Yukinori Nakae

Evidence that Loss of Sonic Hedgehog is an Indicator of Helicobater pylori-induced Atrophic Gastritis Progressing to Gastric Cancer

BACKGROUND:The absence of sonic hedgehog (Shh) correlates with the development of intestinal metaplasia (IM) suggesting the possibility of an association between Shh expression and neoplastic transformation.AIM:To examine Shh expression in the noncancerous mucosa of patients with gastric cancer and compare it to Shh expression in Helicobater pylori-infected and uninfected controls. We also assessed the relationship between the type of IM and Shh expression.METHODS:Fifty-three patients with endoscopic mucosal resection (EMR) for early gastric cancer and 48 sex- and age-matched controls were studied. Two specimens each were obtained from the greater and lesser curves of the corpus and from the greater curve of the antrum. The histopathological grading used was the updated Sydney System. IM was categorized by staining with Alcian blue/high iron diamine. Expression of Shh was evaluated by immunostaining.RESULTS:The Shh immunostaining in the corpus lesser curve significantly correlated with the scores of atrophy and IM. Shh staining in the antrum was significantly higher in H. pylori-negative controls than those in H. pylori-positive controls as well as in patients without IM compared to those with IM (p < 0.001). The Shh staining in the corpus lesser curve decreased in H. pylori-negative controls, -positive controls and the cancer group respectively (P = 0.003), and was significantly higher (P = 0.006) in the complete IM group compared to those in the incomplete IM group.CONCLUSIONS:Loss of Shh is an early change that occurs in the mucosa prior to neoplastic transformation. Its loss correlates with the type of IM and may play a role in carcinogenesis.

Histologic and serum risk markers for noncardia early gastric cancer.

Corpus dominant gastritis and intestinal metaplasia (IM) are considered markers of increased risk of gastric carcinoma. The aim of our study was to determine serum and histologic risk markers of gastric cancer. Antral and corpus histology, pepsinogen and gastrin 17 levels were compared among patients with history of endoscopic mucosal resection (EMR) for early gastric cancer and controls. Serum pepsinogen (PG) and gastrin 17 levels were measured by RIA. There were 53 gastric cancer patients and 75 controls. The scores for IM in each region and atrophy at the lesser curvature of the corpus were significantly higher in the cancer group than in the H. pylori‐positive control group. IM at the greater curvature of the corpus and atrophy at the lesser curvature of the corpus were associated with multiple malignant lesions. Although corpus gastritis was associated with an increased risk of gastric cancer (odds ratio [OR] = 3.4; 95% confidence interval [CI] 1.6–7.0) (p = 0.001), the most important marker was the presence of IM at the lesser curvature of the corpus (OR = 15.1; 95% CI 4.3–52.6) (p < 0.001)). The best cut‐off points of serum markers for gastric cancer were a PG I concentration of 45 ng/mL or less and a gastrin 17 >60 pg/mL (sensitivity = 83%; specificity = 68%). IM at the lesser curvature of the corpus and the combination of serum gastrin 17 and PG I identified a group at high risk for development of gastric cancer. Annual endoscopic follow‐up is warranted for patients with IM found at the greater curvature of the corpus.

Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia

Loss of Sonic Hedgehog (Shh) and aberrant CDX2 expression are early changes correlating with the presence of intestinal metaplasia that occur in the gastric mucosa prior to neoplastic transformation. The aim of this study was to compare the improvement in corpus gastritis with Shh and CDX2 expression after H. pylori eradication between subjects at high risk for gastric cancer and controls. The usefulness of serum pepsinogen levels as a predictor of resolved corpus gastritis was also examined. Seventy patients with endoscopic resection for early gastric cancer and 30 controls were studied. Expression of Shh and CDX2 were evaluated by immunostaining. Serum levels of pepsinogen I before eradication in the patients scored as having improvement of corpus atrophy were significantly higher than in the patients without improvement (<0.01). Residual inflammation at the corpus lesser curve was more frequently detected in the cancer group than in the controls (OR 4.6 95% C.I. 1.6–13.5) and in the mucosa with incomplete intestinal metaplasia rather than in those without incomplete intestinal metaplasia (OR 7.6 95% C.I. 2.4–24.3). Atrophy, expression of Shh and CDX2 at the corpus lesser curve significantly improved in mucosa without incomplete intestinal metaplasia (p < 0.01), but not in mucosa with incomplete intestinal metaplasia. In conclusion, H. pylori eradication prior to development of incomplete intestinal metaplasia improves corpus gastritis and may prevent gastric cancer. Pepsinogen I may be a useful marker in patients with a residual higher risk of gastric cancer after H. pylori eradication.

Epithelial cell turnover in relation to ongoing damage of the gastric mucosa in patients with early gastric cancer: increase of cell proliferation in paramalignant lesions.

BackgroundGastric cancer is typically an end result of Helicobacter pylori-associated chronic gastritis. The pathogenesis is thought to involve effects on gastric mucosal epithelial cell turnover. In this study, we aimed to compare apoptosis and proliferation in the noncancer-containing mucosa of H. pylori-positive patients with early gastric cancer with these phenomena in H. pylori-positive controls.MethodsTwo specimens each were obtained from the greater and lesser curvatures of the corpus and from the greater curvature of the antrum. The histopathological grading used was the updated Sydney System. Apoptotic epithelial cells were detected using the terminal deoxy nucleotidyl transferase-mediated deoxy-uridine triphosphate (dUTP) biotin nick-end labeling (TUNEL) method. The expression of Ki 67 was evaluated by immunostaining.ResultsForty-five H. pylori-positive patients with endoscopic mucosal resection for early gastric cancer and 52 H. pylori-positive controls were studied. Gastric cancer was associated with a higher frequency of incomplete intestinal metaplasia (IM; odds ratio [OR], 19.1; 95% confidence interval [CI], 6.9–53.2; P < 0.001). The apoptotic index (AI) in the greater curvature of the corpus and the proliferation index (PI) in each part were significantly higher in cancer patients than in the control group. The median PI in the antrum was significantly higher in the incomplete IM group than that in the complete IM group (17.6 vs 12.6; P = 0.009). The PI and the AI in the greater curvature of the corpus correlated with the activity score, and the PI correlated with the IM score.ConclusionsIn the cancer patients, H. pylori-induced gastritis was associated with increased cell proliferation and apoptosis compared with mucosal findings in the controls. IM seems to be one of the most important factors affecting cell proliferation and may be one of the components of carcinogenesis that results in proliferation-dominant cell kinetics.

Nodular gastritis in Japanese young adults: endoscopic and histological observations

BackgroundEndoscopic findings of nodular gastritis (NG) are characterized by the presence of Helicobacter pylori infection and follicular gastritis. A possible association with diffuse-type gastric cancer has recently been suggested from observations in Japanese. Our aim was to analyze antral nodularity and histological scores in young adults.MethodsSubjects (55 men and 45 women; age range, 18–25 years) with upper gastrointestinal (GI) symptoms or positive H. pylori antibodies underwent endoscopy. One specimen each was obtained from the greater and lesser curvatures (curves) of the corpus and from those of the antrum. Endoscopic appearance was assessed using 0.2% indigo carmine, and histopathological grading was evaluated by the updated Sydney System.ResultsAntral nodularity was identified in none of 17 H. pylori-negative subjects and in 55 of 83 (66.3%) H. pylori-positive subjects. By the distribution of nodular or granular elevated lesions in the antrum, NG was divided into diffuse (n = 27) or nondiffuse (n = 28) types. The diffuse-type NG predominantly affected women (odds ratio, 3.9; 95% confidence interval, 1.5–10). The atrophy scores in the lesser curve of the antrum were significantly higher in the nondiffuse than in the diffuse group. However, the scores for activity, inflammation, and H. pylori density were not significantly different among the three groups.ConclusionsDiffuse-type NG depended on sex, and antral nodularity seemed to change from the diffuse to the nondiffuse type in association with atrophy.

Histological risk markers for non-cardia early gastric cancer. Pattern of mucin expression and gastric cancer.

There are limited data regarding the prognostic value of the pattern of mucin expression in IM. To examine the role of the type of IM and pattern of mucin expression in IM as histological risk markers of gastric cancer, 80 patients with a history of endoscopic mucosal resection (EMR) for early gastric cancer and 80 sex and age-matched controls were studied. Serum levels of pepsinogen (PG) were measured by RIA, and MUC2, MUC5AC and MUC6 were evaluated immunohistochemically. There is a significant association between types of IM and atrophic scores or PG levels. The most incomplete IM (type II and III) preserving gastric mucin is the gastric and intestinal mixed (GI) type, whereas the complete type is the intestinal (I) type especially in the corpus lesser curve. Gastric cancer was most significantly associated with incomplete IM in the corpus lesser curve (OR=6.4; 95% CI, 2.0–21, p=0.002). Asynchronous multiple lesions were associated with incomplete IM in the corpus greater curve (OR=4.8; 95% CI, 1.4–16, p=0.01). Classification of IM obtained using fixed-point biopsy samples may enhance the ability of surveillance programs to detect patients at increased risk of gastric cancer.

Subclinical syphilitic hepatitis, which was markedly worsened by a Jarisch-Herxheimer reaction

Early syphilitic hepatitis is uncommon and tends to be overlooked. However, the diagnosis of this disease is important, because appropriate treatment results in rapid resolution of the hepatitis. We report a case of subclinical early syphilitic hepatitis exaggerated by a Jarisch-Herxheimer reaction. This reaction helped to realize the diagnosis in this case.

Effectiveness of Daikenchuto, a Traditional Japanese Herbal Medicine, in Accelerating Capsule Endoscopy Transit Time- A Prospective Pilot Study

Capsule endoscopy (CE) is an effective and non-invasive method to exam lesions in the small intestine [1][2]. The battery life is a limiting factor for CE examinations. In approximately 20% of the cases, parts of the small intestine cannot be observed due to the delayed passage of the capsule through the small intestine, and thus it is necessary to shorten the passage time [3][4]. Currently, there is no consensus on the preparation of patients to improve the passage of CEs through their digestive tract, and the establishment of a standardized preparatory treatment is necessary. The purpose of this study was to investigate whether the pre-exam administration of Daikenchuto shortens the time during which a CE remains in the small intestine, and to improve the speed at which the capsules reach the large intestine.