Shigeru Asaki

Double immunostaining for c-erbB-2 and p53 in human stomach cancer cells

We examined 32 cases of surgically resected stomach cancer for the immunohistochemical expression of p53 and c-erB-2 protein and correlated the findings with clinical outcome and established prognostic factors. p53 Was observed in the nuclei of tumor cells in 11 of 32 cases (33%) and c-erbB-2 immunoreactivity was observed in nine of 32 cases (27%). In eight cases both p53 and c-erbB-2 were positive; however, double immunostaining revealed that less than a third of the same tumor cells were positive for both p53 and c-erbB-2 in these cases. The immunohistochemical localization patterns of p53 and c-erbB-2 were not related to the histopathologic differentiation of the carcinoma cells. No correlation was observed between expression of p53 and/or c-erbB-2 and the clinical outcome and established prognostic factors, including clinical stage and histologic types of the tumor examined. These results indicate that abnormalities of p53 and c-erbB-2 may not play major roles in the biologic behavior of human stomach cancer and that abnormalities in p53 and c-erbB-2 do not necessarily occur simultaneously in the development of stomach cancer.

Immunohistochemical Studies on EGF Family Growth Factors in Normal and Ulcerated Human Gastric Mucosa

Expression of members of the epidermal growthfactor family, including epidermal growth factor (EGF),transforming growth factor-α (TGF-α),amphiregulin (AR), and Cripto, as well as their putative receptor, epidermal growth factor receptor(EGFR), was studied immunohistochemically in humangastric mucosa to evaluate their possible roles in cellproliferation of normal and regenerative gastric mucosa. We also examined the correlation between cellproliferation and EGFR by double immunohistochemicalstaining for proliferating cell nuclear antigen (PCNA)and EGFR. In normal gastric mucosa, TGF-α, Cripto, and AR immunoreactivities were observed in thesurface epithelial and parietal cells of gastric fundicglands, respectively. EGF immunoreactivity was notobserved in any of normal mucosa examined. EGFR immunoreactivity was detected on foveolar cellsin proliferative zones and in parietal cells. Doubleimmunostaining revealed that EGFR immunoreactivity wasdistributed much more widely than PCNA immunoreactivity. PCNA positive epithelial cells adjacent togastric ulcer margin expressed relatively intense EGFRbut did not express any of the growth factors examined.On the other hand, relatively intense immunoreactivity of both TGF-α and Cripto was detected inPCNA-negative regenerative epithelium located distantfrom gastric ulcer margin. Relative immunoreactivity ofAR in regenerative gastric epithelium associated with ulcer was not different from that innormal gastric mucosa. TGF-α, AR, and Cripto areconsidered to play important roles in normal gastricmucosal proliferation, and TGF-α and Cripto may be involved in ulcer healing, possibly via aparacrine mechanism.

Effect of lansoprazole on intragastric pH : comparison between morning and evening dosing

Lansoprazole is a newly developed proton pump inhibitor. The purpose of this study was to determine whether morning or evening dosage gave better control of 24-hr intragastric pH. In this study, we examined the antisecretory effect of lansoprazole by repeated intragastric pH monitoring on four occasions in eight normal subjects and compared median 24-hr pH values and pH threshold time of pH≧4 between morning and evening dosing, following the administration of lansoprazole 30 mg once daily in either the morning or evening for seven days. Intragastric pH was monitored before and after seven days of treatment. Both morning and evening dosing caused a rise in the intragastric pH. Median pH for 24 hr was 4.3 and 1.6 with and without lansoprazole morning dosing and 4.6 and 2.1 for evening dosing, respectively. The pH threshold curve shifted to the right with lansoprazole treatment in either case. However, no differences were found between morning and evening dosing in terms of median 24-hr pH values of pH threshold time of pH≧4. These results indicate that lansoprazole can be given once daily in either the morning or evening because of its potent and long-lasting antisecretory activity.

A new endoscopic method of gastric acid secretory testing

Abstract Objective: To date, the effect of Helicobacter pylori on acid secretion remains controversial. To evaluate changes in the gastric acid secretory response before and after H. pylori eradication in a large number of patients, we devised a new endoscopic method of gastric acid secretory testing, the endoscopic gastrin test (EGT). Methods: In EGT, endoscopy was begun 15 min after intramuscular injection of 4 μg/kg tetragastrin. Gastric fluid secreted between 20 and 30 min after gastrin injection was aspirated and collected during endoscopic examination. The amount of acid in the sample collected over this 10-min period was estimated by titration and expressed in H + mEq/10 min. Fifteen subjects underwent a conventional secretory test using a nasogastric tube (conventional method) and EGT on different days to assess the correlation between results obtained with the two methods. In 10 of these subjects, EGT was repeated under the same conditions to assess its reproducibility. Results: EGT values correlated very well with peak acid output determined by the conventional method (n = 15, r = 0.92) and had high reproducibility (n = 10, CV = 5.6). We noted that EGT takes just a little longer to perform than a routine endoscopic examination, and the influence of an endoscope in the stomach on acid secretion was not present. Conclusion: The EGT should be very useful as a rapid, simple substitute for conventional secretory testing when repeated gastric secretory tests are required, especially in investigating the effect of H. pylori on acid secretion in a larger population.

IN SITU ANALYSIS OF TISSUE DYNAMICS AND p53 EXPRESSION IN HUMAN GASTRIC MUCOSA

In situ tissue dynamics were studied in 12 cases of human gastric mucosa, including normal gastric body mucosa and gastric glands with intestinal metaplasia, obtained from gastrectomy specimens of adenocarcinoma. Cell proliferation was determined by Ki67 immunoreactivity. DNA fragmentation was studied in situ by TdT‐mediated dUTP‐biotin nick end labelling (TUNEL). In addition, p53 expression was examined by both immunohistochemistry and mRNA in situ hybridization. In the oxyntic gastric glands, Ki67 immunoreactivity was observed exclusively in the proliferative zone and TUNEL‐positive cells were present predominantly in the surface foveolar epithelium. In the gastric glands with complete intestinal metaplasia, Ki67‐positive cells were present in the lower portion of the glands and TUNEL‐positive cells in the superficial epithelium. In the gastric glands with incomplete intestinal metaplasia, TUNEL‐positive cells were detected in the lower gastric glands adjacent to cells immunoreactive for Ki67; the proportion of these gastric glands with TUNEL‐positive cells (40 out of 108 glands) was significantly higher than for oxyntic glands (94 out of 620 glands) or for glands with complete metaplasia (31 out of 254 glands). Relatively strong p53 immunoreactivity and mRNA hybridization were also observed in the proliferative and apoptotic areas of gastric glands with incomplete intestinal metaplasia. These results indicate that incomplete intestinal metaplasia is associated with increased cell turnover and p53 overexpression, possibly in response to various noxious or DNA‐damaging stimuli.

Endoscopic treatment for submucosal tumors of the esophagus: Studies in 25 patients

SummaryTwenty-five patients with submucosal tumor of the esophagus were treated endoscopically. All patients underwent submucosography. The tumors were classified as intra-luminal or intra-mural types according to growth pattern. Twenty tumors were resected using electrocautery in single sessions. Another 5 lesions (more than 20mm in diameter) were subjected to absolute ethanol injections in multiple sessions to necrotize the tissue, after the overlying mucosa was stripped off by electrocautery. These procedures were not accompanied with serious complications such as perforation or massive bleeding. Oozing bleeding occurred in 3 patients, which was easily stopped by topical injection of absolute ethanol with an endoscope. Esophageal stenosis did not occur. Local reccurence of a submucosal tumor was found in a patient after 14 months, and was retreated successfully. Although the wall of the esophagus is thinner than that of the stomach, endoscopic treatment for a submucosal tumor of the esophagus can be performed safely. Submucosography and endoscopie ultrasonography reveals the extent of the tumor in relation to the esophageal wall thickness. These examinations are helpful in preventing complications. Endoscopie treatment for submucosal tumors using electrocautery and topical injection of absolute ethanol were effective and safe.

MULTICENTRE COLLABORATIVE PROSPECTIVE STUDY OF ENDOSCOPIC TREATMENT OF EARLY GASTRIC CANCER

Aims:  The present study was conducted with the aims of elucidating the present state of endoscopic treatment, in particular endoscopic mucosal resection (EMR) of early gastric cancer, as well as any associated problems, and the prospects for further broadening of the indications for EMR.

Efficacy of Endoscopic Pure Ethanol Injection Method for Gastrointestinal Ulcer Bleeding

We reviewed endoscopic hemostatic effects of the pure ethanol injection (PEI) method for reducting emergency operations and deaths due to gastroduodenal ulcer bleeding. During 17 years beginning in June 1979 in Tohoku University Hospital, 331 patients underwent endoscopic hemostasis by the PEI method. Initial hemostasis was successfully obtained in all cases. Rebleeding occurred in about 4% of the patients, and rehemostasis was obtained successfully in all of them. Complete hemostasis was obtained in 330 of 331 patients (99.7%) using the PEI method; there were no deaths. Only one patient required emergency operation after hemostasis because of repeated neogenetic bleeding complicated with a perforation and another because of an unidentifiable neogenetic ulcer bleeding located just above the Vater papilla. None required other endoscopic hemostasis or interventional radiology. Moreover, after introduction of “second-look” endoscopy, the rebleeding rate decreased to about 1% with PEI hemostasis. Based on these excellent hemostatic effects of the PEI method, we believe that a comparative study with other hemostatic methods is not needed.

Peptic ulcer recurrence during maintenance therapy with H2-receptor antagonist following first-line therapy with proton pump inhibitor

Abstract: We investigated the peptic ulcer recurrence rates during maintenance therapy with H2-receptor antagonists (H2RAs) following first-line therapy with a proton pump inhibitor (PPI). Patients with gastric ulcer (GU) or duodenal ulcer (DU) were enrolled in this study; 583 eligible patients (GU, 325; DU, 258) were administered lansoprazole (30 mg/day for 8 weeks for GU, and the same dosage for 6 weeks for DU) as first-line therapy, and a half dose of H2RA as maintenance therapy for 12 months. Endoscopic photographs were taken before administration and after 8 (GU) and 6 (DU) weeks of lansoprazole administration. Ulcer stage was evaluated using the classification of Sakita and Miwa. Endoscopic examinations were performed 6 months or 12 months after the start of maintenance therapy or when a recurrence was suspected because of the appearance of subjective symptoms. The healing rates for GU and DU patients after completion of lansoprazole therapy were 79% in both groups, while the S2-stage healing rates were 18% and 31%, respectively. At 1 year after the start of maintenance therapy, the recurrence rates were 25% for GU and 39% for DU patients. In DU patients, the recurrence rates from S1-stage and S2-stage were 49% and 20%, respectively (P = 0.004), but no significant difference was found between these rates in GU patients. The recurrence rates in H. pylori-positive patients before lansoprazole administration were 27% for GU and 43% for DU patients. We concluded that the maintenance therapy with a half-dose of H2RA following PPI therapy was insufficient to prevent recurrences of GU and DU.

Gastric mucosal blood flow response to stress in streptozotocin diabetic rats: Regulatory role of nitric oxide

To investigate cytoprotection against mucosal injuries of the stomach in patients with diabetes, we investigated gastric mucosal blood flow (GMBF), its response to a burn stress, and the involvement of nitric oxide (NO) in streptozotocin (STZ) diabetic rats. GMBF was measured by laser-Doppler velocimetry (LDV) and by the hydrogen gas clearance technique (HGC). The steady-state GMBF of STZ rats decreased according to the duration of diabetes, and insulin treatment blocked this decrease. Burn stress caused a rapid decrease in the GMBF. Reduction of the GMBF and gastric mucosal leakage of Evans blue (EB) after the burn stress were greater in the STZ rats than in the controls, but insulin treatment completely blocked this increase in EB leakage in the STZ rats. There was a significant negative correlation between the percent GMBF 3 h after the burn stress and EB leakage at the same time point. In the controls and the insulin-treated STZ rats, N-nitro-l-arginine (l-NNA) an NO synthase inhibitor, enhanced the decrease in postburn GMBF and EB leakage, but was without effect in the STZ rats. These results suggest that NO may be involved in the regulation of GMBF, and that persistent hyperglycemia may impair this regulation. These findings suggest that patients with diabetes have reduced cytoprotection against a variety of gastric mucosal injuries.