HEPATOLOGY Vol. 22, No. 4, P t . 2, 1995 A A S L D A B S T R A C T S 4 5 5 A

1393 EFFECT OF A HIGH CHOLESTEROL DIET ON DNA SYNTHESIS DURING THE FIRST CELL CYCLE OF RAT LIVER REGENERATION. M Massimi, K Soroull, M Acosta, SFI Lear. and SK Erickson. Department of Medicine, University of California, San Francisco, and Department of Veterans Affairs Medical Center, San Francisco.

Cholesterol (Ch) plays an essential role for both cell growth and proliferation. Animal ceils may balance external and internal sources of Ch by regulating low density lipoprotein (LDL) receptor expression and 3-hydroxy-3-methylglutaryl 6oenzyme A reductase (R) activity, a rate-limiting enzyme for 5terol synthesis. In the presence of LDL or other lipeprotein source of Ch, R activity declines; when Ch demand declines both LDL receptors and R are repressed. Besides providing cells with endogenous Ch, R plays an additional and essential role in the control of cell growth by limiting the biosynthesis of mevalonate (MVA), the precursor of isoprenoid groups that are incorporated not only into sterols, but also into non-sterol products required for DNA replication. The present study was designed to determine whether the suppression of MVA synthesis by means of an increased exogenous Ch supply can affect cell proliferation. A unique in viva system for the study of MVA pathways in relation to the cell cycle is provided by the regenerating rat Tiver after partial hepatectomy (PH). As circadian rhythms have been shown to play important roles in regulating both liver regeneration and MVA and Ch metabolism, we performed our experiments on rats kept under either normal or reverse lighting cycles. Rats were fed with a high fat-high Ch diet for 48 h, subjected to 2/3 PH and analyzed at 24-26 h post surgery, the peak of S phase DNA synthesis. DNA synthesis was repressed -50% in normal light cycle animals fed the diet suggesting that a key factor was missing or much decreased. These animals had -5-10% of the R activity present in normal light cycle animals fed a control diet subjected to PH. Further, their LDL receptors were down regulated about 50% accompanied by increased serum ape E levels (2)0: No changes in the alpha-2-macroglobulin receptor (LRP) were observed. These data suggest entry into S phase was delayed or restricted under these conditions perhaps by availability of MVA and/or sterol6. In contrast, the reverse light cycle animals had the same or higher levels of DNA synthesis as their controls, and despite >90-95% inhibition of R, also had the same levels of LDL receptors, serum apoE, and LRP. This suggests that the requirements of the liver for entry of hepatocytes into S phase could be met in this system. The data taken together suggest that these treatment regimens have targeted diurnal rhythm-related elements important for liver regeneration.

1394 META-ANALYSIS OF MEDICAL TREATMENTS IN HEPATOCELLULAR CARCINOMA. P Mathurin 1. O Rixe 2, N ~ 1 p Clu=13, B B e r ~ d l ~ ~ , T-t-Z~ov~ 1Sf.e d'Hdpato-Gastroent~rologie, 2Sce d'Oneologie, 3See de Radiologie, Htpital Pitit-Salp~tri~re, 75651 Paris - France.

Medical treatments in hepatoceUular carcinoma have given conflicting results. The aim of this study was to identify the medical treatments associated with survival benefit at 1 year. Methods: Only mete-analysis of therapeutic medalities including more than 2 randomized trials have been performed. Efficacy has been assessed in intention to treat by Pete, and Der Simonian methods, sensitivity and heterogeneity analyses. Patients: 33 randomized trials have been studied including 2335 patients (pts). Adriamycin, 5 FU, tamoxifen, adjunction of lipiodol to intraarterial chemotherapy and postoperative adjuvant intmarterial chemotherapy have been evaluated. Results: There was no survival benefit at one year with adriamycin (7 trials, 445 pts, survival difference (m) = 4 %, 95 % CI: - 3% to 12%, p=0.24), 5 FU (3 trials, 187 pts, m = -13%, 95 % CI: - 28% to 2%, p=0.09). Adjunction of lipiodol to intraarterial chemotherapy (4 trials, 253 pts, m = 13%, 95 % CI: 5% to 34%, p=0.007) and tamoxifen ( 4 trials, 263 !0ts, m = 15 %, 95% CI: 0% to 31%, p=0.06) were associated with survival benefit at one year. The mean survival at one year, in tamoxifen group and intrarterial lipiodol chemotherapy group, was 44 % and 46 %, respectively. The postoperative adjuvant intraarterial chemotherapy was associated with a significant reduction of hepatocelluiar eareinoma recurrence at 1 year (4 trials, 87 pts,'m = 17 %, 95 % CI: 2%to 31%, p=0.02), and at 2 years (4 trials, 87 pts, m = 27%, 95 % CI: 10% to 44%, p--O.002). In the postoperative adjuvant intraarterial chemotherapy group, the mean percentage of patients free of recurrence at 1 year and 2 years was 75 % and 55%, respectively. Conclusion: 5 FU, adriarnyein and intraarterial chemotherapy (without embolization and lipiodol) were not associated with survival benefit at 1 year. ,In contrast tamoxifen and lipiodol intraarterial chemotherapy improved survival at 1 year.

1395 HEPATIC HEMODYNAMICS iN LIVING RELATED LIVER TRANSPLANTATION. T Matsumura.F Morivasu. T Nada. Y Ito.Y Suoinoshita. K ~gb6vashi. M Okurna.K Tanaka*,andY Yamaoka'. First Department of Internal Medicine,*Second Department of Surgery,Faculty of Medicine, Kyoto University,Kyoto,Japan.

Living related liver transplantation (LRLTx) has been developed as an alternative procedure to overcome the problem of a shortage of grafts for pediatric patients with end-stage liver disease. We pedormed LRLTx in 100 children. Doppler ultrasound (US) studies were carried out in all patients in order to assess the vascular anastomosis intraoperatively and for postoperative fallow-up monitoring of graft pedualon. Patienls and Methods:LRLTx was pedormed for 100 children in Kyoto University Hsspital between June 1990 and May 1995. in all patients, blood flow in the portal vein, hepaticvaln, and hepatlc artery were measured intra- and postoperatively using a Doppler US system. Results: 1 Hepatic artery: The pulsatility index (PI) and peak systolic velocity (Vp) of the reconstructed hepatic artery show Iowervaluasthan normal when anastomotic stenosis is present. Based on our experience regarding postoperative complications, we made it a rule to advise the surgeons to reanastomose the graft artery if intreoperative Doppler US showed a Vp value of less than 25cm/s and a PI value at less than 0.60. 2 Portal vein : Iotmoperative evaluation of portal venous hemodynamiss after implantation can serve as a guide for ligation of portosystemic collaterals and portal re-reconstruction. If intraopemtive Doppler studies revealed decreased portal blood flow (less than 9ml/min/kg) ,it was corrected by additional procedures, such as ,ligation of collateral pathways or re-reconstruction of the pedal vein, and portal blood flow was increased; 3 Hepatic vein: Hepatic venous flow obstruction is caused by anastomotic slenosis. It gradually develops and finally leads to decreased portal blood flow. In this case, the velocity waveform in the hepatievein shows nonpulsatite and is associated with remarkably decreased flow velocity in both the hepatic vein and portal vein. Conclusions: in LRLTx, serial intra- and postoperative Doppler US examination is a useful technique not only for the eariydiagnoalsof abnormal hemodynamics of graft circulation, but also for monitoring the therapeutic effects of procedures to correct vascularcomplicatlons.

1396 SPONTANEOUS BACTERIAL PERITONITIS (SBP);WHAT ISTHE BETTER TREATMENT? AA Mattos. Division of Gastroenterology and Hepatology. FundaGao Faculdade Federal de Ciencias M~dica de Porto Alegre, Brazil.

The aim of this study was to evaluate the importance. of the treatment of SBP with a third-generation cephalosporin. Material and Methods:Twenty four cirrhotic patients with SBPand 44withneutrocytic ascites (NA) werestudied. SBP was diagnosed in patients with positive ascitic culture,ascitic fluid neutrophil count>250/mm3,and no evident source of infection. NA was diagnosed in patients with negative ascitic fluid culture, ascitic fluid neutrophil count> 500/mm s, and no alternative explanation for the elevated ascitic fluid neutrophil count. 32 patients used cefotaxime (CE) in a dose of 2g IV q 8hrsand36usedaccmbination of antibiotics (CA) :gentamicin (3mg IV/Kg/day) plus ampicillin or cephalosporin (ig IV q 4hrs). Results:In the follow-up the complications (porto- systemic encephalopathy,renal insufficiency,upper digestive hemorrhage and septicemia, were similar in those with SBP and, NA - 83,3%and 65,9% (p> 0,05), although the mortality was greater in PBE (66,7%) than in NA (34,1%) (p<0,05).When we considered all patients (PBE and NA) the hospitalization mortality was greater in the group of CA (61,1%) than in the group of CE (28,1%) (p<0,05). Conclusion: In comparison to a combination of antibiotics CE is a better choice in the e~pyrical treatment of SBP incirrhotic patients.