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Gastric polyps can be truly neoplastic but most polypoid dysplastic lesions are manifestations of gastritis-associated dysplasia that happens to form a polypoid lesion rather than true adenomas arising in normal background mucosa as is typically observed in the colon. However, the term adenoma has been used over the years to describe polyps with intestinal and pyloric gland differentiation, and this terminology is entrenched in our lexicon. In this review, we briefly discuss the issue of terminology, gastritis, and the following polyp types: intestinal type adenoma, pyloric gland adenoma, foveolar adenoma, and oxyntic gland adenoma (also termed oxyntic gland neoplasm and adenocarcinoma of fundic gland type.

Gastric neoplasms exhibiting oxyntic gland differentiation typically are composed of cells with mild cytonuclear atypia differentiating to chief cells and to a lesser extent, parietal cells. Such tumors with atypical features have been reported also and terminology for this entity remains a matter of considerable debate. We analyzed and classified 26 tumors as oxyntic gland neoplasms within mucosa (group A, eight tumors) and with submucosal invasion. The latter was divided further into those with typical histologic features (group B, 14 tumors) and atypical features, including high-grade nuclear or architectural abnormality and presence of atypical cellular differentiation (group C, four tumors). Groups A and B tumors shared similar histologic features displaying either a chief cell predominant pattern characterized by monotonous chief cell proliferation, or a well-differentiated mixed cell pattern showing admixture of chief and parietal cells resembling fundic gland. In addition, group C tumors displayed atypical cellular differentiation, including mucous neck cell and foveolar epithelium. Moderate or even marked cytological atypia was noted in group C, whereas it was usually mild in the other groups except for three group B tumors with focal moderate atypia. More than 1000 μm submucosal invasion and lymphovascular invasions were recognized only in group C. Mutation analyses identified KRAS mutation in one group C tumor as well as GNAS mutation in in one group A and group B tumors. Intramucosal tumors appear to behave biologically benign and should be classified as "oxyntic gland adenoma". Those with submucosal invasion also have low malignant potential; however, a subset will have atypical features associated with aggressive histologic features and should be designated as "adenocarcinoma of fundic gland type". Especially, we suggest "adenocarcinoma of fundic gland mucosa type" for tumors with submucosal invasion exhibiting atypical cellular differentiation, because the feature is likely to be a sign of aggressive phenotype.

Introduction and aim: Adequately preserved slides and tissue blocks in pathology archives, when re-reviewed and associated with patient charts, are important tools to further assess prevalence changes and associations of certain pathologies. Our aim was to identify whether proton-pump inhibitor (PPI) use, dose, and duration of use were associated with gastric polyps and their phenotypes in a case-control study. Methods: The slides from patients with a morphologic diagnosis of either hyperplastic polyps or fundic gland polyps were retrieved from the 1980, 1990, 2000, 2010, and 2016 surgical pathology files at a tertiary care hospital in Mexico City and re-evaluated. Cases were paired by age and sex with patients that underwent endoscopy and gastric mucosa biopsy in the same year, with no evidence of polyps. Results: A total of 133 (3.8%) patients with gastric polyps were identified from 3,499 gastric biopsies taken in the abovementioned years and compared with 133 paired controls. Dyspepsia was more prevalent in the controls (p = 0.002) and abdominal pain was more prevalent in the patients with gastric polyps (p = 0.001). PPI use (OR 7.7, 95% confidence interval, 4.4-13.3) and taking more than one PPI medication (OR 4.9, 95% confidence interval, 1.09-22.3) were significantly associated with the presence of gastric polyps. The fundic gland phenotype in the oxyntic mucosa was more frequently associated with PPI use (p

Oxyntic gland adenomas are rare lesions of the stomach, composed of oxyntic-type glands. A variety of nomenclatures have been used to designate it, including adenocarcinoma of fundic gland type and oxyntic mucosa pseudo-polyp. We report a series of five cases that demonstrate a spectrum of clinical and morphological variations in oxyntic gland adenomas. Although all cases showed irregular, dilated oxyntic glands lined by predominantly chief cells with scattered parietal cells, one case showed at least moderate cytological atypia and another showed submucosal invasion. Despite these worrying features, all patients had no evidence of recurrence following successful endoscopic resections. Published version

Gastric polyps include a wide spectrum of lesions with different histology and neoplastic potential. They are found in up to 6% of upper gastrointestinal endoscopy and are usually asymptomatic and incidentally diagnosed, being in the vast majority epithelial gastric polyps. Hyperplastic, fundic gland and adenomas are the most common types of gastric polyps and, although each type may have typical endoscopic appearances, they all must be sampled at the initial endoscopy for histological assessment. Also, the normal appearing gastric mucosa should be sampled to stage atrophic changes, rule out endoscopically non-visible dysplasia and to diagnose Helicobacter pylori. Polyposis syndromes that affect the stomach are rare but should be taken into account. Hamartomatous polyps can be found in Juvenile polyposis, Cowden syndrome and Peutz-Jeghers syndrome. On the other hand, multiple fundic gland polyps are present in the majority of patients with familial adenomatous polyposis. In this study we provide a comprehensive review on the evaluation and management of gastric epithelial polyps, in this way helping physicians to properly handle this type of lesions.

Background Rapidly proliferating stomach stem cells have been predicted to be located at the isthmus of both corpus and antrum. We recently identified such stem cells by using 270 bp Runx1 enhancer element, eR1 (Gastroenterol, 2017). In addition, eR1 also marked small number of fully differentiated chief cells in the corpus. We investigated whether chief cells have stem cell activity and can be an origin of gastric cancer, particularly because there are disagreements among the researchers. Methods We generated knock-in mice of pepsinogen C-CreERT2 and crossed them with Rosa26-EYFP mice or pepsinogen A-CreERT2 and crossed them with Rosa26-tdTomato mice for lineage tracing. PGC-CreERT2 mice were also crossed with K-rasG12D/+, Trp53flox/flox and Apcflox/floxmice for carcinogenesis model. Those mice were injected with Tamoxifen 2 mg alternate days for 6 timesto activate Cre recombinase in the chief cells. Results By activating Cre recombinase, we showed that relatively small number of chief cells was retro-differentiated into neck, parietal, pit and enteroendocrinecells suggesting that chief cells underwent differentiation in exact reverse order to make a complete gland unit. When K-rasG12Dwas activated by pepsinogen C-CreERT2, induction of metaplasia was observed. Addition of p53 knockout with K-rasG12Dinto chief cells showed increasing number of glands with metaplasia. Furthermore, addition of APC knockout combination with K-rasG12Dand p53f/fshowed invasive intestinal type gastric cancer in the corpus. These results suggest that at least small subfraction of chief cell have stem cell activity and potential to give rise to gastric cancer. Recently, new entity of gastric adenocarcinoma has been proposed which called Gastric adenocarcinoma of fundic gland type (chief cell predominant type). We might have showed those type of gastric carcinogenesis. Conclusions Chief cell in stomach have stem cell activity and potential to develop gastric cancer. Legal entity responsible for the study The authors. Funding Singapore Gastric Cancer Consortium. Disclosure All authors have declared no conflicts of interest.

Fundic gland polyps can appear sporadically or in association with familial adenomatous polyposis syndrome. An association between fundic gland polyps and prolonged treatment with proton pump inhibitors has been described, as has their regression after withdrawal of these inhibitors. Dysplastic components are not usually associated. We describe four patients who were receiving chronic treatment with proton pump inhibitors. The results of prior endoscopic analysis were normal. The presence of multiple fundic gland polyps was detected as was their disappearance 6 months after treatment cessation.

This study used mucin immunohistochemistry to investigate differences in the properties of intestinal metaplasia between the antrum and body of the stomach in 28 resected specimens. Intestinal metaplasia was classified as: (1) small intestinal metaplasia (SIM) with a tubule, including CD10-positive brush border on a background of MUC5AC-/ HGM-negative cells; or (2) goblet cell metaplasia (GCM) with MUC2-positive and CD10-negative cells. In the antrum, frequencies of SIM and GCM were nearly equal irrespective of metaplasia grade. Frequency and length of remnant pyloric gland for SIM were significantly greater in the antrum than in the body. In the proliferative zone, there existed a lower level in SIM than in non-intestinalized tubules. These findings suggest that the proliferative zone shifts from the neck zone toward the bottom of the tubule during the SIM process in the antrum. In the body, however, the grade of SIM grade was significantly higher than that of GCM. The proliferative zone was located higher in the fundic gland, pseudopyloric gland and SIM, in that order. Almost all remnant pyloric glands for SIM were negative for pepsinogen I. These facts indicate that SIM in the body originates in a proliferative zone that shifted downward to an area near the bottom of the tubule, with atrophic pyloric glands originating from pseudopyloric gland metaplasia.

We report a patient with familial adenomatous polyposis who developed high-grade dysplasia against a background of fundic gland polyposis. Two large high-grade dysplasia lesions were found in the gastric body, where numerous fundic gland polyps were present. In both lesions, the dysplastic epithelium covered non-neoplastic oxyntic glands that occasionally exhibit cystic changes. A genetic analysis for APC (adenomatous polyposis coli) revealed a somatic 50-bp deletion involving codons 1502-1517 and 2-bp deletion at codon 1465 in each lesion of high-grade dysplasia. In contrast, six of the 18 fundic gland polyps were found to harbor an identical mutation: 1-bp insertion at codon 1556. Both lesions of high-grade dysplasia and the fundic gland polyps were similarly located in the fundic gland area and were caused by the inactivation of APC; however, their mutation profiles of APC were different. These results imply that fundic gland polyps and high-grade dysplasia of the stomach have distinct preferences for APC genotypes in their development.

Sporadic fundic gland polyps account for approxmately 50% of all gastric polyps and may be observed in .8% to 1.9% of patients undergoing upper gastrointesinal endoscopy (Table 1).1,2 They are encountered more ommonly in middle-aged women, although they are lso observed in men and in about 0.3% of pediatric atients undergoing endoscopy with an average age of iagnosis of 14.4 years.3 Fundic gland polyps also occur n 12.5% to 84% of patients with familial adenomatous olyposis (FAP).4 In this setting the occurrence is equivlent in women and men and polyps are observed at uch younger ages. Fundic gland polyps may be single or multiple, but sually fewer than 10 polyps are observed in the sporadic etting, although 50 or more polyps have been reported. hese polyps always occur in the body and fundus of the tomach. In FAP, numerous fundic gland polyps are sually observed, often numbering in the hundreds (Figres 1A–B). The polyps may cover the entire surface of he acid-secreting epithelium and even coalesce to give a matted” appearance of the mucosal surface. Polyps in oth the sporadic setting and in FAP are usually 1-mm o 5-mm in diameter, although larger polyps are oberved. They are sessile, hemispherical-shaped elevations, ith the occasional appearance of a “waist” but not a talk. Their color is pale pink, resembling surrounding ucosa. At endoscopic biopsy the polyps usually “chunk ff” or detach entirely at the base, unlike other gastric olyps. These characteristics together usually make funic gland polyps endoscopically distinguishable from ther types of gastric polyps.1 Histologically, fundic gland polyps are characterized y cystically dilated and irregularly budded fundic lands, which are lined by flattened parietal cells, chief ells, and variable numbers of mucous neck cells.4 The verlying surface and foveolar gastric epithelium is typcally nondysplastic. Surrounding mucosa is uniformly ormal both morphologically and histologically and conurrent atrophy is seldom observed. The pathogenesis and cancer risk of fundic gland olyps is poorly understood. These lesions have usually een considered hamartomas, although up to 25% of AP-associated fundic gland polyps and 1% of sporadic ypes are now known to show foveolar epithelial dysplaia, which is often proceeded by dysregulation of epitheial proliferation.5 Gastric cancer has been reported in AP patients with fundic gland polyps, even arising rom them,6,7 although the lifetime risk of gastric cancer n FAP is estimated to be only 0.6%,8,9 but may be igher in some countries such as Japan.10 Fundic gland polyps in FAP arise from mutational nactivation of the adenomatous polyposis coli (APC) ene, which is the gene mutated in that condition,2 hile sporadic fundic gland polyps are usually caused by ctivating mutations of the beta-catenin gene.4,11 Both enes are involved in the same cell growth-signaling athway,12 which explains why mutations in either gene an give rise to fundic gland polyps that are histologially similar. When dysplasia occurs in fundic gland olyps it is usually in polyps with mutations of the APC ene. This observation appears to explain why dysplasia s sometimes observed in the fundic gland polyps of FAP, ut seldom in sporadic fundic gland polyps.13 c

Fundic gland polyps (FGPs) are the most common gastric polyps. FGPs traditionally have been regarded as nondysplastic hamartomatous or hyperplastic lesions, but their pathogenesis remains unclear. We have recently shown that somatic adenomatous polyposis coli (APC) gene alterations are frequently present in FGPs associated with familial adenomatous polyposis (FAP), raising the possibility that mutations of the β-catenin gene affecting the APC/β-catenin pathway might be involved in the pathogenesis of sporadic FGPs. We analyzed somatic β-catenin gene mutations in 57 sporadic FGPs from 40 patients without FAP and in 19 FGPs from 13 FAP patients. Direct DNA sequencing of exon 3 encompassing the glycogen synthase kinase-3β phosphorylation region for β-catenin was used with confirmation by Hin fI restriction endonuclease digestion. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 22 of 57 sporadic FGPs. Activating β-catenin gene mutations were present in 91% (52 of 57) of sporadic FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the polyps were shown to have the same somatic β-catenin mutation in 21 of 22 (95%) sporadic FGPs. In contrast, β-catenin gene mutations were not present in any of the 19 FAP-associated FGPs ( P

Fundic gland polyps (FGPs) are the most common gastric polyps in patients with familial adenomatous polyposis (FAP). FGPs have traditionally been regarded as nonneoplastic, possibly hamartomatous lesions, but the pathogenesis of FGPs in both FAP and sporadic patients remains unclear. FGPs in FAP can show foveolar dysplasia, and rarely invasive gastric adenocarcinoma has been reported in patients with FAP and fundic gland polyposis. Using direct gene sequencing and allelic loss assays at 5q, we analyzed somatic adenomatous polyposis coli (APC) gene alterations in 41 FAP-associated FGPs (20 with foveolar dysplasia, six indefinite for dysplasia, and 15 nondysplastic) and 13 sporadic FGPs. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 25 of 41 FAP-associated FGPs and 13 of 13 sporadic FGPs. Somatic APC gene alterations were identified frequently (21 of 41 cases, 51%) in FAP-associated FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the FGPs were shown to carry the same somatic APC gene alteration in 24 (96%) of 25 cases. Furthermore, there was no difference in the frequency of somatic APC gene alterations between FGPs with foveolar dysplasia (10 of 20, 50%), indefinite for dysplasia (four of six, 67%), and nondysplastic (seven of 15, 47%) in FAP patients (P = 0.697). In contrast, FGPs from non-FAP patients showed infrequent (one of 13, 8%) APC gene alterations (P = 0.008). These results show that FGPs in FAP patients are pathogenetically distinct from sporadic FGPs. Somatic, second-hit APC gene alterations, which precede morphological dysplasia in many FAP-associated FGPs, indicate that FGPs arising in the setting of FAP are neoplastic lesions.

In order to understand the histogenesis of precancerous and cancerous lesions, we investigated the clonality of normal single fundic gland and single pyloric gland using X-chromosome inactivation. Sixty percent of single fundic glands were cell populations methylated at the same alleles of the X-chromosome (homotypic) and 40% consisted of mixed cells methylated at different alleles of the X-chromosome (heterotypic). Among 28 fundic glands in which the clonality of the upper parts and that of the lower parts were analyzed separately, 11 glands were heterotypic in either part and 4 glands were homotypic with different allelic methylation in the upper part and in the lower part. Ninety-six percent of the single pyloric glands were homotypic and 4% were heterotypic. The results show the differences in the development of the fundic glands and the pyloric glands.

A glycolipid detected in human gastric mucosa with anti-GM2 monoclonal antibody was characterized to be GalNAc beta 1-4[NeuAc alpha 2-3]Gal beta 1-4GlcNAc beta 1-3Gal 1-4Glc-Cer (NGM-1), which was lost in gastric cancer tissue with complementary increase of GM2 sharing the same terminal carbohydrate structure as NGM-1 (Dohi, T., Ohta, S., Hanai, N., Yamaguchi, K., and Oshima, M. (1990) J. Biol. Chem. 265, 7880-7885). The study on differential expression of NGM-1 in gastric fundic mucosa, pyloric mucosa, gastric cancer, and various other tissues indicated that NGM-1 existed specifically in fundic mucosa. The content of GM3 and sialylparagloboside (SPG), which are the substrates for the synthesis of GM2 and NGM-1, respectively, were not significantly different in these tissues. Therefore, the presence of two kinds of beta 1,4GalNAc transferases having different substrate specificity was considered to be critical for the expression of NGM-1 and GM2. The activity of beta 1,4GalNAc transferase which synthesizes GM2 or NGM-1 was determined by detecting the products with specific monoclonal antibodies. The activity of beta 1,4GalNAc transfer to SPG was high in fundic mucosa, while it was absent in pyloric mucosa or cancer. On the other hand, the increased activity of beta 1,4GalNAc transfer to GM3 was observed in cancer tissues and cancer cell lines which were rich in GM2. Our conclusion is that the limited expression of NGM-1 in fundic mucosa and the increase of GM2 in cancer are attributed to two types of beta 1,4GalNAc transferases localized in each region with different substrate specificity; the one in fundic mucosa transfers GalNAc to SPG but not to GM3, and the other one enhanced in cancer transfers GalNAc to GM3 but not to SPG.

Backgrounds and Aims :With gastroesophageal reflux disease (GERD) being increasingly treated with proton pump inhibitors (PPIs), it has been reported that fundic gland polyps (FGPs) occurred or expanded during oral PPI treatment. The cause of FGPs , histologically benign polyps associated with cystic formation and excessive growth of parietal and chief cells, remains unknown. We studied FGP prevalence in patients with PPI therapy and the cause of FGPs in relation to gastrin, which causes cell proliferation, and water channel aquaporin 4, which appeared specifically in the parietal cells. Methods :Investigation 1. The relationship between oral PPI treatment and FGP prevalence detected by histological tests or endoscopic examination was studied in 1573 subjects who underwent gastric endoscopy between April and July 2007. Investigation 2. In 27 subjects with GERD undergoing maintenance therapy with oral PPIs for 1-7 years and developing FGPs, we studied PPI oral administration length before FGPs occurred and fasting serum gastrin. Using biopsy specimens, we also compared aquaporin 4 immunological staining and mRNA expression in real-time polymerase chain reaction between the above subjects and 20 subjects treated with oral PPI who did not develop FGPs. Results : Investigation 1. FGP prevalence was 9.8% (124/1,259) in those not treated with PPIs, 5.8% (10/172) in those treated with oral PPIs for less than 1 year, 15.1% (13/86) in those treated with oral PPIs for 1-3 years, and 19.6% (11/56, p

Background: Pyloric gland adenoma of the gastric mucosa was first described by Borchard et al. and Watanabe et al. in 1990. Similar adenomas with a gastric differentiation were subsequently described in gastric mucosa heterotopia and gastric metaplasia in the duodenum, in the pancreatic duct and, in paticular, in the gall bladder. Aim:We searched our gastric polyp statistics dating from 1998 back to 1990 to gain clinical data about predominant location, age and sex distribution. Results: The incidence of pyloric gland adenoma is 2.7% among 2570 gastric polyps (leaving out of account the fundic gland "Elster's" polyps which are the most common type found in our material). The diagnoses were confirmed immunohistochemically by positivity of foveolar mucin M1 and deep gastric mucin M2. Predominantly these adenomas occur more frequent in old women (m:f = 1:1.5; w=88 years, m=72 years). The preferential site is the corpus/fundic mucosa. At the time of diagnosis, pyloric gland adenomas are already relatively large lesions (mean diameter: 16.5 mm). The predominant gastritis in the stomach was the atrophic autoimmune gastritis of the corpus and fundic mucosa (34%). In 21.7% of the cases we diagnosed a continuous transition to well-differentiated adenocarcinomas. The incidence of adenocarcinoma correlates with the diameter of the lesion. Conclusion: Pyloric gland adenomas are rare neoplastic lesions of the gastrointestinal tract. Since there are apart from the two initial reports no further reports on pyloric gland adenomas in the stomach and clinical data are not available in the literature, presumably, most of these adenomas are diagnosed routinely and are not published. This is indicated by our own statistics on pyloric gland adenomas in the stomach.

The localization of pepsinogens (PG A and PG C) was studied intracellularly in human gastric biopsies embedded in Lowicryl K4M, using affinity purified antibodies and protein A-gold. The homogeneous secretory granules of the chief cells contained both PG A and PG C, as was proved in serial sections. Identical reaction was seen in the core of the biphasic mocous neck cell granules, whereas the mantle did not label. Even the rough endoplasmic reticulum (RER) and Golgi complex of the chief- and mucous neck cells contained label. Transitional cells identified by the presence of granules of both chief- and mucous neck cells were seen. This type of mucous neck cell is thought to transform into a chief cell. However an increase of RER that could explain an increase of the pepsinogen production was not observed. A mixture of these granules were also found in morphologically characterized young parietal cells, suggesting a common precursor for these three cell-types. These observations makes the transformation from mucous neck- into chief cells questionable. In conclusion Lowicryl K4M appeared to be a significant improvement compared to the Epon 812. Its shows a better preservation of both cytoplasmic antigens and cellular fine structure. This improvement adds information on the transformation hypothesis. Lowicryl K4M enables us, firstly to distinguish PG A and C synthesizing RER in different types of cell and secondly to recognize immature cells with the characteristics of chief-, mucous neck-, and parietal cells in the fundic gland. Very likely these three cell-types all arise from a common precursor. It is questionable that in normal human gastric mucosa the mucous neck cells transform into chief cells.

Backgrounds and Aims: It has recently been shown that Helicobacter pylori (Hp) infection impairs acid secretion. This study was designed to determine the effect of Hp infection on H+/K+-ATPase mRNA expression in gastric fundic gland mucosa. Methods: Twenty patients with chronic gastritis and Hp infection were treated with lansoprazole and amoxicillin and/or clarithromycin. Before and one month after treatment, gastroduodenoscopy was performed, several biopsy specimens were obtained from fundic gland mucosa, and serum gastrin levels were measured by radioimmunoassay (RIA). Total RNA was extracted from fundic gland biopsy specimens, and the amount of H÷/K+-ATPase mRNA in the fundic gland mucosa was measured by a competitive RT-PCR method. Results were standardized by ~-actin mRNA level. Hp infection was diagnosed on the basis of results of culture, rapid urease test (RUT), histology, PCR, and [13C]urea breath test as previously reported (Furuta T, et al. J Clin Microbiol 1996; 34: 2421-5). Results: H+/K÷-ATPase mRNA expression was increased and gastric juice pH and serum gastrin levels were significantly decreased in patients with eradication of Hp. On the other hand, no significant changes in any parameters tested before to after treatment were observed in patients without eradication of Hp. Conclusion: These findings suggest that one of the mechanisms by which Hp infection suppresses acid secretion is inhibition of proton pump synthesis in parietal cells.

Upper gastrointestinal polyps have been considered an uncommon finding in patients with Gardner's syndrome and familial polyposis coli. Investigators from Japan, however, have recently reported finding gastric and duodenal polyps in a high percentage of Japanese patients with these conditions. We endoscopically examined 11 affected members of the originally described Gardner's syndrome kindred to determine if upper gastrointestinal polyps also occurred in patients with Gardner's syndrome living in the United States. Six of the patients were found to have numerous small polyps of the gastric fundus and body. Polyp histology in 5 of the 6 patients was consistent with fundic gland hyperplasia. Biopsy specimens from the remaining patient demonstrated normal mucosa only. Another patient with no fundic polyps had a single antral polyp that was an adenoma. Eight patients exhibited small polyps of the duodenum. Biopsy specimens were obtained in 7 of the 8. All polyps biopsied were adenomas. The terminal ileum was examined by endoscopy in 9 of the 11 study patients. All 9 had ileal polyps, but the polyps were adenomas in 6 patients and lymphoid aggregates in 3 patients. The results indicate that upper gastrointestinal polyps are a common pleiotropic manifestation of the genetic defect responsible for Gardner's syndrome.

Histopathologic changes in the regenerative epithelia of 549 foci of gastric ulcer were studied. About 70 per cent of the regenerative epithelia revealed intestinal metaplasia of the so-called complete or incomplete type. Parietal cells and chief cells were occasionally observed in the regenerative epithelia of ulcers located in fundic gland areas or at fundopyloric gland borders. It is possible that the regenerative epithelium frequently reverts to intestinal epithelium during the regenerative process, later re-differentiating into normal gastric mucosa or remaining as intestinal metaplasia and that, thus, only a few foci of intestinal metaplasia are precancerous lesions.

To examine the possible effect of gastritis on the endocrine component of pepsinogen secretion, we determined relationships among gastric mucosal histologic characteristics and serum levels of pepsinogen I and pepsinogen II in 170 first-degree relatives of patients with pernicious anemia. Sixtyfour had normal fundic gland mucosa, 66 had superficial gastritis, 17 had mild or moderate atrophic gastritis, and 23 had severe atrophic gastritis. In superficial gastritis, serum pepsinogen I and pepsinogen II were both significantly higher than normal, but the percentage rise in pepsinogen II was significantly greater than the rise in pepsinogen I. In mildl moderate atrophic gastritis, pepsinogen I did not differ from normal, but pepsinogen II was significantly elevated, while in severe atrophic gastritis, pepsinogen II did not differ from normal, but pepsinogen I was significantly decreased. The nonparallel changes in serum pepsinogen I and pepsinogen II levels resulted in a decrease in the pepsinogen I to pepsinogen II ratio from 6.2 ± 0.2 in subjects with normal fundic gland mucosa to 4.3 ± 0.2, 2.9 ± 0.4, and 0.7 ± 0.2, respectively, in those with superficial gastritis, mild to moderate atrophic gastritis, and severe atrophic gastritis. The pepsinogen I to pepsinogen II ratio in combination with the absolute level of serum pepsinogen I correctly predicted the histologic status of the gastric mucosa in 119 of the 170 subjects, 70.0%. The results indicate that (a) increasing severity of gastritis is associated with nonparallel alterations in serum levels of pepsinogen I and pepsinogen II, (b) that these changes lead to a progressive decrease in the pepsinogen I to pepsinogen II ratio, and (c) that the pepsinogen I to pepsinogen II ratio, in combination with pepsinogen I, is predictive of the histologic status of the gastric mucosa.

Summary Attempts were made to learn about an optimal condition for the induction of intestinal metaplasia in the gastric mucosa. The gastric region of 5-week-old female Wistar rats was irradiated with 500 rad of X-ray daily for 6 times (Group I) or with 1,000 rad of X-ray every two days for 3 times (Group III). In addition, the effect of immunization by allogeneic stomach antigen on the intestinalization was studied in rats irradiated with 500 rad of X-ray daily for 6 times (Group II). In a group of rats (Group II) injected with allogeneic stomach antigen and X-irradiated the process of intestinalization was more accelerated as compared to that in rats treated with X-ray (Group I). The similar results were obtained in rats irradiated with 1,000 rad of X-ray 3 times (Group II). Intestinal metaplasia developed more later in the fundic gland mucosa which became usually atrophic due to the loss of parietal cell mass. There was an intimate association among the parietal cell loss in the fundic gland, a rise in pH value and the development of intestinal metaplasia. In all groups, no case of gastric adenocarcinoma was detected during observation period up to 52nd week.

Twelve patients in Sweden and thirteen patients in Houston underwent selective proximal vagotomy or parietal cell vagotomy, respectively, for the treatment of perforated duodenal ulcer. A drainage procedure was performed in four of the former and in none of the latter group of patients. There were no operative complications and no operative deaths. Twenty-two of the patients were followed from six months to four years. No patient has recurrent ulcer, dumping, diarrhea, or other significant gastric symptoms during the follow-up period. At the time of their last follow-up, the results were considered excellent or good in all twenty-two patients. The results of this study suggest that SPV or PCV without drainage may be the method of choice for the definitive treatment of all patients with perforated duodenal ulcer who have no obstruction and no contraindications to an operative procedure of greater magnitude than simple closure.

We have established an experimental model of chronic gastric ulcer, in rats in which transection of the lower horizontal portion of the duodenum and anastomosis of the forestomach to the upper part of the jejunum caused regurgitation of all duodenal juice into the stomach. After 3, 6, 12, and 30 wk, all treated rats developed an ulcer in the prepyloric region on the lesser curvature of the stomach. More than half of the antrum was finally involved in the ulcer. Histologic studies revealed chronic ulcers quite similar to human ones. As a control series, transection at the pylorus failed to produce an ulcer. Although many papers have appeared regarding the experimental production of chronic gastric ulcer, most of the studies reported have applied chemicals, drugs, or mechanical injury to the gastric mucosa. Our model produced chronic regurgitation of duodenal juice as a natural phenomenon, and uniformly resulted in ulcer formation. Intragastric total bile acid concentrations were significantly elevated in the reflux group. Serum gastrin levels, the thickness of the fundic mucosa, and the height of fundic gland were also significantly increased. Thus, the detergent action of bile acids and the increased acid secretion were assumed to play an important role in ulcer formation. Further studies using this model are warranted on the pathogenesis of chronic peptic ulceration.

Summary A method is described for preparation of extracts containing gastrin from mucosa of the pyloric gland area of the stomach of hogs. These extracts stimulated secretion of acid from Heidenhain pouches in dogs when given by continuous intravenous injection in the dose range 2.5 to 40 gm. per hour (dose of gastrin expressed as wet weight of mucosa from which extract was derived). When given as single rapid intravenous injections to dogs secreting in response to continuous injection of gastrin extract or of histamine, these same extracts caused marked inhibition of secretion of acid. Inhibition of acid secretion was not associated with retching, vomiting, rise in rectal temperature, or fall in blood pressure. Doses as low as 6 gm. given as a rapid intravenous injection produced inhibition. Inhibition began within 15 minutes, reached a maximum of 80 to 90 per cent in 30 to 45 minutes and subsided in 2 to 3 hours. Extracts prepared by the same method from mucosa of the fundic gland area, duodenum, ileum, and colon, or from pancreas produced little or no inhibition of acid secretion. It cannot yet be determined whether the stimulatory and inhibitory actions of these extracts are caused by the same or different constituents, but reasons are given for favoring the view that they are the same.

Summary LDH isoenzyme patterns in fundic and pyloric mucosa and in corresponding muscular layers of the rat stomach were examined (six pooled samples from 12 rats). The LDH isoenzyme pattern and the were used as indicators for the prevalence calculated ratio of monomer H:M synthesis of either an aerobic or an anaerobic type of metabolism. The most striking and most constant feature was the relative prevalence of LDH 1 in the mucosa of the fundic gland area, and vice versa—the prevalence of LDH 5 in the mucosa of the pyloric gland area. From the LDH isoenzyme patterns it is concluded that an aerobic type of metabolism is relatively prevalent in the mucosa of the fundic gland area, and an anaerobic type in the mucosa of the pyloric gland area. The difference between the LDH isoenzyme patterns in the fundic area muscular layer and in the pyloric muscular layer was smaller than that between the mucosae of the corresponding parts. A possible explanation of the observed facts is given.

In study I, 855 peptic ulcers were found in a group of 640 gastric specimens obtained surgically. The locations of these ulcers were observed in their relation to mucosae. It was found that nearly all ulcers were located adjacent to a mucosal boundary and, moreover, the ulcers were located on the side of the boundary opposite the fundic gland area. In study II, 269 ulcers were found in another group of 211 gastric specimens similarly obtained surgically. The locations of these ulcers were observed in their relation to musculature. It was found that nearly all ulcers were located within identifiable special muscular areas. In study III, by means of transparent cellophane overlays, the locations of the 269 ulcers of study II were observed in their relation to both musculature and mucosae. It was found that the locations of nearly all ulcers were seemingly affected or controlled by both mucosal boundaries and muscle bundles. This dual effect or influence of both the mucosae and musculature has been designated “dual control mechanism.” Finally, by means of the concept of dual control mechanism an attempt speculatively has been made to explain the significance of the local pathogenic factor of peptic ulceration, a possible reason for the chronicity and single development of peptic ulcers, and the reason why gastric ulcers frequently appear at the gastric angulus of the lesser curvature of the stomach.

Gastric ulcers have been thought to occur only in the pyloric gland area. However, endoscopic examinations using the Congo red test showed that 18 of the ulcers examined (7.8%) were surrounded by an acid-secreting area, and so were in the fundic gland area. Histological examination of specimens obtained by gastrectomy also showed that five of the lesions examined (4.5%) were located in the fundic gland area. Ulcers in the fundic gland area were found most frequently in the angle and lower gastric body, adjacent to acid-secreting boundary. These ulcers were associated with little or no fundal gastritis, whereas ulcers in the pyloric gland area were usually associated with moderate or severe fundal gastritis. Unlike ulcers of similar depth in the pyloric gland area, ulcers surrounded by normal fundic mucosa healed rapidly and completely. No recurrence of these ulcers was seen in a 1-year endoscopic follow-up period.

Effects of Solcoseryl injection (SS), which is known to stimulate tissue respiration, on gastric mucosal blood flow (GMBF) were investigated by means of H2-gas clearance technique. Male Wistar rats weighting 350g were anesthetized with urethane. After exposing the stomach, wire-type element was fixed in the gastric mucosa of fundic gland area. Gastric microcirculatory disturbances were induced by bleeding and by indomethacin (IM) treatment. Bleeding from carotid (1.5ml/ 100g b.w.) produced a reduction of GMBF by 30-40%/and SS (0.25,0.5ml/kg i.v.) inhibited the reduction of GMBF dose dependently without influence on the systemic blood pressure. Inhibitory effect of SS was not completely blocked by propranolol (1mg/kg s.c.). Cetraxate (20mg/kg i.v.) also exhibited inhibitory effect but its effect,was almost blocked by propranolol. Intra-gastric administration of IM (20mg/kg) decreased GMBF by about 30%. SS (0.25ml/kg i.v.) and prostaglandin E2 (30μg/kg s.c.) improved significantly the reduction of GMBF induced by IM. SS (0.25,0.5ml/kg i.v.) increased GMBF in intact rats. In conclusion, SS improved gastric microcirculatory disturbances and increased normal GMBF. It is assumed that these effects of SS may be mediated by endogenous prostaglandins, activation of capillary endothelium and hemo-rheological improvement.