gastrins and Gastrinoma

Zollinger-Ellison syndrome (ZES) is a distinct syndrome characterized by hyperchlorhydria-induced peptic ulcer disease and chronic diarrhea. It is the result of a gastrin-excess state caused by a duodenal or pancreatic neuroendocrine tumor referred to as gastrinoma. This gastrin-secreting neuroendocrine tumor is usually sporadic in nature, or part of multiple endocrine neoplasia type 1 syndrome. The high rate of malignancy associated with gastrinomas substantiates the need for early diagnosis. In order to diagnose ZES with laboratory tests, patients under antacid medication are required to stay off proton pump inhibitors for at least one week and H2 receptor antagonists for 48 h. Fasting serum gastrin level measurement serves as an initial and fundamental diagnostic test, boasting a sensitivity of 99%. Gastrinoma patients will present with a gastrin level greater than 100 pg/mL, while a serum gastrin level higher than 1000 pg/mL, in the presence of gastric pH <2, is considered diagnostic. Since more common causes of hypergastrinemia exist in the setting of hypochlorhydria, ruling those out should precede ZES consideration. Such causes include atrophic gastritis, Helicobacter pylori (H. pylori)-associated pangastritis, renal failure, vagotomy, gastric outlet obstruction and retained antrum syndrome. The secretin stimulation test and the calcium gluconate injection test represent classic adjuvant diagnostic techniques, while alternative approaches are currently being introduced and evaluated. Specifically, the secretin stimulation test aids in differentiating ZES cases from other hypergastrinemic states. Its principle is based on secretin stimulation of gastrinoma cells to secrete gastrin, while inhibiting normal G cells. The rapid intravenous infusion of 4 μg/kg secretin over 1 min is followed by gastrin level evaluation at specific intervals post-infusion. Localization of the primary tumor and its metastases is the next diagnostic step when gastrinoma-associated ZES is either suspected or biochemically confirmed. Endoscopic ultrasound has showcased sensitivity as high as 83% for pancreatic gastrinomas and is considered the primary modality in such cases, although its tumor detection rates are substantially lower in duodenal lesions. Gallium-68 radiotracers, especially DOTATOC with positron emission tomography, are currently setting the standard in tumor localization, enhancing traditional imaging techniques and showcasing high sensitivity and specificity.

Topics: Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Proton Pump Inhibitors; Secretin; Zollinger-Ellison Syndrome

The Multiple Endocrine Neoplasia I (MEN1) locus encodes the protein MENIN, which functions as a tumor suppressor protein in neuroendocrine tissues. Gastrinomas are neuroendocrine neoplasms that overproduce the hormone gastrin and can arise sporadically or as part of the MEN1 syndrome, in which mutations in the MEN1 gene lead to loss or inactivation of MENIN protein. Gastrin is a peptide hormone that is primarily synthesized in the gastric antrum and stimulates the secretion of histamine from enterochromaffin-like (ECL) cells and subsequently acid from parietal cells in the gastric corpus. In addition, gastrin exerts a mitogenic function primarily on ECL cells and progenitor cells in the gastric isthmus. Current studies seek to understand how MEN1 mutations generate a mutant MENIN protein that abrogates its tumor suppressor function. Mutations in the MEN1 gene are broadly distributed throughout its nine protein-coding exons, making it difficult to correlate protein structure with its function. Although disruption of the Men1 locus in mice causes functional neuroendocrine tumors in the pituitary and pancreas, gastrinomas do not develop in these transgenic animal models. Prior studies of human gastrinomas suggest that tissue-specific microenvironmental cues in the submucosal foregut may contribute to tumorigenesis by reprogramming of epithelial cells toward the neuroendocrine phenotype. Accordingly, recent studies suggest that neural crest-derived cells are also sensitive to reprogramming when MEN1 is deleted or mutated. Thus, the goal of this report is to review our current understanding of how MENIN modulates gastrin gene expression while highlighting its role in the prevention/suppression of neuroendocrine cell transformation.

Topics: Animals; Gastrinoma; Gastrins; Gene Expression; Humans; Mice; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Proto-Oncogene Proteins; Transcription Factors

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.

Topics: Animals; Carcinoma, Neuroendocrine; Chronic Disease; Gastrinoma; Gastrins; Humans; Proton Pump Inhibitors; Risk Factors; Stomach Diseases; Time Factors; Treatment Outcome; Zollinger-Ellison Syndrome

Gastrin measurements are performed primarily for the diagnosis of gastrin-producing tumors, gastrinomas, which cause the Zollinger-Ellison syndrome (ZES). Gastrin circulates as several bioactive peptides, however, and the peptide pattern in gastrinoma patients often deviates from normal. Therefore, it is necessary to measure all forms of gastrin.. Only immunoassays are useful for measurement of gastrin in plasma. The original assays were RIAs developed in research laboratories that used antibodies directed against the C terminus of gastrin peptides. Because the C-terminal tetrapeptide amide sequence constitutes the active site of gastrin peptides, these assays were well suited for gastrinoma diagnosis. More recently, however, most clinical chemistry laboratories have switched to commercial kits. Because of recent cases of kit-measured normogastrinemia in patients with ZES symptoms, the diagnostic sensitivity and analytical specificity of the available kits have been examined. The results show that gastrin kits frequently measure falsely low concentrations because they measure only a single gastrin form. Falsely high concentrations were also encountered, owing to overreactivity with O-sulfated gastrins or plasma proteins. Thus, more than half of the gastrin kits on the market are unsuited for diagnostics.. Gastrinomas are neuroendocrine tumors, some of which become malignant. A delay in diagnosis leads to fulminant ZES, with major, even lethal, complications. Consequently, it is necessary that the diagnostic sensitivity of gastrin kits be adequate. This diagnostic sensitivity requires antibodies that bind the C-terminal epitope of bioactive gastrins without the influence of O-sulfation.

Topics: Amino Acid Sequence; Antibody Specificity; Biomarkers, Tumor; Gastrinoma; Gastrins; Humans; Immunoassay; Molecular Sequence Data; Reagent Kits, Diagnostic; Sensitivity and Specificity; Zollinger-Ellison Syndrome

Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms representing <5% of all pancreatic malignancies with an estimated incidence of 1-1.5 cases/100,000. PNETs are broadly classified as either functional or nonfunctional. Functional PNETs include insulinomas, gastrinomas, vasoactive intestinal peptideomas, glucagonomas, and somatostatinomas. The clinical manifestations associated with these tumors are the result of excessive hormonal secretion and action. The functional nature of these tumors makes pancreatic hormone testing critical not only for initial diagnosis but also for follow-up, because they are important tumor markers. Nonfunctional PNETs typically remain clinically silent until a substantial mass effect occurs. Although the majority of PNETs occur sporadically, it is important to recognize that these tumors may be associated with a variety of familial syndromes and in many cases genetic testing of PNET patients is warranted. This article familiarizes the reader with the clinical presentation and the biochemical, radiologic, and genetic testing indicated for diagnosis and follow-up of patients with PNET.

Topics: Gastrinoma; Gastrins; Glucagon; Glucagonoma; Hormones; Humans; Hypoglycemia; Insulinoma; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatinoma; Vasoactive Intestinal Peptide; Vipoma

Gastrin release is affected by gastric inflammatory conditions. Antral G cells respond to inflammatory mediators by increasing gastrin secretion. Accumulating experimental evidence suggests that gastrin exerts immunomodulatory and proinflammatory effects. Gastrin could be a contributing factor to these pathologies, which may constitute a new justification for pharmacological blockade of gastrin action.

Topics: Animals; Cell Proliferation; Gastric Acid; Gastrin-Secreting Cells; Gastrinoma; Gastrins; Gastritis; Humans; Immunomodulation; Protein Precursors; Receptors, Cholecystokinin; Signal Transduction

Topics: Aged; Calcium; Child; Gastrinoma; Gastrins; History, 20th Century; Humans; Pancreatic Neoplasms; Prognosis; Secretin; Zollinger-Ellison Syndrome

As there is considerable overlap between the fasting serum gastrin concentrations found in Zollinger-Ellison syndrome and various common conditions such as Helicobacter pylori infection and acid suppressing medication use, establishing the cause of hypergastrinaemia in individual cases can sometimes be difficult.. To review the causes of hypergastrinaemia and the role of additional non-invasive investigations in hypergastrinaemic patients.. Review of articles following a Pubmed search.. As gastrinomas may cause serious complications and be potentially life threatening, investigation of hypergastrinaemic patients should particularly focus on confirming or refuting the diagnosis of Zollinger-Ellison syndrome. Establishing the cause of hypergastrinaemia may be difficult when there is only a mild-to-moderate elevation of fasting serum gastrin concentration and concurrent treatment with proton pump inhibitor drugs and the presence of H. pylori infection can both confuse the clinical picture. A variety of provocative tests are therefore useful for establishing whether a hypergastrinaemic patient has a gastrinoma and current evidence suggests that the secretin test should be used first line.. We suggest an algorithm for the investigation of patients found to have an elevated fasting serum gastrin concentration and address the roles of gastrin stimulation tests in current clinical practice.

Topics: Algorithms; Diagnosis, Differential; Gastrinoma; Gastrins; Gastrointestinal Agents; Helicobacter Infections; Helicobacter pylori; Humans; Secretin; Zollinger-Ellison Syndrome

Several circulating or urinary tumour markers can be used for the diagnosis and follow-up of functioning and clinically non-functioning neuroendocrine tumours of the pancreatic islet cells and intestinal tract. Among the specific tumour markers are serotonin and its metabolites--e.g. 5-hydroxyindoleacetic acid (5-HIAA)--in carcinoid tumours and the carcinoid syndrome, insulin and its precursors or breakdown products in insulinoma, and gastrin in gastrinoma. Plasma vasointestinal polypeptide (VIP) determinations have been used in the diagnosis of VIPoma, plasma glucagon for glucagonoma, and serum somatostatin for somatostatinoma. Among the tumour-non-specific markers are: chromogranins, neuron-specific enolase (NSE), alpha-subunits of the glycoprotein hormones, catecholamines, pancreatic polypeptide (PP), ghrelin and adrenomedullin.

Topics: Biomarkers; Biomarkers, Tumor; Carcinoid Tumor; Gastrinoma; Gastrins; Humans; Insulin; Insulinoma; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Pancreatic Neoplasms; Serotonin

The hormone gastrin plays 2 important roles in gastrointestinal physiology--1 as a major factor in meal-stimulated gastric acid secretion and the other as a trophic hormone for epithelial and enterochromaffin cells. These roles are exaggerated to the point of pathology under conditions of chronic hypergastrinemia as exemplified by the Zollinger-Ellison syndrome and pernicious anemia. More recently, the concern about the potential risk of chronic hypergastrinemia has risen because of the widespread use of proton pump inhibitors for maintenance therapy in reflux esophagitis. For this reason, we present a concise overview of the origin, causes, and potential risks of chronic hypergastrinemia.

Topics: Animals; Enzyme Inhibitors; Gastric Acid; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Peptic Ulcer; Proton Pump Inhibitors; Risk Factors; Zollinger-Ellison Syndrome

The most frequent conditions of hypergastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing unrestrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance.

Topics: Autoimmune Diseases; Carcinoid Tumor; Diagnosis, Differential; Duodenal Neoplasms; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Gastric neuroendocrine tumours (NET) are rare. Clinically they are classified in tumours type 1 to 3. The histological classification is according to the WHO 2000 classification for endocrine tumours. NET type 1 occur in coincidence with chronic atrophic gastritis, as single or multiple small tumours. The prognosis of type 1 tumours is excellent, with no tumour related death reported during follow-up. NET type 2 are part of the MEN-1 syndrome. These tumours may be more aggressive and even develop metastasis. However, in most patients with MEN-1 the prognosis is due to other manifestations of the disease as duodenal or pancreatic neuroendocrine tumours. Gastric neuroendocrine tumours type 3 are sporadic tumours without relationship to other gastric pathology. They tend to occur earlier, without sex preference. These tumours may develop an aggressive course, with metastatic disease and an overall poor prognosis. Thus, aggressive surgical therapy is recommended.

Topics: Biopsy; Chronic Disease; Diagnosis, Differential; Duodenal Neoplasms; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Prognosis; Stomach Neoplasms

Gastrinomas are defined as gastrin producing tumors that are associated with an elevated fasting gastrin serum level, a positive gastrin secretin stimulation test and certain clinical symptoms, e.g. recurrent peptic ulcer disease and occasionally diarrhea, the so-called Zollinger-Ellison syndrome. Most gastrinomas occur in the duodenum (approx. 70%) and not in the pancreas. The duodenal gastrinomas are small, and when they occur in association with the genetic syndrome of multiple endocrine neoplasia type 1 (MEN1), they are multicentric and originate from precursor lesions. The prognosis of duodenal gastrinomas is better than that of pancreatic gastrinomas, since despite early lymph node metastasis they progress slowly to liver metastasis.

Topics: Duodenal Neoplasms; Duodenum; Gastrin-Secreting Cells; Gastrinoma; Gastrins; Humans; Hyperplasia; Multiple Endocrine Neoplasia Type 1; Pancreas; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Cross sectional imaging in the assessment of gastrinomas has three major applications: Tumor localization (sporadic gastrinoma, MEN I) in patients undergoing primary or secondary surgery. Staging of metastasized tumors, especially assessment of lymph nodes and liver metastases, possibly including a risk analysis prior to liver resection. Post-surgery follow-up and monitoring of bio- or chemotherapy. Detection of primary tumors is strongly correlated with their size. However, the sensitivity of surgical assessment of the mostly small tumors by experienced surgeons is much higher than that of any imaging modality. Of all imaging modalities, endoultrasonography (EUS) followed by Somatostatin receptor scintigraphy (SRS) is the most sensitive modality for the assessment of pancreatic tumors in asymptomatic patients suffering from a MEN-I syndrome. Scintigraphy has the highest sensitivity in tumors of symptomatic patients and in the assessment of metastases. CT and MRI are only second line diagnostic modalities. Their sensitivity is largely dependent on the selection of patients. As a potential application, 3D reconstruction of nearly isotropic CT data sets for the risk assessment prior to liver resection is currently developing. Due to the absent radiation exposure, MRI is increasingly utilized to monitor the response of metastases under systemic therapy, e.g. in clinical trials.

Topics: Angiography; Clinical Trials as Topic; Duodenal Neoplasms; Duodenum; Gastrinoma; Gastrins; Humans; Liver; Liver Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Multiple Endocrine Neoplasia Type 1; Neoplasm Staging; Pancreas; Pancreatic Neoplasms; Tomography, X-Ray Computed; Ultrasonography; Zollinger-Ellison Syndrome

Somatostatin receptor scintigraphy (SRS) is a valuable method for the detection of somatostatin receptor-positive lesions. Most gastrinomas (over-)express the somatostatin receptor subtype 2 which can be targeted by In-111 labeled Octreotide. Different studies show a high sensitivity of SRS for the localization and staging of gastrinomas. SRS seems to be superior to other non-invasive imaging modalities and has been proven to significantly contribute to patient management. However, the sensitivity depends on the size and exact localization of the tumors. Smaller lesions and lesions located in the duodenum show a significantly lower sensitivity. In any case, SRS belongs to the routine imaging procedure for gastrinomas for localization and staging and can also be used for evaluation of the tumor progression.

Topics: Disease Progression; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Indium Radioisotopes; Multiple Endocrine Neoplasia Type 1; Neoplasm Staging; Octreotide; Pancreatic Neoplasms; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity

Gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with multiple endocrine neoplasia type 1 (MEN1) and one major determinant of mortality in this syndrome. Whether routine surgical exploration should be performed in a patient with MEN1 associated Zollinger-Ellison syndrome (ZES) to possibly reduce the malignant spread and eventually increase survival still remains controversial. There is not only disagreement about the indication for surgical exploration, but also what type of procedure should be performed, since sufficient evidence-based data are not available. The article discusses the available data on treatment strategies of MEN1 associated ZES.

Topics: Disease Progression; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Laparoscopy; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Prognosis; Reoperation; Survival Rate; Zollinger-Ellison Syndrome

Surgical therapy for sporadic gastrinoma profits from innovative pre- and intraoperative diagnostics. Preoperative gastrinoma localization is enhanced by sophisticated endoscopic ultrasonography, scintigraphic and arteriographic studies with hormone sampling. Thereby a concise surgical approach is guided and additional intraoperative control of success may be gained by endoscopic transillumination and measurement of stimulated gastrin levels.

Topics: Diagnostic Imaging; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Intraoperative Period; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Prognosis; Transillumination; Zollinger-Ellison Syndrome

Gastrinomas are functional neuroendocrine tumors of the gastroenteropancreatic system. Surgery is first line treatment in gastrinomas, however often fails to be curative. This manuscript reviews current strategies of medical treatment of surgically non-curable gastrinoma. Symptomatic treatment with H(+)-K(+)-ATPase proton-pump inhibitors suppresses hypersecretion of gastric acid and substantially improves quality of life in patients with Zollinger-Ellison syndrome. Further medical therapy is only recommended in cases of progressive metastatic gastrinoma. In well differentiated neuroendocrine carcinoma (G1 and G2) a so-called biotherapy with somatostatin analogues exists as first-line and chemotherapy with streptocotozin plus doxorubicine/5-FU as second-line medical treatment option. In poorly differentiated neuroendocrine carcinoma (G3) chemotherapy with etoposide plus cisplatin is possible. Prospective future therapeutic strategies may include treatment with novel somatostatin analogues as well as angiogenesis inhibitors and kinase inhibitors targeting tumor-specific signaling cascades.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Interferon-alpha; Octreotide; Pancreatic Neoplasms; Peptides, Cyclic; Proton Pump Inhibitors; Somatostatin; Zollinger-Ellison Syndrome

Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo-/achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.

Topics: Animals; Carcinoid Tumor; Cell Transformation, Neoplastic; Drug Tolerance; Enterochromaffin-like Cells; Gastric Acid; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis; Gastroesophageal Reflux; Gastrointestinal Agents; Helicobacter pylori; Humans; Malabsorption Syndromes; Peptic Ulcer; Proton Pump Inhibitors; Stomach Neoplasms; Time Factors; Zollinger-Ellison Syndrome

Topics: Biomarkers; Diagnosis, Differential; Diagnostic Imaging; Diagnostic Techniques, Digestive System; Gastrinoma; Gastrins; Glucagonoma; Humans; Insulinoma; Laparoscopy; Neuroendocrine Tumors; Pancreatic Neoplasms; Receptors, Somatostatin; Secretin

Zollinger-Ellison syndrome (ZES) is characterised by peptic ulcers of the upper gastrointestinal tract failing to heal despite maximal medical therapy, diarrhoea and marked gastric acid hypersecretion associated with a gastrin-secreting tumour (gastrinoma). ZES might be associated with multiple endocrine neoplasia type 1. The main diagnostic features are hypergastrinemia and acid hypersecretion. When these parameters give borderline results, provocation test (with secretin or calcium) may be required. To identify the localisation of gastrinoma several imaging techniques have been proposed. Somatostatin receptor scintigraphy is capable to localise the tumour in 80% of the cases and to identify it even in anatomic sites other than pancreas and duodenum. Endoscopic ultrasonography has a sensitivity as high as 79-93% and a specificity of 93%. The 2 main principal therapeutic strategies are to control both the gastric acid hypersecretion and the growth of the neoplasia. Proton pump inhibitors (PPIs) are the drugs of choice for patients with ZES. Furthermore, safety of PPIs in the maintenance therapy has been proven both in short- and in long-term studies. The best surgical treatment is excision of gastrinoma before metastatic spread has occurred. Somatostatin-analogues can reduce both gastric acid hypersecretion and serum gastrin levels. Moreover, they have an antiproliferative effect. Chemotherapy, interferon and embolisation are indicated in rapidly evolving tumours or in cases in which the tumoral symptoms cannot be treated by other approaches.

Topics: Antineoplastic Agents; Embolization, Therapeutic; Gastric Acid; Gastrinoma; Gastrins; Humans; Interferons; Prognosis; Proton Pump Inhibitors; Somatostatin; Zollinger-Ellison Syndrome

The physiologic sequelae of a gastrinoma can be well controlled with medical therapy. The role of surgery has shifted from managing acid hyper-secretion and ulcer complications to preventing metastatic disease and managing symptomatic metastases. With improved methods of imaging for the detection of occult gastrinomas, the prospective evaluation of the role for surgery in altering the natural history of these tumors is now possible.

Topics: Algorithms; Diagnosis, Differential; Disease-Free Survival; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Sensitivity and Specificity; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors (NETs) includes 18 patients (23.4%) with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zurich, Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1-associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1-associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1-associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.

Topics: Duodenal Neoplasms; Gastrinoma; Gastrins; Germany; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prognosis; Switzerland; Zollinger-Ellison Syndrome

A 6.2 kg, 8-year-old, spayed female Australian Terrier was presented with weight loss, inappetence, lethargy and a 2-day history of intermittent vomiting.. The dog had cranial abdominal pain and there was melaena present on digital rectal examination. Haematology revealed a marked, acute leucogram.. Fasting serum gastrin levels were markedly elevated and gastrinoma was suspected. Treatment was initiated with omeprazole, ranitidine and sucralfate. The dog remained clinically normal for 26 months, at which time exploratory surgery was undertaken and the dog subsequently euthanised due to extensive metastases. Histopathology and immunocytochemistry confirmed the diagnosis of metastatic gastrinoma.. This is a rare condition infrequently reported. Although the number of cases treated with omeprazole are too few to draw firm conclusions, it would appear that proton pump inhibitors are useful and should be considered for cases of gastrinoma managed medically. Long-term prognosis is poor, and survival times range from 1 to 147 weeks. Many treatment options are discussed in the medical literature though not all are feasible in veterinary patients.

Topics: Animals; Anti-Ulcer Agents; Antineoplastic Agents; Dog Diseases; Dogs; Fatal Outcome; Female; Gastrinoma; Gastrins; Neoplasm Metastasis; Omeprazole; Pancreatic Neoplasms; Ranitidine; Sucralfate; Treatment Outcome

The assessment of fasting serum gastrin (FSG) is essential for the diagnosis and management of patients with the Zollinger-Ellison syndrome (ZES). Although many studies have analyzed FSG levels in patients with gastrinoma, limited information has resulted from these studies because of their small size, different methodologies, and lack of correlations of FSG levels with clinical, laboratory, or tumor features in ZES patients. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of 309 patients with ZES and compare our results with those of 2229 ZES patients in 513 small series and case reports in the literature. In the NIH and literature ZES patients, normal FSG values were uncommon (0.3%-3%), as were very high FSG levels >100-fold normal (4.9%-9%). Two-thirds of gastrinoma patients had FSG values <10-fold normal that overlap with gastrin levels seen in more common conditions, like Helicobacter pylori infection or antral G-cell hyperplasia/hyperfunction. In these patients, FSG levels are not diagnostic of ZES, and gastrin provocative tests are needed to establish the diagnosis. Most clinical variables (multiple endocrine neoplasia type 1 status, presence or absence of the most common symptoms, prior medical treatment) are not correlated with FSG levels, while a good correlation of FSG values was found with other clinical features (prior gastric surgery, diarrhea, duration from onset to diagnosis). Increasing basal acid output, but not maximal acid output correlated closely with increasing FSG. Numerous tumoral features correlated with the magnitude of FSG in our study, including tumor location (pancreatic > duodenal), primary size (larger > smaller) and extent (liver metastases > local disease). In conclusion, this detailed analysis of FSG in a large number of patients with ZES allowed us to identify important clinical guidelines that should contribute to improved diagnosis and management of patients with ZES.

Topics: Adult; Diagnosis, Differential; Fasting; Female; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Multivariate Analysis; Pancreatic Neoplasms; Prospective Studies; Zollinger-Ellison Syndrome

Zollinger-Ellison syndrome (ZES) is characterised by refractory peptic ulcer disease, severe diarrhoea and gastric acid hypersecretion associated with an islet-cell tumor of the pancreas (gastrinoma). ZES is sporadic in 62-80% of cases and in 20-38% of cases is associated with multiple endocrine neoplasia type 1 (MEN 1). The diagnosis of ZES is certain when the plasma gastrin is >1000 pg/mL and the basal acid output is >15 mEq/h in patients with an intact stomach, >5 mEq/h in gastrectomised patients, or when the hypergastrinemia is associated with a pH <2. Treatment is based on the control of gastric acid hypersecretion and of the malignant tumor and its possible metastases. Proton pump inhibitors are the most effective antisecretory drugs and can be administered at high dosages without drug-related adverse effects. All sporadic, localised gastrinomas should be excised if possible. When liver metastases are also present, their debulking may improve symptoms and survival, and facilitate medical treatment. There is some controversy as to the surgical approach for gastrinomas associated with MEN 1. Somatostatin analogues can be useful in reducing gastric acid hypersecretion, serum gastrin and gastric enterochromaffin-like cells, and can thus contribute to treating the disease more effectively. Their antiproliferative effect can be used in treating liver metastases. Chemotherapy and/or interferon are indicated only in patients with malignant progressive disease. Embolisation and chemoembolisation are effective in controlling clinical symptoms; however, they do not seem to improve survival.

Topics: Biomarkers; Gastrinoma; Gastrins; Humans; Zollinger-Ellison Syndrome

Japanese clinicians and scientists have contributed significantly to reporting, investigating, and managing patients with pancreatic endocrine tumors and other multiple endocrine neoplasias for the past several decades. This article summarizes the latest progress in this field in Japan. Particularly, our contribution to the development of diagnostic and localization methods is reviewed. Further, the present use of somatostatin receptor scintigraphy and the application of the laparoscopic surgery for pancreatic endocrine tumor in Japan are discussed.

Topics: Calcium; Gastrinoma; Gastrins; Injections, Intra-Arterial; Injections, Intravenous; Insulinoma; Japan; Laparoscopy; Pancreas; Pancreatic Neoplasms; Receptors, Somatostatin; Secretin; Zollinger-Ellison Syndrome

Topics: Diagnosis, Differential; Gastrinoma; Gastrins; Humans; Indium Radioisotopes; Lymph Node Excision; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Secretin; Survival Rate

Duodenal and pancreatic endocrine tumors are uncommon and their surgical treatment is often difficult. The management of these tumors has changed with recent advancements in tumor localization, intraoperative hormone measurements, standardized surgical techniques, and a better understanding of the genetic basis of multiple endocrine neoplasia syndrome. We present our experience with 191 endocrine tumors and elaborate the contemporary management of functioning duodenopancreatic endocrine tumors.

Topics: Duodenal Neoplasms; Endosonography; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Insulinoma; Liver Neoplasms; Magnetic Resonance Imaging; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatectomy; Pancreatic Neoplasms

Despite general awareness of Zollinger-Ellison syndrome (ZES) by most physicians and more than 3000 articles written about it since 1955, the diagnosis of ZES is still delayed for a mean of 5 years. Recent studies show it is being delayed even more with the widespread use of proton pump inhibitors. A number of tumor markers, in addition to assessing serum gastrin, such as chromogranin A, neuron-specific enolase, and subunits of chorionic gonadotropin, have been proposed for use in either the diagnosis of pancreatic endocrine tumors, such as gastrinomas, or for assessment of tumor extent and growth. In this article important recent insights into the diagnosis of ZES as well as the clinical usefulness of assessing tumor markers for diagnosis and determination of disease extent and growth are discussed. Approximately 25% of ZES cases are due to multiple endocrine neoplasia type 1 (MEN1). A number of important studies in this group of patients are also reviewed. Finally, almost every patient with ZES has marked gastric acid hypersecretion, and its current treatment as well as the long-term possible side effects are reviewed briefly.

Topics: Algorithms; Biomarkers, Tumor; Carcinoid Tumor; Chorionic Gonadotropin; Chromogranin A; Chromogranins; Gastric Acid; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Hyperparathyroidism; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatic Neoplasms; Phosphopyruvate Hydratase; Proton Pump Inhibitors; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Diagnosis, Differential; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prognosis; Zollinger-Ellison Syndrome

Gastrinoma treatment has evolved considerably in the last 20 years. In particular, the advent of effective acid-reducing pharmacologic agents has changed the primary morbidity of this disease entity from one of acid hypersecretion to one of tumor growth and spread. Thus, while symptoms can be temporized using histamine receptor antagonists, proton pump inhibitors, or somatostatin analogs, cure can be effected only by surgical means. Recent advances in operative techniques and pre- and intra-operative imaging studies, including routine duodenotomy, somatostatin-receptor scintigraphy, and intraoperative ultrasound, have allowed for identification and subsequent resection of more than 95% of gastrinoma tumors. Most experts agree that all sporadic cases of localized gastrinoma should be excised. In addition, debulking of metastatic tumor may improve symptoms and survival when cure cannot be ascertained. There is, however, some controversy as to the surgical approach for gastrinoma found in the setting of multiple endocrine neoplasia, type 1. Because of the usual multiplicity and particular indolence of these tumors, two primary strategies have emerged: aggressive approaches have been advocated in an effort to eradicate all present and potential tumor; and less aggressive, or nonoperative, approaches have been suggested because it is unclear whether intervention offers survival or disease-free benefit in this population. We advocate surgical intervention for patients with gastrinoma and multiple endocrine neoplasia, type 1 when tumors exceed 2.5 cm in size. This tumor size has been associated with a higher likelihood of hepatic metastases, which ultimately affects survival. The role of adjuvant therapies for gastrinoma remains limited.

Topics: Anti-Ulcer Agents; Antineoplastic Combined Chemotherapy Protocols; Catheter Ablation; Combined Modality Therapy; Enzyme Inhibitors; Epidemiologic Methods; Gastrectomy; Gastric Acid; Gastrinoma; Gastrins; Histamine H2 Antagonists; Humans; Liver Transplantation; Multiple Endocrine Neoplasia; Neoplasm Metastasis; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Parathyroidectomy; Proton Pump Inhibitors; Somatostatin; Vagotomy; Zollinger-Ellison Syndrome

Topics: Calcium; Calcium-Binding Proteins; Gastrinoma; Gastrins; Glucagonoma; Humans; Infusions, Intra-Arterial; Insulinoma; Pancreatic Function Tests; Pancreatic Neoplasms; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Secretin; Vipoma

Gastrinomas secrete gastrin and cause symptoms related to gastric acid hypersecretion that can be controlled by antisecretory medications. Primary tumors are located within the pancreas or duodenum and 60% metastasize. Liver metastases are associated with decreased survival. Localization studies especially somatostatin receptor scintigraphy are indicated to image the extent of disease. Surgery is indicated to potentially cure the patient, or control the malignant tumoral process and prolong survival.

Topics: Diagnostic Imaging; Duodenal Neoplasms; Gastric Acid; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Survival Rate; Zollinger-Ellison Syndrome

Topics: Animals; Antacids; Autoradiography; Cat Diseases; Cats; Dog Diseases; Dogs; Female; Gastrinoma; Gastrins; Humans; Male; Pancreatic Neoplasms; Prognosis

Topics: Gastrinoma; Gastrins; Humans; Magnetic Resonance Imaging; Pancreatic Neoplasms; Radionuclide Imaging; Tomography, X-Ray Computed; Ultrasonography; Zollinger-Ellison Syndrome

The gastrointestinal neuroendocrine cell proliferations are comprised of a few hyperplasias and various neoplasias. The better characterized hyperplasias include G-cell hyperplasia, either primary or secondary, enterochromaffin-like (ECL)-cell hyperplasias, generally secondary to hypergastrinemia, and EC-cell hyperplasias. The neoplasias include carcinoid tumors, demonstrating low malignancy and divided into foregut, midgut, and hindgut varieties, poorly differentiated neuroendocrine carcinomas resembling their pulmonary counterparts the "oat cell" carcinomas both in histological pattern and in their highly malignant behavior mixed endo-exocrine tumors, which in turn can be divided into composite tumors formed by a population of endocrine cells and a population of exocrine cells, and amphicrine tumors formed by a uniform population of cells with a mixture of endocrine and exocrine phenotypic traits. Although some of these mixed tumors show a degree of malignancy intermediate between the classical carcinoid and an adenocarcinoma, more information must be gathered to establish firm prognostic parameters for these relatively new entities.

Topics: Carcinoid Tumor; Enterochromaffin Cells; Gastrinoma; Gastrins; Gastrointestinal Neoplasms; Humans; Hyperplasia; Neuroendocrine Tumors

Awareness of the sometimes subtle features of Zollinger-Ellison syndrome is important in order not to miss the diagnosis. Immediately after initial diagnostic tests, the patient should be given antisecretory medication, while tests for the type of Zollinger-Ellison syndrome and tumour extent can be delayed. Acid output should be decreased to < 10 mmol/h to control symptoms and prevent complications. Histamine H2-antagonists remain the best available intravenous therapy but omeprazole is the most effective long-term oral therapy and has proved to be safe in nearly 10 years of continuous use. The management of the gastrinoma has changed in recent years since the discovery that the majority of gastrinomas arise outside the pancreas. Exploratory surgery with tumour resection is the treatment of choice in sporadic Zollinger-Ellison syndrome but there are few indications for surgery in patients with Zollinger-Ellison syndrome and multiple endocrine neoplasia type-1. None of the available therapies for metastatic gastrinoma is very effective.

Topics: Diagnosis, Differential; Gastric Acid; Gastrinoma; Gastrins; Histamine H2 Antagonists; Humans; Hydrogen-Ion Concentration; Multiple Endocrine Neoplasia; Omeprazole; Secretin; Zollinger-Ellison Syndrome

A 63-year-old male was admitted to our department for further examination of hypergastrinemia. Secretin provocation test and calcium infusion test suggested Zollinger-Ellison syndrome and percutaneous transhepatic portal venous sampling (PTPVS) demonstrated gastrinoma in the jejunum, although CT, ultrasonography and angiography could not accurately detect the location of the gastrinoma. Laparotomy findings showed a solid tumor 1.5 cm in diameter in the jejunal mesentery 5 cm distal to the ligament of Treitz, and primary gastrinoma was confirmed in the submucosa of the jejunum immediately adjacent to this tumor. An immunohistochemical study using the PAP method revealed gastrin secreting cells in the tumor. In addition to this case of jejunal gastrinoma, a review of literature in Japan and other countries was presented.

Topics: Gastrinoma; Gastrins; Humans; Immunohistochemistry; Jejunal Neoplasms; Lymphatic Metastasis; Male; Methods; Middle Aged; Portal Vein

Topics: Acute Kidney Injury; Duodenal Ulcer; Gastrinoma; Gastrins; Humans; Kidney Failure, Chronic; Pancreatic Neoplasms; Pyloric Antrum; Zollinger-Ellison Syndrome

Of 44 patients with the Zollinger-Ellison syndrome treated at our institution, nine appeared to have undergone "regression" of their gastrinomas. Six of the nine patients had sporadic gastrinomas and became permanently eugastrinemic following excision of nodal metastases and total gastrectomy (n = 4), antrectomy (n = 1), or pancreatoduodenectomy (n = 1) (mean survival, 13 years). The other three patients had Zollinger-Ellison syndrome as part of the multiple endocrine adenopathy type 1 syndrome and became temporarily eugastrinemic after total gastrectomy (mean survival, 11 years). Occult submucosal duodenal-wall microgastrinomas (mean size, 3.0 mm) were found to have been serendipitously excised in four patients. Long-term follow-up of these nine patients, as well as of six other patients described in the literature, demonstrates that excision of occult duodenal-wall gastrinomas provides a plausible explanation for the phenomenon of apparent regression of primary gastrinomas and the eugastrinemia that may follow total gastrectomy.

Topics: Adolescent; Adult; Aged; Duodenal Neoplasms; Female; Follow-Up Studies; Gastrectomy; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Neoplasm Regression, Spontaneous; Neoplasms, Multiple Primary; Neoplasms, Unknown Primary; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Adult; Biomarkers, Tumor; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged

Serum chromogranin A levels (CgA) are reported by some authors to be of clinical utility for assessing the presence or absence of a pancreatic endocrine tumor and tumor extent or growth. The aim of the current study was to assess this finding and compare the results with those from serum gastrin determinations (FSG) in a large cohort of patients with gastrinomas.. In 112 consecutive patients with the Zollinger-Ellison syndrome serum CgA and FSG levels were measured and correlated with disease activity, extent of disease, and the presence of multiple endocrine neoplasia type-1 (MEN-1) or gastric carcinoid tumors.. Serum CgA levels drawn on 2 consecutive days correlated closely (P < 0.00001) as did serum gastrin levels. Serum CgA levels correlated significantly with FSG levels (P < 0.00001). Serum CgA and FSG levels were significantly higher in patients with active disease than in disease free patients (P < 0.00001). The sensitivity for the presence of disease was higher for CgA compared with FSG (92% vs. 80%; P = 0.021). However, the specificity of CgA was 67%. Serum CgA levels were not significantly different in the four disease categories (stable extrahepatic disease, increasing extrahepatic disease, stable liver metastases, and increasing liver metastases). FSG levels were significantly lower in patients with stable extrahepatic disease compared with those with increasing extrahepatic disease. However, both tumor markers decreased significantly with a gastrinoma resection in five patients. The presence of MEN-1 or a gastric carcinoid tumor did not influence the results.. The results of the current study showed that serum CgA and FSG levels both are sensitive tumor markers for the detection of a gastrinoma; however, CgA levels have a relatively low specificity. Neither the magnitude of the serum CgA nor gastrin level correlated with tumor growth or tumor extent and therefore cannot be used to determine these variables. However, in contrast to some other studies, the results of the current study show that changes in serum CgA or gastrin in a given patient with time are related to the tumor extent and not to gastric mucosal changes due to hypergastrinemia.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Prospective Studies; Sensitivity and Specificity; Stomach Neoplasms; Zollinger-Ellison Syndrome

Metastatic gastrinoma is becoming increasingly recognized in patients with Zollinger-Ellison Syndrome. The mean 5-year survival of these patients is < 20%. Chemotherapeutic regimens are of limited benefit. The aim of this study was to evaluate the use of interferon in these patients because a preliminary report suggested it might be effective.. The efficacy and toxicity of interferon was assessed in 13 consecutive Zollinger-Ellison syndrome patients with liver metastases. Patients were treated with human recombinant alpha interferon (5 million IU, subcutaneously [SC]) daily and followed up at 3-month intervals with multiple imaging studies. At each follow-up, toxicity of therapy was assessed and fasting serum gastrin concentrations were obtained.. No patient showed a reduction in tumor size at any follow-up. One patient died after 2 months. At 6 months, six patients (46%) had stable tumor size in the liver, although new bone metastases developed in one patient. Three patients showed stable disease for up to 21 months. Changes in serum gastrin correlated with tumor response at 6 months. All patients developed some side effects of therapy. Thirty-one percent required dose reduction, and one patient (8%) had to have interferon therapy interrupted briefly.. These results fail to define a therapeutic role for interferon in the treatment of metastatic gastrinoma.

Topics: Adult; Female; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Interferon-alpha; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Zollinger-Ellison Syndrome

The chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome has trophic effects on the gastric mucosa, causing increased parietal cell mass reflected by increased maximal acid output (MAO) and basal acid output (BAO). The time course for the development of these gastric changes in humans is unknown, and controversy exists regarding whether reversal of the hypergastrinemia results in rapid normalization of gastric secretory function. To address these uncertainties, gastric secretory function was prospectively evaluated in 20 patients with the Zollinger-Ellison syndrome undergoing successful curative resection of gastrinoma. Each patient had gastric acid measurements, imaging studies, fasting serum gastrin and secretin provocative testing preoperatively, postoperatively at 3-6 months, and yearly thereafter. Preoperative mean BAO was 39 mEq/h, MAO 56 mEq/h, BAO-MAO ratio 0.73, and fasting gastrin output 1020 pg/mL. All patients were evaluated at 6 months, 17 at 1 year, 15 at 2 years, 13 at 3 years, and 9 at 4 years. By 3-6 months, MAO decreased by 50% in men (mean, 30 mEq/h) and by 35% in women (mean, 29 mEq/h) and then remained relatively unchanged for up to 4 years. Before surgery, 14 of 20 patients (70%) had an elevated MAO, whereas 4 years after resection, none of 9 patients had elevated levels. By 3-6 months, BAO decreased by 75% and remained unchanged for up to 4 years. At 3-6 months, 56% of patients were mild hypersecretors and 67% remained hypersecretors up to 4 years. Preoperatively, the BAO-MAO ratio was elevated in 16 of 20 patients (80%); postoperatively, only 5 of 18 patients (28%) at 3-6 months, 2 of 15 (13%) at 1 year, and 2 of 10 (20%) at 4 years continued to have elevated ratios. Preoperatively, the mean ranitidine dose was 1597 mg/day, whereas after surgery the mean dose was 535 mg/day at 3-6 months and approximately 300 mg/day at 1-4 years with 8 patients requiring no antisecretory drug. These results show that the trophic effects of chronic hypergastrinemia are, in general, rapidly reversible with a 50% decrease in MAO within 3-6 months of cure. Similarly, BAO decreased by 75% within 3-6 months. Despite these decreases, careful monitoring of acid secretion is required after reversal of the chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome, because 55% of patients at 3-6 months and up to 67% at 4 years continue to remain mild hypersecretors and require low doses of antisecretory drugs.

Topics: Adult; Aged; Cimetidine; Dose-Response Relationship, Drug; Duodenal Neoplasms; Famotidine; Female; Follow-Up Studies; Gastric Acid; Gastric Mucosa; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Omeprazole; Pancreatic Neoplasms; Postoperative Period; Prospective Studies; Ranitidine; Sex Factors; Time Factors; Zollinger-Ellison Syndrome

We have examined the effects of the somatostatin analogue (SMS 201-995) in 10 patients with gastrinoma syndrome. Four had hepatic metastases, one had a tumor in a peripancreatic lymph node, two had resectable intrahepatic and intraduodenal gastrinomas, and in three the primary tumor was not found. Acutely, SMS 201-995 decreased acid secretion and restored the BAO/MAO ratio to normal in eight of eight patients. Basal and secretin-stimulated gastrin responses were suppressed but not normalized in eight of eight patients. Suppression of endogenous gastrin restored responsiveness to exogenous gastrin. Treatment for up to 12 months with SMS 201-995 controlled symptoms in six of eight patients, suppressed serum gastrin in three of five, and suppressed acid secretion in three of three patients. Treatment with SMS 201-995 in three patients for 5 months decreased tumor secretion of gastrin and diminished basal acid secretion, an effect that persisted in two of three patients 48 hours after withdrawal of SMS. In patients with metastatic disease who had high levels of gastrin, SMS treatment for 5 to 12 months did not inhibit tumor growth or decrease gastrin levels. SMS treatment arrested progression of tumor growth only in patients who had a reduction in gastrin and gastric acid secretion. We conclude that SMS may be useful in the management of gastrinoma patients by decreasing hypersecretion of gastrin and gastric acid and, over a longer term, may even change tumor capacity to release gastrin and gastric acid secretion. SMS may thus be useful as a palliative agent and as an adjunct to conventional treatment of the gastrinoma syndrome. SMS does not appear to shrink tumor mass in patients with very high basal gastrin levels.

Topics: Adult; Clinical Trials as Topic; Drug Administration Schedule; Female; Follow-Up Studies; Gastric Acid; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Octreotide; Somatostatin; Syndrome

Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited endocrine cancer syndrome. Multiple gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) affect 30% to 80% of MEN1 patients, with the most common functioning GEP-NET being gastrinoma. Biochemical identification of hypergastrinemia may help to recognize the presence of gastrinomas before they are detectable by instrumental screening, enabling early diagnosis and start of therapy, preferably before tumor progression and metastases occurrence.. Evaluate the effectiveness of secretin stimulation test to precociously diagnose the presence of gastrin-secreting tumors.. Results of secretin stimulation tests, performed between 1991 and February 2020, were retrospectively analyzed, as aggregate, in a cohort of MEN1 patients with GEP-NETs.. Data were extracted from the MEN1 Florentine database.. The study included 72 MEN1 patients with GEP-NETs who underwent a secretin stimulation test for the evaluation of gastrin secretion.. A positive secretin stimulation test was assumed with a difference between basal fasting serum gastrin (FSG) and the maximum stimulated value of gastrin over 120 pg/mL.. The secretin stimulation test showed a secretin-induced hypergastrinemia in 27.8% (20/72) of patients with GEP-NETs, and a positive test in 18 cases. The test allowed the identification of a positively stimulated hypergastrinemia in 75.0% (3/4) of patients who presented a basal FSG within the normal range.. Diagnosis of gastrinoma is complex, difficult, and controversial. Results of this study confirm that a positive secretin stimulation test allows early diagnosis of gastrinomas, even in the presence of borderline or normal levels of nonstimulated FSG.

Topics: Early Detection of Cancer; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Retrospective Studies; Secretin; Zollinger-Ellison Syndrome

Gastrinomas are gastrin-secreting pancreatic tumours rarely diagnosed in cats. A 12-year-old female spayed cat was presented for vomiting, anorexia and weight loss. Physical exam revealed lethargy, dehydration and thin body condition. Pertinent laboratory abnormalities included a mild mature neutrophilia and borderline hypoalbuminaemia. Imaging of the abdomen revealed a mass-like change to the proximal duodenum. Exploratory laparotomy was performed, and the duodenal mass along with a 3-mm pancreatic nodule was removed. Immunohistochemical staining of the pancreatic nodule confirmed a gastrinoma. Following surgery, treatment was initiated with omeprazole and toceranib. Toceranib was discontinued after 8 weeks due to hyporexia. The patient was continued on omeprazole long term and has survived more than 35 months since diagnosis. Little information regarding treatment and prognosis for feline gastrinomas is available. In this case report, long-term survival was achieved with a combined surgical and medical approach using omeprazole and toceranib.

Topics: Animals; Cat Diseases; Cats; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Omeprazole; Pancreatic Neoplasms; Pyrroles

Gastrinoma may cause refractory esophageal stricture due to gastro-esophageal reflux disease (GERD), but imaging technologies have limited power in its diagnosis. A 74-year-old female with a history of peptic ulcers suffered from repeated epigastralgia, and she visited a local hospital. An esophago-gastro-duodenoscopy (EGD) demonstrated severe reflux esophagitis and multiple peptic ulcers. Blood examination revealed a high value of fasting serum gastrin. Multi-detector computed tomography showed a hypervascular and tiny nodule in duodenal bulb, although other imaging technologies did not. Short-term medication with a proton pump inhibitor or potassium-competitive acid blocker was intermittently provided, but dysphagia was repeatedly worsened, and she was referred to our division. Serum hypergastrinemia was retained, and EGD reexamination depicted esophageal stricture, treated by multiple sessions of endoscopic balloon dilatation. Primary tumor was not identified by the morphological imaging technologies, but a selective arterial secretagogue injection test suggested its existence in the duodenum or pancreatic head. Pancreaticoduodenectomy was performed, and histological study identified 2 mm-sized microgastrinoma buried in Brunner`s glands on the posterior wall of the duodenum bulb. We reported a case with difficulty in diagnosis of the smallest sporadic gastrinoma of the duodenum, which might cause refractory GERD-associated stricture.

Topics: Aged; Duodenum; Esophageal Stenosis; Female; Gastrinoma; Gastrins; Gastroesophageal Reflux; Humans; Pancreatic Neoplasms; Peptic Ulcer; Potassium; Proton Pump Inhibitors; Secretagogues

Neurofibromatosis type (NF-1) is an autosomal dominant disorder characterized predominantly by neurocutaneous manifestations. Involvement of the gastrointestinal tract is uncommon but is associated with a significant risk of malignancy. There are a handful of case reports linking NF-1 with pancreatic neuroendocrine tumors; these include gastrin-secreting variants with the attendant Zollinger-Ellison syndrome. We present the case of a 52-year-old lady who presented with recurrent peptic ulceration and diarrhea. Serum gastrin levels were elevated and magnetic resonance imaging demonstrated the presence of a pancreatic lesion with multiple liver metastases. The lesion was moderately fludeoxyglucose avid on positron emission tomography-computed tomography. Endoscopic ultrasonography-guided sampling revealed the presence of synaptophysin positive neuroendocrine cells with positive gastrin immunostaining. A conservative approach was adopted, and the patient's symptoms improved on proton pump inhibitors. Zollinger-Ellison syndrome is an important condition, which should be kept in mind in the patient with NF-1 who presents with recurrent peptic ulceration and diarrhea. The emerging association between these 2 conditions is being examined on a cellular and immunohistochemical level.

Topics: Diarrhea; Female; Gastrinoma; Gastrins; Humans; Middle Aged; Neuroendocrine Tumors; Neurofibromatosis 1; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Two major forms of gastrin, gastrin-17 (G17) and gastrin-34 (G34), exist in blood. However, conventional immunoassay methods can only quantify total gastrin or G17 alone. Here, we aimed to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify G17 and G34 simultaneously.. Serum samples were prepared by anion-exchange solid-phase extraction. The analytical performance of the LC-MS/MS method was validated and the method was compared to chemiluminescence immunoassay (CLIA) and radioimmunoassay (RIA). The G17 and G34 concentrations in 245 serum samples from healthy controls, individuals with gastrinoma, and individuals with other diseases were analyzed.. The total runtime of the LC-MS/MS method was 6 min. No substantial matrix effect was observed with internal standard correction. The intraassay coefficients of variation (CVs) for G17 and G34 were 4.0%-14.2% and 4.4%-10.4%, respectively, and total CVs were 5.2%-14.1% and 4.6%-12.4%, respectively. The correlation coefficient between LC-MS/MS and CLIA was 0.87, and between LC-MS/MS and RIA was 0.84. The G17+G34 concentrations for 87.5% of individuals with gastrinoma were higher than the 95th percentile of healthy controls (18.1 pg/mL), whereas the concentrations for individuals with other diseases and gastrinoma overlapped. Based on the Youden indices calculated for G17+G34, G34, and G17, the most specific biomarker was G17 (96.9% clinical specificity at 209.8 pg/mL) for gastrinoma.. This method should aid in the diagnosis of diseases associated with increased gastrin concentrations.

Topics: Chromatography, Liquid; Gastrinoma; Gastrins; Humans; Pancreatic Neoplasms; Tandem Mass Spectrometry

The appropriate localization of gastrinoma is still difficult. We aimed to evaluate the diagnostic accuracy of selective arterial calcium injection (SACI) for localization of gastrinomas including multiple lesions. This retrospective study included ten patients with surgically proven gastrinomas (gastrinoma group) and six patients without any findings suggesting Zollinger-Ellison syndrome (non-gastrinoma group). For SACI, calcium gluconate was injected into the arteries supplying pancreas, duodenum, and liver. Blood samples from the hepatic vein were obtained before and 30, 60, and 120 seconds after each injection. The results were considered positive when the increase in serum immunoreactive gastrin (IRG) levels within 60 seconds of calcium gluconate injection were more than 80 pg/mL and more than 20% from baseline. We evaluated the efficacy of SACI by comparing the SACI responses with definitive locations diagnosed by clinical and histopathological findings. In the gastrinoma group, false-positive responses were confirmed in seven of the ten patients. False-negative response was observed in one of the feeding arteries of one patient with gastrinomas in multiple locations. Conversely, the greatest increase in serum gastrin levels from baseline at 30 seconds indicated the true-positive responses in all patients with gastrinomas. In the non-gastrinoma group, calcium gluconate injection into gastroduodenal artery evoked positive responses in five of the six patients. In conclusion, our data suggest the strongest gastrin response evoked by SACI indicates the definitive location in patients with gastrinomas. In contrast, SACI could not accurately locate multiple gastrin-secreting lesions due to poor specificity.

Topics: Aged; Arteries; Calcium Gluconate; Female; Gastrinoma; Gastrins; Humans; Injections; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies

Helicobacter pylori and Multiple Endocrine Neoplasia Type 1 (MEN 1) are risk factors for hypergastrinemia. Gastrin-secreting neoplasms of the foregut mucosa are both a source of, and potentially stimulated by, hypergastrinemia.. To determine the relationship between H pylori exposure and the prevalence and severity of hypergastrinemia in patients with MEN 1.. Cross-sectional analysis of patients with a common MEN1 gene mutation managed at a tertiary referral hospital that underwent fasting serum gastrin and H pylori serum IgG measurement.. H pylori IgG and serum gastrin concentration, determined via immunoassay.. The prevalence and severity of hypergastrinemia and its relationship to past H pylori exposure.. Thirty-four of 95 (36%) patients were H pylori IgG seropositive. H pylori seropositive patients were significantly more likely to exhibit hypergastrinemia compared with seronegative patients (relative risk [RR] 1.72, P = .023). H pylori exposure also predicted severe hypergastrinemia (RR 3.52, P = .026 and RR 9.37, P = .031 for patients with gastrin ≥ ×4 and ≥ ×8 the upper limit of normal [ULN], respectively). Gastrin concentrations ≥ ×10 ULN occurred exclusively in H pylori seropositive patients (0/61 vs 6/34, P = .001). Serum gastrin and alpha subunit were positively associated in H pylori-exposed (β = 0.69, P = .001), but not in H pylori-unexposed patients.. Past H pylori exposure was associated with increased prevalence and severity of hypergastrinemia in MEN 1 patients. Past H pylori-related hypergastrinemia may contribute to the pathogenesis of ongoing gastrin hypersecretion by susceptible foregut neuroendocrine tissues.

Topics: Adolescent; Adult; Aged; Cross-Sectional Studies; Female; Gastrinoma; Gastrins; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prevalence; Severity of Illness Index; Tasmania; Young Adult

Our group observed the first case of synchronous gastric neuroendocrine tumor (NET) and duodenal gastrinoma with autoimmune chronic atrophic gastritis (CAG), in the absence of Helicobacter pylori infection. Demographic, clinical, endoscopic, and pathologic data were abstracted from the electronic medical record at Mount Sinai Hospital from 2013 to 2015. The patient's anonymity was carefully protected, and informed consent was obtained for publication of protected health information. A 53-year-old woman with hypertension presented to Mount Sinai Hospital in June 2013 for a second opinion for management of gastric and duodenal NETs. After evaluation by gastroenterology and surgery, repeat upper endoscopy with ultrasound and fine-needle aspiration revealed multiple diminutive type I gastric NETs and 2 duodenal NETs, against a background of autoimmune CAG, with biopsy pathology negative for H. pylori. She subsequently underwent a transduodenal resection of the duodenal NETs, confirming low-grade, gastrin-positive, stage T2 duodenal NET. On routine follow-up over the next 2 years, clinical, radiographic, and endoscopic surveillance revealed no recurrent or metastatic gastric or duodenal disease. This first report of synchronous duodenal gastrinoma and gastric NET in the setting of autoimmune CAG can broaden our understanding of gastric NET pathophysiology.

Topics: Autoimmune Diseases; Chronic Disease; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hypertension; Middle Aged; Neuroendocrine Tumors; Stomach Neoplasms

Topics: Adult; Bile Duct Neoplasms; Disease-Free Survival; Female; Gastrinoma; Gastrins; Hepatectomy; Humans; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Omeprazole; Prognosis; Prospective Studies; Proton Pump Inhibitors; Secretin; Survival Rate; Zollinger-Ellison Syndrome

The existence of primary lymph node (LN) gastrinoma is questionable and controversial. In fact, the presence of gastrinoma in such uncommon site raises the possibility of metastasis from another occult primary site. An extensive evaluation and careful follow-up is always warranted. A female aged 48 years presented with chronic abdominal pain and watery diarrhoea. Her serum gastrin and chromogranin were elevated, and an underlying gastrinoma was suspected. Further evaluation with an octreotide scan, an endoscopic ultrasound and a secretin stimulation test confirmed the diagnosis. Further evaluation for multiple endocrine neoplasia-1 syndrome was negative. She underwent a surgical enucleation near the head of the pancreas. No other lesions were found after careful exploration of the gastrinoma triangle. Histology showed a LN with a neuroendocrine tumour that tested positively with gastrin and chromogranin stains. Her symptoms resolved postoperatively, her serum gastrin normalised and a repeated octreotide scan was negative.

Topics: Chromogranins; Diarrhea; Female; Gastrinoma; Gastrins; Humans; Lymph Nodes; Middle Aged; Neuroendocrine Tumors; Treatment Outcome

The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia.. Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas.. MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.

Topics: Active Transport, Cell Nucleus; Animals; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Duodenal Neoplasms; Duodenum; Gastrinoma; Gastrins; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Humans; Hyperplasia; Mice, Inbred C57BL; Mice, Knockout; Neuroglia; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Proteolysis; Proto-Oncogene Proteins; Proton Pump Inhibitors; Receptor, Cholecystokinin B; Receptors, Somatostatin; Time Factors; Ubiquitination

Topics: Aged; Biopsy, Fine-Needle; Carcinoid Tumor; Chromogranins; Duodenal Neoplasms; Duodenoscopy; Duodenum; Endosonography; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Male; Stomach Neoplasms; Synaptophysin

Sporadic gastrin-producing neuroendocrine tumors of the duodenum present either with the Zollinger-Ellison syndrome (ZES) or with unspecific symptoms. While syndromic gastrin-producing neuroendocrine tumors often show metastases at the time of diagnosis, those without a syndrome do not. The aim of the study was to search for clinicopathological features that may distinguish the two categories of gastrin-producing duodenal tumors. In a retrospective study, we analyzed the clinical and pathological data in a series of 41 patients with syndromic (i.e., gastrinomas) or non-syndromic duodenal gastrin-producing neuroendocrine tumors (ns-gas-NETs). Twenty-four (59 %) of the 41 patients had tumors that were associated with a ZES and were classified as gastrinomas. These tumors showed a higher Ki-67 index than that of the ns-gas-NETs (1.74 vs. 0.85 %, p = 0.012). In addition, they had more lymph node metastases (75 vs. 6 %, p < 0.001) and showed liver metastases and thus presented much more frequently in TNM stage ≥III (75 vs. 6 %; p < 0.001) than their non-syndromic counterparts. Gastrinomas were removed surgically, ns-gas-NETs endoscopically. We did not observe any significant differences in overall survival or recurrence of disease. Duodenal gastrinomas show no clear morphological features that distinguish them from their non-syndromic counterparts. However, the patients with gastrinomas present in a more advanced stage of disease and need surgical treatment, while non-syndromic gastrin-producing duodenal NETs may be cured by complete endoscopical removal.

Topics: Adult; Aged; Aged, 80 and over; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Pancreatic Neoplasms; Retrospective Studies

Neuroendocrine tumors in the pancreas and the gastrointestinal tract may secrete hormones which cause specific syndromes. Well-known examples are gastrinomas, glucagonomas, and insulinomas. Cholecystokinin-producing tumors (CCKomas) have been induced experimentally in rats, but a CCKoma syndrome in man has remained unknown until now.. Using a panel of immunoassays for CCK peptides and proCCK as well as for chromogranin A, we have examined plasma samples from 284 fasting patients with gastroenteropancreatic neuroendocrine tumors. In hyperCCKemic samples, plasma CCK was further characterized by chromatography.. One of the patients displayed gross hyperCCKemia. She was a 58-year old woman with a pancreatic endocrine tumor, liver metastases, 500-1000-fold elevated basal CCK concentration in plasma, diarrhea, severe weight loss, recurrent peptic ulcer and bilestone attacks from a contracted gallbladder. The CCK concentrations in plasma were not affected by resection of the pancreatic tumor, but decreased to normal after hemihepatectomy with removal of the metastases.. A CCKoma syndrome with severe hypersecretion of CCK exists in man. The duodenal ulcer disease and diarrhea with permanently low gastrin in plasma suggest that CCKomas may mimic gastrinoma-like symptoms, because CCK peptides are full agonists of the gastrin/CCK-B receptor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Child; Cholecystokinin; Denmark; Female; Gastrinoma; Gastrins; Humans; Intestinal Neoplasms; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Rats; Stomach Neoplasms; Young Adult

We report a case of metastatic gastrinoma to the breast morphologically mimicking solid papillary carcinoma of the breast. A 59-year-old woman presented with a hypoechoic right breast mass that histologically revealed solid nests of small monotonous tumor cells, fibrovascular cores, and round to oval nuclei with fine chromatin and small nucleoli. Immunohistochemistry demonstrated chromogranin and synaptophysin positivity. Tumor prognostic markers showed weak positivity for estrogen receptor and negativity for progesterone receptor. Although an initial diagnosis of solid papillary carcinoma was rendered, subsequent identification of the patient's clinical history of pancreatic gastrinoma and an additional immunohistochemical stain for gastrin supported a diagnosis of metastatic gastrinoma. We report this rare case to increase awareness of metastatic neuroendocrine tumors in the breast. Multiple breast lesions and lack of expression of estrogen/progesterone hormone receptors should prompt careful review of the patient's clinical history to rule out metastatic neuroendocrine disease.

Topics: Biomarkers, Tumor; Biopsy; Breast Neoplasms; Carcinoma, Papillary; Chromogranins; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Middle Aged; Pancreatic Neoplasms; Predictive Value of Tests; Receptors, Estrogen; Receptors, Progesterone; Synaptophysin

Topics: Biomarkers; Gastrinoma; Gastrins; Humans; Immunoassay; Reagent Kits, Diagnostic

The value of chromogranin A (CgA) versus gastrin and progastrin in diagnosis and control of gastrinoma patients is not settled because the peptides circulate as variable mixtures. We have addressed this complexity using defined sequence-specific assays.. Six assays were applied to plasma from 40 gastrinoma patients to measure α-amidated gastrins, glycine-extended gastrins, the total progastrin product, and assays for CgA sequence (340-348) and the 'total' CgA product.. The gastrin/progastrin parameters did not add to the diagnosis beyond that of α-amidated gastrins, except in one patient. All gastrin parameters correlated otherwise closely. The CgA results differed. Thus, 11 patients had normal CgA concentrations. By contrast, all total CgA concentrations were elevated but correlated only moderately to gastrin.. Assays measuring α-amidated gastrins have high diagnostic value except for singular patients in whom only progastrin was elevated. By contrast, CgA measurements are not valid in diagnosis or control of gastrinomas.

Topics: Adult; Aged; Biomarkers, Tumor; Chromogranin A; Female; Gastrinoma; Gastrins; Humans; Linear Models; Male; Middle Aged; Peptides; Protein Precursors; Radioimmunoassay

Topics: Barrett Esophagus; Carcinoma, Neuroendocrine; Colonic Polyps; Diagnosis, Differential; Diarrhea; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Recurrence; Vomiting; Weight Loss; Zollinger-Ellison Syndrome

Topics: Gastrinoma; Gastrins; Humans; Laparoscopy; Lymph Node Excision; Male; Young Adult; Zollinger-Ellison Syndrome

Zollinger-Ellison syndrome (ZES) is characterized by gastrinoma and resultant hypergastrinemia, which leads to recurrent peptic ulcers. Because gastrinoma is the most common pancreatic endocrine tumor seen in multiple endocrine neoplasia type I (MEN 1), the possibility of gastrinoma should be investigated carefully when patients exhibit symptoms associated with hormonal changes. Ureteral stones associated with hyperparathyroidism in the early course of MEN 1 are known to be its most common clinical manifestation; appropriate evaluation and close follow-up of patients with hypercalcemic urolithiasis can lead to an early diagnosis of gastrinoma. We report a patient with ZES associated with MEN 1, and urolithiasis as the presenting entity. A 51-year-old man visited the emergency department with recurrent epigastric pain. He had a history of calcium urinary stone 3 years ago, and 2 years later he had 2 operations for multiple jejunal ulcer perforations; these surgeries were 9 months apart. He was taking intermittent courses of antiulcer medication. Multiple peripancreatic nodular masses, a hepatic metastasis, parathyroid hyperplasia, and a pituitary microadenoma were confirmed by multimodal imaging studies. We diagnosed ZES with MEN 1 and performed sequential surgical excision of the gastrinomas and the parathyroid adenoma. The patient received octreotide injection therapy and close follow-up.

Topics: Gastrinoma; Gastrins; Humans; Immunohistochemistry; Liver; Magnetic Resonance Imaging; Male; Mesenteric Artery, Superior; Middle Aged; Multimodal Imaging; Multiple Endocrine Neoplasia Type 1; Pancreas; Pituitary Gland; Positron-Emission Tomography; Radiopharmaceuticals; Thyroid Gland; Tomography, X-Ray Computed; Ultrasonography; Urolithiasis; Zollinger-Ellison Syndrome

The glucagon provocative test is useful for the diagnosis of gastrinoma. The aim of this study was to determine the criteria for the glucagon provocative test.. This study reviewed 8 patients that underwent the glucagon provocative test preoperatively and in whom the diagnosis was confirmed as gastrinoma histologically. The glucagon provocative test was performed by administering glucagon (20 μg/kg) intravenously, followed by 20 μg/kg h for the next 30 min, and plasma gastrin levels were measured 3 and 1 min before and 3, 5, 7, 10, 15, 20, and 30 min after the administration of glucagon. This study evaluated the peak value of plasma gastrin and the time required to reach the peak.. Two of the 8 patients had multiple endocrine neoplasm type 1. The basal plasma gastrin levels ranged from 524 to 10,300 pg/ml. The time required to reach the peak was 3-10 min for all patients. The increase in the peak from the basal value was 235-8,920 pg/ml, and the percentage of increase was 38-337 %.. These results suggest that a diagnosis of gastrinoma should thus be made when plasma gastrin levels peak within 10 min after glucagon administration, with an increase of greater than 200 pg/ml and greater than 35 % of the basal value.

Topics: Aged; Biomarkers, Tumor; Female; Gastrinoma; Gastrins; Glucagon; Humans; Injections, Intravenous; Male; Middle Aged; Pancreatic Function Tests; Pancreatic Neoplasms; Time Factors

We present a case-report of a woman with persisting gastric ulcers, who had elevated gastrin blood levels. First of all, a rare cause of hypergastrinaemia was excluded - a gastrinoma. It was not found despite of extensive investigation. Ulcers were repetitively biopted and transition of high grade dysplasia to adenocarcinoma was detected. Gastrin levels normalised after surgical antrectomia. Afterwards pernicious anaemia was diagnosed as the underlining cause of hypergastrinaemia.

Topics: Adenocarcinoma; Anemia, Pernicious; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Humans; Middle Aged; Pancreatic Neoplasms; Stomach Neoplasms

Helicobacter pylori (HP) has been associated with neuroendocrine tumors of the stomach and duodenum. Gastric enterochromaffin-like (ECL) cell tumors and duodenal gastrinomas have also been associated with HP gastritis in separate series but have not been reported together. With other possible causes excluded, we present a patient with HP-associated atrophy of the oxyntic mucosa that ultimately resulted in stimulation and reactive hyperplasia of gastrin-producing cells in both the antrum and proximal duodenum, the latter progressing to formation of a gastrin-producing cell nodule (gastrinoma). Both of these sources of gastrin resulted in ECL hyperplasia in the atrophied oxyntic mucosa with progression to microcarcinoids and well-differentiated neuroendocrine tumors, along with hypertrophy of residual proximal gastric parietal cells. As atrophy tends to spread from the antrum proximally, residual oxyntic mucosa was still infected with HP and offers 1 explanation for the apparent paradox of atrophic gastritis with ECL hyperplasia and neoplasia in the distal oxyntic mucosa, with proximal oxyntic mucosa showing mild hypertrophic changes in a background of typical HP gastritis.

Topics: Aged; Atrophy; Chronic Disease; Duodenal Neoplasms; Gastrectomy; Gastrinoma; Gastrins; Gastritis; Helicobacter Infections; Humans; Intestinal Mucosa; Male; Neoplasms, Multiple Primary; Neuroendocrine Tumors; Stomach Neoplasms

Topics: Adenocarcinoma; Anemia, Pernicious; Female; Gastrinoma; Gastrins; Humans; Pancreatic Neoplasms; Stomach Neoplasms

The authors present the clinical, laboratory and radiological findings suggestive ofgastrinoma in a patient 1 year and 9 months old. Laboratory tests obtained after fasting revealed elevated serum gastrin, supporting the suspected diagnosis of gastrinoma. In the endoscopy an elevated lesion with central depression was observed. The immunohistochemical examination revealed the benign nature of the tumor and the hyperplasia of argentaffin cells. Gastrinoma is a rare disease that predominantly affects young adults, but it must be considered in the pediatric group when clinical and laboratorial features of this disease are observed.

Topics: Biomarkers, Tumor; Gastrinoma; Gastrins; Humans; Infant; Male; Pancreatic Neoplasms; Rare Diseases

Gastric neuroendocrine neoplasms of the stomach can be divided into the usually well-differentiated, hypergastrinemia-dependent type I and II lesions and the more aggressively behaving gastrin-independent type III lesions. Mainly due to better diagnostics and awareness of this tumor, the observed incidence has increased more than tenfold over the last 30 years. Small (<15-20 mm) localized type I and II lesions that are slowly proliferating (Ki67<2%) can usually be managed conservatively with endoscopic surveillance. Reducing hypergastrinemia by surgical removal of an underlying gastrinoma is important in inhibiting growth and induce reduction of type II lesions, while the specific gastrin receptor antagonist YF476 or gastrin antibodies may become useful for both type I and II lesions. Infiltrating and metastasized tumors and type III lesions require a more aggressive approach with surgical resection and consideration of modalities such as somatostatin analogs, cytotoxics, and peptide receptor targeted treatment.

Topics: Carcinoid Tumor; Gastrinoma; Gastrins; Humans; Neuroendocrine Tumors; Stomach Neoplasms

Serum gastrin levels exceeding 1000pg/ml (normal, <100) usually raise the suspicion for a neuroendocrine tumor (NET) that secretes gastrin. Rarely, such elevated gastrin levels are seen in patients with pernicious anemia which most commonly is associated with autoimmune gastritis (AG). AG can occur concomitantly with other autoimmune disorders including lymphocytic colitis (LC). Gastrin stimulates enterochromaffin-like cells which increase histamine secretion. Histamine excess can cause diarrhea as can bacterial overgrowth or LC. We present a 57-year-old woman with diarrhea, sporadic epigastric pain, and bloating. She also had a history of interstitial cystitis and took pentosan polysulfate and cetirizine. She had no history of ulcers, renal impairment or carcinoid syndrome. Fasting serum gastrin was 1846pg/ml. Esophagoduodenal gastroscopy and biopsies revealed chronic gastritis and a pH of 7 with low stomach acid. Serum gastrin and plasma chromogranin A were suggestive of a gastrinoma or NET. Pernicious anemia was unlikely. Imaging studies did not reveal any tumor. Random colonic biopsy was compatible with LC, possibly explaining her diarrhea, although we also considered excessive histamine from elevated gastrin, bacterial overgrowth, and pentosan polysulfate which can cause diarrhea and be misleading in this setting, pointing to the diagnosis of gastrinoma. At 4year follow-up in 2012, fasting serum gastrin was 1097pg/ml and the patient asymptomatic taking only cetirizine for nasal allergies. This case illustrates that diarrhea may be associated with very high serum gastrin levels in the setting of chronic gastritis, LC, and interstitial cystitis (pentosan use), without clear evidence for a gastrinoma or NET. If no history of ulcers or liver metastases is present in such cases, watchful observation rather than an extensive/invasive and costly search for a NET may be justified. Considering the various forms of polyglandular syndrome, this may represent a variant and we here provide an algorithm for working up such patients, while also reviewing literature on the intertwined relationship between the immune and endocrine systems.

Topics: Autoimmune Diseases; Chronic Disease; Colitis, Lymphocytic; Diagnosis, Differential; Digestive System Neoplasms; Female; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Middle Aged; Neuroendocrine Tumors

Some patients with Zollinger-Ellison syndrome post curative gastrinoma resection continue to show gastric acid hypersecretion; however, the mechanism is unknown.. The aim of this study was to prospectively study acid secretion following curative gastrinoma resection and analyze factors contributing in patients with Zollinger-Ellison syndrome.. Fifty patients cured post gastrinoma resection were studied with serial assessments of acid secretory status, cure status and ECL-cell status/activity (with serial biopsies, CgA, urinary N-MIAA). Correlative analysis was performed to determine predictive factors.. Hypersecretion occurred in 31 patients (62%) and 14 had extreme-hypersecretion. There was an initial decline (3-6 months) in BAO/MAO, which then remained stable for eight years. Preoperative BAO correlated with the postoperative secretion, but not other clinical, tumoral, laboratory variables, the degree of postoperative acid suppression or type of antisecretory drug needed. Hypersecretors had greater postoperative ECL changes (P=0.005), serum CGA (P=0.009) and 24-h urinary N-MIAA (P=0.0038).. Post curative resection, gastric hypersecretion persists long term (mean 8 years) in 62% of patients and in 28% it is extreme, despite normogastrinemia. No preoperative variable except BAO correlates with postresection hypersecretion. The persistent increased ECL-cell extent post curative resection suggests prolonged hypergastrinemia can lead to changes in ECL-cells that are either irreversible in humans or sustained by unknown mechanisms not involving fasting hypergastrinemia and which can result in hypersecretion, in a proportion of which it can be extreme. Whether similar findings may occur in patients with idiopathic GERD treated for prolonged periods (>10 years) with PPIs, at present, is unknown.

Topics: Enterochromaffin Cells; Female; Follow-Up Studies; Gastric Acid; Gastrinoma; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Pancreatic Neoplasms; Parietal Cells, Gastric; Postoperative Period; Prevalence; Prospective Studies; Zollinger-Ellison Syndrome

Controversy exists regarding the role and extent of operation for patients with multiple endocrine neoplasia type 1 (MEN1) and hypergastrinemia.. An institutional MEN1 database was reviewed to identify patients with evidence of hypergastrinemia. The relationship of extent of resection to achievement of eugastrinemia was evaluated.. Operation was performed in 20 patients with MEN1 and hypergastrinemia with a median follow-up of 71 months. Duodenal gastrinomas were identified in 85% of patients who underwent duodenal evaluation. Nodal metastases were identified in 80%. Patients who underwent anatomic regional lymph node dissection (RLND) had a median of 16 nodes removed, vs 1 in patients who did not undergo a formal regional lymphadenectomy. Eugastrinemia was achieved in 12 patients (60%), and 8 (40%) had persistent hypergastrinemia. Compared with patients with persistent hypergastrinemia, patients rendered eugastrinemic more often underwent duodenal evaluation (11/12 vs 2/8; P = .01) and RLND (11/12 vs 3/8; P = .03); there was no relationship between pancreatic resection and achievement of eugastrinemia (P = .32).. For patients with MEN1-associated hypergastrinemia selected for operative treatment, a strategy including duodenal evaluation and anatomic regional lymphadenectomy is associated with long-term eugastrinemia. In contrast, the extent of pancreatic resection should be dictated by the extent and distribution of pancreatic neuroendocrine neoplasms, rather than by the presence of hypergastrinemia.

Topics: Abdomen; Adult; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Lymph Node Excision; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Retrospective Studies; Treatment Outcome

A 26-year-old man was admitted to hospital with a 6-month history of diarrhea and abdominal pain. Before admission, upper and lower gastrointestinal endoscopy had shown a mild erosive duodenitis and the patient was started on a proton pump inhibitor. Physical examination and laboratory tests on admission were not constructive. In addition, repeated gastrointestinal endoscopy, cross-sectional imaging and neuroendocrine markers did not point to a specific etiology. Therefore, as a provocation test, the proton pump inhibitor therapy was discontinued. Discontinuation resulted in a progression of the patient's symptoms and an endoscopic detection of duodenal ulcers. Except for the normal serum gastrin levels, this constellation was suggestive of a gastrinoma, so that further investigations were initiated. Subsequently, the diagnosis could be confirmed and the gastrinoma located. After successful pancreaticoduodenectomy, the patient was symptom-free.. As part of a systematic investigation on chronic diarrhea, the work-up for neuroendocrine causes can play an important role. In this context, it should be kept in mind that some gastrinoma patients present without an elevation of serum gastrin levels. Regardless of a negative gastrin test, a typical symptom constellation should therefore prompt further investigations.

Topics: Abdominal Pain; Adult; Chronic Disease; Diagnosis, Differential; Diarrhea; Duodenal Ulcer; Duodenitis; Follow-Up Studies; Gastrinoma; Gastrins; Gastroscopy; Humans; Lymphatic Metastasis; Male; Pancreatic Neoplasms; Pancreaticoduodenectomy

Preoperative assessment and localization is crucial in the management and outcome of patients with duodenal gastrinoma. Localization can be challenging because of small size and variable location. We describe our experience of managing 1 such patient by localizing the lesion during the preoperative period. Side-viewing endoscopy, endoscopic ultrasound, and somatostatin receptor scintigraphy determined the exact location of the tumor, which was confirmed during surgery on palpation, endoscopic transillumination, and duodenotomy. Antrectomy was performed, and the patient was asymptomatic after 8 months of follow-up and did not require antisecretory medications. His serum gastrin levels returned to normal during the postoperative period.

Topics: Duodenal Neoplasms; Endoscopy, Gastrointestinal; Gastrinoma; Gastrins; Humans; Male; Middle Aged

We report the case of a 22-year-old woman who was referred for evaluation of possible Zollinger-Ellison syndrome because of hypergastrinemia and a positive secretin stimulation test. She was being treated with proton pump inhibitors (PPIs) for severe gastroesophageal reflux disease during her initial evaluation. At cessation of PPI therapy, her fasting serum gastrin levels normalized, as did her response to secretin injection. Previous reports describing false-positive secretin tests have been limited to cases of hypergastrinemia in the setting of chronic atrophic gastritis, presumably a result of achlorhydria. This case represents a clearly documented instance of PPI-related hypergastrinemia with a false-positive secretin test, with subsequent normalization of serum gastrin and a negative secretin test after withdrawal of PPI therapy. The current case emphasizes the need to assess the acid secretory status of individuals with hypergastrinemia and to discontinue the use of potent antisecretory agents, principally PPIs, to avoid the erroneous diagnosis of gastrinoma and before embarking on expensive and potentially invasive evaluations for the purpose of tumor localization.

Topics: Adult; Diagnostic Errors; Female; Gastrinoma; Gastrins; Humans; Proton Pump Inhibitors; Secretin; Young Adult

Most patients with Zollinger-Ellison Syndrome (ZES), even those in whom gastrinoma is found and resected at initial operation, will suffer from persistent or recurrent disease in longterm followup. There is currently no consensus about managing patients with recurrent or persistent ZES. Our unit has historically maintained an aggressive approach toward monitoring and reoperation for patients with sporadic ZES.. We performed a review of a consecutive series of patients evaluated and managed at our institution between 1970 and 2007 for ZES. "Biochemical cure" was defined as normal serum gastrin assays and negative imaging studies. Reoperations were performed for elevations in serum gastrin assays and positive findings on imaging studies.. Fifty-two patients with sporadic ZES were analyzed. Median followup was 14 years. Among patients with sporadic ZES, 37 patients underwent operative management. The most common operations were resection of duodenal gastrinoma (n=8) and total gastrectomy (n=7). Nine patients underwent 15 reoperations for recurrent or persistent disease. "Biochemical cure" was obtained in four patients (44%) undergoing reoperation for ZES. Three of these patients remained without evidence of recurrence at 4, 9, and 12 years after their curative re-resection. Only one of nine patients who underwent reoperation died of metastatic gastrinoma.. Primary and reoperative surgery in patients with sporadic ZES results in a significant rate of "biochemical cure." In selected patients with recurrent or persistent disease, reoperation for resection of gastrinoma is associated with excellent longterm survival and is warranted.

Topics: Adolescent; Adult; Aged; Digestive System Surgical Procedures; Duodenal Neoplasms; Female; Follow-Up Studies; Gastrectomy; Gastrinoma; Gastrins; Hepatectomy; Humans; Male; Middle Aged; Recurrence; Reoperation; Retrospective Studies; Survival Analysis; Treatment Outcome; Young Adult; Zollinger-Ellison Syndrome

We present a rare case of renal gastrinoma. To the best of our knowledge, only one case of renal gastrinoma has been reported in the literature so far. An African American male was diagnosed with Zollinger Ellison syndrome at the age of 15 years, when he underwent surgery for peritonitis secondary to duodenal ulcer perforation. Further evaluation was deferred and proton pump inhibitors were prescribed. Later evaluation showed a left renal mass. Serum gastrin levels were 4,307 pg/ml. A CAT scan of the abdomen showed 4- x 4-cm heterogeneous solid mass in the interpolar region of the left kidney with central hypodensity. Somatostatin scintigraphy confirmed a receptor-positive mass in the same location. Nephrectomy was done and the tumor was diagnosed on histopathological examination as a gastrinoma. At 6-month follow-up, gastrin levels were 72 pg/ml. After a follow-up of 6 years, the patient has no recurrent symptoms.

Topics: Adolescent; Diagnosis, Differential; Gastrinoma; Gastrins; Humans; Kidney; Kidney Neoplasms; Male; Nephrectomy; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Topics: Adult; Biomarkers; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Gluconates; Humans; Injections, Intra-Arterial; Multiple Endocrine Neoplasia Type 1; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins

The insulinoma syndrome is marked by fasting hypoglycemia and inappropriate elevations of insulin. The gastrinoma syndrome is characterized by hypergastrinemia, ulcer disease, and/or diarrhea. Rarely, insulinoma and gastrinoma coexist in the same patient simultaneously.. Our objective was to determine the cause of a patient's hypoglycemic episodes and peptic ulcer disease.. This is a clinical case report from the Clinical Research Center of the National Institutes of Health.. One patient with hypoglycemic episodes and peptic ulcer disease had a surgical resection of neuroendocrine tumor.. The patient was found to have a single tumor cosecreting both insulin and gastrin. Resection of this single tumor was curative.. A single pancreatic neuroendocrine tumor may lead to the expression of both the hyperinsulinemic and hypergastrinemic syndromes.

Topics: Adolescent; Female; Gastrinoma; Gastrins; Humans; Insulin; Insulinoma; Neuroendocrine Tumors; Pancreatic Neoplasms; Syndrome

Topics: Adult; Gastrinoma; Gastrins; Humans; Infarction; Male; Pancreatic Neoplasms; Tomography, X-Ray Computed

Zollinger Ellison syndrome (ZES), an ulcerative disease of the upper gastrointestinal tract that involves the production of high levels of gastrin and gastric acid, is a rare, symptomatic, endocrine neoplastic disease.. We report a rare case of gastrinoma that was first diagnosed during pregnancy in which the primary tumor was located in the liver. The ZES was well controlled with Zoton (Lansoprazole) following surgery. The patient had an uneventful pregnancy and delivery without significant complications.. The present case suggests that treatment with Zoton for ZES during pregnancy is safe and effective.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Anti-Ulcer Agents; Female; Gastrinoma; Gastrins; Humans; Infant, Newborn; Lansoprazole; Male; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Zollinger-Ellison Syndrome

Topics: Autoimmune Diseases; Diagnosis, Differential; Duodenal Neoplasms; Early Diagnosis; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors i

Topics: Diagnosis, Differential; Duodenal Neoplasms; Esophagitis, Peptic; Gastric Acidity Determination; Gastrinoma; Gastrins; Humans; Pancreatic Neoplasms; Peptic Ulcer; Proton Pump Inhibitors; Zollinger-Ellison Syndrome

Correct localisation of pancreatic gastrinomas by endoscopic ultrasound seems to be possible in most cases. However, success rate in the duodenal wall is disappointing, even if the examination is performed under optimal circumstances by a very experienced examiner. Nevertheless, in certain conditions endoscopic ultrasound may yield important information, besides detection of the primary tumor for example about structures suspected to be metastases in the region of the gastrinoma triangle.

Topics: Diagnosis, Differential; Duodenal Neoplasms; Duodenum; Endosonography; Equipment Design; Gastrinoma; Gastrins; Humans; Pancreas; Pancreatic Neoplasms; Sensitivity and Specificity; Transducers

Topics: Cell Transformation, Neoplastic; Enterochromaffin-like Cells; Gastric Acid; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Iatrogenic Disease; Proton Pump Inhibitors; Risk Assessment; Stomach Neoplasms; Zollinger-Ellison Syndrome

Patients with a gastrinoma are treated with proton pump inhibitors (PPI) and histamine type-2 receptor antagonists (H2). In order to diagnose a gastrinoma these drugs must be discontinued, but this increases the risk of gastrointestinal perforation. We aimed to determine if a gastrinoma could be diagnosed without cessation of PPI/H2 therapy.. In all, 90 patients (controls and patients diagnosed with a gastrinoma both on and off PPI/H2 therapy) were recruited, and plasma gastrin measured.. Patients with a gastrinoma on PPI/H2 medication had a significantly higher fasting plasma gastrin concentration than control patients on PPI/H2 medication (298+/-33 versus 204+/-30 pmol/L, P = 0.01). However, there was substantial overlap between gastrin levels in these two groups.. This study confirms that a gastrinoma cannot be diagnosed on the basis of a fasting plasma gastrin assay while patients remain on PPI/H2 therapy.

Topics: Aged; Female; Gastrinoma; Gastrins; Histamine H2 Antagonists; Humans; Male; Middle Aged; Pancreatic Neoplasms; Proton Pump Inhibitors

Type 1 and type 2 diabetes are characterised by a beta cell deficit. Islet hyperplasia has been described in patients with Zollinger-Ellison syndrome secondary to gastrin-producing tumours (gastrinomas), and gastrin therapy has increased beta cell mass in rodents and human islets in vitro. In the present studies we addressed the following questions: (1) In pancreas specimens from gastrinoma cases, is the fractional beta cell area increased? (2) If so, is this restricted to tumour-adjacent islets or also present in tumour-distant islets? (3) Is new beta cell formation (beta cell replication and islet neogenesis) increased and beta cell apoptosis decreased in pancreas specimens from gastrinoma cases?. Pancreas was obtained at surgery from four patients with Zollinger-Ellison syndrome caused by pancreatic gastrinomas and 15 control subjects at autopsy.. Islet fractional beta cell area (p<0.001), islet size (p<0.001) and beta cell replication (Ki67 staining) (p<0.05) were increased in islets adjacent to the tumours, but not in tumour-distant pancreas, compared with control subjects. We did not observe any differences in beta cell apoptosis or in the number of insulin-positive cells in ducts either adjacent to or distant from the tumour.. One or more factors released by human gastrinomas increase beta cell replication in islets immediately adjacent to the tumour, but not in tumour-distant islets. While these findings demonstrate that adult human beta cells can be driven into the cell cycle, they caution against the therapeutic usefulness of gastrin, since islets located >1 cm away from the gastrinomas did not exhibit changes in beta cell turnover, despite markedly elevated systemic gastrin levels sufficient to cause severe gastrointestinal symptoms.

Topics: Body Mass Index; Cell Division; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Gastrinoma; Gastrins; Humans; Insulin-Secreting Cells; Islets of Langerhans; Middle Aged; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The preoperative localization of gastrinomas often fails despite all modern imaging methods. Therefore, after biochemical confirmation of the diagnosis and exclusion of diffuse metastases, a meticulous surgical exploration including intraoperative ultrasound (IOUS) and duodenal exploration after duodenotomy should be performed. The experienced surgeon will be able to identify more than 90% of the primary tumors. Depending on the localization, excision of the tumor in the duodenal wall or enucleation from the pancreatic head should be performed. If the tumor is localized in the tail of the pancreas, distal pancreatectomy is the treatment of choice. Complete resection of the tumor is the only curative approach for the patients. For MEN-1 gastrinomas a spleen-preserving distal pancreatectomy with enucleation of tumors of the pancreatic head and duodenotomy with excision of duodenal gastrinomas should be performed. If the source of gastrin secretion can be regionalized to the pancreatic head by a preoperative SASI angiography, a pylorus-preserving partial pancreaticoduodenectomy might be the treatment of choice.

Topics: Adult; Aged; Chromosomes, Human, Pair 11; Duodenal Neoplasms; Endosonography; Female; Follow-Up Studies; Gastrinoma; Gastrins; Genes, Dominant; Germ-Line Mutation; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pancreaticoduodenectomy; Reoperation; Secretin; Stomach Neoplasms; Survival Rate; Zollinger-Ellison Syndrome

Topics: Adult; Antibodies; Enzyme-Linked Immunosorbent Assay; Female; Gastrin-Secreting Cells; Gastrinoma; Gastrins; Humans; Male; Pancreatic Neoplasms; Radioimmunoassay

Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder with characteristic features of skin and central nervous system involvement. Gastrointestinal involvement is rare, but the risk of malignancy development is considerable. Zollinger-Ellison syndrome is caused by gastrin-secreting tumors called gastrinomas. Correct diagnosis is often difficult, and curative treatment can only be achieved surgically.. A 41-year-old female affected by neurofibromatosis type 1 presented with a history of recurrent epigastric soreness, diarrhea, and relapsing chronic duodenal ulcer. Her serum fasting gastrin level was over 1000 pg/mL. An abdominal CT scan revealed a 3 x 2-cm, well-enhanced mass adjacent to the duodenal loop. She was not associated with multiple endocrine neoplasia type 1. Operative resection was performed and gastrinoma was diagnosed by immunohistochemical staining. The serum gastrin level decreased to 99.1 pg/mL after surgery, and symptoms and endoscopic findings completely resolved without recurrences.. Gastrinoma is difficult to detect even in the general population, and hence symptoms such as recurrent idiopathic peptic ulcer and diarrhea in neurofibromatosis type 1 patients should be accounted for as possibly contributing to Zollinger-Ellison syndrome.

Topics: Adult; Biopsy; Endoscopy; Female; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Neurofibromatosis 1; Proto-Oncogene Proteins c-kit; Tomography, X-Ray Computed; Treatment Outcome; Zollinger-Ellison Syndrome

A five-year-old male Shih-Tzu dog presented with severe vomiting and weight loss. The clinical signs were successfully improved by an eight-day treatment with an H(2)-receptor antagonist, gastrointestinal protectant and antibiotics. Ten days later, however, recurrence of vomiting was seen despite continuous medical treatment. Based on clinical signs and the results of various diagnostic tests including CBC, biochemical analysis, contrast radiography, and endoscopy, a duodenal or pancreatic neoplasm was suspected and exploratory laparotomy was conducted. Some swollen pancreatic regions were found, and biopsy of the pancreas indicated the diagnosis of a gastrin-secreting tumor. Consequently, based on a high serum gastrin level as well as clinical signs and immunohistological findings, we diagnosed the disease as canine gastrinoma, a rare tumor of the pancreas.

Topics: Animals; Dog Diseases; Dogs; Gastrinoma; Gastrins; Immunohistochemistry; Laparotomy; Pancreas; Pancreatic Neoplasms; Radiography

On July 2000, 127 gastrinomas (31.1%) were studied by the Endocrine Tumour Group (GTE) using a 408-patient cohort of Multiple Endocrine Neoplasia Type 1 patients. The aim of this study was to assess clinical, biological, surgical data as well as their trends over three periods (<1980-1980/1989->1990). A Zollinger-Ellison syndrome (SZE) was present in 96% of the cases. Mean age at the onset of the disease was 39.4 years. There were 55.9% of men. Synchronous liver metastasis was present in 7.1%. Taken independently, the positivity of the four main diagnosis tests decreased over the time. The diagnosis of oesophagitis increased (4.5-29.7%), as well as the size of the resected tumours (9.9-16.8 mm). There was an increase in the familial background diagnosis (73.1-80%), an increasing use of Octreoscan scintigraphy and transduodenal ultrasound with positive detection of metastasis and tumours in 81.3% and 92.3%, respectively after 1991. Patients were operated on less frequently (96-52.5%), less frequently from the pancreas (87.5-37.5%), and from the gastro-intestinal tract (70.8-30%). The relative percentage of major pancreatic resections increased (with at least removal of the duodenum and the pancreatic head) (10-26.7%). The operative mortality disappeared. Six out of the seven patients (85.7%) who benefited from major pancreatic resections normalized their gastrine level postoperatively versus 15% in less radical techniques. Overall 5 years survival was 90 +/- 4.4%. Survival increased after 1985 (85 +/- 4.8% versus 95 +/- 3.6, P = 0.1).. SZE in NEM1 were diagnosed at an earlier stage and were less frequently operated on. Nevertheless, the incidence of synchronous metastasis did not change significantly. Patients were mainly operated on for gastric emergencies and pancreatic tumours in order to prevent metastasis without mortality after 1991.

Topics: Adult; Aged; Aged, 80 and over; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prognosis

The dog of this case was a 10-year-old Shih Tzu with refractory vomiting, diarrhea and anorexia. Endoscopy revealed an unclear at gastric angle, a stenosis at pyloric antrum and congestion in duodenal mucosa. Since abnormal shadows of irregular echo-levels were disclosed by pancreas ultrasonography, serum gastrin level was determined with a suspect of gastrinoma. And an increase of serum gastrin was demonstrated. In addition, postmortem histological examination revealed that the pancreatic cells were positive for gastrin. Based on these findings, the dog was diagnosed as pancreatic gastrinoma.

Topics: Animals; Blood Chemical Analysis; Dog Diseases; Dogs; Endoscopy, Digestive System; Gastrinoma; Gastrins; Gastrointestinal Tract; Immunohistochemistry; Pancreas; Pancreatic Neoplasms; Ultrasonography

Hypergastrinemia in patients with pernicious anemia is a major regulator contributing to enterochromaffin-cell hyperplasia and, ultimately, to gastric carcinoids.. Between 1990 and 2003, we studied 8 women and 10 men with pernicious anemia and gastric carcinoids; their mean age was 50 years. Serum gastrin levels ranged from 740 to 4,000 pg/mL (mean 1,000 pg/mL). Six patients underwent antrectomy, four total gastrectomy, and eight endoscopic resection or biopsy. During the same period, 22 patients with Zollinger-Ellison tumors and hypergastrinemia (20 men and 2 women, mean age 49 years) had no gastric carcinoids, but 1 of 7 patients with Zollinger-Ellison and multiple endocrine neoplasia (MEN1) tumors had hypergastrinemia and gastric carcinoids.. Mean followup for pernicious anemia patients was 6 years after antrectomy and 1 to 10 years after endoscopic resection or biopsy. Tumor regression was observed in one patient after antrectomy and one patient after biopsy. There were no deaths in this group in spite of lymph node metastasis in two patients. The patient with Zollinger-Ellison and MEN1 syndrome has been followed 3 years after diagnosis and 2 years after total gastrectomy.. Gastric carcinoids are indolent tumors occurring with increasing frequency in patients with pernicious anemia. Antrectomy or biopsy and observation are preferred methods of treatment. Total gastrectomy is reserved for patients with extensive tumor involvement of the gastric wall or for emergency bleeding.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Pernicious; Biopsy; Carcinoid Tumor; Female; Gastrectomy; Gastric Mucosa; Gastrinoma; Gastrins; Gastroscopy; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Retrospective Studies; Stomach Neoplasms; Zollinger-Ellison Syndrome

To analyze the results of a prospective study of 176 patients with Zollinger-Ellison syndrome (ZES) (138 sporadic, 38 MEN1) undergoing 207 operations over a 17-year period.. The existence of lymph node (LN) primary gastrinoma causing ZES is controversial.. Three groups of patients were compared: LN only resected, cured, and no relapse (likely LN primary); same criteria but relapse (unlikely LN primary); and duodenal primary and LN metastases (Duo-LN).. Forty-five (26%) had only LN(s) as the initial tumor found. Twenty-six of the 45 (58%) fit the definition of a likely LN primary because they were apparently cured postresection. At 10.4 +/- 1.2 years, 69% of the 26 patients with likely LN primary tumors have remained cured and have LN primaries. In the 8 of 26 with recurrent ZES, it occurred at 5 +/- 1 years, and 3 had duodenal gastrinoma that had been missed. Ten percent (13/138) of all patients with sporadic ZES and 0% (0/38) with ZES and MEN1 remained cured with only a LN tumor removed. In patients with sporadic gastrinomas no clinical, laboratory, or radiographic localization feature differed among patients with likely LN primary (n = 16) and those with unlikely LN primary (n = 6) or those with Duo-LN (n = 37). In the likely LN primary group, the largest LN was 2.2 +/- 0.2 cm, the number of LNs removed was 1.3 +/- 0.1 (25% > or =1 LN), and 78% were in the gastrinoma triangle, which also did not differ from the other 2 groups. Disease-free survival was similar in the likely LN primary group, patients with Duo-LN, and those with pancreatic primaries.. These results support the conclusion that primary LN gastrinomas occur and are not rare (approximately 10% of sporadic cases). These results suggest that a proportion (25%) of these tumors are either multiple or malignant. Because no clinical, laboratory, or tumoral characteristic distinguishes patients with LN primary tumors, all patients with ZES undergoing surgery should have an extensive exploration to exclude duodenal or pancreatic tumors and routine removal of lymph nodes in the gastrinoma triangle.

Topics: Adult; Diagnostic Techniques, Endocrine; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Lymphoma; Male; Middle Aged; Pancreatic Neoplasms; Predictive Value of Tests; Prospective Studies; Zollinger-Ellison Syndrome

Topics: Enterochromaffin Cells; Gastrinoma; Gastrins; Humans; Pancreatic Neoplasms

The Zollinger-Ellison syndrome consists of severe peptic ulceration, acid hypersecretion, and islet tumors known as gastrinomas. The discovery of gastrinomas in unusual locations such as lymph nodes, bones, ovaries, and the liver poses a diagnostic dilemma as to whether the tumor is primary or metastatic. Here we present a case of a primary gastrinoma within a lymph node.

Topics: Abdominal Pain; Aged; Biopsy; Gastrinoma; Gastrins; Humans; Jejunum; Lymph Nodes; Male; Peptic Ulcer Perforation; Treatment Outcome; Zollinger-Ellison Syndrome

Assessment of tumor burden changes is essential for the management of patients with neuroendocrine gastrointestinal (GI) tumors. Chromogranin A (CgA) is a tumor marker for such tumors; however, to the authors' knowledge, there is little information on whether serial assessments can assess changes in tumor burden. In this prospective study of patients with gastrinomas, serial changes in serum CgA levels were compared with changes in levels of the specific tumor marker gastrin to determine whether they reflected changes in tumor burden.. In 72 consecutive patients, the mean CgA and gastrin levels from three determinations were measured on each visit. Changes in markers were correlated with changes in tumor burden determined by imaging. By assessing daily changes, significance changes in CgA and gastrin levels were determined.. During 103 follow-up visits (mean, 9.6 months), an increased tumor size occurred in 25% of patients, no change occurred in 62% of patients, and a decrease occurred in 13% of patients. In patients who had increasing tumor size, CgA levels increased numerically in 77% of patients, gastrin levels increased in 54% of patients, and the increases were significant in 60-80% of patients. In patients who had tumor stabilization, CgA levels in 63% of patients and gastrin levels in 73% of patients did not show a significant change. Decreased tumor size postresection showed a significant decrease in CgA and gastrin levels in all patients. The sensitivity of CgA and gastrin was as follows: sensitivity for detecting an increase, 62% for CgA and 31% for gastrin; sensitivity for detecting no change, 42% for CgA and 75% for gastrin; and sensitivity for detecting a decrease in tumor size, 85% for CgA and 85% for gastrin. The specificity varied from 53% to 99% for CgA and from 49% to 93% for gastrin.. In patients with gastrinomas, serum CgA and gastrin levels varied considerably from day to day, and this must be taken into consideration. Both markers had low sensitivity and specificity for detecting tumor increases and stabilization. For large tumor decreases postresection, both markers had high sensitivity and specificity. The current results suggest that these markers do not have sufficient sensitivity to replace serial imaging studies for detecting important smaller changes in tumor burden in patients with gastrinomas.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chromogranin A; Chromogranins; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Sensitivity and Specificity; Zollinger-Ellison Syndrome

Topics: Cell Division; Chronic Disease; Enterochromaffin Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Histamine; Humans; Hyperplasia; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Topics: Adolescent; Biopsy; Diagnosis, Differential; Duodenal Ulcer; Endoscopy, Gastrointestinal; Gastrinoma; Gastrins; Hepatectomy; Humans; Liver; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Pancreatectomy; Peptic Ulcer Hemorrhage; Peptic Ulcer Perforation; Reoperation; Splenectomy

Topics: Adult; Gastrinoma; Gastrins; Humans; Middle Aged; Monitoring, Intraoperative; Radioimmunoassay

Gastrinomas are located more frequently in the pancreas, which normally has no cells that can produce gastrin. They have a more aggressive course than other pancreatic endocrine tumors and extrapancreatic gastrinomas associated with multiple endocrine neoplasia Type 1 syndrome. The current study analyzed immunophenotypes of gastrinomas and compared them with other pancreatic endocrine tumors.. Twenty-one formalin-fixed, paraffin-embedded specimens (15-tumors in the pancreas, 1 in the duodenum, 1 in the stomach, 1 in the liver, and 3 of unknown primary location) accompanied by Zollinger-Ellison syndrome and 17 other pancreatic endocrine tumor specimens were investigated. They were stained immunohistochemically for gastrin, chromogranin A, synaptophysin, insulin, glucagon, somatostatin, pancreatic polypeptide, calcitonin, serotonin, chorionic gonadotropin, adrenocorticotropic hormone, carcinoembryonic antigen, epithelial membrane antigen, and cytokeratin 19.. Gastrinomas coexpressed neuroendocrine and exocrine markers, including chromogranin A, synaptophysin, carcinoembryonic antigen, cytokeratin 19, and epithelial membrane antigen. Carcinoembryonic antigen was found in all 17 gastrinomas (100%), cytokeratin 19 was found in 15 of 17 (88.2%) gastrinomas, and epithelial membrane antigen was found in 16 of 18 (88.9 %) gastrinomas. Cytokeratin 19, epithelial membrane antigen, and carcinoembryonic antigen were not found to be present in the pancreatic endocrine tumors, but chromogranin A and synaptophysin were. Chorionic gonadotropin was found in 16 gastrinomas (100%), but only in 2 of 17 other pancreatic endocrine tumors (11.8 %).. Pancreatic gastrinomas were characterized by the coexpression of neuroendocrine markers, exocrine markers, and chorionic gonadotropin. Therefore, pancreatic gastrinomas made a special intermediate group of tumors, which phenotypically combined features of neuroendocrine and exocrine neoplasms. These findings suggested that sporadic pancreatic gastrinomas and other pancreatic endocrine tumors are different phenotypically and are possibly of different origin.

Topics: Adolescent; Adrenocorticotropic Hormone; Carcinoembryonic Antigen; Female; Gastrinoma; Gastrins; Gastrointestinal Neoplasms; Humans; Immunohistochemistry; Immunophenotyping; Lymphatic Metastasis; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms

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

Preoperative localisation is important for successful surgical treatment of gastrinomas. However, a satisfactory method that achieves this has not been defined, and at present somatostatin receptor scintigraphy and selective intra-arterial stimulation testing with secretin have the greatest sensitivities. As secretin is now difficult to obtain, we decided to explore the use of calcium gluconate as a secretagogue. High extracellular calcium concentrations cause degranulation of neuroendocrine cells and subsequent release of hormone.. Two patients with biochemically proven gastrinomas were investigated pre-operatively. Under angiographic control calcium gluconate was injected into the arteries supplying the pancreas and duodenum, gastrin levels were then determined in hepatic vein samples obtained before and 30, 60, 90, 120 and 180 seconds after each injection. One of the patients had also previously undergone selective intra-arterial stimulation testing with secretin.. Calcium gluconate produced sharp peaks of gastrin which unequivocally localised the tumour to a specific vascular territory in each case. Furthermore, surgery confirmed the localisations of the gastrinomas. Calcium injection, unlike secretin, into vascular territories without gastrinomas caused no rise in gastrin, thereby demonstrating calcium's greater specificity.. Calcium gluconate is a highly sensitive and specific alternative secretagogue to secretin for localisation of pancreatic and duodenal gastrinomas. Furthermore calcium gluconate was found to demonstrate the territory of the tumour more accurately than secretin.

Topics: Adult; Angiography; Calcium Gluconate; Duodenal Neoplasms; Duodenum; Female; Gastrinoma; Gastrins; Hepatic Veins; Humans; Injections, Intra-Arterial; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreas; Sensitivity and Specificity

H. pylori is a major cause of primary chronic gastritis and peptic ulcer disease in children. The authors give an account of H. pylori infection (cagA+, vacA+) in a 15-year-old girl where the initial clinical features included fatigue, collapses, and anorexia, elevated serum gastrin level (> 1000 mIU/l) raised the suspicion of gastrinoma. H. pylori gastric infection was also associated with iron-deficiency anemia. After treatment for H. pylori infection (omeprazole, clarithromycin, amoxycillin), clinical symptoms improved consistently, the serum gastrin level was repeteadly quite normal and hematologic and iron profiles were within the normal range. There is compelling evidence that H. pylori must be taken into account as a cause of hypergastrinemia other than gastrinoma in childhood.

Topics: Adolescent; Anemia, Iron-Deficiency; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Pancreatic Neoplasms

Topics: Adult; Diagnosis, Differential; Duodenal Ulcer; Female; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Proton Pump Inhibitors

Malignant pancreatic endocrine tumors (PETs) have a poor prognosis and existing antitumor treatments are unsatisfactory. Recent studies have shown somatostatin analogues to have antitumor growth effects in patients with malignant PETs; however, to the authors' knowledge, little information exists regarding their efficacy or effect on survival in patients with progressive malignant gastrinoma, the most common symptomatic malignant PET. The purpose of the current study was to study prospectively the efficacy, safety, and effect on survival of long-term treatment with octreotide in consecutive patients with progressive malignant gastrinoma.. Fifteen consecutive patients with malignant gastrinoma with progressive hepatic metastases were studied. All patients underwent conventional imaging studies (computed tomography scan, magnetic resonance imaging, ultrasound, and, if needed, selective angiography) and somatostatin receptor scintigraphy prior to treatment and at 3-6-month intervals while receiving treatment. The patients all were treated initially with octreotide, 200 microg every 12 hours, and at last follow-up were being maintained on long-acting release octreotide, 20-30 mg every month. Tumor size and/or number were used to classify patient responses as either no tumor response or tumor response (stabilization or decrease in size). Treatment response was correlated with tumor and clinical characteristics.. Tumors in 8 of the 15 patients studied (53%) responded at 3 months, with 47% (7 of 15 patients) demonstrating tumor stabilization and 6% (1 of 15 patients) demonstrating a decrease in tumor size. The mean duration of response was 25.0+/-6.1 months (range, 5.5-54.1 months). Six of the eight responders were continuing to respond at the time of last follow-up. Tumor response did not correlate with any clinical parameter (e.g., tumor extent, fasting gastrin, or acid secretory rates). However, slow-growing tumors were more likely to respond prior to treatment (86% vs. 0%) (P < 0.0014). During follow-up (range, 4-8 years), 25% of the responders died compared with 71% of the nonresponders, a difference that approached statistical significance (P = 0.10). Two patients (13%) developed serious side effects that required the withdrawal of octreotide.. Octreotide is an effective antitumor treatment in patients with progressive malignant gastrinoma. In approximately 50% of these patients octreotide has an antigrowth effect; treatment is associated with a low incidence of serious side effects compared with other antitumor treatments commonly used and, in contrast to many studies, the growth response is long-lasting. The results of the current study suggest that octreotide treatment should replace chemotherapy as the standard treatment for these patients, especially those patients with slow-growing tumors. Additional studies involving larger numbers of patients will be needed to determine a convincing effect on survival.

Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Disease Progression; Female; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Octreotide; Pancreatic Neoplasms; Predictive Value of Tests; Prospective Studies; Receptors, Somatostatin; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

A 55-year-old woman, known with multiple endocrine neoplasia (MEN) type 1, had rectal bleeding and later haematemesis but colonoscopy and gastroduodenoscopy revealed no abnormalities. Due to the normal results for serum gastrin concentration, gastroduodenoscopy and CT scanning of the pancreas, Zollinger-Ellison syndrome was considered to be less likely. Yet the diagnosis could be established on the basis of persistent symptoms and a positive somatostatin receptor scintigraphy. The patient was treated with high doses of a proton pump inhibitor and temporary tube feeding due to weight loss. Follow-up will take place at the endocrinology outpatients' department. Zollinger-Ellison syndrome is a relatively common feature of patients with MEN-1. The diagnosis and localisation of the gastrinoma can be difficult: serum gastrin concentrations can be normal and the sensitivity of CT scanning is low. The primary aim of treating gastrinoma is to control gastric acid hypersecretion by means of high doses of a proton pump inhibitor. The question as to whether surgery is indicated remains controversial.

Topics: Decision Making; Female; Gastrinoma; Gastrins; Hemorrhage; Humans; Middle Aged; Multiple Endocrine Neoplasia Type 1; Proton Pump Inhibitors; Rectal Diseases; Zollinger-Ellison Syndrome

The effect of chronic hypergastrinemia alone on gastric enterochromaffin-like (ECL) cells in humans is largely unknown because in the common chronic hypergastrinemic states (atrophic gastritis, chronic proton pump inhibitor use), it is not possible to separate the effect of hypergastrinemia and other factors, such as gastritis or atrophy. Studies of patients with sporadic Zollinger-Ellison syndrome (ZES) allow this separation.. In 106 patients with ZES, gastric biopsies were taken, and the qualitative ECL cell pattern/grade and the alpha-subunit of human chorionic gonadotropin (alpha-hCG) expression were determined.. In patients with active disease, 99% had ECL hyperplasia and abnormal alpha-hCG staining. Fifty percent had advanced changes in both of these, with 7% having dysplasia and 0% having carcinoids. Advanced ECL cell and alpha-hCG changes were most affected by the level of hypergastrinemia. For ECL cell changes, even mild hypergastrinemia had an effect. Advanced ECL change was also affected by the duration of drug treatment, cure status, and presence of atrophic gastritis, but not by sex or previous vagotomy. The alpha-hCG expression independently predicted dysplasia.. In humans, chronic hypergastrinemia alone causes advanced ECL cell change and abnormal expression of mucosal alpha-hCG. No threshold for this effect was detected, as reported by some, and in contrast to animal studies, sex and vagal tone did not play a major role. The long-term risk of developing gastric carcinoids with chronic hypergastrinemia is low in patients with sporadic gastrinomas (at least 100 times less than in patients with multiple endocrine neoplasia type 1 with ZES) for at least 15-20 years.

Topics: Adolescent; Adult; Aged; Child; Chronic Disease; Enterochromaffin Cells; Female; Gastric Mucosa; Gastrinoma; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Hyperplasia; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Zollinger-Ellison Syndrome

Topics: Adult; Biopsy, Needle; Calcinosis; Carrier State; Female; Gastrinoma; Gastrins; Hepatitis B; Humans; Immunohistochemistry; Liver Neoplasms; Tomography, X-Ray Computed

Chromogranin A (CgA) is a sensitive marker for neuroendocrine neoplasia. Enterochromaffin-like cell hyperplasia secondary to hypergastrinemia also leads to CgA increase in blood. Treatment with inhibitors of acid secretion, atrophic gastritis and infection with Helicobacter pylori are prevalent conditions leading to hypergastrinemia. We therefore wanted to study whether concomitant determination of gastrin could increase the utility of CgA as a marker of neuroendocrine neoplasia.. CgA and gastrin concentrations were determined by radioimmunoassay methods, while pepsinogen I (used to diagnose severe atrophic gastritis) was determined by a commercial immunoenzymatic assay.. Among 100 patients with elevated CgA, we found that 29% had hypergastrinemia. Vice versa, CgA was elevated in 23 out of 26 (88.5%) in a population of patients with hypergastrinemia. By determining pepsinogen I in blood in patients with hypergastrinemia, a proportion of them was diagnosed as having severe atrophic gastritis.. We conclude that determination of gastrin in blood in patients with CgA elevation will increase the utility of CgA in the diagnosis of neuroendocrine tumors.

Topics: Biomarkers, Tumor; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis, Atrophic; Humans; Hyperplasia; Immunoenzyme Techniques; Neuroendocrine Tumors; Pepsinogen A; Radioimmunoassay; Stomach; Stomach Neoplasms

The intravenous calcium injection test has been reported to be useful for the diagnosis of gastrinoma. However, the mechanism underlying calcium-evoked gastrin release is not fully understood. We investigated the mechanism of calcium-stimulated gastrin release from gastrinoma cells in vitro with a particular focus on the calcium-sensing receptor (CaR). Human gastrinoma cells were taken from mechanically minced gastrinoma tissues obtained at surgery. In the perifusion system, high [Ca2+]o induced gastrin release from gastrinoma cells. As [Ca2+]o increased, [Ca2+]i rapidly increased, as monitored by fluorometry. The response was not inhibited by nifedipine, a blocker of the voltage-dependent calcium channel. Reverse transcriptase-polymerase chain reaction and subsequent Southern blot hybridization revealed the presence of the CaR gene in human gastrinoma tissues. Moreover, the expression of CaR in gastrinoma tissues was confirmed by immunohistochemistry. Our results demonstrated that CaR was expressed in human gastrinoma cells and could be involved in the mechanism of calcium-evoked gastrin release.

Topics: Blotting, Southern; Calcium; Calcium Chloride; Dose-Response Relationship, Drug; Fluorescent Antibody Technique, Indirect; Fura-2; Gastrinoma; Gastrins; Humans; Nifedipine; Pancreatic Neoplasms; Receptors, Calcium-Sensing; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

To ascertain the frequency and the clinico-functional correlations of intramucosal cysts in the gastric body of patients with the Zollinger-Ellison syndrome (ZES) and to clarify the relevant mechanism of development, a total of 106 consecutive ZES patients (58 M, 48 F; mean age: 53 yrs, range 19-93 yrs) were investigated with a mean of 7.2 biopsy specimens of the body mucosa per patient proved to be suitable for the study. Biopsies of endoscopically detectable polypoid lesions were not considered. Cystic changes were evaluated with respect to their severity by assessing the cyst grade (0, absent, 1; <30%, 2; 30-60%; 3 >60% of the mucosal area of the biopsy specimen of individual patients showing the most pronounced finding, respectively) and to their intragastric distribution by assessing the ratio of biopsy specimens showing cystic changes over the total number of biopsies examined in each patient. Intramucosal cysts were found in biopsies of non-polypoid gastric body mucosa in 71.7% of 106 patients with Zollinger-Ellison syndrome (ZES) and showed grade 2 and 3 severity in 22 and 8 cases, respectively. The severity of cystic changes correlated with the gastrin levels (p = 0.0005) and was more advanced in patients with active than in those with cured disease (p = 0.037). In the former group, furthermore, advanced cystic changes correlated with age (p = 0.03), male gender (p = 0.014), years of disease from onset (p < 0.02), years of omeprazole treatment (p = 0.033), basal acid output (p < 0.02), severity of ECL cell proliferative changes (p = 0.028), and absence of previous gastrinoma resection (p = 0.039) whereas they did not correlate with MEN-1 status, gastritis, maximal acid output, total duration of any antisecretory drug treatment, daily doses of omeprazole (> 20 mg vs 20 mg), years from surgery, duodenal localization of gastrinoma(s), presence of gastric carcinoid tumor(s) and of liver metastases. In groups of patients subdivided according to three levels of serum gastrin, the duration of omeprazole treatment was not related to the severity of cystic changes. It is concluded that intramucosal cysts in non polypoid gastric body mucosa of ZES patients are by far more common than the already reported fundic gland polyps, to which they likely give raise. Circulating levels of gastrin have an important independent role in their development.

Topics: Adult; Aged; Aged, 80 and over; Aging; Biopsy; Cell Division; Cysts; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Omeprazole; Sex Characteristics; Stomach; Stomach Neoplasms; Zollinger-Ellison Syndrome

The term primary lymph node gastrinoma was first used to describe a group of patients with gastrin-producing tumors present in lymph nodes located in a well-defined anatomic region. The patients had no known primary tumors in the pancreas or gastrointestinal tract and had disease-free survival for up to 18 years. The anatomic region in question has a triangular shape that extends from the cystic and common bile ducts to the second and third portion of the duodenum and the neck and body of the pancreas. The term gastrinoma triangle was coined to identify the area; in addition, it was postulated that lymph nodes located in the gastrinoma triangle normally contained neuroendocrine cells capable of secreting gastrin and other neuropeptides. From its inception, the postulate became the subject of controversy.. To extend previous observations, we examined the lymph nodes located in the gastrinoma triangle of 20 autopsy cases for the presence of neuroendocrine cells, as determined by immunohistochemistry, using antibodies to a panneuroendocrine substance (eg, synaptophysin) and a specific neuropeptide (eg, gastrin). Scanning for positive cells was performed by 2 observers (M.E.H. and M.C.C.). We compared the findings in these lymph nodes with lymph nodes obtained from axillary and inguinal dissections during surgical procedures.. In all, 417 lymph nodes were studied. Five of the 20 gastrinoma triangle cases contained synaptophysin reactive cells, whereas 3 had gastrin reactive cells. None of the axillary and inguinal lymph nodes contained neuroendocrine cells.. Our findings support the hypothesis of entrapment of neuroendocrine cells during development and the presence of primary nodal gastrinomas.

Topics: Adult; Aged; Aged, 80 and over; Autopsy; Cause of Death; Female; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Observer Variation; Pancreatic Neoplasms; Synaptophysin

Gastrinoma is a rare endocrine tumor that is frequently associated with liver metastasis. The liver metastasis is usually seen simultaneously or soon after a primary operation. A 47-year-old woman who had had a total gastrectomy 20 years earlier developed liver metastasis. An interval of this length between surgery and metastasis is extremely rare. The total gastrectomy prevented the patient from developing the usual symptoms of hypergastrinemia that would have enabled early diagnosis of the metastasis. Laboratory examinations on admission revealed a high serum gastrin concentration (1500 pg/ml). Computed tomography showed an irregularly enhanced mass lesion with an uneven, low-density central area in the right anterior inferior segment of the liver. An extended right hepatectomy was performed. Intraoperative ultrasonography showed no abnormalities in the remnant pancreas. Examination of the cut surface of the specimen revealed a yellow, firm, elastic tumor, 55 mm in diameter. The interior of the tumor appeared necrotic. Histopathologically, the tumor was composed of cells with hyperchromatic, dysplastic nuclei arranged in a trabecular pattern with nest formation. Gastrin staining was positive. A histologic diagnosis of metastatic gastrinoma was made. The patient's gastrin concentration returned to normal and she was well at 2-year follow-up.

Topics: Female; Gastrectomy; Gastrinoma; Gastrins; Humans; Liver; Liver Neoplasms; Middle Aged; Stomach Neoplasms; Time Factors; Tomography, X-Ray Computed

Measurement of gastrin in serum or plasma in patients with gastrinoma may be complicated by the presence of circulating biosynthetic intermediates which may not be detected by commonly available immunoassays. In contrast, the "processing-independent analysis" of gastrins developed by professor Jens Rehfeld et al in Copenhagen detects gastrin forms irrespective of their size. The authors review gastrinoma pathophysiology, the biochemistry of gastrin and other biomarkers of gastrinoma, the differential diagnosis of hypergastrinemia as well as other methods currently employed in the workup of gastrinoma patients, and illustrate with a clinical case.

Topics: Biomarkers, Tumor; Diagnosis, Differential; Gastrinoma; Gastrins; Humans; International Cooperation; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Practice Guidelines as Topic; Prostatic Neoplasms; Quality Assurance, Health Care; Radionuclide Imaging; Scandinavian and Nordic Countries

We describe herein the case of a 54-year-old Japanese woman in whom an inveterate peptic ulcer developed in association with pseudo-Zollinger-Ellison Syndrome (pseudo-ZES). The patient presented with weight loss and abdominal distension caused by antral and duodenal stenosis due to an inveterate peptic ulcer. Her serum gastrin level was very high; however, no evidence of a gastrinoma or carcinoid tumor was detected by preoperative examinations or surgery. A total gastrectomy and double-tract reconstruction was performed, and pathological examination revealed a gastric ulcer (UL-IV) with no histopathological evidence of a neoplasm. Immunohistochemical staining showed an obvious increase in the number of endocrine cells that were positive for chromogranin A, and marked G-cell hyperplasia was observed in the antral mucosa. Furthermore, the number of enterochromaffin-like cells was remarkably high. From the results of the immunohistochemical examination, the patient was diagnosed as having hypergastrinemia due to antral G-cell hyperplasia. Postoperatively, the patient's serum gastrin level fell rapidly to within the normal range, her nutritional status improved, and her weight increased by about 10 kg within 1 year.

Topics: Diagnosis, Differential; Female; Gastrectomy; Gastrin-Secreting Cells; Gastrinoma; Gastrins; Humans; Hyperplasia; Immunohistochemistry; Middle Aged; Peptic Ulcer; Pyloric Antrum; Treatment Outcome; Zollinger-Ellison Syndrome

The p16INK4a/CDKN2A gene (p16INK4a) is frequently altered by homozygous deletion, mutation, or methylation in many nonendocrine tumors, and these alterations may be predictive of recurrence, tumor growth, or aggressiveness. Whether this is true of neuroendocrine tumors such as gastrinomas is unclear. To address this question we analyzed the gastrinomas from 44 patients for p16INK4a gene mutations and correlated the results to the tumor's biological behavior, growth pattern, and aggressiveness. No gastrinomas had mutations of exon 1 or exon 2 of the p16INK4a gene, although polymorphisms were found in 54%. No homozygous deletions were found. In 52% of the gastrinomas, hypermethylation of a 5'-CpG island of the p16INK4a gene promoter was found. To assess the growth behavior of the gastrinomas, all patients were assessed yearly with at least three conventional imaging studies (computed tomography scan, magnetic resonance imaging, and ultrasound), and since 1994 have been assessed with radionuclide scanning using [111In-diethylenetriamine pentaacetic acid,DPhe1]octreotide. The mean follow-up was 5.1+/-0.4 yr (range, 1.2-11.7). The presence or absence of methylation of the p16INK4a gene did not correlate with clinical characteristics of the gastrinoma, biological behavior (gastrin release and basal or maximal acid output), the presence or absence of known prognostic factors (tumor size, gastrinoma location, lymph node metastases, liver metastases, and curability), or growth pattern of the gastrinoma postresection. These results indicate that methylation of the p16INK4a gene is the most common gene alteration described to date in gastrinomas. Furthermore, because it is independent of disease stage it is probably an early event in the pathogenesis and because it is independent of the primary gastrinoma location, which is now thought to have different origins, methylation of the p16INK4a gene is probably a central process in the molecular pathogenesis of these tumors.

Topics: Adolescent; Adult; Carrier Proteins; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; Duodenal Neoplasms; Exons; Female; Follow-Up Studies; Gastrinoma; Gastrins; Genes, Tumor Suppressor; Humans; Lymphatic Metastasis; Male; Middle Aged; Mutation; Neoplasms, Unknown Primary; Pancreatic Neoplasms; Polymorphism, Genetic; Radionuclide Imaging; Time Factors; Tumor Cells, Cultured

Medical treatment is the elective therapy for patients with gastrinoma when the tumor is not found at surgery or is unresectable or when there is a metastatic disease. H2-blockers and omeprazol are able to control gastric acid secretion and, in addition, somatostatin analogues decrease gastrin levels. A new long-acting and slow release formulation of a somatostatin analogue (lanreotide, SR-L) has been developed. We treated two patients suffering from gastrinoma, total gastrectomy and hepatic metastases with 30 mg intramuscular injections of SR-L every 15 and 10 days, respectively, for a seven-month period. After the treatment, gastrin levels decreased from 35,494 and 15,086 ng/l to 3,211 and 167 ng/l (92 and 98% below pre-treatment levels) in case 1 and 2 respectively, with a relief of symptoms and no side effects.

Topics: Adult; Antineoplastic Agents; Gastrectomy; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Injections, Intramuscular; Liver Neoplasms; Male; Middle Aged; Octreotide; Peptides, Cyclic; Somatostatin

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

Topics: Animals; Chromogranin A; Chromogranins; Enterochromaffin-like Cells; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia Type 1; Prospective Studies; Sensitivity and Specificity

Topics: Diagnosis, Differential; Echinococcosis, Hepatic; Follow-Up Studies; Gastrinoma; Gastrins; Hepatectomy; Humans; Liver Neoplasms; Male; Middle Aged; Phosphopyruvate Hydratase; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Hypergastrinaemia-associated changes of non-antral argyrophil cells in man are of increasing interest, because of the development of potent inhibitors of gastric acid secretion. Using an antibody against chromogranin A, we identified micronodular endocrine cell hyperplasia of the oxyntic mucosa in gastric biopsy specimens of patients with hypergastrinaemia of different backgrounds. Consecutive ultrathin sections were examined at the electron-microscopical level. Endocrine cell types within the (extraepithelial) micronodules closely resembled those in the adjacent mucosa. Micronodules were classified into two groups. The first group was composed of endocrine cells only and predominated in patients with drug-induced hypergastrinaemia and/or chronic gastritis, and in a gastrinoma/MEN I patient. The second group represented "neuroendocrine complexes", showing a close intermingling of non-myelinated nerve fibres with endocrine cells, and was found predominantly in pernicious anaemia. Micronodular argyrophil cell growth in man is therefore heterogeneous and depends on the background of the hypergastrinaemia.

Topics: Anemia, Pernicious; Cell Division; Cell Size; Gastric Mucosa; Gastrinoma; Gastrins; Gastritis; Humans; Microscopy, Electron; Neurosecretory Systems; Parietal Cells, Gastric

This study evaluates whether a new analytic principle, processing-independent analysis (PIA), offers better specificity and sensitivity than the conventional gastrin radioimmunoassay in the diagnosis of gastrinomas.. Plasma concentrations of alpha-amidated gastrins and the total progastrin product were measured with radioimmunoassay and with PIA, respectively, in 512 samples taken for gastrin measurement and in a selected group of gastrinoma patients (n=10).. Among the 512 patients were 9 with gastrinomas. In plasma from these patients the median degree of amidation (ratio of alpha-amidated gastrins to total progastrin product) was 75% (range, 25-98%), whereas in the other groups the medians varied from 41% to 86%. In the second group of gastrinoma patients all had a degree of amidation of less than 50%.. In screening for gastrinomas PIA offered no diagnostic advantages in comparison with conventional gastrin radioimmunoassay. However, in selected patients who in spite of normal or slightly increased concentrations of amidated gastrins were still suspected of having gastrinoma, additional measurement of the total progastrin product showed incomplete processing of progastrin and thus proved helpful in establishing the diagnosis.

Topics: Anti-Ulcer Agents; Case-Control Studies; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Peptic Ulcer; Protein Precursors; Radioimmunoassay; Sensitivity and Specificity; Zollinger-Ellison Syndrome

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

Gastrin has been shown to stimulate growth of human pancreatic cancer, and does so in an autocrine fashion. In this study, a relationship between gastrin mRNA, peptide, and gastrin receptors were studied in a variety of human pancreatic tissues. Low levels of gastrin mRNA were detected in normal human pancreas by quantitative reverse transcription polymerase chain reaction, but gastrin peptide was not present using radioimmunoassay. Pancreatic adenocarcinoma cells and tissues had 34- to 530-fold higher gastrin mRNA and peptide levels than normal pancreas. Gastrin mRNA and peptide levels were 8,000- and 15,000-fold, respectively, greater in a pancreatic islet cell gastrinoma tumor than in normal pancreas. In comparison to age-matched controls, fasting gastrin plasma levels were 2-fold higher in patients with pancreatic adenocarcinoma and 131-fold greater in subjects with gastrinomas. Receptor binding assays revealed that pancreatic cancer cells had a binding capacity 200-fold greater than gastrinoma tumors, and 10-fold greater than normal pancreas; no differences in K(d) values were recorded between specimens. In contrast to the normal pancreas and gastrinoma tumor, the aggressive behavior of pancreatic adenocarcinoma may be attributed to the autocrine production of gastrin and to the presence of its growth-related receptor.

Topics: Aged; Animals; Blotting, Northern; Cell Line, Tumor; Female; Gastrinoma; Gastrins; Humans; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Pancreas; Pancreatic Neoplasms; Radioimmunoassay; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transplantation, Heterologous

This report concerns a case of a Cushing's syndrome 10 years after first diagnosis of a Zollinger-Ellison syndrome within the same patient. In a 69-year-old female patient symptoms of hypergastrinaemia have been successfully treated with a proton pump inhibitor. Cushing's syndrome was the result of ectopic adrenocorticotropic hormone production by a large cystic gastrin-producing tumour of the pancreatic tail. After resection by subtotal pancreatectomy serum adrenocorticotropic hormone, cortisol, gastrin levels and secretin infusion test returned to normal. In contrast to all other previously published cases of ectopic adrenocorticotropic hormone syndrome associated with Zollinger-Ellison syndrome, this tumour had not metastasized into the liver and did not show local invasive growth.

Topics: Adrenocorticotropic Hormone; Aged; Anti-Ulcer Agents; Cushing Syndrome; Female; Gastrinoma; Gastrins; Humans; Hydrocortisone; Immunohistochemistry; Omeprazole; Pancreatectomy; Pancreatic Neoplasms; Radioimmunoassay; Zollinger-Ellison Syndrome

To improve the clinical diagnosis and treatment of gastrinoma.. Twelve cases of gastrinoma found in the recent 30 years in our hospital were analyzed.. The results indicated that in addition to the typical symptoms related to gastric acid overproduction, the frequency of certain uncommon features characteristic of the disease was unusually high in our hands i.e., (1) The majority of them (7/12) had serious diarrhea, even resulting in shock. (2) Multiple endocrine neoplasia type I (MEN) was in 3 out of 12 associated in our series. (3) Multiple nodules in the duodenum (3/12) were found and in two patients were shown to be submucosal gastrinoma confirmed by pathology. (4) Multifocal lesions were found in 9 out of 12 patients, and in 7 cases at least two organs were involved. Most gastrinomas were located in the pancreas, stomach and duodenum. (5) As reported by other authors, multiple hormone secretion was common: in five of six patients the tumor secreted more than two hormones. (6) In some cases, tumors were sensitive to chemotherapy.. In our series gastrinoma was found with the feature of multiple lesions and multiple hormone secretion in addition to the typical symptoms related to gastric acid overproduction.

Topics: Adolescent; Adult; Diarrhea; Duodenal Neoplasms; Duodenal Ulcer; Female; Gastrinoma; Gastrins; Humans; Insulinoma; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms

Topics: Animals; Dog Diseases; Dogs; Duodenum; Gastric Mucosa; Gastrinoma; Gastrins; Intestinal Mucosa; Male; Necrosis; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Gastrinomas in dogs are difficult to diagnose, localise and treat. In humans, somatostatin analogues have improved localisation and treatment of gastrinomas. The somatostatin analogues pentetreotide and octreotide were evaluated for the detection and treatment of gastrinoma in a dog. 111indium-pentetreotide scintigraphy revealed multiple areas of activity in the patient's mid-ventral abdomen which were consistent with masses in the pancreas and liver at laparotomy. Immunohistochemistry, electron microscopy and binding of 125I-[Tyr3]-octreotide in vitro confirmed the lesion as a gastrinoma which expressed somatostatin receptors. Octreotide at doses of 2, 4 and 8 micrograms/kg caused transient decreases in circulating gastrin. Plasma somatostatin peaked at one hour after octreotide and was still detectable at four and six hours after administration of octreotide. Combination therapy with famotidine, omeprazole, sucralfate and increasing doses of octreotide allowed patient survival for 14 months.

Topics: Animals; Anti-Ulcer Agents; Antineoplastic Agents, Hormonal; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Drug Therapy, Combination; Famotidine; Female; Gastrinoma; Gastrins; Immunohistochemistry; Indium Radioisotopes; Injections, Subcutaneous; Microscopy, Electron; Octreotide; Omeprazole; Pancreas; Pancreatic Neoplasms; Radioimmunoassay; Radionuclide Imaging; Receptors, Somatostatin; Somatostatin; Sucralfate

Topics: Aged; Contrast Media; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Image Processing, Computer-Assisted; Intubation, Gastrointestinal; Male; Pyloric Antrum; Receptors, Somatostatin; Stomach Neoplasms; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

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

To evaluate localization of hepatic metastases with the intraarterial secretin injection test in Zollinger-Ellison syndrome (ZES).. Results in 74 patients with ZES (aged 15-70 years) were retrospectively studied. All patients had undergone computed tomography (CT), magnetic resonance (MR) imaging, ultrasound, abdominal angiography, and an intraarterial secretin test, in which venous blood is sampled periodically after injection of secretin.. Twenty-two patients had liver metastases. An increase in venous gastrin concentration of at least 25% at 20 seconds or 50% at 30 seconds after injection indicated a positive result. Results were positive in 41% of patients with and 2% without liver metastases (P < .0001). Sensitivity of the intraarterial secretin test was 41%; of CT and ultrasound, 64%; and of MR imaging and angiography, 77%. Intraarterial secretin test results assisted in clinical management in 22% of patients.. With the criteria developed, the intraarterial secretin test had high specificity but low sensitivity. It should be used when imaging results are unclear.

Topics: Adolescent; Adult; Aged; Angiography; Female; Gastrinoma; Gastrins; Hepatic Artery; Hepatic Veins; Humans; Injections, Intra-Arterial; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Secretin; Sensitivity and Specificity; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Peptide YY (PYY) is a gut hormone localized primarily in the distal bowel. Because circulating PYY inhibits gastric acid secretion, we investigated the effects of gastric acid secretion and gastrin on gene expression and secretion of PYY. In conscious dogs, PYY release in response to oral food was inhibited (P < 0.05) by pharmacologic inhibition of gastric acid secretion (omeprazole, famotidine). In rats, omeprazole treatment resulted in a significant elevation in serum gastrin concentrations and a simultaneous decrease in PYY messenger RNA (mRNA) and peptide levels in the colon; administration of a gastrin receptor antagonist (L365, 260) prevented the inhibitory actions of omeprazole on colonic PYY mRNA levels. In athymic-nude mice, implantation of a human gastrinoma resulted in an elevation of serum gastrin concentrations and a concomitant depression of colonic PYY mRNA levels. We conclude that endogenous gastric acid secretion up-regulates PYY release and PYY mRNA expression. Circulating gastrin acts to down-regulate PYY release and PYY mRNA expression. This study provides evidence that foregut functions (i.e., gastric acid secretion and gastrin release) exert control over an antiacid signal (e.g. PYY release) emanating from the hindgut.

Topics: Animals; Dogs; Famotidine; Female; Gastric Acid; Gastrinoma; Gastrins; Gastrointestinal Hormones; Gene Expression; Homeostasis; Humans; Male; Mice; Mice, Nude; Omeprazole; Peptide YY; Peptides; Rats; Rats, Sprague-Dawley; RNA, Messenger

A rapid method for determining gastrin, quick gastrin, has been developed. Separation/washing procedure has been improved and can be completed within three minutes. It required only 48 minutes for the assay of 22 blood samples. Quick gastrin is a RIA that uses magnetic particles. On magnetic particles, a goat anti-rabbit IgG antibody is bound covalently. An anti-human gastrin rabbit antibody is bound to an anti-rabbit IgG antibody. Assay is started by adding the magnetic particles to a mixture of sample and 125I-gastrin. Following 30 minute incubation at 37 degrees C, the particles are sedimented in a magnetic field and washed. The gastrin content of the sample is then quantitated by counting radioactivity of the particles. Incomplete equilibration of antigen-antibody reaction is corrected using standard solution prepared from charcoal treated plasma. The immunoreactive gastrin values by quick gastrin correlated well with those by a commercial assay kit (Gammadab RIA kit; y = 1.01 x +4.3, r = 0.99). When compared to a reported conventional rapid assay, quick gastrin is easier and more accurate. Quick gastrin is sensitive enough to use for intra-operative determination of gastrin. We applied quick gastrin to the samples obtained from intra-operative secretin test in a gastrinoma patient. Twofold increases in gastrin after injection of secretin clearly indicated the existence of occult gastrinomas in her pancreas. When gastrin was assayed with the conventional rapid method, the increase in gastrin was less and did not reach the criteria for existence of gastrinoma.

Topics: Adult; Animals; Female; Gastrinoma; Gastrins; Humans; Intraoperative Period; Pancreatic Neoplasms; Rabbits; Radioimmunoassay; Reagent Kits, Diagnostic

Gastrinoma is a kind of neuroendocrine tumor very rare in children. It can be described as solitary and has been reported in the liver and in the kidney; or as part of MEN type I (tumors of parathyroids, pancreatic islets and pituitary). We report here, a solitary and huge pancreatic gastrinoma in a young girl with a Zollinger-Ellison (Z-E) syndrome, whose diagnosis was delayed by misunderstanding of the symptoms.

Topics: Adolescent; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Humans; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Pancreas; Pancreatic Neoplasms; Pancreaticoduodenectomy; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

The growth of the human gastrinoma model (PT) in athymic nude mice is stimulated by bombesin (BBS), an amphibian peptide homologous to both human gastrin-releasing peptide (GRP) and neuromedin B (NMB). The mechanism is not known, and a potent and specific GRP-R antagonist BIM26226, which has low affinity for NMB-R, was used in vivo in athymic nude mice bearing gastrinoma subcutaneously. Both the BBS and BIM26226 stimulated the growth of PT, and the growth stimulation was even greater when given together. RT-PCR study of gastrinoma revealed the presence of both GRP-R and NMB-R mRNA, but much more abundant NMB-R mRNA. We conclude that BBS-stimulated growth of gastrinoma involves both GRP-R and NMB-R, and our findings suggest that GRP-R mediates negative and NMB-R produces positive growth effects on gastrinoma.

Topics: Animals; Bombesin; DNA, Neoplasm; Gastrinoma; Gastrins; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Peptide Fragments; Polymerase Chain Reaction; Receptors, Bombesin; RNA, Messenger

During a period of 13.5 years 17 patients with a gastrinoma and an associated Zollinger-Ellison syndrome were treated. In three patients (18%) the gastrinoma was part of a multiple endocrine neoplasia type I (MEN I). The median interval from the initial symptoms to the definite diagnosis was 5.0 years. During this interval seven patients (41%) underwent gastric surgery up to four times. The preoperative imaging studies localized the primary tumor in only seven patients (41%). In five of six diagnostic laparotomies the primary site of the tumor was identified and proved by pathologic work-up. The surgical procedures (n = 13) included five resections of the pancreas (3 x pancreatic head, 2 x left pancreatic resection), two duodenal resections, three enucleations of the tumor and three palliative operations (hospital mortality: 0%). Following laparotomy the gastrinoma could be histologically proved in eleven of 17 patients (6 x pancreas, 4 x duodenum, 1 x in the hepatoduodenal ligament). The rate of metastatic spread as characteristic feature of malignancy was 59%. After complete resection of the primary tumor (n = 8) none of these patients died because of the gastrinoma during the follow-up (median: 7.3 years). In the remaining patients three deaths were caused by the metastatic spread of the gastrinoma. Considering the high rate of preceding operations, the high malignancy rate and the excellent prognosis after RO-resection the diagnostic interval in patients with ZES is too long. Despite the modern radiographic imaging the exploratory laparotomy is of high value in patients with ZES.

Topics: Adult; Aged; Duodenal Neoplasms; Duodenum; Female; Follow-Up Studies; Gastrectomy; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreas; Pancreatic Neoplasms; Postoperative Complications; Reoperation; Zollinger-Ellison Syndrome

Ultrasound-guided, laser-induced thermocoagulation with Nd:YAG laser (1064 nm) was performed in a child with metastatic gastrinoma disease. The emitted laser energy to coagulate a radius of 15-20 mm of metastatic liver tissue was 4 W with a duration time of 300 s. Marked reduction of gastrin was observed after interstitial laser hyperthermia.

Topics: Biomarkers, Tumor; Child; Chromogranin A; Chromogranins; Combined Modality Therapy; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Hyperthermia, Induced; Liver Neoplasms; Lymphatic Metastasis; Patient Care Team

Topics: Adult; Aged; Aged, 80 and over; Diagnosis, Differential; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

The role of surgical resection of gastrinoma in multiple endocrine neoplasia type 1 (MEN 1) is controversial because of low biochemical cure rates, but with adequate duodenal exploration higher cure rates may be possible.. We have prospectively evaluated this proposal in ten consecutive patients with MEN 1 and Zollinger-Ellison syndrome who underwent surgical exploration for gastrinoma resection including a detailed evaluation of the duodenum by palpation, intraoperative endoscopy with transillumination, and duodenotomy.. Duodenal tumors were present in seven patients. Six of seven patients had metastatic deposits in lymph nodes, and two of seven had synchronous pancreatic tumors. Three patients had a single duodenal tumor, one patient had two tumors, and three patients had more than 20 duodenal tumors. Positive gastrin staining by use of immunohistochemistry was seen in all duodenal tumors. None of these seven patients were biochemically cured. Of three patients with negative duodenal explorations, two had single pancreatic tumors removed and one had only lymph node gastrinoma. No patients were biochemically cured.. Not all patients with MEN 1 and Zollinger-Ellison syndrome have duodenal gastrinomas. In the 70% of patients with duodenal tumors, even extensive duodenal exploration with removal of positive lymph nodes does not result in cures because 86% of tumors had metastasized to lymph nodes and 43% of patients had large numbers of tumors.

Topics: Adult; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Lymphatic Metastasis; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Prospective Studies; Zollinger-Ellison Syndrome

Topics: Diarrhea; Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Protein Precursors; Secretin

Primary endocrine neoplasms of intra- and extrahepatic biliary ducts are very rare. We describe the first case of a primary endocrine tumor of the common bile duct producing gastrin. A 53-year-old woman had a 3-year history of recurrent duodenal and gastric ulcers as well as obstructive jaundice. A small neoplasm was found in the lower third of the common bile duct, which showed diffuse gastrin production and focal synthesis of serotonin and pancreatic polypeptide by immunohistochemistry and electron microscopy. Although serum gastrin was within normal levels (90 ng/ml), symptoms of peptic acid disease could have been related to hypergastrinemia, since gastric and duodenal ulcers healed after surgical removal of the tumor. She has remained asymptomatic for 8 months.

Topics: Cholestasis; Common Bile Duct Neoplasms; Duodenal Ulcer; Female; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Middle Aged; Stomach Ulcer

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Anti-Ulcer Agents; Blood Chemical Analysis; Combined Modality Therapy; Duodenal Neoplasms; Female; Gastric Acid; Gastric Mucosa; Gastrinoma; Gastrins; Hepatic Artery; Humans; Interferons; Lansoprazole; Male; Middle Aged; Multiple Endocrine Neoplasia; Omeprazole; Pancreatic Neoplasms; Peptic Ulcer; Splenic Artery; Zollinger-Ellison Syndrome

14 patients with metastatic endocrine gastro-entero-pancreatic carcinoma (6 patients with Carcinoid-syndrome, 3 with gastrinoma and 5 with non-functioning tumor) have been treated with Octreotide 3 x 200 micrograms/die plus Interferon-Alpha 3 x 5 Mio U/week after documented tumor progression during preceding Octreotide-monotherapy. 6 out of 14 patients responded favourable to the treatment: one patient with partial regression and 5 patients with stillstand of tumor growth. In only one patient initial tumor stillstand for 6 months was followed by tumor progression whereas in five patients a beneficial effect on tumor growth could be documented up to 34 months. Inhibition of tumor growth and tumor progression was not necessarily paralleled by respective changes in peripheral hormone levels. These results should initiate a controlled prospective study to prove the hypothesis that in patients with metastasized endocrine gastro-entero-pancreatic tumors the combination of Octreotide and Interferon-Alpha is superior to monotherapy with Octreotide or Interferon-Alpha and to identify those patients who respond to this combined therapy.

Topics: Biomarkers, Tumor; Combined Modality Therapy; Female; Gastrinoma; Gastrins; Gastrointestinal Neoplasms; Humans; Hydroxyindoleacetic Acid; Interferon alpha-2; Interferon-alpha; Liver Neoplasms; Male; Malignant Carcinoid Syndrome; Neoplasm Metastasis; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Recombinant Proteins

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

Although widely reported on, the clinical diversity and eventual varied outcome of patients with extrapancreatic gastrinomas remain a medical mystery. In an attempt to help clarify conflicting management of extrapancreatic gastrinomas, we reviewed our experience with these unique tumors.. Retrospective analysis with long-term follow-up (mean, 8 years).. Tertiary care referral center.. From January 1958 through January 1993, we identified and operated on 23 patients with extrapancreatic gastrinomas (duodenum, n = 18; stomach, n = 3; nodal, n = 2). The 12 men and 11 women (none with multiple endocrine neoplasia type I syndrome) ranged in age from 12 to 68 years (mean, 47 years). Preoperatively, all patients were symptomatic with peptic ulcer disease (duodenal [n = 18, 78%], jejunal [n = 4, 17%]) and/or diarrhea (n = 17, 74%).. Preoperatively, tumor localization was successful in only three patients (13%). Surgical management included tumor excision only in 14 patients (61%), partial gastroduodenectomy in six (27%), total gastrectomy in one (4%), limited enterectomy in one (4%), and tumor biopsy alone in one (4%). Seven patients had evidence of lymphatic metastases at the time of operation, including a single patient with hepatic metastases (malignancy rate, 30%). Postoperatively, complications developed in seven patients (30%): wound infection in two, ileus in two, pulmonary sepsis in one, intra-abdominal abscess in one, and diabetic ketoacidosis in one. The postoperative mortality rate was 4%.. Emphasis was placed on rendering patients eugastrinemic.. Long-term follow-up (mean, 8 years) of all patients revealed that 11 patients (48%) were eugastrinemic, asymptomatic, and not receiving gastric acid-reducing medication. Sixteen patients remain alive and well. Of the six now decreased patients who had been participating in long-term follow-up (mean survival, 14 years), death was due to atherosclerotic coronary artery disease in four and tumor progression in two.. Following surgical excision, patients with extrapancreatic gastrinomas have a favorable outcome, with nearly half being cured.

Topics: Adolescent; Adult; Aged; Child; Duodenal Neoplasms; Female; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Lymphatic Metastasis; Male; Middle Aged; Postoperative Complications; Reoperation; Retrospective Studies; Stomach Neoplasms; Surgical Procedures, Operative; Survival Rate; Time Factors; Treatment Outcome

Evolution of gastrinoma tumoral mass, fasting serum gastrin concentrations, and gastric endocrine cells has been analyzed in 21 patients with the Zollinger-Ellison syndrome committed to long-term omeprazole treatment (up to 7.75 years, median 37 months). Gastrinoma growth was seen in eight patients. Significant increase in serum gastrin was only observed in the group of patients with gastrinoma growth. Fundic argyrophil cell densities were correlated with serum gastrin (r' = 0.68, P = 0.002). Argyrophil and antral gastrin cell densities significantly increased during the survey, but increases were greater in the group with gastrinoma growth (respectively, +136% and +131%) than in the other group (respectively, +34% and +43%). Progression in the degree of argyrophil cell hyperplasia, noted qualitatively, was observed in 11 patients. Fundic carcinoids developed in three of these 11 patients, all three having multiple endocrine neoplasia type 1 (MEN 1). Positive linear individual correlations (r > or = 0.85) between argyrophil cell densities and corresponding durations of omeprazole treatment were found in nine of the 10 patients studied at least three times and who had a clear-cut increase in those cell densities. Thus, increase in serum gastrin and fundic argyrophil cell densities appeared closely associated with gastrinoma growth; however, duration of drug-induced hypochlorhydria may also affect cell proliferation.

Topics: Adult; Aged; APUD Cells; Chi-Square Distribution; Chronic Disease; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Omeprazole; Pancreatic Neoplasms; Prospective Studies; Stomach; Time Factors; Zollinger-Ellison Syndrome

We reviewed the age of presentation, malignant potential, and outcome of gastrinomas and pancreatic tumors in patients with multiple endocrine neoplasm, type 1.. Screening of one very large and one smaller, possibly related family on an island, including serum gastrin estimations and, when indicated, pancreatic ultrasound.. Over 2000 family members and their family physicians were advised on screening procedures.. Data were collected and reviewed retrospectively and prospectively for all medical records, investigations, surgical procedures, and available tissue samples.. Criteria for diagnosis were established for radiological, biochemical, and histological studies.. Sixty-two patients had evidence of gastrinoma or pancreatic neoplasm. In 19 patients the diagnosis was based on demonstration of a tumor. In 21 patients the diagnosis was based on elevated serum gastrin concentration in the absence of demonstrable tumor. None of these patients required gastric surgery if they first underwent parathyroidectomy. In 18 patients the diagnosis was based on the combination of demonstrated pancreatic tumor plus elevated glucagon (two patients), gastrin (11 patients), or insulin (five patients) concentration. Peptic ulcer was difficult to control in seven of the 11 patients with elevated gastrin concentrations plus demonstrated tumor. Four patients had liver metastases that appeared to be secondary to the pancreatic gastrinoma. In patients with insulinomas, the first symptoms occurred before age 20 years. Elevated serum gastrin concentrations were not seen before age 24 years and were observed to occur for the first time in two patients after age 50 years.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Female; Follow-Up Studies; Gastrinoma; Gastrins; Glucagon; Humans; Insulin; Insulinoma; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies; Zollinger-Ellison Syndrome

Gastrin and pancreastatin-like immunoreactivity were determined by radioimmunoassay methods and chromogranin A was determined by enzyme-linked immunoassay in sera from 18 patients with gastrinomas (Zollinger-Ellison syndrome) and in 20 age and sex matched controls. Gastrin serum levels in the gastrinoma patients were in the range 26-80,000 pmol/l, and in the controls 5-31 pmol/l. Chromogranin A serum levels in the gastrinoma group were in the range 6-2,700 ng/ml (mean +/- SEM: 400 +/- 147 ng/ml). The mean value of chromogranin A was significantly higher than in the control group (8 +/- 2 ng/ml, p = 0.008). The serum levels of pancreastatin-like immunoreactivity in the gastrinoma patients were in the range 23-1,994 pg/ml (597 +/- 123 pg/ml). The mean value of pancreastatin-like immunoreactivity in the gastrinoma group was significantly higher than in the control group (104 +/- 25 pg/ml, p = 0.0002). The levels of chromogranin A and pancreastatin-like immunoreactivity were significantly higher in patients with verified metastatic disease (p = 0.04, p = 0.01 respectively). There was a significantly positive correlation between levels of gastrin and pancreastatin-like immunoreactivity (r = 0.7, p = 0.002), while no correlation was found between gastrin and chromogranin A levels or between levels of chromogranin A and pancreastatin-like immunoreactivity. The study demonstrates an elevation of both chromogranin A and pancreastatin-like immunoreactivity in serum of gastrinoma patients. The lack of correlation between gastrin and chromogranin A, however, gives an indication that the gastrinoma cells are not the main source of serum chromogranin A elevation.

Topics: Adult; Aged; Biomarkers, Tumor; Chromogranin A; Chromogranins; Female; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Pancreatic Hormones; Pancreatic Neoplasms; Radioimmunoassay

Gastrin expression occurs in the pancreas in only two situations: (1) in cases of gastrinoma and (2) in the embryonic/fetal pancreas. The initiation of gastrin expression in the embryonic pancreas may be recapitulated during gastrinoma tumorigenesis. For this reason, we have tried to identify the point of onset of gastrin expression in the developing pancreas. Previously, determining the point of onset for genes in embryonic tissues has been difficult because of low expression levels and small tissue samples. Using the sensitive polymerase chain reaction assay, we were able to determine, with a sensitivity of 10 molecules of mRNA, the earliest expression of gastrin in the developing pancreas. This expression occurred at 30 somites, or at a gestation of 9.5 to 10 days.

Topics: Animals; Female; Gastrinoma; Gastrins; Gene Expression; Gene Expression Regulation; Male; Mice; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction

Our previous studies have shown that increased expression of GLUT1/erythrocyte and GLUT3/brain type glucose transporter genes in human tumors is associated with cellular transformation. We have now determined the levels of messenger RNAs (mRNAs) encoding these two glucose transporter isoforms as well as that of GLUT2/liver isoform in insulin-, glucagon-, and gastrin-secreting islet cell tumors. Northern blot analysis and reverse transcriptase-polymerase chain reaction revealed the presence of GLUT1 and GLUT3 mRNA in all human islet cell tumors and normal islets examined. In contrast, GLUT2 mRNA, which is present at high levels in normal islets, was not detected in insulinomas or other types of islet cell tumors. These results imply that GLUT1 and GLUT3 are primarily responsible for glucose uptake by these tumors.

Topics: Base Sequence; Female; Gastrinoma; Gastrins; Gene Expression; Gene Expression Regulation, Neoplastic; Glucagon; Glucagonoma; Humans; Insulin; Insulinoma; Male; Middle Aged; Molecular Sequence Data; Monosaccharide Transport Proteins; Oligodeoxyribonucleotides; Pancreatic Neoplasms; Polymerase Chain Reaction; RNA, Messenger

Results of cell culture and cytogenetic analysis (standard and fluorescent in situ hybridization, FISH) of two sporadic gastrinomas are reported. Maintenance of hormonal activity was assessed by detection of gastrin levels during the first 3 months in culture. Case 1 showed clonal aberrations consisting of two marker chromosomes: marker 1 is a large metacentric chromosome and marker 2 is a small acrocentric chromosome. Case 2 showed a constitutional polymorphism with chromosome 15p+ and a clone in the tumor cell culture with trisomy for chromosome 3. To our knowledge, this is the first cytogenetic report of sporadic gastrinomas (Zollinger-Ellison syndrome).

Topics: Aged; Chromosome Aberrations; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Male; Middle Aged

Topics: Adenocarcinoma; Animals; Antigens, Viral, Tumor; Carcinoma; Gastrinoma; Gastrins; Genetic Engineering; Hyperplasia; Liver Neoplasms; Mice; Mice, Transgenic; Pancreatic Neoplasms; Pyloric Antrum; Stomach Neoplasms

Gastrinomas from 25 patients were examined by immunohistochemistry (IHC) and in situ hybridization histochemistry (ISH). Most patients (84%) presented with the Zollinger-Ellison syndrome. Six had multiple endocrine neoplasia type I (MEN-I). Twelve patients (48%) had duodenal primaries and 11 of 12 of these had metastases to regional lymph nodes and/or liver in spite of the small sizes of the primary tumors (mean size of 0.9 cm). Five patients had pancreatic gastrinomas and eight patients had metastatic tumor in regional lymph nodes or liver at surgery but a primary was not found. IHC and ISH analyses showed that all cases were positive for gastrin protein and 24 of 25 (96%) expressed gastrin mRNA that was easily detected in formalin-fixed, paraffin-embedded tissue sections. Both benign and malignant tumors expressed alpha subunit of human chorionic gonadotropin protein (alpha-HCG). However, only malignant gastrinomas (29%) expressed adrenocorticotropic hormone protein or proopiomelanocortin (POMC) mRNA. ISH and Northern hybridization analysis revealed that chromogranin A mRNA was the most common member of the chromogranin/secretogranin (Cg/Sg) family which was expressed in both benign and malignant gastrinomas. These results indicate that duodenal gastrinomas are common in both sporadic and MEN-1-associated cases, and small duodenal primaries may be associated with extensive regional lymph node and liver metastases. Expression of ACTH/POMC protein and mRNA was consistently associated only with malignant gastrinomas while gastrin protein, gastrin mRNA and Cgs/Sgs mRNAs were readily detected in both benign and malignant gastrinomas.

Topics: Adrenocorticotropic Hormone; Base Sequence; Chromogranins; DNA, Neoplasm; Duodenal Neoplasms; Gastrinoma; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Immunohistochemistry; In Situ Hybridization; Molecular Sequence Data; Multiple Endocrine Neoplasia; Oligonucleotide Probes; Pancreatic Neoplasms; Pro-Opiomelanocortin; Proteins; RNA, Messenger; Zollinger-Ellison Syndrome

The authors report the case of a 48 years old man presenting a pancreatic islet cell carcinoma (gastrinoma) with liver, nodes and peritoneal metastases, associated with an elevated alpha-fetoprotein (AFP) concentration. Incomplete remission was first obtained with a chemotherapy using Streptozotocin combined with 5-Fluorouracil, in association with a Somatostatin analogue (SMS 201-995). But when relapses occur, another chemotherapy was not so effective. Serum gastrin and AFP levels had the same evolution and appear to have the same interest to follow the course of the disease.

Topics: alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Fatal Outcome; Fluorouracil; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Peritoneal Neoplasms; Remission Induction; Streptozocin

Although gastrinoma resection is generally advocated for patients with the sporadic form of nonmetastatic Zollinger-Ellison syndrome, there is controversy regarding the surgical management of the gastrinoma among patients with multiple endocrine neoplasia type I (MEN-I). Using strict criteria, to date no biochemical cures of the Zollinger-Ellison syndrome lasting greater than 5 months have been achieved by gastrinoma resection among patients with MEN-I. Whereas resections of hepatic metastases have been performed in patients with sporadic gastrinoma, none have been reported among patients with MEN-I. The current report describes a patient with MEN-I, closely followed up for 30 years, in whom enlargement of pancreatic gastrinoma and development of hepatic gastrinoma was observed to occur over 3 years. After preoperative localization, an 80% pancreatectomy and a left lateral segmentectomy of the liver were performed. Sixteen months after the operation, secretin and calcium provocative testing showed that the patient's fasting gastrin and stimulated plasma gastrin concentrations were normal; also, results of computerized tomographic angiography, selective abdominal angiography, and hepatic venous sampling for gastrin after intra-arterial secretin injection were negative for gastrinoma. By achieving a 16-month cure of gastrinoma, this case shows that an aggressive surgical approach can benefit certain patients with gastrinoma who have MEN-I even in the presence of hepatic metastases.

Topics: Angiography; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasms, Second Primary; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

In a 30-year-old man with Zollinger-Ellison syndrome, the only detectable gastrinoma was in the right liver lobe. Removal of the lobe, without additional gastric surgery, was followed by normalization of the gastrin level. Long-term follow-up confirmed the good result. The usefulness of quick intraoperative gastrin assay is stressed.

Topics: Adult; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Time Factors; Zollinger-Ellison Syndrome

The case of a patient who had Zollinger-Ellison syndrome caused by a primary peripancreatic lymph node gastrinoma is presented. Accompanying diffuse pancreatic islet cell hyperplasia, a well-documented occurrence in hypergastrinemia, was present. A perforated esophageal ulcer in a Barrett's esophagus led to right-sided necrotizing pleuritis, septicemia, and death. The diffuse parathyroid hyperplasia also noted in the patient is thought to be secondary to chronic hypertensive renal failure rather than MEN-I syndrome.

Topics: Aged; Female; Gastrinoma; Gastrins; Humans; Immunoenzyme Techniques; Lymph Nodes; Neoplasms, Second Primary; Pancreas; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Duodenal gastrinomas producing Zollinger-Ellison syndrome (ZES) are rarely imaged on preoperative studies. Measurement of serum gastrin levels by transhepatic portal venous sampling (PVS) or by sampling from hepatic veins after intraarterial secretin injection have been advocated as useful tests to identify these tumors before operation.. As part of a prospective study, selective intraarterial secretin injection has been performed in 36 consecutive patients with ZES, PVS has been performed in 30 of these patients, and the results have been compared.. Gastrinomas were found at laparotomy in 33 of 36 patients (92%). Duodenal tumors were found in 18 patients (50%). The remaining patients had liver, pancreatic, or nodal disease (n = 15). Thirty-two of 36 patients (89%) had positive results with intraarterial secretin injection study, whereas 18 of 30 (60%) had a positive PVS gradient (p = 0.02, Fisher's exact test). The most common positive gradient with intraarterial secretin injection was found with injections of the gastroduodenal artery, and the most common positive gradient with PVS was found in the inferior pancreaticoduodenal (IPDV) or superior pancreaticoduodenal vein (SPDV). Fourteen of 18 (78%) patients with duodenal gastrinomas had a positive GDA injection, whereas five of 18 (28%) without duodenal tumors had a positive GDA injection (p = 0.006). Five of 16 patients with duodenal gastrinomas had a positive gradient in the IPDV or SPDV, whereas four of 14 without duodenal tumors had a positive gradient in the IPDV or SPDV (not significant).. Intraarterial secretin injection is more sensitive than PVS at localizing duodenal gastrinomas and should replace PVS in patients with ZES and occult tumors.

Topics: Adult; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Injections, Intra-Arterial; Laparotomy; Male; Middle Aged; Portal Vein; Prospective Studies; Secretin; Zollinger-Ellison Syndrome

We have previously reported the first establishment and characterization of a functioning human gastrinoma (PT) xenograft. Bombesin, the equivalent of the mammalian gastrin-releasing peptide, has trophic effects on normal and neoplastic tissues of the gastrointestinal tract; the effects of gut hormones on the growth of gastrinoma are not known. The purpose of this study was twofold: (1) to determine the presence of various gut peptides in PT and (2) to determine the effect of bombesin on the growth of PT xenografts.. PT tumors were examined for expression (mRNA and protein) of various gut peptides by Northern hybridization and immunohistochemistry. In addition, PT xenografts were implanted as 3 mm2 pieces bilaterally subcutaneously in athymic nude mice. Mice were divided into two groups to receive either bombesin (5 micrograms/kg) or saline administered as intraperitoneal injections every 8 hours. Tumor area was measured twice weekly until mice were sacrificed (day 28), when tumor and normal pancreas were removed, weighed, and assayed for DNA and protein content.. Both mRNAs and peptides of gastrin and chromogranin A were present in PT tumors. Bombesin significantly stimulated growth of PT tumors from day 18 until mice were sacrificed (day 28). As expected, bombesin stimulated pancreatic growth.. We have demonstrated for the first time that bombesin is a trophic hormone for gastrinoma. The unique cell line PT contains gastrin and chromogranin A and will be a useful model to define the biologic mechanisms controlling the growth of human gastrinomas.

Topics: Animals; Bombesin; Cell Division; Chromogranin A; Chromogranins; Gastrinoma; Gastrins; Humans; Mice; Mice, Nude; Neoplasm Transplantation; RNA, Messenger; Transplantation, Heterologous; Tumor Cells, Cultured

Nine patients with Zollinger-Ellison syndrome were treated with octreotide acetate (100 micrograms delivered subcutaneously three times daily) and followed up for 1 to 48 months. Serum gastrin levels were obtained at predetermined intervals. All patients had elevated baseline fasting gastrin levels (greater than 150 ng/L [greater than 150 pg/mL]). One month after administration of octreotide, gastrin levels were in the reference range for five (62%) of eight patients, and a mean gastrin suppression rate of 76% was achieved (ie, values were a mean of 76% less than baseline values). One year after administration of octreotide, five (71%) of seven evaluable patients had gastrin levels of less than 200 ng/L (200 pg/mL), and the mean gastrin suppression rate was more than 80% for these seven patients. During the second year, control at these levels was maintained in four patients; one patient continued to have controlled levels for 42 months. Complete symptomatic response occurred in seven patients (78%), and partial response in two patients (22%). All six patients with diarrhea before treatment were cured of it. Octreotide acetate provides efficacious long-term suppression of elevated gastrin levels and excellent symptomatic relief in patients with Zollinger-Ellison syndrome.

Topics: Abdominal Pain; Adolescent; Aged; Diarrhea; Fasting; Female; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Injections, Subcutaneous; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Prospective Studies; Zollinger-Ellison Syndrome

A 40-year-old woman had persistent Zollinger-Ellison syndrome despite excision of a 4-cm duodenal gastrinoma. Localizing studies including ultrasonography, computed tomography, magnetic resonance imaging, duodenal endoscopy, endoscopic ultrasonography, and intraoperative endoscopic transillumination of the duodenum failed to detect a tumor. Selective intra-arterial methylene blue injection was used to identify a 6-mm gastrinoma in the duodenum, which was locally excised. Postoperatively, the patient had a negative secretin provocative test result. This novel method uses selective arterial secretin injection with hepatic venous gastrin sampling to identify the vessel feeding the gastrinoma. An angiographic catheter is then positioned in this artery. At laparotomy, methylene blue is injected through this catheter to selectively stain the gastrinoma, facilitating its identification. Selective intra-arterial methylene blue injection can enhance intraoperative detection of small gastrinomas and may improve the rate of curative resection in the Zollinger-Ellison syndrome. Further evaluation of this novel localizing technique is warranted.

Topics: Adult; Endoscopy; Female; Gastrinoma; Gastrins; Humans; Injections, Intra-Arterial; Intraoperative Period; Magnetic Resonance Imaging; Methylene Blue; Pancreatic Neoplasms; Secretin; Tomography Scanners, X-Ray Computed; Ultrasonography; Zollinger-Ellison Syndrome

Gastrin immunocytochemistry and non-radioactive in situ hybridization, using biotinylated oligonucleotide probes, for gastrin mRNA have been used for studying a retrospective material of six gastrin-producing (Zollinger-Ellison) tumors. Hybridization results for gastrin mRNA were positive in all six, while gastrin immunoreactivity could be detected in five tumors. In one of the patients, different areas of the same tumor displayed differences in immunoreactivity to gastrin, but were uniformly hybridization positive. Weak hybridization signals were detected in liver metastases from a necropsy case, while the gastrin immunostaining was more pronounced. The results show that non-radioactive hybridization methods are applicable to routine clinical specimens stored for as long as 16 years and that in situ hybridization may be a useful complement to immunocytochemical diagnosis, particularly in cases where high synthesis and little storage of hormonal products occur.

Topics: Base Sequence; Gastric Mucosa; Gastrinoma; Gastrins; Humans; Immunoenzyme Techniques; Molecular Sequence Data; Nucleic Acid Hybridization; Pancreatic Neoplasms; Pyloric Antrum; RNA, Messenger; Zollinger-Ellison Syndrome

Following the curative resection of a pancreatic gastrinoma in a cat, gastrin peptides were purified from the tissue and sequenced. The sequence of cat gastrinoma G17 (18-34) confirms the previously published sequence. The sequence of cat G34 (1-34) is reported for the first time. The NH2-terminal portion of cat G34 differs from that of dog by having a Q (Gln) for L (Leu) at position 10 from the NH2-terminus.

Topics: Amino Acid Sequence; Animals; Cats; Chromatography, High Pressure Liquid; Female; Gastrinoma; Gastrins; Molecular Sequence Data; Pancreatic Neoplasms; Sequence Alignment

Specimens from the pancreas and duodenum of 26 patients with sporadic Zollinger-Ellison syndrome (ZES) and 18 patients with multiple endocrine neoplasia type 1 (MEN-1) and hypergastrinemia (17 with ZES) were screened immunocytochemically for gastrinomas. Location, size, multicentricity, and malignancy of the gastrinomas were evaluated. The MEN-1 patients had gastrinomas in the duodenum (nine of 18), pancreas (one of 18), and periduodenal lymph nodes (two of 18). No gastrinoma was identified in six patients. Most duodenal gastrinomas were multiple (five of nine) and smaller than 0.6 cm (six of nine). Lymph node metastases were present in eight of 12 patients. All 26 patients with sporadic ZES had a solitary gastrinoma; 14 were found in the pancreas and had a diameter greater than 2 cm. Ten patients had a duodenal gastrinoma, two with a diameter less than 0.6 cm. In two patients, only periduodenal "lymph node gastrinomas" were detected. Eighteen of the sporadic gastrinomas were malignant. These results suggest that duodenal location and multicentricity of gastrinomas are associated with the MEN-1 syndrome, and solitary gastrinomas, either in the pancreas or the duodenum, are predominantly seen in sporadic ZES.

Topics: Duodenal Neoplasms; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Liver Neoplasms; Lymphatic Metastasis; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

We have evaluated the peripheral blood natural killer (NK) cell activity and the in vitro effect of recombinant gamma-interferon (r gamma-IFN) on NK cell activity in 23 patients with a neuroendocrine tumour of the pancreas, small intestine or liver, and 23 healthy controls. Patients with a gastrinoma showed a NK cell activity which was not different from that of the control group, whereas patients with another type of neuroendocrine tumour had a decreased NK cell activity compared to the controls (p less than 0.05) and the gastrinoma patients (p less than 0.02). The impaired NK cell activity in these patients was as such not related to the presence of liver metastasis or performance status of the patients. r gamma-IFN significantly stimulated the NK cell activity in patients and controls. However, the cytotoxic response of the patients with a hormone production other than gastrin remained lower than in the two other groups. Follow-up studies in 8 patients showed NK cell activities not to vary with stable disease, to decrease with progressive disease, and to increase with regression of disease. In conclusion, NK cell activity is suppressed in patients with neuroendocrine tumours that produce hormones other than gastrin. This impairment is not related to the presence of metastasis but seems to be related to the course of the disease.

Topics: Adult; Aged; Carcinoid Tumor; Cell Line; Female; Gastrinoma; Gastrins; Gastrointestinal Hormones; Humans; Interferon-gamma; Intestinal Neoplasms; Killer Cells, Natural; Lipoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Recombinant Proteins; Somatostatinoma; Tumor Cells, Cultured

The salient contributions of the Zollinger-Ellison syndrome have made it unique. No pancreatic endocrine tumor described before (insulinoma) or subsequently (glucagonoma, somatostatinoma, vipoma, pancreatic-polypeptidoma) has been the topic of such a variety of studies, or has been such an inspiration and rich source of new ideas for investigation and ultimate improvement in patient care.

Topics: Gastrinoma; Gastrins; Humans; Lymphatic Metastasis; Pancreatic Neoplasms; Peptic Ulcer; Research; Zollinger-Ellison Syndrome

Topics: Diagnosis, Differential; Digestive System Neoplasms; Female; Gastrinoma; Gastrins; Humans; Mesenteric Vascular Occlusion; Middle Aged; Radiography; Secretin

Posttranslational processing is an important phase of the expression of most eucaryotic genes in terms of functional proteins. Among these, secretory proteins and peptides are of particular interest for clinical chemists, since diagnostic measurements of circulating proteins and peptides constitute a major discipline in clinical chemistry. The posttranslational covalent maturation of secretory proteins and peptides involves multiple enzymatic modifications of the corresponding proproteins along the intracellular secretory pathway. During the eighties, an increasing amount of evidence has indicated that sick secretory cells fail to process their secretory products normally. The diseased cells therefore fail to process their secretory products normally. The diseased cells therefore release also incompletely processed precursors and processing-intermediates. In order to measure the degree of disease, assays that measure proteins and peptides independent of the degree of processing are therefore desirable. We have now designed a new analytical principle, according to which secretory proteins, peptides and their precursors can be accurately quantitated irrespective of the degree of processing. This principle, named processing-independent analysis (PIA), is generally applicable to all cellular synthesized substances. The principle has been applied to and developed first for a well-defined secretory peptide system, progastrin and its products. Using this model, the results obtained so far confirm the diagnostic superiority of processing-independent analysis in comparison with conventional assays for bioactive peptides.

Topics: Amino Acid Sequence; Animals; Chemistry, Clinical; Clinical Laboratory Techniques; Duodenal Ulcer; Gastrinoma; Gastrins; Humans; Molecular Sequence Data; Peptides; Protein Precursors; Protein Processing, Post-Translational; Proteins; Radioimmunoassay; Zollinger-Ellison Syndrome

Several peptides derived from the gastrin-predicted preprohormone sequence were isolated from a human gastrinoma by gel permeation, anion exchange, and reverse phase chromatography. The peptides were identified and characterized structurally by a combination of radioimmunoassays, mass spectral analysis, and microsequence analysis. The largest peptide, progastrin-(1-35) (cryptagastrin), extends from the putative processing site for the signal peptidase to the double basic residues adjacent to the amino terminus of gastrin 34. A shorter form of this peptide, progastrin-(6-35) (cryptagastrin-(6-35), was also isolated in smaller amounts. In addition, sulfated and nonsulfated gastrin 17 amides (progastrin-(55-71)) and the glycine-extended nonsulfated gastrin 17 (progastrin-(55-72)) were identified by radioimmunoassay, and their structures were confirmed by mass spectral analysis. Isolation of cryptagastrin indicates that the signal peptide of human preprogastrin contains 21 amino acid residues, and progastrin, therefore, contains 80 amino acids. There is minimal processing of the cryptic peptide preceding the sequence of gastrin 34. An amidated gastrin form larger than gastrin 34 could contain 71 amino acids. No evidence was obtained for processing that would produce gastrins containing more than 34 but less than 71 amino acid residues.

Topics: Amino Acid Sequence; Amino Acids; Chromatography, Gel; Chromatography, Ion Exchange; Endopeptidases; Gastrinoma; Gastrins; Humans; Membrane Proteins; Molecular Sequence Data; Peptides; Protein Precursors; Protein Processing, Post-Translational; Radioimmunoassay; Serine Endopeptidases; Spectrometry, Mass, Fast Atom Bombardment

Topics: Female; Gastrinoma; Gastrins; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

In patients with multiple endocrine neoplasia type 1 (MEN-1), gastrinomas are common and thought to occur predominantly in the pancreas. We describe eight patients with MEN-1 and hypergastrinemia (seven with the Zollinger-Ellison syndrome) in whom we searched for neuroendocrine tumors in the pancreas and duodenum. Tumors were found in the proximal duodenum in all eight patients: solitary tumors (diameter, 6 to 20 mm) in three patients and multiple microtumors (diameter, 2 to 6 mm) in the other five. Paraduodenal lymph-node metastases were detected in four patients. Immunocytochemical analysis revealed the presence of gastrin in all the duodenal tumors and in their lymph-node metastases. In contrast, no immunoreactivity for gastrin was present in the endocrine tumors found in the seven pancreatic specimens available for study, except for one tumor with scattered gastrin-positive cells. In four of the six patients whose duodenal gastrinomas were removed, serum gastrin levels returned to normal; in the other two patients gastrin concentrations decreased toward normal. We conclude that in patients with MEN-1 and the Zollinger-Ellison syndrome, gastrinomas occur in the duodenum, but the tumors may be so small that they escape detection.

Topics: Adult; Aged; Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Immunohistochemistry; Lymphatic Metastasis; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Our experience with 47 sporadic gastrinomas suggests that no less than 85% of these tumors are located to the right of the superior mesenteric artery. This finding is unexpected because approximately 75% of insulinomas and glucagonomas are located to the left of the superior mesenteric artery. All of our extrapancreatic gastrinomas have been located to the right. These observations prompted us to determine if other extrapancreatic gastrinomas were also predominantly located to the right side. We searched the world's literature and found 10 cases of ovarian gastrinomas and one case of a renal gastrinoma. Nine of these remote extrapancreatic gastrinomas were located on the right side. This distribution of remote extrapancreatic gastrinomas is similar to our experience with peripancreatic gastrinomas. This unexpected right-sided preponderance of both remote and peripancreatic gastrinomas suggests a common origin for both.

Topics: Adult; Aged; Female; Gastrinoma; Gastrins; Humans; Kidney Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Ovarian Neoplasms; Secretin

The effect of epinephrine on the plasma gastrin level was investigated in three patients with Zollinger-Ellison syndrome (ZES) and in 14 normal subjects. Two ZES patients had undergone total gastrectomy, and the third had undergone subtotal gastrectomy before our study. A significant increase in plasma gastrin, from 23 +/- 5 pg/ml to 53 +/- 20 pg/ml, in response to intravenous epinephrine (40 ng/kg.min), was observed in the normal subjects. This response was completely abolished by beta-blockade. In the ZES patients, epinephrine (40 ng/kg.min) also resulted in an increase in the plasma concentration of gastrin. The basal and maximum concentrations of gastrin were 580 and 1680 pg/ml in patient 1, 145000 and 320000 pg/ml in patient 2, and 200 and 1800 pg/ml in patient 3, respectively. beta-Adrenergic blockade suppressed the epinephrine-stimulated gastrin release in these patients as well. Graded intravenous doses of epinephrine given to the ZES patients resulted in elevation of the plasma gastrin in a dose-dependent manner. Insulin hypoglycemia caused an increase in both plasma epinephrine and plasma gastrin in ZES patients and normal subjects. A significant correlation between plasma gastrin and epinephrine during insulin hypoglycemia was observed in both groups. Exercise, with use of a bicycle ergometer, resulted in an increase in plasma epinephrine. An increase in plasma gastrin with exercise was observed in the ZES patients, and this was also suppressed by beta-blockade. The results suggest that gastrinoma cells, like normal G cells, are equipped with beta-adrenergic receptors that regulate gastrin release.

Topics: Adult; Epinephrine; Female; Gastrinoma; Gastrins; Humans; Male; Physical Exertion; Receptors, Adrenergic, beta; Zollinger-Ellison Syndrome

In two patients with malignant gastrinoma and the Zollinger-Ellison syndrome, we were able to use selective arterial stimulation with secretin as a technique to localize the lesions accurately, allowing resection. The technique of selected arterial secretin stimulation is one of measuring variations in gastrin levels in both the hepatic vein and a peripheral artery at specified times after injection of secretin into a specific artery. When the criteria for localization have been met, one can plot the presence of the gastrinoma within the blood supply of the injected artery and, using angiograms, thus accurately localize the lesion. This method promises to be a valuable additional tumor-localizing procedure, particularly when gastrinomas are extrapancreatic.

Topics: Adenoma, Islet Cell; Angiography; Drug Evaluation; Female; Gastrinoma; Gastrins; Hepatic Veins; Humans; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Secretin; Time Factors; Zollinger-Ellison Syndrome

The effects of octreotide in vivo and in vitro on hormone release, in vivo [123I]Tyr3-octreotide scanning, and in vitro [125I]Tyr3-octreotide autoradiography were compared in five patients with endocrine pancreatic tumors. [123I]Tyr3-octreotide scanning localized the primary tumor and/or previously unknown metastases in four of the five patients. The patient with a negative scan had an insulinoma that did not respond to octreotide in vivo. No Tyr3-octreotide-binding sites were subsequently found at autoradiography of the tumor, whereas somatostatin-14 receptors were present at a high density. In parallel, culture studies with the cells prepared from this adenoma showed that insulin release was not affected by octreotide, while both somatostatin-14 and -28 significantly suppressed hormone release. Culture studies of the tumor cells from two gastrinomas showed a dose-dependent inhibition of gastrin release by octreotide. Octreotide exerted direct antiproliferative effects in one of these gastrinomas, which had been shown to be rapidly growing in vivo. Both gastrinomas had specific somatostatin receptors, as measured by in vitro receptor autoradiography. Somatostatin release by the cultured somatostatinoma cells from one of these patients was suppressed by octreotide. In conclusion, 1) the [123I]Tyr3-octreotide scanning procedure is valuable in the localization of primary endocrine pancreatic tumors as well their often clinically not yet recognized metastases; 2) the in vitro detection of somatostatin receptors in those tumors that were also visualized in vivo after injection of [123I] Tyr3-octreotide indicates that the ligand binding to the tumor in vivo indeed represents binding to specific somatostatin receptors; and 3) the parallel between the presence of somatostatin receptors on tumors and in in vivo and in vitro effects of octreotide on hormonal release from these tumors indicate that a positive scan predicts a good suppressive effect of octreotide on hormonal hypersecretion by these tumors.

Topics: Adult; Autoradiography; DNA, Neoplasm; Female; Gastrinoma; Gastrins; Humans; Insulin; Iodine Radioisotopes; Laparotomy; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Radionuclide Imaging; Receptors, Neurotransmitter; Receptors, Somatostatin; Tumor Cells, Cultured

Functional gastrin-containing tumor cells were maintained for up to 8 wk without fibroblastoid cell overgrowth. Short-term cultures consisted mainly of colonies composed of small polygonal cells, 70%-90% of which stained positive for immunoreactive gastrin. Cultures exhibited limited growth but viability remained high for 2-3 wk. Culture medium contained component I, and gastrin 34, 17, and 14. With time the major C-terminal gastrin species in medium changed from gastrin 17 at 3 days to gastrin 34 at 5 wk. Extracts of cultured cells contained gastrin 34, 17, and 14; gastrin 17 was the major form detected at all times. Ultrastructurally, cultured tumor cells retained morphological integrity for several weeks; however, with time changes in the appearance of the secretory granules accompanied by evidence of cellular retrodifferentiation were gradually observed. Secretin, gastrin-releasing peptide, 8-bromoadenosine 3':5'-cyclic monophosphate, and phorbol, 12-myristate, 13-acetate stimulated the release of gastrin from cultured cells in a time-dependent fashion. Secretin, bombesin, gastrin-releasing peptide, L-tryptophan, and ethylamine stimulated gastrin release in a dose-dependent fashion. Somatostatin 14 inhibited secretin, bombesin, and gastrin-releasing peptide stimulated gastrin release but did not alter basal release. Cultured cells demonstrated de novo gastrin synthesis, evidenced by their ability to incorporate radiolabeled amino acids into immunoadsorbable gastrinlike material. Primary cultures of gastrin-containing tumor cells free from stromal contamination offer unique advantages for studies of factors that regulate the synthesis and secretion of gastrin and may prove of potential value for studies on cell differentiation and growth.

Topics: Culture Media; Gastrinoma; Gastrins; Humans; Immunoenzyme Techniques; Pancreatic Neoplasms; Protein Precursors; Time Factors; Tumor Cells, Cultured

Processing-independent radioimmunoanalysis for progastrin showed that extracts of normal pancreatic tissue from normal subjects (n = 5) and from patients with adenocarcinoma of the papilla of Vater (n = 4) contain progastrin and its products. The concentrations varied from 0.1 to 5.8 pmol/g tissue, of which carboxyamidated bioactive gastrins constituted 0.03-1.9 pmol/g. In histologically normal and nonneoplastic pancreatic tissue from patients with duodenal (n = 3) and pancreatic (n = 2) gastrinomas the expression of gastrin was significantly higher-14.5 pmol/g (median), of which 28% was bioactive amidated gastrins. Gastrin-17 was the main bioactive product, but its immediate precursor, glycine-extended gastrin-17, constituted the predominant part of the preprogastrin product in pancreatic tissue. Proper gastrinoma tissue contained several precursor forms, including intact unprocessed progastrin. Progastrins were also found in high concentrations in plasma from the gastrinoma patients. The results raise the possibility that increased expression of progastrin and its products in non-neoplastic pancreatic tissue is a primary defect predisposing to neoplasia.

Topics: Adenocarcinoma; Ampulla of Vater; Common Bile Duct Neoplasms; Gastrinoma; Gastrins; Gene Expression; Humans; Pancreas; Pancreatic Neoplasms; Protein Precursors; Protein Processing, Post-Translational; Zollinger-Ellison Syndrome

Extracellular matrices have recently been demonstrated to alter cell morphology in culture. Altered cell morphology has been associated with changes in gene transcription and translation, but it is not known whether it also affects posttranslational processing. Using tyrosine-O-sulfation as a marker of processing, we studied the effects of various substrates on biologically active gastrin (IRG) production and sulfation in gastrin-containing tumor cells (GT cells). Dispersed GT cells were plated onto different substrates and then incubated. Culture media from days 4, 7, and 28 were assayed with specific antibodies that recognize total IRG and nonsulfated IRG. Cells cultured on plastic and dried films of laminin, collagen, and Matrigel (Collaborative Research Inc., Lexington, Mass.) flattened and formed monolayers of GT cells. Cells cultured on a porous membrane and hydrated gels of collagen and Matrigel did not flatten but formed spheroids of GT cells. The monolayer cultures showed an increase in sulfation with time but a decrease in IRG production. The spheroid cultures maintained a constant level of sulfation over time and, with the exception of Matrigel (gel), also showed a decrease in IRG production. These results indicate that the level of sulfation was unchanged from that of the original tumor when cells were grown in spheroids but increased when cultured as monolayers. It appears that alteration of the cellular milieu alters colony morphology, which in turn alters gastrin processing.

Topics: Cell Survival; Cytological Techniques; Gastrinoma; Gastrins; Humans; Microscopy, Phase-Contrast; Pancreatic Neoplasms; Protein Processing, Post-Translational; Sulfates

Topics: Bombesin; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

Small doses (30 U) of secretin were injected directly into the splenic, gastroduodenal, hepatic, and superior mesenteric arteries of 13 patients with Zollinger-Ellison syndrome who were undergoing angiography to localize gastrin-secreting tumors of the islet cells. Blood samples from the right hepatic vein and a peripheral vein were drawn before and 30, 60, 120, and 210 seconds after each intraarterial secretin (IAS) injection. A 50% rise in gastrin level in the 30-second sample from the hepatic vein localized the gastrinoma to the head, body, or tail of the pancreas, depending on the artery into which secretion was injected. IAS results were positive in seven of 13 patients (54%); selective angiography was positive in five of 13 (38%); and the combined study, selective angiography with IAS injection, was positive in 10 of 13 (77%). Portal venous sampling was positive in six of 13 (46%). Selective IAS injection, combined with angiography, is the most sensitive study for localizing gastrinomas and avoids percutaneous transhepatic catheterization for portal venous sampling.

Topics: Adult; Aged; Angiography; Female; Gastrinoma; Gastrins; Humans; Injections, Intra-Arterial; Male; Middle Aged; Pancreatic Neoplasms; Secretin

Topics: Angiography; False Negative Reactions; False Positive Reactions; Gastrinoma; Gastrins; Humans; Injections, Intra-Arterial; Pancreatic Neoplasms; Secretin

The role of surgery in the treatment of gastrinoma is unclear. The purpose of this study was to determine prospectively the surgical cure rate using a controlled clinical trial. Eleven patients who fit the entry criteria underwent abdominal exploration and attempted tumor resection for cure. A historical control group was used for comparison. Cure was defined as: (1) normal serum gastrin level, (2) no response to intravenous secretin, (3) no symptoms when antisecretory medications are stopped, and (4) no tumor recurrence on follow-up examination. Tumors found in both groups tended to be small (1.5 cm vs. 2.2 cm), multiple (71% vs. 40%), and in lymph nodes (70% vs. 70%). All tumors identified were located anatomically within the gastrinoma triangle. Tumors were found in 10 of 11 patients (91%) in the study group, and significantly more patients had their tumors excised for cure as compared to controls (82% vs. 27%, p less than 0.05). The current prospective cure rate for gastrinoma is higher than previously appreciated and tumors within lymph nodes do not preclude curative resection.

Topics: Adult; Aged; Duodenal Neoplasms; Female; Follow-Up Studies; Gastrectomy; Gastrinoma; Gastrins; Humans; Lymph Nodes; Male; Middle Aged; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Prospective Studies; Remission Induction

Chromogranin A (Cg A) is a protein that is coreleased with peptide hormones from gut endocrine cells and tumors. Plasma levels of Cg A, pepsinogen group I, and gastrin were measured in 31 patients with gastrinoma. Mean Cg A level in 10 patients with gastrinoma who were not operated on was 169 +/- 32 ng/mL, while in 9 control patients it was 28 +/- 5 ng/mL. In 18 patients with gastrinoma with residual tumor after total gastrectomy, the mean Cg A level was 45 +/- 6 ng/mL, and in 10 patients with normal gastrin levels after total gastrectomy and tumor excision, the mean Cg A level was 40 +/- 4 ng/mL. In 7 patients in whom pregastrectomy and postgastrectomy Cg A levels were measured, the mean reduction was 94 +/- 27 ng/mL, or 66%. There was no correlation between Cg A levels and amount of tumor, presence of metastases, or multiple endocrine neoplasia type I syndrome. There was a significant correlation between Cg A and pepsinogen I levels but no correlation between Cg A and gastrin levels. The results suggest that the elevated plasma Cg A levels in patients with gastrinoma are determined primarily by the trophic effects of gastrin on gastric enterochromaffinlike cells rather than by corelease from the gastrin-producing tumor itself.

Topics: Adult; Aged; Calcium; Chromogranin A; Chromogranins; Female; Gastrectomy; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Nerve Tissue Proteins; Pancreatic Neoplasms; Pepsinogens

Topics: Fasting; Gastric Acid; Gastrinoma; Gastrins; Humans; Zollinger-Ellison Syndrome

We have used the gastrinoma syndrome to examine the effects of SMS. Acutely, SMS decreased acid secretion and restored the BAO/MAO to normal in eight of eight patients. Basal and secretin-stimulated gastrin responses were suppressed but not normalized. Treatment for up to 2 years with SMS controlled symptoms, suppressed serum gastrin, and suppressed acid secretion. Treatment for 1 year or longer decreased tumor secretion of gastrin and diminished basal acid secretion, an effect that persisted for 48 hours after withdrawal of SMS. SMS treatment arrested progression of tumor growth only in patients in whom there was a reduction in gastrin and gastric acid secretion. In patients with metastatic disease who had high levels of gastrin, SMS treatment for 5 to 24 months did not inhibit tumor growth or decrease gastrin levels. In those patients in whom a reduction in the blood flow to liver tumors was shown angiographically, there was a progressive improvement in hormone secretion and in tumor size in the ensuing year of treatment, suggesting that a major target of SMS is that vascular supply of the tumors. Tumors shown to produce peptides other than gastrin, for example ACTH, were found to be markedly resistant to the action of SMS and continued to grow in an unbridled manner.

Topics: Adult; Bone Neoplasms; Combined Modality Therapy; Female; Gastric Acid; Gastrinoma; Gastrins; Gastrointestinal Neoplasms; Humans; Liver Neoplasms; Male; Octreotide; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes

The characterization of the tumors and their metastasis in patients with the Zollinger-Ellison syndrome is currently based on the immunohistochemical identification of gastrin cells. However, sometimes tumoral cells fail to react with common C-terminal gastrin antibodies. In order to clarify this failure, we carried out morphologic, morphometric and immunocytochemical analyses performed on light and electron microscope levels of 6 pancreatic and 1 metastatic gastrinomas, using antibodies raised against various sequences of human progastrin. On the basis, in light microscopy, of qualitative analysis of immunostaining within cells and of immunostained cell numbers, gastrin 34 residue seemed to be the prominent form in 2 of the tumor tissues, G-17 in 1 tumor which was not responsive with C terminus progastrin and N terminus G-34 antisera, and progastrin in the metastatic tissue that did not contain typical gastrin (G-like) cells. Two tumors failed to react with all antisera used. At the electron microscope level, immunogold staining revealed that progastrin was present only in the progranules and gastrin 34 in both progranules and intermediate granules. Quantitative studies performed on 3 tumors showed that, within a given tumoral cell, about 25 percent of progranules contained progastrin while 75 percent contained gastrin 34. We concluded that different forms of gastrin can be immunodetected in a gastrinoma tissue, depending on the regions, and that the distribution of progastrin fragments is variable from tumor to tumor. So, specific antibodies to different fragments of progastrin may help to the characterization of gastrinomas.

Topics: Antibodies; Epitopes; Gastrinoma; Gastrins; Humans; Immune Sera; Immunohistochemistry; Microscopy, Electron; Pancreatic Neoplasms; Protein Precursors

There is a general agreement on the cell specificity of gastrin processing. In order to investigate this processing in Zollinger-Ellison (ZE) patients, we have studied in two primary gastrinoma cultures (one from a pancreatic tumor, the other from a liver metastasis) the proportion of progastrin fragments using immunochemical and immunohistological methods. In tumor extracts as well as in sera, the predominant gastrin form differed between the two patients (i.e. being G17 and G34, respectively). In the two gastrinoma cultures, RIA determinations and electron microscopic observations indicated that the proportion of progastrin increased with time while that of G17 and G34 decreased. On the other hand, as the culture time extended, an increasing proportion of nonimmunostained secretory granules was observed suggesting the presence of other gastrin precursors (e.g. Gly-extended progastrin). From these findings, we suggest that gastrinoma culture cells could be a valuable tool in the biochemical approach to gastrin processing in ZE tumors.

Topics: Cells, Cultured; Gastrinoma; Gastrins; Humans; Pancreatic Neoplasms; Protein Precursors; Staining and Labeling

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 case of Zollinger-Ellison syndromes in a fifty year-old male that was successfully treated with a H+-K+ ATPase inhibitor (Omeprazol) is reported. The patient underwent a partial gastrectomy in 1984, but had been suffering from multiple refractory stomal and jejunal ulcers after the operation. In 1987, hypergastrinemia (760 pg/ml) was detected, and the presence of gastrinomas in the pancreatic head accompanied by a multiple liver metastasis was subsequently confirmed by CT-angiography and by the gastrin level detected in percutaneous, transhepatic, portal venous samples. A secretin provocation test proved to be negative, and the ulcers resisted the H2-receptor antagonists, but the patient was successfully cured shortly after the administration of an H+-K+ ATPase inhibitor.

Topics: Adenosine Triphosphatases; Gastrinoma; Gastrins; H(+)-K(+)-Exchanging ATPase; Humans; Male; Middle Aged; Omeprazole; Pancreatic Neoplasms; Secretin; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

The purpose of this work was to evaluate the proposed usefulness of a standard meal-stimulated gastrin provocative test in: (1) distinguishing Zollinger-Ellison syndrome (ZES) from antral syndromes; (2) localizing duodenal gastrinomas; or (3) suggesting that patients with multiple endocrine neoplasia type I (MEN-I) may have an increased incidence of antral syndromes.. Seventy-four consecutive patients with ZES referred to the National Institutes of Health were studied prospectively. The extent and location of gastrinomas, acid secretory studies, and the presence or absence of MEN-I were determined and correlated with the results of the gastrin response to standard meal provocative testing.. For patients with fasting serum gastrin levels less than 1,000 pg/mL (n = 43), only 44% had a less than 50% increase over the pre-meal value, which is reported to be the typical response in ZES, and 40% had a 50% to 99% increase. Furthermore 16% had a 100% or greater increase, 9% a 150% or greater increase, and 5% a 200% or greater increase, which overlaps with values reported to be characteristic of 98%, 92%, and 46% of patients with antral syndromes. Results did not differ for patients with or without MEN-I, depend on the extent of the gastrinoma (duodenal versus pancreatic gastrinomas), the presence of previous gastric surgery or type of gastric surgery, or for patients with fasting serum gastrin concentrations greater than or equal to 1,000 pg/mL or less than 1,000 pg/mL. studies of four patients before and after resection of the gastrinoma, who prior to surgery had a greater than 100% increase in gastrin secretion after the meal, demonstrated that all patients had a less than 100% increase postoperatively even though no gastric resection was done.. Approximately half of the patients with ZES have a greater than 50% increase in serum gastrin concentration following a standard test meal and one fifth have a 100% or greater increase. Therefore, they cannot be distinguished on this basis from patients with antral syndromes. The increased serum gastrin level after the meal in these patients with ZES appears to be due to the gastrinoma. Furthermore, the current study provides no evidence for the proposals that antral syndromes are more common in patients with MEN-I, that gastric surgery affects the meal response in patients with gastrinomas, or that the meal test is useful in localizing duodenal gastrinomas.

Topics: Adolescent; Adult; Aged; Duodenal Neoplasms; Eating; Female; Gastric Acid; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prospective Studies; Zollinger-Ellison Syndrome

The pancreatic component of the multiple endocrine neoplasia type I (MEN I) syndrome is a difficult and controversial problem because the entire endocrine pancreas is diffusely involved with varying degrees of islet-cell hyperplasia, microadenomatosis, and nesidioblastosis. In addition, in patients with functional syndromes, islet-cell tumors usually develop, and these may or may not be malignant. Because of the presumed inability to alleviate or cure the Zollinger-Ellison syndrome (ZES) in MEN patients, total gastrectomy was the treatment of choice before the introduction of H2 antagonists and omeprazole. At present, many physicians and surgeons consider H2 antagonists the best treatment and advise pancreatic exploration only when a gross pancreatic tumor is demonstrated on imaging studies. During the past 10 years we have studied all MEN I patients with ZES without hepatic metastases or gross pancreatic tumors using percutaneous transhepatic selective venous gastrin samplings. Two patterns of gastrin secretion were identified: (1) diffuse from multiple pancreatic sites and (2) localized regional secretion. Four patients from the latter group were selected for attempted surgical "cure" without gastrectomy or total pancreatectomy. Two additional patients are included who had resection of gastrinomas and have maintained basal serum gastrin levels within the normal range for extended periods. The follow-up on these patients ranges from 5 months to 12 years. All six patients have normal basal gastrin values, and those with remaining stomachs require no drug therapy.

Topics: Adult; Biomarkers, Tumor; Female; Gastrectomy; Gastrinoma; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatectomy; Pancreatic Neoplasms

Sixty patients with surgically correctable hypergastrinemia were treated between 1960 and 1988. Provocative testing was used when available to select appropriate operations. Sources of hypergastrinemia included antral G cell hyperplasia (AGCH) (17), pancreatic gastrinomas (14), duodenal gastrinomas (11), multiple gastrinomas in patients with type I multiple endocrine neoplasia (MEN I) (five), lymph node gastrinomas (four), and the source not found in nine patients. Eugastrinemia was achieved by resection in 17 of 17 patients with AGCH, nine of 11 patients with duodenal gastrinomas, three of four patients with lymph node gastrinomas, zero of 14 patients with pancreatic gastrinomas, zero of five patients with MEN I, and zero of nine patients in whom the source was not found. Hepatic metastases developed in 11 patients with pancreatic gastrinomas, two patients with MEN I, one patient with duodenal gastrinomas, and one patient with lymph node gastrinomas. One patient in whom the source of the hypergastrinemia was not found developed hepatic metastases, and seven required total gastrectomy. This experience suggests the following: (1) that patients with AGCH, duodenal gastrinomas, or lymph node gastrinomas can usually be rendered eugastrinemic by resection; (2) that patients with pancreatic gastrinomas, whether sporadic or familial (MEN I), are rarely cured by resection and frequently develop hepatic metastases; and (3) that patients in whom the source of the hypergastrinemia is not identified and removed frequently require total gastrectomy, but antroduodenectomy should be considered because it may uncover an occult duodenal microneurogastrinoma or may correct AGCH.

Topics: Biomarkers, Tumor; Duodenal Neoplasms; Eating; Female; Follow-Up Studies; Gastrinoma; Gastrins; Humans; Hyperplasia; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prognosis; Secretin; Stomach; Stomach Neoplasms

We have followed 14 patients with the Zollinger-Ellison syndrome for a median period of 9 years. All patients have suffered from peptic ulcer disease and six of the 14 have had complications such as bleeding or perforated ulcer. Almost half the patients have had diarrhoea as a dominant symptom and 4 patients suffered from multiple endocrine neoplasia. Before 1978, the year when the H2-receptor antagonists were introduced, the majority of the patients were operated with total gastrectomy. After that year there has been no need for gastrectomies, but all but two patients have undergone an explorative laparotomy. We have been able to localize the gastrinoma in 9 of 12 operated patients; in 7 cases it was localized within the gastrinoma triangle. Three of the patients are considered to have been cured after surgery. Eight patients have needed adjuvant acid-reducing medical therapy. Five of these have been failures to high doses of H2-receptor antagonists and have been successfully treated with omeprazole. Five patients have died during the follow-up period and death in two of these cases was related to tumor progression.

Topics: Aged; Female; Follow-Up Studies; Gastrinoma; Gastrins; Histamine H2 Antagonists; Humans; Male; Middle Aged; Omeprazole; Zollinger-Ellison Syndrome

A 59-year-old female presented with multifocal peptic ulcer disease and diarrhea. A fasting serum gastrin level obtained while the patient was receiving no antacid therapy was normal. A secretin stimulation test was positive. A small gastrinoma was found in the anterior duodenal wall at exploratory laparotomy. Normal fasting gastrin levels do occur in patients with overt Zollinger-Ellison syndrome and should not deter further investigation if clinical suspicion of this syndrome is high.

Topics: Duodenal Neoplasms; Female; Gastrinoma; Gastrins; Humans; Middle Aged; Zollinger-Ellison Syndrome

Topics: Amino Acid Sequence; Animals; Base Sequence; DNA; Exons; Gastrinoma; Gastrins; Gene Expression Regulation; Humans; Introns; Pancreatic Neoplasms; Protein Precursors; Species Specificity

Tissue pieces of a metastatic human gastrinoma (ultrastructural Type II) were successfully transplanted to the anterior eye-chamber of rats immunosuppressed with Cyclosporin A. Immunocytochemical investigation of the transplants showed evidence for preserved endocrine activity of tumour cells with immunoreactivity towards the C-terminal of the gastrin/cholecystokinin molecule. Studies of gastric acid secretion in tumour-bearing rats and sham-operated controls with chronic gastric fistulas showed that the basal acid output did not differ between the groups during 3 weeks of study. However, the stimulated gastric acid secretion decreased after 5 days in both groups to remain significantly depressed throughout the study, an effect probably due to Cyclosporin A treatment of the groups. The concentration of immunoreactive gastrin in plasma from rats with tumours in oculo was 5 times higher than in sham-operated rats. Gastrin-34 was the major immunoreactive component in both patient serum and rat plasma. An immunoreactive fraction corresponding to component I was found in the patient serum, but not in the rat plasma, although present in the chamber fluid. Components corresponding to gastrin-17 were found both in the patient serum and in the rat plasma. The chromatographic pattern of the tumour was similar to that in rat chamber fluid. The dominating component corresponded to gastrin-17, while gastrin-34 represented the quantitatively smaller component. Gastrin-34 was, however, relatively more abundant in the tumour extract than in the chamber fluid. The study also indicates that a gastrin-producing tumour transplanted in oculo in immunosuppressed rats may increase the rat plasma concentration of the same molecular forms of gastrin as seen in the clinical situation.

Topics: Adolescent; Animals; Anterior Chamber; Chromatography, Gel; Female; Gastric Acid; Gastrinoma; Gastrins; Humans; Immunosuppression Therapy; Male; Microscopy, Electron; Neoplasm Transplantation; Pancreatic Neoplasms; Protein Precursors; Radioimmunoassay; Rats; Rats, Inbred Strains

Topics: Duodenal Neoplasms; Gastric Mucosa; Gastrinoma; Gastrins; Glycine; Humans; Pancreatic Neoplasms; Protein Precursors

Gastrinomas are now being detected at an earlier stage than was formerly the case. Furthermore, with the ability to control acid secretion, emphasis has been placed on identifying gastrinoma patients who are potentially curable by tumor resection rather than by palliative gastrectomy. Despites estimates suggesting that 20-40% of sporadic gastrinoma patients can be successfully resected for cure, as many as 40% of such patients have occult tumors that elude detection. In an effort to better localize gastrinomas, we have used percutaneous transhepatic venous (THVS) gastrin sampling over the past 10 years. From 1978 to 1988, THVS was used in 46 patients in whom there was no other evidence of metastatic gastrinoma by conventional studies. Gastrinomas were found at operation in all but one patient. The purpose of this report is to emphasize that occult tumors are most often found in the duodenal wall, and frequently they may be no greater than 2 mm in diameter. Five recent cases illustrate that these small tumors or microgastrinomas may be the sole source of hypergastrinemia and can be cured by local excision. These recent cases emphasize that microgastrinomas are not usually palpable through the duodenal wall. They may be detected only after duodenotomy and meticulous evaluation of the mucosa by eversion and direct palpation. Duodenotomy and intraluminal exploration should be considered an essential component of the operation for patients with extrapancreatic gastrinomas.

Topics: Aged; Duodenal Neoplasms; Duodenum; Female; Gastrinoma; Gastrins; Humans; Intestinal Mucosa; Male; Middle Aged; Zollinger-Ellison Syndrome

Gastrinoma cells from surgical specimens of a primary pancreatic tumor and an hepatic metastasis in two patients with a Zollinger-Ellison syndrome were grown and subcultured for 7 mo. Cultured cells displayed a strong reactivity to heptadecapeptide gastrin antibody and maintained an ultrastructural appearance resembling that of the original tumor cells with the presence of secretory granules of variable size and electron density. Cultured cells also showed the ability to secrete immunoreactive gastrin, and this secretion was further concentration-dependently stimulated by secretin (10(-10)-10(-6) M), carbachol (10(-6) M), and bombesin (10(-10)-10(-6) M). The latter peptide was the more potent stimulant with a maximal effect at 10(-9) M (460 +/- 20% of basal release; P less than 0.05). This stimulation occurred in the absence of extracellular Ca2+ and was potentiated by the addition of dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP; 10(-3) M) into the culture medium. The somatostatin analogue, somatostatin-(201-995), did not alter basal gastrin release but inhibited secretin, carbachol, and bombesin stimulation. Moreover, DBcAMP (10(-3) M) and Ca2+ (1-3 mM) stimulated gastrin release; Ca2+ ionophore A23187 (6 micrograms/ml) enhanced gastrin response to Ca2+ in the early time intervals of incubation. Furthermore the phorbol ester derivative, 12-O-tetradecanoyl phorbol-13-acetate, dramatically stimulated gastrin release (10 times the basal value). We conclude that gastrinoma cells can be cultured over an extended period with maintenance of their capacity to secrete gastrin in response to various hormones and mediators.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Bombesin; Bucladesine; Calcimycin; Calcium; Carbachol; Culture Media; Gastrinoma; Gastrins; Humans; In Vitro Techniques; Liver Neoplasms; Pancreatic Neoplasms; Secretin; Stimulation, Chemical; Tumor Cells, Cultured

Fifty-five consecutive patients with Zollinger-Ellison syndrome who underwent exploratory laparotomies for gastrinoma resection were evaluated prospectively to determine the effect of gastrinoma resection on acid secretion and to establish criteria for safe and effective perioperative management of gastric acid hypersecretion. In 15 patients (27%) no tumor was found and postoperative serum gastrin, basal acid output (BAO), and maximal acid output (MAO) were unchanged. Twenty-one patients (38%) had gastrinomas resected and were biochemically cured. Median fasting gastrin, median delta secretin, mean BAO, and mean MAO decreased 89%, 94%, 80%, and 43%, respectively, at 3-month follow-up in these patients. In 19 patients gastrinomas were resected, but patients were not cured, and median fasting gastrin, median delta secretin, mean BAO, and mean MAO decreased 47%, 10%, 26%, and 25%, respectively. Forty percent of patients with gastrinoma resected and cured and 81% of patients with gastrinoma resected but not cured continued to hypersecrete acid (BAO greater than 10 mEq/hr) at 3- to 6-month follow-up. Acid control was managed perioperatively during gastrinoma resection by continuous intravenous infusion of H2 receptor antagonists at a dose established by preoperative titration to decrease acid output to less than 10 mEq/hr. Thirty patients were treated with cimetidine at a mean dose of 3.2 mg/kg/hr for a mean of 13.8 days. Twenty-one patients were treated with ranitidine at a mean dose of 1.1 mg/kg/hr for a mean of 8 days. No patients suffered any complications related to acid hypersecretion or side effects of the H2 antagonists. Patients undergoing gastrinoma resection can be managed safely by continuous infusion of H2 antagonists. Successful gastrinoma resection can reduce acid output, but even 40% of biochemically cured patients will continue to hypersecrete acid at short-term follow-up and will require continuation of antisecretory medication.

Topics: Adult; Fasting; Female; Gastric Acid; Gastrinoma; Gastrins; Histamine H2 Antagonists; Humans; Infusions, Intravenous; Laparotomy; Male; Middle Aged; Osmolar Concentration; Pancreatic Neoplasms; Postoperative Period; Prospective Studies; Zollinger-Ellison Syndrome

Recent studies have suggested that patients with multiple endocrine neoplasia type I (MEN I) may have abnormal serum gastrin secretion in the absence of gastrin producing tumours. G-(gastrin) cell function by three provocation tests in 20 patients with hyperparathyroidism from six MEN I-families were studied: each patient was an obligate carrier of the MEN I-gene. The serum gastrin response to secretin was used to identify the presence of gastrinoma, that to a test meal of G-cell hyperfunction of the antral and/or duodenal mucosa, and that to bombesin to differentiate antral from duodenal G-cell hyperfunction. Seven patients had basal hypergastrinaemia and hyperchlorhydria. These patients had increased serum gastrin responses to secretin (p less than 0.01) and to bombesin (p less than 0.02), but normal postprandial responses. In the 13 normogastrinaemic patients the responses to the three stimuli were normal. In families with MEN-I gastrinoma is the only endocrine disorder accounting for abnormal gastrin secretion. G-cell function is normal in obligate carriers of the MEN I-gene.

Topics: Adult; Aged; Bombesin; Duodenum; Eating; Female; Gastrinoma; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia; Pyloric Antrum; Secretin

An analysis of data concerning 37 patients with the Zollinger-Ellison syndrome (ZES) has been made, 36 of them were operated upon. Gastrinoma was found in 21 patients. Diagnosis of ZES was made in two steps: the first one is fulfilled in general medical institutions, the second one-in specialized clinics. The diagnosis of ZES must be either confirmed or rejected with certainty. When choosing the method of operative treatment several groups of patients must be born in mind: ZES without a gastrinoma detected, ZES with a gastrinoma, ZES with malignant ulcerogenic tumour. The main operation for ZES remains to be gastrectomy.

Topics: Adult; Gastrectomy; Gastrinoma; Gastrins; Humans; Middle Aged; Pancreatic Neoplasms; Pyloric Antrum; Suture Techniques; Vagotomy; Zollinger-Ellison Syndrome

An ovarian gastrinoma would appear to be an extremely rare cause of the Zollinger-Ellison syndrome. Nevertheless, two consecutive cases of Zollinger-Ellison syndrome seen at our institution each proved to be caused by a gastrin-producing ovarian mucinous cystadenoma. That the ovarian tumor was the source of gastrin production was established by preoperative and postoperative gastrin and gastric secretory studies and by specific immunocytochemistry of the excised tissue. After oophorectomy, each patient was apparently cured of the disease. Ovarian gastrinomas may not be as uncommon as is generally believed and should be considered as a possible cause of the Zollinger-Ellison syndrome in any female patient in whom a primary gastrointestinal or pancreatic tumor cannot be located.

Topics: Adult; Cystadenoma; Female; Gastrinoma; Gastrins; Humans; Middle Aged; Ovarian Neoplasms; Zollinger-Ellison Syndrome

There is a potential phosphorylation site in the C-terminal region of the precursor for the acid-stimulating hormone gastrin, which is immediately adjacent to an important cleavage point. In the present study we have sought to identify, separate, quantify and characterize phosphorylated and unphosphorylated forms of human progastrin and its fragments. Identification was made by two radioimmunoassays: (a) a novel assay employing an antibody raised to intact human progastrin; and (b) an assay using antibody reacting with the C-terminal tryptic fragment of human progastrin, as well as progastrin itself. Two forms of human progastrin isolated from a gastrinoma were separated by ion-exchange h.p.l.c., and had similar elution positions on reverse-phase h.p.l.c. and on gel filtration. The more acidic peptide contained close to equimolar amounts of phosphate. On trypsinization, peptides were released that co-eluted on ion-exchange h.p.l.c. with, and had the immunochemical properties of, naturally occurring C-terminal fragments of progastrin. One of the latter was isolated and shown by Edman degradation after derivatization with ethanethiol to have the sequence Ser (P)-Ala-Glu-Asp-Glu-Asn. Similar peptides occur in antral mucosa resected from ulcer patients. The unphosphorylated forms of progastrin predominated, whereas the phosphorylated forms of the C-terminal fragments were predominant. This distribution could be explained by preferential cleavage of phosphorylated progastrin. We conclude that in human progastrin, Ser-96 can occur in the phosphorylated form; this residue immediately follows a pair of basic residues (Arg-Arg) that are cleaved during synthesis of the biologically active product.

Topics: Amino Acid Sequence; Chromatography, High Pressure Liquid; Gastric Mucosa; Gastrinoma; Gastrins; Humans; Liver Neoplasms; Molecular Sequence Data; Peptide Fragments; Phosphorylation; Protein Precursors; Trypsin

Most peptide hormone assays measure only fully processed bioactive peptides. Such assays are unsuited to detect hormone gene expression by alternative or attenuated prohormone processing (tissue- or cell-specific processing). The gastrin system is expressed in several different tissues and is therefore useful for studies of tissue-specific processing. Consequently we have developed a simple processing-independent radioimmunoanalysis for progastrin. Using antisera against the NH2-terminus of a sequence, devoid of processing sites (preprogastrin76-86) after trypsination of neighboring cleavage sites, the assay quantitates the mRNA product irrespective of degree of processing. Used together with a conventional assay for the mature carboxyamidated gastrins, the processing-independent analysis shows that in different tissues only 1 to 55% of the total translation product is processed to bioactive gastrins. Thus processing-independent analysis greatly improves the detection of gastrin gene expression at the peptide level. The principle of the assay should be applicable to all protein and peptide systems.

Topics: Amino Acid Sequence; Chromatography, Gel; Gastric Mucosa; Gastrinoma; Gastrins; Humans; Lung Neoplasms; Molecular Sequence Data; Peptide Fragments; Protein Precursors; Protein Processing, Post-Translational; Radioimmunoassay; Trypsin