gastrins and Adenoma

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; beta Catenin; Calcium-Calmodulin-Dependent Protein Kinases; Carcinoma; Colorectal Neoplasms; Cyclin D1; Cyclooxygenase 2; Cytoskeletal Proteins; Gastrins; Glycogen Synthase Kinase 3; Humans; Hyaluronan Receptors; Intestinal Mucosa; Isoenzymes; Matrix Metalloproteinase 7; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Signal Transduction; Trans-Activators

Topics: Adenoma; Carcinoid Tumor; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasms, Multiple Primary; Parathyroid Glands; Parathyroid Neoplasms; Stomach; Stomach Neoplasms; Zollinger-Ellison Syndrome

The accumulating evidence of an association between antrum-sparing hypergastrinaemic atrophic gastritis, frequently associated with pernicious anaemia, and the occurrence of gastric carcinoid tumours is briefly reviewed. The development of argyrophil cell carcinoid tumours in the atrophic fundic mucosa seems to be related to argyrophil cell hyperplasia caused by hypergastrinaemia. Epidemiologic considerations indicate that the gastric carcinoid generally is underdiagnosed and that the incidence of this tumour is higher than previously recognized. The clinical relevance of minute gastric carcinoids, or endocrine cell 'adenomas', is obscure. However, larger tumours should be regarded as potentially malignant. These findings are relevant to the aspect of long-term medically induced achlorhydria leading to hypergastrinaemia.

Topics: Achlorhydria; Adenoma; Anemia, Pernicious; Atrophy; Carcinoid Tumor; Cell Division; Epidemiologic Methods; Gastrins; Gastritis; Humans; Stomach Neoplasms

Topics: Adenoma; Carcinoid Tumor; Endocrine System Diseases; Gastrins; Gastrointestinal Diseases; Glucagonoma; Histocytochemistry; Humans; Hyperinsulinism; Immunochemistry; Insulinoma; Islets of Langerhans; Pancreatic Diseases; Pancreatic Neoplasms; Peptic Ulcer; Somatostatinoma; Stomach; Vipoma

Topics: Achlorhydria; Acromegaly; Adenoma; Adenoma, Islet Cell; Adolescent; Adult; Aged; Calcium; Cushing Syndrome; Diarrhea; Female; Gastric Acid; Gastrins; Glucagon; Humans; Hyperinsulinism; Hyperparathyroidism; Hypoglycemia; Hypokalemia; Male; Middle Aged; Neoplasms, Multiple Primary; Pancreatic Polypeptide; Pancreatitis; Parathyroid Glands; Parathyroid Neoplasms; Pituitary Neoplasms; Syndrome; Thyroid Diseases; Zollinger-Ellison Syndrome

Topics: Adenoma; Diagnosis, Differential; Gastrectomy; Gastric Juice; Gastrins; Humans; Neoplasm Metastasis; Peptic Ulcer; Radioimmunoassay; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Acetylcholine; Achlorhydria; Adenoma; Anemia, Pernicious; Atrophy; Duodenal Ulcer; Endocrine System Diseases; Gastrectomy; Gastric Juice; Gastric Mucins; Gastric Mucosa; Gastrins; Gastritis; Humans; Hyperplasia; Intrinsic Factor; Stomach Ulcer; Vagus Nerve; Zollinger-Ellison Syndrome

Topics: 5-Hydroxytryptophan; Adenoma; Adenoma, Islet Cell; Adrenocorticotropic Hormone; Calcitonin; Catecholamines; Corticosterone; Gastrins; Glucagon; Growth Hormone; Humans; Insulin; Insulin Secretion; Kinins; Pancreas; Pancreatic Neoplasms; Peptides; Prostaglandins; Secretin; Thyrotropin; Vasopressins; Zollinger-Ellison Syndrome

In patients with adenoma, assessing premalignant changes in the surrounding mucosa is important for surveillance. This study evaluated atrophic and metaplastic progression in the background mucosa of adenoma or early gastric cancer (EGC) cases.. Among 146 consecutive patients who underwent endoscopic resection for intestinal-type gastric neoplasia, the adenoma group included 56 patients with low-grade dysplasia and the ECG group included 90 patients with high-grade dysplasia or invasive carcinoma. For histology, 3 paired biopsies were obtained from the antrum, corpus lesser curvature (CLC), and corpus greater curvature (CGC). Serological atrophy was determined based on pepsinogen A (PGA), progastricsin (PGC), gastrin-17, and total ghrelin levels. Topographic progression of atrophy and/or metaplasia was staged using the operative link on gastritis assessment (OLGA) and operative link on gastric intestinal metaplasia assessment (OLGIM) systems.. Rates of moderate-to-marked histological atrophy/metaplasia in patients with adenoma were 52.7%/78.2% at the antrum (vs. 58.8%/76.4% in EGC group), 63.5%/75.0% at the CLC (vs. 60.2%/69.7% in EGC group), and 10.9%/17.9% at the CGC (vs. 5.6%/7.8% in EGC group). Serological atrophy indicated by PGA and PGC occurred in 23.2% and 15.6% of cases in the adenoma and ECG groups, respectively (p = 0.25). Mean serum gastrin-17 concentrations of the adenoma group and EGC group were 10.4 and 9.0 pmol/L, respectively (p = 0.54). Mean serum total ghrelin levels were 216.6 and 209.5 pg/mL, respectively (p = 0.71). Additionally, between group rates of stage III-IV OLGA and OLGIM were similar (25.9% vs. 25.0%, p = 0.90; 41.8% vs. 44.9%, p = 0.71, respectively).. Atrophic and metaplastic progression is extensive and severe in gastric adenoma patients. A surveillance strategy for metachronous tumors should be applied similarly for patients with adenoma or EGC.

Topics: Adenoma; Aged; Biomarkers; Disease Progression; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Male; Metaplasia; Middle Aged; Neoplasms, Second Primary; Pepsinogen C; Risk Factors; Stomach Neoplasms

The ABCD screening method was developed for risk stratification of gastric cancer. It is unclear whether the ABCD method can predict the risk of gastric neoplasms, including gastric adenomas, as observed for gastric cancer. We aimed to devise a modified ABCD method for predicting gastric neoplasms.. We reviewed 562 patients who had undergone upper gastrointestinal tract endoscopy and whose serum IgG anti-Helicobacter pylori antibody, gastrin, and pepsinogen (PG) I and PG II data were available. Patients were classified into the following four groups: H. pylori antibody negative and normal PG level (group A), H. pylori antibody positive and normal PG level (group B), H. pylori antibody positive and low PG level (group C), and H. pylori antibody negative and low PG level (group D).. The PG I/PG II ratio was lower in patients with gastric neoplasms than in patients without these lesions (gastric adenoma vs gastric cancer vs no neoplasm, 3.7 ± 2.0 vs 3.8 ± 1.8 vs 4.9 ± 2.1, P < 0.001). The optimal cutoff values of the PG I/PG II ratio for predicting gastric neoplasms were 3.1 for H. pylori antibody negative patients and 4.1 for H. pylori antibody positive patients. A higher group grade was associated with a significantly higher proportion of gastric neoplasms [odds ratio (95 % confidence interval), group A, reference; group B, 1.783 (1.007-3.156); group C, 3.807 (2.382-6.085); and group D, 5.862 (2.427-14.155)].. The modified ABCD method using two different cutoff values according to the H. pylori antibody status was useful for predicting the presence of gastric neoplasms. This method might be a supplementary screening tool for both gastric adenoma and gastric cancer. However, further studies will be required to provide a definitive conclusion.

Topics: Adenoma; Aged; Antibodies, Bacterial; Endoscopy, Gastrointestinal; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Male; Middle Aged; Pepsinogen A; Pepsinogen C; Retrospective Studies; Stomach Neoplasms

In contrast to sessile serrated adenomas and traditional serrated adenomas which are associated with a significant cancer risk, the role of hyperplastic polyps (HP) in colorectal carcinogenesis as well as the molecular mechanisms underlying their development remain controversial and still need to be clarified. Several reports suggest that a subset of HP may represent precursor lesions of some colorectal cancers. However, biomarkers are needed to identify the subset of HP that may have a malignant potential. The hormone precursor, progastrin (PG) has been involved in colon carcinogenesis and is known to activate pro-oncogenic pathways such as the ERK or the STAT3 pathway. We therefore analyzed PG expression and the activation of these signaling factors in HP.. We retrospectively analyzed PG expression as well as the phosphorylation of ERK and STAT3 by immunohistochemistry in HP from 48 patients.. Mean percentages of epithelial cells positive for PG or phospho-ERK were respectively, 31% and 33% in HP and were significantly higher in these lesions compared to normal colon (3%, p=0.0021 and 7%, p=0.0008, respectively). We found a significant correlation between PG and phospho-ERK expression in HP with ERK activation significantly stronger in lesions with high progastrin expression (p=0.015). In contrast, STAT3 was not significantly activated in HP compared to normal colon and we did not observe a significant correlation with PG expression.. HP overexpressing PG that have the highest activation of the ERK pathway might reflect less latent lesions that might have a malignant potential.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Colonic Polyps; Extracellular Signal-Regulated MAP Kinases; Female; Gastrins; Humans; Hyperplasia; Intestinal Mucosa; Male; Middle Aged; Oncogene Proteins; Protein Precursors; Retrospective Studies; Risk Factors; Signal Transduction; STAT3 Transcription Factor

Atrophic gastritis of the corporal mucosa is a frequent cause of hypergastrinemia. Hypergastrinemia is implicated in colorectal cancer development.. To assess whether hypergastrinemic atrophic gastritis is associated with a higher risk of neoplastic colorectal lesions.. Among 441 hypergastrinemic atrophic gastritis patients, 160 who were aged >40 and underwent colonoscopy for anaemia, diarrhoea or colorectal cancer-screening were retrospectively selected. Each patient was age- and gender-matched with a normogastrinemic control with healthy stomach. Controls had colonoscopy, gastroscopy with biopsies and gastrin assessment.. 160 hypergastrinemic atrophic gastritis patients and 160 controls were included. 28 atrophic gastritis patients and 36 controls had neoplastic colorectal lesions (p=0.33). Patients and controls did not differ for frequency of colorectal adenomas (10.6% vs. 13.1%, p=0.60) or cancer (6.9% vs. 9.4%, p=0.54). Hypergastrinemic atrophic gastritis was not associated with a higher probability of developing colorectal cancer (OR 1.03, 95% CI 0.34-3.16). Age >50 years (OR 3.86) but not hypergastrinemia (OR 0.61) was associated with colorectal cancer.. Hypergastrinemic atrophic gastritis is not associated with higher risk for colorectal cancer. Atrophic gastritis-related hypergastrinemia is not associated with an increased risk of neoplastic colorectal lesions. Closer surveillance of colonic neoplasia in atrophic gastritis patients seems not appropriate.

Topics: Adenocarcinoma; Adenoma; Adult; Age Factors; Aged; Aged, 80 and over; Case-Control Studies; Colorectal Neoplasms; Confidence Intervals; Female; Gastrins; Gastritis, Atrophic; Humans; Male; Middle Aged; Odds Ratio; Retrospective Studies; Risk Factors; Statistics, Nonparametric

Gastric cancer is the fourth most common cancer in the world and the second most prevalent cause of cancer related death. The development of gastric cancer is mainly associated with H. Pylori infection leading to a focus in pathology studies on bacterial and environmental factors, and to a lesser extent on the mechanistic development of the tumour. MicroRNAs are small non-coding RNA molecules involved in post-transcriptional gene regulation. They are found to regulate genes involved in diverse biological functions and alterations in microRNA expression have been linked to the pathogenesis of many malignancies. The current study is focused on identifying microRNAs involved in gastric carcinogenesis and to explore their mechanistic relevance by characterizing their targets.. Invitrogen NCode miRNA microarrays identified miR-449 to be decreased in 1-year-old Gastrin KO mice and in H. Pylori infected gastric tissues compared to tissues from wild type animals. Growth rate of gastric cell lines over-expressing miR-449 was inhibited by 60% compared to controls. FACS cell cycle analysis of miR-449 over-expressing cells showed a significant increase in the sub-G1 fraction indicative of apoptosis. ß-Gal assays indicated a senescent phenotype of gastric cell lines over-expressing miR-449. Affymetrix 133v2 arrays identified GMNN, MET, CCNE2, SIRT1 and CDK6 as miR-449 targets. Luciferase assays were used to confirm GMNN, MET, CCNE2 and SIRT1 as direct targets. We also show that miR-449 over-expression activated p53 and its downstream target p21 as well as the apoptosis markers cleaved CASP3 and PARP. Importantly, qPCR analyses showed a loss of miR-449 expression in human clinical gastric tumours compared to normal tissues.. In this study, we document a diminished expression of miR-449 in Gastrin KO mice and further confirmed its loss in human gastric tumours. We investigated the function of miR-449 by identifying its direct targets. Furthermore we show that miR-449 induces senescence and apoptosis by activating the p53 pathway.

Topics: Adenoma; Animals; Base Sequence; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Down-Regulation; Gastrins; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Humans; Mice; Mice, Knockout; MicroRNAs; Molecular Sequence Data; Pyloric Antrum; Signal Transduction; Stomach Neoplasms; Tumor Suppressor Protein p53

Expression of gastrin and cholecystokinin 2 (CCK(2)) receptor splice variants (CCK(2)R and CCK(2i4sv)R) are upregulated in human colonic adenomas where they are thought to contribute to tumor growth and progression. To determine the effects of ectopic CCK(2) receptor variant expression on colonic epithelial cell growth in vitro and in vivo, we employed the non-tumorigenic colonic epithelial cell line, NCM356. Receptor expression was induced using a retroviral expression vector containing cDNAs for either CCK(2i4sv)R or CCK(2)R. RT-PCR and intracellular Ca(2+) ([Ca(2+)](i)) imaging of RIE/CCK(2)R cells treated with conditioned media (CM) from NCM356 revealed that NCM356 cells express gastrin mRNA and secrete endogenous, biologically active peptide. NCM356 cells expressing either CCK(2)R or CCK(2i4sv)R (71 and 81 fmol/mg, respectively) grew faster in vitro, and exhibited an increase in basal levels of phosphorylated ERK (pERK), compared with vector. CCK(2) receptor selective antagonist, YM022, partially inhibited the growth of both receptor-expressing NCM356 cells, but not the control cells. Inhibitors of mitogen activated protein kinase pathway (MEK/ERK) or protein kinase C (PKC) isozymes partially inhibited the elevated levels of basal pERK and in vitro growth of receptor-expressing cells. Vector-NCM356 cells did not form tumors in nude mice, whereas, either CCK(2) receptor-expressing cells formed large tumors. Autocrine activation CCK(2) receptor variants are sufficient to increase in vitro growth and tumorigenicity of non-transformed NCM356 colon epithelial cells through a pathway involving PKC and the MEK/ERK axis. These findings support the hypothesis that expression of gastrin and its receptors in human colonic adenomas contributes to tumor growth and progression.

Topics: Adenoma; Animals; Calcium; Carcinoma; Cell Culture Techniques; Cell Division; Colon; Colorectal Neoplasms; Disease Progression; DNA Primers; Gastrins; Genetic Variation; Humans; Intestinal Mucosa; Mice; Mutation; Neoplasm Staging; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction

Autoimmune metaplastic atrophic gastritis (AMAG) is an early manifestation of pernicious anemia that precedes the hematologic changes by years to decades. It is associated with metaplastic changes and neoplasms, including pyloric gland adenomas (PGAs). We investigated the frequency of PGAs and other lesions in all nonconsultation gastric biopsies and resections (1988 to 2008) diagnosed as AMAG. We further selected cases confirmed as AMAG by immunohistochemical identification of the gastric body (negative gastrin) and linear and nodular enterochromaffin-like cell hyperplasia (chromogranin). From this subset, all polyps and neoplasms were reviewed. We identified a total of 41,245 patients with gastric biopsies or resections from 46.7% males and 53.3% females comprising patients self-identified as 67.0% white, 23.6% African-American, 1.4% Asian, 0.8% non-White Hispanic, and 7.2% other or unknown. AMAG was diagnosed in 461 patients (1.1%), and had the following percentages based on race: 1.1% White, 1.3% African-American, 1.4% Asian, and 2.7% non-White Hispanic. The female:male ratio was 2:1 with an overall median age at presentation of 67.0 years. Of the 461 patients with AMAG, 143 had endoscopically identifiable lesions. These lesions (n=240) consisted of 179 polyps (138 hyperplastic polyps, 20 oxyntic mucosa pseudopolyps, 18 intestinal-type gastric adenomas, and 3 PGAs), 46 well-differentiated neuroendocrine neoplasms (carcinoid), 1 gastrointestinal stromal tumor, 3 lymphomas, and 11 adenocarcinomas. In summary, AMAG occurred with similar frequency across all racial groups. Although PGAs are associated with AMAG, they remain rare in the setting of AMAG.

Topics: Adenoma; Aged; Autoimmune Diseases; Baltimore; Biopsy; Chromogranins; Female; Gastrectomy; Gastric Mucosa; Gastrins; Gastritis, Atrophic; Humans; Immunohistochemistry; Male; Metaplasia; Middle Aged; Polyps; Precancerous Conditions; Stomach; Stomach Neoplasms

Hypergastrinemia and Helicobacter pylori (Hp) infection have been associated with an increased risk for colorectal neoplasia in some studies. However, data from large prospective studies of both associations are lacking. The aim of this study was to evaluate whether serum gastrin levels and/or infection with Hp are associated with the subsequent development of colorectal adenomas.. Subjects (all with a history of adenoma formation) were drawn from 2 previously completed adenoma chemoprevention trials. Participants underwent clearing colonoscopy at baseline with follow-up colonoscopy 1 and 4 years after enrollment. We used commercially available assays on fasting blood specimens to measure serum gastrin levels and Hp serologies 1 year after randomization. Risk ratios for adenoma and advanced adenoma development during the subsequent 3 years were computed by generalized linear regression.. Of the 1794 subjects randomized in the 2 trials, 685 had available serum and were included in the analyses. Gastrin levels were significantly higher in the 239 subjects with Hp titers indicating infection (mean, 88.3 pg/mL) than in those not infected (mean, 73.9 pg/mL; P < .001). In fully adjusted models, gastrin levels were not associated with incident adenoma development (risk ratio [RR], 1.10; 95% confidence interval [CI], 0.78-1.54) or advanced adenoma formation (RR, 0.82; 95% CI, 0.33-2.03). A positive Hp serology was associated with a decreased risk for adenoma formation (RR, 0.76; 95% CI, 0.60-0.96).. Neither hypergastrinemia nor serologic evidence of Hp infection were associated with an increased risk for recurrent adenoma development. These results do not support the notion that gastrin promotes colorectal carcinogenesis, at least at the stage of adenoma development.

Topics: Adenoma; Antibodies, Bacterial; Colorectal Neoplasms; Female; Gastrins; Helicobacter Infections; Humans; Male; Middle Aged; Odds Ratio; Risk Assessment

Aberrant activation of the beta-catenin/Tcf-4 transcriptional complex represents an initiating event for colorectal carcinogenesis, shifting the balance from differentiation toward proliferation in colonic crypts. Here, we assessed whether endogenous progastrin, encoded by a target gene of this complex, was in turn able to regulate beta-catenin/Tcf-4 activity in adenomatous polyposis coli (APC)-mutated cells, and we analyzed the impact of topical progastrin depletion on intestinal tumor growth in vivo.. Stable or transient RNA silencing of the GAST gene was induced in human tumor cells and in mice carrying a heterozygous Apc mutation (APCDelta14), which overexpress progastrin but not amidated or glycine-extended gastrin.. Depletion of endogenous progastrin production strongly decreased intestinal tumor growth in vivo through a marked inhibition of constitutive beta-catenin/Tcf-4 activity in tumor cells. This effect was mediated by the de novo expression of the inhibitor of beta-catenin and Tcf-4 (ICAT), resulting from a down-regulation of integrin-linked kinase in progastrin-depleted cells. Accordingly, ICAT down-regulation was correlated with progastrin overexpression and Tcf-4 target gene activation in human colorectal tumors, and ICAT repression was detected in the colon epithelium of tumor-prone, progastrin-overexpressing mice. In APCDelta14 mice, small interfering RNA-mediated progastrin depletion not only reduced intestinal tumor size and numbers, but also increased goblet cell lineage differentiation and cell apoptosis in the remaining adenomas.. Thus, depletion of endogenous progastrin inhibits the tumorigenicity of APC-mutated colorectal cancer cells in vivo by promoting ICAT expression, thereby counteracting Tcf-4 activity. Progastrin targeting strategies should provide an exciting prospect for the differentiation therapy of colorectal cancer.

Topics: Adaptor Proteins, Signal Transducing; Adenoma; Adenomatous Polyposis Coli; Animals; Apoptosis; beta Catenin; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Gastrins; Gene Expression Regulation, Neoplastic; Genes, APC; Humans; Mice; Mice, Nude; Phosphatidylinositol 3-Kinases; Protein Precursors; Random Allocation; Repressor Proteins; RNA, Small Interfering; Signal Transduction; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein; Transcription Factors; Transcriptional Activation; Transplantation, Heterologous

Topics: Adenoma; Antigens, Bacterial; Bacterial Proteins; Colorectal Neoplasms; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans

Helicobacter pylori infection is a recognized cause of hypergastrinemia, but the association of blood gastrin levels with colonic adenomas (CAs) is controversial. The aim of this study is to investigate if hypergastrinemia, H. pylori infection and/or cagA protein are risk factors for CAs.. In this prospective case-control study, fasting serum samples from 78 consecutive patients with CAs and 78 demographically matched colonoscopy-negative controls were assayed for anti-H. pylori immunoglobulin G, cagA protein and serum gastrin levels. Multivariate analysis was performed to identify risk factors for colon adenomas.. Though prevalence of H. pylori antibodies was not significantly different, the prevalence of cagA protein was significantly higher in patients with adenomas (42.3%) as compared with controls (25.6%, p < 0.03). Mediangastrin levels were significantly higher in patients with CAs (55, 20-975 pg/ml) than in controls (45.2, 23-529 pg/ml) (p < 0.001). Hypergastrinemia (>110 pg/ml) was commoner in patients with CAs than in controls (29.5 vs. 11.5%, p = 0.006) and was the only independent risk factor for adenomas (odds ratio 3.2, 95% CI 1.4-7.5) by multivariate analysis, but not H. pylori infection or cagA positivity. There was a significant association of hypergastrinemia and distal distribution of adenomas (p < 0.002).. Our study shows that hypergastrinemia is a risk factor for CAs, especially of the distal colon.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Antigens, Bacterial; Bacterial Proteins; Case-Control Studies; Colonic Neoplasms; Female; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Risk Factors

It is controversial as to whether the development of gastric cancer is influenced by Helicobacter pylori eradication. If eradication itself influences the tumour morphology, this may affect the tumour discovery rate.. To investigate the morphological changes in the gastric neoplasm after H. pylori eradication.. We studied 37 patients with eradication therapy. After a 1-month follow-up, endoscopic re-evaluation was performed and the appearance was compared with first image. All lesions were resected endoscopically, and were subjected to histological assessment and to immunohistochemistry. Serum gastrin levels were determined before and after eradication.. Twenty-nine of 37 patients underwent successful eradication. The appearance of 11 lesions (33% of 33 lesions) became indistinct after successful eradication. All lesions were of the superficial-elevated type and the height of the lesions decreased. We detected normal columnar epithelium over the neoplasm in eight of the lesions. Higher expression of single-stranded deoxyribonucleic acid in the deep area was characteristic in tumours with an indistinct appearance. These changes did not correlate with the serum gastrin levels.. The morphology of the gastric neoplasm change after eradication in the short-term. This may contribute to the decreased tumour discovery rate.

Topics: Adenocarcinoma; Adenoma; Aged; Aged, 80 and over; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Pepsinogen A; Stomach Neoplasms

We have developed a mouse model of gastric cancer that resembles human intestinal-type adenocarcinoma. The aim of this study was to determine the identity and temporal changes in mediators of IL-6 signaling regulating tumor development.. gp130(757F/F) Mice that lack the SHP2-binding site on the IL-6 family receptor gp130 and have increased STAT 3 activity and wild-type littermates were used. Cohorts were assessed by quantitative histology and immunohistochemistry for gastric cell phenotype and proliferation markers from 4 to 40 weeks of tumor development. Northern blotting and in situ hybridization were used to quantify expression of the tumor suppressor TFF1 and the mitogens gastrin and Reg I. Expression of epidermal growth factor receptor (EGFr) and its ligands was measured by RT-PCR analysis. Age-matched differences in gene expression profiles were tested by ANOVA.. Hyperplastic antral tumors with inflammation and ulceration were evident in gp130(757F/F) mice at 4 weeks of age and reached maximum size by 20 weeks. Tumor progression was marked by gastritis, atrophy, intestinal metaplasia, dysplasia, and submucosal invasion after 30 weeks. Both TFF1 and gastrin expression were progressively inhibited during tumorigenesis, whereas Reg I was stimulated. The EGFr and its ligands transforming growth factor (TGF)-alpha and heparin-binding EGF had increased expression corresponding to maximal tumor growth.. gp130(757F/F) Mice rapidly develop distal stomach tumors, with loss of SHP2/Erk/AP-1 transcriptional regulation exemplified by decreased TFF1 expression and increased STAT1/3 regulated genes such as Reg I. Tumor development occurs in a hypogastrinemic environment. Balanced IL-6 signaling is required for maintaining gastric homeostasis.

Topics: Adenoma; Animals; Antigens, CD; Binding Sites; Calcium-Binding Proteins; Cytokine Receptor gp130; Down-Regulation; Gastric Mucosa; Gastrins; Lithostathine; Membrane Glycoproteins; Mice; Mice, Transgenic; Mucins; Muscle Proteins; Mutation; Nerve Tissue Proteins; Peptides; Stomach Neoplasms; Trefoil Factor-1; Trefoil Factor-2

We describe a patient with multiple endocrine neoplasia type 1 characterized by the simultaneous occurrence of parathyroid cancer, parathyroid adenomas, and pancreatic gastrinoma, who presented with an episode of acute hypercalcemia. The rapid parathyroid hormone assay provided a basis for the diagnosis of parathyroid hyperfunction. Mediastinal metastasis of the parathyroid carcinoma was found at autopsy. However, the staining of pancreatic and gastric tissue for parathyroid hormone-related protein does not make it possible to exclude completely the contribution of this peptide in mediating the hypercalcemia. To our knowledge, this is the first reported case of parathyroid carcinoma as part of the multiple endocrine neoplasia type 1 syndrome.

Topics: Acute Disease; Adenoma; Adult; Carcinoma; Fatal Outcome; Gastrinoma; Gastrins; Humans; Hypercalcemia; Hyperparathyroidism; Male; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Parathyroid Hormone; Parathyroid Neoplasms

The role of hyper-gastrinaemia in the incidence of colonic cancer remains to be clarified. The aim of this study was to determine whether cholecystokinin-2 (CCK-2) receptor expression predicts the sensitivity of human colonic adenomas to the proliferative effects of serum hyper-gastrinaemia. Gene expression of the classical (74 kDa) CCK-2 receptor in human colonic adenoma specimens and cell lines, was quantified by real-time PCR. Western blotting, using a CCK-2 receptor antiserum, confirmed protein expression. A transformed human colonic adenoma was grown in SCID mice, with hyper-gastrinaemia induced by proton pump inhibitors. CCK-2 receptor blockade was achieved by using neutralising antiserum. Both human colonic adenoma cell lines and biopsies expressed CCK-2 receptor mRNA at levels comparable with CCK-2 receptor transfected fibroblasts and oxyntic mucosa. Western blotting confirmed immunoreactive CCK-2 receptor bands localised to 45, 74 and 82.5 kDa. Omeprazole and lansoprazole-induced hyper-gastrinaemia (resulting in serum gastrin levels of 34.0 and 153.0 pM, respectively) significantly increased the weight of the human adenoma grafts (43% (P=0.016) and 70% (P=0.014), respectively). The effect of hypergastrinaemia on tumour growth was reversed by use of antiserum directed against the CCK-2 receptor. Hyper-gastrinaemia may promote proliferation of human colonic adenomas that express CCK-2 receptor isoforms.

Topics: Adenocarcinoma; Adenoma; Animals; Colonic Neoplasms; Computer Systems; Enzyme Inhibitors; Female; Fibroblasts; Gastric Mucosa; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Introns; Male; Mice; Mice, SCID; Neoplasm Proteins; Neoplasm Transplantation; Omeprazole; Parietal Cells, Gastric; Polymerase Chain Reaction; Protein Isoforms; Protein Processing, Post-Translational; Proton Pump Inhibitors; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; RNA, Messenger; Secretory Rate; Tumor Cells, Cultured

Previous studies in our laboratory demonstrated that pancreatic carcinomas in rodents express receptors for the peptide hormone gastrin that are not present in normal adult pancreas. In view of an abundant literature suggesting that gastrin may promote growth of various gastrointestinal tissues and tumors, the effect of hypergastrinemia on the process of pancreatic carcinogenesis was evaluated.. Rats received subcutaneous injections of the pancreatic carcinogen azaserine at 19 and 26 days of age. Starting at 12 months of age, animals were randomized to treatment with the proton pump inhibitor lansoprazole or vehicle by gavage for 6 months. At autopsy, pancreatic wet weight normalized to body weight was recorded, as well as the number of benign and malignant pancreatic lesions.. Serum gastrin levels were determined by radioimmunoassay and showed a greater than two-fold increase in lansoprazole-treated animals. Pancreatic wet weight in hypergastrinemic rats was increased compared to controls (p <0.05). Premalignant lesions such as acidophilic atypical acinar cell foci, adenomas, heterogeneous phenotypic populations of nodules within nodules, and carcinoma-in-situ were not increased in the hypergastrinemic group. Likewise, there was no difference in the incidence of invasive carcinoma in hypergastrinemic animals (10%) compared to controls (5.7%).. Hypergastrinemia stimulated an increase in pancreatic weight, but did not stimulate development of premalignant lesions or progression to cancer in the azaserine model of rat pancreatic acinar cell carcinoma.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adenoma; Animals; Anti-Ulcer Agents; Azaserine; Carcinoma in Situ; Carcinoma, Acinar Cell; Disease Models, Animal; Gastrins; Lansoprazole; Male; Omeprazole; Organ Size; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Lew

Serum hypergastrinemia promotes the growth of colorectal adenocarcinoma. Some colorectal adenomas express cholecystokinin B/gastrin receptor mRNA, and thus hypergastrinemia may increase progression through the adenoma-carcinoma sequence. This was investigated in the multiple intestinal neoplasia APC(Min-/+) mouse. Serum gastrin levels in APC(Min-/+) mice were elevated 5-6-fold by oral administration of omeprazole (75 mg/kg). Terminal tumor burden was monitored by onset of anemia. A labeling index was generated by immunohistochemical detection of bromodeoxyuridine incorporation. Serum gastrin was neutralized by antigastrin antibodies raised in situ by use of a gastrin immunogen, Gastrimmune. Hypergastrinemia resulted in reduced survival of the APC(Min-/+) mice from a median survival of 13 weeks in the controls to 10 weeks following omeprazole treatment (P < 0.00001, log-rank test). The labeling indices of adenomas from the small and large intestines of omeprazole-treated mice were increased 35 and 29%, respectively (P < 0.05 and P < 0.025, respectively). Gastrimmune immunization reversed both the survival effect and the increased proliferation resulting from serum hypergastrinemia. Hypergastrinemia may promote the progression of existing premalignant colonic lesions by increasing proliferation. Clinical investigations should determine whether this occurs in the human scenario, considering the widespread use of proton pump inhibitors.

Topics: Adenoma; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Bromodeoxyuridine; Cancer Vaccines; Colorectal Neoplasms; Cytoskeletal Proteins; Diphtheria Toxoid; Disease Models, Animal; Disease Progression; Female; Gastrins; Gene Expression Regulation; Heterozygote; Immunization; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Omeprazole; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; RNA, Messenger; Survival Rate

Processing intermediates of preprogastrin (gly-gastrin and progastrin), termed nonamidated gastrins, are mitogenic for several cell types including colonic epithelial cells. However, presently it is not known if nonamidated gastrins play a role in colon carcinogenesis and if the effects are similar to those of amidated gastrins.. Colon carcinogenesis in response to azoxymethane (AOM) was examined in transgenic mice overexpressing either progastrin (hGAS) or amidated gastrin (INS-GAS), compared with that in wild-type (WT) mice.. In AOM-treated groups, the total number of tumors per colon was significantly higher in hGAS (4.8+/-0.34) than INS-GAS (3.0+/-0.16) and WT (2.7+/-0.35) mice. Total numbers of adenocarcinomas and adenomas per animal colon were also significantly higher in hGAS than INS-GAS and WT mice. The size of the tumors was greater in hGAS mice, resulting in a significantly higher tumor burden per mouse in the hGAS mice than INS-GAS and WT mice. Although >90% of the tumors were located in the distal half of the colon in INS-GAS and WT mice, a significant number (42%) were present at the proximal end of the colon in hGAS mice.. The results suggest that the risk for developing colon carcinomas and adenomas in response to AOM is significantly increased in mice expressing high levels of progastrin, but not amidated gastrins.

Topics: Adenoma; Amides; Animals; Azoxymethane; Carcinogens; Carcinoma; Colonic Neoplasms; Gastrins; Incidence; Mice; Mice, Transgenic; Neoplasms, Multiple Primary; Protein Precursors; Reference Values; Survival Analysis

Gastrin and the cholecystokinin type B/gastrin receptor (CCKBR) have been shown to be expressed in colorectal adenocarcinoma. Both exogenous and autocrine gastrin have been demonstrated to stimulate growth of colorectal cancer but it is not known if gastrin affects the growth of colonic polyps. The purpose of this study was to determine if gastrin and CCKBR are expressed in human colonic polyps and to determine at which stage of progression this occurs.. A range of human colonic polyps was assessed for gastrin and CCKBR gene and protein expression.. Normal colonic mucosa did not express gastrin or CCKBR. Gastrin and CCKBR reverse transcription-polymerase chain reaction products were detected and verified by specific hybridisation with an oligo probe on Southern blots. Gastrin and CCKBR were expressed in 78% and 81% of polyps, respectively. Both genes were coexpressed in 97% of cases. Immunohistochemistry identified progastrin in 91%, glycine extended gastrin 17 in 80%, and amidated gastrin 17 in only 47% of polyps. CCKBR was present in 96% of polyps. Expression of gastrin and CCKBR was seen in all histological types and sizes of polyps.. This study is the first to show widespread expression of both gastrin and its receptor in colorectal polyps. Their activation occurs early in the adenoma-carcinoma sequence. Gastrin may promote progression through the adenoma-carcinoma sequence.

Topics: Adenoma; Aged; Carcinoma; Colonic Neoplasms; Colonic Polyps; Disease Progression; Female; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Proteins; Precancerous Conditions; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction

Gastrin (G17) has a CCKB receptor-mediated growth-promoting effect on the AR42J rat acinar cell line that is linked to induction of both mitogen-activated protein kinase (MAPK) and c-fos gene expression. We investigated the mechanisms that regulate the growth factor action of G17 on the rat pituitary adenoma cell line GH3. Both AR42J and GH3 cells displayed equal levels of CCKB receptor expression and similar binding kinetics of 125I-labeled G17. G17 stimulation of cell proliferation was identical in both cell lines. G17 stimulation of GH3 cell proliferation was completely blocked by the CCKB receptor antagonist D2 but not by the MEK inhibitor PD-98059 or the protein kinase C inhibitor GF-109203X, which completely inhibited G17 induction of AR42J cell proliferation. G17 induced a c-fos SRE-luciferase reporter gene plasmid more than fourfold in the AR42J cells, whereas it had no effect in the GH3 cells. In contrast to what we observed in the AR42J cells, G17 failed to stimulate MAPK activation and Shc tyrosyl phosphorylation and association with the adapter protein Grb2. Epidermal growth factor induced the MAPK pathway in the GH3 cells, demonstrating the integrity of this signaling system. G17 induced Ca2+ mobilization in both the GH3 and AR42J cells. The calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide inhibited AR42J cell proliferation by 20%, whereas it completely blocked G17 induction of GH3 cell growth. The Ca2+ ionophore ionomycin stimulated GH3 cell proliferation to a level similar to that observed in response to G17, but it had no effect on AR42J cell proliferation. Thus there are cell type specific differences in the requirement of the MAPK pathway for the growth factor action of G17. Whereas in the AR42J cells G17 stimulates cell growth through activation of MAPK and c-fos gene expression, in the GH3 cells, G17 fails to activate MAPK, and it induces cell proliferation through Ca2+-dependent signaling pathways. Furthermore, induction of Ca2+ mobilization in the AR42J cells appears not to be sufficient to sustain cell proliferation.

Topics: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Adenoma; Animals; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinases; Cell Division; Cell Line; Enzyme Activation; Epidermal Growth Factor; Gastrins; Gene Expression; Growth Substances; Pancreas; Phosphorylation; Pituitary Neoplasms; Protein Kinase C; Proteins; Proto-Oncogene Proteins c-fos; Rats; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Shc Signaling Adaptor Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1

Interferon-alpha (IFN alpha) may exert direct inhibitory effects on cell proliferation and on the production of different peptide hormones. We investigated the effect of IFN alpha on hormone production by 15 GH-secreting pituitary adenomas, 4 clinically nonfunctioning or gonadotroph pituitary adenomas, and 4 prolactinomas in vitro. In the GH-secreting pituitary adenoma cultures, a short term (72-h) incubation with IFN alpha (50-100 U/mL) significantly inhibited GH secretion in 3 of 7 cases and PRL secretion in 6 of 7 cultures. During prolonged incubation (14 days) with IFN alpha, GH and/or PRL secretion was significantly inhibited in 7 of 8 cultures (GH, 17-78% inhibition; PRL, 39-88% inhibition). In the clinically nonfunctioning or gonadotroph cultures, incubation with IFN alpha resulted in inhibition of the secretion of gonadotropins and/or alpha-subunit in all cases (27-62%), whereas in the prolactinoma cultures PRL secretion was inhibited by IFN alpha in all cases (37-76%). The effect of IFN alpha was additive to the inhibitory effects of the dopamine agonist bromocriptine (10 nmol/L) or the somatostatin analog octreotide (10 nmol/L). The inhibition of hormone secretion by IFN alpha was accompanied by inhibition of the intracellular hormone concentrations. The effect of IFN alpha was dose dependent, with an IC50 for inhibition of hormone secretion of 2.3 +/- 0.3 U/mL (n = 5), which is relatively low compared with the concentrations that are reached in patients treated with IFN alpha for various malignancies. In conclusion, the potent antihormonal effect of IFN alpha on cultured pituitary adenomas suggests that this drug might be of benefit in the treatment of selected patients with secreting pituitary adenomas. As treatment with IFN alpha is associated with considerable adverse reactions, studies with this drug should only be considered in inoperable, invasive aggressive, and dopamine agonist- and/or somatostatin analog-resistant functioning pituitary macroadenomas.

Topics: Adenoma; Bromocriptine; Dopamine Agonists; Gastrinoma; Gastrins; Human Growth Hormone; Humans; Insulin; Insulin Secretion; Insulinoma; Interferon alpha-2; Interferon-alpha; Octreotide; Pancreatic Neoplasms; Pituitary Neoplasms; Prolactin; Prolactinoma; Recombinant Proteins; Somatostatin; Tumor Cells, Cultured

Enteropancreatic malignancy is an important cause of morbidity and mortality associated with multiple endocrine neoplasia type 1 (MEN 1). However, the risk factors and mechanisms of the tumorigenesis of this malignancy are poorly understood.. The authors conducted a retrospective study of factors associated with the development of malignant enteropancreatic tumor in 69 patients with MEN 1 belonging to a single family.. Metastatic enteropancreatic tumor and gastrinoma were identified in 20% and 36% of patients, respectively. Compared with MEN 1 patients who did not have an immediate family history of enteropancreatic malignancy, MEN 1 patients with a first-degree relative affected by enteropancreatic malignancy had an increased risk of developing disseminated tumor (odds ratio, 3.7; P < 0.05). In addition, hypergastrinemia and advanced age were both associated with a significant increase in the risk of enteropancreatic malignancy. Elevated serum glycoprotein alpha subunit levels were associated with enterochromaffin-like cell hyperplasia, gastric carcinoid formation, and disseminated enteropancreatic tumor in hypergastrinemic patients (P < 0.05).. Disease modifier factors act in concert with the MEN 1 gene to modulate the development of enteropancreatic neoplasia. It is possible to identify MEN 1 patients at high risk for developing aggressive enteropancreatic tumors. Heritable disease modifier factor(s) affecting enteropancreatic malignancy appear to reside at loci distinct from that of the MEN 1 gene.

Topics: Adenoma; Adult; Female; Gastrinoma; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasm Metastasis; Pancreatic Neoplasms; Retrospective Studies; Risk Factors

The endocrine cells in intraductal papillary-mucinous neoplasms (IPN) of the pancreas have rarely been investigated. In the normal pancreatic ducts of normal pancreases (n = 5) there were a few endocrine cells: argyrophil in 5 (100%), chromogranin A in (100%), pancreatic polypeptide (PP) in 3 (60%), and insulin in 7 (20%). These endocrine cells were scattered, and located in the basal portions of pancreatic ducts. In IPN of the pancreas (n = 9), there were many endocrine cells: argyrophil in 7 (78%), argentaffin in 8 (89%), chromogranin A in 8 (89%), PP in 7 (78%), serotonin in 7 (78%), insulin in 4 (44%), and gastrin in 5 (56%). In invasive ductal adenocarcinoma of the pancreas (n = 6), many endocrine cells were also detected: argyrophil cells in (67%), chromogranin A in 3 (50%), insulin in 3 (50%), glucagon in 4 (67%), and somatostatin in 3 (50%). In positive cases, endocrine cells were situated under or among the neoplastic cells and the proportion of endocrine cells in IPN was less than 5% of the total neoplastic cell population. These data show that normal pancreatic ducts contain endocrine cells and that IPN frequently contain argyrophil, argentaffin, chromogranin A, and hormone-containing endocrine cells. These data also suggest that endocrine differentiation occurs during neoplastic transformation and progression of IPN of the pancreas.

Topics: Adenocarcinoma, Mucinous; Adenoma; Aged; Aged, 80 and over; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Chromogranin A; Chromogranins; Enterochromaffin Cells; Female; Gastrins; Glucagon; Histocytochemistry; Humans; Immunohistochemistry; Insulin; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Serotonin; Vasoactive Intestinal Peptide

Thirty-two cases of so-called sclerosing hemangioma of the lung observed by light microscopy were further studied by electron microscopy and/or immunohistochemistry. Three histologic patterns were seen: hemangioma-like, papillary, and solid. The only significant component representing the nature of the lesion is characteristic round cells within the stroma in all these patterns, whereas the surface cells lining the papillary projections or cystic spaces are normal or are hyperplastic bronchioloalveolar cells with a few neuroendocrine cells. Immunohistochemical findings showed that the "stromal cells" (tumor cells) were positive for neuroendocrine markers, namely, chromogranin A (19 of 22 cases), neuron-specific enolase (24 of 24), synaptophysin (six of 10), adrenocorticotropic hormone (14 of 15), growth hormone (14 of 15), calcitonin (11 of 15), and gastrin (11 of 14). Besides, some tumor cells were positive for epithelial membrane antigen (four of four), carcinoembryonic antigen (one of four), and vimentin (one of one). All tumor cells were negative for polyclonal antikeratin antibody (25 cases), AE1 (one case), and AE3 (one case). However, in contrast to the "stromal cells," the surface cells of the cystic spaces stained positively for keratin (25 of 25 cases), AE1 (one of one), AE3 (one of one), epithelial membrance antigen (four of four), and carcinoembryonic antigen (four of four); only a few of them expressed neruoendocrine markers. Both surface and tumor cells were negative for factor VIII-related antigen (25 cases), CD31 (one case), and alpha1-antitrypsin (25 cases). Ten cases further studied by electron microscopy and six examined by ultrastructural morphometry showed that the surface cells were mainly type 2 pneumocytes containing many lamellar bodies in the cytoplasm. Lying among them, neuroendocrine cells were occasionally seen. The stromal tumor cells had no lamellar body, but dense core granules (neurosecretory granules) and microtubules. In six cases, 92.3% (345 of 374) of tumor cells contained neurosecretory granules, which were pleomorphic and 73 to 1056 nm in diameter (mean, 302 nm). Two to 193 (mean, 12) neurosecretory granules were found in each tumor cell. Both immunohistochemical findings and ultrastructural evidence indicate that so-called sclerosing hemangioma of the lung is a benign lesion composed of neoplastic neuroendocrine cells with areas of sclerosis. A suggested name for this tumor is benign neuroendocrine tumor of the lung

Topics: Adenocarcinoma, Bronchiolo-Alveolar; Adenoma; Adrenocorticotropic Hormone; Adult; Aged; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoid Tumor; Cell Transformation, Neoplastic; Chromogranin A; Chromogranins; Diagnosis, Differential; Female; Gastrins; Histiocytoma, Benign Fibrous; Human Growth Hormone; Humans; Immunohistochemistry; Lung Neoplasms; Male; Microscopy, Electron; Middle Aged; Neuroendocrine Tumors; Phosphopyruvate Hydratase; Synaptophysin; von Willebrand Factor

A 48-year-old male with type A atrophic gastritis developed multiple gastric carcinoids and a pituitary adenoma. Laboratory tests revealed high levels of serum gastrin and growth hormone (GH). He underwent subtotal gastrectomy, resulting in a return of the previously elevated gastrin level to normal. Serum GH concentration remained high. Three months after the surgery, the pituitary tumor, composed greatly of GH-immunoreactive cells, was partially removed. Since hypergastrinemia plays a pivotal role in gastric carcinoid formation and induces GH-releasing factor (GHRH) release resulting in GH-producing pituitary tumor formation, GH-producing pituitary adenoma might be a clinical manifestation in type A gastritis.

Topics: Adenoma; Carcinoid Tumor; Follow-Up Studies; Gastrectomy; Gastrins; Gastritis, Atrophic; Gastroscopy; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasms, Multiple Primary; Pituitary Neoplasms; Stomach Neoplasms; Tomography, X-Ray Computed

We have investigated the prevalence of MEN 1 in patients with recognized pituitary adenomas. Since hyperparathyroidism is present in nearly 95-100% of patients with MEN 1 and frequently is the first condition to be identified, the study was limited to the identification of patients with hyperparathyroidism while the screening for gastroenteropancreatic (GEP) lesions was carried out in patients with both pituitary and parathyroid lesions.. Serum total and ionized calcium, phosphate and intact PTH 1-84 (EASIA) were measured in 166 patients (68 with non-functioning pituitary adenoma, 42 with prolactinoma, 35 with GH-secreting adenoma, 17-with ACTH-screening adenoma, 1 with TSH-secreting adenoma, 1 with FSH-secreting adenoma and 2 with an only alpha-subunit secreting adenoma) referred to our clinic from 1990 to 1996. Plasma gastrin, somatostatin, pancreatic polypeptide and vasoactive intestinal peptide were measured by RIA in patients with hyperparathyroidism.. Eight of 166 patients (4.8%) were found to have primary hyperparathyroidism and among these 2 also had a gastrinoma while there was no evidence of other GEP tumours. Considering the tumour type, 6 had prolactinoma (14.3%), 1 GH-secreting adenoma (2.8%) and 1 non-functioning adenoma (1.5%). In most patients the diagnosis of pituitary tumour was made several years before that of hyperparathyroidism (from 1 to 15 years) although 6 patients had previously suffered from urolithiasis and one had undergone gastric resections for recurrent peptic ulcers. One patient was identified as a MEN 1 gene carrier and 2 had relatives with signs and symptoms referable to parathyroid or GEP lesions.. The study shows a prevalence of 4.8% of primary hyperparathyroidism in unselected patients with known pituitary tumours similar to that reported in a previous study. By contrast, the prevalence of MEN 1 in patients with prolactinoma was definitely high (14.3%). In most patients the diagnosis of pituitary tumours was made several years before that of hyperparathyroidism. Although the patients were believed to harbour a sporadic pituitary tumour, most of them had had signs and/or symptoms referable to one or both of the other organs involved in MEN 1, often concomitantly with those of pituitary tumours. These data indicate that the diagnosis of MEN 1 syndrome is missed in a substantial proportion of patients with prolactinomas and therefore the screening of these patients for the syndrome is strongly recommended.

Topics: Adenoma; Adolescent; Adult; Aged; Biomarkers; Calcium; Female; Gastrinoma; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Polypeptide; Parathyroid Hormone; Phosphates; Pituitary Neoplasms; Prevalence; Prolactinoma; Somatostatin; Vasoactive Intestinal Peptide

A case of MEN type I in a 64-year-old man is reported. He had undergone partial duodenectomy because of gastric ulcer and multiple duodenal polyps (gastrin secreting carcinoid). Blood examination revealed hypercalcemia, hyperPTHemia, and hyperprolactinemia. Neck US and CT showed enlargement of 4 parathyroid glands. Brain MRI revealed the microadenoma in left pituitary gland. Total parathyroidectomy with auto-transplantation in the left forearm were performed. Histological examination showed the hyperplasia of the parathyroid. Three and a half year after parathyroidectomy, there was no evidence of recurrence of gastrin secreting tumor and hyperparathyroidism, and enlargement of pituitary microadenoma. This is the first MEN type I case in Japan which have detected 3 endocrine tumors clinically with gastrin secreting duodenal carcinoid.

Topics: Adenoma; Carcinoid Tumor; Duodenal Neoplasms; Gastrins; Humans; Hyperparathyroidism; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Parathyroid Glands; Pituitary Neoplasms; Prolactin

Several reports have shown an increase in serum gastrin levels in patients with Cushing's syndrome (CS). However, the actual origin of this hypergastrinaemia is not known. Two hypotheses have been proposed: concomitant ACTH and gastrin secretion by corticotrophic pituitary adenomas or hypergastrinaemia induced by hypercortisolism.. We performed simultaneous, bilateral inferior petrosal sinus (IPS) sampling in nine patients with Cushing's disease (CD), proven by histological studies. In all of them, blood samples were taken from both IPS and a peripheral vein to measure plasma ACTH and serum gastrin. In addition, we measured peripheral serum gastrin levels after an overnight fast in 10 patients with CS (seven with pituitary tumours and three with adrenal tumours) before and after surgical treatment.. Petrosal-peripheral and interpetrosal gradients of ACTH were higher than 2.0 and 1.4, respectively, confirming the pituitary origin of ACTH. Mean serum gastrin levels were 149.1 +/- 53.6 ng/l in peripheral vein, 183.4 +/- 71.7 ng/l in dominant IPS and 181.4 +/- 68.9 ng/l in non-dominant IPS. No significant differences in gastrin concentrations in these locations were found. Mean preoperative gastrin level in patients with CD was 194.6 +/- 47.9 ng/l, whereas in patients with adrenal tumours it was 247.3 +/- 125.9 ng/l. After surgical treatment, the gastrin levels decreased to 62.1 +/- 13.2 ng/l (P < 0.05) and 90.3 +/- 50.3 ng/l (NS), respectively.. These results suggest that hypergastrinaemia is a common finding in patients with Cushing's syndrome. The lack of significant petrosal-peripheral gradient in individuals with Cushing's disease and the reduction in gastrin level following adrenal tumour resection argues against the hypothesis of a predominantly pituitary source of gastrin, suggesting a glucocorticoid related mechanism as an explanation for the hypergastrinaemia.

Topics: Adenoma; Adolescent; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Gastrins; Glucocorticoids; Humans; Hydrocortisone; Male; Middle Aged; Petrosal Sinus Sampling; Pituitary Gland; Pituitary Neoplasms; Postoperative Period

The occurrence of H. pylori infection and the levels of fasting serum gastrin (SEGA) were examined in 97 patients with different morphological types of endoscopically diagnosed gastric polyps. According to the histology of the polyps the series was divided into three groups: inflammatory polyps (43 cases), polyps with foveolar hyperplasia (25 cases), and hyperplastic polyps including adenomas (29 cases). The prevalence of H. pylori infection was significantly lower in patients with hyperplastic polyps (45%) and foveolar hyperplasia (48%) than in the group with inflammatory polyps (81%). SEGA levels were higher in patients with hyperplastic polyps (mean +/- sd: 335 +/- 298 pmol/l) and foveolar hyperplasia (183 +/- 216) than in patients with inflammatory polyps (89 +/- 127). Signs of so-called "autoimmune" gastric, i.e. corpus atrophy and presence of parietal cell antibodies, were commonly found in patients with hyperplastic polyps and foveolar hyperplasia, but rarely in patients with inflammatory polyps. These results suggest that the polyps with hyperplastic changes (hyperplastic polyps and foveolar hyperplasia) are in some of the cases closely related to autoimmune gastritis. The presence of corpus atrophy, hypoacidity and various types of metaplasia, which characterizes autoimmune gastritis, could explain the low prevalence of H. pylori and the high SEGA levels found in these patients.

Topics: Adenoma; Aged; Female; Gastrins; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Hyperplasia; Male; Middle Aged; Polyps; Stomach Neoplasms

In the present study we investigated the effects of the somatostatin (SS) analogs octreotide, RC-160, and BIM-23014 on GH release by cultured cells of human GH-secreting pituitary tumors, in normal rat anterior pituitary cells, and on gastrin release by cultured cells from a human gastrinoma. In all GH-secreting adenomas and in rat anterior pituitary cells, RC-160 was the most potent compound. RC-160 significantly inhibited GH-, PRL, and/or alpha-subunit release by human GH-secreting pituitary adenoma cells in concentrations as low as 10(-12)-10(-14) M, whereas at the same concentrations, octreotide and BIM-23014 did not inhibit or were significantly less effective in inhibiting GH release (P < 0.01, RC-160 vs. octreotide and BIM-23014). In rat anterior pituitary cell cultures, the IC50 values for inhibition of GH release were, in rank order of potency, 0.1, 5.3, 47, 48, and 99 pM for RC-160, SS-14, BIM-23014, octreotide, and SS-28, respectively. Maximal inhibitory effects by the three analogs were the same in the human GH adenoma cell cultures and the rat anterior pituitary cell cultures (-60%). On the basis of these data, RC-160 appears to be about 500 times more potent than octreotide and BIM-23014 in inhibiting GH release by rat anterior pituitary cells in vitro. Forskolin (100 microM) as well as pretreatment of the cells with pertussis toxin significantly diminished the inhibitory effects of the three SS analogs and those of SS-14 and SS-28 to the same extent. The latter data suggest that octreotide, RC-160, and BIM-23014 act mainly via a pertussis toxin-sensitive G-protein and an adenylyl cyclase-dependent mechanism. In the human gastrinoma culture, RC-160 inhibited gastrin release significantly more than octreotide at 10(-12)- and 10(-14)-M concentrations (P < 0.01). In conclusion, the SS analogs octreotide, RC-160, and BIM-23014 may have significant different potencies of inhibition of hormone release in vitro, with RC-160 being the most potent SS analog and octreotide and BIM-23014 having similar potencies. Depending on the pharmacokinetic properties of these three octapeptide SS analogs, these observations may have consequences for the medical therapy of patients with SS receptor-positive endocrine tumors.

Topics: Adenoma; Animals; Cells, Cultured; Endocrine Gland Neoplasms; Female; Gastrinoma; Gastrins; Growth Hormone; Humans; Octreotide; Peptides, Cyclic; Pituitary Gland, Anterior; Rats; Rats, Wistar; Reference Values; Somatostatin; Somatostatin-28; Tumor Cells, Cultured

Topics: Adenoma; Adrenal Gland Neoplasms; Adrenocortical Hyperfunction; Aged; Carcinoma; Carcinoma, Papillary; Female; Gastrins; Humans; Hypercalcemia; Hypothyroidism; Multiple Endocrine Neoplasia; Pituitary Neoplasms; Thyroid Neoplasms

Gastrin has a trophic effect on the mucosa of the gastrointestinal tract and seems to have the potential for promoting colonic cancerogenesis through a chronic stimulation of the epithelial proliferation. Plasma gastrin has been reported to be elevated in patients with colorectal neoplasms. The aim of the present study was to verify this observation. Presurgical serum levels of gastrin were compared between 49 patients with colorectal neoplasms and 47 controls hospitalized for other surgical lesions. Results show significantly higher gastrin levels of case group than controls: 72.72 + 85.41 vs. 46.79 + 24.09 pg/ml (p < 0.05), and provide support for the hypothesis of a gastrin-stimulated neoplastic growth enhancing at the same time the potential therapeutic role of reducing gastrin secretion.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Carcinoma; Colorectal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged; Radioimmunoassay

Information concerning the influence that gastrin may exert on the colon is fragmentary and somewhat controversial. This study analyzed the effect of chronic endogenous hypergastrinemia on cell proliferation and tumor occurrence in the human colonic mucosa.. Twenty-three consecutive hypergastrinemic patients presenting with the Zollinger-Ellison syndrome and 18 normogastrinemic subjects were studied. All had fasting serum gastrin determination, colonoscopy, and cell kinetic measurement in two colonic sites using in vitro 5'-bromodeoxyuridine incorporation.. Macroscopic tumors, one endocrine and five adenomas, were found in 5 of 23 hypergastrinemic patients, without apparent relationship with the level of gastrin. The labeling indices were significantly higher in hypergastrinemic than in normogastrinemic individuals in the right and left colon, (P < 0.002 to P < 0.001) without resulting in colonic cell hyperplasia. There was no correlation between labeling indices and serum gastrin concentrations or duration of hypergastrinemia. The DNA labeling distribution along the crypt was normal in the two groups, without expansion of the proliferative zone towards the surface.. These results showed for the first time that long-lasting endogenous hypergastrinemia is accompanied by increased in vivo cell proliferation in the human colonic mucosa. However, the prevalence of adenomas (17.4%) in patients, all more than 50 years old, may not be different from that in the general population.

Topics: Adenoma; Adult; Aged; Cell Division; Chronic Disease; Colon; Colonic Neoplasms; Colonoscopy; DNA; Female; Gastrins; Humans; Intestinal Mucosa; Male; Middle Aged; Zollinger-Ellison Syndrome

Two previous studies have shown higher circulating gastrin levels in subjects with colonic neoplasia than in colonoscopy-negative controls. In this much larger study, sera were collected from fasting subjects undergoing colonoscopy. Colonoscopy with biopsy classified participants as having colonic adenomas (N = 139), colon carcinoma (N = 29), or controls without colonic neoplasia (N = 150). Frozen, stored sera were later analyzed for gastrin by radioimmunoassay. Serum gastrin values were no higher in subjects with colonic adenomas or carcinoma than in colonoscopy-negative controls. We conclude that elevated serum gastrin levels play little, if any, role in the initiation of colonic neoplasia.

Topics: Adenocarcinoma; Adenoma; Case-Control Studies; Colonic Neoplasms; Colonoscopy; Female; Gastrins; Humans; Male; Middle Aged; Radioimmunoassay

The effects of ad libitum feeding of synthetic, low-protein diets on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), on the norepinephrine concentration in the colon wall tissue and on the labelling index of colon mucosa were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of AOM and were given synthetic diets of equal calorie content containing 25% casein (normal-protein diet), 10% casein (low-protein diet) or 5% casein (very-low-protein diet). Administration of the low- and very-low-protein diets resulted in significant increases in the incidence and number of colon tumors at week 30. However, it did not affect the histology of the colon tumors. The low- and very-low-protein diets also resulted in significant increases in norepinephrine concentration in the proximal and distal portions of the colon wall and in the labelling indices of both parts of the colon mucosa. Our findings indicate that low- and very-low-protein diets enhance colon carcinogenesis and that this may be related to their effects in increasing the norepinephrine level in the colon wall and in stimulating proliferation of colon epithelial cells.

Topics: Adenocarcinoma; Adenoma; Animals; Azoxymethane; Cell Division; Colon; Colonic Neoplasms; Dietary Proteins; Gastrins; Intestinal Mucosa; Male; Norepinephrine; Rats; Rats, Inbred Strains

A case of Zollinger-Ellison syndrome of multiple endocrine neoplasia type 1 (MEN 1) origin with hyperparathyroidism and with a rise in serum gastrin due to an unusual parathyroid "gastrinoma" has been investigated. The patient had multiple endocrine tumours (pituitary and parathyroid), but no evidence of pancreatic or duodenal gastrin-producing neoplasm. Radio-immunoassay, immunohistochemistry and electron microscopy showed gastrin in one parathyroid adenoma. These findings, together with a decrease of gastrinaemia after parathyroidectomy suggest that true gastrin was produced by parathyroid tumour cells and that they themselves may be the origin of the hypergastrinaemia. Our ultrastructural investigation extends these observations and the results are discussed.

Topics: Adenoma; Female; Gastrins; Humans; Immunohistochemistry; Microscopy, Electron; Middle Aged; Multiple Endocrine Neoplasia; Parathyroid Glands; Parathyroid Hormone; Parathyroid Neoplasms; Zollinger-Ellison Syndrome

The presence of gastrin in pituitary tissue as well as gastrin hypersecretion by some pituitary adenomas have been documented using different methodological approaches. In the present study, serum gastrin levels were measured in 93 patients with nonfunctioning pituitary adenoma, i.e. a condition lacking a reliable marker of the disease. Elevated gastrin levels (85-2, 180 ng/l; normal range: 15-80 ng/l) were found in 14/93 patients (15%), the highest values being observed in one patient with MEN I syndrome. In all but MEN I hypergastrinemic patient, a severe gastric hypochlorhydria (Basal Acid Output: 0.04 +/- 0.1 mmol H+/h) unresponsive to pentagastrin (Maximum Acid Output: 0.1 +/- 0.2 mmol H+/h) was seen. Secretin injection caused gastrin to increase in the patient with MEN I and in another hypergastrinemic patient. Antiparietal cells autoantibodies were positive in 3/11 patients. No changes in gastrin concentrations were found after administration of several agents usually employed in the evaluation of pituitary function, except a significant gastrin reduction after octreotide injection. In two hypergastrinemic patients who underwent pituitary adenomectomy, the high gastrin levels did not change after surgery. Finally, gastrin was undetectable in the culture media of 15 pituitary adenomas surgically removed from both normo- and hypergastrinemic patients and immunocytological studies of tumor cells did not show any gastrin staining. In conclusion, although in patients with pituitary adenomas serum gastrin evaluation is indicated in order to document the presence of a MEN I syndrome, the present data show that high gastrin levels cannot be taken as a specific marker of nonfunctioning pituitary adenomas unless the peripheral origin of hypergastrinemia is excluded.

Topics: Adenoma; Adult; Aged; Analysis of Variance; Biomarkers, Tumor; Bromocriptine; Corticotropin-Releasing Hormone; Female; Gastrins; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Middle Aged; Octreotide; Pentagastrin; Pituitary Gland; Pituitary Neoplasms; Secretin; Thyrotropin-Releasing Hormone

The effects of neurotensin on the incidence, number, size, and histology of colon tumours induced by azoxymethane (AOM) were investigated in Wistar rats. Rats were given 10 weekly injections of AOM (7.4 mg kg-1 body weight) and were also given 200 micrograms kg-1 of neurotensin in depot form every other day until the end of the experiment. In week 40, prolonged alternate-day administration of neurotensin resulted in significant increases in the number and size of colon tumours and the incidence of adenocarcinomas penetrating muscle layer and deeper. However, neurotensin did not influence the incidence of tumour-bearing rats and the histological appearance of colon tumours. Administration of neurotensin caused a significant increase in the labelling index of the colon cancers but not that of colon mucosa. These findings indicate that neurotensin enhanced the growth of colon tumours, possibly related to its effect in increasing proliferation of colon cancer cells.

Topics: Adenocarcinoma; Adenoma; Animals; Azoxymethane; Body Weight; Colonic Neoplasms; Drug Synergism; Gastrins; Male; Neurotensin; Rats; Rats, Inbred Strains

A 43 year old man is presented who suffered from the association of a toxic adenoma of the thyroid gland and a Zollinger-Ellison syndrome (ZES) due to a metastasizing duodenal gastrinoma. There were no other signs of a multiple endocrine neoplasia syndrome, type I (MEN-I). The patient presented here shows that the association of ZES and thyroid disease may also occur in patients with sporadic ZES.

Topics: Adenoma; Adult; Duodenal Neoplasms; Gastrectomy; Gastrinoma; Gastrins; Humans; Hyperthyroidism; Immunohistochemistry; Male; Thyroid Neoplasms; Zollinger-Ellison Syndrome

A 74-year-old acromegalic found to have an intrasellar gangliocytocytoma and GH-secreting pituitary adenoma is described. The gangliocytoma contained immunoreactive gastrin and, to a lesser extent, GHRH, and the adenoma immunostained for GH. Gastrin has not been previously reported in hypothalamic gangliocytomas. Since this peptide has been demonstrated in normal hypothalamus and pituitary, and provokes GH release when administered intraventricularly, it may have caused GHRH release from the gangliocytoma by a local paracrine action and led to adenoma formation and acromegaly.

Topics: Adenoma; Aged; Ganglioneuroma; Gastrins; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Hypothalamic Neoplasms; Male; Neoplasms, Multiple Primary; Pituitary Neoplasms

Topics: Adenoma; Adenoma, Islet Cell; Adrenal Cortex; Female; Gastrins; Glucagon-Like Peptides; Humans; Hydrocortisone; Hyperplasia; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms; Peptides; Thyroid Gland; Thyroid Hormones

The effects of cysteamine (2-aminoethanethiol hydrochloride) on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on the norepinephrine concentration in the colon wall tissue and the labelling indices of colon mucosa and colon cancers were investigated in Wistar rats. Rats received 10 weekly injections of 7.4 mg/kg body weight of AOM and alternate-day subcutaneous injections of 25 mg/kg of cysteamine in 0.9% NaCl solution until the end of the experiment. At week 40, prolonged administration of cysteamine significantly reduced the incidence and number of colon tumors. Histologically, the adenocarcinomas that did develop in rats treated with cysteamine exhibited high mucin-producing activity. Administration of cysteamine caused significant decreases in the norepinephrine concentration in colon tissue and in the labelling indices of colon mucosa and cancers. Our findings indicate that cysteamine inhibits the development of colon tumors. This action may be related to its effect in decreasing norepinephrine concentration in the colon wall tissues and subsequently in decreasing proliferation of colon cancer cells.

Topics: Adenocarcinoma; Adenoma; Animals; Azoxymethane; Carcinoma; Cell Division; Colon; Colonic Neoplasms; Cysteamine; Gastrins; Male; Norepinephrine; Rats; Rats, Inbred Strains

Serum concentration of gastrin determined by radioimmunoassay in 90 consecutive patients who underwent colonoscopy, and serum levels of gastrin in patients with colorectal neoplasia and controls were compared. Based on clinical history, findings of colonoscopy, and pathologic examinations of biopsies, 80 patients were considered eligible for the study. Serum levels of gastrin in 36 controls were 54.1 +/- 13.1 pg/ml and did not differ from serum levels of gastrin in 44 patients with colorectal neoplasia. There was also no significant difference in serum levels of gastrin among 28 patients with adenomas and 16 patients with carcinoma. The present study disclosed that carcinogenesis of the colon and rectum was not associated with hypergastrinemia.

Topics: Adenoma; Carcinoma; Colorectal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged

Six patients were studied with pituitary adenomas and elevated concentrations of gastrin similar to those found in cases of benign antral gastrinoma syndrome. Chromatography of the serum using Sephadex-G50 revealed different molecular forms of gastrin according to the type of adenomas. In those cases of acromegaly and gonadotrophinoma, gastrin-34 and unsulphated gastrins constitute the predominant forms. In contrast, in cases of Cushing's disease, gastrin-17, sulphated as well as non-sulphated were the predominant types; the chromatographic pattern was similar to that observed in two patients with antral gastrinoma syndrome who acted as controls. These findings demonstrate that pituitary adenomas might secrete gastrin. Taking into account that gastrin-34 and unsulphated gastrins were the predominant forms in cases of acromegaly, gonadotrophinoma and non-functioning adenoma, it is assumed that those molecular forms are mainly produced in the anterior lobe of the hypophysis. Conversely, gastrin-17 was the principal molecular form in cases of Cushing's disease confirming the close relationship of the synthesis of gastrin and corticotrophin peptides. The cases with Cushing's disease exhibited a serum gastrin pattern similar to that observed in the two cases with antral syndrome in which the predominant immunoreactive form of gastrin in gastrin-17 exhibiting a degree of sulphation corresponding to that of antral gastrin. It is concluded that the circulating excess of gastrin originated in the pituitary tumour tissue and the molecular form varied with the type of pituitary adenoma.

Topics: Adenoma; Adult; Chromatography, Gel; Female; Gastrins; Humans; Male; Middle Aged; Pituitary Hormones; Pituitary Hormones, Anterior; Pituitary Neoplasms; Protein Precursors

Twelve of 87 pituitary adenomas from patients with acromegaly, Cushing's syndrome. Nelson's syndrome, hyperprolactinaemia and without symptoms of hormone hypersecretion contained gastrin in concentrations from 0.5 to 166 pmol/g. Only ACTH-producing tumours contained gastrin, which occurred in forms smaller than those present in the normal adenohypophysis. The results indicate that corticotropic tumours may synthesize gastrin in moderate amounts.

Topics: Adenoma; Chromatography, Gel; Gastrins; Humans; Molecular Conformation; Pituitary Gland, Anterior; Pituitary Neoplasms; Radioimmunoassay

Hyperplasia of the parathyroid glands is a central feature of familial multiple endocrine neoplasia type 1. We used cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with this disorder. Normal plasma stimulated [3H]thymidine incorporation, on the average, to the same extent as it was stimulated in a plasma-free control culture. This contrasted with the results of the tests with plasma from patients with familial multiple endocrine neoplasia type 1, in which parathyroid mitogenic activity increased 2400 percent over the control value (P less than 0.001). Plasma from these patients also stimulated the proliferation of bovine parathyroid cells in culture, whereas plasma from normal subjects inhibited it. Parathyroid mitogenic activity in plasma from the patients with familial multiple endocrine neoplasia type 1 was greater than that in plasma from patients with various other disorders, including sporadic primary hyperparathyroidism (with adenoma, hyperplasia, or cancer of the parathyroid), sporadic primary hypergastrinemia, sporadic pituitary tumor, familial hypocalciuric hypercalcemia, and multiple endocrine neoplasia type 2 (P less than 0.05). Parathyroid mitogenic activity in the plasma of patients with familial multiple endocrine neoplasia type 1 persisted for up to four years after total parathyroidectomy. The plasma also had far more mitogenic activity in cultures of parathyroid cells than did optimal concentrations of known growth factors or of any parathyroid secretagogue. This mitogenic activity had an apparent molecular weight of 50,000 to 55,000. We conclude that primary hyperparathyroidism in familial multiple endocrine neoplasia type 1 may have a humoral cause.

Topics: Adenoma; Adult; Animals; Cattle; Cells, Cultured; Gastrins; Growth Substances; Humans; Hypercalcemia; Hyperparathyroidism; Hyperpituitarism; Hyperplasia; Multiple Endocrine Neoplasia; Parathyroid Glands; Parathyroid Neoplasms; Thymidine; Tritium

To determine if gastrin in hyperparathyroid glands is true gastrin or artifact and to determine the frequency of gastrin in parathyroid glands, 20 parathyroid glands from 11 patients with hyperparathyroidism but without MEA were extracted and analyzed for gastrin. The parathyroid glands from 4 out of 11 patients had measurable gastrin immunoreactivity (10.7 + 6 pg/mg tissue). Column separation chromatography confirmed that this was true gastrin (40% G-34; 50% G-17). Immunohistochemistry with ABC (avidin biotin complex) immunoperoxidase confirmed the presence of gastrin in cytoplasmic vesicles in scattered parathyroid cells. True gastrin does exist in some cells in some patients with hyperparathyroidism.

Topics: Adenoma; APUD Cells; Gastrins; Humans; Hyperparathyroidism; Hyperplasia; Immunoenzyme Techniques; Parathyroid Glands; Parathyroid Neoplasms; Protein Precursors; Radioimmunoassay

The localization of immunoreactive calcitonin (IR-CT) in the human gastric mucosa and tumor tissues was studied using an immunohistochemical peroxidase-antiperoxidase method. A small number of IR-CT-containing cells were observed in both infant and adult gastric antral mucosa and the ratio of IR-CT-containing cells to G cells was about 1:50-100. Moreover, tissue content of IR-CT in normal antral mucosa was 2.37 +/- 0.35 ng/g wet weight. IR-CT-containing cells and G cells decreased with the progress of chronic atrophic gastritis and were totally absent in intestinal metaplastic glands. IR-CT was detected in G cells, suggesting a paracrine relation between gastrin and CT. IR-CT was not found in tumor cells of 35 gastric adenomas and 40 well differentiated adenocarcinomas. On the other hand, it was demonstrated in a very small number of tumor cells in 4 of 46 poorly differentiated adenocarcinomas, and in a good number in 3 of 7 scirrhous argyrophil cell carcinomas. IR-CT in plasma could serve, therefore, as a tumor marker of scirrhous endocrine cell carcinoma, and its production in cancer cells was considered to be eutopic rather than ectopic.

Topics: Adenocarcinoma, Scirrhous; Adenoma; Adult; Aged; Calcitonin; Female; Gastric Mucosa; Gastrins; Humans; Immunoenzyme Techniques; Infant; Male; Microscopy, Electron; Middle Aged; Peptic Ulcer; Pregnancy; Stomach Neoplasms; Tissue Distribution

Results of preparathyroidectomy and postparathyroidectomy studies in a patient with multiple endocrine neoplasia type I and gastrinoma suggest that hyperparathyroidism unmasks occult gastrinoma and related secretory abnormalities. Three of four diagnostic findings were later obscured by parathyroidectomy and normalization of serum calcium concentration. Basal acid output, basal acid output/maximal acid output ratio, and serum gastrin concentration were decreased from values consistent with gastrinoma to normal. The secretin stimulation test, though still positive, was attenuated. These observations suggest that in multiple endocrine neoplasia type I, normal values for serum gastrin concentration, gastric secretion, and secretin stimulation may not exclude gastrinoma. The investigations clarify the interpretation of a voluminous but confusing literature on the interrelationship between hyperparathyroidism and altered gastric function in the presence or absence of Zollinger-Ellison syndrome.

Topics: Adenoma; Adult; Calcium; Drug Interactions; Female; Gastric Acid; Gastrins; Humans; Hyperparathyroidism; Multiple Endocrine Neoplasia; Parathyroid Hormone; Pituitary Neoplasms; Secretin; Thyroid Neoplasms; Zollinger-Ellison Syndrome

In eight of 10 patients with Zollinger-Ellison syndrome resection of all visible tumor tissue was combined with gastrectomy. The results in this group of patients, as in other series reported in the literature, suggest that excision of gastrinoma by partial pancreatectomy or enucleation can be combined safely with gastrectomy. Perhaps excision of tumor is preferable in the management of patients with solitary tumor who do not have the multiple endocrine neoplasia syndrome. We await further follow-up studies and experience with additional patients before judging this thesis of tumor resection with gastric preservation.

Topics: Adenoma; Adult; Aged; Carcinoma; Female; Gastrectomy; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatectomy; Zollinger-Ellison Syndrome

Neuroendocrine tumours of the lung and gut are known to possess bombesin-like immunoreactivity. The recent observation that gastrin releasing peptide (GRP), a 27 amino acid peptide isolated from the porcine intestine, may be the mammalian analogue of bombesin led us to look for this peptide in a variety of human neoplasms. Formalin-fixed tissues from 85 tumours were examined by the immunoperoxidase technique, using specific antisera to the GRP molecule (1-27) and the GRP fragment (1-16). Intense cytoplasmic GRP immunoreactivity was seen in thyroid medullary carcinomas (3/3), carcinoids of lung, pancreas, and intestine (22/36), and paragangliomas (2/3). Less frequent staining was present in pulmonary small cell (oat cell) carcinomas (1/8) and pituitary adenomas (1/6). Complete absence of immunoreactivity was observed in three phaeochromocytomas, five Merkel cell tumours, six neuroblastomas and 15 non-neuroendocrine tumours. Normal neuroendocrine cells of the thyroid (C-cells) and bronchial mucosa (Kulchitsky cells) exhibited GRP immunoreactivity; nerve fibres from all sites failed to demonstrate staining for GRP. In each positive case, the pattern of staining for GRP (1-27) and GRP (1-16) was identical, although the GRP (1-16) immunostaining was weaker. These findings indicate that bombesin immunoreactivity in human neuroendocrine cells and tumours is attributable to GRP-like molecules and that GRP is a useful marker of neuroendocrine differentiation in many tumours.

Topics: Adenoma; Adrenal Gland Neoplasms; Amino Acid Sequence; Bombesin; Carcinoid Tumor; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Gastrins; Humans; Intestinal Neoplasms; Lung Neoplasms; Neoplasms; Neurosecretory Systems; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Pituitary Neoplasms; Thyroid Neoplasms

Immunohistochemical and histological investigations were undertaken on 24 surgically-removed pituitary adenomas. By histology (haemalu-eosin staining), 7 chromophobe, 12 acidophil and 5 basophil pituitary adenomas were revealed. For immunohistochemical purposes the peroxidase-antiperoxidase technique was applied. Primary antisera against 10 hormones were used. By immunohistochemistry, 7 prolactin-containing, 2 TSH-containing, 2 GH-containing and 1 beta-endorphin-containing pituitary adenomas were identified. Furthermore, 1 mixed thyrotropic-prolactin human pituitary adenoma was detected. A possible connection between histological and immunocytochemical findings is discussed.

Topics: Adenoma; Cholecystokinin; Gastrins; Glucagon; Hormones, Ectopic; Humans; Immunoenzyme Techniques; Insulin; Insulin Secretion; Paraneoplastic Endocrine Syndromes; Pituitary Gland; Pituitary Hormones; Pituitary Neoplasms

Glicentin-containing cells (Glic. cells) in intestinal metaplasia, adenoma and carcinoma of the stomach were examined using immuno-histochemical techniques. Glic. cells first occurred in the gastric mucosa of the transitional area between metaplastic and intact gastric glands. They frequently showed hyperplasia or micronoduli in the budding area of the deeper metaplastic glands, but in completely intestinalized mucosa these endocrine cells decreased remarkably. Gastric adenomas with mild dysplasia had a good number of glicentin-immunoreactive cells which were located in the deeper adenoma glands. Gastrin- and somatostatin-positive cells were also detected in the adenomas. The incidence of glicentin-positive tumor cells was significantly higher in well differentiated adenocarcinoma than in poorly differentiated adenocarcinoma. Among the seven cases of scirrhous argyrophil cell carcinoma, three showed glicentin- and glucagon-immunoreactivity in the same area of the tumor. These findings suggest that the selective increase of Glic. cells in intestinal metaplasia may be closely related to the development of gastric adenoma. Glicentin positive tumor cells in gastric carcinomas can be regarded to be an expression of intestinal or fetal markers.

Topics: Adenoma; Carcinoma; Gastrins; Glucagon; Growth Hormone-Releasing Hormone; Hormones, Ectopic; Humans; Intestinal Mucosa; Intestines; Metaplasia; Proglucagon; Protein Precursors; Stomach Neoplasms

A patient with intractable diarrhea was found to have hyperchlorhydria, hypergastrinemia, and an increase in serum gastrin in response to secretin. At surgery the pancreas was completely normal, and an 8-cm adrenal adenoma was removed. Postoperatively the diarrhea ceased, and serum gastrin and gastric acid levels returned to normal. Tissue gastrin levels in the adrenal tumor were 1,000 times the expected values. Circumstantial evidence suggests that this tumor may have been secreting gastrin.

Topics: Adenoma; Adrenal Gland Neoplasms; Adult; Female; Gastric Acid; Gastrins; Humans

The effect of tetragastrin on the incidence and histology of colonic tumors induced by intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine was investigated in Wistar rats. Prolonged administration of tetragastrin in depot form during and after treatment with N-methyl-N'-nitro-N-nitrosoguanidine resulted in a significant reduction in the incidence of colonic tumors in Experimental Week 35. Histological examinations showed that, unlike the well-differentiated adenocarcinomas with a typical glandular pattern in control groups, the adenocarcinomas that developed in rats treated with tetragastrin had high mucin-producing activity.

Topics: Adenocarcinoma; Adenoma; Animals; Colonic Neoplasms; Gastrins; Injections, Subcutaneous; Male; Methylnitronitrosoguanidine; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Sarcoma; Tetragastrin

In three families with the multiple endocrine adenomatosis type I (MEA I) trait, 51 members were investigated by measurement of circulating peptide hormones as tumor markers. Twenty-five of 51 members (49 percent) were considered to be affected by MEA I disorders. The incidence rose with age (75 percent in generation II). Both sexes were affected equally. Hyperparathyroidism was present in 20 of 25 affected members (80 percent), and pituitary tumors (prolactinomas) were found in four of 25 (16 percent). Endocrine pancreatic tumors were found in nine of 25 affected members (36 percent), but when "probable" tumors (seven) are included the frequency rises to 72 percent. Hyperparathyroidism was found in all except one member with proved lesions in other organs. Among patients with proved and possible endocrine pancreatic tumors, elevated serum levels of gastrin and pancreatic polypeptide were frequently found, 78 percent and 67 percent, respectively, and we suggest that serum gastrin and pancreatic polypeptide levels are the most useful screening markers at present for pancreatic lesions in MEA I.

Topics: Adenoma; Adolescent; Adult; Age Factors; Aged; Female; Gastrins; Humans; Hyperparathyroidism; Insulinoma; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Parathyroid Neoplasms; Pedigree; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Percutaneous transhepatic sampling of blood in the portal venous system (TPVS) was used to; (1) localize hormone secreting tumors and help in differentiating tumors from diffuse disease (nesideoblastosis and hyperplasia with adenomata) in 9 patients with fasting hypoglycemia and hyperinsulinism, and (2) study the concentration an distribution of the immunoreactive peptides: insulin (IRI), gastrin (IG), glucagon (IRG), pancreatic polypeptide (hPP), and somatostatin (SRIF-LI), in the venous drainage of the uninvolved portion of the pancreas and GI tract. Localized elevations of IRI (64-920 microunits/ml) predicted tumor localization in 6 patients with single tumors that were not demonstrable angiographically. In one patient with nesideoblastosis and another with islet cell hyperplasia with adenoma, elevated IRI concentrations at multiple locations suggested a diffuse or multicentric process. Elevations of SRIF-LI in the same region as IRI elevations in one patient and of IRG in another patient suggested that these tumor produced two hormones. Some problems in the interpretation of portal venous insulin concentrations are discussed. The locations of maximum portal venous system plasma concentrations and portal-arterial gradients (mean +/- SE pg/ml) in five patients with small single insulinomas were: IG, gastrocolic trunk (126 +/- 27, 46 +/- 22); IRG, proximal splenic vein (130 +/- 30, 47 +/- 13) and gastrocolic trunk (131 +/- 23, 60 +/- 13); hPP, portal vein (164 +/- 48, 49 +/- 22); SRIF-LI, superior mesenteric vein (186 +/- 50, 57 +/- 20) and gastrocolic trunk (178 +/- 59, 55 +/- 21). It is concluded; (1) TPVS can be used successfully to localize single insulin-secreting tumors of the pancreas and to help distinguish them from diffuse disease but problems in such differentiation do occur, (2) circulating SRIF-LI and IRG are derived from both the pancreas and the gut, IG predominantly from the proximal gut and hPP from the head of the pancreas, and (3) The data provide new information for the interpretation of portal insulin concentrations in patients with organic hyperinsulinism and of hormone concentrations for localization of peptide-producing tumors of the pancreas other than insulinomas.

Topics: Adenoma; Adenoma, Islet Cell; Adult; Female; Gastrins; Glucagon; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Portal Vein; Somatostatin

In a pancreatic adenoma approximately 78.7% of the endocrine cells reacted specifically with antisera to neurotensin, 17.5% to gastrin, 2.8% to pancreatic polypeptide, and 1% to glucagon. The electron microscope revealed that the majority of the endocrine cells were N-cells--morphologically similar to the ileal N-cells which are known to represent the neurotensin-producing cells. Neurotensin was extracted from the tumor and identified by Sephadex, ion-exchange, and high-pressure liquid chromatography. Gastrin, pancreatic polypeptide, and glucagon cells were also identified by the electron microscope; the peptides were extracted and demonstrated by chromatography. The serum concentrations of these hormones were elevated. After total gastrectomy which was necessary because of Zollinger-Ellison syndrome, a jejunoesophageal alkaline reflux, reaching the upper esophagus appeared. As intravenous infusion of synthetic neurotensin in rats caused an increase of luminal enteric pressure, it is suggested that severe jejunoesophageal reflux after gastrectomy may be a clinical feature of a neurotensinoma.

Topics: Adenoma; Adult; Esophagitis, Peptic; Gastrins; Glucagon; Histocytochemistry; Humans; Jejunal Diseases; Male; Neurotensin; Pancreatic Neoplasms; Pancreatic Polypeptide

Topics: Acromegaly; Adenoma; Adult; Female; Gastrins; Growth Hormone; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin

In 36 patients with verified hyperparathyroidism (HPT), serum gastrin and its response to secretin was studied before and after parathyroidectomy. In most of the patients gastric secretion-basal acid output (BAO) and maximal acid output (MAO)--was also studied. Seventeen patients had increased serum gastrin values preoperatively and/or postoperatively. Most of the serum gastrin increases were moderate and all but one of the patients with values above 250 pmol/l had hypochlorhydria. Nine patients had a positive secretin test according to conventional criteria preoperatively or postoperatively, but showed no other signs suggestive of a gastrin-producing tumour. Most of the patients with a serum gastrin increase after injection of secretin had hypochlorhydria or achlorhydria. The BAO/MAO ratio was less than 0.6 in all patients. The results of this study do not support the view that primary HPT is often associated with a gastrin-producing tumour as part of a multiple endocrine adenomatosis (MEA type I), but indicate that the observed hypergastrinemia in HPT is almost exclusively related to hypo- or achlorhydria. The findings also give reason to doubt the value of the secretin test.

Topics: Adenoma; Female; Gastric Acid; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Parathyroid Neoplasms; Peptic Ulcer; Secretin

Radio-immunoassay of serum gastrin may now be carried out in all laboratories of radio-immunology. Comparison of two commercial kits A: Schwartz-Mann and B: CEA-SORIN according to criteria of specificity, sensitivity and reproducibility within and between systems, shows that they both permit the detection of pathological hypergastrinemias (Zollinger Ellison and atropic gastritis). Both kits have an identical intra-system coefficient of variation (10 p. cent and 7 p. cent for A, 5 p. cent and 8 p. cent for B) on the other hand, the inter-system coefficient of variation is better for kit B (22,4 p. cent and 37 p. cent for kit A, and 11,5 p. cent and 14,2 p. cent for kit B). The normal values for each kit are quite different: 97 + 64 pg.ml-1 for A and 51 . 23 pg.ml-1 for B preventing one from comparing estimations carried out with two different kits.

Topics: Adenoma; Evaluation Studies as Topic; Gastrins; Radioimmunoassay; Reference Values; Zollinger-Ellison Syndrome

The high incidence of gastroduodenal ulcers in patients with hyperparathyroidism has been ascribed to gastric hyperacidity induced by hypercalcaemia. In a clinical study comprising 40 patients with solitary parathyroid adenoma, a negative correlation between serum calcium and spontaneous gastric acid secretion was found. At the same time a positive correlation was found between serum calcium and gastrin. It is concluded that gastric hyperacidity is not part of the syndrome provoked by parathyroid adenomas, and that a mechanism inhibitory to gastrin is active in these patients. It is suggested that the inhibitor could be calcitonin.

Topics: Adenoma; Adult; Aged; Calcitonin; Calcium; Female; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Parathyroid Hormone; Parathyroid Neoplasms

A patient initially showed symptoms of peptic ulcer disease in 1953 and was later found to have hypercalcemia and hyperparathyroidism. Peptic ulcer symptoms persisted after parathyroidectomy, and results of studies provided evidence of the Zollinger-Ellison syndrome. Evaluation of the patient's family showed a classic pattern of multiple endocrine adenomatosis type 1. The patient underwent total gastrectomy and excision of a gastrin cell adenoma in 1971 with relief of symptoms, but with persistent hypergastrinemia. He remained in good health until January 1976, when symptoms of hypoglycemia developed. Results of laboratory studies were compatible with the diagnosis of a pancreatic beta-cell adenoma. At the time of operation, an adenoma of the head of the pancreas was found. The tumor was excised; no other metastatic tumors were found. The tumor was compatible with a beta-cell adenoma and was found to contain high concentrations of insulin; there was no important amount of gastrin. Symptoms of hypoglycemia have entirely disappeared.

Topics: Adenoma; Adenoma, Islet Cell; Gastrins; Humans; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms

A father and son each presented with severe watery diarrhea. The son was found to have a pancreatic islet-cell tumor associated with the pancreatic cholera syndrome, as well as a parathyroid adenoma. The father was found to have multiple islet-cell adenomas and the Zollinger-Ellison syndrome. Pancreatic tumor tissue from each patient contained detectable gastrin and vasoactive intestinal peptide; however, a much higher gastrin concentration was found in the tumor tissue from the father and a much higher vasoactive intestinal peptide content in the tumor tissue from the son. Thus, watery diarrhea may be mediated by different hormones in families having multiple endocrine neoplasia; the precise cause of the diarrheal syndrome should be defined to ensure the proper therapy.

Topics: Adenoma; Adenoma, Islet Cell; Adult; Diarrhea; Endocrine System Diseases; Gastrins; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Parathyroid Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

A rare case of the Zollinger-Ellison syndrome associated with hyperparathyroidism and ectopic gastric tissue in the lower esophageal mucosa is reported. Preoperatively the patient, a 53-year-old woman, had hyperchlorhydria and her fasting serum gastrin concentration was mildly elevated. There was a considerable increase in the gastric acid output and concentration of serum calcium after secretin infusion. At operation the patient had a gastric ulcer 10 cm in diameter, an islet cell tumour of the pancreas 14 cm in diameter, and ectopic gastric mucosa in the distal third of the esophagus. A gastrectomy was perfomed, the pancreatic tumour excised and part of the distal esophagus removed through a left thoracotomy. Four months after the operation the gastrin concentration had returned to low normal, but the serum calcium values remained high. One month later two parathyroid adenomas were removed which effectively cured the hypercalcemia.

Topics: Adenoma; Calcium; Choristoma; Esophageal Neoplasms; Esophagus; Female; Gastric Juice; Gastric Mucosa; Gastrins; Hormones, Ectopic; Humans; Hyperparathyroidism; Middle Aged; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Parathyroid Neoplasms; Stomach; Zollinger-Ellison Syndrome

Bromocriptine was administered to 2 subjects with gastrin-secreting tumors of the pancreas. The absorption of the drug was confirmed by a rise in growth hormone levels but no change in the elevated serum gastrin levels were observed. Bromocriptine does not appear to affect gastrin hypersecretion in the way that it influences the hypersecretion of pituitary hormones.

Topics: Adenoma; Adenoma, Islet Cell; Adult; Bromocriptine; Gastrins; Growth Hormone; Humans; Male; Middle Aged; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

In a patient with a duodenal ulcer, with acid hypersecretion and moderately disturbed gastrin secretion tests, immunocytochemical examination of the vagotomy-antrectomy specimen revealed a pyloric microgastrinoma (clinically silent and apparently benign) and focal antropyloric gastrinosis. These localised lesions represent a new variant of abnormalities affecting the gastrin cells in the context of hypersecretory duodenal ulcers.

Topics: Adenoma; Carcinoid Tumor; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pyloric Antrum; Pylorus; Stomach Neoplasms

Insulin, proinsulin, glucagon and gastrin were determined in extracts of tumors of 27 patients with pancreatic islet cell neoplasia of pancreas, in one patient with nesidioblastosis, in extracts of uninvolved portions of the pancreas in 11 of the tumor patients and of 15 control pancreases. Mean insulin concentration in solitary adenomas and in adenomas of patients with adenomatosis was higher than in control pancreases; however, in all but 1 patient the insulin concentration in neoplastic islet tissue was lower than in islet tissue of control pancreas, assuming islet volume is 1% of pancreas. The percentage of proinsulin was elevated in 52% of tumors. Adenoma insulin content correlated with increments of plasma insulin after tolbutamide administration. Insulin and proinsulin concentrations in pancreas uninvolved by tumor were not suppressed. Fasting plasma glucagon was elevated in patients with islet cell adenomatosis and in patients with islet cell carcinoma some of whom had multiple endocrine adenomatosis. The mean concentration of glucagon in tumors was lower than in control pancreases. Elevated concentration of gastrin was found in some adenomas. The data indicate: 1) insulin-secreting islet cell tumors have decreased storage capacity for insulin, 2) elevated concentration of proinsulin in tumors may be due to decreased capacity to store insulin and in some to decreased conversion of proinsulin to insulin as well, 3) tolbutamide stimulates the exaggerated release of a relatively constant fraction of insulin stored in adenomas. 4) solitary adenomas may contain excess amounts of pancreatic hormones in addition to insulin, 5) elevated plasma glucagon in patients with organic hyperinsulinism may indicate malignancy, microadenomatosis or multiple endocrine adenoma syndrome, and 6) chronic hyperinsulinism and hypoglycemia due to adenoma do not suppress insulin and proinsulin content of uninvolved pancreas.

Topics: Adenoma; Adenoma, Islet Cell; Adolescent; Adult; Aged; Antigen-Antibody Reactions; Carcinoma; Female; Gastrins; Glucagon; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreas; Pancreatic Hormones; Proinsulin; Tolbutamide

1. Due to their common origin from the neural crest the hormonogenic cells of the intestinal tract show similar cyto-chemical and ultra-structural characteristics. 2. Hyperplasiae and tumors of these cells lead to excessive hormone production with its consequences on the reacting organs. 3. Hormone producing tumors can be confined to one organ only, but as multiple endocrine adenomatosis they can afflict several organs. 4. Diagnosis of most hormone producing tumors is possible with the adequate radio-immunologic tests. Radiologic and endoscopic examinations can contribute to the localization of the tumor. 5. Surgical resection of the tumor or of the reacting organs impaired by the overproduction of hormones from the tumor is the indicated therapy. Medicamentous therapy is rarely successful. 6. The growth of most hormonogenic tumors is relatively slow. Rates of survival of up to 30 years have been known, even after formation of metastases of the tumor. Effects of hormone overproduction on other organs can reduce the prognosis.

Topics: Adenoma; Carcinoid Tumor; Diarrhea; Gastrectomy; Gastrins; Humans; Hypokalemia; Intestinal Neoplasms; Multiple Endocrine Neoplasia; Pancreas; Paraneoplastic Endocrine Syndromes; Syndrome; Zollinger-Ellison Syndrome

Topics: Adenoma; Adult; Aged; Carcinoma; Cell Differentiation; Female; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Humans; Male; Middle Aged; Stomach Neoplasms

Topics: Adenoma; Adult; Aged; Cushing Syndrome; Gastric Juice; Gastrins; Glucagon; Humans; Hypercalcemia; Hyperinsulinism; Islets of Langerhans; Middle Aged; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Hyperparathyroidism has been associated with an increased incidence of duodenal ulcer, increased acid secretion, and increased plasma gastrin levels. A relationship between these changes, increased serum calcium levels, and the increased incidence of peptic ulceration has been suggested, especially since increased plasma gastrin levels, serum calcium levels, and gastric acid secretion decrease after parathyroidectomy. We have previously suggested that the decrease in plasma gastrin levels after parathyroidectomy may suggest an extragastric source of gastrin, whereas others using immunofluorescent studies have suggested that the parathyroid adenomas themselves might be the source of this gastrin. We prospectively studied in fifteen patients with primary hyperparathyroidism, plasma gastrin and serum calcium levels before and after parathyroidectomy, as well as the gastrin content of parathyroid tumor tissue. The mean basal plasma gastrin level before operation was significantly greater than that of a control group and decreased insignificantly after operation, in contrast to serum calcium levels. No positive correlation could be found between plasma gastrin and serum calcium levels before and after operation. Parathyroid tumor tissue was assayed for gastrin content by radioimmunoassay and no detectable amounts of gastrin could be recovered from any tumor. The results do not support the concept that the extragastric source of gastrin in patients with hyperparathyroidism is the parathyroid adenoma itself.

Topics: Adenoma; Adult; Aged; Duodenal Ulcer; Female; Gastrins; Hormones, Ectopic; Humans; Hyperparathyroidism; Male; Middle Aged; Parathyroid Neoplasms

Foregut endocrine polypeptide-secreting APUD cells (Amine-Precursor-Uptake and Decarboxylation), in their embryologic migration from neural crest to foregut may become "arrested" in the mesoderm or in other ectopic locations. They may become hyperplastic, adenomatous or malignant. Eight illustrative patients are reported. One patient had "pancreatic hyperparathyroidism" with hypercalcemic crises, pancreatic apudocarcinoma, normal parathyroids, biologically active parathormone, but inert immunochemically to the usual parathyroid antisera. Two had gastrin-secreting malignancies in the mesoderm. Remission after excision, but eventual recurrence of the syndrome due to islet cell hyperplasia required total gastrectomy. One patient had a gastric corpus apudocarcinoma found prospectively with hypergastrinemia which required excision of the tumor. One patient had acromegaly with hypergastrinemia and antral gastrinosis treated by pituitary irradiation, One patient had the antral or intermediary type of the Zollinger-Ellison syndrome with moderate hypergastrinemia, duodenal ulcer and antral gastrinosis, treated by vagotomy and antrectomy. One patient had hyperparathyroidism with antral gastrinosis, treated by parathyroidectomy. One patient had malignant Zollinger-Ellison syndrome and developed associated thyroid parafollicular cell hyperplasia and parathyroid chief cell hyperplasia, treated by total gastrectomy and multiple endocrine excisions. These investigative observations demonstrate ectopic loci and associated hyperplasias which support the concept of migration and bizarre potentiality of polypeptide-secreting cells of the foregut.

Topics: Adenoma; Adult; Aged; Amines; Child; Decarboxylation; Endocrine System Diseases; Endoderm; Female; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasms; Pancreatic Neoplasms; Parathyroid Diseases; Parathyroid Hormone; Peptides; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adenoma; Adult; Cushing Syndrome; Female; Follow-Up Studies; Gastrectomy; Gastrins; Glucagon; Humans; Hyperinsulinism; Hyperparathyroidism; Male; Middle Aged; Pancreatic Neoplasms; Secretin; Streptozocin; Zollinger-Ellison Syndrome

Topics: Adenoma; Adult; Aged; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Endocrine Glands; Female; Gastrins; Glucagon; Humans; Hyperparathyroidism; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Parathyroid Neoplasms; Radiography; Stomach Neoplasms; Syndrome; Zollinger-Ellison Syndrome

Topics: Adenoma; Adult; Aged; Blood Glucose; Diazoxide; Duodenal Ulcer; Female; Gastrectomy; Gastrins; Glucagon; Hormones, Ectopic; Humans; Hyperparathyroidism; Hypoglycemia; Insulin; Insulin Secretion; Lymphatic Metastasis; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatectomy; Pancreatic Neoplasms; Parathyroid Neoplasms; Peptic Ulcer Perforation; Splenectomy; Zollinger-Ellison Syndrome

Topics: Adenoma; Aged; Duodenal Ulcer; Fluorescent Antibody Technique; Gastrins; Humans; Islets of Langerhans; Male; Pancreas; Pancreatic Ducts; Stomach Neoplasms

Topics: Adenoma; Adult; Aged; Calcium; Female; Gastric Acidity Determination; Gastric Juice; Gastrins; Histamine; Humans; Hyperparathyroidism; Intestinal Mucosa; Male; Middle Aged; Parathyroid Neoplasms; Pepsin A; Phosphorus; Stimulation, Chemical; Stomach

Topics: Adenoma; Animals; Drug Tolerance; Gastric Acidity Determination; Gastric Juice; Gastrins; Histamine; Hormones, Ectopic; Humans; Hydrogen-Ion Concentration; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Pentagastrin; Radioimmunoassay; Rats; Stomach; Zollinger-Ellison Syndrome

Topics: Adenoma; Calcium; Gastric Juice; Gastrins; Gastrointestinal Hormones; Humans; Hypercalcemia; Parathyroid Glands; Parathyroid Neoplasms; Pentagastrin; Peptides; Stomach

Topics: Adenoma; Adolescent; Adrenal Gland Neoplasms; Adult; Calcium; Diabetes Complications; Female; Gastrins; Humans; Hyperparathyroidism, Secondary; Male; Parathyroid Diseases; Parathyroid Neoplasms; Pituitary Neoplasms

Topics: Adenoma; Adult; Aged; Biological Assay; Calcium; Female; Gastric Juice; Gastrins; Histamine; Humans; Hyperparathyroidism; Male; Middle Aged; Parathyroid Neoplasms; Radioimmunoassay

Topics: Adenoma; Adenoma, Islet Cell; Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Child; Child, Preschool; Female; Gastrins; Humans; Infant; Insulin; Insulin Secretion; Male; Melanocyte-Stimulating Hormones; Middle Aged; Pancreatic Neoplasms; Serotonin; Zollinger-Ellison Syndrome

Topics: Adenoma; Adenoma, Islet Cell; Adult; Calcium; Gastrectomy; Gastrins; Humans; Hyperparathyroidism; Male; Pancreatic Neoplasms; Parathyroid Glands; Zollinger-Ellison Syndrome

Topics: Adenoma; Animals; Biopsy; Cell Count; Fluorescent Antibody Technique; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Hyperparathyroidism; Hyperplasia; Microscopy; Microscopy, Electron; Parathyroid Neoplasms; Peptides; Pylorus; Rabbits; Television; Thyroid Diseases

Topics: Acromegaly; Adenoma; Adult; Anemia, Pernicious; Animals; Biopsy; Gastric Mucosa; Gastrins; Guinea Pigs; Histocytochemistry; Humans; Hyperparathyroidism; Microscopy, Electron; Rats; Zollinger-Ellison Syndrome

Topics: Adenoma; Adult; Duodenal Ulcer; Gastric Juice; Gastric Mucosa; Gastrins; Humans; Male; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Adenoma; Adenoma, Islet Cell; Gastrins; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Microscopy, Electron; Multiple Endocrine Neoplasia; Neoplasm Metastasis; Pancreas; Zollinger-Ellison Syndrome

Topics: Adenocarcinoma; Adenoma; Aortography; Diagnosis, Differential; Diarrhea; Gastrectomy; Gastric Juice; Gastrins; Gastrointestinal Hemorrhage; Gastrointestinal Motility; Humans; Hyperplasia; Intestine, Small; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Adenoma; Adenoma, Islet Cell; Gastrins; Hormones; Humans; Neoplasm Metastasis; Neoplasms, Multiple Primary; Pancreas; Pancreatic Neoplasms; Peptic Ulcer