Masaharu Sumii

Helicobacter pylori eradication therapy improves atrophic gastritis and intestinal metaplasia: a 5-year prospective study of patients with atrophic gastritis.

Aim : To investigate the effect of the eradication of Helicobacter pylori on histological gastritis.

Expression of Vascular Endothelial Growth Factor and Angiogenesis in Gastrointestinal Stromal Tumor of the Stomach

Vascular endothelial growth factor (VEGF) is associated with the malignant potential of several types of carcinoma. The aim of this study was to elucidate the clinical significance of VEGF expression in gastrointestinal stromal tumor (GIST). Methods: Specimens obtained from 53 patients who had underwent surgical resection for GIST of the stomach were used in this study. Specimens were examined immunohistochemically for VEGF expression and Ki-67 expression. Tumor microvessel density (MVD) was determined immunohistochemically with anti-CD31 antibody, and was estimated by averaging the counts from three high-power fields in the area showing the greatest neovascularization. Results: VEGF expression was detected in 14 (26.4%) of the 53 lesions and correlated significantly with tumor size, liver metastasis, Ki-67 labeling index, and MVD. Prognosis was significantly poorer than in patients with tumors expressing VEGF than in patients with tumors lacking VEGF expression. Multiple logistic regression analysis for 10-year survival showed VEGF expression and high mitotic rate to be independent predictor of a poor outcome. Conclusions: Angiogenesis associated with VEGF may play an important role in the progression of GIST. VEGF expression may serve as an indicator of a poor prognosis.

Clinical Significance of Angiogenic Factor Expression at the Deepest Invasive Site of Advanced Colorectal Carcinoma

Tumor angiogenesis is a complicated process for which the mechanisms remain unclear. The aim of this study was to elucidate the clinical significance of several angiogenic factor expression as a predictor of the invasive/metastatic potential and of the prognosis of advanced colorectal carcinoma (CRC) in relation to their intratumoral histologic heterogeneity. One hundred fifty two patients who had undergone surgical resection for advanced CRC entered this study. PD-ECGF, VEGF, and VEGF-C were examined immunohistochemically with antibodies 1C6-203, A-20, and C-20, respectively. Tumor microvessel density (MVD) was determined immunohistochemically with anti-CD34 antibody. Expression of PD-ECGF, of VEGF, and of VEGF-C at the deepest invasive site were detected in 77 (50.7%), 62 (30.8%), and 71 (46.7%) of the 152 lesions, respectively. PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site in lesions with liver metastasis (77, 67, and 70%) was significantly higher than that in those without liver metastasis (44, 34, and 41%). In cases with curative surgery, patients with PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site had a significantly poorer prognosis than those without PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site. PD-ECGF, VEGF, and VEGF-C expression at the deepest invasive site correlated significantly with MVD. Multivariate analysis with logistic regression for 5-year survival in patients with curative surgery showed that lymph node metastasis and VEGF expression were significant risk factors. Expression of PD-ECGF, VEGF, and VEGF-C was correlated significantly with metastatic potential and prognosis in relation to MVD. Of the several angiogenic factors, VEGF expression at the deepest invasive site of tumor was the most statistically significant indicator of prognosis in advanced CRC.

Infliximab Therapy for Crohn's Disease in a Patient with Chronic Hepatitis B

Infliximab, a chimeric anti‐tumor necrosis factor-α (TNFα) monoclonal antibody, has proven to be an effective treatment for Crohn’s disease (CD). However, the safety of infliximab has not been evaluated in patients infected with hepatitis B virus (HBV). We describe herein the case of a 28-year-old woman, positive for HBV surface antigen (HBsAg), who developed a mild transient increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and HBV DNA levels after a single infusion of infliximab for refractory CD.

p53 Codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori-associated chronic gastritis

p53 codon 72, which produces variant proteins with an arginine (Arg) or proline (Pro), has been reported to be associated with cancers of the lung, esophagus and cervix. However, there have been no reports on the p53 codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori‐associated chronic gastritis (H. pylori‐CG). We, therefore, examined the polymorphism in 117 gastric cancer patients (72 intestinal type and 45 diffuse type) with H. pylori‐CG and 116 H. pylori‐CG patients without gastric cancer as controls. Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) analysis was performed to analyze the p53 codon 72 polymorphism. The crude genotypic frequencies in the gastric cancer patients were similar to those of the controls. However, when gastric cancers were classified by histologic subtype, the Pro/Pro was more frequent in the patients with diffuse type gastric cancer than in the controls (22.2% of cases vs. 12.1% of controls). The Pro/Pro genotype was associated with a 2.98‐fold higher risk of diffuse‐type cancer compared to the Arg/Arg genotype (95% confidence interval [CI] 1.07–8.32, p = 0.038). These results suggest that the Pro/Pro genotype at p53 codon 72 contributes to susceptibility for diffuse‐type gastric cancer in patients with H. pylori‐CG. The p53 codon 72 polymorphism may serve as the genetic marker for the risk assessment of the diffuse‐type gastric cancer development in patients with H. pylori‐CG.

Single dose of OCH improves mucosal T helper type 1/T helper type 2 cytokine balance and prevents experimental colitis in the presence of Vα14 natural killer T cells in mice

Background and Aims: V&agr;14 natural killer T (NKT) cells seem to play important roles in the development of various autoimmune diseases. However, the pathophysiologic role of NKT cells in inflammatory bowel disease remains unclear. To clarify the mechanism by which the activation of NKT cells mediates protection against intestinal inflammation, we investigated the antiinflammatory role of specifically activated V&agr;14 NKT cells by glycolipids in a mouse experimental model of colitis induced by dextran sulfate sodium (DSS). Methods: Colitis was induced in C57BL/6 mice by the oral administration of 1.5% DSS for 9 days. A single dose of OCH or &agr;‐galactosylceramide, a ligand for NKT cells, was administered on day 3 after the induction of colitis. Body weights and colonic mucosal injury were assessed in each glycolipid‐treated group. Interferon‐&ggr; and interleukin‐4 levels in the supernatants from colonic lamina propria lymphocytes (LPLs) were measured by enzyme‐linked immunosorbent assay. Results: The administration of a single dose of OCH attenuated colonic inflammation, as defined by body weights and histologic injury. The protective effects of OCH could not be observed in V&agr;14 NKT cell‐deficient mice. In vivo treatment with OCH had improved the interferon‐&ggr;/interleukin‐4 ratio from colonic LPLs on day 9 after DSS treatment. Conclusion: The present data indicated that the activation of V&agr;14 NKT cells by OCH plays a pivotal role in mediating intestinal inflammation via altered mucosal T‐helper type 1/type 2 responses. Therapeutic strategies that are designed to activate specifically V&agr;14 NKT cells may prove to be beneficial in treating intestinal inflammation.

Role of Anti-Parietal Cell Antibody in Helicobacter pylori-associated Atrophic Gastritis: Evaluation in a Country of High Prevalence of Atrophic Gastritis

Background: Helicobacter pylori plays an important part in the progression of atrophic gastritis; however, markers for predicting the progression of atrophic gastritis remain unidentified. We investigated the relation between the degree of atrophic gastritis and the amount of anti-parietal cell antibodies (APCAs) present. Methods: In 219 Japanese patients, APCA was investigated by enzyme-linked immunosorbent assay (ELISA) and by Western blotting. The grade of corpus atrophy was estimated by histology and serum pepsinogen levels. Serum levels of pepsinogen were evaluated by radio-immunoassay. Results: Helicobacter pylori infection did not affect the APCA levels determined by ELISA. Long-term administration of proton-pump inhibitors and H. pylori eradication did not influence the levels of APCAs. However, in H. pylori -positive patients, the levels of APCA determined by ELISA were statistically higher in patients with severe atrophy than in those with mild atrophy as determined histologically (0.67 ± 0.48 versus 0.45 ± 0.40; A492, mean ± s , P = 0.01) and serologically by pepsinogen levels (0.66 ± 0.51 versus 0.44 ± 0.40, P = 0.002). The levels of pepsinogen I/II ratio were correlated with APCA levels only in the H. pylori -positive group. Western blotting showed that major antigen was identical with the β -subunit of H + ,K + -ATPase. Conclusion: APCA plays an important part in the progression of corpus atrophy after H. pylori infection.

Long-term rebamipide therapy improves Helicobacter pylori-associated chronic gastritis.

We investigated an antiinflammatory effect of rebamipide {2-{4-chlorobenzoylamino}-3-[2(1H)-quinolinon-4-yl] propionic acid}, a gastroprotective agent, in H. pylori-associated gastritis. Eighty-six patients with H. pylori-positive chronic gastritis were enrolled: 53 were treated with rebamipide (300 mg daily for 12 months) and 33 served as controls. Significant decreases in mononuclear cell infiltration into the antrum and corpus were noted in the rebamipide treatment group (before vs after, 1.42 ± 0.15 vs 1.02 ± 0.15; P < 0.01 and 1.60 ± 0.15 vs 1.21 ± 0.14; P < 0.05, respectively). Levels of infiltrating neutrophil were also decreased in the antrum (before vs after, 0.98 ± 0.14 vs 0.70 ± 0.13; P < 0.05) and were associated with a decrease in iNOS production. Sera from patients treated with rebamipide showed a significant decrease in gastrin (276.3 ± 58.3 pg/ml vs 173.0 ± 34.2 pg/ml; P < 0.05), whereas no change was observed in the control group. These suggest that long-term rebamipide treatment improved histologic gastritis and decreased serum gastrin levels in H. pylori-associated gastritis.

Magnifying colonoscopic features of ulcerative colitis reflect histologic inflammation.

Background:Colonoscopy plays an important role in the diagnosis of ulcerative colitis and the determination of disease activity. Standard colonoscopic findings, however, do not often agree with histologic findings. The aim of this study was to clarify the relation between magnifying colonoscopic features and histologic inflammation in the course of ulcerative colitis. Methods:We performed magnifying colonoscopy examinations in 60 patients with ulcerative colitis. We classified the features into six types and analyzed the relations among these features, standard colonoscopic features (Matts grades), and pathohistological findings. Results:It was difficult to distinguish the remission stage from the active stage by standard colonoscopy in cases of Matts grade 2 disease. There was a relation, however, between the magnifying colonoscopic types and the degrees of histologic inflammation. The magnifying colonoscopic types reflected histologic inflammation status more accurately than did standard colonoscopic findings. Conclusion:Magnifying colonoscopy is useful for determining the degree of histologic change without biopsy in patients with ulcerative colitis.

Helicobacter pylori Infection Influences Tumor Growth of Human Gastric Carcinomas

Background: Helicobacter pylori infection is considered a risk factor for gastric carcinoma. However, the effect of eradication therapy in gastric carcinoma patients is not well known. The aim of this study was to investigate the relationship between H. pylori infection and tumor growth of gastric carcinoma. Methods: Fifty-one patients with gastric carcinoma participated in the study. Thirty-three were H. pylori-positive, 6 were H. pylori-negative, and 12 were diagnosed with gastric carcinoma after eradication of H. pylori. To investigate tumor growth of gastric carcinoma, cell proliferation and angiogenesis of the tumors were evaluated by immunohistochemical techniques using Ki-67 and CD34. Results: The Ki-67 labeling index was 47.9 ± 2.6 (mean ± s) in the H. pylori-positive group, 38.1 ± 3.6 in the H. pylori-eradicated group, and 22.2 ± 5.5 in the H. pylori-negative group. It was significantly lower in the H. pylori-eradicated and H. pylori-negative groups than in the H. pylori-positive one, and a significant difference was also found between the H. pylori-positive and H. pylori-eradicated groups. The microvessel counts were 62.5 ± 3.0, 50.2 ± 4.0, and 66.0 ± 9.8 in the positive, eradicated, and negative groups, respectively. A significant difference was found between the H. pylori-positive and H. pylori-eradicated groups. Conclusion: Our results suggest that H. pylori infection is associated with cell proliferation, and its eradication may influence tumor vascularity of gastric carcinoma. Therefore, H. pylori eradication therapy may contribute to the suppression of tumor growth.