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Aims Netazepide, a gastrin/cholecystokinin 2 receptor antagonist, once daily for 12 weeks reduced the number of tumours and size of the largest one in 16 patients with autoimmune chronic atrophic gastritis (CAG), achlorhydria, hypergastrinaemia and multiple gastric neuroendocrine tumours (type 1 gastric NETs), and normalized circulating chromogranin A (CgA) produced by enterochromaffin-like cells, the source of the tumours. The aim was to assess whether longer-term netazepide treatment can eradicate type 1 gastric NETs. Methods After a mean 14 months off netazepide, 13 of the 16 patients took it for another 52 weeks. Assessments were: gastroscopy; gene-transcript expression in corpus biopsies using quantitative polymerase chain reaction; blood CgA and gastrin concentrations; and safety assessments. Results While off-treatment, the number of tumours, the size of the largest one, and CgA all increased again. Netazepide for 52 weeks: cleared all tumours in 5 patients; cleared all but one tumour in one patient; reduced the number of tumours and size of the largest one in the other patients; normalized CgA in all patients; and reduced mRNA abundances of CgA and histidine decarboxylase in biopsies. Gastrin did not increase further, confirming that the patients had achlorhydria. Netazepide was safe and well tolerated. Conclusions A gastrin/cholecystokinin 2 receptor antagonist is a potential medical and targeted treatment for type 1 gastric NETs, and an alternative to regular gastroscopy or surgery. Treatment should be continuous because the tumours will regrow if it is stopped. Progress can be monitored by CgA in blood or biomarkers in mucosal biopsies. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the expression of erythropoietin and neuroendocrine markers in clear cell renal cell carcinoma ( CCRCC). We retrospectively reviewed the medical records and re-evaluated histopathological specimens of 33 patients with CCRCC and compared with those of 11 cases of non- CCRCC. All patients were treated with a partial or radical nephrectomy at St. Olavs Hospital, Trondheim University Hospital, between 2010 and 2016. Thirty-three patients who were diagnosed with CCRCC had a total of 35 tumours, where 34 of the tumours were CCRCC and one was papillary adenoma. Thirty-three (97%) of 34 CCRCCs were positive for erythropoietin, and the same 33 (97%) tumours demonstrated strong expression for neuron-specific enolase ( NSE). Two (6%) of 34 CCRCCs had a positive reaction for synaptophysin, and three (9%) of 34 were positive for CD56. Erythropoietin and NSE were negative in non- CCRCCs, and chromogranin A was negative in all tumours. The above findings suggest that there is a strong association between CCRCC and the expression of erythropoietin and NSE. [ABSTRACT FROM AUTHOR]

A family with a missense variant of the ATP4A gene encoding the alpha subunit of the gastric proton pump (H+K+ATPase) has recently been described. Homozygous siblings were hypergastrinemic (median gastrin 486 pM) and had gastric tumours diagnosed at a median age of 33 years. In the current histopathological study, we further characterized the tumours found in the gastric corpus. The tumours had the histological appearance of carcinoids (NET G1 or G2) and were immunoreactive for the general neuroendocrine markers chromogranin A (CgA) and synaptophysin as well as the ECL-cell markers vesicular monoamine transporter 2 (VMAT2) and histidine decarbozylase (HDC). One of the tumours consisted of a NET G2 component, but also had a component with glandular growth, which morphologically was classified as an intestinal type adenocarcinoma. Many glands of the adenocarcinoma contained a large proportion of cells positive for neuroendocrine markers, especially the small vesicle marker synaptophysin and the cytoplasmic enzyme HDC. In conclusion, patients homozygous for an inactivating ATP4A mutation develop gastric ECL-cell carcinoids in their 3rd or 4th decade. The adenocarcinoma may be classified as neuroendocrine with ECL-cell differentiation. [ABSTRACT FROM AUTHOR]

Hypergastrinemia causes carcinoids or carcinomas in the gastric corpus in animal models. Helicobacter pylori ( HP) infection in patients causes atrophy, hypergastrinemia and promotes gastric carcinogenesis. Many patients with gastric cancer have hypergastrinemia and it has therefore been hypothesized that hypergastrinemia promotes carcinogenesis. We have examined the associations between serum gastrin, the anatomical localization of gastric cancer, histological classification and patient survival. Patients with non-cardia gastric adenocarcinomas were included prospectively (n = 80). Tumour localization, histological classification according to Laurén and disease stage were recorded. Preoperative fasting serum gastrin was analysed by radioimmunoassay and HP serology by ELISA. Patient survival was determined after a median postoperative follow-up of 16.5 years. Hypergastrinemic patients had carcinomas located in the gastric corpus more often compared to normogastrinemic patients (81.8 vs 36.2%, p = 0.002). Patients with disease stage 2-4 and hypergastrinemia had shorter survival than normogastrinemic patients [5.0 (1.1-8.9) vs 10.0 (6.4-13.6) months (p = 0.04)]. There was no significant difference in serum gastrin or survival between patients with intestinal and diffuse type carcinomas. Hypergastrinemia was associated with adenocarcinomas in the gastric corpus and shorter survival. The findings support the hypothesis that hypergastrinemia promotes carcinogenesis and affects biological behaviour. [ABSTRACT FROM AUTHOR]

Histamine is produced by mast cells and many other types of cells. The role of histamine released from mast cells in promoting tumor angiogenesis has been intensively studied; however, the role of non-mast cell histamine in regulating tumor angiogenesis has been largely ignored. In this study, tissue specimen sections from 43 patients with esophageal squamous cell carcinoma (ESCC) and normal esophageal biopsies from 17 heath individuals obtained from a high incidence area of north China were used to assess changes in microvessel density (MVD) and non-mast cell L-histidine decarboxylase (HDC) (the only rate-limiting enzyme that catalyzes the formation of histamine from L-histidine) expression in the tumor microenvironment by immunohistochemistry (IHC). In addition, the cellular characterization of non-mast cell HDC-positive cells in microvessels was examined by double IHC combined with HDC/CD34 and HDC/PCNA antibodies. These IHC analyses revealed a significantly increased HDC-positive MVD in ESCC as compared with normal controls, which accounted for ∼61% of CD34-labeled general MVD in ESCC. Furthermore, IHC in serial sections and double IHC showed that most of these HDC-positive cells were CD34-positive endothelial cells in microvessels with an increased proliferative capacity. Thus, our results suggest that non-mast cell histamine expressed in endothelial cells of microvessels could be an additional cellular source and might play a role in regulating angiogenesis in ESCC. [ABSTRACT FROM AUTHOR]

The article discusses the epidemiology of neuroendocrine tumor (NET) in the U.S. and Norway. It highlights that African Americans possess high incidence of NET. It mentions that the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program is the main resource of NET. Moreover, it states that NET is an indolent tumor which poses five years of survival.

Neuroendocrine (NE) differentiation is reported in some cases of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the expression of NE markers in NSCLC using novel sensitive methods. 20 cases of NSCLC were examined using immunohistochemical (IHC) and immunoelectron microscopy (IEM) methods. In addition, circulating levels of the NE markers chromogranin A (CgA) and neuron-specific enolase (NSE) were measured. Using conventional IHC methods, two tumours (10%) showed immunoreactivity for synaptophysin (SYN), one (5%) for Cg and four (20%) for neural cell adhesion molecule (NCAM). Adding the tyramide signal amplification (TSA) technique, the number of immunoreactive tumours for both SYN and CgA increased to five (25%). No increased immunoreactivity was achieved for NCAM. Nine tumours (45%) were immunoreactive for SYN, CgA or NCAM. Using IEM, one of five representative samples that revealed IHC reactivity for CgA showed immunogold labelling of CgA in cytoplasmic vesicles. Elevated levels of circulating CgA or NSE did not correlate with positive IHC findings. In conclusion, using sensitive IHC methods NE differentiation was seen in a greater proportion of NSCLC than previously reported. Sensitive methods may improve our understanding of the tumour biology and represent an important diagnostic tool for future therapeutic modalities. [ABSTRACT FROM AUTHOR]

Fossmark R, Martinsen TC, Qvigstad G, Bendheim MØ, Kopstad G, Kashima K, Waldum HL. Ultrastructure and chromogranin A immunogold labelling of ECL cell carcinoids. APMIS 2005;113:506–12. Poorly differentiated neuroendocrine cells can be difficult to recognise. Sensitive methods are needed to label cells that have lost their ultrastructural features and have reduced concentrations of neuroendocrine markers. In gastric neoplasms, enterochromaffin-like cells might dedifferentiate and lose their characteristic granules and secretory vesicles, making detection of such cells increasingly difficult. However, chromogranin A (CgA) immunogold labelling could provide sensitive and specific detection of gastric neuroendocrine cells. We present ultrastructural findings, CgA immunogold labelling as well as conventional immunohistochemical findings of two human enterochromaffin-like cell carcinoids. Electron-dense granules of poorly differentiated cells were less intensely labelled than granules in well-differentiated cells. Granules with atypical shape as well as punctuate granules previously found in neuroendocrine neoplasms were also CgA labelled. The CgA labelling efficacy after antigen retrieval in an alkaline solution was higher after heating in an autoclave at 135 °C compared to a microwave at 100 °C for both granules and secretory vesicles without significant deterioration of the ultrastructure. In conclusion, the use of CgA immunogold labelling could ensure a specific classification of cells with neuroendocrine granules and be a supplement to immunohistochemical examination of poorly differentiated tumours. [ABSTRACT FROM AUTHOR]

Fossmark R, Zhao CM, Martinsen TC, Kawase S, Chen D, Waldum HL. Dedifferentiation of enterochromaffin-like cells in gastric cancer of hypergastrinemic cotton rats. APMIS 2005;113:436–49. The role of enterochromaffin-like (ECL) cells in gastric carcinogenesis is not fully understood. Spontaneous tumours developing in hypergastrinemic female cotton rats have an adenocarcinoma phenotype, but numerous cells in the dysplastic mucosa as well as in the carcinomas are positive for neuroendocrine markers. In the present study of female cotton rats with 2 and 8 months' hypergastrinemia, the oxyntic mucosa of the stomach was examined histologically and immunolabelled for histidine decarboxylase (HDC) and pancreastatin, and hyperplastic and neoplastic ECL cells were evaluated by electron microscopy. These animals developed hyperplasia of the oxyntic mucosa in general and of the ECL cells in particular after 2 months and dysplasia and carcinomas after 8 months. The immunoreactivity of the ECL cells in the oxyntic mucosa was increased at 2 months and declined at 8 months. These histological changes were associated with progressive loss of secretory vesicles and granules in ECL cells. We suggest that ECL cells in hypergastrinemic cotton rats dedifferentiate with time and that the gastric carcinomas may develop from ECL cells. [ABSTRACT FROM AUTHOR]

All vertebrates produce gastric acid. Its main function is inactivation of ingested microorganisms. The majority of microbiological pathogens ingested never reaches the intestine because of the gastric barrier. Although gastric hypochlorhydria is fairly common due to atrophic gastritis, gastric surgery or use of inhibitors of gastric acid secretion, the resulting susceptibility to infection has not been studied extensively. Drug-induced blockade of acid secretion leads to gastrointestinal bacterial overgrowth; the clinical significance of this is still controversial. Gastric acidity is known to protect against non-typhoid salmonellosis and cholera and it is suspected that it protects against several parasitic diseases as giardiasis and strongyloides. There is a lack of studies focusing on the impact of the gastric acidic barrier on viral infections. Concerning prion infections only a single study has been performed, demonstrating a possible role of gastric acidity in the protection against foodborne prion disease in mice. The combination of malnutrition and hypochlorhydria may contribute to the high prevalence of gastrointestinal infections in developing countries. Further studies are needed to evaluate the clinical consequences of impaired gastric acidity with respect to susceptibility to infections. [ABSTRACT FROM AUTHOR]

The role of the gastric acid secretagogues acetylcholine, gastrin and histamine has been debated for decades. Initially, the mast cell was considered the source of acid stimulatory histamine. Later, Håkanson & Owman (1969) showed that the entero-chromaffinlike (ECL) cell produces and stores histamine in several species, including rat and man. Kahlson et al. (1964) showed that food and gastrin stimulated oxyntic mucosal histamine synthesis and release, Berglindh et al. (1976) that histamine and cholinergics but not gastrin induced acid secretion in isolated oxyntic glands and parietal cells, and Rangachari (1995) that acetylcholine or gastrin released histamine in isolated mucosa. These findings suggested that gastrin stimulates acid secretion through release of ECL cell histamine. Studying simultaneous histamine release and acid secretion in isolated oxyntic mucosal cells, we found that gastrin stimulated acid secretion only in preparations releasing histamine. Moreover, in the isolated rat stomach, gas trin stimulated both histamine release and acid secretion. Maximal acid output was higher with histamine than with gastrin, and augmented by acetylcholine but not by gastrin. These findings strongly suggested that gastrin acts by releasing histamine. Finally, a fluorescein-labelled gastrin analogue bound to the ECL cell, not to the parietal or stem cell regions. This is interesting, recalling that gastrin has a potent and specific trophic effect on the ECL cell and only a general effect on all other oxyntic cell types. In conclusion, physiological observations are best explained by localising the CCK2 receptor only to the ECL cell, the other effects of gastrin on the gastric mucosa being secondary to the release of mediators from the ECL cell. [ABSTRACT FROM AUTHOR]

Smoking is associated with endothelial dysfunction and increased plasma levels of endothelin-1. The component of tobacco smoke inducing these effects is unknown. Carbon monoxide induces hypoxia, and there is evidence of carbon monoxide acting as a local mediator in both endothelial and smooth muscle cells. The purpose of this study was to determine whether chronic carbon monoxide exposure similar to that experienced by smokers affects myocardial endothelin-1 expression. Sprague-Dawley female rats were exposed to carbon monoxide 100 ppm for one week or to 100 ppm for one week and 200 ppm for a second week. Carboxyhaemoglobin was 12+0.9% in the low and 23+1.1% in the high carbon monoxide exposure group. Endothelin-1 expression was measured by competitive reverse transcriptase polymerase chain reaction. High carbon monoxide exposure increased endothelin-1 mRNA by 54+12% (P<0.001) in the left ventricle and by 53+12% (P<0.001) in the right ventricle. In the low carbon monoxide exposure group corresponding changes were 43+14% (P=0.06) and 12+16% (P=0.29). Right ventricular weight increased by 18+7% (P=0.02) after high and by 16+5% (P=0.02) after low exposure. Left ventricular weight was elevated by 5+2% (P=0.05) when both exposure groups were compared to controls. We conclude that chronic carbon monoxide exposure leading to carboxyhaemoglobin levels similar to those observed in smokers increases endothelin-1 gene expression and induces myocardial hypertrophy in the rat. [ABSTRACT FROM AUTHOR]

Discusses gastroduodenal carcinoids occurring in patients having used omeprazole. Association of carcinoids to Zollinger-Ellison syndrome; Presence of rebound acid hypersecretion; Cause of acid rebound hypersecretion.

Since the late sixties, the pentagastrin test has been the standard method to examine maximal gastric acid secretion in humans. However, studies on rats and dogs have shown that maximal pentagastrin-stimulated acid secretion can be augmented by concomitant cholinergic stimulation. The aim of this study was to examine whether the combined stimulation of the vagal nerves and pentagastrin infusion could increase maximal gastric acid secretion compared with pentagastrin alone. Eight healthy medical students (seven males) were included in the study. Gastric acid secretion was determined thrice in each subject. On day one, pentagastrin (6 μg kg-1 h-1) was infused. On day two, insulin-induced hypoglycaemia (plasma glucose ≈2.3 mM during 30 min) was obtained by applying the glucose clamp technique. On day three, pentagastrin infusion and insulin induced-hypoglycaemia were combined. The combination of insulin-induced hypoglycaemia and pentagastrin infusion increased peak acid output about 20% (P = 0.018) compared with pentagastrin alone. The hypoglycaemia did not cause significant release of gastrin. It is concluded that vagal stimulation of gastric acid secretion may be safely obtained by insulin-induced hypoglycaemia when applying the glucose clamp technique. In addition, maximal pentagastrin-stimulated acid secretion does not represent the maximal acid secretory capacity in humans. [ABSTRACT FROM AUTHOR]