Polypoid-Type Adenomyomatous Lesion of the Cystic Duct: Report of a Case and Review of Literature.

Adenomyomatous hyperplasia, a common non-neoplastic lesion in the gallbladder, is rarely identified in the extrahepatic bile duct. Typically, these lesions appear as a nodule or mural thickening/elevation. However, in exceptional circumstances, pedunculated/polypoid adenomyomatous lesion occurs in the biliary tract; two cases in the gallbladder and only one case in the common bile duct have been reported. Despite their benign nature, adenomyomatous lesions, especially those with a polypoid appearance, are clinically difficult to exclude a possibility of malignant neoplasms. We describe a case of polypoid-type adenomyomatous lesion of the cystic duct in a 72-year-old man, which was considered as a cystic duct neoplasm preoperatively. Gross examination of the resected specimen revealed that the 9 mm-sized cystic duct polyp. Histologically, the polypoid lesion consisted of glands without atypia, fibrous stroma, smooth muscle bundles, and accompanying stromal inflammation, leading to the diagnosis of benign adenomyomatous lesion. The lesion might be considered as adenomyomatous hyperplasia arising in the valve of Heister, while true nature of the lesion is uncertain. Recognition and accumulating for this rare disease will contribute to better clinical management in the future.

Duodenal stenosis associated with an ectopic opening of the common bile duct into the duodenal bulb: a case report.

BACKGROUND: Ectopic opening of the common bile duct is a rare congenital biliary anomaly. Herein, we present a case of duodenal stenosis with ectopic opening of the common bile duct into the duodenal bulb. CASE PRESENTATION: A 54-year-old man was referred with fever, nausea, and vomiting. He had experienced epigastric pain several times over the past 30 years. Endoscopy showed a post-bulbar ulcer, a submucosal tumor of the duodenum, and a small opening with bile secretion. Contrast duodenography revealed duodenal stenosis and bile reflux with a common bile duct deformity. Pancreatoduodenectomy was performed because of the clinical suspicion of a biliary neoplasm or groove pancreatitis. The resected specimen showed an ectopic opening of the common bile duct into the duodenal bulb and no tumor. CONCLUSIONS: Ectopic opening of the common bile duct into the duodenal bulb is complicated by a duodenal ulcer, deformity, and stenosis mimicking groove pancreatitis or pancreatic tumors. Although rare, we should be aware of this anomaly for an accurate diagnosis.

Mouse CD11b+Kupffer Cells Recruited from Bone Marrow Accelerate Liver Regeneration after Partial Hepatectomy.

TNF and Fas/FasL are vital components, not only in hepatocyte injury, but are also required for hepatocyte regeneration. Liver F4/80+Kupffer cells are classified into two subsets; resident radio-resistant CD68+cells with phagocytic and bactericidal activity, and recruited radio-sensitive CD11b+cells with cytokine-producing capacity. The aim of this study was to investigate the role of these Kupffer cells in the liver regeneration after partial hepatectomy (PHx) in mice. The proportion of Kupffer cell subsets in the remnant liver was examined in C57BL/6 mice by flow cytometry after PHx. To examine the role of CD11b+Kupffer cells/Mφ, mice were depleted of these cells before PHx by non-lethal 5 Gy irradiation with or without bone marrow transplantation (BMT) or the injection of a CCR2 (MCP-1 receptor) antagonist, and liver regeneration was evaluated. Although the proportion of CD68+Kupffer cells did not significantly change after PHx, the proportion of CD11b+Kupffer cells/Mφ and their FasL expression was greatly increased at three days after PHx, when the hepatocytes vigorously proliferate. Serum TNF and MCP-1 levels peaked one day after PHx. Irradiation eliminated the CD11b+Kupffer cells/Mφ for approximately two weeks in the liver, while CD68+Kupffer cells, NK cells and NKT cells remained, and hepatocyte regeneration was retarded. However, BMT partially restored CD11b+Kupffer cells/Mφ and recovered the liver regeneration. Furthermore, CCR2 antagonist treatment decreased the CD11b+Kupffer cells/Mφ and significantly inhibited liver regeneration. The CD11b+Kupffer cells/Mφ recruited from bone marrow by the MCP-1 produced by CD68+Kupffer cells play a pivotal role in liver regeneration via the TNF/FasL/Fas pathway after PHx.

Intrahepatic Cholangiocarcinoma With Lymphoepithelioma-like Carcinoma Components Not Associated With Epstein-Barr Virus: Report of a Case.

A carcinoma displaying undifferentiated features with dense lymphoplasmacytic infiltration is defined as lymphoepithelioma-like carcinoma (LELC). Intrahepatic cholangiocarcinoma (ICC) with LELC components is rare, and most LELCs are associated with Epstein-Barr virus (EBV). We report here on a case of ICC with LELC components not associated with EBV. A 65-year-old woman was incidentally found to have a hepatic tumor in the caudate lobe. An extended right hepatectomy with lymphadenectomy was performed. Histologically, the tumor was mainly composed of large undifferentiated epithelial cells with vesicular nuclei, prominent nucleoli, indistinct cell borders, and heavy small lymphocytic infiltration, which are the characteristic features of LELC. Immunohistochemical studies revealed that the tumor cells were positive for cytokeratin 19 but were negative for glypican 3. In situ hybridization using EBV-encoded RNA was negative. Therefore, a diagnosis of ICC with LELC components not associated with EBV was made. Because there is limited information available regarding the prognosis and treatment of ICC with LELC components because of the limited number of reported cases, additional studies will be needed to clarify the clinicopathologic features of this disease.

Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells.

BACKGROUND & AIMS: Acyl-coenzyme A: cholesterol acyltransferase (ACAT) catalyzes the conversion of free cholesterol (FC) to cholesterol ester, which prevents excess accumulation of FC. We recently found that FC accumulation in hepatic stellate cells (HSCs) plays a role in progression of liver fibrosis, but the effect of ACAT1 on liver fibrosis has not been clarified. In this study, we aimed to define the role of ACAT1 in the pathogenesis of liver fibrosis. METHODS: ACAT1-deficient and wild-type mice, or Toll-like receptor 4 (TLR4)(-/-)ACAT1(+/+) and TLR4(-/-)ACAT1(-/-) mice were subjected to bile duct ligation (BDL) for 3 weeks or were given carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis. RESULTS: ACAT1 was the major isozyme in mice and human primary HSCs, and ACAT2 was the major isozyme in mouse primary hepatocytes and Kupffer cells. ACAT1 deficiency significantly exaggerated liver fibrosis in the mouse models of liver fibrosis, without affecting the degree of hepatocellular injury or liver inflammation, including hepatocyte apoptosis or Kupffer cell activation. ACAT1 deficiency significantly increased FC levels in HSCs, augmenting TLR4 protein and downregulating expression of transforming growth factor-ß (TGFß) pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor), leading to sensitization of HSCs to TGFß activation. Exacerbation of liver fibrosis by ACAT1 deficiency was dependent on FC accumulation-induced enhancement of TLR4 signaling. CONCLUSIONS: ACAT1 deficiency exaggerates liver fibrosis mainly through enhanced FC accumulation in HSCs. Regulation of ACAT1 activities in HSCs could be a target for treatment of liver fibrosis.

Involvement of the TNF and FasL produced by CD11b Kupffer cells/macrophages in CCl4-induced acute hepatic injury.

We previously reported that F4/80(+) Kupffer cells are subclassified into CD68(+) Kupffer cells with phagocytic and ROS producing capacity, and CD11b(+) Kupffer cells with cytokine-producing capacity. Carbon tetrachloride (CCl4)-induced hepatic injury is a well-known chemical-induced hepatocyte injury. In the present study, we investigated the immunological role of Kupffer cells/macrophages in CCl4-induced hepatitis in mice. The immunohistochemical analysis of the liver and the flow cytometry of the liver mononuclear cells showed that clodronate liposome (c-lipo) treatment greatly decreased the spindle-shaped F4/80(+) or CD68(+) cells, while the oval-shaped F4/80+ CD11b(+) cells increased. Notably, severe hepatic injury induced by CCl4 was further aggravated by c-lipo-pretreatment. The population of CD11b(+) Kupffer cells/macrophages dramatically increased 24 hour (h) after CCl4 administration, especially in c-lipo-pretreated mice. The CD11b(+) Kupffer cells expressed intracellular TNF and surface Fas-ligand (FasL). Furthermore, anti-TNF Ab pretreatment (which decreased the FasL expression of CD11b(+) Kupffer cells), anti-FasL Ab pretreatment or gld/gld mice attenuated the liver injury induced by CCl4. CD1d-/- mouse and cell depletion experiments showed that NKT cells and NK cells were not involved in the hepatic injury. The adoptive transfer and cytotoxic assay against primary cultured hepatocytes confirmed the role of CD11b(+) Kupffer cells in CCl4-induced hepatitis. Interestingly, the serum MCP-1 level rapidly increased and peaked at six h after c-lipo pretreatment, suggesting that the MCP-1 produced by c-lipo-phagocytized CD68(+) Kupffer cells may recruit CD11b(+) macrophages from the periphery and bone marrow. The CD11b(+) Kupffer cells producing TNF and FasL thus play a pivotal role in CCl4-induced acute hepatic injury.

Multifocal lesions with pancreatic atrophy in IgG4-related autoimmune pancreatitis: report of a case.

We herein report a case of IgG4-related autoimmune pancreatitis (AIP). A 72-year-old male with jaundice visited our hospital complaining of epigastralgia. A blood chemistry analysis revealed elevated serum levels of total bilirubin and DUPAN-II. Computed tomography (CT) revealed irregularly shaped pancreatic masses with a stricture of the main pancreatic duct (MPD) in the head and tail that were interposed by marked atrophy with MPD dilation in the body. F-18 fluorodeoxyglucose (FDG)-positron emission tomography/CT revealed abnormally intense FDG uptake only at the masses. During surgery, another small tumor was also found in the atrophied body; therefore, a total pancreatectomy was performed under the diagnosis of multiple pancreatic cancers. The histological analysis revealed fibrosis with dense and diffuse infiltrations of lymphocytes and IgG4-positive plasma cells. The pancreatic parenchyma of the body was firmly replaced by fibrosis. AIP can lead to the formation of multiple pancreatic lesions, and thus the correct diagnosis is occasionally difficult to establish in atypical cases.

Distinct development and functions of resident and recruited liver Kupffer cells/macrophages.

Although mouse liver F4/80(+) Kupffer cells consist of cytokine-producing CD11b(+) cells and phagocytic CD68(+) cells, an undefined CD11b(-) CD68(-) subset (30%) also exists. We herein demonstrate a more fundamental classification by adding CD32 (FcγRII), which covers most liver F4/80(+) cells and the distinct functions of them. Among the F4/80(+) cells, 50%, 40%, and 30% of cells were CD32(+), CD68(+), and CD11b(+), respectively, and one-half of the CD68(+) cells coexpressed CD32. CD68(+) and CD32(+) cells, but not CD11b(+) cells, expressed a phagocytosis-related CRIg. Gy (6) irradiation depleted liver CD11b(+) cells and those in the spleen, bone marrow, and peripheral blood but not liver CD32/CD68(+) cells. Transfer of bone marrow cells into the irradiated mice reconstituted liver CD11b(+) cells. Conversely, clodronate pretreatment depleted only liver CD32/CD68(+) cells but not liver CD11b(+) cells and peripheral blood or spleen CD11b(+) monocytes/macrophages. Moreover, the CD32(+) cells might be precursors of CD68(+) cells, as a large proportion of CD32(+) cells expressed the c-kit (CD117), and CD34 and CD32(+) cells acquired CD68 immediately after bacteria administration. CD32/CD68(+) cells, but not CD11b(+) cells, expressed resident macrophage-specific MerTK and CD64 (FcγRI). Challenge with Staphylococcus aureus or liver metastatic EL-4 tumor cells indicated that the CD68(+) subset is engaged in systemic bactericidal activity, whereas the CD11b(+) subset is pivotal for liver antitumor immunity. Human liver CD14(+) Kupffer cells could also be classified into three similar subsets. These results suggest that liver CD68(+) Kupffer cells and CD11b(+) Kupffer cells/macrophages are developmentally and functionally distinct subsets.

Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice.

Although ursodeoxycholic acid (UDCA) has long been used for patients with chronic cholestatic liver diseases, particularly primary biliary cirrhosis, it may modulate the host immune response. This study investigated the effect of UDCA feeding on experimental hepatitis, endotoxin shock, and bacterial infection in mice. C57BL/6 mice were fed a diet supplemented with or without 0.3% (wt/vol) UDCA for 4 wk. UDCA improved hepatocyte injury and survival in concanavalin-A (Con-A)-induced hepatitis by suppressing IFN-γ production by liver mononuclear cells (MNC), especially NK and NKT cells. UDCA also increased survival after lipopolysaccharide (LPS)-challenge; however, it increased mortality of mice following Escherichia coli infection due to the worsening of infection. UDCA-fed mice showed suppressed serum IL-18 levels and production of IL-18 from liver Kupffer cells, which together with IL-12 potently induce IFN-γ production. However, unlike normal mice, exogenous IL-18 pretreatment did not increase the serum IFN-γ levels after E. coli, LPS, or Con-A challenge in the UDCA-fed mice. Interestingly, however, glucocorticoid receptor (GR) expression was significantly upregulated in the liver MNC of the UDCA-fed mice but not in their whole liver tissue homogenates. Silencing GR in the liver MNC abrogated the suppressive effect of UDCA on LPS- or Con-A-induced IFN-γ production. Furthermore, RU486, a GR antagonist, restored the serum IFN-γ level in UDCA-fed mice after E. coli, LPS, or Con-A challenge. Taken together, these results suggest that IFN-γ-reducing immunomodulatory property of UDCA is mediated by elevated GR in the liver lymphocytes in an IL-12/18-independent manner.

p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice.

BACKGROUND & AIMS: The tumor suppressor p53 is a primary sensor of stressful stimuli, controlling a number of biologic processes. The aim of our study was to examine the roles of p53 in non-alcoholic steatohepatitis (NASH). METHODS: Male wild type and p53-deficient mice were fed a methionine- and choline-deficient diet for 8 weeks to induce nutritional steatohepatitis. mRNA expression profiles in normal liver samples and liver samples from patients with non-alcoholic liver disease (NAFLD) were also evaluated. RESULTS: Hepatic p53 and p66Shc signaling was enhanced in the mouse NASH model. p53 deficiency suppressed the enhanced p66Shc signaling, decreased hepatic lipid peroxidation and the number of apoptotic hepatocytes, and ameliorated progression of nutritional steatohepatitis. In primary cultured hepatocytes, transforming growth factor (TGF)-ß treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-ß-induced p66Shc signaling, ROS accumulation, and hepatocyte apoptosis. Furthermore, expression levels of p53, p21, and p66Shc were significantly elevated in human NAFLD liver samples, compared with results obtained with normal liver samples. Among NAFLD patients, those with NASH had significantly higher hepatic expression levels of p53, p21, and p66Shc compared with the group with simple steatosis. A significant correlation between expression levels of p53 and p66Shc was observed. CONCLUSIONS: p53 in hepatocytes regulates steatohepatitis progression by controlling p66Shc signaling, ROS levels, and apoptosis, all of which may be regulated by TGF-ß. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH.

Importance of maintaining left gastric arterial flow at Appleby operation preserving whole stomach for central pancreatic cancer.

The safety of whole stomach-preserving Appleby operation with resection of the left gastric artery (LGA) for pancreatic cancer cannot be assured. The anatomy of the celiac axis (CA) with special regard to the position of the origin of the LGA was examined. Using 3D images of the vascular architecture reconstructed from volume data of helical CT, the length of the CA and the position of the origin of the LGA from the CA were measured in 53 patients. Among 53 patients, 47 patients (89%) had classical anatomy of the CA branches. The mean length(2 standard deviation) of the CA and the distance from the root of the LGA to the bifurcation of the CA were 25.2mm (-4.9) (range 14.6-36.5) and 10.3mm (+4.5)(range 2.4-21.9), respectively. In 23 (45%) cases, the LGA arose farther than 10mm away from the bifurcation of the CA. Among six patients with anatomical variation of the arteries, two (4%) had the LGA directly arising from the aorta. Conservation of the LGA at modified Appleby operation would give complete cancer removal by en bloc resection of the nerve plexus, without risk of ischemic complications of the stomach and liver.

[Multicenter comparative study of the recurrence-inhibitory effect of oral fluoropyrimidine drugs in patients with colorectal cancer following curative resection].

HCFU and UFT were reported effective in adjuvant chemotherapy for colorectal cancer. This investigation was planned as a randomized study to compare the usefulness of combination therapies with mitomycin C (MMC)+HCFU and MMC+UFT as postoperative adjuvant chemotherapy in patients with colorectal cancer following curative resection, in terms of survival rate, recurrence rate, and adverse drug reactions. A total of 501 patients consisting of 252 patients with stage III/IV colon cancer (Colorectal Cancer Handling Rules, 4th Ed.) for which macroscopic curative resection was possible and 249 patients with stage II/III/IV rectal cancer (ibid, 4th Ed.) were registered from 40 participating institutions. The patients were randomly allocated to two groups with colon cancer and rectal cancer employed as stratification factors. Beginning on Day 14 after surgery, HCFU at 300 mg/day was administered to one group and UFT at 300 mg/day or 400 mg/day to another group, both orally and daily for one year. MMC 6 mg/m2 was administered intravenously to both groups on the day of surgery and the day following. Among the 501 patients, 496 patients (99%) were eligible. The 5-year survival rates were 77.1% for the MMC+ HCFU group and 79.2% for the MMC+UFT group, with the 5-year recurrence-free survival rates were 76.1% and 72.9%, respectively, neither showing a significant difference between the groups. Adverse drug reactions appeared in 23% of patients in the MMC+HCFU group and in 19% in the MMC+UFT group, with no serious reactions. One year after surgery the administration completion rates were good, at 82% for the MMC+HCFU group and 83% for the MMC+UFT group. No clear difference in effectiveness was noted between MMC+HCFU therapy and MMC+UFT therapy as postoperative adjuvant chemotherapy for colorectal cancer. The administration completion rates were good, and no serious adverse drug reactions were observed for either therapy. It was thus considered that both therapies could be administered safely, and both were useful as postoperative adjuvant chemotherapies for colorectal cancer. It is considered necessary to compare them with standard therapies in Western countries in the future.

Pharmacokinetic and pharmacodynamic study of IST-622, a novel synthetic derivative of chartreusin, by oral administration in a phase II study of patients with breast cancer.

The aim of this study was to analyze the pharmacokinetics and pharmacodynamics (PK/PD) of 6- O-(3-ethoxypropionyl)-3',4'- O-exo-benzylidene-chartreusin (IST-622) and its metabolites, and to develop limited sampling models (LSM). Based on the data from 18 patients with breast cancer who were treated orally with 280 or 525 mg/m(2) of IST-622 once daily after breakfast for five consecutive days, we analyzed the relationship between the area under the plasma concentration versus time curve (AUC) and toxicities using a sigmoid E-max model and logistic regression. Plasma concentrations of IST-622 and its metabolites, 3',4'- O-exo-benzylidene-chartreusin (A-132) and 3"-demethyl-3',4'- O-exo-benzylidene-chartreusin (A-132M), were measured at 1, 2, 4, 8 and 24 h after administration on day 1. The AUC was calculated using the trapezoidal method. We also developed a LSM using stepwise linear regression analysis. IST-622 was detected in very few patients, and its concentration was very low and could be disregarded. It was suggested that meals promoted absorption of IST-622. AUCs of A-132 plus A-132M showed a better correlation with the rates of decrease and nadir counts of leukocytes, neutrophils and platelets than the AUC of each metabolite separately. Patients with the sum of AUCs more than 70 microg.h/ml showed severe myelotoxicities. Moreover, logistic regression analysis showed that grade 4 myelotoxicities would be seen in 30% of patients at an AUC of 65 microg.h/ml. We also developed an unbiased and precise LSM: AUC_0-24h=C_8hx17.6-0.95, where C(8h) denotes the sum of plasma concentrations of A-132 and A-132M. Myelotoxicities showed a good correlation with AUC(0-24h), and based on the results, it was decided that the target AUC was 65 microg.h/ml. The LSM was very convenient for estimating AUC(0-24h) and sufficiently accurate. These results show the possibility of predicting toxicities and dose adaptation for interpatient variability using LSM.