VS LAPAROSCOPIC CHOLEDOCHOTOMY CLEARANCE OF BILE DUCT CALCULI

Leslie K Nathanson, Nicholas O'Rourke, George Fielding and Ian Martin, Royal Brisbane Hospital, Brisbane and Princess Alexandra Hospital, Brisbane, Australia

Secondary bile duct stones detected on cholangiogram during laparoscopic cholecystectomy unable to be cleared via the cystic duct, require either a choledochotomy or postoperative ERCP. This is a randomised study of these two approaches in the Brisbane metropolitan area. From June 1998 to February 2003, 372 patients had cholangiographically documented bile duct stones during laparoscopic cholecystectomy. 286 had successful transcystic duct clearance, leaving 86 patients randomised into the trial. Operative time was 154 min for the ERCP group [45 patients], 160 min for choledochotomy [41 patients]. Morbidity in terms of bile leak, retained stones, GI bleeding and sepsis occurred in 13% vs 14.6%. Hospital stay was 8.5 days for ERCP vs 6.5 days for choledochtotomy [ns]. These data reveal a balanced outcome in terms of major morbidity and confirm our view that the majority of secondary bile duct stones should be cleared trans-cystically, with those failing having either choledochotomy or postoperative ERCP based on local surgical and gastroenterologic expertise, equipment availability and patient preference.

178 LAPAROSCOPIC TRANSCYSTIC EXPLORATION OF THE COMMON BILE DUCT-AN ATRAUMATIC ALTERNATIVE

Cecilia Strömberg, John Blomberg, Mats Möller and Carl-Eric Leijonmarck, St Göran's Hospital, Stockholm, Sweden

BACKGROUND: Laparoscopic cholecystectomy has become the gold standard in Sweden. At the time of operation 5–10% of the patients have coexisting stones in the common bile duct [CBD]. There are several alternatives in treating these patients. We have chosen to try to extract the stones at the primary operation, preferably by laparoscopic transcystic exploration of the CBD. METHODS: During the years 1994–2002 laparoscopic attempts at exploration of the CBD was made in 222 patients. A retrospective chart review was made and the patients in whom the operation could be completed using the transcystic technique were included in this study. RESULTS: In 40 patients a primary cholangiotomy was chosen. In the remaining 182 of 222 patients an attempt at transcystic CBD exploration was made and it was successful in 135 cases [74%]. The majority [68%] were women and their median age was 52 years [range 19–84 years] at the time of operation. In 126 patients one or more stones were extracted, in nine no stone could be found during choledochoscopy. The median operating time was 162 minutes [range 89–384 minutes] and the median postoperative hospital stay was one day [range 1–31 days]. Eight patients had postoperative complications; three had cardiopulmonary complications, three bleeding, one pancreatitis and one bile leakage needing percutaneous drainage. One of the patients with postoperative bleeding was reoperated due to infection of the hematoma. Otherwise there were no reoperations and no mortality 30-days postoperatively. Two patients had postoperative ERC with sphincterotomy, in one of them a retained stone was found. CONCLUSION: After laparoscopic transcystic exploration of the common bile duct the hospital stay is short. The frequency of retained stones is low. The papilla is saved and the potentially dangerous complications of ERC can be avoided. A single-stage laparoscopic procedure with transcystic common bile duct exploration is an atraumatic alternative.

179 TRANSCYSTIC STENTING FOR CBD STONES AT LAPAROSCOPIC CHOLECYSTECTOMY FACILITATES POST OPERATIVE ERCP

Michael R Cox, Nepean Hospital, Penrith, NSW, Australia

BACKGROUND: There are several strategies to treat stones in the common bile duct [CBD] at laparoscopic cholecystectomy [LC]. The most frequent method is post LC ERCP. Transcystic stenting of the CBD was developed to facilitate post operative ERCP. AIM: To compare the efficacy and morbidity of conventional post LC ERCP to ERCP that has been facilitated with the insertion of a transcystic stent. METHOD: A prospective, non-randomized, single unit study from June 1996 until June 2002. The conventional ERCP group were referred from other surgeons for a post LC ERCP for CBD stones found at operative cholangiography [OC]. The stented group had the LC done by the authors, a transcystic stent was inserted and proceeded to post LC ERCP. All ERCPs were performed by the authors. RESULTS: See Table. CONCLUSIONS: Insertion of a transcystic stent at LC does facilitate post LC ERCP for CBD stones. There is an increased rate of cannulation and clearance of the CBD and a significant reduction in the incidence of post ERCP pancreatitis.

ParameterConventionalStentedNumber of patients101157Post LC pancreatitis00Successful CBD canulation at ERCP90 [90%]155 [99%]Need for repeat ERCP12 [12%]9 [6%]CBD clearance at initial ERCP90 [90%]151 [96%]Post ERCP complications [definition]Pancreatitis [pain and elevated amylase]8 [8%]1 [1%]Cholangitis [fever post ERCP]2[1%]2 [1%]Bleeding [malaena within 1 week]1 [1%]0Perforation [pain and retroperitoneal gas on CT]02 [1%]Total11 [11%]5 [3%]

180 NATURAL PROGRESSION OF HEPATOLITHIASIS THAT SHOWS NO CLINICAL SIGNS AT ITS INITIAL PRESENTATION

Toshiomi Kusano, Masato Furukawa*, Kazuyuki Tachibana, Takashi

Takao and Masahiro Kamachi, Tenjin-Kai Shin-Koga Hospital, Kurume and *Nishi-Isahaya Hospital, Isahaya, Japan

BACKGROUND: Hepatolithiasis is common in East Asian countries and is more refractory to surgical treatment than most other benign diseases of the biliary tract. Long-standing cholangitis caused by retained and recurrent stones and the development of intrahepatic cholangiocarcinoma remain major problems in performing effective management. PURPOSE: To elucidate the natural progression of hepatolithiasis that showed no signs at the time of initial presentation. METHODS: Over a 20-year period, we observed 122 of 311 patients with hepatolithiasis who reported no symptoms and thus, who received no treatment at initial presentation. The follow-up periods were for up to 18 years [mean, 13 years and 1 month]. RESULTS: Fourteen of 112 patients [11.5%] developed some symptoms attributed to hepatolithiasis. The interval until the onset of symptoms ranged from 9 months to 7 years and 4 months [mean, 3 years and 5 months]. The developing symptoms included abdominal pain, hepatic abscess, cholangitis, and cholangiocarcinoma. Nine of the 14 patients [64.3%] developed stone migration to the extrahepatic bile duct at the onset of clinical symptoms. The incidence of lobar liver atrophy on computed tomography in the patients with symptomatic hepatolithiasis [13 of 14 patients; 92.9%] was significantly higher than that in the patients with asymptomatic hepatolithiasis [14 of 108 patients; 13.0%]. The prognosis of the patients with symptomatic hepatolithiasis was as follows: 2 died of cholangiocarcinoma, 1 died of hepatic failure, and 11 survived. Fifteen of the asymptomatic patients died, but none of these deaths were attributed to hepatolithiasis. CONCLUSIONS: Close observation is an alternative management at initial presentation for patients whith asymptomatic hepatolithiasis without extrahepatic stones or lobar liver atrophy.

181 ENTERAL NUTRITION RICH IN FAT REDUCES INFLAMMATION AND GUT BARRIER FAILURE IN BILEDUCTLIGATED RATS WITH SYSTEMIC HYPOTENSION

Misha DP Luyer, Wim A Buurman, M'Hamed Hadfoune, Jan A Jacobs, Cornelis H Dejong and Jan Willem M Greve, University Maastricht and University Hospital Maastricht, Maastricht, The Netherlands

BACKGROUND: Cholestatic patients have an increased risk for septic complications after major surgery due to an increased susceptibility to endotoxin and systemic hypotension. Thus far, no effective therapy has been reported to reduce postoperative complications. Recently, enteral nutrition with high amounts of fat has been shown to be very efficient against endotoxemia and inflammation. However, it is unknown to what extent an intact bile flow is required for the observed protection. PURPOSE: To study the effect of high-fat enteral nutrition on endotoxemia, inflammation and intestinal permeability in bile duct-ligated rats subjected to hemorrhagic shock. METHODS: Bile duct-ligated [BDL] Sprague-Dawley rats were either fasted or fed with a low-fat or high-fat enteral nutrition before hemorrhagic shock. At 90 minutes, endotoxin and TNF-α were determined in plasma. Distrubution of the tight junction protein zonula occludens protein 1 [ZO-1] was assessed by immunofluorescence. Intestinal permeability to horseradish peroxidase [HRP] was determined ex vivo in the ileum. RESULTS: Plasma endotoxin significantly decreased after hemorrhagic shock in BDL rats fed with high-fat nutrition [15±3pg/ml] compared with rats that were fasted [32±1 pg/ml, p < 0.001] or those fed with low-fat nutrition [26±6 pg/ml, p< 0.01]. In line, circulating TNF-α was reduced in rats pretreated with high-fat nutrition [61±20 pg/ml] compared with fasted [188±26 pg/ml, p < 0.05] or low-fat pretreated rats [105±20, p < 0.01]. A disappearance of ZO-1 was observed in intestinal epithelium cells of ileum and colon of non-treated rats demonstrating a breakdown of tight junctions. However, in high-fat pretreated rats ZO-1 distribution remained unaffected. In parallel, the increased intestinal permeability to HRP in low-fat pretreated [2.4±0.3 µg/ml] and fasted BDL rats [7.6±0.3 µg/ml] was reduced by high-fat enteral nutrition [0.9±0.1 µg/ml, p< 0.001 and p < 0.001, respectively]. CONCLUSION: These results suggest that an intact bile flow is not required for the protective effect of high-fat enteral nutrition on hemorrhagic shock-induced endotoxemia, inflammation and gut barrier loss. Pretreatment with high-fat enteral nutrition may be a new, simple and effective strategy to prevent endotoxin-mediated complications in cholestatic patients undergoing major surgery.

182 ROLE OF TLR 4 IN CHOLANGITIS

Dhiresh R Jeyarajah, Mariusz L Kielar, Nicole Frantz, Prameela Karimi, Reji John and Christopher Y Lu, Southwestern Medical School, Dallas, TX, USA

INTRODUCTION: Cholangitis is a common clinical problem that can be fatal. We have developed a murine model of cholangitis and have shown that animals are very susceptible to biliary infection with E. coli or LPS in the obstructed bile duct. We now examine the role of TLR 4 in cholangitis. METHODS: 6–8-week-old C3H/HeJ [TLR4-deficient] or C3H/HeouJ [TLR4-sufficient] mice were subjected to bile duct ligation [BDL] and injection of 0.5 mg/mouse of LPS [Sigma]. Survival was monitored. A cohort of animals was sacrificed at 6 h after induction of cholangitis. Liver injury was assessed by measuring serum ALT levels. Liver tissue was harvested and RNAse protection assay [Pharmingen] was used to examine mRN A levels of TNF-α and interleukin-6 [IL-6]. Histologic examination of liver was performed by standard H&E staining. RESULTS: TLR-4-deficient mice were resistant to biliary LPS – survival was 100% versus 13% in TLR-4-sufficient mice. Hepatic TNF-α and IL-6 mRNA levels were elevated in the TLR-4-sufficient mice compared with the TLR-4-deficient mice. However, liver injury, as measured by ALT and histologic examination of necrotic foci and neutrophil infiltrate in liver tissue, was similar between the two groups. CONCLUSIONS: Presence of TLR-4 is critical to LPS responsiveness in our novel murine model of cholangitis. Interestingly, despite increased hepatic pro-inflammatory cytokine profile and increased susceptibility to LPS in TLR-4-sufficient mice, histologic liver injury was not different to that in TLR-4-deficient mice. This suggests that TLR-4-induced lethality is dependent on factors other than liver injury in cholangitis

183 PROGNOSTIC IMPLICATIONS OF PRESERVED BILE DUCT CONFLUENCE AFTER IATROGENIC INJURY

Miguel Angel Mercado, Carlos Chan, Héctor Orozco and Eitan Podgaetz, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico, DF, Mexico

INTRODUCTION: Biliary reconstruction is performed according to the level at which the injury occurred. A comparative study between patients in whom the biliary junction was preserved and another group where the biliary junction was not preserved was done. METHODS: A retrospective review of the biliary reconstructions performed for iatrogenic lesions between 1990 and 2002 was carried out. Postoperative outcome, functional status of the anastomosis, recurrent cholangitis, need for radiological instrumentation and/or reoperation were analysed. RESULTS: We reviewed 204 cases, 130 cases had a preserved biliary junction while in 74 the injury included the junction. All patients were treated with a Roux-en-Y hepatojejunostomy. In the first group, 4% required reoperation, 4% underwent radiological percutaneous instrumentation, 8% had anastomo-tic dysfunction and 4% had cholangitis. In the second group, 24% needed reoperation and 80% radiological instrumentation. Anastomotic dysfunction was observed in 64% and cholangitis in 55%. It is important to note that 52 of the 74 cases in the second group had a history of more than two reconstruction attempts. CONCLUSION: When the biliary junction is preserved after iatrogenic injury we found a significantly better outcome. The results of biliary reconstruction in this type of patient are better at long term compared to those where the junction was not preserved, evidenced by a lower reoperation and radiological instrumentation rate.

184 EFFECT OF ISCHAEMIC PRECONDITIONING ON HEPATIC INTRACELLULAR TISSUE OXYGENATION DURING ISCHAEMIA REPERFUSION INJURY IN MODERATE HEPATIC STEATOSIS

W Yang, G Glantzounis, J Taanman, M Winslet, B Davidson and A Seifalian, Royal Free and University College Medical School, UCL, London, UK

Our previous study showed that ischaemic preconditioning [IPC] significantly improves blood flow in the microcirculation during the reperfusion phase and preconditioned liver exposed to hypoxia maintains the cytochrome oxidase redox state. The present study aimed to investigate whether IPC could protect the liver with moderate steatosis form ischaemia reperfusion [IR] injury through improving intracellular tissue oxygenation. Female New Zealand rabbits were subjected to a rich [2%] cholesterol diet for 8 weeks to induce moderate hepatic steatosis. Following which animals were subjected to 1 h lobar ischaemia followed by 7 h reperfusion [IR]. Animals were divided into three groups [n=6 each]: [1] sham laparotomy; [2] IR and [3] IPC with 5 min ischemia and 10 min reperfusion before IR. Hepatic microcirculation [HM] and tissue oxygenation including deoxyhaemoglobin, oxyhaemoglobin and cytochrome oxidase redox state were directly measured by laser Doppler flowmeter and near-infrared spectroscopy [NIRS]. Fresh liver tissue samples were taken at baseline, 2 h and 7 h after reperfusion for the assay of activity of cytochrome C oxidase and citrate synthase. Hepatocellular injury was assessed by indocyanine green [ICG] clearance which was directly measured by NIRS. HM was significantly deteriorated in the IR group [94.0±5.0 vs 73.3 ±33 flux unit, p30%, central venous pressures were maintained no higher than 6 mmHg during the parenchymal dissection, and the patient was placed in the Trendelenberg position during dissection. No patients in either group required transfusion of banked blood or blood products. These data clearly demonstrates the following. 1] The use of intraoperative IH allows right hepatic lobectomy to be safely and effectively performed, both in donors and non-donors, without the use of banked blood/blood product transfusions. 2] As the OR time is significantly longer in living donors, blood loss and subsequent fluid replacement are higher, although not significant. 3] Overall length of stay is longer in the donor group; however, 2 patients had prolonged stays due to complications. One patient required emergent transplantation due to hepatic vein thrombosis related to previously undiagnosed factor V Leiden deficiency, and the other had a postoperative bile leak. If we remove these patients from analysis, the overall length of stay in this group is 7.25 days, virtually identical to the non-donor group.

188 IMPACT OF CONTRAST-ENHANCED INTRAOPERATIVE ULTRASONOGRAPHY DURING LIVER RESECTION

Guido Torzilli, Daniele Del Fabbro, Andrea Gambetti, Piera Leoni and Natale Olivari, Hepatobiliary Surgery Unit, Chirurgia Generale 1, Azienda Ospedaliera Provincia Di Lodi, Lodi, Italy

AIM: Intraoperative ultrasonography [IOUS] is the most accurate diagnostic technique for detecting focal liver lesions but suffers from a few drawbacks in differentiating and detecting focal liver lesions [FLL]. The aim of this pilot study was to evaluate the potentiality of contrast-enhanced IOUS [CE-IOUS] in this sense. MATERIALS AND METHODS: Twenty-nine consecutive patients underwent liver resection using IOUS and CE-IOUS. Mean age was 64.2 years [range 38–87]; there were 19 males and 10 females. Seventeen patients had HCC, 10 colorectal [CRC] liver metastases, one GIST metastases and one had inflammatory pseudotumor preoperatively misdiagnosed as a peripheral mass-forming type cholangiocellular carcinoma. In all patients 4.8 ml of SonoVue [Bracco Imaging, Milan, Italy] was injected intravenously through a peripheral vein. SonoVue consists of sulphur hexafluoride-containing phospholipid micro-bubbles in saline. RESULTS: In the 10 patients with metastatic lesions CE-IOUS detected in 3 patients, 5 FLL undiscovered by IOUS. In patients with HCC, IOUS confirmed all but one of the preoperative FLL and in 10 patients depicted a total of 18 new FLL of uncertain origin: 12 had no enhancement peculiar to HCC at CE-IOUS pattern and at histology proved to be dysplastic nodules or did not show any change at postoperative follow-up [9–16 months]; the remaining 6 in 3 patients had enhancement peculiar to HCC and histology confirmed this diagnosis. CE-IOUS added findings to those of unenhanced IOUS in 44.8% of patients [13/29]. CONCLUSIONS: These preliminary results show that IOUS accuracy is improved by CE-IOUS with an impact on surgical strategy. In particular, CE-IOUS increases specificity in differentiating nodules detected in the cirrhotic liver by IOUS and the sensitivity of IOUS itself in detecting tiny fore-sites in patients who undergo surgery for CRC liver metastases.

189 NON-ALCOHOLIC STEATOHEPATITIS: A COMMON DISORDER IN PATIENTS WITH GALLBLADDER DISEASE

Michael R Cox, Nepean Hospital, Penrith, NSW, Australia

BACKGROUND: Non-alcoholic fatty liver disease [NAFLD] affects up to 20% of the Western world. It is now one the commonest reasons for outpatient hepatology consultations. NAFLD is also known to progress to forms involving hepatic inflammation and/or fibrosis non-alcoholic steatohepatitis [NASH]. AIMS: 1. To evaluate the prevalence of NAFLD/NASH in a group of patients undergoing laparoscopic cholecystectomy [LC]. 2. To ascertain the accuracy/value of ultrasonography commonly used to diagnosis fatty liver. 3. To correlate liver enzyme abnormalities found in NAFLD/NASH. METHODS: 142 patients undergoing LC were recruited, and had simultaneous laparoscopic liver biopsy. Biopsy results were compared to preoperative abdominal ultrasound examination and correlated with liver enzyme tests. RESULTS: NAFLD was found in 76% whilst 41% of the study group had at least moderate to severe steatosis [Brunt classification]. NASH was found in 22.5%, of whom 56.2% had some degree of peri-sinusoidal fibrosis. In diagnosing moderate to severe degrees of steatosis, ultrasonography has a sensitivity of 74.1% and specificity of 75.0%; OR: 8.6[3.99–18.54, p60 IU/L, and only 21% with NASH had an elevated AST/ALT ratio [with ALT > normal]. CONCLUSIONS: This represents to date the largest histologically controlled study evaluating the accuracy of ultrasound in hepatic steatosis. NAFLD is very common in the LC patient group and is likely to reflect the high population prevalence, and shared risk factors. The accuracy of ultrasonography as performed in the general outpatient setting has been shown to be reasonable in diagnosing hepatic steatosis. Liver enzyme abnormalities often used to aid the diagnosis of NASH may not be very sensitive.

190 ALL FAT ISN'T THE SAME: GC/MS ANALYSIS OF TWO COMMON STEATOTIC MODELS

Ryan Fiorini, Z Evans, C Campbell, C Milliken, H May, M Schmidt and KD Chavin, Medical University of South Carolina, Charleston, SC, USA

BACKGROUND: Hepatic steatosis is associated with diabetes, cirrhosis, and susceptibility to ischemia-reperfusion injury. It is a primary determinant in donor liver selection for transplantation. Evaluation of total hepatic fat content by H&E; staining and classification as macro- or microsteatosis may ignore underlying fatty acid [FA] variability. We hypothesized that the liver fatty acid profile of genetically fat [ob/ob] mice would be different to that of lean mice fed a high fat diet. By adapting a gas chromatography mass-spectroscopy [GC/MS] protocol for whole tissue hepatic analysis we believed we would observe different fatty acid profiles between the two models of steatosis. METHODS: 6-week-old ob/ob mice [n=5], lean littermates [n=4], and lean littermates given 60% by wt fat food for 14 days [n=4] were sacrificed and liver tissue was collected. Frozen section slides were stained with Oil Red O [ORO] stain content. Liver tissue was also homogenized and FAs were extracted in chloroform/methanol. Methyl esters were derived with BF3 and internal standards were added. Each sample FA methyl ester [FAME] mix was employed for instrument standardization. GC/FID instrument parameters were set based on internal standards at extinction. Samples were also standardized to protein.

RESULTS. Total liver fat content for the steatotic groups determined by ORO was similar in both groups [approx. 80%]. Results from the GC/FID showed no significant difference [p < 0.05] in the content of decanoic, linoleic, eicosapent, and docosahex acids, between lean, ob/ob, and fat fed mice. Furthermore, we found that butyric and oleic acids were elevated in the ob/ob mouse, but not the fat-fed lean mouse. No methyl-delta or elaidic acid was detectable in the lean or fat fed liver; and interestingly, steric acid was highest in the lean liver. CONCLUSIONS: Although both groups of mice demonstrated similar degrees of steatosis by ORO staining, we found considerable difference between the liver fatty acid profiles of ob/ob and fat fed mice. Understanding specific differences in fatty acid content by GC/MS may give us more insight into which steatotic livers are truly marginal.

191 PLATELETS: A NOVEL PATHWAY OF LIVER REGENERATION

Mickael Lesurtel, Boris Aleil, Wolfram Jochum, Rolf Graf, Christian Gachet and Pierre-Alain Clavien, University Hospital, Zurich, Switzerland and Etablissement Français du Sang-Alsace, Strasbourg, France

BACKGROUND: Leukocyte recruitment triggers hepatocyte proliferation after partial hepatectomy. Since platelets interact with leukocytes and play an important role in liver ischemia/reperfusion injury, we attempted to assess the role of platelets in liver regeneration after partial hepatectomy. METHODS: To assess liver regeneration, proliferating cell nuclear antigen expression and bromo-deoxyuridine incorporation were determined in male C57BL6 mice subjected to 70% hepatectomy. Two models of thrombocytopenia and a model of inhibition of platelet aggregation were developed. Immune thrombocytopenia was induced by intraperitoneal injection of a monoclonal rat antiplatelet antibody [immune group]. Central thrombocytopenia was induced by a single intraperitoneal injection of busulfan [busulfan group]. To inhibit platelet aggregation, mice were pretreated with clopidogrel, the active substance of Plavix. A forth group of mice was treated with SR 25989, an enantiomer of clopidogrel which has the antiangiogenic property of clopidogrel but lacks its antiaggregant property [SR group]. RESULTS: In the immune group, platelet counts decreased below 10% of normal. Busulfan induced both thrombocytopenia and leucopenia as assessed by platelet and leukocyte counts which were below 15% of normal. Clopidogrel did not affect platelet and leukocyte counts. In both thrombo-cytopenic groups and the clopidogrel group, liver regeneration was significantly reduced when compared to the control group. Liver regeneration was not impaired in the SR group, in which platelet aggregation was normal. CONCLUSION: These results suggest that platelets are involved in liver regeneration after hepatectomy. Platelets could play a role in a novel pathway by synergistically acting with leukocytes to enhance liver regeneration.

192 MODULATION OF MITOCHONDRIAL CALCIUM OVERLOAD ATTENUATES ISCHEMIA-INDUCED HEPATOCYTE NECROSIS

Christopher D Anderson, Ian B Nicoud, Janene Pierce, Andrey Belous, Aya Wakata, C Wright Pinson and Ravi S Chari, Vanderbilt University Medical Center, Nashville, TN, USA

INTRODUCTION: Ischemia and reperfusion injury is a significant problem in hepatic surgery. Mitochondrial calcium regulation plays an important role in ischemia and reperfusion injury in liver. We have shown that inhibition of mitochondrial calcium [mCa + 2] overload by ruthenium red [RR] attenuates cell death secondary to hypoxic exposure in a hepatocyte cell culture model. We hypothesized that RR pretreatment would attenuate hepatic warm ischemia-reperfusion injury in a rat model. METHODS: Under isoflorane anesthesia, 16 rats underwent 1 h of 70% hepatic ischemia using an atraumatic microvessel clamp or sham operation. Rats were treated with RR, a mitochondrial calcium uniporter inhibitor [50 mg/kg IV], or vehicle [0.9% NaCl] 30 minutes prior to the initiation of ischemia. After removal of the vessel clamp, the animals were killed immediately [n=8] or after 6 h of reperfusion [n=8]. Serum was sampled to measure AST and ALT levels. Liver samples were taken for H&E histology, and TUNEL staining. RESULTS: 1] RR significantly decreased both AST [1381 vs 681, p = 0.008] and ALT [956 vs 322, p = 0.010] serum levels following 1 h ischemia and 6 h reperfusion. Sham values were 267 and 131, respectively. 2] TUNEL demonstrated 5% hepatocellular apoptosis following 1 h ischemia and 6 h reperfusion vs 1.5% apoptosis with RR pretreatment [p = 0.232]. Sham = 1.5% apoptosis. 3] H&E histology under l00×magnification demonstrated marked areas of hepatocyte necrosis [pyknotic nuclei, cytoplasmic blanching, and loss of distinct cellular border] following 1 h ischemia and 6 h reperfusion. RR greatly decreases this occurrence. CONCLUSIONS: These data indicate that hepatocellular injury following 1 h of warm ischemia and 6 h of reperfusion occurs mostly in the form of necrotic cell death. RR pretreatment decreases hepatocyte injury as measured by AST and ALT levels via a mechanism which protects hepatocytes from necrotic cell death during ischemia. This action of RR implicates mitochondrial calcium overload in warm ischemic hepatocyte injury.

193 HEP3B HUMAN HEPATOCELLULAR CARCINOMA CELLS EXHIBIT RESISTANCE THROUGH INCREASED PHOSPHO-ERK SIGNALING AFTER LONG-TERM EXPOSURE TO MEK INHIBITORS

Patrick Klein, Chad Wiesenauer, Eric A Wiebke and C Max Schmidt, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, Department of Surgery, Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN, Departments of Surgery and Biochemistry/Molecular Biology, Indiana University Cancer Center, Indiana University School of Medicine; Richard L Roudebush VAMC and Walther Oncology Center, Indianapolis, IN, USA

Human hepatocellular carcinoma [HCC] is associated with increased expression and activity of MAPK intermediates. Short-term treatment of HCC in vitro with MEK inhibitors results in a concentration-dependent decrease in phospho-ERK. The purpose of this study was to investigate the effects of U0126, PD098059, and PD181461 on HCC cell lines following long-term MEK inhibitor treatment. Human HCC cell lines, Hep3B and HepG2, were treated with MEK inhibitors U0126 [1.0–100.0 µM], PD098059 [1–20 µM], and a novel MEK inhibitor, PD181461 [0.1–1 µM] for 12–72 h. ERK and MEK expression were determined by Western blot. Activity of MEKK and MEK was determined by phospho-MEK and phospho-ERK immunoblots. Cell growth was determined by an MTS proliferation assay and confirmed by cell counts. HepG2 cells exhibited a concentration-dependent p-ERK downregulation with U0126, PD098059 and PD181461 that was similar at all time points observed. In Hep3B cells, however, p-ERK expression returned to control levels at all doses measured at both 24- and 48-h time points. When medium containing U0126 was removed from Hep3B cells after 24 h and placed on naïve Hep3B cells, there was a decrease in p-ERK that was equivalent to that seen following treatment with freshly prepared U0126, effectively ruling out degradation of the drug. Exposing previously treated Hep3B cells to new U0126 did not result in an equivalent decrease in p-ERK, as to that seen in naive cells. Total ERK and MEK expression did not change with any of these manipulations. Phospho-MEK, however, was increased up to 5-fold over control in a concentration- [5–10 µM] and time-[0.5–48 h] dependent manner with U0126 treatment. Cell proliferation assays confirmed that within the first 24 h Hep3B cells were sensitive to the antiproliferative effects of MEK inhibitors, but this effect did not continue when the cells were examined after 48 and 72 h of treatment. The large increase in MEK activation as a result of U0126 treatment may alter the effectiveness of U0126 as an inhibitor of downstream ERK phosphorylation. Hep3B cells are able to circumvent the effects of pharmacologically active MEK inhibitor after 24 h, possibly through a hyperactive upstream positive feedback mechanism or by a novel MEK-independent mechanism.

194 COMPARISON OF MOLECULAR PATHWAYS BETWEEN LOSS OF HETEROZYGOSITY AND MICROSATELLITE INSTABILITY IN HEPATOCELLULAR CARCINOMA

Wen Ming Cong, Sydney D Finkelstein, Anthony J Demetris and Meng Chao Wu, Eastern Hepatobiliary Surgery Hospital, Shanghai, China and University of Pittsburgh of Medical Center, Pittsburgh, PA, USA

OBJECTIVE: The multiple genetic alterations involved in the tumorigenesis of human hepatocellular carcinoma [HCC] have not been well studied. The aim of this study was to explore the role of loss of heterozygosity [LOH] of tumor suppressor genes [TSG] and/or microsatellite instability [MSI] during hepatocarcinogenesis, as well as their correlation with clinicopathological features. METHODS: LOH on 6 TSG [APC, DCC, MCC, OGG1, p53 and RBI] in 36 informative HCC and 13 polymorphic microsatellite markers in 15 HCC were analysed by using microdissection-based PCR amplification and direct DNA sequencing. RESULTS: The overall incidence of LOH in HCC was 41.7% [15/36]. The frequency of genetic alterations of TSG in informative HCC were p53 [87.5%], APC [58.8%], OGG1 [50%], RBI [37.5%], DCC [25%] and MCC [0%]. 46.2% [6/13] microsatellites showed LOH in nine of 15 HCC [60%], but none of HCC showed MSI. If taking LOH of APC, OGG1 and DCC as type I [n=6], and LOH of p53 and RBI as type II [n=7], the mean tumor size of these two types were 2.9 ±1.7 cm and 7.2±3.4 cm, respectively [p < 0.01], and clinical outcomes were 72.0 ±38.6 months and 51.0 ±30.4 months, respectively [p < 0.05]. No significant differences were found between genetic alterations and age, sex, serum AFP level, frequency of HBV infection, liver cirrhosis, tumor differentiation and tissue type [p > 0.05]. CONCLUSIONS: Compared with MSI pathway, LOH pathway plays a more important role during the development of HCC. Based on the present study, a multistep model of hepatocarcinogenesis is proposed, in which, LOH of APC,OGGl and DCC might be an early event, whereas LOH of p53 and RBI is an advanced event, whereas MCC may play no more role in that process.

195 CLINICAL APPLICATION OF ANTI-ANGIOGENIC TREATMENT FOR HEPATOCELLULAR CARCINOMA-WITH SPECIAL REFERENCE TO MATRIX METALLOPROTEINASES AND CYTOKINE NETWORK

Tokuyasu Yokota, Yuji Ishii, Yuichi Nakasato, Tatsuo Ohkubo, Susumu Kobayashi, Yoji Yamazaki and Katsuhiko Yanaga, Jikei University School of Medicine, Tokyo, Japan

PURPOSE: For the development of primary hepatocellular carcinoma [HCC], tissue remodeling and angiogenesis are key factors. In this study, angiogenesis-related matrix metalloproteinases [MMPs] and angiogenesis-related cytokine [IL-8, IFN-γ] network of HCC were evaluated. MATERIALS AND METHODS: We examined the expression rates of angiogenesis-related MMPs [MMP-2, -3, -7, -9 and MT1,2-MMP] in the cancer and non-cancer areas of resected tumors in 30 patients by immunohistological analysis. In addition, the serum cytokines [IL-6, IL-8, and IFN-γ] were measured in 7 patients to trace the course of hepatocarcinogenesis. Furthermore, using a diethylnitrosamine [DEN] HCC model in rats, MMPI [Marimastat] was administered by 4 routes [systemic, hepatic artery, portal vein, local]. The chemopreventive effect was also examined. The evaluation was made on tumor diameter, nodular number, immunohistochemistry [MMP-2, -9 and MT1-MMP], zymography [MMP-2, -9], Northern blotting and the hepatic microvascular casts [red: artery; blue: portal vein]. RESULTS: The expression of MT1-MMP was frequently observed to a similar extent as that MMP-2 in cancer areas. MMP-9 in HCC-infiltrated region was often observed. These findings in the DEN model are fundamentally the same as those for clinical cases. In the clinical cases, the expressions of MMP-7 and -9 were closely related to the cancer infiltration. In addition, enhanced expression of MMP-7 was interestingly observed in HCC viable cells after transcatheter arterial embolization. Furthermore, MT1 -MMP appeared to be the most important factor in HCC because of its widespread pattern of expression. Serum cytokine study of the patients with HCC, a switch-on angiogenic status including decreased IFN-γ and increased IL-8 was suggested [before and after carcinogenesis]. In the systemic group of MMPI as compared with the control, the number of red nodules [HCC] successfully decreased by 70%. In the intra-arterial and portal groups as well, the red nodules was significantly decreased. Chemoprevention was also observed. In the vascular casts by SEM, suppressed tumor angiogenesis of portal area and maintained sinusoidal structure were observed in the treatment groups. Expressions of MMP-2 and -9, especially decrease of its activated type [zymography] and of MT1-MMP [Northern blotting] were evident in the treatment groups. CONCLUSION: Various anti-angiogenic treatments such as MMPI and its combinations seem to have a possible contribution to chemoprevention, tumor dormancy, and tumor shrinkage in cases of HCC.

196 ADJUVANT ARTERIAL INFUSION CHEMOTHERAPY AFTER RESECTION OF HCC WITH TUMOR THROMBOSIS OF THE PORTAL VEIN

Takefumi Niguma, Tetusige Mimura, Ryuichi Yosida and Nobumasa Tutui, Okayama Saiseikai General Hospital, Okayama, Japan

The prognosis of hepatocellular carcinoma [HCC] with tumor thrombosis of the main trunk or major branches of portal vein is extremely poor, even if it is resectable. Uncontrollable multiple metastases often appear in the residual liver within several months after the operation. Recently, arterial infusion chemotherapy has been attempted for HCC that resists conventional therapies. This study was designed to evaluate the efficacy of adjuvant arterial infusion chemotherapy after resection of HCC with tumor thrombosis of the portal vein. The regimen consists of induction and following therapy. The induction therapy is daily administration of cisplatin [CDDP 5–10 mg/day for 1–5 days] and continuous infusion of 5-fluorouracil [5-FU 250 mg/day for 1–5 days]. In principle, patients receive four serial courses of chemotherapy. The following therapy is weekly or bi-weekly administration of CDDP [5–10 mg] and subsequent infusion of 5-FU [750–1000 mg for l0h]. Between January 1997 and December 2002, 21 patients with intractable HCC were treated in our hospital by arterial infusion chemotherapy. 11 patients completed the regimen. 4 patients showed a complete response, and 2 patients showed a partial response. The response rate is 54.5%. Based on the encouraging results, we applied this regimen to the adjuvant chemotherapy after the resection of the HCC with portal tumor thrombosis. The adjuvant therapy was terminated when the cumulative dose of 5-FU reached 15 g. In a retrospective study, 12 patients had curative resection of HCC with tumor thrombosis of the main trunk or major branches of portal vein, and 6 patients received the adjuvant chemotherapy. Liver function and tumor pathology were not different between patients with adjuvant chemotherapy and without chemotherapy. The mean survival is 47.3 months with chemotherapy and 10.8 months without chemotherapy. The mean disease-free interval is 25.8 months with chemotherapy and 4.5 months without chemotherapy. The current pilot study indicated that adjuvant arterial infusion chemotherapy is a very promising strategy after aggressive surgery to the HCC with tumor thrombosis of the portal vein. However, a controlled study is essential to obtain conclusive evidence.

197 DIAGNOSIS AND SURGICAL TREATMENTS OF HEPATOCELLULAR CARCINOMA WITH TUMOR THROMBOSIS IN BILE DUCT: AN EXPERIENCE OF 34 PATIENTS FROM ONE CLINICAL CENTER

Lun-Xiu Qin, Zeng-Chen Ma, Zhi-Quan Wu, Jia Fan, Xin-da Zhou, Hui-Chuan Sun, Qing-Hai Ye, Lu Wang and Zhao-You Tang, Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, China

AIM: Hepatocellular carcinoma [HCC] with bile duct tumor thrombosis [BDT] is a rare event. The prognosis of this type of patient is very dismal. This study aime to further improve the prognosis of these patients, and share our experiences on the diagnosis and treatment of HCC with BDT. METHODS: Thirty-four patients with HCC with BDT who received surgical treatment in the authors’ institute from July 1987 to January 2003 were reviewed retrospectively. The diagnosis, treatment, and outcome of these patients were summarized. RESULTS: Thirty of the 34 patients [88.2%] were positive for alpha-fetoprotein [AFP] [>20µg/L], and 12 patients [35.3%] were found to have obstructive jaundice before operation, 18 cases were suspected ‘obstruction of bile duct’ preoperatively. The primary tumors were frequently located at the left medial [13 cases] or right anterior lobe [14 cases]. Thirty-one patients received liver resections and removal of BDT, while the other 3 patients received removal of BDT combined with hepatic artery ligation and canulation [HAL + HAI], or only removal of BDT because their liver function reservation and general condition could not tolerate the primary tumor resection. The 1-year survival rate was 71.4% [20/28]. The longest disease-free survival was over 15 years. Intrahepatic tumor recurrence within 1 year after operation was found in 14 patients [14/28, 50.0%]. CONCLUSIONS: Surgical removal of primary tumors and BDT is safe and beneficial for HCC patients with BDT. Early detection, diagnosis, and surgical treatment are the key points to prolong the survival time of patients.

198 ACTIVIN A STIMULATES VASCULAR ENDOTHELIAL GROWTH FACTOR GENE TRANSCRIPTION IN HUMAN HEPATOCELLULAR CARCINOMA CELLS

Christoph Benckert, Armin Thelen, Antonino Spinelli, Peter Neuhaus and Sven Jonas, Humboldt University, Charité, Campus-Virchow Clinic, Berlin, Germany

BACKGROUND AND AIM: Upregulation of vascular endothelial growth factor [VEGF] is known to play a critical role in hepatocellular tumor biology. In an attempt to identify factors responsible for VEGF induction in human hepatocellular carcinoma [HCC], we evaluated the effects of activin A on VEGF gene expression. METHODS: Expression of VEGF, activin A and its receptors was analysed by immunohistochemistry, PCR, and enzyme-linked immunosorbent assay. Functional VEGF promoter analysis and gel shift assays were performed to define minimal promoter requirements and potential transcription factors. RESULTS: In vivo activin A, VEGF and its receptors were detected immunohistochemically in 9/9 HCC tumor specimens. In vitro the expression of VEGF the activin A/ receptor system was confirmed by ELISA and RT-PCR in three HCC cell lines. Incubation of HCC cell lines with activin A for 96 h led to time- and dose-dependent increase of VEGF protein and mRNA concentrations. Transient transfections with a human VEGF reporter gene construct [hVEGF –2018/ + 50] showed transactivation of the VEGF promoter through activin A. 5'deletional analysis revealed the −85 to −50 region of the human VEGF promoter to be responsible for basal as well as inducible promoter activity. CONCLUSION: This study identifies activin A as a novel stimulus of VEGF gene expression in HCC. Activin A indirectly stimulates angiogenesis in human hepatocellular carcinoma through upregulation of VEGF gene expression by transactivation of the −85 to −50 region of the VEGF promoter.

199 RUPTURED HEPATOCELLULAR CARCINOMA: A TERMINAL OR SALVAGEABLE EVENT?

Felicia Tan, Yu-Meng Tan, Alexander Chung, Pierce Chow and London Lucien Ooi, Singapore General Hospital, Singapore and National Cancer Center Singapore, Singapore

PURPOSE: Ruptured hepatocellular carcinoma [HCC] is often regarded as a terminal event of the disease. Aggressive resucitation, the introduction of interventional radiology techniques and improved surgical outcome with surgical resection may have altered the outcome in this once dismal presentation. We reviewed our experience with treatment and outcome of this acute abdominal emergency to determine if this is a terminal or salvageable event. Methods: Between January 1996 and October 2003, 28 patients were admitted with the diagnosis of acute ruptured HCC. All patients were followed up for a minimum of 3 months. Clinical data were obtained and reviewed retrospectively. Definition of terminal event was classified as death during the same hospital admission for rupture of HCC. RESULTS: The mean age at presentation was 64 years [range 31–90 years] with male predominance [86%]. The average maximal diameter of the ruptured tumour was 8.6 cm [range 4–16cm]. 68% of patients had a background of cirrhosis, largely secondary to hepatitis B infection. The most common presentation was abdominal pain, followed by abdominal distension and shock. Various modes of treatment were administered: conservative management [n=1], surgery [6], transarterial embolization alone [6] and transarterial embolization followed by surgery [5]. In-hospital mortality rate was 25% [7 of 28 patients], median survival time was 4 days. The only significant factors affecting outcome were presence of shock at time of presentation [p=0.003], underlying cirrhosis and Child-Pugh grading. Survival time was substantially long in the remaining patients who were discharged after treatment [median survival of 365 days]. CONCLUSION: Early mortality of ruptured HCC was associated with a poor pre-rupture disease state and presence of shock at presentation. In the majority of patients, rupture of HCC is not a terminal, but rather, a salvageable event. With current management and careful selection of patients, prolonged survival can be achieved.

200 SURGICAL RESULTS OF HEPATIC RESECTION FOR HEPATOCELLULAR CARCINOMA WITH DIAPHRAGMATIC INVOLVEMENT

Min-Che Lin and Cheng-Chung Wu, Department of Surgery, Taichung Veterans General Hospital, Taichung and Taichung Veterans General Hospital, Taichung, Taiwan Republic of China

PURPOSE: Direct diaphragmatic involvement is not uncommon in patients undergoing hepatectomy for hepatocellular carcinoma [HCC]. The purpose of the study was to retrospectively evaluate the surgical results of HCC with diaphragmatic involvement undergoing curative en bloc resection. MATERIALS AND METHODS: Between January 1989 and December 2002 53 patients who had HCC with clinical diaphragmatic involvement underwent curative en bloc resection in our hospital. During operation if a tumor was found to invade or densely adhere to the diaphragm, a cuff of the involved diaphragm was removed en bloc. The clinicopathological features, operative risks, 5-year disease-free and actuarial survival of the 53 patients were retrospectively studied. RESULTS: Of the 53 HCC patients with clinical diaphragm involvement, seven [13.2 %] were pathologically proved to have muscular invasion of diaphragm, the other 46 [86.8%] were fibrous adhesion only or free of tumor. Primary repair of diaphragm was adequate in 52 patients [98.1%] and one needed mesh repair. Thirteen patients [24.5%] developed postoperative complication with the leading cause of pleural effusion and no operative mortality occurred. Until March 2003 after a median follow-up of 25.0±26.4 [range 2.6–150.5] months the 5-year disease-free and actuarial survival were 11.0% and 21.0%, respectively. There is no significant difference between the patients with histological muscular invasion and those without muscular invasion in disease-free survival [p = 0.23] and actuarial survival [p = 0.59]. CONCLUSION: En bloc resection of involved diaphragm in HCC patients with clinical diaphragm involvement is justified as it is associated with acceptable operative risks and may achieve long-term survival.

201 A PROSPECTIVE ANALYSIS OF PERIHEPATIC LYMPH NODE STATUS IN PATIENTS UNDERGOING HEPATIC RESECTION FOR MALIGNANCY

Stephen R Grobmyer, Wang Liang, Yuman Fong, Ronald P Dematteo, Michael D'Angelica, Mithat Gonen, Lawrence H Schwartz, Leslie H Blumgart and William R Jarnagin, Memorial Sloan Kettering Cancer Center, New York, NY, USA

PURPOSE: Perihepatic lymph node metastasis is a significant negative prognostic factor in patients undergoing hepatic resection for malignancy. However, preoperative identification of patients with perihepatic nodal involvement is often difficult and previous studies have suggested a high incidence of occult metastatic disease. METHODS: Perihepatic lymph nodes were sampled from up to 3 stations [portal, hepatic artery, and periduodenal] at the time of hepatic resection in 79 patients undergoing partial hepatectomy for primary or secondary hepatic malignancy. Lymph nodes were measured on preoperative CT scan by radiologists blinded to operative and pathologic findings. Intraoperatively, lymph nodes were graded by the surgeon for suspicion of metastatic disease using a scale of 1–5 [1 = lowest suspicion of metastatic disease, 5 = highest suspicion of metastatic disease]. For the analysis, grades 1 or 2 were considered ‘low suspicion’ and grades 3, 4 or 5 were considered ‘high suspicion’. For CT measurements hepatic artery and periduodenal nodes were considered ‘positive’ if detectable; portal nodes were defined as positive if the cross-product of the dimensions was ≥0.65 cm . Pathologic findings were then correlated with radiographic findings and intra-operative findings. RESULTS: Indications for planned hepatectomy were metastatic colorectal cancer [n=60], hepatocellular carcinoma [9], peripheral cholangiocarcinoma [5], and other [5]. The percentage of patients in this series having a histologically positive lymph node was 13.9%. None of these lymph nodes were considered ‘low suspicion’ by the surgeon and 50% were considered ‘negative’ by radiologic criteria. The incidence of truly occult metastatic nodal disease was 0%. There was no significant difference in the percentage of positivity at each station: portal [6.8%], hepatic artery [7.1%], and periduodenal [6.8%]. Both clinical and radiologic assessments were valuable in assessing nodes [Table]. CONCLUSIONS: Routine perihepatic nodal sampling in patients undergoing resection for primary or secondary hepatic malignancy has a low yield. Preoperative CT scans and intra-operative assessment of nodes are useful in identifying patients in whom nodal sampling has a high yield.

SensitivitySpecificityCT assessment50%90%Intra-operative assessment100%88%

202 SELECTIVE INHIBITION OF IKB DEGRADATION BY CALPAIN-1 INHIBITOR AMELIORATES THE INDICES OF MURINE CERULEIN-INDUCED ACUTE PANCREATITIS

Ioannis Virlos, Ivana Serraino, Christoph Thiemermann, Salvatore Cuzzocrea and Ajith K Siriwardena, HPB Unit, Department of Surgery, Manchester Royal Infirmary, Manchester, UK, Institute of Pharmacology, Messina, Italy and Department of Experimental Medicine and Nephrology, London, UK

INTRODUCTION: Prevention of NF-κB activation down-regulates inflammatory gene expression and oxidative stress in acute pancreatitis [AP]. Calpain-1, an intracellular protease, plays an essential role in NF-κB activation by selectively degrading inhibitor factor B [iκB]. Specific inhibition of calpain activation by calpain-1 inhibitor may permit selective modulation of inflammatory pathways upregulated in AP. METHODS: Studies conformed to American Physiology Association guidelines. Male wild-type mice had free access to food and water and were randomly allocated to one of four groups [n=animals]: group 1 [n=10] sterile normal saline intraperitoneally [i.p.] [control]; group 2 [n=17] cerulein [50 µg/kg, in saline] i.p hourly for 5 h; group 3 [n=17] calpain-I inhibitor i.p. [5–20 mg/kg] 30 min before induction of AP and thereafter hourly cerulein i.p [×5] and group 4 [n=10] calpain-I inhibitor [5–20 mg/kg] 30 min before normal saline i.p. hourly [×5]. Mice were sacrificed 6 h after AP. Pancreata and lungs were snap-frozen in liquid nitrogen and stored at −80 °C until assayed. Histologic injury was quantified morphometrically. Principal end-points were: serum amylase and lipase, expression of adhesion molecule ICAM-1, nitrotyrosine, inducible nitric oxide synthase [iNOS], myeloperoxidase [MPO], malondialdehyde [MDA], and histologic evidence of lung and pancreas injury. Results were analysed by one-way analysis of variance with Bonferroni's correction. Significance was at p < 0.05. RESULTS: Intraperitoneal cerulein caused severe AP characterized by neutrophil infiltration, hemorrhagic necrosis and elevated amylase and lipase. Calpain-1 pretreatment resulted in significant reduction in amylase and lipase [p < 0.001 vs cerulein; p = NS vs control]. Immuno-histochemistry demonstrated a marked increase in activity for nitrotyrosine, iNOS and ICAM-1 in pancreata and lungs of cerulein-i.p. mice, which was abolished by calpain-1 pretreatment. MPO and MDA in both lung and pancreas were elevated in cerulein-induced AP. Calpain-1 pretreatment reduced MPO activity in lung [p < 0.05 vs cerulein] and pancreas [P < 0.05 vs cerulein]. Similarly, calpain-1 pretreatment reduced MDA in lung and pancreas. CONCLUSION: These findings provide the first evidence that calpain-1 inhibitor, a potent inhibitor of NF-κB activation, selectively attenuates both pancreatic and lung injury and the inflammatory pathways upregulated in experimental acute pancreatitis.

No. of patients12345678910Med.SDPancreatic necrosis [mg/kg]1726817614711312610067102129120+/ − 34Omental ascites [mg/kg]190101210261176187156190200159183+/ − 37

203 ANTIBIOTIC PENETRATION INTO PANCREATIC NECROSIS IN PATIENTS WITH NECROTIZING PANCREATITIS

Krzysztof Komorzycki, Wlodzimierz Otto and Krawczyk M, Medical University of Warsaw, Warsaw, Poland

AIM: To evaluate the rate of antibiotic penetration into pancreatic necrosis in patients treated for necrotizing pancreatitis with prophylactic piperacyline/tazobactam antibiotherapy. MATERIALS AND METHODS: The study was performed on necrotic tissue of the pancreas and inflammatory peripancreatic ascites derived from 10 patients [m.7, f.3, m.a.46] treated for necrotizing pancreatitis in 2001/2002. The treatment started with prophylactic piperacyline/tazobactam antibiotherapy that was maintained up to 14 days, in addition to TPN and intensive care, according to the prospective protocol. Patients were operated on day 18–21 of treatment for pancreatic necrosis. Samples of necrotic tissue of the pancreas and samples of the inflammatory ascites from omental bursa were collected during the operation and investigated for the concentration of the antibiotic by fluoroscopic/spectroscopic methods of registration in an HPLC system. The spectrometer was supplied with two independent monochromatic inductors and registration, xenon lamp and luminescence signal detector PMT with a spectrum range of 210–370 nm. Results: See Table below. CONCLUSIONS: The study indicates effective penetration of piperacyline/tazobactam to the inflammatory ascites surrounding the pancreas and to the tissue of the necrotic pancreas itself in acute necrotizing pancreatitis.

204 INTRAVENOUS SELENIUM MODULATES L-ARGININE-INDUCED EXPERIMENTAL ACUTE PANCREATITIS

Jon Hardman, Conor Shields, Paul Redmond and Ajith K Siriwardena, HPB Unit, Department of Surgery, Manchester Royal Infirmary, Manchester, UK and Academic Department of Surgery, Cork, Ireland

INTRODUCTION: Selenium is an essential cofactor in the antioxidant glutathione peroxidase pathway: one of the mechanisms of propagation of acinar cell injury in acute pancreatitis [AP]. Serum selenium levels are depleted in clinical acute pancreatitis with degree of depletion corresponding to severity. A clinical trial has suggested that oral selenium supplementation improves outcome in clinical AP but these findings remain unsubstantiated. This study tests the hypothesis that intravenous selenium supplementation given after disease induction modulates the course of experimental AP. METHODS: All studies complied with American Physiology Association guidelines for animal care. Male Sprague-Dawley rats were randomly allocated to one of 3 groups [n=5 per group] as follows: group 1 [control], no intervention; group 2, acute pancreatitis [AP] induced by intraperitoneal 1-arginine hydrochloride, 250 mgper 100 g body weight on day 0; group 3, AP + selenium [15 µg/kg] at 24 and 48 h after induction of AP. All animals were given buprenorphine for analgesia [previously demonstrated to have no effect on outcome in this model] and sacrificed at 72 h. Samples for pancreatic and lung histology were snap-frozen in liquid nitrogen and examined after H&E staining by a histopathologist blind to group allocation. Biochemical end-points were: serum amylase, serum antioxidant levels, bronchoalveolar lavage [BAL] protein and lung myeloperoxidase activity [MPO]. Statistical comparisons were by non-parametric tests with p < 0.05. RESULTS: L-Arginine induced AP characterized by oedema, neutrophil infiltration, acinar cell degranulation and elevated serum amylase. Selenium supplementation had no effect on serum selenium levels. However, selenium supplementation was associated with a reduction in BAL protein when compared with AP [p < 0.01; Mann-Whitney U-test]. In addition, acinar cell degranulation and pancreatic inflammatory cell infiltration were absent in selenium-treated animals. CONCLUSION: In this relatively prolonged study model intervention with selenium starting 24 h after induction of AP ameliorated histological stigmata of acinar cell injury and reduced pancreatic inflammatory infiltrate and had a protective effect on lung injury. These findings suggest that post-induction selenium can modulate pancreatic and lung injury in experimental AP.

205 SURGICAL TREATMENT OF CHRONIC PANCREATITIS WITH PANCREATIC MAIN DUCT DILATATION–LONG-TERM RESULTS AFTER HEAD RESECTION AND DUCT DRAINAGE

Wolfgang Schlosser, Andreas Schwarz and Hans Beger, University of Ulm, Ulm, Germany

INTRODUCTION: Tissue and duct hypertension is considered as a major factor in the etiology of pain in patients with chronic pancreatitis [CP]. Duct dilatation is a consequence of duct obstruction due to scars or duct stones. Nevertheless, the procedure of choice, drainage or resection, is still under discussion. We present long-term results of patients operated with duodenum-preserving pancreatic head resection [DPPHR] combined with a Partington-Rochelle duct drainage in cases of chronic pancreatitis with multiple stenosis and dilatation of the side ducts. METHODS AND PATIENTS: From April 1982 to September 2001 in 55 out of 538 patients with chronic pancreatitis a DPPHR with additionally Partington-Rochelle duct drainage was performed [44 male, 11 female, mean age 45.8 years]. 92% of the patients suffered from alcoholic pancreatitis. Medical respective pain treatment for chronic pancreatitis was in median 64.5 month prior to surgery. The indications for surgery were in 87% pain, 59% of the patients had an inflammatory mass in the head of the pancreas, 36% had a common bile duct stenosis and 5% had a severe stenosis of the duodenum. The endocrine function [OGGT] was impaired in 79% of the patients preoperatively. Hospital mortality was 0%, postoperative complications occurred in 11 patients. FOLLOW-UP: All except 2 patients were followed up in the outpatient clinic with a mean follow-up time of 69.7 month [8–61 months], the late mortality was 9%. 68% of the patients were completely free of pain, 29% had occasional pain, 3% suffered from a further attack of pancreatitis. Body weight increased in 79%, 58% were professionally rehabilitated. Late postoperative endocrine function was unchanged in 85% [improved in 5%, deteriorated in 10%]. CONCLUSION: The pain control in patients with multiple duct stenosis after duodenum-preserving pancreatic head resection with duct drainage leads to long-standing absence of pain and low recurrence rate of attacks of pancreatitis.

206 A CLINICALLY-BASED CLASSIFICATION SYSTEM FOR CHRONIC PANCREATITIS: ASSESSMENT IN COMPARISON TO THE MARSEILLES, CAMBRIDGE, HEIDELBERG AND ABC SYSTEMS OVER A 9-YEAR STUDY PERIOD

Anil Bagul, Srinivasan Balachandra, Santosh Rao and Ajith K Siriwardena, HPB Unit, Department of Surgery, Manchester Royal Infirmary, Manchester, UK

INTRODUCTION: Classifications of chronic pancreatitis [CP] based on either histologic [Marseilles] or endoscopic [Cambridge] criteria are not widely used. The aim of this study was to design a clinically based classification [CBC] for CP and to evaluate this in comparison to other systems over a prolonged period. METHODS: Patients with a diagnosis of CP [577.1:ICD-9] for 1994 were identified from the records of the Hepatobiliary Service of a University Hospital. Endoscopic [ERCP] or CT evidence were mandatory for inclusion. Twenty-three new patients met criteria and were allocated a category according to the Marseilles, Cambridge, Heidelberg and ABC systems and also according to a novel clinically based 3-stage system. Mild CP: abdominal pain + either ERCP or CT evidence of CP + obligatory; no regular [weekly] opiate, preserved endocrine, exocrine [ex/end] function and no peri-pancreatic complications [PPC]. Moderate CP: abdominal pain + at least one of: regular opiates, impaired ex/end function, no PPC. End-stage CP: ERCP or CT + at least one obligatory: biliary stricture, portal hypertension, duodenal stenosis±one of: pain, diabetes, steatorrhoea. Charts were reviewed for the subsequent 9-years with annual categorical allocation. Principal outcomes were death and progression to end-stage CP. RESULTS: [See Table]. The Cambridge, ABC, Heidelberg and clinically based systems all demonstrated a significant progression to end-stage disease over 9 years [P < 0.01 Kruskal-Wallis with post-correction]. CONCLUSION: This is the first study to compare multiple classification systems for CP, evaluating change in disease category over a prolonged observation period. The results confirm that for clinical categorization, the Heidelberg, ABC and clinically based scoring systems are valid and practical.

MarseillesCambridgeHeidelbergABCCBC1994–96N = 6;1 = 2;0 = 1;A = 4;Ml = 2;F = 15;2 = 10;A = 11;B = 16;M0 = 14;O = 23 = 7; 4 = 4B = 8; C = 3C = 3ES = 71996–99N = 2;1 = l; 2 = 7;0 = 0; A = 0;A = 0;Ml = 0;F = 12;3 = 3; 4 = 8B = 8;B = 4;M0 = 2;O = 4C = 12C = 14ES = 162000–03N = 0;1 = l; 2 = 3;0 = 0; A = 0;A = 0;Ml = 0;F = 4;3 = l; 4 = 8B = 2;B = 1;M0 = 0;O = 7C = 10C = 12ES = 13

Marseilles: N = CP + necrosis; F = CP + fibrosis; O = CP + Obs.

Cambridge: 0 = norm; 1 = equivocal; 2 = mild; 3 = moderate; 4 = marked

Heidelberg: 0 = stage0; A = stage A; B = stage B; C = stage C.

CBC system: Ml = mild; Mo = moderate; ES = end-stage.

207 RESECTION VERSUS HEAD CORING FOR HEAD MASSES IN CHRONIC PANCREATITIS

Hariharan Ramesh, George Jacob, Kurumboor Prakash, Deepak Varma, Vijayalakshmi Lekha, Ambadi Venugopal and Manoj Jacob, Lakeshore Hospital and Research Center, Cochin, India

AIM: Comparative study of resection [Whipple procedure] versus head coring [Frey procedure] in treatment of head masses in chronic pancreatitis. PATIENTS: During the period 1991–1997, 34 patients underwent head resection and 123 patients, a head coring. The two groups were similar in age, sex, etiology of pancreatitis, preoperative pancreatic function, associated co-morbid illnesses and size of mass. METHODS: The parameters studied were: 1. pain relief using a pain grading system, 2. functional results [endocrine and exocrine], 3. quality of life estimation. RESULTS: The resuls are shown in the Table. Patients with head coring had comparable relief of pain, with greater preservation of exocrine and endocrine function. CONCLUSION: Head resection causes severe pancreatic insufficiency and a poor quality of life in >50% of patients. Parenchyma-conserving operations are more suitable for patients with chronic pancreatitis.

ParameterHead resectionHead coringp valueNumber34123Mortality11NSHospital stay [days]1713NSPain relief31116NSDeterioration in endocrine status2122 1 cm should be attempted as an adequate margin is often underestimated.

227 COMBINED MODALITY TREATMENT AT OPERATION FOR HEPATIC METASTASES OF NEUROENDOCRINE AND CARCINOID TUMORS

Jennifer F Tseng, Lee C Pederson, Eddie K Abdalla, Carmen C Solorzano, Vickie G Ellis, Jean Nicolas Vauthey and Steven A Curley, UT MD Anderson Cancer Center, Houston, TX and University of Miami, Miami, FL, USA

BACKGROUND: Surgical cytoreduction and endocrine manipulation are the standard of care for neuroendocrine liver metastases. Recently, ablation has been used in conjunction with liver resection in patients who cannot be completely resected. METHODS/RESULTS: 82 patients [pts] undergoing operation for neuroendocrine liver metastases from 1995 to 2003 were identified from a prospectively gathered database. 45 [55%] were female. Mean age was 55.9 years [+/ − SD 13.5]. 49 [59.8%] of pts had carcinoid tumors; 31 pts [37.8%] had islet cell or non-carcinoid neuroendocrine tumors. 52% had evidence of endocrinopathy. Primary sites included pancreas [35.4%], small bowel [29.3%], colorectum [12.2%], and appendix/cecum [8.5%]. Mean time from primary resection to hepatic operation was 40 months [median 15.9] [Table] overleaf. Mean length of stay was 7.25 days [median 7, SD 3.4]. 19.5% of pts had complications, including abscess [n=4], hepatic insufficiency, biliary leak, and wound infection [n=2 each]. There were no perioperative deaths. Mean follow-up from liver diagnosis was 45.7 months [range 2.3–236.8]. Kaplan-Meier survival curves were generated for pts with carcinoid versus non-carcinoid tumors. Mean survival for pts with non-carcinoid neuroendocrine tumors was estimated at 109.5 months after liver diagnosis [mean 90.2, SE 7.5]. Pts with carcinoid tumors survived longer than patients with other neuroendocrine tumors; lack of deaths precluded precise estimates with current follow-up. CONCLUSIONS: Pts with neuroendocrine hepatic metastases can undergo surgical therapy with a moderate complication rate and hospital stay. Pts with carcinoid liver metastases may have longer survival than those with other neuroendocrine tumors. We recommend a combined strategy of liver resection performed together with ablative therapy of unresectable lesions, in order to debulk these progressive, often symptomatic tumors, because a significant proportion of affected patients will have meaningful long-term survival.

OperationNumber%Lobectomy1923.2Segmentectomy89.8Wedge56.1Ablation1417.1Anatomic + ablation2429.3Non-anatomic + ablation33.7Exploration/ biopsy only911Total82100

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228 EVOLUTION OF MISSING COLORECTAL LIVER METASTASES FOLLOWING INDUCTIVE CHEMOTHERAPY AND HEPATECTOMY

Dominique M Elias, Omar Youssef, Michel Ducreux and Valérie Boige, Institut Gustave Roussy, Villejuif, France

BACKGROUND: A dramatic response to chemotherapy in some patients with multiple bilateral and initially unresectable liver metastases [LM] from colorectal cancer sometimes leads to their disappearance from imaging studies. Our study was aimed at assessing the evolution of these metastases when they were also not found during liver surgery. PATIENTS: Among 104 hepatectomized patients for colorectal LM in 4 years, 15 patients were retrospectively eligible. Eligibility criteria were: initially unresectable LM, a dramatic response to chemotherapy and the complete disappearance of at least one LM on imaging studies [ultrasonography, computed tomography and magnetic resonance] during >3 months. In 4 patients [27%], the disappeared LM could be found and treated at laparotomy. The main selection criterion for the 11 studied patients of this series was the impossibility of finding and treating the disappeared LM sited in the remaining liver after hepatectomy, resulting in ‘missing LM’. RESULTS: After a median follow-up of 19 months [range 6–50] for the series, 8 patients among the 11 [73%] did not present any recurrence of the missing LM. The median follow-up was 20.5 months for these 8 patients. The 3 recurrences occurred respectively at 5, 5, and 8 months after surgery. CONCLUSION: The disappearance of LM after chemotherapy on high-quality imaging studies and after intraoperative liver exploration resulted in their definitive cure in approximately 70% of cases. The current dogma stipulating an obligatory resection of the initially affected part of the liver is no longer acceptable.

229 RESECTION MARGIN IN PATIENTS UNDERGOING HEPATECTOMY FOR COLORECTAL LIVER METASTASIS [A CRITICAL APPRAISAL OF THE 1-CM RULE]

Zaed Z Hamady, IC Camern, KR Prasad, GJ Toogood, J Wyatt and JPA Lodge, Hepatobiliary and Transplant Surgery Department and Pathology Department, Leeds Teaching Hospitals, Leeds, UK

AIMS: To evaluate the influence of resection margin involvement and its width on survival and postoperative disease recurrence after hepatectomy for colorectal liver metastasis. PATIENTS AND METHODS: Retrospective, longitudinal study of 294 consecutive patients, all underwent primary liver resection for colorectal metastasis between January 1993 and December 2001. Clinical, pathological and outcome data were reviewed using a prospectively collected database. Patients who died in hospital were excluded from disease recurrence analysis. Cases were stratified into those with involved and non-involved resection margins. Different non-involved margin widths were analysed against survival, recurrence rate, pattern [hepatic, extra hepatic] and timing [12 months] of recurrence. Univariate and multivariate analysis was carried out to assess which variables influenced patients’ survival. RESULTS: The 1-, 3-, 5-, and 10 years actuarial survival rates were 82%, 58%, 43%, 35%, respectively. The median survival was 46 months. Six factors were found to have an effect on survival by univariate analysis: age, primary nodal status, intraoperative blood transfusion, histological liver resection margin involvement, size of largest liver metastasis and presence of multiple satellite nodules. On multivariate analysis only primary tumour nodal status, intraoperative blood transfusion and resection margin involvement were significant predictors of survival after surgery. Further analysis of survival was then undertaken in patients whose resection margin was free of tumour. 1-, 2-, 5-, and 10-mm resection margin widths were found not to be significant in influencing patients’ survival or recurrence rate. They had no significant correlation to the recurrence pattern and timing of recurrence. CONCLUSION: A positive hepatic resection margin was associated with a higher incidence of postoperative recurrence and lower survival rate. The width of the resection margin did not influence the postoperative recurrence rate, pattern and timing of recurrence.

230 A STAGED OPERATIVE APPROACH FOR PATIENTS WITH SYMPTOMATIC CARCINOID-RELATED CARDIAC AND LIVER DISEASE

Michael L Kendrick, John D Christein, David M Nagorney and Florencia G Que, Mayo Clinic, Rochester, MN, USA

BACKGROUND: In patients with metastatic carcinoid disease, liver resection has been shown to be a useful method of palliation and improves survival. Carcinoid syndrome with significant right heart failure and liver congestion occasionally precludes liver resection due to operative risk. Our aim was to evaluate the outcome of patients following a staged operative approach of cardiac valve replacement prior to liver resection for symptomatic carcinoid syndrome. METHODS: A retrospective review of all patients from 1976 to 2003 of all patients having staged cardiac valve procedures and liver resection for carcinoid syndrome. RESULTS: A total of 5 patients [3 male] with a mean age of 54 [range 34–70] underwent liver resection for symptomatic metastases after cardiac valve replacement. Preoperatively, all patients all had significant symptomatic right heart failure and ‘pulsatile’ liver congestion presenting an operative risk preclusive for liver resection. All patients underwent tricuspid valve replacement with significant clinical improvement and subsequently underwent liver resection after a mean of 3 months [range 2–5]. Liver resection included a mean of 3 segments [range 2–4] in addition to subsegmental wedge resections to achieve a gross curative resection or maximal tumor debulking. Morbidity and mortality were 40% and 0% respectively. All patients are alive at follow-up for a mean of 52 [range 28–94] months. All patients had resolution of carcinoid-related symptoms after liver resection. Only two patients developed recurrent symptoms after 11 and 19 months requiring reinstitution of octreotide acetate [Sandostatin]. These data compare favorably with our institutional controls of patients undergoing liver resection for carcinoid syndrome without significant right heart failure. CONCLUSION: A staged surgical approach for patients with significant carcinoid-related, right heart failure and hepatic metastases is feasible, rendering a subgroup of patients candidates for liver resection to provide optimal palliation and improve survival.

231 HEPATOPANCREATODUODENECTOMY WITH ZERO MORTALITY FOR ADVANCED BILIARY MALIGNANCIES

Norihiro Kokudo, Masatoshi Makuuchi, Keiji Sano, Satoshi Matsukura, Hiroshi Imamura and Yasuhiko Sugawara, University of Tokyo, Tokyo, Japan

Hepatopancreatoduodenectomy [HPD] is theoretically a most curative en bloc resection for advanced biliary malignancies involving hepatoduodenal ligament. However, reported mortality and morbidity after HPD have been inhibitory high, around 20% and 100%, respectively, and HPD has not been accepted as a routine procedure for biliary cancers. To increase the safety of this aggressive procedure, we have devised three modifications: 1. preoperative portal vein embolization [PVE] to increase remnant liver volume over 40% and thus reducing the risk of postoperative liver failure, 2. omental graft to cover major arteries including common hepatic artery and the stump of gastroduodenal artery, 3. two-staged pancreatojejunostomy following complete external drainage of pancreatic juice. The latter two avoid the fatal outcome associated with pancreatojejunal anastomotic leakage. The whole procedures of HPD including the above modifications are presented in the video. PATIENTS: From January 1996 to July 2003, 10 cases underwent HPD. There were 6 cases with wide-spread bile duct cancer and 4 cases with gallbladder cancer. Eight cases underwent PVE and subsequent extended right hepatectomy. The %volume of the left liver increased from 36.0±2.5% [mean±SE] to 45.5±1.9%. Mean operative time was 822 min [range 625–1060] and mean intraoperative blood loss was 1256 ml [500–2060]. There was no mortality, and maximal postoperative serum level of total bilirubin was 2.3 mg/dl [0.4–7.9]. Morbidity rate was 50%, but most of them were not severe. Postoperative complications were intra-abdominal abscess [1 case], pancreatic leakage [3 cases], pulmonary embolism [1 case], and ileus [1 case]. Mean hospital stay was 34.7 days [16–63]. The 2nd stage reconstruction was performed 99–160 days [mean 116 days] after HPD. The median follow-up period was 15 months [2–91] and 3 patients died of recurrent disease. CONCLUSION: We have established a safe HPD procedure with 3 modifications listed above. Patient selection for HPD is yet to be determined.

232 PROXIMAL SPLENORENAL SHUNT FOR MASSIVE SYMPTOMATIC SPLENOMEGALY IN NON-CIRRHOTIC PORTAL HYPERTENSION

Sudeep R Shah, PD Hinduja Hospital, Mumbai, India

BACKGROUND: Massive splenomegaly with concommitant hypersplenism is a presenting feature in non-cirrhotic portal hypertension. Splenectomy with proximal splenorenal shunt is an effective solution for this. PATIENTS AND RESULTS: Six patients with non-cirrhotic portal hypertension were subjected to proximal splenorenal shunt surgery over the past 18 months for giant splenomegaly [>15 cm] with concommittant hypersplenism [platelets