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As experience with laparoscopic cholecystectomy (LC) has increased, so have the number and variety of complications. We report a case of choledocholithiasis caused by migration of a surgical clip applied during LC. A 57-year-old Japanese man who had undergone LC 6 years previously was referred to our hospital with pruritus and jaundice. Magnetic resonance cholangiopancreatography and ultrasonography revealed a solid mass in the common hepatic duct and dilatation of the intrahepatic bile ducts. Abdominal arteriography demonstrated interruption of the right hepatic artery by surgical clips. Five days after a biopsy of the mass was performed through a percutaneous transhepatic biliary drainage tube, the mass moved to the terminus of the common bile duct along with one of the surgical clips. A basket catheter was used to remove the mass via endoscopy. Despite the fact that other clips in the common hepatic duct were partially exposed, the patient has been well for 2 years with no additional interventions.

The mechanism of nitrate tolerance is poorly defined. We studied the rat P450 (CYP)-catalyzed conversion of organic nitrate to nitric oxide (NO) by purified CYP isoforms and the relationship between P450 expression and nitrate tolerance following continuous infusion of organic nitrates in rats. CYP1A2 effectively formed NO from isosorbide dinitrate and nitroglycerine (NTG). The hypotensive effect of an NTG bolus injection was abolished in rats which had been previously given a continuous 48 h infusion of NTG. Nitrate tolerance was reversible to control levels 2 days after cessation of the continuous infusion. At 48 h after infusion, NTG-induced NO generation of the vessels increased in acetone (a P450 inducer)-pretreated rats, and nitrite and nitrate levels were markedly greater than in normal rats. The appearance and disappearance of P450 isoforms paralleled the conversion of organic nitrates to NO as assessed by immunohistochemistry and Western blotting. Our observations indicate that nitrate tolerance is in large part the result of decreased P450 expression and activity. Interventions that maintain or increase P450 activity may be a useful strategy to provide sustained relief from ischemic conditions in humans.

Dietary nitrate is reduced to nitrite by some oral bacteria and the resulting nitrite is converted to nitric oxide (NO) in acidic gastric juice. The aim of this study is to elucidate the pathophysiological role of dietary nitrate in the stomach. Intragastric administration of nitrate rapidly increased nitrate and NO in plasma and the gastric headspace, respectively. Water-immersion-restraint stress (WIRS) increased myeloperoxidase (MPO) activity in gastric mucosa and induced hemorrhagic erosions by a nitrate-inhibitable mechanism. In animals that had received either cardiac ligation or oral treatment with povidone-iodine, a potent bactericidal agent, administration of nitrate failed to increase gastric levels of NO and to inhibit WIRS-induced mucosal injury. WIRS decreased gastric mucosal blood flow by a mechanism which was inhibited by administration of nitrate. These data suggested that the enterosalivary cycle of nitrate and related metabolites consisted of gastrointestinal absorption and salivary secretion of nitrate, its conversion to nitrite by oral bacteria and then to NO in the stomach might play important roles in the protection of gastric mucosa from hazardous stress.

Background. Preoperative percutaneous transhepatic portal vein embolization (PTPE) increases the safety of liver resection and improves the outcome after surgery for hepatocellular carcinoma. Scintigraphy with 99mTc-galactosyl human serum albumin (GSA) causes specific binding to viable hepatocytes and serves as an index of liver function. Materials and methods.99mTc-GSA scintigraphy was performed before and 2 weeks after PTPE of the right portal vein in 16 patients. The total receptor index, reflecting overall liver function, right receptor index (right lobe), and left receptor index (left lobe) were calculated. Results. After PTPE, the proportion of the volume of the nonembolized lobe (left lobe) increased (P = 0.0002). The total receptor index slightly decreased after PTPE (P = 0.090), the right receptor index decreased (P < 0.0001), and the left receptor index increased (P < 0.0001). The average increase rate in the left receptor index was 30% of the pre-PTPE value. In 2 patients with portal hypertension (≥30 cm H2O) after PTPE, the left receptor index did not change. In 4 patients whose left receptor index after PTPE (including the 2 patients with portal hypertension) was

To identify clinicopathologic features of distant metastatic recurrence (DMR) after hepatic resection for hepatocellular carcinoma, we investigated 352 recurrent patients. Of them, 261 with only intrahepatic recurrence were compared with 91 with DMR. Between two groups, there was significantly difference with respect to preoperative liver function, positive tests for protein induced by vitamin K absence or antagonist-II (PIVKA-II), major resection, tumor-free interval, tumor diameter, extrahepatic progression of the tumor, single nodular configuration, and portal vein invasion. Survival rates at 1 and 5 years after intrahepatic recurrence were 73% and 17%, while these were 57% and 18% when recurrences were DMR (p = .0362). DMR was frequent when a resected tumor was large, extrahepatic, ill defined or multinodular or associated with portal vein invasion, good preoperative liver function, or PIVKA-II positivity. Such patients should receive particularly careful follow-up during the first 2 years after hepatic resection focusing on early detection of DMR.

The prognosis after curative resection for patients with carcinoma of the papilla of Vater is relatively better than that for other peripancreatic cancer. However, prognostic factors after resection of the carcinoma have not been identified.From 1983 to 1999, 16 patients with carcinoma of the papilla of Vater underwent standard pancreatoduodenectomy and dissection of regional lymph nodes. We followed the patients for 63 days to 17 years (median, 27 months) and analyzed clinicopathologic variables in relation to prognosis.The survival rate at 5 years was 50.5%. The morphologic factors predicting poor outcome were macroscopic ulcer formation and microscopic pancreatic, venous, or perineural invasion. Tumors with ulcer formation tended to infiltrate into the duodenum and pancreas, but not into veins or the perineural space. Eight of 16 patients died due to recurrence of the cancer; liver metastasis (n = 6) or peritoneal dissemination (n = 2).Patients with carcinoma of the papilla of Vater demonstrating ulcer formation or invasion into the pancreas, vein, or perineural space may benefit from adjuvant therapy to reduce the risk of liver metastasis. Careful observation is essential for liver metastasis or peritoneal dissemination after surgery; especially in patients with ulcer formation or venous invasion.

The patient was a 65-year-old woman who came to our hospital because she had noticed swelling of a left supraclavicular lymph node. Endoscopy revealed an ulcerous lesion in the L chain region, and poorly differentiated adenocarcinoma of the stomach was diagnosed as a result of a biopsy. Oral therapy was impossible because of pyloric stenosis, and a gastrojejunal bypass operation was performed. Serious hepatic dysfunction occurred postoperatively due to swelling that was suspected of being due to lymph node metastasis in the porta hepatis. For this reason, the TS-1 therapy that had been initially scheduled was abandoned, and low-dose FP therapy was instituted for 4 weeks. Afterward, the swelling resolved and the patient's hepatic disorder and systemic condition improved. Administration of TS-1, 80 mg/day (bid), was started in the outpatient clinic 4 weeks after the completion of FP therapy. Administration had to be discontinued after the first course of TS-1 therapy because of grade 3 thrombocytopenia and neutropenia. However, since marked decreases in tumor markers were observed, TS-1 administration was resumed after recovery. After completion of the second course of TS-1 therapy, a decrease in size of the Virchow lymph node was noted, and PR was diagnosed. TS-1 as initial chemotherapy had to be abandoned for this patient because of a serious hepatic disorder, in which TS-1 administration is contraindicated. However, a favorable response was obtained by concomitant use of FP therapy.

Interferon (IFN) therapy decreases the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV). One hundred and fifty-nine consecutive patients who underwent liver resection for HCV-related HCC were studied. In 17 (group 1) of the 159 patients, HCC was detected during or after IFN therapy. The incidences of recurrence after surgery in the group 1 patients and the other 142 patients (group 2) were compared. Eight patients had a complete response to IFN, 4 had a partial response, and 5 had no response. The proportion of patients without HCV viremia was significantly higher in the group 1 patients (P < 0.0001). The tumor-free survival rate was significantly higher in the group 1 patients (P = 0.0010). By multivariate analysis of various risk factors for recurrence, no previous IFN was a significant independent risk factor for recurrence (risk ratio = 6.336; 95%CI, 1.512 - 26.50). The patients with HCC who underwent IFN therapy previously are good candidates for liver resection because recurrence after the operation was rarely observed.

Although various antioxidants have been tested as therapeutics for endotoxemic subjects, the results of their efficacy are conflicting. Antioxidant biofactor (AOB) is a unique processed grain food that exhibits strong antioxidant activity (Minamiyama et al, J Nutr Sci Vitaminol, 40: 467-477, 1994). The present study was carried out to test the effect of AOB on hepatic injury in rats induced by lipopolysaccharide (LPS). Intravenous administration of LPS induced liver injury with a concomitant increase in hepatic generation of nitric oxide (NO) and 4-hydroxy-2-nonenal (HNE) modified proteins in the control group. The administration of AOB significantly inhibited the LPS-induced hepatic injury and generation of HNE-modified proteins and increased the survival rate of endotoxemic rats without affecting NO generation and plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). AOB scavenged superoxide radicals without affecting NO production by LPS-stimulated macrophage cell line J 774.2 cells. AOB also inhibited lipid peroxidation induced by LPS in the cells. These results suggested that AOB might scavenge superoxide radicals and decrease toxic metabolites including HNE, thereby inhibiting liver injury in endotoxemic rats.

Nitric oxide (NO) reacts with iron, superoxide, thiols and oxygen. Although NO reversibly interacts with the heme-iron of P450, the pathophysiological role of this interaction remains to be elucidated. We found that hepatic levels of P450 markedly decreased in endotoxemic rats, particularly when the rate of NO generation was increased. To determine the possible role of NO in the modulation of the structure and function of P450, changes in the levels and activities of P450 isozymes were determined in liver microsomes from normal and endotoxemic rats. Electron spin resonance analysis revealed that incubation of microsomes with the NO donor NOC-7 rapidly generated NO-P450 adducts. Microsomal levels of NO-P450 adducts increased and peaked at 10 min after incubation and decreased thereafter; it disappeared completely within 60 min. In contrast, microsomal levels of the low-spin ferric form and CO-differential spectrally detectable P450 rapidly decreased during the initial 10 min; the signal intensity for P450 recovered thereafter. Western blot analysis using specific antibodies against CYP3A2 and CYP2C11 isozymes revealed no detectable degradation of these isoforms. Effect of NO on the catalytic activity of the enzymes was also determined by using testosterone as the substrate. The hydroxylation activity in microsomes rapidly decreased during the initial 10 min and disappeared slowly thereafter. These results suggested that NO might form dissociable complexes with the heme moiety of P450 and irreversibly inactivate them. The mechanism for P450 inactivation by NO and the role of NO-P450 interaction in the pathogenesis of liver injury in endotoxemia are discussed.

The resistance of portal vein and hepatic artery plays an important role in the regulation of the circulatory status in the liver, but the regulatory mechanisms for these hepatic vessels have still to be elucidated. The aim of this study was to discover the tonus regulation of the hepatic vasculature.The effects of adenosine, adenosine 5'-monophosphate, adenosine 5'-diphosphate, adenosine 5'-triphosphate and uridine triphosphate on the force generation of the portal vein, superior mesenteric artery, inferior caval vein and aorta of the rat were studied in vitro. Each vessel was removed and cut into 5-mm ring strips. The strips were fixed vertically between triangle hooks and incubated in organ baths containing Krebs-Henseleit solution. The change in vascular tension was continuously monitored by a force-displacement transducer and recorded isometrically with a polygraph.Adenosine 5'-diphosphate and adenosine 5'-triphosphate induced relaxation of superior mesenteric artery and aorta precontracted with prostaglandin F2alpha dose-dependently. The effects of adenosine 5'-diphosphate and adenosine 5'-triphosphate were attenuated in the presence of N(G)-nitro-L-arginine, indicating nitric oxide dependency. In contrast, all these nucleotides dose-dependently induced contraction of the portal vein obtained from the hepatic hilus. N(G)-nitro-L-arginine decreased the EC50 values for these metabolites. Interestingly, all the nucleotides failed to induce contraction of the inferior caval vein and the portal vein distal to the hepatic hilus.These results suggest that some purinoceptor-dependent pathway regulates contraction of the portal vein close to the hepatic hilus and elicits, in contrast, the relaxation of superior mesenteric artery and aorta. Nitric oxide may participate in the tonus regulation of hepatic vasculature.

Antioxidant biofactor (AOB®) is an unique processed grain food obtained from soybean, wheat, rice germ, rice bran, tear grass, green tea, sesame, citron, green leaves extracts and malted rice. These ingredients were degraded to low molecular weight compounds by roast and fermentation with Aspergilus oryzae (Fig. 1). AOB contains a variety of compounds with antioxidant activity including flavonoids, α-tocopherol, vitamin C, tannins and vitamin B2. These ingredients have potent activity to scavenge reactive oxygen species, such as Superoxide radical dose-dependently. Plasma of AOB-treated rats also scavenge Superoxide and diphenyl-p-picrylhydrazyl (DPPH) radicals1). Fenton’s reaction and lipid peroxidation are also inhibited by AOB1). Thus, AOB is a potent antioxidant both in vitro and in vivo. The present work demonstrates its effect on ischemia/reperfusion-induced renal injury and the fate of NO in the rat.

Plasma albumin reacts with nitric oxide (NO) to form S-nitroso-albumin (albumin-S-NO). The present study was designed to elucidate whether NO-induced response on blood pressure may differ between analbuminemic rats (NAR) and normal rats. When NOC7, a NO donor, was intravenously injected in rats, blood pressure decreased and the initial depressor response was the same in both the NAR and the normal rats. However, the duration of NO-induced hypotension was 0.5 times longer in NAR than in the normal rat. After NOC7 injection, plasma thiol levels decreased and S-nitrosothiols levels increased in the normal rats, whereas these levels slightly changed in NAR. These results suggested that NO reacts with albumin-SH, resulting in albumin-S-NO formation, which produces a continuous hypotensive response in blood pressure as a slow releaser of NO.

Publisher Summary This chapter discusses the dynamic aspects of nitric oxide (NO) metabolism in the circulation and tissues. NO is an unstable gas with a free radical nature and is synthesized from arginine by NO synthase in various cells, such as endothelial cells, neurons, and hepatosplenic cells. NO forms dissociable complexes with various thiols and iron-containing proteins, such as guanylate cyclase and hemoglobin (Hb), thereby regulating vascular resistance, platelet aggregation, neurotransmission, and diverse functions of tissues. Because the half-life of NO is extremely short, particularly under aerobic conditions, in practice it is difficult to determine the in vivo generation and dynamic aspects of NO. To determine the generation of NO in vivo , various spin-trapping agents such as PTIO are used. NO forms dissociable complexes with thiols and iron-containing proteins. The paramagnetic nature of the nitrosylhemoglobin adduct (NO–Hb), is determined by electron spin resonance (ESR). The efficient mechanism by which circulating erythrocytes capture NO play a critical role in restricting the functions of the second messenger only at or near the site of generation.

Background The difference of prognosis between patients with unresectable and recurrent biliary tract cancer (BTC) receiving chemotherapy has not been clarified. In this study, we aimed to compare the prognosis of unresectable BTC with that of recurrent BTC. We also evaluated other prognostic factors of BTC. Methods This study retrospectively reviewed the data of 403 consecutive patients with pathologically-proven unresectable or recurrent BTC who received palliative chemotherapy from 18 hospitals in Japan between April 2006 and March 2009. The 1-year survival rate and overall survival (OS) and patient characteristics were compared between unresectable and recurrent cases. Univariate and multivariate analyses were carried out to identify the prognostic factors. Results The 1-year survival rate and OS were significantly better in 192 patients with recurrent BTC than 211 patients with unresectable BTC (1-year survival 57.3% versus 43.1%, P = 0.005; OS 398 days [95% confidence interval (CI) 365–430] versus 323 days [95% CI 282–364], P = 0.004). In baseline characteristics, the proportion of patients who had distant metastasis was significantly greater in recurrent BTC than unresectable BTC (77.1% versus 66.8%, P 5 ng/ml) (HR 1.71, 95% CI 1.36–2.15, P Conclusions The status of unresectable/recurrent disease is identified as one of the prognostic factors for patients with BTC receiving chemotherapy and recommended to be used as a stratification factor in the clinical trials.

e14518 Background: The difference of prognosis between patients (pts) with unresectable and recurrent biliary tract cancer (BTC) receiving chemotherapy has not been clarified although some studies reported prognostic factors of BTC. In this study, we aimed to compare the prognosis of unresectable BTC with that of recurrent BTC. We also evaluated other prognostic factors of BTC. Methods: This study retrospectively reviewed the data of 403 consecutive pts with pathologically proven unresectable or recurrent BTC who received palliative chemotherapy from 18 hospitals in Japan between April 2006 and March 2009. The 1-year survival rate and overall survival (OS) and patient characteristics were compared between unresectable and recurrent cases. Univariate and multivariate analyses were performed to identify prognostic factors. Results: 380 pts (94.3%) received chemotherapy using gemcitabine and/or S-1. The 1-year survival rate and OS were significantly better in 192 pts with recurrent BTC than 211 pts with unresectable BTC (1-year survival 57.3% vs. 43.1%, p=0.005; OS 398 days [95% confidence interval (CI) 365-430] vs. 323 days [95% CI 282-364], p=0.004). In baseline characteristics, the proportion of pts who had distant metastasis was significantly greater in recurrent BTC than unresectable BTC (77.1% vs. 66.8%, p

When hepatic stellate cells were stimulated by UTP, ATP, or ADP, cellular levels of inositol phosphates significantly increased (UTP > ATP > ADP > 5′-O-(3-thiotriphosphate). Thirty min after incubation with 100 μM of UTP, ATP, or ADP, levels of inositol monophosphate increased to 1318 ± 116, 616 ± 87 and 591 ± 234% of control levels, respectively, with concomitant increase in the production of inositol trisphosphate and bisphosphate. These nucleotides transiently increased the [Ca2+]i of fura-2-loaded stellate cells. Moreover, UTP, ATP, ADP and adenosine 5′-O-(3-thiotriphosphate) were able to induce contraction of stellate cells as detected using the silicone-rubber membrane method. These results suggested that hepatic stellate cells have nucleotide receptors which react predominantly with extracellular UTP and ATP and trigger the receptormediated contraction of the cells.