To clarify the characteristics of hepatocellular carcinoma (HCC) with bile duct invasion, we retrospectively analyzed clinical features and surgical outcome of HCC with bile duct invasion (b(+) group, n = 15) compared to those without bile duct invasion (b(-) group, n = 256). In the b(+) group, four patients (27%) showed obstructive jaundice, and a diagnosis of bile duct invasion was obtained preoperatively in seven patients (47%). The levels of serum bilirubin and carbohydrate antigen 19-9 were significantly higher in the b(+) group. Macroscopically, confluent multinodular type and infiltrative type were predominant in the b(+) group (P = 0.002). Microscopically, capsule infiltration (P = 0.040) and intrahepatic metastasis (P = 0.013) were predominant in the b(+) group. Portal vein invasion was associated significantly with the b(+) group (P = 0.004); however, the frequency of hepatic vein invasion was similar (P = 0.096). The median survival after resection was significantly shorter in the b(+) group than in the b(-) group (11.4 vs. 56.1 months, P = 0.002), and eight of 11 intrahepatic recurrences in the b(+) group occurred within 3 months after surgery. HCC with bile duct invasion has an infiltrative nature and a high risk of intrahepatic recurrence, resulting in poor prognosis.

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-associated Kunitz-type serine proteinase inhibitor that was initially identified as a potent inhibitor of hepatocyte growth factor activator. HAI-1 is also a cognate inhibitor of matriptase, a membrane-associated serine proteinase. HAI-1 is expressed predominantly in epithelial cells in the human body. Its mRNA is also abundant in human placenta, with HAI-1 specifically expressed by villous cytotrophoblasts. In order to address the precise roles of HAI-1 in vivo, we generated HAI-1 mutant mice by homozygous recombination. Heterozygous HAI-1 ؉/؊ mice underwent normal organ development. However, homozygous HAI-1 ؊/؊ mice experienced embryonic lethality which became evident at embryonic day 10.5 postcoitum (E10.5). As early as E9.5, HAI-1 ؊/؊ embryos showed growth retardation that did not reflect impaired cell proliferation but resulted instead from failed placental development and function. Histological analysis revealed severely impaired formation of the labyrinth layer, in contrast all other placental layers, such as the spongiotrophoblast layer and giant cell layer, which were formed. Our results indicate that mouse HAI-1 is essential for branching morphogenesis in the chorioallantoic placenta and lack of HAI-1 function may result in placental failure.

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Hepatocyte growth factor (HGF) promotes pleiotropic signaling through its specific receptor tyrosine kinase, MET. As such, it has important roles in the regeneration of injured tissues. Since HGF is produced mainly by mesenchymal cells and MET is expressed in most epithelial, endothelial and somatic stem cells, HGF functions as a typical paracrine growth factor. HGF is secreted as an inactive precursor (proHGF) and requires proteolytic activation to initiate HGF-induced MET signaling. HGF activator (HGFAC) is a serum activator of proHGF and produces robust HGF activities in injured tissues. HGFAC is a coagulation factor XII-like serine endopeptidase that circulates in the plasma as a zymogen (proHGFAC). Thrombin, kallikrein-related peptidase (KLK)-4 or KLK-5 efficiently activates proHGFAC. The activated HGFAC cleaves proHGF at Arg494-Val495, resulting in the formation of the active disulfide-linked heterodimer HGF. Macrophage stimulating protein, a ligand of RON, is also activated by HGFAC in vivo. Although HGFAC functions primarily at the site of damaged tissue, a recent report has suggested that activated HGFAC relays a signal to stem cells in non-injured tissues via proHGF activation in the stem cell niche. This review focuses on current knowledge regarding HGFAC-mediated proHGF activation and its roles in tissue regeneration and repair.

We have previously demonstrated significantly decreased immunoreactivity of hepatocyte growth factor activator inhibitor type 1 (HAI-1), an integral membrane protein that exhibits potent inhibitory activity against hepatocyte growth factor activator (HGFA) and matriptase, in colorectal adenocarcinomas. In this report, we describe further detailed analysis of HAI-1 expression in colorectal adenocarcinoma by using three kinds of anti-HAI-1 antibodies, each of which recognizes a distinct epitope of the HAI-1 molecule, and also by in-situ hybridization for HAI-1 mRNA. The results indicated that the decreased immunoreactivity of HAI-1 in colorectal carcinoma cells is largely a result of enhanced ectodomain shedding of HAI-1 in these cells. In contrast, immunoreactivity of mature membrane-form HAI-1 was paradoxically en- epatocyte growth factor activator inhibitor type 1 (HAI-1) is a recently identified Kunitz-type serine proteinase inhibitor.1) HAI-1 has a unique molecular structure consisting of two extracellular Kunitz-type serine proteinase inhibitor domains (bikunin), an extracellular LDL receptor class A domain, a transmembrane domain, and a short intracellular domain at the carboxyl-terminal end. Thus, this inhibitor is a type-1 transmembrane protein that functions on the cellular surface. It should be noted that the membrane-form HAI-1 can be secreted by ectodomain shedding, resulting in secreted-form HAI-1. 1, 2)Two important proteinases have been identified as the target enzymes of HAI-1, these being hepatocyte growth factor activator (HGFA) and matriptase. In addition to HGFA and matriptase, HAI-1 also inhibits other serine proteinases such as plasmin and trypsin.2) HGFA is a factor XII-like serine proteinase that specifically converts a single-chain inactive form of hepatocyte growth factor/scatter factor (HGF/SF) to an active two-chain form in response to tissue injury. 3,4) Since HGF/SF is a potent mediator of invasive growth of cancer cells via its high-affinity receptor, MET receptor tyrosine kinase, HGFA might be involved in the malignant behavior of tumors. 2,5,6) Matriptase is also a cognate proteinase of HAI-1 and is identical to membrane-type serine protease 1. 2,7,8) This proteinase is a type-2 transmembrane protein having an extracellular catalytic domain. Like HGFA, matriptase also activates HGF/SF. 9, 10) Thus, HAI-1 would be a critical regulatory molecule in the pericellular activation of HGF/SF.2) In addition to HGF/SF, matriptase also shows processing activities towards pro-urokinase-type plasminogen activator and protease activated receptor 2.9, 11) Extracellular matrices, such as gelatin and fibronectin are also sensitive to matriptase, and enhanced expression of matriptase has been reported in several types of carcinoma cells.12) Thus, cellular matriptase could have important roles in invasion and metastasis of cancer cells. 13)Recent studies have suggested that membrane-form HAI-1 has diverse roles in the pericellular activities of HGFA and matriptase, acting not only as an inhibitor of...

Accessory spleen is an anomaly that is observed in about 10% of individuals by the autopsy study, and most accessory spleens are located close to the splenic hilum. Although accessory spleen is a frequently encountered entity, intrapancreatic accessory spleen (IPAS) is rarely recognized radiologically and is sometimes mistaken for another type of pancreatic neoplasm. Only 10 IPAS cases surgically resected as solid pancreatic mass have been reported in the English literature. We herein report a case of IPAS mimicking an endocrine tumor of the pancreas and review of the literature.

Multiple hepatic peribiliary cysts were found in three autopsy cases of patients who had had underlying liver diseases and obstructive jaundice. Macroscopically, the cysts were visible and present exclusively in the hepatic hilum and larger portal tracts. Histologically, the cysts were of varying size and were lined by a single layer of cuboidal or flattened epithelial cells without atypia. Intimate association between the cysts and peribiliary glands was found in the walls of large bile ducts. All three cases were associated with liver cirrhosis in patients with portal hypertension, and two of the patients had also had hepatocellular carcinoma. These findings support the previous assumption that multiple hepatic peribiliary cysts may be closely related to a portal hypertensive condition. Although peribiliary cysts have been considered to be clinically asymptomatic in general, in one of our patients, the cystic dilatation appeared to have been responsible for the progression of obstructive jaundice.

Postoperative morbidity and mortality do not appear to differ between men and women with esophageal cancer treated by surgical resection. Long-term survival after surgical resection of the esophagus appears to be significantly better for women than for men.