Sulindac and exisulind exhibit a significant antiproliferative effect and induce apoptosis in human hepatocellular carcinoma cell lines.

This is the first report enumerating a superb antiproliferative effect of both sulindac and exisulind on hepatocellular cancer cell lines. The growth inhibition and cytotoxicity of sulindac in human hepatocellular carcinoma cell lines HepG2, Huh-7, and KYN-2 were investigated by studying cell growth, cell cycle distribution, and induction of apoptosis. In the presence of sulindac, there was a marked time- and dose-dependent decrease in cell proliferation and viability. Also, exisulind exhibited a similar growth-inhibitory effect on the KYN-2 cell line. The findings of this study suggest that sulindac exhibits a growth-inhibitory effect on human hepatocellular carcinoma cell lines; therefore, these drugs might serve as an effective tool for hepatocellular carcinoma chemoprevention.

Synergistic effect of ubiquitin on lipopolysaccharide-induced TNF-alpha production in murine macrophage cell line RAW 264.7 cells.

Ubiquitin synergistically augmented the production of tumor necrosis factor alpha (TNF-alpha) in the presence of lipopolysaccharide (LPS) in murine macrophage cell line RAW 264.7. To investigate the mechanism of this augmentation, we analyzed the effect of ubiquitin during TNF-alpha mRNA synthesis and degradation, and TNF-alpha degradation on RAW 264.7 cells stimulated by LPS. It is found that ubiquitin augmented TNF-alpha mRNA synthesis. Ubiquitin did not affect the degradation of TNF-alpha mRNA and TNF-alpha. In the presence of LPS, extracellular accumulation of TNF-alpha by ubiquitin was twice than those by LPS, but intracellular accumulation of TNF-alpha produced by ubiquitin with LPS or by LPS had no difference. These data indicate that ubiquitin might induce TNF-alpha accumulation mainly by up-regulation of the TNF-alpha gene transcription. Although extracellular functions of ubiquitin remain largely unknown, we postulate that ubiquitin might be involved in the modulatory mechanisms of immune response.

The clinicopathological significance of heparanase and basic fibroblast growth factor expressions in hepatocellular carcinoma.

Heparan sulfate plays an essential role for insolubility of the components of extracellular matrix and represents a storage depot for various growth factors. Therefore, heparanase produced by a given tumor may facilitate tumor invasiveness and angiogenesis through the release of heparan sulfate-bound growth factors. Although the growth factors responsible for angiogenesis in hepatocellular carcinoma (HCC) have recently been investigated, the clinicopathological significance of heparanase in connection with basic fibroblast growth factor (bFGF) expression in HCC has not been evaluated so far. Fifty-five patients who had undergone hepatic resection for HCC without preoperative treatment were included in the present study. Expression of heparanase mRNA was evaluated by reverse transcription-PCR, and bFGF was examined by Western blotting using a monoclonal antibody. Tumor angiogenesis was evaluated by immunostaining with a factor VIII-related monoclonal antibody. Expression of heparanase mRNA was detected in 47% of HCCs and was significantly correlated with larger tumor size (P = 0.01), presence of portal vein invasion (P = 0.01), and higher overall tumor invasiveness (P = 0.02). Moreover, its expression was correlated with tumor microvessel density (MVD; P = 0.02). There was a direct correlation between the levels of bFGF proteins and MVD in HCCs (P = 0.0001), and, furthermore, concomitant expression of bFGF and heparanase was associated with higher tumor MVD as compared with expression of either factor alone (P = 0.01). In conclusion, the expression of heparanase in HCC enhances growth, invasion, and angiogenesis of the tumor, and bFGF seems to be a potent angiogenic factor for HCC.

Spontaneous apoptosis in advanced esophageal carcinoma: its relation to Fas expression.

The prognostic importance of spontaneous apoptosis and its correlation with clinicopathological characteristics and Fas expression have yet to be delineated in esophageal carcinoma. Specimens from 65 patients with advanced squamous cell carcinoma of the esophagus were used for immunohistochemical evaluation of Fas, proliferating cell nuclear antigen, and apoptosis. The mean apoptotic index (AI) of 65 tumors was 1.38 +/- 0.99% (range, 0.10-4.49%). Thirty-nine (60.0%) patients had a high AI, and 26 (40.0%) patients had a low AI. Low AI was correlated with advanced tumor stage (P = 0.0197) and weak Fas expression (P = 0.0093). Patients with a low AI had significantly (P = 0.0095) worse survival than those with a high AI. However, by multivariate analysis, low AI alone was not an independent prognosticator. When combined with cellular proliferation index, AI became an independent prognostic factor (P = 0.0283) in this group of patients. Our results suggest that enhanced Fas expression is responsible for high AI in squamous cell carcinoma of the esophagus. High AI, combined with the cellular proliferation labeling index, could be an independent prognostic indicator.

Prognostic significance of Fas and Fas ligand expressions in human esophageal cancer.

Esophageal carcinomas have recently been shown to express Fas ligand (FasL) and down-regulate Fas to escape from host immune surveillance. However, the prognostic importance of Fas/FasL and their correlation with clinicopathological characteristics are yet to be delineated in this highly malignant carcinoma. Specimens from 106 esophageal squamous cell carcinoma patients were used for immunohistochemical evaluation of Fas, FasL, and CD8 expressions. Fifty-two (49%) and 34 (32%) patients were positive for FasL and Fas, respectively. There were no associations between FasL expression and clinicopathological characteristics except lymph vessel invasion. Strong FasL expression correlated with significant (P = 0.0011) decrease in tumor nest CD8+ cells. However, neither FasL nor CD8+ had any impact on patient survival. Strong Fas expression was correlated with depth of invasion (40.3% in pT1,T2 versus 20.5% in pT3,T4; P = 0.0308), histological differentiation (45.7% in well versus 25.4% in nonwell; P = 0.0347), and lymph node metastasis (22.6% in positive versus 45.5% in negative; P = 0.0129). Fas expression was one of the independent favorable prognosticators for patients' survival (risk ratio, 3.26; P = 0.0103) in esophageal SCC. Fas expression was an independent prognosticator for recurrence-free survival, whereas FasL expression did not influence the survival in esophageal squamous cell carcinoma. Down-regulation of tumor Fas may be the hallmark of immune privilege for the tumor, thus causing the patients' poorer outcome. Tumor FasL may counterattack the host immune cells to such an extent that the prognosis is not affected.

Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients.

The role of cyclooxygenase-2 (COX-2) in tumor neovascularization of human colorectal carcinoma is yet to be delineated. One hundred colorectal carcinoma specimens were evaluated for COX-2 expression and CD34-stained microvessel density (MVD) by immunohistochemical methods. The relationships between COX-2 expression and clinicopathological feature of the patients, MVD, and survival time were analyzed. Increased COX-2 expression was significantly correlated with pathologically unfavorable findings such as tumor size (> 3.0 cm), tumor differentiation (poor, moderate > well differentiated), number of metastatic lymph nodes (24), and Dukes' stage (Dukes' B, C, and D). Larger number of microvessels congregated around the COX-2-expressing area, and the Spearman rank correlation test showed a strong correlation between COX-2 expression and tumor MVD (P < 0.0001). Patients with COX-2-positive tumors had a significantly (P = 0.037, by log-rank test) shorter survival time than those with negative tumors did. In the multivariate analysis, however, only Dukes' stage and number of metastatic lymph nodes remained as independent prognostic factors. Augmented tumor neovascularization may be one of the several effects of COX-2 responsible for poor prognosis in human colorectal carcinoma patients.

Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases.

Expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) has been reported to be responsible for enhanced tumor growth and angiogenesis in various tumors. However, the relationships between tumor vascularity and COX-2 and iNOS expression have not been evaluated in hepatocellular carcinoma (HCC). In this study, we examined the expression of iNOS and COX-2 and microvessel density (MVD) by immunohistochemical staining in 100 tissue sections collected from HCC patients. iNOS expression was significantly higher in hepatitis C virus (HCV)-positive HCCs (P = 0.011). COX-2 expression was significantly correlated with iNOS expression (P = 0.046) and tumor MVD (P = 0.011) in HCV-positive HCCS: iNOS expression was neither correlated with MVD nor had any influence on patient survival; however, combined negative expression of iNOS and COX-2 had a significant impact on patient survival (P = 0.041 and 0.018, log-rank test for overall and recurrence-free survival rate, respectively). The present findings suggest that combined expression of iNOS and COX-2 may play an important role in prognosis of HCV-positive HCC patients and that this could be partially attributable to modulation of angiogenesis by COX-2.

Preventive effect of FK143, a 5alpha-reductase inhibitor, on chemical hepatocarcinogenesis in rats.

The incidence of hepatocellular carcinoma (HCC) is more prevalent in males than in females. 5alpha-Dihydrotestosterone is the most potent form of androgen and is converted from testosterone by 5alpha-reductase. The antitumor effect of a 5alpha-reductase inhibitor (FK143) was evaluated in a rat chemical hepatocarcinogenesis model (Solt-Farber). Male Fischer 344 rats were used in three groups: (a) control group; (b) low-dose FK143 (FKL) group (20 ppm FK143); and (c) high-dose FK143 (FKH) group (200 ppm FK143). The numbers of both glutathione S-transferase placental form-positive foci (P < 0.05) and hyperplastic nodules (HNs; P < 0.01) in the liver were significantly lower in the FKL group than in the control group. The numbers (P < 0.05) and tumor volume (P < 0.01) of HCCs per liver were significantly lower in the FKL group when compared with the control group. All HCCs were well differentiated in the FKL group, whereas 38% and 36% of HCCs were moderate to poorly differentiated in the control group and the FKH group, respectively. The proliferating cell nuclear antigen labeling index:apoptotic index ratios of enzyme-altered foci, HNs, and HCCs were significantly lower in the FKL group than in the control group. Serum 5alpha-dihydrotestosterone was significantly lower in both the FKL and FKH groups. However, a high dose of FK143 (200 ppm) provided no protection against hepatocarcinogenesis, and the level of serum testosterone was elevated in this group when compared with that in the control group. The low dose of FK143 significantly suppressed the formation of enzyme-altered foci, HNs, and HCCs in rat hepatocarcinogenesis. This may indicate that 5alpha-dihydrotestosterone enhances hepatocarcinogenesis. We conclude that an optimal dose of FK143 may have a suppressive effect on hepatocarcinogenesis.

Adjuvant chemotherapy with epirubicin and carmofur after radical resection of hepatocellular carcinoma: a prospective randomized study.

The intrahepatic recurrence rate is extremely high, even after radical resection of hepatocellular carcinoma (HCC). One report showed intra-arterial administration of epirubicin to be effective in the treatment of nonresectable HCC. We evaluated the effect of postoperative adjuvant chemotherapy including this drug. Fifty-seven patients who had undergone radical resection of HCC were entered in this study. Using the sealed-envelope method, 27 patients were assigned to a group undergoing resection only and 29 patients to a group also receiving adjuvant chemotherapy after resection. The protocol of the chemotherapy was intra-arterial administration of epirubicin (40 mg/m2) at 1 month after resection followed by intravenous administration of epirubicin (40 mg/m2) every 3 months for 2 years. In addition, 1-hexylcarbamoyl-5-fluorouracil (HCFU; carmofur), 300 mg/d, was administered orally every day, beginning from 1 month after the resection and continuing (in principle) for 24 months. The clinicopathologic backgrounds were well randomized between the two groups. The chemotherapy protocol was performed completely in only five patients (7.2%). Twenty-four (82.8%) patients had to cease the protocol due to various reasons: change to a new therapy after recurrence of HCC in 19 cases (79.2%), severe side effects of the chemotherapy in three cases (12.5%), liver failure in one case (4.2%), and a postoperative complication in one case (4.2%). The mean total doses were 128 +/- 114 mg for epirubicin and 144 +/- 84 g for HCFU. The cumulative overall and disease-free survival rates for 5 years were not significantly different between the two groups. The results of this prospective randomized study suggest that this adjuvant chemotherapy protocol with epirubicin and HCFU after radical resection of HCC was not effective.

Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: a comparison of epirubicin and doxorubicin (second cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan.

A randomized, controlled clinical trial was conducted to compare the use of epirubicin (EPI) and doxorubicin (DOX) in Lipiodol (Laboratoire Guerbet, Roissy-Charles-de-Gaulle Cedex, France)-transcatheter arterial chemoembolization as a treatment of hepatocellular carcinoma. One hundred ninety-two hospitals participated, and 415 patients were enrolled in the study during the period between October 1989 and December 1990. The patients were randomly allocated to group A (EPI) or group B (DOX) by a centralized telephone registration. The actual doses of EPI and DOX were 72 mg/body and 48 mg/body, respectively. The 1-, 2-, and 3-year survival rates were, respectively, 69%, 44%, and 33% for group A and 73%, 54%, and 37% for group B. There were no statistically significant differences (P = .2296, log-rank test). When each group of patients was classified retrospectively into high-risk and low-risk subgroups based on the severity index calculated by the Cox regression model from the significant prognostic factors (the pretreatment tumor size, the pretreatment serum alpha-fetoprotein level, tumor encroachment, and Child's classification), the survival curve of the low-risk DOX subgroup was significantly superior to that of the low-risk EPI subgroup (P = .0182). However, there was no significant difference between the high-risk subgroups (P = .4606). The change in the serum alpha-fetoprotein level, the extent of Lipiodol accumulation in the tumor, and the extent of tumor reduction after the treatment did not show any significant differences between the groups. The white blood cell count in group B showed a tendency to decrease slightly more than in group A at 3 weeks after Lipiodol-transcatheter arterial chemoembolization. In conclusion, there was no statistically significant difference between the survival curves of the EPI and DOX groups in Lipiodol-transcatheter arterial embolization treatment of hepatocellular carcinoma.

Beneficial effect of cyclosporine pretreatment in canine liver ischemia. Enzymatic and electronmicroscopic studies.

The effect of cyclosporine on hepatic ischemia was investigated. Hepatic ischemia was produced for 90 min in mongrel dogs. Experimental dogs were divided into three groups as follows: group A (control group), group B (CsA pretreatment group), group C (CsA posttreatment group). CsA was administered at a dose of 10 mg/kg body weight/day for 3 days in the pre- or postoperative period. Survival rates were 61.5% in group A, 84.6% in group B, and 30.8% in group C. Enzymatic activity such as aspartate aminotransferase and lactate dehydrogenase was highest in group C, lowest in group B, and intermediate in group A. Opposite results were obtained for serum albumin concentrations. The mechanisms of the effect was investigated using a 60-min hepatic ischemia model. Serum levels of beta-glucosidase and beta-galactosidase in group B were lower than those in group A and group C. Electronmicroscopic specimens taken at 16 h after 60-min hepatic ischemia demonstrated that the extent of ischemic injury was mildest in group B. The present study demonstrated a beneficial effect on hepatic ischemia of CsA administered for 3 days prior to the ischemia. One of the mechanisms for this beneficial effect could be the stabilization of lysosomal membranes. These results suggest that CsA should be administered to a donor before organ harvesting for liver transplantation because of this beneficial effect.

Attenuation of ischemia-reperfusion injury of the liver in dogs by cyclosporine. A comparative study with allopurinol and methylprednisolone.

The effects of pretreatment with cyclosporine, allopurinol, or methylprednisolone on ischemia-reperfusion injury of the liver were investigated. A total of 32 adult mongrel dogs that received one of the pretreatments were divided into four groups and were subjected to 90 min liver ischemia. Serum activities of aspartate aminotransferase (s-AST) and lactate dehydrogenase, (s-LDH) as well as animal survivals were used as indicators of liver injury. The elevation of both s-AST and s-LDH was significantly suppressed by pretreatment with cyclosporine as much as by allopurinol. However a significant improvement in animal survival was obtained only in the cyclosporine-pretreated group. Pretreatment with methylprednisolone did not affect either the activities of s-AST and s-LDH or animal survivals when compared with the control group. These data suggest that cyclosporine is a potent protector against ischemic liver injury--as effective as allopurinol or methylprednisolone. Although the precise mechanism of the effect of cyclosporine on liver ischemia still remains unknown, these observations may be of use in liver transplantation.

The salutary effect of FK506 in ischemia-reperfusion injury of the canine liver.

The present study was designed to elucidate the effect of FK506 on 90 min of warm ischemia of the liver and reperfusion in 30 dogs. Three groups of animals were studied. Group 1 animals received FK (0.15 mg/kg/day) for three days prior to the ischemia and group 2 animals got 2 ml of saline solution for three days instead of FK and were considered controls. In group 3 FK (0.15 mg/kg/day) was injected immediately upon reperfusion and two days thereafter. Evaluation of the effectiveness of the drug was monitored by measuring the serum activities of AST, ALT, LDH, serum total bilirubin, malondialdehyde, and by histopathological examinations of the liver specimens and survival of the animals for 7 days after reperfusion. The 7 day survival of the animals in group 1 (80%) was significantly (P < 0.05) improved compared with those in group 2 (30%) and group 3 (20%). The serum activities of AST, ALT, and LDH and total bilirubin were significantly lower in group 1 than in group 2 and group 3. FK pretreatment significantly prevented hepatocellular necrosis and neutrophilic infiltration in group 1 in comparison with those in group 2 and group 3. Although the malondialdehyde level in hepatic venous blood was relatively lower in group 1, this difference was not statistically significant. Three days FK pretreatment prevented hepatocellular injury and enzyme leakage after 90 min of hepatic ischemia, whereas FK treatment immediately upon reperfusion failed to do so. In conclusion, donor organ pretreatment with FK may become a promising strategy for improved allograft survival in liver transplantation.

Beneficial effects of FK409, a novel nitric oxide donor, on reperfusion injury of rat liver.

BACKGROUND: Nitric oxide (NO) seems to play an important role in modulating tissue injury during reperfusion of the liver. In this study, we have evaluated and compared the effects of FK409 (FK), a potent spontaneous NO releaser, and L-arginine in ischemia-reperfusion injury of the rat liver. METHODS: Male Sprague-Dawley rats underwent 90 min of hepatic ischemia followed by reperfusion. FK or L-arginine was used (intravenously) in two different doses for each drug (group I, 3.2 mg/kg FK; group II, 1.6 mg/kg FK; group IV, 100 mg/kg L-arginine; and group V, 300 mg/kg L-arginine). Saline was used in control animals (group III). Hepatic enzyme status, microcirculation, serum nitrite (NO2-) and nitrate (NO3-) and tissue injury score were evaluated at predetermined times. RESULTS: Serum NO2-/NO3- was elevated immediately by FK treatment dose-dependently but not by L-arginine. However, L-arginine caused late (6-24 hr) elevation of the NO metabolites dose-dependently. The elevation of serum aspartate aminotransferase and alanine aminotransferase was suppressed and hepatic microcirculation was improved in the FK-treated groups dose-dependently. L-Arginine also improved the microcirculation, but hepatic enzymes at 24 hr of reperfusion were significantly higher in group V than in the control group. These findings were well reflected by the extent of tissue injury in respective groups. CONCLUSION: FK treatment in the immediate reperfusion period improves hepatic microcirculation and confers a significant protective effect on hepatic ischemia-reperfusion injury in the rat.

Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues.

Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule. The susceptibility of tumors to fluoropyrimidines is reported to correlate with tumor levels of these enzymes. To obtain some insight into the tumor types susceptible to fluoropyrimidine therapy, we measured expression levels of these two enzymes in various types of human cancer tissues (241 tissue samples) by the ELISA methods. DPD exists in all the cancer types studied, such as bladder, breast, cervical, colorectal, esophageal, gastric, hepatic, pancreatic, prostate, and renal cancers. Among them, the cervical, hepatic, pancreatic, esophageal, and breast cancer tissues expressed high levels of DPD (median >70 U/mg protein), while high concentrations of the dThdPase were expressed in esophageal, cervical, breast, and pancreatic cancers and hepatoma (median >150 U/mg protein). The dThdPase/DPD ratio, which was reported to correlate with the susceptibility of human cancer xenografts to capecitabine, was high in esophageal, renal, breast, colorectal, and gastric cancers (median ratio of >1.5). In any of these three parameters, the inter-patient DPD variability for each cancer type was much larger than the DPD variability among cancer types; highest/lowest ratios for dThdPase, DPD, and dThdPase/DPD were 10-321, 7-513, and 2-293, respectively. These results indicate that measurements of the three parameters, DPD, dThdPase and dThdPase/DPD, would be useful criteria for selecting cancer patients suitable for fluoropyrimidine therapy rather than for selecting cancer types.

Dukes' classification as a useful staging system in resectable squamous cell carcinoma of the esophagus.

Dukes' classification for colorectal cancer is simple and has been widely used as a valuable prognostic indicator. It has been used as an assessment of gastric cancer, but it has not been evaluated for esophageal cancer. Of 251 patients with primary squamous cell carcinoma of the thoracic esophagus between February 1981 and April 1999, 155 patients underwent esophagectomy with a curative intent. Clinicopathologic characteristics of those 155 patients were retrospectively investigated according to the Dukes', tumor node metastasis (TNM) and Japanese staging systems. Dukes' classification showed a clear correlation between tumor stage and survival. The 3-year and 5-year survival rates of 64 Dukes' A cases were excellent (97.4% and 93.7%), good for 12 Dukes' B (75% and 75%), and poor for 79 Dukes' C (50.5% and 43.4%), respectively (P < 0.05; Dukes' A vs B, P < 0.0001; Dukes' A vs C, P < 0.10; Dukes' B vs C). TNM stage classification also showed a good correlation between tumor stage and survival, but there were no significant differences between stage 0, I and stage IIA cases (P = 0.2678) and between stage III and stage IV cases (P = 0.8298). In the Japanese staging system, there were no significant differences among stage 0, stage 1, and stage 2 cases (P = 0.4093). Dukes' classification was significantly correlated with tumor size, Borrmann type, histological type, and vessel invasion. Subdivision of Dukes' C according to the number of positive lymph nodes (1-4 vs > or = 5) showed a clearer correlation with survival rather than other subdivisions, such as the metastatic lymph node ratio (< 1.0 vs > 1.0) or the site of lymph node metastasis. Dukes' classification, which incorporates the number of positive lymph nodes, correlates well with tumor progression and provides a simple useful staging system after curative esophagectomy for esophageal cancer. Dukes' A tumor could be proposed as a criterion of early esophageal carcinoma.

Modified distal splenorenal shunt with expanded polytetrafluoroethylene interposition.

Two types of modified distal splenorenal shunt with expanded polytetrafluoroethylene (Gore-Tex; WL Gore & Associates Inc., Elkton, Md.) interposition were performed in 18 consecutive patients with esophageal or esophagogastric varices. There were 12 men and six women ranging in age from 32 to 76 years. The causes of portal hypertension were cirrhosis of the liver in 15 patients, chronic hepatitis in two, and idiopathic portal hypertension in one. In five patients the left gastric vein branched off from the splenic vein; bilateral gastric venous decompression was achieved by preserving the splenic vein. Porta-azygos disconnection was routinely performed by confirming repeated intraoperative direct splenoportography. The operations were elective in seven and were emergencies in five patients. Six patients underwent a prophylactic shunt; all patients had "red color signs" endoscopically, and three of them had concomitant hepatocellular carcinoma. Postoperative morbidity was minimal and there was no mortality. Shunt patency was confirmed angiographically in all patients 14 to 56 days after surgery. The varices disappeared or significantly improved in all patients. No patients had variceal bleeding postoperatively. Hepatic encephalopathy was transiently seen in one (the oldest) patient.

Clinical comparison between original and modified distal splenorenal shunts.

This article reports on a retrospective clinical comparison between the original Warren shunt and one that we modified with Gore-Tex (expanded polytetrafluoroethylene) interposition. The former operation was performed on 35 patients between June 1969 and November 1983 and the latter on 29 patients between October 1983 and January 1986. There were no significant differences in the patients' backgrounds between the two study groups. Blood loss during surgery was significantly greater and operation time was longer in the original shunt group than in the modified shunt group. The incidence of postoperative morbidity and mortality was also significantly higher in the former group than in the latter (major complication rate: 20.0% versus 3.4%; operative death within 1 month: 5.7% versus 0%; in-hospital death: 11.4% versus 3.4%). The modified shunts had a 100% patency rate, and no variceal bleeding was evident, whereas shunt occlusion was observed in two patients and portal thrombosis in one patient of the original shunt group. The incidence of hepatic encephalopathy was 14.3% in the original shunt group and 6.9% in the modified shunt group, and the follow-up time was shorter in the latter group. A significantly greater rate of survival was achieved with the modified Warren shunts. Thus the current study seems to indicate that our modifications could be alternatives to the original distal splenorenal shunt in terms of postoperative morbidity, mortality, and survival.

Suppressed endothelin-1 production by FK506 and cyclosporin A in ischemia/reperfusion of rat small intestine.

BACKGROUND: Endothelin-1 (ET-1), a novel vasoconstrictor, possibly plays a role in the mediation of ischemia/reperfusion (I/R) injury. Tacrolimus (FK506) and cyclosporin A (CsA) were reported to maintain tissue microcirculation of the liver subjected to I/R. This study investigated the effects of these immunosuppressants on intestinal I/R in terms of intestinal tissue microcirculation associated with ET-1. METHODS AND RESULTS: Male S-D rats were pretreated twice with FK506 (0.2 mg/kg), CsA (10 mg/kg) or only saline solution (0.5 mL). The tissue microcirculation in the control was reduced after I/R (29% +/- 10%) accompanied by hypotension, increased tissue ET-1 expression (25.0% +/- 6.4% to 67.9% +/- 5.0% 60 minutes after reperfusion), and increased ET-1 level in the portal blood (3.4 +/- 0.9 to 23.6 +/- 6.1 pg/mL). FK506 suppressed ET-1 expression (27.3% +/- 5.2%, 4.1 +/- 2.2 pg/mL), maintained microcirculation (96% +/- 16%), and blood pressure, reduced histologic damage, and improved survival. CsA had a similar but weaker effect compared with FK506. An additional experiment was performed with BQ485Na (BQ), an ETA receptor antagonist, to evaluate the genuine role of ET-1. BQ showed almost the same effects as FK506. CONCLUSIONS: FK506 and CsA, particularly the former, maintain microcirculation and protect the tissue from I/R injury by suppressing the production and release of ET-1.

Results of left gastric vena caval shunt for esophageal varices: Analysis of one hundred clinical cases.

A new selective shunt operation, namely left gastric vena caval shunt, has been applied to 100 patients with esophageal varices, including 77 with cirrhosis of the liver and 19 with so-called idiopathic portal hypertension. Early death occurred in 3.0 percent and postoperative rebleeding from esophageal varices in 10.4 percent. The 5 year survival rate was 78.0 percent and the rehabilitation status of the surviving patients has been satisfactory, without any signs of hepatoencephalopathy. The shunt was proved to be patent in about 90 percent of the patients.