DNA methylation: a marker for carcinogen exposure and cancer risk

Cancers arise as a consequence of multiple genetic and epigenetic alterations. Many genes aberrantly methylated in cancers have been identified in recent years, and their use in cancer diagnosis and therapy is currently under investigation. During our genome-wide screening for a novel tumor-suppressor gene in gastric cancers, we found that only a small amount of aberrant methylation was present, even in non-cancerous gastric mucosae. A subsequent large-scale analysis of the gastric mucosae of healthy individuals and gastric cancer patients using quantitative methylation-specific PCR (qMSP) revealed that Helicobacter pylori infection potently induced aberrant DNA methylation in non-cancerous gastric mucosae and that these high methylation levels can decrease following cessation of the H. pylori infection. Helicobacter pylori infection induced the methylation of specific genes among 48 genes that can be methylated in gastric cancer cell lines. Most importantly, the methylation levels in the gastric mucosae of individuals without H. pylori infection correlated with their risk of gastric cancer. These findings show that a field for cancerization is formed by H. pylori infection and that this field can be measured using DNA methylation as a marker. The concept of an “epigenetic field for cancerization” has been also demonstrated for colon and breast cancers, and it is possibly present for other cancers and other diseases. Applied knowledge of epigenetic changes in human diseases has now started to make an impact on the prevention, diagnostics, and therapeutics of these diseases.     

Massive hemorrhage in a patient with intestinal Behçet's disease: report of a case

Major gastrointestinal bleeding is a rare manifestation of intestinal Behçet's disease. We report herein the case of a 64-year-old man with intestinal Behçet's disease complicated by myelodysplastic syndrome who suffered massive hemorrhage. Colonoscopy demonstrated ulceration of the entire colon from the cecum to the rectum, characterized by punched-out ulcers. Angiography demonstrated apparent extravasation of contrast material in the terminal ileum, and embolization was not successful. Continued and massive bleeding necessitated surgical resection of the involved segment of ileum; however, massive bleeding recurred. Re-endoscopy showed oozing hemorrhage from the multiple colon ulcerations. Intra-arterial prednisolone injection therapy was given, following which the melena gradually subsided and completely stopped within a few days.     

Primary hepatic leiomyosarcoma in a woman after renal transplantation: report of a case

In contrast to malignant lymphomas or skin cancer, smooth muscle tumors including leiomyosarcoma are rarely associated with transplant recipients. We herein present a 33-year-old woman with end-stage renal disease who received a transplant at 27 years of age. Four years after the transplantation, at age 31, she underwent a mastectomy because of primary right breast cancer, which was found to be a 5-mm-sized mucinous carcinoma with no regional lymph node metastasis. Six years after the transplantation, a liver tumor was unexpectedly discovered. An explorative laparotomy revealed a well-encapsulated tumor occupying the posterior portion of the right lobe of the liver. The patient underwent a posterior segmentectomy. Histologically, the tumor possessed intermingling fascicles of spindle cells with eosinophilic cytoplasm and elongated nuclei. Based on an immunohistochemical examination, the tumor cells were positive for the muscle-associated antibody. In addition, RNA probes for Epstein-Barr virus were negative based on in situ hybridization. The histologic, immunohistochemical findings were considered to be diagnostic for leiomyosarcoma, which is a low-grade malignancy. Two years after surgery, the patient is doing well with no recurrence of liver tumors or breast cancer. Received: April 16, 2001 / Accepted: September 11, 2001     

Different effects of oral administration of synthetic trypsin inhibitor on the pancreas between cholecystokinin-A receptor gene knockout mice and wild type mice

The synthetic trypsin inhibitor camostat has been used for the treatment of acute and chronic pancreatitis in Japan based on the evidences obtained from a rat experimental model. However, rats differ from other rodents and from humans in terms of lacking a gallbladder and no response of pancreatic bicarbonate secretion to cholecystokinin (CCK). In the present study, we determined whether oral administration of camostat showed a trophic effect in mice as observed in rats and whether the trophic effect, if substantial, was mediated via the CCK-A receptor, using CCK-A receptor gene targeting mice. The chow containing 0.1% camostat was fed to 8-month-old mice. Three- and seven-day treatments with camostat did not affect pancreatic wet weight in CCK-A receptor (+/-) mice. After 14-day treatment, the ratio of pancreatic wet weight/body weight was significantly lower in CCK-A receptor (-/-) than (+/+) mice. The protein and chymotrypsin contents were lower and amylase content was higher in CCK-A receptor (-/-) mice, compared to (+/+) mice. No pathological findings were observed by histological examination. Camostat has a trophic effect on the pancreas in mice and this effect is mediated via the CCK-A receptor, but is less potent than in rats.     

Review of fexofenadine in the treatment of chronic idiopathic urticaria

Chronic idiopathic urticaria (CIU), characterized by the appearance of itchy wheals of unknown etiology, can be extremely debilitating and can significantly reduce a patient's quality of life (QOL). Fexofenadine, a non-sedating, H1-receptor selective, long-acting antihistamine, is licensed worldwide for the treatment of CIU. A number of dose-ranging studies have evaluated the efficacy and safety of fexofenadine for the the treatment of CIU. In two similar North American studies, patients received either fexofenadine HCI (20, 60, 120, or 240 mg bid) or placebo. All four doses of fexofendine were statistically superior to placebo at reducing pruritus and reducing the number of wheals (P < or = 0.0238). A dose-finding study undertaken in Japanese patients confirmed that fexofenadine HCI (60 mg and 120 mg bid) is an effective treatment for CIU. A similar dose response was shown in all three studies when the results were compared. Furthermore, health outcome analyses of the North American studies indicated that fexofenadine HCI 60 mg bid significantly improved patient's QOL. In these studies, fexofenadine had a consistently comparable safety profile to placebo, with no dose-related trends in the incidence of adverse events. In conclusion, fexofenadine is an effective and well-tolerated treatment for CIU, with a wide therapeutic window. Importantly, the lack of ethnic differences between the studies from North America and Asia indicate that the efficacy and safety of fexofenadine demonstrated in these studies are cross-culturally applicable.     

High-concentration (20 mug/g) tacalcitol ointment therapy on refractory psoriasis vulgaris with low response to topical corticosteroids

The efficacy and safety of the application of high-concentration (20 mug/g) tacalcitol ointment once daily for 12 weeks to psoriasis vulgaris lesions which showed low response to topical corticosteroids, were evaluated in a prospective, multicenter, open-label study. Eighty patients were enrolled in the safety analysis of the test drug, and 54 of the 80 patients in the efficacy analysis. The efficacy rate based on the number of cases graded as "moderate improvement" or better in the final global improvement rating of the 54 cases included in the efficacy analysis, was 88.9% (95% CI: 77.4-95.8%). Significant improvement in erythema, thickness, and scaling was observed from 2 weeks of treatment onward (p < 0.001). Five local adverse reactions (2 events of irritation, 2 events of itching, and 1 event of redness) were observed in 3 of the 80 patients included in the safety analysis. There were no significant changes in mean serum calcium values. Tacalcitol 20 mug/g ointment is concluded to be effective and safe for the treatment of refractory psoriasis vulgaris with low response to topical corticosteroids.     

Large acinar cell carcinoma of the pancreas in a patient with elevated serum AFP level

A pancreatic carcinoma, associated with elevated serum alpha-fetoprotein level, was resected from a 67-year-old man. The tumor was strongly suggested to be an acinar cell carcinoma of the pancreas, based on the histological findings of the resected specimen. The tumor measured 12 × 10 × 9 cm, and the cut surface was soft, whitish-yellow, focally necrotic, and hemorrhagic. Under a light microscope, the tumor cells were not arranged in a tubular and trabecular pattern, but rather, showed a tendency toward an acinar structure. Immunohistochemically, α 1-antitrypsin- and α 1-antichymotrypsin-positive reactions were diffusely positive in most of the tumor cells, while staining for chromogranin, neuron-specific enolase, Grimelius, glucagon, insulin, and alpha-fetoprotein was negative in the tumor cells. We report a large acinar cell carcinoma (associated with elevated serum alpha-fetoprotein level), which had been misdiagnosed as hepatocellular carcinoma preoperatively. Received for publication on May 9, 1998; accepted on Sept. 20, 1999     

Resectable carcinoma of the pancreatic head developing 7 years and 4 months after distal pancreatectomy for carcinoma of the pancreatic tail

A 67-year-old woman was referred with an abnormal finding on an abdominal echogram but presented with no symptoms; a pancreatic tail tumor was detected by ultrasonography. Biochemical examinations showed slight elevation of serum carcinoembryonic antigen level. The lesion was resected by tail and body pancreatectomy and her postoperative course was uneventful. Seven years and 4 months after the initial operation, however, her serum level of carbohydrate antigen 19-9 was found to be elevated, and a recurrence of pancreatic cancer was suspected. Examinations revealed a mass in the head of the remnant pancreas. The lesion was radically resected by total remnant pancreatectomy. Histological examinations showed that the initial tumor was a well differentiated tubular adenocarcinoma, while the second tumor was characterized as a moderately differentiated tubular adenocarcinoma. The surgical margins of the distal pancreatectomy specimen were free of atypical cells. Therefore, the position of the second lesion diminished the likelihood that it had developed by intrapancreatic metastasis. This suggests that the second carcinoma in the head of the pancreas may have been a second primary lesion. Received for publication on June 1, 1999; accepted on Sept. 20, 1999     

All-trans-retinoic Acid-dependent Inhibition of E-Cadherin-based Cell Adhesion with Concomitant Dephosphorylation of β-Catenin in Metastatic Human Renal Carcinoma Cells

We previously described an in vitro invasion assay model, using a monolayer of vascular endothelial cells grown on collagen gel, that mimics the metastatic abilities of the highly metastatic human renal carcinoma cell lines, MM-1,3 and 8 and their poorly metastatic counterparts, SN12C and Q-8. MM-1, 3 and 8 cells were observed to penetrate the monolayer of vascular endothelial cells and grew in a spreading or scattering manner with loose cell-cell contact on collagen gel or on vascular endothelial cells. SN12C and Cl-8 cells failed to penetrate and grew in a clustering manner with tight cell-cell contact. Treatment with all- trans -retinoic acid (ATRA) at non-toxic concentrations induced clustering or growth of MM-1, 3 and 8 cells on collagen gel or on vascular endothelial cells with tight cell-cell contact, and inhibited penetration. The clustering induced by ATRA was virtually blocked in the presence of anti-E cadherin antibody. E-Cadherin and β -catenin were each localized mainly at the cell-cell adherent junctions of colonizing cell populations that had been treated with ATRA. While the cellular levels of E-cadherin and β -catenin did not change significantly following ATRA treatment, the tyrosine residue of β -catenin was rapidly dephosphorylated. The concomitant administration of Na vanadate, an inhibitor of tyrosine dephosphorylase, inhibited both the ATRA-induced clustering and the dephosphorylation of β -catenin tyrosine. ATRA-induced clustering of MM-3 cells may be linked to the state of tyrosine phosphorylation of β -catenin.