The insulin-like growth factor receptor type 1 (IGF1R) and epidermal growth factor receptor (EGFR) are reportedly overexpressed in pancreatic cancer. However, the correlation between activated EGFR and IGF1R and their clinicopathological implications still remain unclear. The cellular localization and overexpression of IGF1R and EGFR were investigated immunohistochemically in primary invasive ductal pancreatic carcinomas obtained from 74 patients who underwent radical surgical resection. We also compared the status of IGF1R and EGFR overexpression between primary tumors and hepatic metastatic tumors obtained from 44 autopsied patients. Among the 74 surgically resected primary tumors, cytoplasm-and membrane-dominant EGFR overexpression was detected in 22 (30%) and 7 (9%), respectively, whereas cytoplasm-and membranedominant IGF1R overexpression was detected in 8 (11%) and 28 (38%), respectively. Membrane-dominant EGFR and cytoplasm-dominant IGF1R were more frequent in lower-grade tumors and correlated with favorable prognosis, whereas cytoplasm-dominant EGFR and membrane-dominant IGF1R were more frequent in highergrade tumors and correlated with poor prognosis. In 36 autopsy specimens of pancreatic tumor with concurrent overexpression of IGF1R and EGFR, there was an inverse correlation between the IGF1R and EGFR localization patterns (P ¼ 0.001). In the hepatic metastatic tumors obtained by autopsy, the incidences of both IGF1R and EGFR overexpression were much higher than in the surgically resected primary tumors. More than half of the autopsy cases consistently showed membrane-dominant EGFR expression in both the primary tumor and hepatic metastases, whereas IGF1R expression showed considerable variation. Crosstalk between differently localized IGF1R and EGFR might play a role in determining the biological aggressiveness of pancreatic cancer, although their cellular localization may often alter during the process of metastasis.

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.

Although patients with obstructive jaundice are susceptible to bacterial infections and cancers, the mechanisms remain to be elucidated. In the present study, liver mononuclear cells (MNCs) of bile duct-ligated (BDL) mice were immunologically assessed. Liver natural killer T cells were greatly decreased within 24 h after BDL. Upon injection of Escherichia coli (E. coli; 10 colony-forming units) at 7 days after the procedure, all BDL mice had died, but no sham mice died. Consistently, an overgrowth of E. coli was seen in the livers of BDL mice. Although the serum IL-12 and IL-18 levels after E. coli challenge in BDL mice were higher than those in sham mice, the IFN-gamma level was greatly suppressed. However, exogenous IFN-gamma injection significantly increased BDL mouse survival after E. coli challenge. Furthermore, liver MNC of BDL mice exhibited a lower cytotoxic activity against tumors, and BDL mice intravenously injected with liver metastatic EL-4 cells showed markedly increased EL-4 metastases. The total bile acids, as well as the bile acid fractions, increased in the sera and liver. IFN-gamma production by liver MNC from normal mice stimulated with LPS in vitro was inhibited by the addition of bile acids, whereas, conversely, the production of IL-12 and IL-18 increased. In conclusion, liver natural killer T cells were diminished in BDL mice, and the function of liver MNC (IFN-gamma production) was also impaired presumably due to increased bile acids. This may partly explain the increased susceptibility of BDL mice to bacterial infections and tumor metastasis.

It is suggested that examination of Skp2 expression might be clinically useful for prognostication in patients with pancreatic carcinoma and that Skp2 protein might be a novel therapeutic molecular target.

Pilonidal sinus is known to be common among soldiers but not among Asian individuals. Few reports have discussed the occurrence of pilonidal sinus in the navy. We analyzed the incidence and etiological factors of 12 cases (11 patients, with 1 recurrence) of pilonidal sinus diagnosed between 1998 and 2004 in Japan Self-Defense Force Hospital Yokosuka. All patients were male, and all lesions were in the sacral area. The patients' average age and body mass index were 29.1 years and 27.4, respectively. The surgical procedures used were primary closures (10 cases, 83.3%) and flaps (two cases, 16.7%), and the number of postoperative hospital days averaged 11.8. Pilonidal sinus was not found to be significantly common among Japan Self-Defense Force personnel in general (7 of 11 patients with pilonidal sinus; not significant); however, it was significantly more common among the crew members of Japan Self-Defense Force ships (seven of seven patients; p < 0.05), which suggests that the on-board lifestyle contributes to the occurrence of pilonidal sinus.