Hypergastrinemia is associated with an increased risk of gastric adenocarcinoma with proximal location: A prospective population-based nested case-control study.

The incidence of proximal gastric adenocarcinoma is increasing among younger adults. Rodent models have shown that hypergastrinemia causes carcinogenesis in the proximal stomach. The aim of our study was therefore to assess if hypergastrinemia was associated with an increased risk of developing gastric adenocarcinoma also in humans. A prospective population-based nested case-control study within the Nord-Trøndelag Health Study (HUNT) cohort, Norway, was used to assess this association. Serum was collected from 78 962 participants in 1995 to 1997 and 2006 to 2008. In the cohort, 181 incident gastric adenocarcinoma cases were identified from the Norwegian Cancer and Patient Registries through 2015 and matched with 359 controls. The risk of gastric adenocarcinoma was compared between participants with prediagnostic hypergastrinemia (>60 pmol/L) and normal serum gastrin (≤60 pmol/L). Logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for body mass index, tobacco smoking and comorbidity. Hypergastrinemia was associated with increased risk of gastric adenocarcinoma overall (OR 2.2, 95% CI 1.4-3.4) and in particular for gastric adenocarcinoma with proximal location (OR 6.1, 95% CI 2.7-13.8), but not with gastric adenocarcinoma with distal location (OR 1.7, 95% CI 0.9-3.4). Moreover, hypergastrinemia was associated with an increased risk of gastric adenocarcinoma of intestinal histological type (OR 3.8, 95% CI 1.8-7.9), but not for diffuse histological type (OR 1.6, 95% CI 0.7-3.7). In conclusion, hypergastrinemia was associated with an increased risk of proximal and intestinal type gastric adenocarcinoma.

Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice.

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.

Somatostatin-receptor 2 (sst2)-mediated effects of endogenous somatostatin on exocrine and endocrine secretion of the rat stomach.

Somatostatin is a potent inhibitor of gastric acid secretion. Its effects are mediated through five specific receptor subtypes (sst(1-5)), of which sst(2) is dominant on the enterochromaffin-like (ECL) cell and the parietal cell. To study the paracrine mechanisms of somatostatin, the sst(2)-specific antagonist PRL-2903 was used. Effects of PRL-2903 on acid secretion and release of histamine were studied in the totally isolated, vascularly perfused rat stomach. Further, the release of histamine and gastrin after bombesin, alone and in combination with PRL-2903, were studied. Results are presented as mean+/-standard error of the mean (s.e.m.). PRL-2903 concentration-dependently increased the venous histamine concentration from basal 55.6+/-7.5 to 367+/-114 nM at 50 microM PRL-2903. With 10 microM PRL-2903, venous histamine output increased from baseline 6.2+/-0.5 to 20.9+/-4.9 nmol h(-1); P=0.008. The combination of 520 pM gastrin and 10 microM PRL-2903 increased venous histamine output from 41.7+/-7.3 nmol h(-1) with gastrin alone to 95.2+/-9.8 nmol h(-1); P=0.016. Further, 10 microM PRL-2903 increased acid output from baseline 8.5+/-1.8 to 37.4+/-11 micromol h(-1); P=0.017. When combined with 10 microM ranitidine, PRL-2903 did not significantly stimulate acid secretion. Bombesin/PRL-2903 increased venous histamine concentration from 50.4+/-14.8 to 292+/-64.2 nM; P=0.008, and gastrin concentration from 38.6+/-13.1 to 95.8+/-20.3 pM; P=0.037. Endogenous somatostatin exerts a continuous restraint on histamine and gastrin release from the gastric mucosa and significantly reduces baseline acid secretion.

One-year follow-up study of patients with enterochromaffin-like cell carcinoids after treatment with octreotide long-acting release.

OBJECTIVE: In a one-year study of 5 patients with chronic atrophic gastritis (CAG), pernicious anaemia (PA), hypergastrinaemia and enterochromaffin-like (ECL) cell tumours, the somatostatin analogue octreotide LAR (long-acting release) in a dose of 20 mg given intramuscularly at monthly intervals had an antiproliferative effect on the ECL cells. The aim of the present study was to follow neuroendocrine (NE) markers in the blood and macroscopic and histopathological changes in the stomach during a 12-month follow-up after discontinuation of octreotide LAR treatment. MATERIAL AND METHODS: Five patients underwent upper gastrointestinal endoscopy at 6 and 12 months' follow-up after octreotide LAR treatment. Biopsies from flat, oxyntic mucosa and from tumours were obtained. Sections were stained with haematoxylin-erythrosin and immunostained for the NE cell marker chromogranin A (CgA). Serum gastrin and CgA were measured every 3 months. RESULTS: The number of visible tumours was unchanged (7) at 12 months' follow-up. One lesion showed carcinoid tumour and the others various degrees of linear and micronodular NE hyperplasia. At the same time-point, biopsies from flat, oxyntic mucosa showed a slightly (non-significant) elevated number of CgA immunoreactive (IR) cells. Serum gastrin increased from 186+/-50 pM (mean+/-SEM) to 603+/-109 pM (normal < 40 pM); p<0.05, and serum CgA increased non-significantly from 25+/-2 ng/ml (normal < 30 ng/ml) to 61+/-11 ng/ml. CONCLUSIONS: During follow-up, slightly elevated levels of serum CgA and CgA IR cells in the oxyntic mucosa, without significant recurrence of ECL cell carcinoids, were observed.