Gastric neuroendocrine neoplasms (NENs) are increasing in frequency and have a varied spectrum with regard to histology, clinicopathologic background, stage, and prognosis. They are usually discovered incidentally, are for the most part benign and are associated with hypergastrinaemia (secondary either to chronic atrophic gastritis or rarely Zollinger-Ellison syndrome; types 1 and 2, respectively) or more rarely sporadic type 3. Applications of recent staging and grading systems - namely using Ki-67 proliferative indices - (from ENETS and WHO 2010) can be particularly helpful in further categorising these tumours. The natural history of Type 1 gastric carcinoids is generally (>95%) favourable and simple surveillance is usually recommended for small (<1 cm) T1 tumours, with local (endoscopic or surgical) resection for larger lesions. Other potential therapies such as somatostatin analogues and gastrin receptor antagonists may offer newer therapeutic possibilities. Rarely, gastric NENs have a malignant course and this is usually confined to Type 2 and especially Type 3 tumours; the latter mimic the biological course of gastric adenocarcinoma and require radical oncological therapies. Most duodenal NENs, apart from gastrinomas (that are not dealt with here) are sporadic and non functional. They are also increasing in frequency probably due to incidental discovery at endoscopy or imaging for other reasons and this may account for their overall good prognosis. Peri-ampullary and ampullary NENs may have a more aggressive outcome and should be carefully appraised and treated (often with surgical resection).

Neuroendocrine tumors (carcinoids) are tumors originating from neuroendocrine cells. The distinction between different types of gastric carcinoids is important for their management. We present the case of a 38-year old woman with type 1 gastric neuroendocrine tumors (NETs) associated with autoimmune atrophic gastritis. The management of these tumors has not been yet codified and different therapeutic strategies have been suggested. A proper evaluation before therapy is indicated in order to rule out both the malignant transformation as well as the presence of synchronous lesions, such as dysplasia or gastric adenocarcinoma. We describe our diagnostic and therapeutic strategies with references to previously published reports.

Autoimmune gastritis (AIG), an organ-specific autoimmune disease, is accompanied by achlorhydria, pernicious anemia, gastric carcinoid tumors, and gastric cancer. Patients with AIG initially respond to corticosteroids but have a great potential to relapse after treatment is withdrawn. This study examines the roles of cytokines in order to identify potential therapeutic options for AIG patients.Using a mouse model of AIG, we monitored disease progression and administered antibodies in vivo to block cytokines.We developed a mouse model of AIG with early onset and rapid progression in which neonatal thymectomy (NTx) was performed on programmed cell death 1-deficient (PD-1(-/-) ) mice on the BALB/c background. Using NTx-PD-1(-/-) mice, we found that in AIG lesions, interferon-γ, and tumor necrosis factor (TNF)-α together with interleukin-21 (IL-21) were highly expressed in the inflamed gastric mucosa. In addition, as with the injection of dexamethasone, in vivo administration of either anti-TNF-α or anti-IL-21 suppressed the development of AIG in NTx-PD-1(-/-) mice.These data reveal the essential role of IL-21 in the development of AIG and suggest that in addition to corticosteroids, anti-TNF-α as well as anti-IL-21 have the potential to induce the remission of AIG, offering additional therapeutic options for AIG patients.

Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers.To assess the effect of netazepide on type 1 GC.Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks.Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment.The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.

This review summarizes adverse effects of potential proton pump inhibitors (PPIs), including nutritional deficiencies (B12 and magnesium), rebound acid hypersecretion, acute interstitial nephritis, gastric carcinoid tumor, cardiovascular risk with clopidogrel and PPI coprescription, bone fractures, enteric infections and pneumonia. An epidemiologic framework is applied to assess clinical relevance and reinforce best practice recommendations.The evidence for PPI adverse events is limited by the absence of Level 1 (randomized controlled trial) studies. The best evidence supports Clostridium difficile and bone fractures in susceptible populations. A substantial reduction in gastrointestinal bleeding risk without increase in cardiovascular events was observed in the COGENT trial when clopidogrel was coprescribed with omeprazole. The risk of pneumonia is inconsistent, and although acute interstitial nephritis, nutritional deficiencies (including B12 and hypomagnesemia), gastric carcinoid and rebound hyperacidity are biologically plausible, studies have failed to demonstrate supportive clinical relevance.Prescribe PPI for robust indications only. Strong data supporting risk of adverse events are lacking; however, exercise caution in the elderly and in patients with other risk factors for bone fractures or C. difficile infection.

Microscopic forms of colitis have been described, including collagenous colitis, a possibly heterogeneous disorder. Collagenous colitis most often appears to have an entirely benign clinical course that usually responds to limited treatment. Sometimes significant extracolonic disorders, especially arthritis, spondylitis, thyroiditis and skin disorders, such as pyoderma gangrenosum, dominate the clinical course and influence the treatment strategy. However, rare fatalities have been reported and several complications, some severe, have been attributed directly to the colitis. Toxic colitis and toxic megacolon may develop. Concomitant gastric and small intestinal inflammatory disorders have been described including celiac disease and more extensive collagenous inflammatory disease. Colonic ulceration has been associated with the use of nonsteroidal anti-inflammatory drugs, while other forms of inflammatory bowel disease, including ulcerative colitis and Crohn disease, may evolve directly from collagenous colitis. Submucosal 'dissection', colonic fractures, or mucosal tears and perforation, possibly from air insufflation during colonoscopy, have been reported. Similar changes may result from increased intraluminal pressures that may occur during radiological imaging of the colon. Neoplastic disorders of the colon may also occur during the course of collagenous colitis, including colon carcinoma and neuroendocrine tumours (ie, carcinoids). Finally, lymphoproliferative disease has been reported.

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and give hypergastrinemia secondary to gastric hypoacidity. PPI treatment therefore induces enterochromaffin-like (ECL) cell hyperplasia. Long-term hypergastrinemia in rodents and man also leads to ECL cell neoplasia. Whether long-term PPI treatment will induce ECL cell neoplasia in man has been disputed.To describe gastric carcinoids in two patients with a history of long-term PPI use.Two patients had been taking PPI for 12-13 years due to gastro-oesophageal reflux disease. At routine upper gastrointestinal endoscopy a solitary tumour was found in the oxyntic mucosa of both patients. Histology from the tumours showed in both cases a well-differentiated neuroendocrine tumour. Biopsies from flat oxyntic mucosa showed no signs of atrophic gastritis and a normal presence of parietal cells in both cases, but hyperplasia of ECL cells. The tumour in patient 1 was resected endoscopically. After cessation of PPI treatment the tumour regressed in patient 2 and the ECL cell hyperplasia regressed in both patients. In patient 2 serum gastrin and chromogranin A were elevated during PPI treatment, and normalised after cessation of treatment. In patient 1, unfortunately, we had serum only after treatment, and at that time both parameters were normal.These cases show that hypergastrinemia secondary to proton pump inhibitors treatment, like other causes of hypergastrinemia, may induce enterochromaffin-like cell carcinoids in man.

Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract. Although the stomach is the most common location for gastrointestinal stromal tumor with the co-primary tumors, the synchronous appearance of a neuroendocrine tumor and gastrointestinal stromal tumor in the stomach is rare. We present here the case of a 48-year-old male with gastric well-differentiated neuroendocrine tumor and gastrointestinal stromal tumor discovered incidentally during surgical treatment of the neuroendocrine tumor. We discuss the current guidelines for the management of small gastrointestinal stromal tumors (&lt;2 cm in diameter) and the gastric carcinoids. We also review the literature for the co-occurrence of gastrointestinal stromal tumor and neuroendocrine tumor in a gastric location.

Early detection of gastric cancer by screening endoscopy facilitates endoscopic treatment in place of open surgery. The aim of this study was to evaluate whether 2 years intensive training improved the detection of gastric cancer by screening endoscopy.An endoscopist who had trained for 6 years as a general physician, performed screening endoscopy at Imari Arita Kyoritsu Hospital before (group I) and after (group II) intensive training in the diagnosis of early gastric cancer in consecutive patients.Background characteristics, including age (61.6 vs. 62.2 years) and sex, did not differ between the groups. Before training, 10 gastric neoplasms were detected in 937 patients in group I: four early gastric cancers, one gastric adenoma, and five advanced gastric cancer. After training, 36 gastric neoplasms were detected in 937 patients in group II: 18 early gastric cancers, 11 gastric adenoma, five advanced gastric cancer, and one each of gastric carcinoid and malignant lymphoma. The detection rate for early gastric cancer was significantly improved by training [group I: 4/937 (0.4%) vs. group II: 18/937 (1.9%)], although the detection rate for advanced gastric cancer did not differ before and after training. The proportion of early gastric cancer + adenoma to advanced cancer was higher in group II (5/5 vs. 29/5 in group I).Intensive training in upper gastrointestinal endoscopy screening dramatically improved the detection rate for early gastric cancer, although the detection rate for advanced gastric cancer was not affected.