Kazuo Shimada

Fibronectin : a possible factor promoting cholesterol monohydrate crystallization in bile

To examine the hypothesis that fibronectin physiologically present in bile might be a possible nucleating factor, the concentrations of fibronectin in gallbladder bile were determined and its induced effect on nucleation time and on the form of vesicle were examined in bile-model and human gallbladder bile. The gallbladder bile samples taken from patients with cholesterol gallstone had a significantly higher concentration of fibronectin and the faster nucleation time than the control. However, no significant correlation was found between nucleation time and endogenous fibronectin concentration. The addition of 0.5, 1.2, 10 micrograms/ml of fibronectin into two kinds of bile-model significantly shortened the nucleation time in a dose-related manner. Nucleation time was significantly shortened by the addition of 1 microgram/ml exogenous fibronectin into abnormal bile while such an effect was absent in the control. The addition of fibronectin increased the size of vesicles observed by the electron microscope. The results suggest that fibronectin physiologically present in bile may be one of the possible nucleating factors.

Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat)

Aromatase inhibitors (AIs) are important drugs for treating postmenopausal patients with hormone receptor-positive breast cancer. However, acquired resistance to AI therapies is a significant problem. Our study has revealed that the histone deacetylase inhibitor LBH589 treatment abrogated growth of AI-resistant cells in vitro and in vivo, causing cell cycle G2/M arrest and induced apoptosis. LBH589 treatment also reduced the level of NF-κB1 which is overexpressed when AI resistance develops. Analyzing paired tumor specimens from 12 patients, we found that NF-κB1 expression was increased in recurrent AI-resistant tumors as compared to the paired primary tumors before AI treatment. This finding was consistent with up-regulated NF-κB1 expression seen in a collection of well-established AI-resistant cell lines. Furthermore, knockdown of NF-κB1 expression significantly suppressed the proliferation of AI-resistant cells. Treatment of AI-resistant cell lines with LBH589 suppressed NF-κB1 mRNA and protein expression. In addition, LBH589 treatment abrogated growth of AI-resistant tumors in mice, and was associated with significantly decreased levels of NF-κB1 in tumors. In all, our findings strongly support further investigation of LBH589 as a novel therapeutic strategy for patients with AI-resistant breast cancer, in part by suppressing the NF-κB1 pathway.

Inhibition of inducible nitric oxide synthase prevents hepatic, but not pulmonary, injury following ischemia-reperfusion of rat liver

The aim of this study was to investigate the contribution of inducible nitric oxide synthase (iNOS)-derived nitric oxide on the liver and lung injury following hepatic ischemia-reperfusion (I/R) using a novel and potent iNOS inhibitor, ONO-1714. Rats were subjected to 90 min of partial hepatic ischemia followed by 3, 6, 12, and 24 hr of reperfusion. Expression of iNOS mRNA peaked at 3 hr of reperfusion in the liver and lung. Plasma nitric oxide levels were increased fourfold at 24 hr of reperfusion and plasma ALT was increased, reaching a peak at 12 hr of reperfusion; both were significantly inhibited by ONO-1714. Histological examination revealed extensive liver damage, whereas this was not seen in the ONO-1714 group. Lung injury was not significantly changed in groups with versus without ONO-1714. Nitrotyrosine expression was seen in regions similar to those of the histological injuries of the liver, while this staining was absent in the ONO-1714 group. These data show that generation of peroxynitrite could be involved in the pathogenesis of liver injury but not lung injury after hepatic I/R. Inhibition of iNOS could be applied for attenuation of liver injury following hepatic I/R.

A Case of Breast Cholesterol Granuloma Accompanied by Cancer

Cholesterol granuloma of the breast is a very rare benign disease with clinical and imaging features that are often indistinguishable from cancer preoperatively. We report a case of breast cholesterol granuloma accompanied by cancer. The patient was a 78-year-old woman who complained of a lump in her right breast. Mammography and ultrasonography showed a well-circumscribed mass. Fine needle aspiration cytology showed many cholesterol crystals and inflammatory cells without malignancy. With a diagnosis of cholesterol granuloma, tumor extirpation was performed. Histopathologic examination revealed cholesterol granuloma together with breast cancer, and additional partial mastectomy was subsequently performed. It is noted that breast cholesterol granuloma could be accompanied by cancer.

Biliary bile acids in the gall-bladder and the common bile duct of patients with anomalous pancreaticobiliary ductal junction

The high incidence of biliary tract carcinoma in patients with anomalous pancreaticobiliary ductal junction (APBDJ) with or without choledochal cyst (CC) has been well documented. Twenty‐two patients with APBDJ were divided into three groups: Group A, four patients not associated with CC and biliary tract carcinoma; Group B, 13 patients with CC but without biliary tract carcinoma; and Group C, five patients with biliary tract carcinoma (four with and one without CC). Profiles of bile acids in the gall‐bladder and/or common bile duct were analysed in these patients and compared with those in the control patients with cholecystlithiasis to examine the hypothesis that the levels of deoxycholic acid (DCA) and lithocholic acid (LCA) are elevated in patients with APBDJ because these secondary bile acids are mutagenic. Bile acids were quantified by gas—liquid chromatography. Total bile acid concentration in the gall‐bladder bile was significantly lower in any group with APBDJ than that of controls. In the gall‐bladder, increased proportion of chenodeoxycholic acid (CDCA) in Groups A and B, decreased proportion of DCA in Group B and increased proportion of cholic acid (CA) in Group C were found in bile. In the bile duct, total bile acid concentration and proportion of DCA were significantly low in bile from Group C and decreased proportion of DCA and increased proportion of CDCA were found in bile from Group B. In both the gall‐bladder and hepatic bile, proportion of LCA was not significantly different between any intergroups. Thus no increase of DCA and LCA was found in either the bile from the gall‐bladder and the bile duct of APBDJ patients. It is concluded that bile acid plays little role, if any, in the pathogenesis of biliary tract carcinoma in patients with APBDJ.

Section 1. Parathyroid: Endoscopic neck surgery: current status for thyroid and parathyroid diseases

During the last 3 years, 59 patients underwent endoscopic neck surgery. We started the video-assisted neck surgery with the gasless skin-lifting method for benign thyroid and parathyroid diseases to avoid complications of carbon dioxide (CO2) insufflation. Hemithyroidectomy was performed for benign thyroid tumors and subtotal thyroidectomy was selected for Graves disease. Parathyroid adenomas were extirpated for primary hyperparathyroidism with precise preoperative localization by imaging modalities. In order to obtain a better visual field and to improve the cosmetic results, we have adopted the complete endoscopic method via breast approach with low CO2 insufflation pressure since August 2001. An intraoperative parathormone assay was introduced recently to confirm the complete removal of parathyroid adenomas. Both gasless and insufflation methods are feasible for endoscopic neck surgery with excellent cosmetic results.