gastrins and Pancreatic-Neoplasms

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

Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.

Topics: Bacterial Vaccines; Cancer Vaccines; Carcinoembryonic Antigen; Carcinoma, Pancreatic Ductal; Clinical Trials as Topic; Fowlpox virus; Gastrins; Genes, ras; Heat-Shock Proteins; Inhibitor of Apoptosis Proteins; Kinesins; Listeria monocytogenes; Mucin-1; Mutation; Pancreatic Neoplasms; Peptides; Survivin; Telomerase; Vaccines, Attenuated; Vascular Endothelial Growth Factor Receptor-2; Viral Vaccines; WT1 Proteins

The gastrointestinal (GI) peptide gastrin is an important regulator of the release of gastric acid from the stomach parietal cells and it also plays an important role in growth of the gastrointestinal tract. It has become apparent that gastrin and its related peptide cholecystokinin (CCK) are also significantly involved with growth of GI cancers as well as other malignancies through activation of the cholecystokinin-B (CCK-B) receptor. Of interest, gastrin is expressed in the embryologic pancreas but not in the adult pancreas; however, gastrin becomes re-expressed in pancreatic cancer where it stimulates growth of this malignancy by an autocrine mechanism. Strategies to down-regulate gastrin or interfere with its interface with the CCK receptor with selective antibodies or receptor antagonists hold promise for the treatment of pancreatic cancer and other gastrin--responsive tumors.

Topics: Animals; Gastrins; Humans; Pancreatic Neoplasms; Receptors, Cholecystokinin

Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like cells, via gastrin/cholecystokinin-2 receptor (CCK

Topics: Animals; Antineoplastic Agents; Benzodiazepinones; Disease Models, Animal; Drug Design; Gastric Acid; Gastrins; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Phenylurea Compounds; Receptor, Cholecystokinin B; Stomach Neoplasms

Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrin-sensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer. The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active 'adjuvant' treatment.

Topics: Adenocarcinoma; Autoimmune Diseases; Cancer Vaccines; Carcinoid Tumor; Colorectal Neoplasms; Gastrins; Gastritis; Humans; Liver Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms

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

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

The experience of synthesising a novel gastrin receptor antagonist gastrazole and taking it into 3 small clinical studies in pancreatic cancer in man is described. The need for such a compound is illustrated by the observation that inhibition of gastric acid secretion by H2 receptor antagonists results in hypergastrinaemia. A large number of cell types have gastrin receptors including pancreatic cancer cells which have been shown to be stimulated by gastrin. Small numbers of pancreatic cancer patients given gastrazole by continuous intravenous infusion showed prolonged survival compared with best supportive care or placebo, and equivalent survival to those given 5 fluouracil. The results suggest a greater benefit for patients with early stage disease. An alternative gastrin receptor antagonist YF 476 is also described which has the advantage of efficacy given by the oral route. This new compound requires to be studied in pancreatic cancer and other diseases associated with hypergastrinaemia.

Topics: Animals; Antineoplastic Agents; Benzodiazepinones; Clinical Trials as Topic; Cyanoacrylates; Drug Design; Fluorouracil; Gastric Acid; Gastrins; Humans; Infusions, Intravenous; Mice; Pancreatic Neoplasms; Phenylurea Compounds; Pilot Projects; Receptor, Cholecystokinin B; Receptors, Histamine H2; Xenograft Model Antitumor Assays

Pancreatic endocrine tumors are rare neoplasms accounting for less than 5% of pancreatic malignancies. They are broadly classified into either functioning tumors (insulinomas, gastrinomas, glucagonomas, VIPomas, and somatostatinomas) or nonfunctioning tumors. The diagnosis of these tumors is difficult and requires a careful history and examination combined with laboratory tests and radiologic imaging. Signs and symptoms are usually related to hormone hypersecretion in the case of functioning tumors and to tumor size or metastases with nonfunctioning tumors. Surgical resection remains the treatment of choice even in the face of metastatic disease. Further development of novel diagnostic and treatment modalities offers potential to greatly improve quality of life and prolong disease-free survival for patients with pancreatic endocrine tumors.

Topics: Adenoma, Islet Cell; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Islet Cell; Catheter Ablation; Chemoembolization, Therapeutic; Evidence-Based Medicine; Gastrins; Glucagon; Humans; Insulin; Insulin Secretion; Pancreatic Neoplasms; Quality of Life; Somatostatin; Survival Analysis; Treatment Outcome

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 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

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

There is still a substantial need for the development of new treatments for patients with pancreatic cancer. In this chapter, we will document that there is quite a bit of an increase in research activity with development in two major areas including (1) agents in the pipeline which already have hints of antitumor activity in patients with pancreatic cancer (therapeutic monoclonal antibodies and vaccines as well as more conventional cytotoxics), and; (2) agents in the pipeline which have just started (or will soon start) in clinical trial. These agents range from a gene-therapy approach to radiation enhancement to inhibitors of protein with increased expression in the very hypoxic pancreatic cancer tissue, to new monoclonal antibodies. With the level of investigational activity in pancreatic cancer it is very likely that several new therapeutic approaches to the disease will be forthcoming.

Topics: Adenoviridae; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzenesulfonates; Bevacizumab; Cancer Vaccines; Cetuximab; Cyclic N-Oxides; Deoxycytidine; Drug Combinations; Gastrins; Gemcitabine; Humans; Niacinamide; Oxonic Acid; Pancreatic Neoplasms; Phenylurea Compounds; Pyridines; Sorafenib; Sulfonamides; Tegafur; Tumor Necrosis Factor-alpha

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

Gastrointestinal (GI) hormones are chemical messengers that have been recognized for over a century as regulatory factors for normal physiologic functions in the GI tract and pancreas, including absorption, secretion, motility, and digestion. These hormones traditionally act in a true endocrine fashion with release from a distant site to regulate physiologic functions of specific target organs. In general, GI hormones bind to their G-protein-coupled receptors (GPCRs) to produce their endocrine effects. In addition to effects on physiologic functions of the GI tract and pancreas, selected GI hormones can act in an endocrine, paracrine, and/or autocrine fashion to stimulate the proliferation of normal and neoplastic GI tissues as well as non-GI tissues. This review will focus on effects of GI hormones on neoplastic tissues concentrating on the hormones that have been best characterized for these effects.

Topics: Biomarkers, Tumor; Colorectal Neoplasms; Female; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Growth Substances; Humans; Male; Pancreatic Neoplasms; Prognosis; Receptors, Gastrointestinal Hormone; Risk Assessment; Sensitivity and Specificity; Signal Transduction; Stomach Neoplasms; Survival Analysis

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

The gastrointestinal peptide hormones gastrin and cholecystokinin (CCK) are well known for their ability to stimulate gastric acid secretion and pancreatic enzyme secretion, respectively. The suggestion that gastrin and CCK might also promote the development of cancers of the gastrointestinal tract has been controversial, but an increasing body of evidence now supports the view that the amidated and non-amidated forms of gastrin act as growth factors via different receptors in different regions of the gut. For example, animal experiments indicate that amidated gastrins are involved in cellular differentiation and repair in the gastric mucosa, and synergize with Helicobacter pylori infection in the development of gastric carcinoma. In contrast, non-amidated gastrins stimulate colonic mucosal growth, accelerate the early steps in colorectal carcinoma formation, and are elevated in the tumour and circulation of patients with colorectal cancer. Although human pancreatic carcinomas express CCK-1 and CCK-2 receptors, the role of gastrins and CCK in pancreatic carcinogenesis is yet to be established. Further investigation of the possible role of the CCK-2 receptor in gastric and pancreatic neoplasia, and of the hypothesis that gastrin precursors act as autocrine growth factors in colorectal carcinoma, is warranted. However, therapies aimed at the gastrins must be targeted to the relevant gastrin/gastrin receptor combination.

Topics: Cholecystokinin; Colorectal Neoplasms; Gastrins; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms; Receptors, Cholecystokinin; Stomach Neoplasms; Tumor Cells, Cultured

Accumulating evidence in literature suggests that amidated and non-amidated gastrins (gastrin precursors) may play an important role in the proliferation and carcinogenesis of gastrointestinal and pancreatic cancers, especially in the presence of DNA damaging agents and/or infectious agents. Amidated gastrins appear to have a protective role, while progastrins exert growth promoting effects in cancers. Several receptor subtypes and signal transduction pathways mediate the biological effects of the gastrin peptides. Progastrin and gastrins also exert anti-apoptotic effects, which may additionally contribute to the growth and co-carcinogenic effects of these peptides on GI mucosal cells in vivo. Amidated gastrins additionally play an important role in the migration of GI epithelial cells, and in glandular morphogenesis, while progastrins may play an important role in invasion and metastasis. Therefore, targeting progastrins, gastrins, and their cognate receptors may provide a therapeutic tool for treating GI and pancreatic cancers. Targeting CCK2-receptors has, so far, not provided optimal beneficial effects. However, targeting gastrins via a vaccine approach has provided some encouraging results for treating GI and pancreatic cancers. It is expected that targeting precursor gastrins (progastrins and gly-gastrins), exclusively rather than amidated gastrins, may be more effective for treating GI cancers. Since GI cancers at advanced stages are largely responsive to autocrine and intracrine progastrins, down-regulation of intracellular progastrins will likely be more effective at this stage.

Topics: Animals; Antineoplastic Agents; Apoptosis; Gastrins; Gastrointestinal Neoplasms; Humans; Immunotherapy; Neoplasm Metastasis; Pancreatic Neoplasms; Protein Precursors; Receptor, Cholecystokinin B; Signal Transduction

The objectives of this review are to summarize, analyse and discuss the roles played by the CCK receptor subtypes and their agonists on pancreatic enzyme secretion, pancreas growth and regeneration, define the receptors specific target cells and evaluate the role of gastrin in pancreatic pathologies including cancer. In rodents, it is clear that the CCKARs present on pancreatic acinar cells play a major role in enzyme secretion. In large mammals, CCK does not seem to be the final mediator of enzyme release. In rat, gastrin and its CCKBR seem responsible for foetal pancreas growth while after birth, CCK was shown to be the most potent trophic factor via occupation of its CCKAR. In pig and human, no one has yet established a direct link between CCK, gastrin and pancreas growth. In rodent's pancreas, the CCKAR were observed on acinar cells as well as on islet's alpha and beta cells; in six other species, the CCKAR were present only on alpha and beta cells with the CCKBR always present on delta cells. The CCKBRs were overexpressed in acute pancreatitis and in metaplastic pancreas following duct ligation. In pancreatic cancer cells, a gastrin autocrine loop involving the CCKBR was suggested. The presence of both CCKR-subtypes and gastrin was observed in many pancreatic tumors; however, their role in cancer growth remains controversial.

Topics: Animals; Gastrins; Humans; Pancreas; Pancreatic Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Regeneration

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

Aphton is developing an anti-gastrin vaccine [Anti-gastrin 17 immunogen, G17DT, Gastrimmune], which neutralises the gastrin 17 hormone and the Gly-G17 hormone. Gastrin 17 is a growth factor for pancreatic, stomach and colorectal cancers, and a potent stimulator of gastric acid secretion.The anti-gastrin immunogen, G17DT, consists of a large carrier protein, called Diptheria Toxoid (DT). A synthetic peptide, which is similar to a portion of the gastrin 17 hormone (GT), is attached to the carrier protein. These are then contained in a liquid suspension vehicle. When administered to patients, G17DT induces an immune response producing antibodies, which cross-react and neutralise the target hormone thus preventing its interaction with disease-causing or -participating cells. Aphton has entered into an agreement with Aventis Pasteur for the marketing of G17DT in all human cancer indications in North America and Europe. Under the terms of the agreement, Aphton is responsible for product development, clinical trials and regulatory agency approvals. The agreement was originally with Pasteur Mérieux Connaught, a subsidiary of Rhône-Poulenc. However, in December 1999, Rhône-Poulenc merged with Hoechst to form Aventis. As a result of the merger, Pasteur Mérieux Connaught underwent a name change to Aventis Pasteur. In July 2002, Aphton announced that it would negotiate with companies wanting to licence the vaccine in territories other than North America and Europe. In February 2003, Aphton announced it had received fast track designation for G17DT in combination with cisplatin and fluorouracil for use in stage IV gastric cancer to improve overall survival. In July 2002, the US FDA granted G17DT orphan drug status for the treatment of gastric cancer, an indication that was broader than the indication Aphton originally sought. The vaccine was also granted orphan drug status in Australia for gastric cancer in December 2002. In July 2002, Aphton announced that the US FDA had granted G17DT orphan drug status for the treatment of adenocarcinoma of the pancreas. In September 2002, the US FDA also granted G17DT, used in combination with gemcitabine, fast track status for the treatment of pancreatic cancer patients. In addition, the vaccine was also granted orphan drug status in Australia for pancreatic cancer in December 2002. In March 2003, Aphton announced that the Committee for Orphan Medicinal Products had recommended to the European Commission that G17DT be granted orph

Topics: Animals; Cancer Vaccines; Clinical Trials as Topic; Colorectal Neoplasms; Gastrins; Humans; Orphan Drug Production; Pancreatic Neoplasms; Peptic Ulcer; Rats; Stomach Neoplasms; Vaccines

This past year has proved to be a relatively disappointing one for the development of agents that could improve the survival rates of patients with advanced pancreatic cancer. A well designed randomized trial of treatment of patients with gemcitabine with or without a farnesyl transferase inhibitor (tried because pancreatic cancers have a high incidence of K- abnormalities) showed no improvement in survival rates. A definitive randomized controlled trial with a histone deacetylase inhibitor also proved negative. There are some signs of hope in that in early nonrandomized studies there are some new agents that appear to have some activity against the disease. These agents include the thymidylate synthase inhibitor capecitabine (which is possibly activated at the tumor site), the antigastrin immunogen G17DT (which is an immunization designed to neutralize the pancreatic growth factor gastrin), and the topoisomerase I inhibitor 9-nitrocamptothecin. In addition, the combination of the new agent oxaliplatin to high-dose 5FU plus leucovorin, which gave a median survival rate of 12.5 months, is also worthy of further study. Supportive care findings of interest for the patient with advanced pancreatic cancer of note include: the study in which eicosapentaenoic acid (fish oil) caused a modest weight gain (median of 1 kg), and the finding that ofloxacin plus ursodeoxycholic acid was not superior to ursodeoxycholic acid alone for the prevention or occlusion of biliary stents.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cancer Vaccines; Capecitabine; Deoxycytidine; Diphtheria Toxoid; Fluorouracil; Gastrins; History, 16th Century; Humans; Palliative Care; Pancreatic Neoplasms; Prognosis; Randomized Controlled Trials as Topic

Pancreatic secretion can be influenced by cholecystokinin (CCK) either directly via actions on acinar cells or indirectly via actions on nerves. The presence and functional roles of CCK receptors on human pancreatic acinar cells remains unclear. In the current study human pancreatic acini were isolated and then treated with CCK-8, gastrin and/or carbachol. Functional parameters were measured including intracellular [Ca2+] and amylase secretion. It was observed that human acini did not respond to CCK agonists but did respond to carbachol with robust increases in functional parameters. Adenoviral-mediated gene transfer of CCK1 or CCK2 receptors to the human cells resulted in cell responses to CCK agonists. In order to determine the reason for the lack of responsiveness of the human acini, expression of receptor mRNAs was determined using quantitative RT-PCR and localized by in situ hybridization. mRNA levels for CCK1 receptors were approximately 30 times lower than those of CCK2 receptors, which were approximately 10 times lower than those of m3 Ach receptors as measured by quantitative PCR. Neither CCK1 nor CCK2 receptors were localized in adult human pancreas by in situ hybridization. These results indicate that human pancreatic acinar cells do not respond directly to CCK receptor activation and this is likely due to an insufficient level of receptor expression.

Topics: Amylases; Carcinoma, Acinar Cell; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization; Pancreatic Neoplasms; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; Sincalide

In this paper the possible roles of cholecystokinin (CCK), gastrin, or gastrin-related peptides and their receptors in human gastrointestinal diseases are reviewed. For CCK/CCK(A) receptors (CCK(A)-R), the evidence for their proposed involvement in diseases caused by impaired CCK release or CCK(A)-R mutations, pancreatic disorders (acute/chronic pancreatitis), gastrointestinal motility disorders (gallbladder disease, irritable bowel syndrome), pancreatic tumor growth and satiety disorders, is briefly reviewed. The evidence that has established the involvement of gastrin/CCK(B)-R in mediating the action of hypergastrinaemic disorders, mediating hypergastrinaemic effects on the gastric mucosa (ECL hyperplasia, carcinoids, parietal cell mass), and acid-peptic diseases, is reviewed. The evidence for their possible involvement in mediating growth of gastric and pancreatic tumours and possible involvement of gastrin-related peptides in colon cancers, is reviewed briefly.

Topics: Animals; Cholecystokinin; Gastrins; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms; Receptors, Cholecystokinin

Pancreatic cancer is rarely curable, and only 5% of patients achieve long-term survival. The vast majority of patients present with metastatic or unresectable disease. Standard chemotherapy with gemcitabine provides clinical benefit to only a small minority of patients. Thus, the development and investigation of new therapies is clearly needed. As knowledge of the underlying biology of pancreatic cancer has increased, targeted therapies based upon preclinical laboratory work have been developed, and are entering clinical trials. Some of these agents lack traditional dose-limiting toxicities (DLTs) at biologically active doses, and therefore clinical evaluation may not follow traditional guidelines for cytotoxic drug development. This article focuses on targeted therapies currently undergoing clinical evaluation in pancreatic cancer. Classes of therapeutics reviewed include those targeting tumor-microenvironment interactions (matrix metalloproteinase inhibitors, vascular endothelial growth-factor blockade), signal transduction (e.g., farnesyltransferase inhibitors), growth-factor receptors (epidermal growth-factor receptor blockade, Her-2/neu, gastrin), and vaccine approaches. Currently, there is a renewed optimism that the clinical application of biologic understanding will lead to an improved outcome for patients with pancreatic cancer.

Topics: Antineoplastic Agents; Cancer Vaccines; Enzyme Inhibitors; Gastrins; Genes, erbB-2; Humans; Matrix Metalloproteinase Inhibitors; Pancreatic Neoplasms; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction

Gastrointestinal peptides including mammalian bombesin-like peptides, cholecystokinin (CCK), gastrin, and neurotensin stimulate DNA synthesis and cell proliferation in cultured cells and are implicated as growth factors in a number of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation. These agonists bind to G protein-coupled receptors (GPCRs) that promote Galpha q-mediated activation of beta isoforms of phospholipase C to produce two second messengers: Inositol (1,4,5) trisphosphate {Ins (1, 4, 5) P3} that mobilises Ca2+ from internal stores, and diacylglycerol that activates the classic and new isoforms of the protein kinase C (PKC) family. PKCs play a critical part in transducing bombesin/gastrin releasing peptide (GRP) receptor signals into activation of protein kinase cascades. Protein kinase D (PKD), a serine/threonine protein kinase with distinct structural and enzymological properties, is activated by phosphorylation in living cells through a new PKC-dependent signal transduction pathway. GPCR agonists including bombesin/GRP induce a rapid and striking activation of PKD by PKC. These results indicate that PKD functions downstream from PKCs and identify a new phosphorylation cascade that is activated by gastrointestinal peptide agonists. The bombesin/GRP GPCR also promotes rapid Rho-dependent assembly of focal adhesions, formation of actin stress fibres and tyrosine phosphorylation of multiple cellular proteins. We identified p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (CAS) and paxillin as prominent targets of gastrointestinal peptide-stimulated tyrosine phosphorylation and developed a model that envisages a G12/Rho-dependent pathway connecting GPCR activation to the tyrosine phosphorylation of these focal adhesion proteins. Separate pathways mediate gastrointestinal peptide stimulation of additional tyrosine kinase pathways including transactivation of Src and epidermal growth factor receptor (EGFR). Tyrosine phosphorylation has a critical role in gastrointestinal peptide-induced cellular migration and cooperates with Gq-stimulated events to promote mitogenesis. The growth-promoting effects of neuropeptides and the elucidation of the signalling pathways that mediate their effects assume an added importance because these agonists and their receptors are increasingly implicated in sustaining the proliferation of clinically aggressive solid tumours including those from lu

Topics: Animals; Bombesin; Carcinoma, Small Cell; Cholecystokinin; Colonic Neoplasms; ErbB Receptors; Gastrins; Humans; Lung Neoplasms; Mice; Neuropeptides; Neurotensin; Pancreatic Neoplasms; Phosphorylation; Protein Kinase C; Receptors, Leukotriene B4; Receptors, Purinergic P2; rho GTP-Binding Proteins; Signal Transduction; Swiss 3T3 Cells

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

Several gastrointestinal (GI) hormones, such as gastrin, cholecystokinin, and bombesin, have been reported to affect the development of pancreatic cancer. The receptors for these hormones are found in normal and neoplastic pancreatic cells. Activation of these receptors enhances pancreatic carcinogenesis and promotes the growth of established pancreatic carcinoma either in vitro or in vivo. On the other hand, some studies have shown that these GI hormones may have no effect or may play an inhibitory role in the development of pancreatic cancer. The reasons for the apparent discrepancies in the published literature are discussed in this review. In recent years, increasing emphasis has been placed on the effects of GI hormones on cancer invasion and metastasis. As the transition from noninvasion to the invasive state is the crucial event in cancer development, further investigation of the way in which GI hormones affect the invasion and metastasis of pancreatic cancer may be important for the development of new therapeutic approaches with eventual clinical utility.

Topics: Animals; Bombesin; Carcinogens; Cholecystokinin; Cricetinae; Gastrins; Gastrointestinal Hormones; Humans; Lymphatic Metastasis; Pancreas; Pancreatic Neoplasms; Rats; Risk Assessment; Sensitivity and Specificity; Vasoactive Intestinal Peptide

The objective of this study was to investigate spontaneous islet cell carcinomas with particular reference to possible existing strain differences between Sprague Dawley (SD) and Wistar (W) rats in incidence and immunohistochemical staining pattern. Secondly the occurrence of somatostatin and/or gastrin-positive islet cell tumors should be tested. Islet cell adenocarcinomas (34 from SD, 43 from W-rats) were selected from the RITA-data base and company in-house data base out of an animal pool of 3915 (1681 SD, 2234 W-rats). They were untreated or sham-treated (vehicle) control animals from carcinogenicity studies and whole life-span experiments. Islet cell carcinomas occurred in a higher incidence in male rats (2.98% for SD, 3.23% for W) than in female rats (1.07% for SD, 0.63% for W). All specimens were immunohistologically stained with antibodies against insulin, glucagon, somatostatin and gastrin and, selected specimens with additional antibodies (pancreatic polypeptide, lipase, chymotrypsin, S100-protein, actin and cytokeratin). 94% (SD) and 93% (W), respectively, were insulin-positive and the mean staining intensity (on a scale ranging from 0-4) for insulin was 3.58 (SD) versus 3.37 (W). This high insulin staining incidence and intensity characterized most islet cell carcinomas as malignant insulinomas. 24% (SD) and 37% (W), respectively, were glucagon-positive. Except two tumors in W-rats with a focal strong glucagon expression, the mean staining intensity for glucagon was low (0.38 SD, 0.72 W). 38% (SD) and 44% (W), respectively, were somatostatin-positive, but except for five cases having a focal to multifocal, moderate to marked staining, only a few tumor cells were positive for somatostatin in the other cases and the mean staining intensity for somatostatin was low (0.50 SD, 0.84 W). 6% (SD) and 23% (W), respectively, were gastrin-positive, but only one case of a male Wistar rat exhibited a focal strong staining in parts of the tumor. The other cases showed only a few tumor cells which were positive for gastrin. The mean staining intensity for gastrin was low (0.06 SD, 0.35 W). In all tumors with marked glucagon, somatostatin or gastrin expression, the immunostaining for insulin was still predominating. Thus, insulin was the major hormone produced by most of the tumor cells. Five out of 77 tumors evaluated were immunohistologically negative with all applied antibodies.. This study presents the first immunohistochemical survey on spontaneous islet cell carcinomas in SD and Wistar rats stained with antibodies against the endocrine pancreas hormones insulin, glucagon, somatostatin and gastrin. No major differences in incidence or immunohistochemical staining pattern between SD and W-rats could be detected. In contrast to SD rats, Wistar rats had multihormonal coexpression in 16.3%. The multihormonal appearance of the neoplasms is well comparable with the findings in other animal species and human insulinomas. Moreover, this is the first study in rats which reports five cases with a marked co-expression of somatostatin and one case with marked focal co-expression of gastrin in malignant islet cell adenocarcinomas.

Topics: Animals; Antibodies, Neoplasm; Biomarkers, Tumor; Carcinoma, Islet Cell; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Insulin; Male; Pancreatic Neoplasms; Rats; Rats, Sprague-Dawley; Rats, Wistar; Registries; Somatostatin

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

The rationale for a multifaceted operative procedure in all MEN 1 patients with pancreaticoduodenal neuroendocrine disease who present without liver metastases is presented. The results in 36 patients with MEN 1 ZES are encouraging in that more than two-thirds are eugastrinemic and none have liver metastases after follow-up as long as 20 years.

Topics: Adult; Duodenal Neoplasms; Female; Follow-Up Studies; Gastrins; Hormones; Humans; Liver Neoplasms; Male; Mass Screening; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Octreotide; Pancreatectomy; Pancreatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; 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

There is no question that gut peptides are trophic for normal gut mucosa. Gut peptides can function in an endocrine, paracrine or autocrine fashion. We examined the effects of gut peptides on the growth of animal and human cancers of the gastrointestinal (GI) tract and pancreas in vivo and in vitro. We also examined the role of growth factors and bioamines in the regulation of growth of human endocrine tumors. Our studies have shown that gut peptides (gastrin, VIP, neurotensin, and bombesin) regulate growth of some cancers of the GI tract and pancreas. We have found that peptide action is mediated through specific receptors and that cell-specific differences in receptor expression occur. We have also begun to examine the intracellular signal-transduction pathways involved in endocrine and autocrine actions of these peptides on growth of GI cancers. We have found that cell-type-specific differences exist among the various signal-transduction pathways (cyclic AMP, phosphatidylinositol hydrolysis (PI), intracellular calcium ([Ca2+]i) mobilization, and tyrosine phosphorylation) and that different receptors for the same hormone may be linked to different signal-transduction pathways depending upon cell type. We have also found that autocrine growth regulation of human pancreatic carcinoid occurs through specific receptor-mediated signal-transduction pathways. We will discuss the mechanisms of action and potential therapeutic uses of manipulation of gut hormone levels or hormone antagonists to inhibit the growth of GI tract cancers.

Topics: Animals; Bombesin; Cell Division; Cell Line, Transformed; Cell Transformation, Neoplastic; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Humans; Neurotensin; Pancreatic Neoplasms; Receptors, Gastrointestinal Hormone; Signal Transduction; Vasoactive Intestinal Peptide

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

Histopathological and experimental observations indicate that tumors composed wholly or in part of neuroendocrine elements may arise in tissues derived from ectoderm (including neuroectoderm), mesoderm, and endoderm. These tumors frequently exhibit multidirectional differentiation as manifested by multihormonality and by the presence of morphological features indicative of divergent differentiation both in vivo and in vitro. The existence of stem cells, plasticity of differentiated cells, microenvironmental influences, and random events are factors which might all interact to determine the characteristics of any particular tumor. The production of characteristic regulatory peptide products in association with tumors of specific histological subtypes and with other neuroendocrine markers suggests mechanisms for nonrandom activation of multiple genes common to neuroendocrine-programmed cells. Future studies applying new molecular biological techniques to intact tissues and to in vitro models may help to clarify the mechanisms that regulate the expression of the neuroendocrine phenotype in normal and neoplastic states.

Topics: Adrenal Gland Neoplasms; Animals; Apudoma; Calcitonin; Carcinoid Tumor; Cricetinae; Female; Gastrins; Hormones, Ectopic; Humans; Neurotensin; Ovarian Neoplasms; Pancreatic Neoplasms; Pheochromocytoma; Rats; Somatostatin; Thyroid Neoplasms; Uterine Neoplasms; Vasoactive Intestinal Peptide

The Zollinger-Ellison syndrome (ZES) is caused by mainly pancreatic, gastrin-producing tumours, which show a high rate of malignancy. The clinical picture is dominated by gastric hypersecretion, which results in the development of peptic ulcerations of the stomach and duodenum, reflux esophagitis, or diarrhea. The differentiation from other types of hypergastrinemia is done by provocative tests, mainly the secretin-test. Because of the high malignancy rate, therapeutically, a symptomatic treatment of gastric hypersecretion by H2-receptor antagonists or in cases of ineffective conservative treatment total gastrectomy is performed. In patients with duodenal gastrinomas or in the rare cases with benign pancreatic tumours resection of the tumours is the therapy of choice.

Topics: Benzimidazoles; Calcium; Cimetidine; Diarrhea; Duodenal Ulcer; Female; Fluorouracil; Gastrectomy; Gastric Acid; Gastrins; Glucagon; Humans; Male; Middle Aged; Omeprazole; Pancreatic Neoplasms; Prognosis; Ranitidine; Secretin; Streptozocin; Zollinger-Ellison Syndrome

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

The application of radioimmunoassay of insulin, C-peptide, gastrin, glucagon, vasoactive intestinal polypeptides (VIP), somatostatin, human pancreatic polypeptides (hPP), substance P and neurotensin to detect endocrine tumors of the pancreas and other organ systems is undoubtedly important in the clinical management of patients suspected of having tumors that secrete these hormones. Radioimmunoassays of the above gut peptides have certain degrees of specificity and sensitivity; however, there are several factors that need to be considered in the interpretation of results since heterogeneity of molecular forms does occur and the varied radioimmunoassay techniques use different antibodies that may yield different results. It is, therefore, important that each laboratory establish its own normal values, determine the molecular species that each assay is detecting, and also determine the false positivity of the methodology. The same endocrine tumor may contain and secrete several detectable peptides, but the syndrome may relate to only one peptide. Although the simultaneous measurement of multiple peptides in patients with benign gastrointestinal disease has yielded information that contributes to our understanding of the complexities of gut neuroendocrine interaction, the pathophysiological role of gut peptides and their clinical relevance need further evaluation.

Topics: Animals; Diagnosis, Differential; Digestion; Food; Gastrins; Gastrointestinal Diseases; Gastrointestinal Hormones; Humans; Kidney Diseases; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Vagus Nerve; Vasoactive Intestinal Peptide; Vipoma; Zollinger-Ellison Syndrome

Topics: Diabetes Mellitus; Gastrins; Humans; Pancreatic Hormones; Pancreatic Neoplasms; Peptic Ulcer; Somatostatin; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Gastrins; Humans; Insulin; Insulin Secretion; Insulinoma; Pancreatectomy; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Topics: APUD Cells; Apudoma; Cholecystokinin; Endocrine Glands; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Humans; Neurotransmitter Agents; Pancreatic Neoplasms; Peptides; Secretin

Topics: Adenoma, Islet Cell; Animals; Cytoplasmic Granules; Gastrins; Glucagon; Humans; Insulin; Multiple Endocrine Neoplasia; Neoplasms, Hormone-Dependent; Pancreatic Neoplasms; Proinsulin; Somatostatin

Gastrointestinal hormones (GI hormones) have received growing interest in endocrinology, gastroenterology and neuroendocrinology. Because of new methodological techniques, they can be measured in plasma and therefore be related to different pathophysiological conditions. In childhood, our present knowledge is as yet limited to the physiological rôle of gastrin at different ages and in some diseases (gastrinoma; Verner-Morrison syndrome) caused by humoral dysfunction. The present review relates the clinical important GI hormones to chemically classified families. The diagnostic value of determining endogenous hormone concentration in plasma and the validity of function tests carried out by administration of exogenous hormones are pointed out. Particular emphasis is given to the trophic action of GI hormones in the development and function of the gastrointestinal tract during childhood. More speculatively, GI hormones are involved in the complex function of the central nervous system, thus making food intake a trophotropic action in a broader sense.

Topics: Adenoma, Islet Cell; Bombesin; Ceruletide; Child; Cholecystokinin; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Motilin; Neurotensin; Pancreatic Neoplasms; Pancreatic Polypeptide; Secretin; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Female; Gastrins; Humans; Insulin; Insulin Secretion; Male; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Chenodeoxycholic Acid; Cholecystokinin; Cholelithiasis; Dehydration; Diabetes Mellitus; Duodenal Ulcer; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Humans; Motilin; Pancreatic Neoplasms; Secretin; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

The identification and description of a widely dispersed group of cells of common origin and biochemical characteristics, APUD cells, has allowed a better understanding and classification of endocrine tumors of the pancreas. Similarly, it has enabled the relationships between the endocrine tumors of the multiple endocrine neoplasia type I syndrome and the endocrine tumors of the pancreas to be better appreciated. This has facilitated both diagnosis and management of these conditions. The pluripotentiality of the cells of the APUD system combined with the certain existence of many unidentified peptides suggests the likelihood of other undescribed pancreatic endocrine tumors. Many of these are probably part of the heterogenous group of neoplasms currently designated as carcinoids, since their secretory products and exact cell types are not known. The recognition of the physiologic characteristics and cells of origin of these peptides, amines or other bioactive agents will allow delineation of the symptom complex and the identification of further functional tumors of the pancreas. The development of plasma radioimmunoassays for the various hormones and the appreciation of the specific clinical syndromes related to each tumor have enabled earlier diagnosis. The understanding of the hormonal physiopathologic functions has led to the evolution of specific therapeutic maneuvers. Provocative tests have allowed increased precision of the differential diagnosis, while selective arteriography and pancreatic venous sampling have greatly enhanced the accuracy of topical localization. The role of operation in tumor removal is still prominent, but malignant and recurrent tumors may now also be controlled with specific pharmacotherapy or appropriate endocrine cytotoxic agents. The use of peptides with antagonistic actions or the administration of specific antibodies to the active tumor products are areas of therapy that require further exploration.

Topics: Adult; Apudoma; Carcinoid Tumor; Child; Diagnosis, Differential; Gastrins; Glucagon; Humans; Infant; Insulin; Insulin Secretion; Islets of Langerhans; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Animals; Gastric Mucosa; Gastrins; Humans; Intestinal Mucosa; Nervous System; Pancreas; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Apudoma; Dehydration; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Parathyroid Neoplasms; Pheochromocytoma; Postgastrectomy Syndromes; Somatostatin; Syndrome; Thyroid Neoplasms; Zollinger-Ellison Syndrome

Topics: APUD Cells; Diagnosis, Differential; Gastrins; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The pathology and cell biology of endocrine pancreatic tumors are reviewed. It is probable that all these tumors are "functioning" in the sense that they elaborate hormones that cause more or less conspicuous clinical syndromes. Identification of such secretory products is essential for an optimal diagnosis, localization, treatment, and follow-up. Recent data indicate that endocrine pancreatic tumors evolve from progenitor cells of ducts. This histogenetic mechanism may explain the occurrence not only of mixed or multihormonal tumors but also of tumors producing hormones that are absent from the adult human pancreas. In addition to their clinically apparent effects, many endocrine pancreatic tumors affect the surrounding endocrine pancreas in a characteristic way. The mechanisms behind and the potential diagnostic usefulness of these changes are discussed.

Topics: Adenoma, Islet Cell; Adult; Animals; APUD Cells; Child; Gastrins; Glucagon; Humans; Infant, Newborn; Islets of Langerhans; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides; Somatostatin

Topics: Adenoma, Islet Cell; Cholecystokinin; Gastric Juice; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Neoplasms; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides; Precancerous Conditions; Secretin; Somatostatin; Stomach Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Adolescent; Adult; Aged; Carcinoid Tumor; Child; Dehydration; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Hyperplasia; Hypokalemia; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Precancerous Conditions; Serotonin; Somatostatin; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

The familial aggregation of peptic ulcer disease has been well established, as has its association with such clear-cut genetic factors as blood group O and nonsecretor status. However, the genetics of this disorder, or group of disorders, is still in question. Polygenic inheritance is the prevailing hypothesis that has been proposed for peptic ulcer. This hypothesis was based primarily on the exclusion of a simple mode of inheritance for all ulcer disease. Genetic heterogeneity is an alternative hypothesis that can explain both the familial aggregation of peptic ulcer disease and the lack of a simple Mendelian pattern of inheritance. The evidence for genetic heterogeneity in peptic ulcer disease is reviewed, and studies are proposed to test this hypothesis.

Topics: ABO Blood-Group System; Antigens; Chromosome Aberrations; Chromosome Disorders; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms; Pepsinogens; Peptic Ulcer; Phenotype; Pituitary Neoplasms; Stomach Ulcer; Werner Syndrome

Topics: Adrenocorticotropic Hormone; Blood Glucose; Diabetes Mellitus; Gastric Juice; Gastrins; Glucagon; Growth Hormone; Humans; Hypoglycemia; Insulin; Islets of Langerhans; Male; Organ Specificity; Pancreas; Pancreatic Neoplasms; Somatostatin; Thyrotropin; Thyrotropin-Releasing Hormone

Topics: Adenoma, Islet Cell; Animals; Diabetes Mellitus; Diarrhea; Gastrins; Glucagon; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Pancreatic Hormones; Pancreatic Neoplasms; Peptic Ulcer; Somatostatin; Transplantation, Homologous

The Verner-Morrison Syndrome is a clinically defined entity caused by an islet cell tumor of the pancreas. More than 60 cases have been described so long. The syndrome is characterized by diarrhea, hypokalemia and hypochlorhydria. In addition to a diabetic disposition, raised calcium levels and skin alterations may be present. The diagnosis is a clinical one. A pancreatic tumor should be searched for and removed. Morphologically a benign and a maligne islet cell tumor or a diffuse hyperplasia of the islets of Langerhans can be found. Until now identification of the tumor cells has not been possible. There seems no doubt that the tumor cells produce a peptide hormone. Secretin, gastric inhibitory polypeptide, vasoactive intestinal polypeptide and combinations of hormones are discussed. The results are contradictory. Theories concerning the formal and causal pathogenesis are only incomplete and unproved up to now.

Topics: Achlorhydria; Adenoma, Islet Cell; Adolescent; Adult; Aged; Diarrhea; Female; Gastrins; Glucagon; Humans; Hypokalemia; Kidney Diseases; Male; Middle Aged; Pancreatic Neoplasms; Peptides; Pregnancy; Secretin; Syndrome

Topics: Adenoma, Islet Cell; Diagnosis, Differential; Diarrhea; Gastrins; Germany, West; Glucagon; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Malignant Carcinoid Syndrome; Pancreatic Neoplasms; Syndrome; Zollinger-Ellison Syndrome

The treatment with streptozotocin of a patient with metastatic gastrinoma is described. Two courses of intravenous streptozotocin were without effect. However, three months after two doses of 4 g streptozotocin were given into the coeliac axis, there was a marked reduction in hepatic size and a fall in fasting plasma gastrin levels from 1430 pmol/l to 240 pmol/l. Seven months after treatment fasting plasma gastrin levels were 125 pmol/l.

Topics: Adenoma, Islet Cell; Adult; Female; Gastrectomy; Gastrins; Hepatectomy; Humans; Liver Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Streptozocin; Zollinger-Ellison Syndrome

The islet cell tumors of the pancreas are now known to produce a variety of polypeptides in addition to insulin. These include glucagon, serotonin, corticotropin, melanocyte-stimulating hormone, gastrin and a secretinlike hormone that may be VIP or a combination of such polypeptides. The development and wide availability of the newer immunoassays for the various recognized hormones as well as candidate hormones of the gut will simplify the diagnosis of these challenging tumors, which up until this time have produced symptoms that were bizarre and often fatal to the patient.

Topics: Achlorhydria; Adenoma, Islet Cell; Angiography; Calcium; Diagnosis, Differential; Diarrhea; Gastrins; Glucagon; Hormones, Ectopic; Humans; Hyperinsulinism; Hyperparathyroidism, Secondary; Neoplasm Metastasis; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Animals; Biogenic Amines; Carcinoid Tumor; Decarboxylation; Gastric Mucosa; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Histocytochemistry; Intestinal Mucosa; Islets of Langerhans; Pancreatic Neoplasms; Serotonin; Zollinger-Ellison Syndrome

Topics: Acromegaly; Adenoma, Islet Cell; Adrenocorticotropic Hormone; Bronchial Neoplasms; Diabetes Mellitus; Gastrins; Glucagon; Growth Hormone; Humans; Hypoglycemia; Neoplasms; Pancreatic Neoplasms; Somatostatin; Thyrotropin; Zollinger-Ellison Syndrome

Functioning tumors of the pancreatic islets are now recognized as the source of clinical syndromes affecting the gastrointestinal tract which have a wide variety of catastrophic symptoms. Experiences with thirty-six cases suggest at least four separate diagnostic categories in the ulcerogenic tumor syndrome. These include: a typical history, gastric analysis, and roentgenographic findings with boderline fasting serum gastrin levels; ulcerogenic tumor with evidence of hyperparathyroidism; iatrogenic ulcerogenic syndrome associated with failure of a previous operation for duodenal ulcer; and the classic ulcerogenic syndrome associated with a fulminating ulcer diathesis or diarrhea and high serum gastrin levels. The problems presented at operation include: decisions to be make in the presence of a negative exploration; the finding of a solitary tumor in the wall of the duodenum; solitary pancreatic tumors particularly in the body and tail; ulcerogenic tumors in the very young; liver metastases in the elderly; and the wisdom of removing gross metastases in combination with total gastrectomy. The long-term survival in the ulcerogenic tumor syndrome approximated 50 per cent, with 40 per cent of those having proved malignancy living five years. Evidence of hyperparathyroidism is relatively common in association with both the ulcerogenic and the diarrheogenic tumor syndromes. The association may by a result of a congenital abnormality, metabolic alkalosis, or a direct effect of the islet cell tumor. Parathyroidectomy may be indicated when both the serum calcium and parathormone levels are elevated in the presence of borderline fasting gastrin levels. The latter may return to normal after parathyroidectomy. The evidence of hyperparathyroidism closely parallels the episodes of diarrhea in the diarrheogenic syndrome, and hyperparathyroidism may regress spontaneously after total removal of the pancreatic tumor. Just as routine calcium determinations made the diagnosis of hyperparathyroidism more commonplace, it is suggested that the gastrointestinal syndromes associated with islet cell tumor would receive wider recognition if radioimmunoassays for gastrin as well as secretin, and the other secretin-like polypeptides, were carried out routinely.

Topics: Adenoma, Islet Cell; Age Factors; Celiac Disease; Diagnosis, Differential; Diarrhea; Duodenal Neoplasms; Follow-Up Studies; Gastrins; Humans; Hyperparathyroidism; Liver Neoplasms; Neoplasm Metastasis; Pancreatic Hormones; Pancreatic Neoplasms; Preoperative Care; Secretin; Zollinger-Ellison Syndrome

Topics: Adrenocorticotropic Hormone; Calcitonin; Calcium; Feedback; Gastrins; Gastrointestinal Hormones; Hypercalcemia; Hypocalcemia; Melanocyte-Stimulating Hormones; Pancreatic Neoplasms; Thyroid Gland; Zollinger-Ellison Syndrome

Tumoral secretions and pathophysiology of diarrhea were studied in 1 patient with pancreatic cholera. High concentrations of vasoactive intestinal peptide were found in both systemic blood and tumoral extracts, together with increased plasma levels of calcitonin and protaglandins E and Falpha. Gastric inhibitory peptide and gastrointestinal and pancreatic hormones were absent from the tumor, except for small amounts of glucagon, and their blood levels were normal. Decreased basal but normal pentagastrin-stimulated gastric acid secretion, normal basal and secretin-stimulated pancreatic secretion, increased volume of gallbladder bile with high bicarbonate, and low bile salt concentrations were observed, but the electrolyte content and flow rate of fluid passing the duodenojejunal junction were within normal limits. Small intestine was found to be the origin of the water and electrolyte fasting losses. Jejunum was the site of bicarbonate secretion. Jejunal glucose and leucine-stimulated water and sodium transports were also strikingly decreased, whereas the absorption rates of the sugar and amino acid were normal. Colon reabsorbed high amounts of water and sodium but increased potassium losses. Biological effects of vasoactive intestinal peptide may explain most of the patient's upper digestive secretion abnormalities and small intestinal function impairments, whereas secondary aldosteronism might explain the modified colonic function.

Topics: Adult; Bile; Blood Vessels; Calcitonin; Cholecystokinin; Cholera; Colon; Depression, Chemical; Diarrhea; Duodenum; Feces; Female; Gastric Mucosa; Gastrins; Glucagon; Humans; Ileostomy; Insulin; Insulin Secretion; Intestinal Secretions; Intestine, Small; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Peptides; Prostaglandins E; Prostaglandins F; Secretin; Stomach

Topics: Adenoma, Islet Cell; Blood Glucose; Calcium; Endocrine System Diseases; Gastrins; Humans; Insulin; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms; Pheochromocytoma; Pituitary Neoplasms; Radioimmunoassay; Syndrome; Thyroid Neoplasms; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Child; Duodenal Neoplasms; Duodenal Ulcer; Female; Gastrectomy; Gastric Juice; Gastrins; Humans; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Peptic Ulcer; Radiography; Radioimmunoassay; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: Achlorhydria; Acute Kidney Injury; Adenoma, Islet Cell; Adult; Cholecystokinin; Dehydration; Diarrhea; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypercalcemia; Hypokalemia; Kidney Diseases; Male; Pancreatic Neoplasms; Protein Precursors; Secretin; Syndrome; Zollinger-Ellison Syndrome

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Gastric Acidity Determination; Gastrins; Glucagon; Humans; Islets of Langerhans; Pancreatic Neoplasms; Syndrome; Zollinger-Ellison Syndrome

Topics: Digestion; Enzyme Therapy; Fats; Gastric Juice; Gastrins; Gastrointestinal Hemorrhage; Gastrointestinal Hormones; Humans; Methods; Pancreas; Pancreatectomy; Pancreatic Diseases; Pancreatic Juice; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Angiography; Biological Assay; Diarrhea; Duodenum; Endocrine System Diseases; Gastrectomy; Gastric Juice; Gastrins; Humans; Intestinal Neoplasms; Islets of Langerhans; Malabsorption Syndromes; Pancreatic Neoplasms; Peptic Ulcer; Prognosis; Radioimmunoassay; Stomach; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Angiography; Antacids; Celiac Disease; Diarrhea; Gastric Juice; Gastrins; Humans; Hyperparathyroidism; Malabsorption Syndromes; Pancreatic Neoplasms; Physical Examination; Radioimmunoassay; Radionuclide Imaging; Zollinger-Ellison Syndrome

Topics: Animals; Biogenic Amines; Carcinoid Tumor; Cholecystokinin; Chromaffin System; Diabetes Mellitus; Digestive System; Digestive System Physiological Phenomena; Gastric Juice; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Insulin; Insulin Secretion; Intestines; Pancreas; Pancreatic Neoplasms; Peptic Ulcer; Secretin; Syndrome

Topics: Adenoma, Islet Cell; Blood Glucose; Diagnosis, Differential; Gastrins; Glucose Tolerance Test; Humans; Hyperparathyroidism; Insulin; Pancreatic Neoplasms; Parathyroid Neoplasms; Radioimmunoassay; Tolbutamide; Zollinger-Ellison Syndrome

Topics: Acute Disease; Adenoma, Islet Cell; Cholecystokinin; Chronic Disease; Gastrins; Humans; Methods; Pancreas; Pancreas Transplantation; Pancreatic Diseases; Pancreatic Neoplasms; Pancreatitis; Radiography; Secretin; Transplantation, Homologous; Zollinger-Ellison Syndrome

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

Topics: Adenoma, Islet Cell; Diarrhea; Digestive System; Fasting; Gastrins; Glucagon; Glucose; Glucose Tolerance Test; Humans; Hypoglycemia; Hypokalemia; Leucine; Pancreatic Neoplasms; Tolbutamide; Zollinger-Ellison Syndrome

The pharmacodynamic effects of everolimus on gastrointestinal hormone levels have not been described in patients with pancreatic neuroendocrine tumors (pNETs). We report the effects of everolimus on gastrin and glucagon levels in patients with progressive pNET in RADIANT-1 (a single-arm phase II trial) and RADIANT-3 (a placebo-controlled, randomized, phase III trial).. Serum gastrin and glucagon levels were determined by immunoassay at baseline and at predose in subsequent treatment cycles in patients with elevated baseline hormone levels. The analyses included 158 patients from RADIANT-1 and 404 patients from RADIANT-3.. In RADIANT-1, everolimus induced a rapid, sustained decrease in median gastrin and glucagon levels to approximately 60% and 70% of baseline levels, respectively. In RADIANT-3, everolimus consistently reduced median gastrin and glucagon levels by greater than 50% and approximately 40%, respectively (everolimus vs placebo, P < 0.0001), whereas with placebo, both hormones at each time point were essentially the same as their baseline levels. In patients with concomitant octreotide long-acting repeatable treatment, the moderate pharmacodynamic effect on lowering gastrin was greater than that seen with everolimus alone.. In addition to prolonging progression-free survival in patients with pNET, everolimus down-regulates excess production of 2 gastrointestinal hormones, which may help control their associated clinical syndromes.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Disease-Free Survival; Double-Blind Method; Down-Regulation; Everolimus; Female; Gastrins; Glucagon; Humans; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Time Factors; Treatment Outcome; Young Adult

Pancreatic neuroendocrine tumors (NETs) are rare but are frequently diagnosed at advanced stages and require systemic therapy.. This multicenter, open-label, phase II study evaluated sunitinib in Japanese patients with well-differentiated pancreatic NET. Patients received sunitinib 37.5 mg/day on a continuous daily dosing (CDD) schedule. The primary endpoint was clinical benefit rate (CBR; percentage of complete responses [CRs] plus partial responses [PRs] plus stable disease [SD] ≥ 24 weeks). Secondary endpoints included objective response rate (ORR), tumor shrinkage, progression-free survival (PFS) probability, safety, pharmacokinetics, and biomarkers.. Twelve patients received treatment. The CBR was 75 % (95 % confidence interval [CI], 43-94) and included 6 patients with a PR and 3 with SD. The ORR was 50 % (95 % CI, 21-79). PFS probability was 91 % (95 % CI, 54-99) at 6 months and 71 % (95 % CI, 34-90) at 12 months. Commonly reported treatment-emergent (all-causality), any-grade adverse events included diarrhea (n=10), hand-foot syndrome and hypertension (both n=8), fatigue and headache (both n=7), and neutropenia (n=6). No deaths on study were reported; one death due to disease progression occurred >28 days after end of treatment. Sunitinib on a CDD schedule resulted in sustained drug concentrations without accumulation across cycles. Tumor responses in all 12 patients did not appear to correlate with decreases in chromogranin A levels.. Sunitinib 37.5 mg/day on a CDD schedule demonstrated antitumor activity in Japanese patients with unresectable, well-differentiated pancreatic NET. Commonly reported adverse events were consistent with the known safety profile of sunitinib.

Topics: Adult; Aged; Angiogenesis Inhibitors; Asian People; Biomarkers, Tumor; Chromogranin A; Female; Gastrins; Humans; Indoles; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Pyrroles; Sunitinib; Treatment Outcome

This study aimed to investigate G17DT, an immunogen producing neutralizing antibodies against the tumor growth factors amidated and glycine-extended forms of gastrin-17, in the treatment of pancreatic cancer.. A randomized, double-blind, placebo-controlled, group-sequential multicenter trial of G17DT in patients with advanced pancreatic cancer unsuitable for or unwilling to take chemotherapy. Inclusion criteria were a Karnofsky performance score of 60 or higher and a life expectancy of more than 2 months. Patients received G17DT or placebo emulsion at weeks 0, 1, 3, 24, and 52. The primary end point was survival, and secondary end points were tolerability, Karnofsky performance.. A total of 154 patients were recruited: 79 G17DT and 75 placebo. A final analysis of the intention-to-treat population, using a proportional hazards model, stratifying by disease stage and adjusting for interim analysis, gave a hazard ratio for mortality of 0.75 (95% confidence interval, 0.51-1.10, P = 0.138; G17DT/placebo). A conventional analysis without adjustment for disease stage or interim analysis, censoring for chemotherapy and excluding protocol violators, gave median survival periods of 151 (G17DT) and 82 days (placebo) (log-rank test, P = 0.03).Patients developing anti-G17DT responses (73.8%) survived longer than nonresponders or those on placebo (median survival, 176 vs 63 vs 83; log-rank test, P = 0.003). G17DT was well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Cancer Vaccines; Double-Blind Method; Europe; Female; Gastrins; Humans; Kaplan-Meier Estimate; Karnofsky Performance Status; Life Expectancy; Male; Middle Aged; Pancreatic Neoplasms; Placebos; Proportional Hazards Models; Prospective Studies; Time Factors; Treatment Outcome

Proton pump inhibitors (PPIs) are used primarily to treat gastroesophageal reflux disease. Proton pump inhibitor-induced achlorhydria increases circulating gastrin and chromogranin A (CGA). Chromogranin is a widely used biomarker for the diagnosis and follow-up for gut-based neuroendocrine tumors (NETs). Proton pump inhibitor-induced increases in CGA or gastrin may falsely suggest the presence of a NET when none exists. Pancreastatin, a fragment of CGA, is also commonly used to diagnose and follow NETs. We hypothesized that chronic PPI use would increase circulating plasma gastrin, CGA, and pancreastatin levels.. Thirty patients who used PPIs for 6 months or more (mean ± SD duration, 3.1 ± 2.5 years) and a separate control group of 30 patients who never used antacid medications were prospectively evaluated with plasma gastrin, CGA, and pancreastatin determinations.. Chronic PPI use resulted in significant increases in CGA (15.1 ± 11 vs 131 ± 207 ng/mL; P = 0.005) and significant increases in gastrin (34.8 ± 22.3 vs 167.8 ± 136.2 pg/mL; P = 0.001) compared to controls. In contrast, pancreastatin level in nonusers and chronic PPI users were identical (81.6 ± 36.4 vs 89.4 ± 43.4 pg/mL; P = 0.46).. Pancreastatin levels do not change with chronic PPI use and normal pancreastatin levels may be used to distinguish between drug-induced changes in biomarkers and tumor-related increases in circulating biomarkers.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Chromogranin A; Female; Gastrins; Gastroesophageal Reflux; Humans; Male; Middle Aged; Neuroendocrine Tumors; Pancreas; Pancreatic Hormones; Pancreatic Neoplasms; Prospective Studies; Proton Pump Inhibitors

To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer.. Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded.. Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain.. Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepinones; Deoxycytidine; Female; Gastrins; Gemcitabine; Humans; Male; Middle Aged; Pancreatic Neoplasms; Quality of Life; Receptor, Cholecystokinin B; Severity of Illness Index; Survival Analysis; Treatment Outcome

The aim of this study was to determine the ability of G17DT to generate anti-gastrin antibodies in jaundiced patients with biliary obstruction due to advanced pancreatic cancer.. G17DT was administered to 41 patients with advanced pancreatic adenocarcinoma by intramuscular (i.m.) injection at a dose of 250mcg at weeks 0, 1 and 3 of the study.. Thirty-five of 41 patients participating in the study were categorized as responders in terms of their gastrin-17 antibody response. There was no correlation between the maximum G17 antibody response and the bilirubin level at either week 0 or week 12. The median survival of patients from the time of the first injection of G17DT was 204 days with 25% of patients surviving for or=305 days.. This study shows that G17DT administered to jaundiced patients with advanced pancreatic cancer is immunogenic and well tolerated.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibody Formation; Bilirubin; Cancer Vaccines; Cholestasis; Disease Progression; Female; Gastrins; Humans; Immunization; Injections, Intramuscular; Jaundice; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Time Factors; Treatment Outcome; United Kingdom

The prognosis for advanced pancreatic cancer remains poor. Gastrin acts as a growth factor for pancreatic cancer. We describe the first study of the antigastrin immunogen G17DT in pancreatic cancer. Our aims were to determine the antibody response, safety, tolerability, and preliminary evidence of efficacy of G17DT in advanced pancreatic cancer.. Thirty patients with advanced pancreatic cancer were immunized with three doses of either 100 micro g or 250 micro g of G17DT.. In the whole group, 20 (67%) of 30 patients produced an antibody response. The 250- micro g dose resulted in a significantly greater response rate of 82% compared with 46% for the 100- micro g group (P =.018). The most significant side effects, seen in three patients, were local abscess and/or fever. The median survival for the whole group from the date of the first immunization was 187 days; median survival was 217 days for the antibody responders and 121 days for the antibody nonresponders. The difference in survival between the antibody responders and nonresponders was significant (P =.0023).. Patients with advanced pancreatic cancer are able to mount an adequate antibody response to G17DT. The 250- micro g dose is superior to the 100- micro g dose, and it appears to be generally well tolerated. Antibody responders demonstrate significantly greater survival than antibody nonresponders. Phase III studies are currently underway in order to determine efficacy.

Topics: Adult; Aged; Antibody Formation; Antineoplastic Agents; Cancer Vaccines; Diphtheria Toxoid; Female; Gastrins; Humans; Immunization; Male; Middle Aged; Pancreatic Neoplasms; Quality of Life; Survival Analysis

Use of a standardized meal stimulation test has been recommended for the early diagnosis of pancreaticoduodenal endocrine tumours (PETs) in patients with multiple endocrine neoplasia type 1 (MEN 1). The diagnostic value of this test was re-evaluated.. In a prospective, controlled trial 58 standardized meal stimulation tests (563 kcal) were performed in 12 patients with MEN 1 and histologically, biochemically and/or radiologically confirmed PETs (group 1), 11 carriers of an MEN 1 mutation with no evidence of PETs (group 2) and in 27 healthy controls (group 3). Serum pancreatic polypeptide (PP) and gastrin concentrations were measured before and during the test meal.. Patients in group 1 had significantly higher mean basal serum PP and gastrin concentrations than patients in group 2 and controls (P < 0.05). In all three groups an increase in serum PP was observed after meal stimulation, but there was no significant difference between the groups. No increase in gastrin level was found in any of the groups after meal stimulation.. The standardized meal stimulation test does not reliably indicate the presence of PETs in patients with MEN 1, whereas raised basal serum PP and gastrin levels do. The expensive and time-consuming meal test can be excluded from MEN 1 screening programmes.

Topics: Adult; Aged; Duodenal Neoplasms; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Mutation; Pancreatic Neoplasms; Pancreatic Polypeptide; Prospective Studies

Apart from smoking, known risk factors for the development of pancreatic carcinoma are few, gastric resection being proposed as one. The trophic effect of cholecystokinin (CCK) on the pancreatic gland is well known from animal experience and increased concentrations of CCK in plasma have been shown to induce pancreatic neoplasia experimentally. In several studies the release of CCK in response to food ingestion has been shown to be increased following gastric surgery. However, in those studies, the time between surgery and investigation of the CCK response was short, and methods of CCK analysis have since improved.. In patients, partially gastrectomized 8 years (median) earlier, we studied the plasma concentrations of CCK, insulin and gastrin, as well as some specific pancreatic enzymes. The findings were compared to an age-matched control group of individuals not subjected to gastric surgery.. Basal CCK concentrations in the operated group were found to be lower, but increased postprandially to the same level as in controls. Serum levels of specific pancreatic enzymes were equal in the 2 groups.. It is possible that a disturbed regulation of pancreatic secretion, or a secretory dysfunction within the gland, following partial gastrectomy, could contribute to the development of pancreatic carcinoma. However, our findings do not favor the idea of plasma CCK as a promotor of pancreatic carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Cholecystokinin; Cohort Studies; Female; Gastrectomy; Gastrins; Humans; Insulin; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Postoperative Period; Radioimmunoassay; Reference Values; Sensitivity and Specificity

Palliative operation plays an important part in the treatment of periampullary carcinoma. However, gastric bypass such as the widely practiced side-to-side gastrojejunostomy frequently fails to provide adequate drainage. Here we attempted to fashion an end-to-end duodenojejunostomy in the hope of establishing physiological continuity of the stomach and duodenum. Biliary bypass with side-to-side choledochojejunostomy is performed simultaneously. Eight patients underwent this surgery. In seven of these, radical resection proved to be impossible, and in one the duodeno-biliary decompression was attempted before the radical operation. Early results were satisfactory in all patients. They began to eat liquid meals within a week, and were discharged uneventfully within the third postoperative week, when they were able to eat a regular diet. No ulcer developed in any of the patients. Plasma gastrin levels following a test meal was significantly lower after the operation, but plasma CCK-N and GIP levels showed no statistical difference prior to and after surgery. This duodenojejunal bypass is recommended as a means of improving the quality of the remaining life of the patients.

Topics: Aged; Ampulla of Vater; Biliopancreatic Diversion; Choledochostomy; Common Bile Duct Neoplasms; Duodenostomy; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Transit; Humans; Jejunostomy; Male; Middle Aged; Palliative Care; Pancreatic Neoplasms; Postoperative Care; Sincalide; Survival Rate

Although patients with neuroendocrine tumors typically exhibit an indolent clinical course, the pace of disease accelerates and the prognosis deteriorates once objective progression of disease begins. Thirty-four patients with advanced neuroendocrine tumors were treated with octreotide as antineoplastic therapy. This treatment was begun only after documentation of clear objective progression of disease.. A Phase II trial was performed at a tertiary comprehensive cancer center.. The median survival for this patient population from the start of octreotide therapy has not been reached, with a median follow-up of 29 months (range, 1-47 months). No major objective tumor regressions were seen. Seventeen patients (50%) experienced a computed tomography-documented stabilization of disease that was maintainable for a minimum of 2 months (median, 5 months; range, 0-27 months). Of the 34 patients, 20 patients received octreotide as their first antineoplastic therapy. The median survival for these 20 patients has not been reached, with a median follow-up also of 29 months (range, 12-41 months).. Octreotide may influence the natural history of neuroendocrine tumors. The survival in patients treated with octreotide, as measured from the time of progression of disease, compares favorably with that of historical controls. Proof of a survival advantage for patients treated with octreotide would require a multicenter, randomized trial.

Topics: Adenoma, Islet Cell; Adult; Aged; Carcinoid Tumor; Female; Gastrins; Humans; Male; Middle Aged; Neoplasm Staging; Octreotide; Pancreatic Neoplasms; Survival Analysis

Since 1980, 73 patients with Zollinger-Ellison syndrome (ZES) without radiographic evidence of liver metastases were studied on a prospective protocol including medical management of gastric acid hypersecretion, extensive radiographic tumor localization, and exploratory surgery to find and resect gastrinoma for potential cure. Each patient had gastric acid hypersecretion effectively controlled with either H2-blockers or omeprazole. Patients were divided prospectively into two groups, with all patients undergoing the same preoperative localization studies and extensive laparotomy. In contrast to group 1 (1980-1986) (36 patients), group 2 (1987-Oct. 1990) (37 patients) also underwent additional procedures (transillumination and duodenotomy) at surgery to find duodenal gastrinomas. Preoperative imaging studies localized tumor in 38 (52%) patients, and portal venous sampling for gastrin determinations was positive in 49 (67%) patients. Gastrinomas were found and resected in 57 (78%) patients. Significantly more gastrinomas (92% of patients) were found in group 2 than in group 1 patients (64%) (p less than 0.01). This increase was due to increased numbers of duodenal gastrinomas in group 2 than in group 1 patients (43% versus 11%; p less than 0.01). The increased ability to find duodenal gastrinomas did not significantly improve the immediate disease-free rate, which was 58% for all patients. Duodenal primary gastrinomas were found to have a significantly greater incidence of metastases (55%) and a significantly shorter disease-free interval (12 months) than pancreatic gastrinomas (22% and 84 months, respectively) suggesting that duodenal gastrinomas may be more malignant and not more frequently curable than pancreatic gastrinomas. Operations were performed with no deaths and 11% morbidity rate. Long-term follow-up showed that 50% of patients initially rendered disease free would develop recurrent disease by 5 years. Survival was excellent for all patients, and none died of malignant spread of the tumor or uncontrolled peptic ulcer disease, with a mean follow-up of 5 years. This finding is in contrast to patients who presented with metastatic disease on imaging studies and had a 20% 5-year survival rate. This study suggests that all patients with localized sporadic ZES can have the gastric acid hypersecretion managed medically, that overall survival of these patients is excellent, most (78%) can have all gastrinoma found and resected, and some (30%) will be cu

Topics: Adult; Aged; Anti-Ulcer Agents; Combined Modality Therapy; Duodenal Neoplasms; Female; Follow-Up Studies; Gastric Acid; Gastric Acidity Determination; Gastrins; Humans; Laparoscopy; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Postoperative Complications; Prospective Studies; Survival Rate; Time Factors; Treatment Outcome; 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

Topics: Acromegaly; Adult; Anemia, Pernicious; Blood Glucose; Fasting; Female; Food; Gastric Juice; Gastrins; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Infusions, Parenteral; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides; Radioimmunoassay; Time Factors; Zollinger-Ellison Syndrome

Loss of the tumor suppressor protein menin is a critical event underlying the formation of neuroendocrine tumors (NET) in hormone-expressing tissues including gastrinomas. While aberrant expression of menin impairs its tumor suppression, few studies explore the structure-function relationship of clinical multiple endocrine neoplasia, type 1 (. We examined the function of somatic and germline mutations and a variant of

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

Patients with multiple endocrine neoplasia 1 syndrome (MEN1) often develop multifocal duodenopancreatic neuroendocrine tumors (dpNETs). Nonfunctional pancreatic neuroendocrine tumors (PanNETs) and duodenal gastrinomas are the most frequent origins of metastasis. Current guidelines recommend surgery based on tumor functionality, size ≥2 cm, grade or presence of lymph node metastases. However, in case of multiple primary tumors it is often unknown which specific tumor metastasized. This study aims to unravel the relationship between primary dpNETs and metastases in patients with MEN1 by studying endocrine differentiation. First, it was shown that expression of the endocrine differentiation markers ARX and PDX1 was concordant in 18 unifocal sporadic neuroendocrine tumors (NETs) and matched metastases. Thereafter, ARX, PDX1, Ki67 and gastrin expression, and the presence of alternative lengthening of telomeres were determined in 137 microscopic and macroscopic dpNETs and 36 matched metastases in 10 patients with MEN1. ARX and PDX1 H-score clustering was performed to infer relatedness. For patients with multiple metastases, similar intrametastases transcription factor expression suggests that most metastases (29/32) originated from a single NET of origin, while few patients may have multiple metastatic primary NETs. In 6 patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases expressed gastrin, and clustered with minute duodenal gastrinomas, not with larger PanNETs. PanNET metastases often clustered with high grade or alternative lengthening of telomeres-positive primary tumors. In conclusion, for patients with MEN1-related hypergastrinemia and PanNETs, a duodenal origin of periduodenopancreatic lymph node metastases should be considered, even when current conventional and functional imaging studies do not reveal duodenal tumors preoperatively.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Databases, Factual; Duodenal Neoplasms; Female; Gastrins; Homeodomain Proteins; Humans; Ki-67 Antigen; Lymphatic Metastasis; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasm Grading; Pancreatic Neoplasms; Trans-Activators; Transcription Factors

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

We report a rare case of functional insulinomas in a 16.7-year-old female Rhesus macaque (Macaca mulatta) that was presented with neuroglycopenic signs to the breeding colony hospital at the Tulane National Primate Research Center. At initial and follow-up examinations, the animal was consistently hypoglycaemic and was clinically maintained with additional fruits, other high-sugar food items and dextrose supplementation. Occasional episodes of seizure and collapse resolved quickly on administration of high-sugar food items. At necropsy, the uncinate process of the pancreas had a 2.2 cm diameter, red, round, firm neoplastic mass, and another neoplasm was identified on histological examination of the head of pancreas. Histologically, neoplastic cells exhibited neuroendocrine packeting, resembled pancreatic islet cells and immunolabelled for chromogranin A, synaptophysin and insulin but not for somatostatin, gastrin or pancreatic polypeptide. A few cells immunolabelled for glucagon. The clinical signs and gross and histological findings were consistent with functional insulinomas.

Topics: Animals; Chromogranin A; Female; Gastrins; Glucagon; Glucose; Hypoglycemic Agents; Insulinoma; Insulins; Macaca mulatta; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Sugars; Synaptophysin

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

Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a "cold" tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS; formerly called G17DT and Gastrimmune), used alone or in combination with a programmed cell death receptor (PD)-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME). Immune-competent female C57BL/6 mice bearing syngeneic orthotopic murine pancreatic cancer treated with PAS had significantly smaller tumors and fewer metastases. Examination of the TME demonstrated decreased fibrosis with fewer M2 and more M1 tumor-associated macrophages. Expression of the

Topics: Animals; beta Catenin; Cadherins; Cancer Vaccines; Cell Line; Cell Line, Tumor; Female; Gastrins; Immunotherapy; Macrophages; Matrix Metalloproteinase 7; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Pancreatic Neoplasms; Programmed Cell Death 1 Receptor; Receptor, Transforming Growth Factor-beta Type II; Tumor Microenvironment

Pancreatic cancer has been termed a 'recalcitrant cancer' due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown to prolong survival of patients with pancreatic cancer. Here, we report that PAS vaccination monotherapy elicits both a humoral and cellular immune response when used in immune competent mice-bearing pancreatic tumors and that PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors. Isolated peripheral lymphocytes elicited cytokine release upon re-stimulation with gastrin in vitro demonstrating specificity of immune activation for the target peptide. Combination therapy with PAS and PD-1 Ab activated CD4 -/CD8 - TEMRA cells important in T-cell-mediated tumor death and memory. Tumors of mice treated with PAS (250 μg) or PAS (100 and 250 μg) in combination with a PD-1 Ab were significantly smaller compared to tumors from PBS or PD-1 Ab-treated mice. When PAS was given in combination with PD-1 Ab, tumors had less fibrosis, fewer inhibitory Treg lymphocytes, and fewer tumor-associated macrophages. These findings reveal a novel approach to improve treatment strategies for pancreatic cancer.

Topics: Animals; Cancer Vaccines; Cell Line, Tumor; Gastrins; Immunologic Memory; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Male; Mice; Mice, Inbred C57BL; Pancreatic Neoplasms; Programmed Cell Death 1 Receptor; T-Lymphocytes; Tumor Microenvironment; Vaccination

Peptide receptor radionuclide therapy (PRRT) with the radiolabeled somatostatin analogue [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) is widely applied for inoperable metastatic small intestinal and nonfunctioning pancreatic neuroendocrine tumors (pNETs). The aim of this study is to describe the safety and efficacy of the treatment of functioning pNETs.. Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gbq per cycle. Radiological (Response Evaluation Criteria in Solid Tumors 1.1), symptomatic, and biochemical response were analyzed retrospectively for all patients with a functioning pNET (insulinoma, gastrinoma, VIPoma, and glucagonoma) treated with 177Lu-DOTATATE. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module questionnaire.. Thirty-four patients with a metastatic functioning pNET (European Neuroendocrine Tumor Society grade 1 or 2) were included: 14 insulinomas, 5 VIPomas, 7 gastrinomas, and 8 glucagonomas. Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL.. Treatment with 177Lu-DOTATATE is a safe and effective therapy resulting in radiological, symptomatic and biochemical response in a high percentage of patients with metastatic functioning pNETs. Hormonal crises occur relatively frequent and preventive therapy should be considered before and/or during PRRT.

Topics: Adult; Aged; Coordination Complexes; Female; Gastrins; Glucagon; Humans; Insulin; Lutetium; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreas; Pancreatic Neoplasms; Quality of Life; Radiation Dosage; Radioisotopes; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Vasoactive Intestinal Peptide

The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis.. LSL-Kras; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas.. In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls.. This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.

Topics: Animals; Carcinogenesis; Carcinoma in Situ; Cell Line, Tumor; Cell Proliferation; Gastrins; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Mice, Knockout; Mice, Transgenic; MicroRNAs; Mutation; Pancreas; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras)

The mechanism by which gastrin promotes pancreatic cancer cell metastasis is unclear. The process of directing polarized cancer cells toward the extracellular matrix is principally required for invasion and distant metastasis; however, whether gastrin can induce this process and its underlying mechanism remain to be elucidated. In this study, we found that gastrin-induced phosphorylation of paxillin at tyrosine 31/118 and RhoA activation as well as promoted the metastasis of PANC-1 cancer cells. Depletion of Gα12 and Gα13 inhibited the phosphorylation of paxillin and downstream activation of GTP-RhoA, blocked the formation and aggregation of focal adhesions and facilitated polarization of actin filaments induced by gastrin. Suppression of RhoA and ROCK also exhibited identical results. Selective inhibition of the CCKBR-Gα12/13-RhoA-ROCK signaling pathway blocked the reoriented localization of the Golgi apparatus at the leading edge of migrated cancer cells. YM022 and Y-27632 significantly suppressed hepatic metastasis of orthotic pancreatic tumors induced by gastrin in vivo. Collectively, we demonstrate that gastrin promotes Golgi reorientation and directional polarization of pancreatic cancer cells by activation of paxillin via the CCKBR-Gα12/13-RhoA-ROCK signal pathway.

Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Polarity; Disease Progression; Focal Adhesions; Gastrins; Golgi Apparatus; GTP-Binding Protein alpha Subunits, G12-G13; Humans; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Neoplasm Invasiveness; Organic Chemicals; Pancreatic Neoplasms; Paxillin; Phosphorylation; Phosphotyrosine; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Time Factors

With the widespread use of endoscopy, small and low-grade type 3 gastric neuroendocrine tumours (NETs) are increasingly being detected. The clinicopathological features, biological behaviour and appropriate treatment strategy for these NETs remain unclear.. Patients with biopsy-proven gastric NET and a normal fasting serum gastrin level were identified from a prospectively maintained database. Clinicopathological features and long-term outcome of local resection for type 3 NETs were reviewed retrospectively and compared according to tumour grade.. Some 32 patients with type 3 gastric NETs were included (25 patients with NET grade G1, 5 with G2 and 2 with G3). Pathological tumour size was 2·0 cm or less in 30 patients. All tumours were well differentiated, even G3 lesions, and all tumours but one were confined to the submucosal layer. G1 NETs were significantly smaller and had a significantly lower lymphovascular invasion rate than G2 and G3 NETs. Twenty-two patients with a G1 NET without lymphovascular invasion were treated with wedge or endoscopic resection. After a median follow-up of 59 (range 6-102) months, no patient with a G1 NET of 1·5 cm or smaller developed recurrence and one patient with a G1 NET larger than 1·5 cm had recurrence in a perigastric lymph node. Among seven patients with a G2 or G3 NET, two had lymph node metastasis and one had liver metastases.. Low-grade type 3 gastric NET has non-aggressive features and a favourable prognosis. Wedge or endoscopic resection may be a valid option for patients with type 3 gastric G1 NET no larger than 1·5 cm without lymphovascular invasion.

Topics: Adult; Aged; Biomarkers, Tumor; Biopsy; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Gastrectomy; Gastrins; Humans; Intestinal Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Pancreatic Neoplasms; Prognosis; Prospective Studies; Stomach Neoplasms; Time Factors

Currently, serum chromogranin A is a well-established biomarker for pancreatic neuroendocrine tumors; however, other pancreatic diseases, oral use of a proton pump inhibitor and renal impairment can affect chromogranin A. Meanwhile, chromogranin B, belonging to the same granin family as chromogranin A, is not fully examined in these conditions. The present study aimed to evaluate the utility of chromogranin B as a pancreatic neuroendocrine tumor biomarker.. Serum chromogranin B levels were determined by radioimmunoassay and serum chromogranin A levels by enzyme-linked immunosorbent assay in pancreatic neuroendocrine tumor (n = 91) and other pancreatic conditions, and in healthy people (n = 104), to assess the relationships with clinical features.. The diagnostic ability of chromogranin B was as good as chromogranin A. The area under the curve was 0.79 for chromogranin B (sensitivity/specificity: 72%/77%), and 0.78 for chromogranin A (sensitivity/specificity: 79%/64%). Chromogranin B was not affected by proton pump inhibitor use and age, which affected chromogranin A. The number of cases without liver metastases was larger in pancreatic neuroendocrine tumor patients with positive chromogranin B and negative chromogranin A. Though chromogranin A significantly elevated cases with proton pump inhibitor treatment and had positive correlation with age, chromogranin B did not have the tendencies. However, both chromogranin B and chromogranin A elevated in the case with renal impairment. In addition, the logistic regression analysis showed that chromogranin B was superior to chromogranin A in differentiation of pancreatic neuroendocrine tumor from other pancreatic diseases.. Compared with chromogranin A, chromogranin B may be more useful during proton pump inhibitor treatment and can detect tumors without liver metastases. In addition, chromogranin B may be an excellent biomarker when differentiation of pancreatic neuroendocrine tumor from other pancreatic diseases is required.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Chromogranin A; Chromogranin B; Enzyme-Linked Immunosorbent Assay; Female; Gastrins; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neuroendocrine Tumors; Pancreatic Neoplasms; Proton Pump Inhibitors; ROC Curve; Young Adult

The aim of the study was to evaluate the anti-tumor mechanism of Z-360, a gastrin/cholecystokinin-2 receptor (CCK2R) antagonist, in MIA PaCa-2 cells and in a subcutaneous xenograft mice model.. The anti-tumor effects of Z-360 and/or gemcitabine were monitored using a MIA PaCa-2 xenograft model. The effect of Z-360 on apoptosis in the model was examined by TUNEL staining and real-time PCR analysis and the effect in MIA PaCa-2 cells stably expressing human CCK2R was also evaluated by caspase-3/7 activity.. In this xenograft model, Z-360 significantly reduced the tumor weight, increased TUNEL-positive cells and suppressed the expression of anti-apoptosis factors such as survivin, XIAP and Mcl-1, and these effects of Z-360 combined with gemcitabine were more effective. Furthermore, gastrin-17 and gastrin-34 inhibited apoptosis in vitro and Z-360 dose-dependently abrogated this effect.. These results suggest that Z-360 exerts an anti-tumor effect through a reduction in anti-apoptosis factors by blocking CCK2R.

Topics: Animals; Apoptosis; Benzodiazepinones; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Endopeptidases; Gastrins; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Pancreatic Neoplasms; Receptor, Cholecystokinin B; Survivin; X-Linked Inhibitor of Apoptosis Protein; Xenograft Model Antitumor Assays

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

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry-based proteomics) and show that 29-amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.

Topics: Aged; Blood Glucose; Case-Control Studies; Cholecystokinin; Chromatography, Liquid; Enzyme-Linked Immunosorbent Assay; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Tract; Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Glucose Tolerance Test; Humans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis; Peptide Fragments; Proteomics; Radioimmunoassay; Tandem Mass Spectrometry

Pancreatic neuroendocrine tumors (PNETs) are known to have heterogeneity in terms of their ability to produce multiple hormones. The aim of this study was to evaluate the heterogeneity of PNETs from the viewpoint of hormonal expression.. The expressions of 4 representative hormones, gastrin, insulin, glucagon, and somatostatin, in both primary and metastatic lesions, were analyzed by immunohistochemical staining in 20 patients with metastatic PNETs (6 gastrinomas, 1 insulinoma, 1 glucagonoma, and 12 nonfunctioning PNETs [NF-PNETs]). Metastatic sites included lymph nodes in all 20 patients and liver metastasis in 7 patients (2 gastrinomas and 5 NF-PNETs).. There were 6 PNETs with multiple hormone secretion (30%), and positive expression of 1 or more hormones was found in 9 of 12 patients whose primary tumors were diagnosed as NF-PNETs. The positive concordance rate of the hormonal expression pattern between primary tumors and metastatic lymph nodes and between primary tumors and hepatic metastasis were 50% and 11%, respectively. Three patients had metastatic lesions with positive hormonal expression, whereas their primary tumors were negative.. Hormonal expressions are often different between the primary tumors and metastatic sites of PNETs.

Topics: Adult; Aged; Aged, 80 and over; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Insulin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin

Neuroendocrine tumors of the pancreas (PanNETs) are rare neoplasms, and not much is known about their pathogenesis. We aimed to evaluate ATRX/DAXX immunoexpression in PanNETs a cohort of well-characterized PanNETs.. PanNETs diagnosed over a 10-year period were retrieved and clinicopathogical features reviewed. Immuohistochemistry for pancreatic hormones, and for ATRX and DAXX was performed.. Sixty-eight PanNETs were included (30 males and 38 females) with median age of 39 years. Histologically, there were 37 Grade 1 (54.4%), 27 Grade 2 (39.7%), and 4 Grade 3 (5.9%) cases. On immunostaining for hormones, insulin expression was most frequent (22 cases; 38.6%), followed by gastrin (7 cases; 12.3%); 25 cases (43.9%) were negative for all hormones. Loss of ATRX/DAXX immunoexpression was noted in 18 cases (39.1%), and was significantly more frequent in tumors larger than 5 cm. Lymphovascular invasion, infiltrative borders, and infiltration of adjacent organs were also more frequent in tumors with loss of ATRX/DAXX immunoreactivity. A little over half the tumors with ATRX/DAXX loss showed negative immunostaining for all hormones (55.6%).. Loss of ATRX/DAXX expression is frequent in PanNETs, indicating a role in their pathogenesis. As ATRX/DAXX loss is more frequent in larger tumors, and in those with lymphovascular invasion, adjacent organ infiltration and infiltrative borders, this suggests that loss of ATRX/DAXX expression is a late event in pathogenesis and is associated with an aggressive phenotype. Immunohistochemical detection of ATRX/DAXX loss is a simple method for ATRX/DAXX evaluation and can easily be incorporated into routine pathological evaluation of PanNETs.

Topics: Adaptor Proteins, Signal Transducing; Adult; Co-Repressor Proteins; DNA Helicases; Female; Gastrins; Humans; Immunohistochemistry; Insulin; Male; Molecular Chaperones; Neuroendocrine Tumors; Nuclear Proteins; Pancreatic Hormones; Pancreatic Neoplasms; X-linked Nuclear Protein

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

Pancreatic neuroendocrine tumours (PNETs) are the major source of disease-specific mortality in multiple endocrine neoplasia type 1 (MEN1) patients. Chromogranin A (CgA), pancreatic polypeptide (PP), glucagon and gastrin have some diagnostic value in sporadic PNETs, but there is very little evidence for their efficacy in diagnosing PNETs in MEN1 patients.. We performed a retrospective chart review of the existing MEN1 database in our institution.. One hundred and thirteen patients were eligible for diagnostic value analysis of tumour markers. Patients were excluded if measurement of tumour markers was missing, either 3 months prior to PNET diagnosis (PNET patients) or prior to abdominal imaging (non-PNET patients).. Clinicopathologic characteristics and of tumour marker measurements were analysed.. Of 293 confirmed MEN1 cases, 55 PNETs and 58 non-PNETs met inclusion criteria. The area under the curve (AUC) for CgA, PP, glucagon and gastrin in MEN1 cases was 59·5%, 64·1%, 77·0% and 75·9%, respectively. The AUC for the combination of CgA, PP and gastrin was 59·6%. PP, but not CgA, glucagon or gastrin was significantly associated with both age and PNET functional status (P = 0·0485 and 0·0188, respectively). No markers were significantly associated with sex, PNET size, tumour number, tumour location, American Joint Committee on Cancer (AJCC) stage, presence of lymph node metastasis, lymphovascular invasion or overall survival. CgA values were not significantly lower following PNET resection than pre-operatively (P = 0·554).. The value of blood markers for diagnosing PNETs in MEN1 patients is relatively low, even when used in combination.

Topics: Adolescent; Adult; Aged; Area Under Curve; Biomarkers, Tumor; Chromogranin A; Female; Gastrins; Glucagon; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreatic Polypeptide; Retrospective Studies; Young Adult

Gastrin is absent in most normal adult pancreatic tissues but is highly expressed in pancreatic cancer tissues. Although Gastrin expression was reported to be associated with tumor proliferation in human pancreatic cancer, studies on the relationship between Gastrin and tumor metastasis in pancreatic cancer are rare. In this study, we performed an analysis to determine the effects of Gastrin on modulating the side populations, cell proportion and tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. We indicated that Gastrin and ABCG2 were widely expressed in pancreatic cancer cell lines and overexpressed in cancer tissues. Gastrin induced ABCG2 expression, and this effect was mediated by NF-κB activation. Gastrin regulated the SP proportion of BxPC-3 cells via modulating ABCG2 expression. Through the regulation of the functions of NF-κB/ABCG2, Gastrin functionally promoted the migration and invasion in pancreatic cancer cell. The present study indicated that Gastrin induced ABCG2 expression by activating NF-κB and thereby modulated the SP proportion, tumor cell metastatic potential and invasion activity in pancreatic cancer. Gastrin could serve as an effective therapeutic target for the metastasis of pancreatic cancer.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Cell Line, Tumor; Cell Movement; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasm Proteins; NF-kappa B; Pancreatic Neoplasms; Promoter Regions, Genetic; RNA, Messenger; Side-Population Cells; Signal Transduction; Transcription, Genetic

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

Pancreatic neuroendocrine tumors (PNETs) may evolve and cause hormonal hypersecretion-related symptoms that were not present at the initial diagnosis, termed metachronous hormonal syndromes (MHSs). Their setting, characteristics, and outcomes are not well-described.. To describe MHSs in patients with sporadic PNETs.. Retrospective, multicenter study.. 4 French referral centers.. Patients with PNETs who developed MHSs related to hypersecretion of insulin, gastrin, vasoactive intestinal peptide, or glucagon between January 2009 and January 2014.. Tumor extension, biological markers, and treatments at initial PNET diagnosis and MHS onset. Pathologic specimens were evaluated centrally, including Ki-67 index and hormone immunolabeling.. Of 435 patients with PNETs, 15 (3.4%) were identified as having MHSs involving the hypersecretion of insulin (5 patients), vasoactive intestinal peptide (5 patients), gastrin (2 patients), or glucagon (4 patients). Metachronous hormonal syndromes developed after a median of 55 months (range, 7 to 219) and in the context of PNET progression, stability, and tumor response in 8, 6, and 1 patients, respectively. The median Ki-67 index was 7% (range, 1% to 19%) at PNET diagnosis and 17.5% (range, 2.0% to 70.0%) at MHS onset. Immunolabeling of MHS-related peptides was retrospectively found in 8 of 14 of pathologic PNET specimens obtained before MHS diagnosis. Median survival after MHS onset was 28 months (range, 3 to 56). Seven patients with MHSs died during follow-up, all due to PNETs, including 4 patients with insulin-related MHSs.. Retrospective data collection and heterogeneity of pathologic specimen size and origin.. Metachronous hormonal syndromes were identified more often in the context of PNET progression and increased Ki-67 indices. Patients with insulin-related MHSs may have decreased survival rates.. None.

Topics: Adult; Aged; Biomarkers, Tumor; Disease Progression; Female; Gastrins; Glucagon; Hormones; Humans; Insulin; Insulin Secretion; Ki-67 Antigen; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Syndrome; Vasoactive Intestinal Peptide

The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a(+) and neurogenin 3-expressing (Ngn3(+)) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors.

Topics: Animals; Carcinogenesis; Gastrins; Humans; Islets of Langerhans; Mice, Inbred C57BL; Mice, Knockout; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Proto-Oncogene Proteins

Topics: Collagen Diseases; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplastic Syndromes, Hereditary; Pancreatic Neoplasms; Skin Neoplasms

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: Animals; Cholecystokinin; Chromogranin A; Diagnosis, Differential; Fatal Outcome; Female; Gastrins; Humans; Liver; Liver Neoplasms; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Topics: Cancer Vaccines; Female; Gastrins; Humans; Male; Pancreatic Neoplasms

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 show that the gastric hormone gastrin induces the expression of the prosurvival secretory clusterin (sCLU) in rat adenocarcinoma cells. Clusterin mRNA was still upregulated in the presence of the protein synthesis inhibitor cycloheximide, although at a lower level. This indicates that gastrin induces clusterin transcription independently of de novo protein synthesis but requires de novo protein synthesis of signal transduction pathway components to achieve maximal expression level. Luciferase reporter assay indicates that the AP-1 transcription factor complex is involved in gastrin-mediated activation of the clusterin promoter. Gastrin-induced clusterin expression and subsequent secretion is dependent on sustained treatment, because removal of gastrin after 1-2 h abolished the response. Neutralization of secreted clusterin by a specific antibody abolished the antiapoptotic effect of gastrin on serum starvation-induced apoptosis, suggesting that extracellular clusterin is involved in gastrin-mediated inhibition of apoptosis. The clusterin response to gastrin was validated in vivo in hypergastrinemic rats, showing increased clusterin expression in the oxyntic mucosa, as well as higher levels of clusterin in plasma. In normal rat oxyntic mucosa, clusterin protein was strongly expressed in chromogranin A-immunoreactive neuroendocrine cells, of which the main cell type was the histidine decarboxylase-immunoreactive enterochromaffin-like (ECL) cell. The association of clusterin with neuroendocrine differentiation was further confirmed in human gastric ECL carcinoids. Interestingly, in hypergastrinemic rats, clusterin-immunoreactive cells formed distinct groups of diverse cells at the base of many glands. Our results suggest that clusterin may contribute to gastrin's growth-promoting effect on the oxyntic mucosa.

Topics: Adenocarcinoma; Animals; Apoptosis; Carcinoid Tumor; Cell Line, Tumor; Chromogranin A; Clusterin; Enterochromaffin Cells; Female; Gastrins; Histidine Decarboxylase; Humans; Neuroendocrine Cells; Pancreatic Neoplasms; Parietal Cells, Gastric; Promoter Regions, Genetic; Rats; Rats, Sprague-Dawley; Stomach Neoplasms; Transcription Factor AP-1; Up-Regulation

The cholecystokinin-2 receptor (CCK2R), is expressed in cancers where it contributes to tumor progression. The CCK2R is over-expressed in a sub-set of tumors, allowing its use in tumor targeting with a radiolabel ligand. Since discrepancies between mRNA levels and CCK2R binding sites were noticed, we searched for abnormally spliced variants in tumors from various origins having been previously reported to frequently express cholecystokinin receptors, such as medullary thyroid carcinomas, gastrointestinal stromal tumors, leiomyomas and leiomyosarcomas, and gastroenteropancreatic tumors. A variant of the CCK2R coding for a putative five-transmembrane domains receptor has been cloned. This variant represented as much as 6% of CCK2R levels. Ectopic expression in COS-7 cells revealed that this variant lacks biological activity due to its sequestration in endoplasmic reticulum. When co-expressed with the CCK2R, this variant diminished membrane density of the CCK2R and CCK2R-mediated activity (phospholipase-C and ERK activation). In conclusion, a novel splice variant acting as a dominant negative on membrane density of the CCK2R may be of importance for the pathophysiology of certain tumors and for their in vivo CCK2R-targeting.

Topics: Alternative Splicing; Amino Acid Sequence; Animals; Binding Sites; Carcinoma, Medullary; Chlorocebus aethiops; Cholecystokinin; COS Cells; Extracellular Signal-Regulated MAP Kinases; Gastrins; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Insulinoma; Leiomyoma; Leiomyosarcoma; Molecular Sequence Data; Pancreatic Neoplasms; Protein Structure, Tertiary; Receptor, Cholecystokinin B; RNA, Messenger; Signal Transduction; Thyroid Neoplasms; Type C Phospholipases

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

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

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

Various aspects of radiopeptide receptor-mediated cell internalisation and externalization assays were assessed, including the integrity of externalized peptides and the effect of varying the pH and incubation time of the acid wash step (to remove surface receptor-bound ligand) on efficacy and cell viability. The observed intact proportion of externalized peptide was 5-10%, and acid wash buffers with pH 2.8 or below were found to be detrimental to cell viability and integrity, particularly following prolonged incubation times.

Topics: Animals; Cell Line, Tumor; Cell Survival; Endocytosis; Exocytosis; Gastrins; Indium Radioisotopes; Organometallic Compounds; Pancreatic Neoplasms; Radiopharmaceuticals; Rats

To present our experience of 93 neuroendocrine tumors (NETs) in the pancreas and peripancreatic region, with emphasis on how resectability affects long-term survival and the impact of functional status on the survival outcome.. Ninety-three patients with NETs in the pancreas and peripancreatic region were included to compare the clinical features between functional and nonfunctional NETs. Prognostic factors were determined by univariate and multivariate analyses.. There were 39 functional (41.9%) and 54 nonfunctional NETs (58.1%). According to World Health Organization (WHO) tumor categories, there were 57 well-differentiated tumors (61.3%), 26 well-differentiated carcinomas (28%), and 10 poorly differentiated carcinomas (10.8%). Univariate analysis showed that functional status of the tumor, tumor stage, lymph node status, and pathological classification were prognostic factors for both disease-free survival and disease-specific survival. Resectability did not influence the survival outcome, with the resectable and unresectable groups demonstrating a 5-year disease-specific survival of 86.4% and 65.6%, respectively (P = 0.210). Only the WHO pathological classification was an independent prognostic factor after multivariate analysis.. Irresectability does not necessarily preclude long-term survival for both functional and nonfunctional NETs. It is the WHO pathological classification, instead of hormonal functional status, that is an independent prognostic factor and has impact on the survival outcome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cell Differentiation; Chi-Square Distribution; Child; Disease-Free Survival; Female; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Insulin; Insulin Secretion; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neuroendocrine Tumors; Odds Ratio; Pancreatectomy; Pancreatic Neoplasms; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Taiwan; Time Factors; Treatment Outcome; Vasoactive Intestinal Peptide; Young Adult

Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer. Although down-regulation of gastrin inhibits growth of pancreatic cancer, the contribution of endogenous CCK to tumor growth is unknown. The purpose of this study was to evaluate the role of endogenous CCK on autocrine growth of pancreatic cancer. Pancreatic cancer cell lines were analyzed for CCK mRNA and peptide expression by real-time RT-PCR and radioimmunoassay, respectively. The effect of endogenous CCK on growth was evaluated by treating cancer cells with CCK neutralizing antibodies and by down-regulating CCK mRNA by RNAi. Wild-type pancreatic cancer cells expressed significantly lower CCK mRNA and peptide levels than gastrin. Neither treatment of pancreatic cancer cells with CCK antibodies nor the down-regulation of CCK mRNA and peptide by shRNAs altered growth in vitro or in vivo. Conversely, when gastrin mRNA expression was down-regulated, the same cells failed to produce tumors in spite of having sustained levels of endogenous CCK. Pancreatic cancer cells produce CCK and gastrin; however, the autocrine production of gastrin is more important for stimulating tumor growth.

Topics: Adenocarcinoma; Animals; Antibodies, Neutralizing; Autocrine Communication; Cell Line, Tumor; Cell Proliferation; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; RNA, Messenger; RNA, Small Interfering; Tissue Distribution; Xenograft Model Antitumor Assays

Gastrin, acting through peripheral cholecystokinin (CCK) 2 receptors, is a major hormonal regulator of gastric acid secretion. The effects of gastrin on acid secretion occur both acutely and chronically because gastrin directly stimulates gastric acid secretion and also exerts trophic effects on the enterochromaffin-like and parietal cells that together constitute the acid secretory apparatus of the stomach. Several antagonists that target the CCK2 receptor have been identified and investigated for the treatment of gastroesophageal reflux disease and pancreatic cancer. In this paper, we discuss the contribution of gastrin to these disease pathologies and the data generated to date from clinical studies investigating CCK2 receptor antagonists.

Topics: Animals; Drug Delivery Systems; Enterochromaffin-like Cells; Gastric Acid; Gastrins; Gastroesophageal Reflux; Humans; Pancreatic Neoplasms; Parietal Cells, Gastric; Receptor, Cholecystokinin B

We recently identified the transcription factor (TF) islet 1 gene product (ISL1) as a marker for well-differentiated pancreatic neuroendocrine tumors (P-NETs). In order to better understand the expression of the four TFs, ISL1, pancreatico-duodenal homeobox 1 gene product (PDX1), neurogenin 3 gene product (NGN3), and CDX-2 homeobox gene product (CDX2), that mainly govern the development and differentiation of the pancreas and duodenum, we studied their expression in hormonally defined P-NETs and duodenal (D-) NETs. Thirty-six P-NETs and 14 D-NETs were immunostained with antibodies against the four pancreatic hormones, gastrin, serotonin, calcitonin, ISL1, PDX1, NGN3, and CDX2. The TF expression pattern of each case was correlated with the tumor's hormonal profile. Insulin-positive NETs expressed only ISL1 (10/10) and PDX1 (9/10). Glucagon-positive tumors expressed ISL1 (7/7) and were almost negative for the other TFs. Gastrin-positive NETs, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). CDX2 was mainly found in the gastrin-positive P-NETs (5/8) and rarely in the D-NETs (1/10). Somatostatin-positive NETs, whether duodenal or pancreatic in origin, expressed ISL1 (9/9), PDX1 (3/9), and NGN3 (3/9). The remaining tumors showed labeling for ISL1 in addition to NGN3. There was no association between a particular TF pattern and NET features such as grade, size, location, presence of metastases, and functional activity. We conclude from our data that there is a correlation between TF expression patterns and certain hormonally defined P-NET and D-NET types, suggesting that most of the tumor types originate from embryologically determined precursor cells. The observed TF signatures do not allow us to distinguish P-NETs from D-NETs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Calcitonin; CDX2 Transcription Factor; Duodenal Neoplasms; Female; Gastrins; Glucagon; Homeodomain Proteins; Humans; Immunohistochemistry; Insulin; LIM-Homeodomain Proteins; Male; Middle Aged; Nerve Tissue Proteins; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Trans-Activators; Transcription Factors; Young Adult

To analyse αv integrin expression induced by gastrin in pancreatic cancer models.. αv integrin mRNA expression in human pancreatic cancer cells was analysed using a "cancer genes" array and confirmed by real-time reverse transcription-polymerase chain reaction (PCR). Western blotting and semi-quantitative immunohistochemistry were used to examine protein levels in human pancreatic cancer cell lines and pancreatic tissues, respectively. The role of αv integrin on gastrin-induced cell adhesion was examined using blocking anti-αv integrin monoclonal antibodies. Adherent cells were quantified by staining with crystal violet.. Using a "cancer genes" array we identified αv integrin as a new gastrin target gene in human pancreatic cancer cells. A quantitative real-time PCR approach was used to confirm αv integrin gene expression. We also demonstrate that Src family kinases and the PI 3-kinase, two signalling pathways specifically activated by the CCK-2 receptor (CCK2R), are involved in gastrin-mediated αv integrin expression. In contrast, inhibition of the ERK pathway was without any effect on αv integrin expression induced by gastrin. Our results also show that gastrin modulates cell adhesion via αv integrins. Indeed, in vitro adhesion assays performed on fibronectin show that gastrin significantly increases adhesion of pancreatic cancer cells. The use of blocking anti-αv integrin monoclonal antibodies completely reversed the increase in cell-substrate adhesion induced by gastrin. In addition, we showed in vivo that the targeted CCK2R expression in the pancreas of Elas-CCK2 mice, leads to the overexpression of αv integrin. This process may contribute to pancreatic tumour development observed in these transgenic animals.. αv integrin is a new gastrin target in pancreatic cancer models and contributes to gastrin effects on cell adhesion.

Topics: Animals; Cell Adhesion; Cell Line, Tumor; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Integrin alphaV; Mice; Mice, Transgenic; Microarray Analysis; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Real-Time Polymerase Chain Reaction; Receptor, Cholecystokinin B; Signal Transduction; src-Family Kinases

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

Recent advances in localization techniques, such as the selective arterial secretagogue injection test (SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors (PNET). For patients with sporadic functioning PNET, curative resection surgery has been established by localization with the SASI test using secretin or calcium. For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1 (MEN 1) which are usually multiple and sometimes numerous, resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test. As resection surgery of PNET has increased, several important pathological features of PNET have been revealed. For example, in patients with Zollinger-Ellison syndrome (ZES), duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma, and in patients with MEN 1 and ZES, gastrinomas have been located mostly in the duodenum, and pancreatic gastrinoma has been found to co-exist in 13% of patients. Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation. The most important prognostic factor in patients with PNET is the development of hepatic metastases. The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit. The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.

Topics: Animals; Diagnosis, Differential; Gastrins; Humans; Liver Neoplasms; Male; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

This report presents a case of pancreatic neuroendocrine cell carcinoma with multiple liver metastases secreting gastrin and parathyroid hormone-related protein (PTHrP) related to lumbar bone fracture and hypercalcemia. A 58-year-old woman visited an affiliated hospital with a chief complaint of lumbago without any evidence of trauma. She was diagnosed with hepatic dysfunction and hypercalcemia as well as multiple lumbar compression fractures without osteolytic lesions. Abdominal computed tomography (CT) showed a hypervascular mass in the pancreatic tail and multiple liver tumors. Duodenal ulcers were found with gastrointestinal endoscopy. There was a marked increase in the serum gastrin level. She was diagnosed as gastrinoma with multiple liver metastases and was admitted to the hospital. She had an increase in serum PTHrP level without the elevation of intact parathyroid hormone at the time of admission. She underwent an extended right hepatectomy in addition to a distal pancreatectomy with a regional lymphadenectomy and splenectomy. The postoperative course was uneventful, and serum gastrin and PTHrP activities reduced to normal levels. She remained symptom-free, and serum calcium, gastrin, and PTHrP levels remain within the normal ranges 19 months after surgery without adjuvant therapy.

Topics: Endoscopy, Gastrointestinal; Female; Gastrins; Hepatectomy; Humans; Hypercalcemia; Liver Neoplasms; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Parathyroid Hormone-Related Protein; Spinal Fractures; Tomography, X-Ray Computed

This study evaluated the effects of gastrin messenger RNA (mRNA) down-regulation on growth of human pancreatic cancer.. Gastrin expression was examined in human pancreatic cancer cell lines by reverse transcriptase-polymerase chain reaction, and peptide expression was assessed by immunocytochemistry. Gastrin was down-regulated using either stable transfection of an antisense gastrin cDNA or 1 of 3 shRNA (short hairpin RNA) constructs. Tumor formation was evaluated after either subcutaneous or orthotopic injections into nude mice. The effect of nanoliposomes loaded with gastrin siRNA (small interfering RNA) was tested in mice bearing pancreatic tumors.. Stable transfection of gastrin antisense or shRNAs into BxPC-3 cells resulted in clones with more than 90% reduction in gastrin mRNA. Tumor growth rate and incidence of metastases in both wild-type and transfected pancreatic cancer cells were directly proportional to the degrees of gastrin mRNA expression. Immunofluorescence analysis confirmed that gastrin peptide levels were decreased in antisense and shRNA tumors. Gastrin knockdown clones had lower Ki-67 and increased cleaved caspase-3 staining, consistent with known effects of gastrin on proliferation and apoptosis. Tumors in mice treated with gastrin siRNA were smaller than controls.. These results suggest that RNAi targeting of gastrin could serve as an effective treatment for pancreatic cancer.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Fluorescent Antibody Technique; Gastrins; Humans; Ki-67 Antigen; Liposomes; Mass Spectrometry; Mice; Mice, Nude; Nanotechnology; Pancreatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger; RNA, Small Interfering; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

The purpose of this study is to describe outcomes of MEN-1 patients with recurrence requiring completion pancreatectomy and duodenectomy after initial treatment of pancreatic endocrine neoplasms (PENs) and hypergastrinemia with distal pancreatectomy, enucleation of pancreatic head PENs, and duodenotomy.. After undergoing this initial operation, 8 of 49 patients (16%) have required completion pancreatectomy and duodenectomy for recurrent PENs and hypergastrinemia. Retrospective review was performed.. Median age was 39 years (27-51) at completion pancreatectomy compared to 31 years (20-40) at initial operation. Pathology revealed multiple PENs in 100%, duodenal neoplasms in 63%, and metastatic lymph nodes in 75%. There was no operative mortality and 88% of patients are currently alive. Preoperative gastrin levels were 934 +/- 847 pg/mL while postoperative levels are 93 +/- 79 pg/mL (normal 25-111 pg/mL). Mean Hemoglobin A1C levels are 8.3 +/- 3.3% (normal 3.8%-6.4%). Mean follow-up is 44 +/- 25 months.. This initial operation may provide tumor control and prevent metastases but recurrent PENs are multifocal and progressive. Completion pancreatectomy and duodenectomy is arduous but outcomes are acceptable. Considering the radical nature of this treatment, individual consideration should be given to MEN-1 patients amenable to initial alternative pancreatic resections that preserve pancreatic mass and allow future pancreas-preserving reoperations.

Topics: Adult; Duodenal Neoplasms; Duodenum; Female; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Diethylenetriamine-pentaacetic acid (DTPA)-coupled minigastrins are unsuitable for therapeutic application with the available beta-emitting radiometals due to low complex stability. Low tumour-to-kidney ratio of the known radiopharmaceuticals is further limiting their potency. We used macrocyclic chelators for coupling to increase complex stability, modified the peptide sequence to enhance radiolytic stability and studied tumour-to-kidney ratio and metabolic stability using (111)In-labelled derivatives.. Gastrin derivatives with decreasing numbers of glutamic acids were synthesised using (111)In as surrogate for therapeutic radiometals for in vitro and in vivo studies. Gastrin receptor affinities of the (nat)In-metallated compounds were determined by receptor autoradiography using (125)I-CCK as radioligand. Internalisation was evaluated in AR4-2J cells. Enzymatic stability was determined by incubating the (111)In-labelled peptides in human serum. Biodistribution was performed in AR4-2J-bearing Lewis rats.. IC(50) values of the (nat)In-metallated gastrin derivatives vary between 1.2 and 4.8 nmol/L for all methionine-containing derivatives. Replacement of methionine by norleucine, isoleucine, methionine-sulfoxide and methionine-sulfone resulted in significant decrease of receptor affinity (IC(50) between 9.9 and 1,195 nmol/L). All cholecystokinin receptor affinities were >100 nmol/L. All (111)In-labelled radiopeptides showed receptor-specific internalisation. Serum mean-life times varied between 2.0 and 72.6 h, positively correlating with the number of Glu residues. All (111)In-labelled macrocyclic chelator conjugates showed higher tumour-to-kidney ratios after 24 h (0.37-0.99) compared to (111)In-DTPA-minigastrin 0 (0.05). Tumour wash out between 4 and 24 h was low. Imaging studies confirmed receptor-specific blocking of the tumour uptake.. Reducing the number of glutamates increased tumour-to-kidney ratio but resulted in lower metabolic stability. The properties of the macrocyclic chelator-bearing derivatives make them potentially suitable for clinical purposes.

Topics: Animals; Cell Line, Tumor; Chelating Agents; Drug Delivery Systems; Gastrins; Macrocyclic Compounds; Metabolic Clearance Rate; Organ Specificity; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Inbred Lew; Receptor, Cholecystokinin B; Tissue Distribution

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

Gastrin is known to enhance the growth of pancreatic carcinoma via the cholecystokinin (CCK)-2/gastrin receptor. We investigated the anti-tumor effect of Z-360 (calcium bis [(R)-(-)-3-[3-{5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}ureido]benzoate]), a novel orally active CCK-2 receptor antagonist alone or combined with the chemotherapeutic agent, gemcitabine in human pancreatic adenocarcinoma cell lines.. Z-360 potently inhibited specific binding of [3H]CCK-8 to the human CCK-2 receptor, with a Ki value of 0.47 nmol/l, and showed antagonistic activity for this receptor. The anti-tumor effect of Z-360 alone or combined with gemcitabine was assessed using subcutaneous xenografts of MiaPaCa2 and PANC-1 and an orthotopic xenograft model (PANC-1). Oral administration of Z-360 significantly inhibited the growth of MiaPaCa2 (41.7% inhibition at 100 mg/kg, P<0.01). Combined administration of Z-360 and gemcitabine significantly inhibited subcutaneous PANC-1 tumor growth compared with either agent alone (27.1% inhibition compared to effect with gemcitabine, P<0.05), and significantly prolonged survival compared with the vehicle control (median survival of 49 days in vehicle compared to 57 days in the combination group, P<0.05). In vitro studies showed that Z-360 significantly inhibited gastrin-induced proliferation of human CCK-2 receptor-expressing cells, and also significantly reduced gastrin-induced PKB/Akt phosphorylation to the level of untreated controls.. In the present study, we have shown that Z-360 combined with gemcitabine can inhibit pancreatic tumor growth and prolong survival in a pancreatic carcinoma xenograft model, on a possible mode of action being the inhibition of gastrin-induced PKB/Akt phosphorylation through blockade of the CCK-2 receptor. Our results suggest that Z-360 may be a useful adjunct to gemcitabine for the treatment of pancreatic carcinoma and a therapeutic option for patients with advanced pancreatic cancer.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzodiazepinones; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Disease Models, Animal; Female; Gastrins; Gemcitabine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, Cholecystokinin B; Survival Rate; Xenograft Model Antitumor Assays

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

The interaction of gastrin with the cholecystokinin 2 (CCK2)/gastrin receptor has been studied extensively in relation to gastric acid secretion. However, not much is known about the contribution of individual amino acids of gastrin interacting with the CCK2 receptor, when gastrin is acting as a tumor growth factor. The purpose of the present study was to determine the significance of each individual amino acid residue of human gastrin-17 with respect to CCK2 receptor-mediated cell proliferation. Activation of this receptor was assessed using an in vitro bioassay based on gastrin-induced expression of a c-fos-luciferase reporter, transfected in AR42JB13 and Colo 320 cells, a rat pancreatic and human colorectal cell line respectively. Gastrin-17 dose dependently increased c-fos induction in both cancer cell lines. L365,260, a known CCK2 receptor antagonist, completely blocked the gastrin signal, demonstrating the specificity of this assay. We demonstrated for the first time that four carboxy-terminal amino acids of gastrin-17 are essential for activation of the CCK2 receptor with respect to c-fos induction. Also other residues of gastrin-17, notably glycine-2 for the rat CCK2 receptor and glutamic acid 8-10 and tyrosine-12 for the human receptor, were found to be important, although to a lesser extent. Alanine-substitution variants of each of the four carboxy-terminal amino acids of gastrin-17 showed strongly reduced receptor activation but did not act as competitive inhibitors of gastrin-17. Identification of the essential role of the carboxy-terminal tetrapeptide of gastrin-17 in CCK2 receptor-mediated c-fos induction indicates that gastrin inhibitory therapeutic strategies should mainly be targeted toward this region of gastrin.

Topics: Alanine; Amino Acid Substitution; Animals; Cell Proliferation; Colorectal Neoplasms; DNA Primers; Gastrins; Genes, fos; Humans; Luciferases; Pancreatic Neoplasms; Pentagastrin; Promoter Regions, Genetic; Protein Precursors; Rats; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

We report the case of a 49-year-old caucasian woman, in whom an endocrine tumor arising in gastric heterotopic pancreas was diagnosed. The patient was treated surgically with a gastric wedge resection. Heterotopic pancreas is a benign anatomic condition, probably widely underdiagnosed because usually asymptomatic. The malignant transformation of aberrant pancreas is very rare and almost always in adenocarcinoma. The endocrine tumors developed in heterotopic pancreas are exceedingly rare. Of our knowledge, only four cases have been published and only one case in the gastric location similar to this reported case.

Topics: Carcinoma, Islet Cell; Cell Transformation, Neoplastic; Choristoma; Female; Follow-Up Studies; Gastrins; Humans; Islets of Langerhans; Middle Aged; Pancreas; Pancreatic Neoplasms; Somatostatin; Stomach Diseases

As the hormone gastrin promotes gastrointestinal (GI) cancer progression by triggering survival pathways, regulation of gastrin expression at the translational level was explored. Sequence within the 5' untranslated region of a gastrin transcript expressed in GI cancer cells was investigated, then cloned into a bicistronic vector upstream of firefly luciferase and transfected into a series of GI cancer cell lines. Firefly luciferase activity was measured relative to that of a cap-dependent Renilla luciferase. A gastrin transcript that was different from that described in Ensembl was expressed in GI cancer cells. Its transcription appears to be initiated within the region designated as the gene's first intron. In GI cancer cells transfected with the bicistronic construct, firefly luciferase activity increased 8-15-fold compared with the control vector, and there was a further induction of the signal (up to 25-fold) following exposure of the cells to genotoxic stress or hypoxia, suggesting that the sequence acts as an internal ribosome entry site. These data suggest that the gastrin transcript within GI cancer cells contains an internal ribosome entry site that may allow continued expression of gastrin peptides when normal translational mechanisms are inactive, such as in hypoxia, thereby promoting cancer cell survival.

Topics: 5' Untranslated Regions; Adenocarcinoma; Apoptosis; Cell Survival; Gastrins; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hypoxia; Luciferases; Luciferases, Renilla; Pancreatic Neoplasms; Protein Biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Survival Analysis; Transcription, Genetic; Transfection

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

Progastrin (PG) exerts proliferative and antiapoptotic effects on intestinal epithelial and colon cancer cells via Annexin II (ANX-II). In here, we show that ANX-II similarly mediates proliferative and antiapoptotic effects of PG on a pancreatic cancer cell line, AR42J. The role of several signaling molecules was examined in delineating the biological activity of PG. PG (0.1-1.0 nmol/L) caused a significant increase (2- to 5-fold) in the phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt (Thr(308)), p38 mitogen-activated protein kinase (MAPK; Thr(180)/Tyr(182)), extracellular signal-regulated kinases (ERK; Thr(202)/Tyr(204)), IkappaB kinase alpha/beta (IKKalpha/beta; Ser(176)/(180)), IkappaBalpha (Ser(32)), and p65 nuclear factor-kappaB (NF-kappaB; Ser(536)). Inhibition of p44/42 ERKs (PD98059), p38 MAPK (SB203580), Akt, and PI3K (LY294002), individually or combined, partially reversed antiapoptotic effects of PG. The kinetics of phosphorylation of IKKalpha/beta in response to PG matched the kinetics of phosphorylation and degradation of IkappaBalpha and correlated with phosphorylation, nuclear translocation, and activation of p65 NF-kappaB. NF-kappaB essential modulator-binding domain peptide (an inhibitor of IKKalpha/beta) effectively blocked the activity of p65 NF-kappaB in response to PG. Activation of p65 NF-kappaB, in response to PG, was 70% to 80% dependent on phosphorylation of MAPK/ERK and PI3K/Akt molecules. Down-regulation of p65 NF-kappaB by specific small interfering RNA resulted in the loss of antiapoptotic effects of PG on AR42J cells. These studies show for the first time that the canonical pathway of activation of p65 NF-kappaB mediates antiapoptotic effects of PG. Therefore, targeting PG and/or p65 NF-kappaB may be useful for treating cancers, which are dependent on autocrine or circulating PGs for their growth.

Topics: Annexin A2; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Gastrins; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Kinase; Immunoprecipitation; NF-kappa B; Pancreatic Neoplasms; Phosphorylation; Promoter Regions, Genetic; Protein Precursors; RNA, Small Interfering; Transcription Factors

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

Peroxisome proliferator-activated receptor gamma (PPAR gamma) are members of the largest nuclear hormone receptor family of transcription factors (1). PPAR gamma (PPARgamma) plays an important role in adipogenesis, control of sensitivity to insulin, inflammation and atherosclerosis but recent studies also suggest that PPARgamma is involved in cell cycle withdrawal. PPARgamma can promote cell differentiation, exert an antiproliferative action and inhibit angiogenesis (2, 3). However, there are studies showing that activation of PPARgamma promotes the development of colon cancer (4). These data are in sharp contrast with studies that attribute anticancer effects to PPARgamma in gastrointestinal malignancies. Probably, the action of PPARgamma on cell cycle and proliferation depends on the cell type and presence of other stimuli that predispose cells to cancer development. Amidated and non-amidated gastrins may play an important role in the proliferation and carcinogenesis of GI cancers. It is known that gastrin peptides activate phosphorylation of Protein Kinase B (PKB/Akt) and anti-apoptotic signalling but there is little known about the link between gastrins and PPARgamma receptors in relation to apoptosis.

Topics: Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Gastrins; Humans; Pancreatic Neoplasms; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Thiazolidinediones; Transcription, Genetic; Up-Regulation

Topics: Gastrins; Gastrointestinal Neoplasms; Humans; Immunotherapy; Pancreatic Neoplasms; Vaccination

The frequency of pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1 (MEN1) remains unknown.. To evaluate prospectively with endoscopic ultrasonography (EUS) the frequency of nonfunctioning (asymptomatic) pancreaticoduodenal tumors.. MEN1 patients without functioning pancreatic involvement underwent systematic pancreaticoduodenal EUS in nine GTE (Groupe des Tumeurs Endocrines) centers. Demographic and clinical factors predictive of pancreatic involvement were sought, and standardized biochemical measurements obtained.. Between November 1997 and July 2004, 51 patients (median age: 39 [range: 16-71] yr) were studied. MEN1 had been diagnosed 3 [0-20] yr earlier, notably by genetic screening for 26 (51%) with asymptomatic disease. Twenty-five patients had minor biochemical anomalies (<2 x normal (N)) and serum somatostatin was 10.8 N in 1; EUS detected pancreatic lesions in 28 patients (54.9%; 95% CI: 41.3-68.7%). A median of three [1-9] tumors with a median diameter of 6 [2-60] mm was found per patient; for 19 (37.3%) patients a tumor measured > or =10 mm and > or = 20 mm in 7 (13.7%) patients. Only one duodenal lesion was found and three patients had peripancreatic adenopathies. Pancreatic tumors were not associated with any of the studied parameters, notably age, family history, biochemical anomalies. Sixteen of twenty-six patients underwent EUS monitoring over 50 [12-70] months; six (37.5%) had more and/or larger pancreatic lesions.. The frequency of nonfunctioning pancreatic endocrine tumors is higher (54.9%) than previously thought. The size and number of these tumors can increase over time. Pancreatic EUS should be performed once MEN1 is diagnosed to monitor disease progression.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Diagnosis, Differential; Disease Progression; Duodenal Neoplasms; Endosonography; Female; Follow-Up Studies; Gastrins; Glucagon; Humans; Incidence; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pancreatic Polypeptide; Peptides; Prospective Studies; Severity of Illness Index; Vasoactive Intestinal Peptide

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

Several lines of evidence suggest that gastrin and the CCK-2 receptor (CCK2R) could contribute to pancreatic carcinogenesis by modulating processes such as proliferation, cell adhesion or migration. In the current study, we used a 'cancer gene array' and identified beta1-integrin subunit as a new gastrin-regulated gene in human pancreatic cancer cells. We also demonstrated that Src family kinases and the phosphatidylinositol-3-kinase (PI-3-kinase) pathway play a crucial role in the expression of beta1-integrin induced by gastrin. Our results also showed that gastrin modulates cell-substrate adhesion via beta1-integrin. Indeed, using blocking anti-beta1-integrin monoclonal antibodies, we completely reversed the increase in cell-substrate adhesion induced by gastrin. In addition, we observed that in response to gastrin, beta1-integrin is tyrosine phosphorylated by Src family kinases and associates with paxillin, a scaffold protein involved in focal adhesion and integrin signalling. This mechanism might be involved in gastrin-induced cell adhesion. Moreover, we showed in vivo that targeted CCK2R expression in the pancreas of Elas-CCK2 mice leads to the overexpression of beta1-integrin. This process may contribute to pancreatic tumour development observed in these transgenic animals.

Topics: Animals; Cell Adhesion; Cell Line, Tumor; Gastrins; Humans; Integrin beta1; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pancreatic Neoplasms; Receptor, Cholecystokinin B

SHP-2 is a tyrosine phosphatase which functions as a positive regulator downstream of RTKs, activating growth-stimulatory signalling pathways. To date, very few G protein-coupled receptors (GPCRs) have been shown to be connected to SHP-2 and very little is known about the positive role of SHP-2 in GPCR signalling. The CCK2 receptor (CCK2R), a GPCR, is now recognized to mediate mitogenic effects of gastrin on gastrointestinal cells. In the present study, we demonstrate the role of SHP-2 in the activation of the AKT pathway by the CCK2R in COS-7 cells transfected with the CCK2R and in a pancreatic cancer cell line expressing the endogenous receptor. Using surface plasmon resonance analysis, we identified a highly conserved ITIM motif, containing the tyrosine residue 438, located in the C-terminal intracellular tail of the CCK2R which directly interacts with the SHP-2 SH2 domains. The interaction was confirmed by pull down assays and co-immunoprecipitation of the receptor with SHP-2. This interaction was transiently increased following gastrin stimulation of the CCK2R and correlated with the tyrosine phosphorylation of SHP-2. Mutational analysis of the key ITIM residue 438 confirmed that the CCK2R ITIM sequence is required for interaction with SHP-2 and the activation of the AKT pathway.

Topics: Amino Acid Motifs; Amino Acid Sequence; Animals; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Gastrins; Intracellular Signaling Peptides and Proteins; Mice; Molecular Sequence Data; NIH 3T3 Cells; Pancreatic Neoplasms; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases; Proto-Oncogene Proteins c-akt; Rats; Receptor, Cholecystokinin B; Signal Transduction; Tyrosine

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

To investigate the effects of gastrin and cholecystokinin (CCK) and their specific antagonists on the growth of pancreatic and biliary tract cancer cell lines.. Five pancreatic and 6 biliary cancer cell lines with 2 conrtol cells were used in this study. Cell proliferation study was done using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) test and direct cell count method. Reverse transcription-polymerase chain reaction (RT-PCR) and slot blot hybridization were performed to examine and quantify the expression of hormonal receptors in these cell lines.. SNU-308 showed a growth stimulating effect by gastrin-17, as did SNU-478 by both gastrin-17 and CCK-8. The trophic effect of these two hormones was completely blocked by specific antagonists (L-365, 260 for gastrin and L-364, 718 for CCK). Other cell lines did not respond to gastrin or CCK. In RT-PCR, the presence of CCK-A receptor and CCK-B/gastrin receptor mRNA was detected in all biliary and pancreatic cancer cell lines. In slot blot hybridization, compared to the cell lines which did not respond to hormones, those that responded to hormones showed high expression of receptor mRNA.. Gastrin and CCK exert a trophic action on some of the biliary tract cancers.

Topics: Biliary Tract Neoplasms; Cell Count; Cell Division; Cell Line, Tumor; Cholecystokinin; Gastrins; Hormone Antagonists; Humans; Pancreatic Neoplasms; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Reverse Transcriptase Polymerase Chain Reaction; Tetrazolium Salts; Thiazoles

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

Gastrin and cholecystokinin (CCK) have trophic action on cells expressing wild type A or B CCK receptors. Potential relevance to pancreatic and colonic cancers was raised by the demonstration of a misspliced type B CCK receptor that, when expressed in Balb3T3 cells, had constitutive activity to stimulate intracellular calcium. We attempted to confirm and extend this observation in CHO cells by establishing lines expressing similar densities of variant or wild type B CCK receptor. While both were capable of normal binding and agonist-induced signaling, neither expressed constitutive signaling and both had similar basal growth. Agonist stimulation of cells expressing misspliced receptor had greater increases in calcium and greater growth rates than control cells despite similar MAP kinase phosphorylation responses. Thus, this variant receptor can potentiate peptide-stimulated signaling and trophic action and may contribute to the proliferation of neoplasms expressing it.

Topics: Alternative Splicing; Animals; Binding, Competitive; Cell Proliferation; CHO Cells; Cholecystokinin; Colonic Neoplasms; Cricetinae; Cricetulus; Gastrins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation; Pancreatic Neoplasms; Phosphorylation; Receptor, Cholecystokinin B; RNA, Messenger; Transfection

Patients with the Zollinger-Ellison syndrome are characterized by islet-cell tumors, striking gastric acid hypersecretion, and peptic ulcer disease. They often experience severe abdominal pain, diarrhea, and gastrointestinal bleeding with potentially life-threatening consequences. It is a rare syndrome caused by non-beta cell islet-cell tumors (gastrinomas) located in or in proximity to the pancreas. These tumors freely secrete gastrin, a peptide hormone that serves as a powerful stimulant of gastric acid secretion. Exuberant secretion of gastrin from the gastrinomas produces severe gastric acid hypersecretion that often leads to impressive peptic ulcer disease and the constellation of symptoms listed above. We describe a patient presenting with clinical manifestations characteristic of the ZES with strikingly elevated gastric acid secretion,multiple ulcers in the first and second portions of the duodenum and diarrhea, but in absence of islet-cell tumor and/or hypergastrinemia.

Topics: Adenoma, Islet Cell; Diarrhea; Duodenal Ulcer; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Phenotype; Zollinger-Ellison Syndrome

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

Neoplasms of the pancreas usually show ductal, acinar or endocrine differentiation. Tumors with mixed exocrine and endocrine components are unusual. We herein describe a case of a mixed ductal-endocrine tumor.. A 65-year-old woman was referred to our department with a diagnosis of carcinoma of the tail of the pancreas. The patient had a short history of upper abdominal pain, nausea and melena. Upper gastrointestinal endoscopy revealed gastric fundus varices and CT scan demonstrated an inhomogeneous tumor located in the tail of the pancreas infiltrating the spleen and the splenic vein. The patient underwent distal pancreatectomy and splenectomy, and had an uneventful recovery. Pathological examination revealed a mixed ductal-endocrine tumor. The endocrine component was immunoreactive for glucagon, gastrin and somatostatin, and non-reactive for insulin.. Because of the rarity and unpredictable biologic behavior of these tumors, the need for adjuvant therapy has not yet been well-defined. The patient has had a follow-up CT scan every six months, and one and a half years later remains disease free.

Topics: Aged; Carcinoma, Islet Cell; Carcinoma, Pancreatic Ductal; Chromogranins; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Mixed Tumor, Malignant; Pancreatic Neoplasms; Phosphopyruvate Hydratase; Somatostatin

The aim of this study was to evaluate 3 new (99m)Tc-labeled minigastrin analogs modified with open chain tetraamines at the N-terminus for their suitability in the CCK-2/gastrin-R-targeted imaging of tumors (CCK-2/gastrin-R = cholecystokinin subtype 2/gastrin receptor).. The [(D)Glu(1)]minigastrin sequence was assembled on the solid support and the respective tetraamine precursors coupled at the N-terminus. Purified peptide conjugates were labeled with (99m)Tc under alkaline conditions. Saturation binding experiments were performed for (radio)metallated peptides [(99m)Tc/(99g)Tc]Demogastrin 1-3 in rat acinar pancreatic AR4-2J cell membranes. Internalization was studied in AR4-2J cells at 37 degrees C. Radiopeptide stability was tested in murine plasma, urine, and kidney homogenates. Tissue distribution of the peptides was compared in healthy mice and athymic mice bearing AR4-2J tumors.. Peptide conjugates were obtained in 10%-30% overall yields by solid-phase techniques. Radiolabeling afforded >98% pure [(99m)Tc]Demogastrin 1-3 species in specific activities of approximately 37 GBq/mumol. Radiopeptides retained a high affinity for the CCK-2/gastrin-R in vitro (50% inhibitory concentration values of approximately 1 nmol/L) and internalized rapidly in CCK-2/gastrin-R-positive cells. After injection in mice they displayed rapid, high, and specific localization in the CCK-2/gastrin-R-expressing tissues (stomach and AR4-2J tumor) and were excreted from the body via the kidneys in the form of hydrophilic metabolites.. The promising characteristics of [(99m)Tc]Demogastrin 1-3 both in vitro and in animal models illustrate their suitability for CCK-2/gastrin-R-targeted tumor imaging. These qualities could be confirmed for [(99m)Tc]Demogastrin 2, which provided excellent delineation of tumor deposits in a first patient with metastatic medullary thyroid cancer.

Topics: Animals; Biomarkers, Tumor; Drug Delivery Systems; Gastrins; Humans; Isotope Labeling; Male; Metabolic Clearance Rate; Mice; Middle Aged; Organ Specificity; Pancreatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Receptor, Cholecystokinin B; Tissue Distribution

The gastrointestinal peptide, gastrin, stimulates the growth of human pancreatic cancer. A receptor for gastrin activity, the cholecystokinin-C (CCK-C) receptor, has been identified in binding assays, cloned and sequenced, and is a splice variant of the CCK-B receptor. The relationship of gastrin and the CCK-C receptor to the growth of cancer cells was examined in vitro and in vivo. Stable transfection of the sense cDNA of gastrin into human MDA Amp-7 ampullary cancer cells, which normally lack gastrin gene expression but possess CCK-C receptors, increased cell growth up to 10-fold over wild type (WT) and vector-transfected (VT) cells. MDA Amp-7 tumors of gastrin-transfected cells reduced latency time for a visible tumor by 35%, decreased the timetable of tumor incidence, and increased tumor size by at least 2-fold in comparison to WT and VT groups. Transfection of human BxPC-3 pancreatic cancer cells, which normally express gastrin and possess CCK-C receptors, with the antisense cDNA to human gastrin decreased cell number by 30% in culture and tumor size by 53% compared to the WT and VT groups. Transfection of sense gastrin cDNA to monkey COS-1 cells, which normally lack both the gastrin and the CCK-C receptor genes, had no effect on growth. These studies demonstrate that gastrin and the CCK-C receptor form an autocrine loop in human pancreatic cancer that plays a role in regulating growth.

Topics: Animals; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; DNA, Antisense; DNA, Complementary; Gastrins; Gene Expression; Humans; Mice; Pancreatic Neoplasms; Receptors, Cholecystokinin; Transfection

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 gastrin gene is expressed widely in pancreatic adenocarcinomas and the study aimed to assess its role in both the resistance of cancer cells to apoptosis and the sensitivity of cells to chemotherapeutic agents. Two human pancreatic cell lines, PAN1 and BXPC3, expressed gastrin at both the RNA and protein levels and are shown to be representative of human pancreatic adenocarcinomas in terms of gastrin expression. Inhibition of endogenous gastrin production by tumor cells was achieved with neutralizing gastrin antiserum and transfection with a gastrin antisense plasmid. Gastrin antiserum synergized with both taxotere and gemcitabine in inhibiting the in vitro growth of the PAN1 cell line with the inhibitory effect of the antiserum increasing from 12.7% to 70.2% with taxotere (P < 0.05) and 28.6% with gemcitabine (P < 0.01) after controlling for the effects of the cytotoxics. Synergy was only achieved with taxotere in BXPC3 cells with the inhibitory effect of gastrin antiserum increasing from 22.9% to 50.0% (P < 0.005). Cells transfected with gastrin antisense had reduced in vitro growth in low serum conditions and were poorly tumorigenic in nude mice at an orthotopic site. Gastrin antisense-transfected PAN1 cells had increased sensitivity to the antiproliferative effects of both gemcitabine (IC50 of > 100 microg/ml reduced to 0.1 microg/ml) and taxotere (IC50 of 20 microg/ml reduced to < 0.01 microg/ml) when compared with vector controls. The increased sensitivity of PAN1 antisense coincided with increased caspase-3 activity and reduced protein kinase B/Akt phosphorylation in response to both gemcitabine and taxotere. Gastrin gene circumvention may be an optimal adjunct to chemotherapeutic agents, such as taxotere and gemcitabine, in pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Deoxycytidine; DNA, Antisense; Docetaxel; Gastrins; Gemcitabine; Gene Expression; Genetic Therapy; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; Protein Precursors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Taxoids; Transfection

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

Topics: Animals; Gastric Mucosa; Gastrins; Kidney Cortex; Liver; Magnetic Resonance Imaging; Mice; Organ Specificity; Pancreatic Neoplasms; Radiopharmaceuticals; Receptor, Cholecystokinin B; Stomach; Subtraction Technique; Technetium; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

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

Patients with multiple endocrine neoplasia (MEN) type 1 risk premature death from pancreatic endocrine tumours (PETs). Endoscopic ultrasonography (EUS) is the most sensitive imaging modality for small PETs. A screening and therapeutic approach for asymptomatic patients is delineated in which EUS plays a pivotal role.. This was a retrospective study of 15 patients with MEN-1 but with no symptoms of a PET. All patients underwent serum hormone measurement, including gastrin, and EUS. The findings were used to facilitate operative treatment.. Six of 15 patients had a normal basal gastrin level and nine had a raised level. EUS demonstrated PETs in 14 patients and identified multiple lesions in 12. There was no predictive relationship between age or gastrin level and the number or size of PETs discovered. Thirteen patients have undergone enucleation or resection of PETs and two remain under observation. Nine of the 13 patients underwent transduodenal exploration to excise gastrinoma(s). One patient had lymph node metastases found at operation. There was no death. Self-limiting pancreatic fistula in five patients and biliary fistula in one.. Early and aggressive screening using EUS identifies PETs in asymptomatic patients with MEN-1. Detection of tumours at an early stage, before the development of symptoms, lymph node metastases or liver metastases, may facilitate prompt surgical intervention and improve prognosis.

Topics: Adolescent; Adult; Endoscopy, Digestive System; Endosonography; Gastrins; Humans; Linear Models; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Splenectomy

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

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

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

We demonstrated previously, in two different rodent models of pancreatic cancer, that the gastrin receptor is present on malignant pancreatic tumors in spite of the fact that the normal adult rat and mouse pancreas does not express gastrin receptors.. To determine whether gastrin receptors mediate pancreatic growth or promote carcinogenesis or both, we created a transgenic mouse that constitutively expresses gastrin receptors in the exocrine pancreas. The transgene construct contained the full-length rat gastrin receptor cDNA sequence under the control of the rat elastase promoter.. Receptor presence and function on exocrine pancreatic tissue of transgenic but not control mice were confirmed by (125)I-gastrin-I binding studies and by gastrin stimulation of intracellular calcium release. Eighteen-month-old transgenic animals had larger pancreas-to-body weight ratios than their nontransgenic littermate controls (p < 0.001 for females; p < 0.01 for males); however, histopathologic examination revealed no neoplasms or other abnormalities.. In both female and male transgenic mice, the expression of the gastrin receptor in the exocrine pancreas is associated with a significant increase in pancreas weight, but it does not appear to promote the development of spontaneous pancreatic tumors.

Topics: Adenocarcinoma; Animals; Calcium; Female; Gastrins; Gene Expression; Iodine Radioisotopes; Male; Mice; Mice, Transgenic; Pancreas; Pancreatic Neoplasms; Phenotype; Rats; Receptors, Cholecystokinin

Topics: Cholecystokinin; Gastrins; Humans; Pancreatic Neoplasms

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

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

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

Current literature data on the clinical course, diagnosis and treatment of gastrinoma, one of the most frequent neuroendocrine tumors of the thyroid, as well as 23 cases with Zollinger-Ellison syndrome treated by the authors are analysed in detail. Peculiarities of the clinical course, difficulties of syndrome diagnosis, principles of updated topical diagnosis of gastrinoma, conservative and surgical treatments including treatment of multiple endocrine neoplasia syndrome are described.

Topics: Female; Gastrins; Humans; Middle Aged; Pancreatic Neoplasms

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

The diagnostic value of the determination of the serum pancreatic polypeptide (PP) and gastrin concentrations after a standard meal for early diagnosis of patients with multiple endocrine neoplasia type 1 (MEN 1) is controversial. The aim of this study was to clarify this issue. Thirteen patients with MEN 1, seven healthy family members, and eight healthy controls were studied. Plasma PP and serum gastrin were measured before and after the ingestion of a standardized meal. The meal caused a statistically significant (p < 0.05) increase of both PP and gastrin in all three groups studied. Concerning PP, no statistically significant difference was observed between patients and controls. In family members, the values were significantly (p < 0.05) lower than in the other two groups. On the whole, no significant differences in gastrin levels were noted between patients and controls; in family members, the values were significantly (p < 0.05) lower than in patients. All patients who had abnormally high postprandial values of PP and gastrin also had abnormally high basal values of these two peptides. The determination of serum PP and gastrin levels after a meal stimulation test in patients with MEN 1 adds no information about the presence of pancreatic endocrine tumors over that provided by basal values of the two peptides.

Topics: Adolescent; Adult; Female; Food; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pancreatic Polypeptide; Postprandial Period

A 58-year-old patient had been treated for recurrent gastritis. Numerous gastroscopies indicated hemorrhagic gastritis combined with increasingly severe anemia. The patient was admitted with a hemoglobin of 4.4 g/dL. Gastroscopy showed marked antral angiodysplasia. Serum samples for gastrin were taken and found to be elevated (170-250 U/mL). The search for a gastrin-producing tumor with abdominal ultrasound, computed tomography, octreotide scan, and secretin test was negative, but angiography detected a pancreas tumor with a 2-cm diameter. Partial pancreatectomy and partial gastrectomy were performed. Immunohistochemical examination of the tumor did not show a gastrinoma but did show glucagon-reactive tissue. Further tumors or elevated plasma hormone levels were not detected, and a multiple endocrine neoplasia type I syndrome could be excluded. We thus found antral angiodysplasia with hypergastrinemia leading to detection of a glucagonoma diagnosed by immunohistochemistry. After more than 4 years of follow-up, the patient is without any symptoms or signs of relapse or secondary hormone syndrome.

Topics: Diagnosis, Differential; Gastric Antral Vascular Ectasia; Gastrins; Glucagon; Glucagonoma; Humans; Immunohistochemistry; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Pyloric Antrum

Topics: Adenocarcinoma; Aged; Case-Control Studies; Cholecystokinin; Female; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms

It has been assumed that gastrin stimulates the growth of pancreatic cancer in an autocrine way through co-expression of gastrin and the cholecystokinin-B receptor (CCK-BR). However, pancreatic cancer cell lines established directly from patients have revealed a great heterogeneity in cell proliferation when exposed to CCK, gastrin and their receptor antagonists. The aim of this study was therefore to examine co-expression of CCK-A and CCK-B receptor (CCK-AR and CCK-BR), and gastrin mRNA as well as the secretion of CCK and gastrin peptides in these cell lines.. Fourteen cell lines were established from primary pancreatic cancers or their metastases. Total RNA was isolated from the cell lines and reverse-transcribed into single-stranded cDNA. A PCR technique based on Taq polymerase-antibody interaction and CCK-AR, CCK-BR and gastrin-specific primers, followed by Southern blot analysis, were the methods used. The incubation mediums were analysed for the presence of secreted CCK/proCCK and gastrin/progastrin peptides by specific radioimmunoassays (RIA).. By means of nested Reverse-Transcribed Polymerase Chain Reaction (nested RT-PCR), combined with Southem blot analysis of the PCR amplified products, CCK-AR and gastrin mRNA co-expression was detected in cell lines LPC-6p and LPC-10m, whereas CCK-BR and gastrin mRNA could be detected in cell lines LPC-8p and LPC-12m. A low level of secreted CCK peptides was detected in cell line LPC-6p, which also expressed CCK-AR mRNA. In no other cases were CCK or gastrin peptides detected in the cell culture mediums.. The lack of CCK-BR and gastrin mRNA co-expression, and not detectable levels of secreted CCK and gastrin in culture media, does not lend support to the hypothesis that concomitant gene-expression of CCK receptors and gastrin or CCK are essential to maintaining pancreatic cancer cell proliferation.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Aged; Biopsy; Blotting, Southern; Carcinoma, Ductal, Breast; Carcinoma, Papillary; Cell Division; Cholecystokinin; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Radioimmunoassay; Receptors, Cholecystokinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

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

Topics: Adrenocorticotropic Hormone; Carcinoma, Islet Cell; Cushing Syndrome; Diagnosis, Differential; Gastrins; Heartburn; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Tomography, X-Ray Computed

Depending upon experimental model, the CCK-B/gastrin receptor ligand CI-988 exhibits either agonist or antagonist activity. To confirm that CI-988 behaves as an antagonist toward gastrin-stimulated growth, its effects on cell proliferation were investigated in unsynchronized and synchronized AR42J rat pancreatic tumour cells. In unsynchronized cultures CI-988 alone had no effect, but inhibited gastrin-stimulated cell proliferation. In contrast, in synchronized cultures, CI-988 stimulated cell proliferation. Similarly, CI-988 inhibited gastrin-stimulated cAMP production in unsynchronized cells, but stimulated cAMP formation in synchronized cultures. Therefore, CI-988 stimulation of cAMP production and proliferation in AR42J cell cultures appears to be cell cycle-dependent. CI-988 inhibited gastrin-stimulated intracellular calcium ([Ca2+]i) mobilization in both populations and thus acted as an antagonist toward this pathway. Because CCK receptor densities and affinities were similar in both cell populations, the data suggest that CI-988's divergent effects on cell proliferation are governed by postreceptor signalling events which vary with cell cycle.

Topics: Animals; Antineoplastic Agents; Cell Division; Gastrins; Hormone Antagonists; Indoles; Ligands; Meglumine; Pancreatic Neoplasms; Rats; Receptors, Cholecystokinin; Signal Transduction; Tumor Cells, Cultured

Metallothioneins (MTs) are intracellular proteins that bind to metal ions and are involved in heavy metal homeostasis and detoxification. Pancreatic islets were shown to be positive for zinc-containing matrix metalloproteinase-2 and -9 by immunocytochemical staining. The immunolocalization of matrix metalloproteinases in pancreatic islets prompted us to study further the link between zinc and MT in 34 cases of pancreatic endocrine neoplasms, including insulinomas, glucagonomas, gastrinomas, pancreatic polypeptide-omas, and non-functioning endocrine neoplasms. Four types of islet cells were found to be positive for MT, whereas pancreatic endocrine neoplasms mostly were either weakly positive or negative for MT. The presence of MT in normal islet cells and pancreatic endocrine neoplasms is consistent with the notion that MTs modulate zinc homeostasis and metabolism in pancreatic islet cells and pancreatic endocrine neoplasms as those tissues contain zinc-containing matrix metalloproteinases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chromogranin A; Chromogranins; Endocrine Gland Neoplasms; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Insulin; Islets of Langerhans; Male; Metallothionein; Middle Aged; Pancreatic Neoplasms

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

Gastrin is a trophic hormone and promotes growth of gastrointestinal and non-gastrointestinal cancers. Studies both in vitro and in vivo have suggested that pancreatic cancer cells not only have the ability to respond to circulating forms of gastrin but also to respond to the autocrine production of gastrin and its precursors. The aim of this study was to identify the expression of CCK-B/gastrin receptor, progastrin, glycine-extended gastrin and amidated gastrin in both normal pancreas and pancreatic adenocarcinoma.. Tissue sections from patients with normal pancreas (n = 10) and pancreatic cancer (n = 22) were assessed using immunohistochemical methods for CCK-B/gastrin receptor, progastrin, glycine-extended gastrin and amidated gastrin expression.. Normal pancreas showed no expression of receptor or gastrin isoforms except for occasional cells in the islets. Definite expression of CCK-B/gastrin receptor, progastrin, glycine-extended gastrin and amidated gastrin was observed in 95, 91, 55 and 23 per cent of sections from patients with pancreatic cancer respectively.. Pancreatic cancer cells express CCK-B/gastrin receptor and gastrin precursor forms in most patients. Expression of the gastrin precursor forms is probably related to autocrine production. New therapeutic strategies need to be developed for the management of pancreatic cancer. Targeting gastrin and its receptor may provide a novel treatment option.

Topics: Adenocarcinoma; Gastrins; Humans; Immunohistochemistry; Neoplasm Proteins; Pancreatic Neoplasms; Receptors, Cholecystokinin

Duct cell adenocarcinomas may produce neuroendocrine markers such as pancreatic polypeptide, gastrin and gastrin releasing hormones. A 53 year old patient, with a history of insulin dependent diabetes, was found to have a pancreatic mass which was later pathologically demonstrated to be a duct cell adenocarcinoma. The tumor produced elevated circulating neuroendocrine markers specifically gastrin and pancreatic polypeptides. An 111In Octreotide imaging showed definite uptake of Octreotide by the tumor. The patient was subsequently treated with Somatostatin analog which resulted in the reduction of some of the circulating endocrine markers. The patient had essentially six months of asymptomatic clinical remission but then she relapsed. Octreotide scanning could be useful for selected patients with pathologic diagnosis of duct cell adenocarcinoma, because some tumors may have neuroendocrine features and can be imaged, and might even respond to Somatostatin analog therapy.

Topics: Adenosarcoma; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Female; Follow-Up Studies; Gastrins; Humans; Indium Radioisotopes; Middle Aged; Octreotide; Pancreatic Neoplasms; Pancreatic Polypeptide; Radionuclide Imaging

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

The major phenotypes of multiple endocrine neoplasia type 1 (MEN 1) consist of three lesions characterized by hyperparathyroidism, pituitary tumors, and endocrine pancreatic tumors. The endocrine pancreatic tumors are a significant cause of disease-related mortality in MEN 1. Although symptomatic pancreatic tumors such as insulinoma and gastrinoma should be resected, the management of asymptomatic pancreatic tumors is not established. In asymptomatic pancreatic tumors, the most important factor is the propensity for malignant transformation of the tumors. Although there are no means to foresee it, the size of the pancreatic tumors might be predictive of malignant development in MEN 1. We report here a patient with MEN 1 who had a large asymptomatic pancreatic tumor. The patient (72-yr-old man) was diagnosed with primary hyperparathyroidism and underwent a total parathyroidectomy. Genetic examination showed a germline mutation of the MEN1 gene (E45G). Abdominal magnetic resonance imaging revealed a large (>6 cm) tumor with a heterogeneous pattern in the tail of the pancreas. No metastases of the tumor were evident. Serum levels of insulin, gastrin, and glucagon were normal, and the patient had no symptoms. Operative resection was performed, and microscopic examination revealed that the tumor was an islet cell tumor stained with multiple hormones. This is a case indicating that asymptomatic pancreatic tumors associated with MEN 1 might be indolent independent of their size.

Topics: Adenoma, Islet Cell; Aged; Angiography; Gastrins; Germ-Line Mutation; Glucagon; Humans; Hyperparathyroidism; Immunohistochemistry; Insulin; Magnetic Resonance Imaging; Male; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Parathyroidectomy; Serotonin; Spleen

Human pancreatic cancer is stimulated by the autocrine production of gastrin. In this study, the effects of administration of antisense oligonucleotides to gastrin on growth of pancreatic cancer were evaluated in vitro and in vivo. Log phase BxPC-3 human pancreatic cancer cells in culture were exposed to increasing concentrations (0.5-10 microM) of a synthetic 20-mer antisense phosphorothioate oligonucleotide to gastrin for 48 h and growth was assessed by the cellular proliferation assay. Growth was inhibited up to 88% by anti-gastrin oligonucleotides in a dose-related fashion compared to cells treated with diluent or a randomized sequence with the same composition as the anti-gastrin oligonucleotide. In vivo nude mice bearing BxPC-3 xenografts were treated daily for 14 days with a 0.1-ml intratumoral injection of either anti-gastrin (5 microM), the scrambled sequence control phosphorothioate oligonucleotide (5 microM), or buffer. Tumors from the anti-gastrin-treated mice were significantly smaller in volume and weight and had less gastrin detected by radioimmunoassay than either controls. These results support the role of gastrin as a stimulatory peptide for growth of human pancreatic cancer. Antisense oligonucleotide to gastrin may have a role in the future treatment of patients with pancreatic cancer.

Topics: Animals; Antineoplastic Agents; Gastrins; Growth Inhibitors; Humans; Male; Mice; Mice, Nude; Neoplasm Transplantation; Oligonucleotides, Antisense; Pancreatic Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured

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

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant tumor syndrome associated with parathyroid, gastroenteropancreatic (GEP), and pituitary neoplasia. Gastrinoma and GEP malignancy are common life-threatening endocrine complications of MEN-1. An effective management strategy for these disorders remains to be determined. The authors attempted to determine the role of the somatostatin analogue, octreotide, in ameliorating features of hypergastrinemic GEP neoplasia associated with MEN-1.. Five MEN-1 patients with hypergastrinemia and either symptoms of GEP neoplasia or hepatic metastases received a trial of octreotide, 100 microg subcutaneously, three times daily for 3 months.. Treatment with octreotide was associated with a rapid symptomatic and biochemical response. In all patients serum gastrin fell to < 25% of the pretreatment value. The serum glycoprotein-alphasubunit (a marker of enterochromaffin-like [ECL] cell hyperplasia, gastric carcinoidosis, and disseminated enteropancreatic malignancy) was elevated at baseline in three patients. In each case the serum glycoprotein-alphasubunit normalized after treatment with octreotide. Hepatic metastases were present in two patients at baseline. The size of the metastases diminished by up to 15% during the period of octreotide treatment. Four patients reported symptoms prior to treatment: lethargy, easy fatigability, and generalized musculoskeletal discomfort. A marked symptomatic improvement occurred in each case. No patient experienced side effects related to octreotide therapy and all elected to remain on treatment after completion of the trial.. Octreotide is a safe and effective adjunct to surgical strategies for the management of GEP neoplasia in hypergastrinemic MEN-1 patients.

Topics: Aged; Antineoplastic Agents, Hormonal; Female; Gastrins; Gastrointestinal Neoplasms; Humans; Middle Aged; Models, Biological; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatic Neoplasms

The role of cholecystokinin (CCK) and gastrin in the development and growth of pancreatic cancer cells is controversial. The aim of this study was to evaluate the role of CCK-8S, gastrin-17, bombesin, and their antagonists on cell lines from patients with pancreatic cancer.. Cell lines were established from pancreatic cancers operated on at our department. The cells were grown in 10% fetal calf serum (FCS). The effects of CCK-8S, gastrin-17, bombesin, and their antagonists in different concentrations and for different time intervals were studied. The cell number was evaluated with the XTT method.. The cell line LN 36 responded with increased cell number to stimulation by gastrin-17 and decreased cell number to inhibition by the CCK-B receptor antagonist L-365,260. In contrast, LPC 1 responded with increased cell number to CCK-8S and decreased cell number to the CCK-A receptor antagonist devazepide. LPC 2, 6, and 7 were stimulated by CCK-8S, gastrin-17, and their antagonists. LPC 3 showed decreased cell number after inhibition by the antagonists, and LPC 5 and 10 showed increased cell number after stimulation by CCK-8S and gastrin-17. LPC 4 was stimulated by CCK-8S, and LPC 8 was stimulated by all substances except gastrin-17. Intermittent administration of the substances to LN 36 led to a greater effect on the cell number than administration every day, which was not the case with LPC 1 and LPC 3. Bombesin led to an increased growth in LPC 5 but not in LPC 3.. CCK-8S and gastrin-17 led to an increased cell number in some cell lines. A blockade of the CCK-A and CCK-B receptors by their antagonists led to an increased, an unaffected, or a decreased cell number of the cell lines. The effect of bombesin on different cell lines also varied. This shows a great heterogenicity among pancreatic cancer cells from different patients.

Topics: Benzodiazepinones; Bombesin; Cell Division; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Gastrins; In Vitro Techniques; Pancreatic Neoplasms; Phenylurea Compounds; Receptors, Cholecystokinin; Tumor Cells, Cultured

It is well known that an islet cell tumor can secrete multiple hormones depending on its cell type. We report the case of a 70-year-old woman who initially presented with peptic ulcer symptoms, an elevated serum gastrin level, and multiple liver tumors. Liver biopsy and distal pancreatectomy were performed, and the pathological diagnosis was malignant islet cell tumor. Additionally, the immunohistochemical staining revealed scattered positivity for gastrin, and then also positivity for insulin 14 months later. A subsequent hypoglycemic episode and elevated serum gastrin and insulin levels suggested that the disease had developed into a condition of multiple hormone secretion. The plasma gastrin and insulin levels decreased from 584 pg/ml and 90.8 microIU/ml to 49.1 pg/ml and 20.9 microIU/ml, respectively, 5 days after treatment with subcutaneous octreotide 100 micrograms every 6 to 8 hours. In addition, follow-up computed tomography showed shrinkage of the metastatic liver tumors. In conclusion, we found a case of malignant islet cell tumor with variable hormone secretion which could be effectively controlled with octreotide.

Topics: Aged; Carcinoma, Islet Cell; Female; Gastrins; Humans; Immunohistochemistry; Insulin; Octreotide; Pancreatic Neoplasms

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

Topics: Adult; Female; Gastrins; Gastritis; Humans; Insulinoma; Pancreatic Neoplasms; Pancreatitis; 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

For more than two decades, our research group has been studying the pancreatic actions of three groups of regulatory peptides: members of the cholecystokinin/gastrin family, bombesin-like peptides and somatostatin. Investigating these peptides, our work has focused on three particularly interesting aspects: peptidergic regulation of pancreatic enzyme secretion and growth in adult rats, peptidergic control of pancreatic enzyme secretion and growth during postnatal development in rats, and peptidergic regulation of proliferation and differential gene expression in pancreatic adenocarcinoma cells. Our data confirmed that the control of the exocrine function of the pancreas is complex, and that it involves peptides such as the cholecystokinin/gastrin-like peptides, bombesin-like peptides and somatostatin. In these investigations, it became evident that selective peptide receptor agonists, antagonists and monoclonal antibodies raised against peptides are useful tools to identify the role of these bioactive peptides in pancreatic exocrine secretion and cell proliferation.

Topics: Adenocarcinoma; Animals; Bombesin; Cell Division; Cholecystokinin; Gastrins; Gene Expression; Pancreas; Pancreatic Neoplasms; Rats; Somatostatin

The intracellular events involved in normal pancreatic growth have been extensively investigated in response to cholecystokinin. Recent data indicate that tyrosine kinase, phospholipase D, phosphatidylinositol 3-kinase, and p42/p44 MAPK are stimulated in rat pancreatic acinar cells. Although we begin to understand the intracellular signaling pathways activated in normal pancreas, such information is not yet available in pancreatic cancer cells. This study was undertaken to identify the growth factors and hormones involved in cell proliferation of two human pancreatic cancer cell lines of ductal origin, the MIA PaCa-2, and PANC-1 cells, and to establish the intracellular events involved in the control of their growth. We demonstrated that FGF-2, IGF-1, cerulein, and gastrin but not FGF-1, HGF, secretin, and PACAP, stimulated proliferation of MIA PaCa-2 and PANC-1 cells. Autocrine factors such as gastrin and IGF-1 were also responsible for their proliferation. In response to EGF, FGF-2, IGF-1, cerulein, gastrin and bombesin, tyrosine kinase, and tyrosine phosphatase activities were stimulated in both cell lines. The close relationship established between cell growth and tyrosine kinase activation results from the observation that maximal growth stimulation paralleled with maximal enzyme activation and that genistein, the tyrosine kinase inhibitor, blocked cell growth and enzyme activation. The implication of PLD in growth-stimulated processes is doubtful since all growth factors and hormones tested failed to stimulate an already very active PLD activity. We finally observed a constitutive activity of p44 MAPK in both cell lines and of p42 in MIA PaCa-2 cells. However, p38 and p42 were stimulated in MIA PaCa-2 and PANC-1 cells, respectively, by all growth factors and hormones.

Topics: Animals; Bombesin; Cell Division; Ceruletide; Enzyme Activation; Fibroblast Growth Factor 2; Gastrins; Growth Substances; Hormones; Humans; Insulin-Like Growth Factor I; Pancreatic Neoplasms; Phospholipase D; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Rats; Signal Transduction; Tumor Cells, Cultured

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

Endocytosis of gastrin was studied in a number of gastrin-receptor-expressing cell lines by confocal laser scanning microscopy (CLSM) with the aid of a biologically active fluorescent derivative, rhodamine green heptagastrin. Rapid clustering (within 4-7 min) and internalization of fluorescent ligand upon binding at room temperature and 37 degrees C were observed in the rat pancreatic acinar carcinoma cell line AR42J, human gastric carcinomas AGS-P and SIIA, human colon carcinomas HCT116 and HT29, and in NIH/3T3 cells transfected with human and rat gastrin/cholecystokinin-B receptor cDNA. Internalization was inhibited by hypertonic medium. Fluorescent heptagastrin and transferrin colocalized in the same endocytic vesicles at different stages of internalization suggesting that endocytosis occurred predominantly through a clathrin-dependent mechanism. At 37 degrees C partial colocalization with the lysosomal marker neutral red was detected by CLSM, implying that internalized gastrin accumulated in the lysosomes. Immunoelectron microscopy studies with antibodies against gastrin revealed the presence of the internalized hormone in multivesicular vesicles and endosomes. Almost no hormone was detected in lysosomes with the antibodies to gastrin, suggesting that the degradation of the peptide is rapid in those vesicles. Continuous accumulation of fluorescent label was observed by CLSM in the presence of the protein synthesis inhibitor cycloheximide, suggesting that the gastrin receptor is recycled back to the cell membrane after hormone delivery to intracellular compartments. An estimated average recycling time for the receptor molecules was 1 h in NIH/3T3 cells.

Topics: 3T3 Cells; Animals; Carcinoma; Carcinoma, Acinar Cell; Coated Pits, Cell-Membrane; Cycloheximide; Endocytosis; Gastrins; Gastrointestinal Neoplasms; Humans; Lysosomes; Mice; Microscopy, Confocal; Microscopy, Immunoelectron; Neoplasm Proteins; Pancreatic Neoplasms; Protein Synthesis Inhibitors; Rats; Receptors, Cholecystokinin; Recombinant Proteins; Transfection; Transferrin; Tumor Cells, Cultured

In order to examine the effect of cholecystokinin on spontaneous and induced pancreatic carcinogenesis in the hamster, two sets of experiments were carried out, one involving long-term hypercholecystokininemia and one involving cancer induction during hypercholecystokininemia. The effect of hypercholecystokininemia, induced by pancreaticobiliary diversion (PBD), was studied for 8 months. Neither PBD animals nor sham-operated controls developed premalignant or malignant pancreatic lesions. However, in the PBD group the mean pancreatic weight, total protein content and DNA content were increased by 30, 29 and 27% respectively. No such increases were found in PBD animals receiving a cholecystokinin-A receptor antagonist during the last 24 days of the experiment. In the cancer induction study, the effect of PBD on N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis was studied for 3 months. Putative premalignant pancreatic lesions were diagnosed in all PBD hamsters and in four of 15 sham-operated controls. Pancreatic ductular carcinoma in situ was only found in PBD animals. The [3H]thymidine labeling index of the pancreatic lesions was significantly higher in the PBD group than in the controls. No such increase was observed in PBD animals receiving a cholecystokinin-A receptor antagonist during the last 5 days of the experiment. It is concluded that chronic endogenous hypercholecystokininemia promotes early phase pancreatic carcinogenesis, but does not per se cause development of premalignant or malignant pancreatic lesions in the hamster.

Topics: Animals; Carcinogens; Cholecystokinin; Cricetinae; Duodenum; Gastrins; Male; Mesocricetus; Nitrosamines; Organ Size; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms

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

To examine the effect of gastrin on spontaneous and induced pancreatic carcinogenesis in the hamster.. Two sets of experiments were carried out, one involving long term hypergastrinaemia and one involving cancer induction during hypergastrinaemia. The effect of hypergastrinaemia accomplished by gastric fundectomy was studied for eight months. Neither fundectomised hamsters nor sham operated controls developed premalignant or malignant pancreatic lesions. In the fundectomy group, the mean pancreatic weight, total protein content, and DNA content was increased by 28%, 25%, and 25% respectively. No such increases were found in fundectomised animals receiving a cholecystokinin-B receptor antagonist during the last 24 days of the experiment. In the cancer induction study, the effect of fundectomy on N-nitrosobis(2-oxopropyl) amine induced pancreatic carcinogenesis was studied for three months. There were no significant differences in the incidence or [3H]-thymidine labelling index of focal pancreatic lesions between fundectomised and sham operated control animals.. Fundectomy with chronic hypergastrinaemia induces pancreatic hypertrophy, but does not enhance N-nitrosobis (2-oxopropyl)amine induced pancreatic carcinogenesis in the hamster. The increases in growth were inhibited by a cholecystokinin-B receptor antagonist, indicating that the trophic effect of fundectomy is mediated by gastrin.

Topics: Animals; Benzodiazepinones; Carcinogens; Cholecystokinin; Cricetinae; Disease Models, Animal; Gastric Fundus; Gastrins; Hypertrophy; Male; Mesocricetus; Neoplasms, Experimental; Nitrosamines; Pancreas; Pancreatic Neoplasms; Phenylurea Compounds; Receptors, Cholecystokinin

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

Glycine-extended gastrin precursors (G-Gly) were considered as processing intermediates devoid of biological activity. However, we have recently identified selective receptors for G-Gly which mediate the proliferative effects of this precursor. Little is known about the signaling pathways activated by G-Gly. In the present study, we demonstrate that PI-3-kinase is rapidly and transiently activated by G-Gly. We also observed a rapid increase in the tyrosine phosphorylation of IRS-1 and an activation of the PI-3-kinase in anti-IRS-1 immunoprecipitates, suggesting that PI-3-kinase may be activated by association with tyrosine phosphorylated IRS-1. We also demonstrated that gastrin precursors activate the serine/threonine kinase, p70 kDa S6 kinase (p70S6K), through a wortmannin sensitive pathway.

Topics: Androstadienes; Animals; Enzyme Activation; Enzyme Inhibitors; Gastrins; Glycine; Insulin Receptor Substrate Proteins; Kinetics; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Phosphotyrosine; Protein Precursors; Protein Serine-Threonine Kinases; Rats; Tumor Cells, Cultured; Wortmannin

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

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

The gastrin/CCKB (G/CCKB) G protein-coupled receptor has been shown to mediate the proliferative effects of gastrin on normal and neoplastic gastro-intestinal tissues. In the present study, we examined the signal transduction mechanisms coupled to this receptor. We report here that phosphorylation and activity of the p70S6K, whose major substrate is the ribosomal S6 protein, are enhanced in response to gastrin. These effects were completely reversed by a commonly used PI-3-kinase inhibitor, wortmannin, suggesting that p70S6K may be a downstream target of PI-3-kinase in a signaling cascade induced by gastrin. In addition, blocking PI-3-kinase activity by wortmannin partially decreased gastrin-induced MAPK activation (42% +/- 3) as well as the tyrosine phosphorylation of She (50% +/- 6), an upstream regulator of the Ras-dependent MAPK pathway. These results indicate that at least two signaling pathways lead to MAPK activation by gastrin, only one of which is sensitive to PI-3-kinase inhibitors.

Topics: Androstadienes; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Activation; Gastrins; GTP-Binding Proteins; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Polyenes; Protein Serine-Threonine Kinases; Rats; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Ribosomal Protein S6 Kinases; Ribosomal Proteins; Sirolimus; src Homology Domains; Tumor Cells, Cultured; Wortmannin

A nongastrin acid-stimulating peptide (NGASP) has been found in ulcerogenic pancreatic tumor syndrome without hypergastrinemia. The mechanism of gastric acid hypersecretion by NGASP was investigated in rats.. In vivo, gastric acid secretion and in vitro histamine release from enterochromaffin-like (ECL) cells in responses to tumor extract (TE) and synthetic human gastrin-17 I or pentagastrin (PG) were studied. Whether the 2 secretagogues potentiate each other was determined.. TE dose-dependently stimulated histamine release, which was not blocked by a cholecystokinin (CCK)-B receptor antagonist. When TE was incubated with trypsin, the activity was abolished but was not affected by antibody. However, when rats were pretreated with antigastrin serum or CCK-B receptor antagonist, the acid secretion by TE was virtually abolished. The dose response of acid secretion to TE in the rats receiving PG in a threshold dose was significantly greater than that achieved by TE alone. Similarly, the dose response to PG combined with a threshold dose of TE was significantly greater than that produced by PG alone.. NGASP stimulates histamine release from ECL cells, but the release is not mediated via CCK-B/gastrin receptor. NGASP and gastrin may potentiate each other to produce acid hypersecretion in ulcerogenic pancreatic tumor syndrome.

Topics: Adenoma, Islet Cell; Animals; Enterochromaffin Cells; Gastric Acid; Gastric Mucosa; Gastrins; Histamine Release; Humans; Male; Middle Aged; Pancreatic Neoplasms; Pentagastrin; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tissue Extracts

It was recently found that cholecystokinin (CCK) activates mitogen-activated protein kinases (MAPK) in isolated rat pancreatic acini. The present study evaluates whether one or both types of CCK receptors are capable of MAPK activation in pancreatic AR42J acinar cells as well as CHO cells transfected with CCK-A or CCK-B receptors. CCK significantly increased p44 MAPK and p42 MAPK activities in AR42J cells. Minimal, half-maximal, and maximal responses were observed at 30 and 500 pM and 10 nM, respectively, after CCK-8 stimulation and at 100 pM and 1.5 and 30 nM, respectively, after gastrin stimulation. Glycine-extended gastrin had no effect at 100 nM and a small but significant effect at 1 microM. The CCK-B receptor antagonist L365,260 almost totally blocked MAPK activation in AR42J cells after stimulation with gastrin and glycine-extended gastrin and substantially reduced the activation of both kinases by CCK-8, while the CCK-A receptor antagonist L364,718 was much less effective. The CCK-A-selective agonist A71376, however, was an effective stimulant of MAPK activity. In an alternative approach, stably transfected CHO cells bearing either CCK-A or CCK-B receptors were stimulated with CCK-8. Each receptor induced a time-dependent increase in activity of both MAPKs by five- to sixfold in CCK-A- and CCK-B-bearing cells. In conclusion, both CCK-A and CCK-B receptors activate MAPK in AR42J cells and in transfected CHO cells.

Topics: Animals; Benzodiazepinones; Blotting, Western; Carcinoma, Acinar Cell; Cells, Cultured; CHO Cells; Cricetinae; Devazepide; Dose-Response Relationship, Drug; Gastrins; MAP Kinase Kinase Kinase 4; MAP Kinase Kinase Kinases; Oligopeptides; Pancreatic Neoplasms; Phenylurea Compounds; Protein Kinases; Rats; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reference Values; Sincalide; Transfection; Tumor Cells, Cultured

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

Gastrin/CCKB G protein-coupled receptors have been shown to mediate proliferative effects of their endogenous ligands. In the present study, we examined the signal transduction mechanisms linked to the G/CCKB receptor occupancy. We report here that gastrin stimulates MAP kinase activation in a dose- and time-dependent manner, a pathway known to play a key role in cell proliferation. We also characterized the molecular events, upstream of p21-Ras, that may link the MAP kinase pathway to G/CCKB receptors. Gastrin induced a rapid and transient increase in tyrosine phosphorylation of several proteins including the 2 isoforms (46 and 52 kDa) of the adaptor protein Shc. Phosphorylated Shc subsequently associated with a complex that includes Grb2 and the p21-Ras activator, Sos. Our results also indicate that Sos becomes phosphorylated in response to gastrin as shown by a reduction in electrophoretic mobility of the protein. Tyrosine phosphorylation of Shc and subsequent complex formation with Grb2 and Sos appear to be a common mechanism by which tyrosine kinase receptors and the G/CCKB G protein-coupled receptor stimulate the Ras-dependent MAP kinase pathway.

Topics: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Calcium-Calmodulin-Dependent Protein Kinases; Enzyme Activation; Gastrins; GRB2 Adaptor Protein; Kinetics; Membrane Proteins; Pancreatic Neoplasms; Phosphorylation; Phosphotyrosine; Proteins; Rats; Receptors, Cholecystokinin; Shc Signaling Adaptor Proteins; Signal Transduction; Son of Sevenless Proteins; Src Homology 2 Domain-Containing, Transforming Protein 1; Tumor Cells, Cultured

Glycine-extended gastrin (gastrin-Gly) stimulates proliferation of AR4-2J pancreatic tumor cell line through a specific receptor, different from the gastrin-cholecystokinin B receptor. Our purpose was to determine whether AR4-2J cells produced gastrin-Gly and then whether the peptide was involved in an autocrine loop. First, proliferation of AR4-2J cells in serum-free medium was inhibited by a gastrin anti-sense oligodeoxynucleotide phosphorothioate and by antibodies specific for gastrin-Gly. In contrast, antibodies specific for alpha-amidated gastrin were without effect. By using RT-PCR, we have shown that AR4-2J cells expressed gastrin mRNA. The presence of gastrin-Gly, but not alpha-amidated gastrin, in serum-free media was detected by radioimmunoanalysis. Gel chromatography revealed that the predominant molecular forms secreted were glycine-extended gastrin-34 and gastrin- 17. Furthermore, epidermal growth factor (EGF), a stimulator of gastrin gene transcription, modulates gastrin-Gly secretion by AR4-2J. These data together suggest that gastrin-Gly is an autocrine growth factor for AR4-2J cells and that it participates with EGF in the regulation of AR4-2J-cell proliferation.

Topics: Amino Acid Sequence; Animals; Antibodies; Cell Division; Epidermal Growth Factor; Gastrins; Gene Expression; Humans; Molecular Sequence Data; Oligonucleotides, Antisense; Pancreatic Neoplasms; Rats; Stimulation, Chemical; Thionucleotides; Tumor Cells, Cultured

The hormone gastrin is thought to stimulate the growth of certain pancreatic carcinoma cell lines. We have previously detected the presence of the gastrin receptor in rat pancreatic carcinoma cell lines but not in normal rat pancreas. We had not, however, previously demonstrated that gastrin receptor is expressed in pancreatic carcinomas developing in the rat in vivo. Therefore, in the present study, we examined rat pancreatic tissue at various stages in azaserine-induced pancreatic carcinogenesis for gastrin binding and for the presence of gastrin receptor mRNA to determine the temporal expression pattern of the gastrin receptor during the in vivo development of pancreatic cancer. Autoradiography of pancreatic tissue using (125)I-gastrin-17-I from all azaserine-treated and control animals at 2, 4, 8, and 12 months of age demonstrated no specific gastrin binding. At 18 months of age, normal pancreas, azaserine-induced premalignant pancreatic nodules, and internodular pancreas demonstrated no specific gastrin binding. One of three azaserine-treated animals developed an area of pancreatic acinar cell carcinoma at 18 months of age which exhibited significant specific gastrin binding of 141.8 - 32.8 fmole/gm of tissue. Southern blot analysis of pancreatic RNA isolated from animals at 12 months of age revealed no gastrin receptor mRNA; however, by 18 months of age, gastrin receptor mRNA was present in all azaserine-treated animals but absent in control animals. In summary, specific gastrin binding is present in in vivo azaserine-induced pancreatic acinar cell carcinoma but absent in normal pancreas and azaserine-induced premalignant pancreatic nodules. Gastrin receptor mRNA is first expressed in azaserine-treated rat pancreas at some point between 12 and 18 months of age. These results demonstrate that expression of gastrin receptor is altered in azaserine-treated rat pancreas and may play a role in the development of pancreatic cancer.

Topics: Animals; Autoradiography; Azaserine; Base Sequence; Carcinogens; Carcinoma, Acinar Cell; DNA Primers; Gastrins; Gene Expression; Male; Molecular Sequence Data; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Precancerous Conditions; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; 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

Topics: Adult; Aged; Gastrins; Humans; Insulin; Insulin Secretion; Male; Neuroendocrine Tumors; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Proteins; Somatostatin

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 histological and immunohistochemical characteristics of a case of pancreatic neuroendocrine tumor are described in a 14-yr-old female Bengal tiger (Panthera tigris tigris) housed at the New Biblical Zoo of Jerusalem, Jerusalem, Israel, 1994. The neoplastic cells were immunohistochemically negative for insulin and glucagon, slightly positive for neuron-specific enolase, moderately positive for serotonin and somatostatin, and markedly positive for chromogranine A and gastrin. This is the first documentation of a pancreatic neuroendocrine tumor in the tiger.

Topics: Animals; Carnivora; Chromogranin A; Chromogranins; Female; Gastrins; Glucagon; Immunohistochemistry; Insulin; Neuroendocrine Tumors; Pancreatic Neoplasms; Phosphopyruvate Hydratase; Serotonin; Somatostatin

The gastrointestinal peptides gastrin and cholecystokinin (CCK) stimulate growth of human pancreatic cancer through a CCK-B/gastrin- like receptor. In the present study we evaluated whether growth of human pancreatic cancer is endogenously regulated by gastrin. Immunohistomical examination of BxPC-3 cells and tumor xenografts revealed specifc gastrin immunoreactivity. Gastrin was detected by radioimmunoassay in pancreatic cancer cell extracts and in pancreatic cancer cell extracts and in the growth media. With use of reverse-transcriptase polymerase chain reaction gastrin gene expression was detected in both cultured BxPC-3 cancer cells and transplanted tumors, as well as seven addition human pancreatic cancer cell lines. Growth of BxPC-3 human pancreatic cancer cell in serum-free medium was inhibited by the addition of the CCK-B/gastrin receptor antagonist L-365,260, and gastrin treatment reversed the inhibitory effect of the antagonist. A selective gastrin antibody (Ab repressed growth of BxPC-3 cells. Gastrin immunoreactivity was detected in fresh human pancreatic cancer specimens but not in normal human pancreatic tissue. These data provide the first evidence that growth of a human pancreatic cancer is tonically stimulated by the autocrine production of gastrin. Evidence for the ubiquity of this system was provided by the detection of gastrin gene expression in multiple human pancreatic cancer cell lines and detection of gastrin in cell lines and fresh pancreatic tumors.

Topics: Animals; Culture Media, Serum-Free; Dipeptides; Gastrins; Gene Expression; Hormones; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Middle Aged; Molecular Probes; Pancreas; Pancreatic Neoplasms; Peptides; Radioimmunoassay; Reference Values; Tumor Cells, Cultured

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

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

Administration of raw soya containing a trypsin inhibitor stimulated excessive release of cholecystokinin (CCK) which led to pancreatic hypertrophy, hyperplasia and cancer in the rats (Booth et al. (1964) Proc. Soc. Exp. Biol. Med., 116, 1067). More postprandial CCK release in healthy humans was observed after ingestion of a single dose of raw soya than heat-treated soya (Calam et al. (1989) Br. J. Nutr., 58, 175). The effect of chronic ingestion of a heat-treated soya product on postprandial CCK release was investigated in six healthy adult males after ingestion of a 36-oz. portion of soymilk daily for 1 month and at 2-3 months after termination of soymilk ingestion. Subjects fasted for 15 h, ingested Lipomul (1.5 g/kg) and provided blood at timed intervals for CCK analysis. The results show that 1-month ingestion of soymilk decreased the magnitude of Lipomul-induced postprandial CCK release in plasma of all six subjects by 5-60% (P < 0.05) compared to those obtained at 2-3 months after the withdrawal from soymilk ingestion. Plasma pancreatic polypeptide (PP) levels were similarly decreased in five of the six subjects by 19-67% (P = 0.03) in line with the regulation of PP by CCK. Thus, prolonged exposure of humans to a heat-treated soya inhibited slightly meal-induced CCK release in contrast to that found in rats after raw soya diets.

Topics: Adult; Animals; Anticarcinogenic Agents; Cholecystokinin; Corn Oil; Gastrins; Glycine max; Hot Temperature; Humans; Male; Pancreatic Neoplasms; Pancreatic Polypeptide; Rats; Trypsin Inhibitors

The present study reports the first evidence that the gastrointestinal peptide gastrin stimulates the growth of several human pancreatic cancer cells in culture and in tumors transplanted to nude mice. Gastrin promoted growth of all cell lines tested at a dose comparable to the binding affinity, providing evidence for a physiologically relevant receptor. The stimulatory effects of gastrin were blocked by the CCK-B/gastrin receptor antagonist L-365,260 and not by the CCK-A receptor antagonist L-364,718. Growth of PANC-1 cells in culture were inhibited by L-365,260, suggesting that gastrin is tonically produced by PANC-1 cells for regulation of growth. Athymic nude mice bearing PANC-1 xenografts were treated for 24 days subcutaneously with either 1% bovine serum albumin (diluent), pentagastrin (1 mg/kg), or L-365,260 (1 mg/kg) twice daily. Tumors from the pentagastrin-treated mice were found to weigh more and have greater protein and DNA content than controls, whereas these values were all decreased in tumors of L-365,260-treated mice. Receptor binding capacity changed in tumors of animals treated with the peptide or antagonist, suggesting a regulatory process. Gastrin immunoreactivity was detected in a transplanted PANC-1 human tumor. These results identify gastrin as a potent trophic peptide that actively stimulates growth of human pancreatic cancer and does so through a CCK-B/gastrin-like receptor.

Topics: Animals; Benzodiazepinones; Cell Division; Cell Line; Cholecystokinin; Devazepide; Gastrins; Growth Substances; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Pentagastrin; Phenylurea Compounds; Receptors, Cholecystokinin; Transplantation, Heterologous; Tumor Cells, Cultured

Double immunofluorescence and in situ hybridizations performed on adjacent thin sections show that a population of normal antropyloric cells of the human stomach expresses both gastrin and somatostatin mRNA's and the corresponding peptides. Such cells were present in both adult and fetal antropyloric mucosa and were situated in the regenerative (isthmus) region of the antropyloric tubes. It is, hence, likely that these cells represent immature endocrine cells that yet have to be committed to either the gastrin or somatostatin lineage. Cells coexpressing gastrin and somatostatin were also detected in pancreatic endocrine tumours. The presence of gastrin-somatostatin cells during development and in tumours suggests that gastrin and somatostatin cells may differentiate from such multipotent precursor cells.

Topics: Adult; Cell Differentiation; Cells, Cultured; Fluorescent Antibody Technique, Direct; Gastric Mucosa; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Hybridization; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms; Tumor Cells, Cultured

The importance of Ca2+ in the regulation of secretion is well-known. However, recent experiments suggest that a rise in intracellular Ca2+ (Ca2+i) does not necessarily trigger secretion in pancreatic acinar cells. In AR4-2J cells the role of the Ca2+ mobilization induced by cholecystokinin/gastrin (CCK/G), which is dependent of the intracellular calcium store and the calcium influx operating through voltage-dependent calcium channels, has never been directly demonstrated. Therefore, we attempted to determine whether Ca2+i and/or extracellular Ca2+ (Ca2+e) mobilized by CCK/G plays a role in the amylase secretion of these cells. We measured the [Ca2+]i by spectrofluorometry and amylase release in different experimental procedures modulating the two pools of calcium. Ionomycin increased both [Ca2+]i and amylase related. In Ca(2+)-depleted cells or in the presence of thapsigargin the transient rise in Ca2+i and the amylase secretion induced by CCK/G were suppressed. A 50 mM K+ solution or Bay K 8644, which activated the Ca2+ influx, did not induce any variation of the basal amylase secretion. Moreover, amylase secretion induced by CCK/G did not change significantly in Ca(2+)-free medium or in the presence of nifedipine. These results indicate that in AR4-2J cells, amylase secretion is dependent of the large increase in Ca2+i induced by CCK/G and independent of the Ca2+ influx through voltage-dependent calcium channels dihydropyridine sensitive.

Topics: Amylases; Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Cholecystokinin; Enzyme Inhibitors; Gastrins; Intracellular Fluid; Ion Channel Gating; Ionomycin; Ionophores; Nifedipine; Pancreatic Neoplasms; Rats; Spectrometry, Fluorescence; Terpenes; Thapsigargin; Tumor Cells, Cultured

The exact intracellular mechanisms by which gastrin enhances the proliferation of AR4-2J cells, a tumor pancreatic acinar cell line, are not precisely known. Calcium has long been considered as an intracellular signal involved in growth-regulatory control of many cell types. Moreover, Ca++ channel blockers show growth-suppressing effects in most proliferating cells. In the present study, we analyzed the role of nifedipine, a voltage-dependent Ca++ channel antagonist, on AR4-2J cells which possess well-defined voltage-dependent Ca++ channels. The results showed that 10 nM gastrin induced a transient rise in intracellular calcium (Ca++)i followed by a sustained phase which was dependent upon a Ca++ influx operating through nifedipine-dependent and -independent Ca++ channels. Both influxes are necessary for reloading the agonist-sensitive Cai++ pools. In parallel, we demonstrated that nifedipine at doses of 1 microM and 3 microM preferentially blocked the increase in cell number elicited by 10 nM gastrin and 0.1 microM Bay K 8644, a Ca++ channel agonist, suggesting that voltage-sensitive Ca++ channel activity was required for gastrin-stimulated mitogenesis. Moreover, nifedipine had no effect on the proliferation of AR4-2J cells growing in serum-free medium, indicating that this drug did not simply exert a toxic effect. Therefore, Ca++ influx through voltage-dependent Ca++ channels might be an important initial step representing a component of a synergistic cooperation between different signal transduction pathways involved in gastrin-regulated growth.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Calcium; Calcium Channel Blockers; Cell Division; Cell Line; Dose-Response Relationship, Drug; Gastrins; Kinetics; Nifedipine; Pancreatic Neoplasms; Rats; Tumor Cells, Cultured; Verapamil

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

Using AR4-2J rat pancreatic carcinoma cells, the effects of a novel bombesin (BN) receptor antagonist [D-F5Phe6, D-Ala11]BN(6-13)OMe (BIM26226) on BN- or GRP-stimulated amylase release and binding of radio-labeled bombesin-like peptides to these cells were examined and compared to [D-Phe6,Leu13 psi(CH2NH)Leu14]BN(6-14) (Psi Bn(6-14)), one of the most potent BN receptor antagonists presently known. BN and GRP both stimulated amylase release with EC50 values in the nanomolar range. Both antagonists were devoid of agonist activity when tested alone. BIM26226 was most potent, antagonizing BN- or GRP-stimulated amylase release with IC50 values in the nanomolar range, whereas Psi Bn(6-14) was approximately ten times less potent. With 125I-[Tyr15]GRP bound to these cells, the binding affinities were BIM26226 > GRP > Psi Bn(6-14) >> neuromedin B. BIM 22626 was not able to inhibit binding of radio-labeled CCK-33, gastrin-17 or VIP. These results suggest that BIM26226 is one of the most potent and specific bombesin receptor antagonists in vitro and seems to be a useful tool to define the physiologic role of GRP in vivo.

Topics: Amylases; Animals; Binding, Competitive; Bombesin; Cell Line; Dose-Response Relationship, Drug; Gastrin-Releasing Peptide; Gastrins; Humans; Kinetics; Pancreatic Neoplasms; Peptide Fragments; Peptides; Rats; Receptors, Bombesin; Tumor Cells, Cultured

Endocrine cells (EC) were found in 19 out of 42 cases of the pancreas carcinoma (42.5%). Among them, 4 cases had a positive rate of EC more than 50%. The positive rate of EC in the well differentiated carcinomas (5/20) was lower than that of the poorly-differentiated ones (12/19) or mucinous carcinoma (2/2), and the positive rate in histologic grade I cases (5/18) was significantly lower than that of the grade III cases (7/8). The number of mast cells infiltrating in the matrix in EC positive cases was significantly higher than that of the negative ones. The positive rate of EC in the cases with metastasis (8/14) was higher than that of the non-metastasis cases (7/21). Immunocytochemical staining showed that GN (8), SS(4), HCG(5), CK(12), EMA(13) and CEA(9) were positive in 19 EC positive cases.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Female; Gastrins; Humans; Keratins; Male; Middle Aged; Neurosecretory Systems; Pancreatic Neoplasms

Bombesin (BBS), a tetradecapeptide, stimulates growth of various types of cells, including fibroblasts and human small cell lung cancer, and has been termed the universal "on-switch" due to its ability to stimulate the release of numerous hormones. In addition, BBS receptors have been identified in normal and neoplastic pancreatic tissue. A pancreatic ductal adenocarcinoma cell line (H2T), established in our laboratory, possesses specific binding sites for BBS. The purpose of this study was to examine the effect of BBS on the growth of H2T tumors transplanted into athymic nude mice. H2T cells (5 x 10(6) cells/mouse) were injected s.c. into the interscapular region of the nude mice and then the mice were randomized into two groups (n = 10/group). Mice received either 0.1 ml of saline with 0.1% bovine serum albumin (BSA) (control) or 0.1 ml BBS (5 micrograms/kg) intraperitoneally, three times/day. Tumor area was measured twice weekly until the mice were killed (day 32), when tumor and normal pancreas were removed, weighted, and assayed for DNA and protein content. Administration of BBS significantly inhibited H2T tumor area, weight, and DNA and protein content. Conversely, growth of normal pancreas, removed as an in vivo bioassay so as to ensure the efficacy of BBS, was stimulated. We conclude that BBS is a growth inhibitory factor for H2T tumors and that different mechanisms may be responsible for the differential growth effects elicited by normal and neoplastic pancreas in response to BBS.

Topics: Animals; Bombesin; Carcinoma, Ductal, Breast; Cell Division; Cricetinae; Evaluation Studies as Topic; Gastrins; Male; Mesocricetus; Mice; Mice, Nude; Pancreatic Neoplasms; Tumor Cells, Cultured

AR42J, a rat pancreatic cell line expressing receptors for both gastrin and epidermal growth factor (EGF), has been used to examine the effect of the gastrin receptor antagonist CR2093 on basal, gastrin-17 (G17), EGF and transforming growth factor (TGF)-alpha stimulated growth in vitro. In serum-free conditions, CR2093 reduced the basal growth of AR42J at a concentration known to displace physiological levels of G17 from gastrin receptors and this effect was reversed by G17 at 1 x 10(-9) M. Alone, G17 had little effect on growth, but EGF and TGF-alpha stimulated growth to 181 and 176% of control values, respectively, and marked synergy was observed when G17 was used in combination with both EGF (212%) and TGF-alpha (259%). When CR2093 was added, the synergistic effects of the G17/EGF and G17/TGF-alpha combinations were reduced to basal levels. In addition, CR2093 inhibited the growth stimulation induced by EGF and TGF-alpha alone. When the ability of CR2093 to bind to EGF receptors was assessed in a ligand binding assay, it was found that the antagonist displaced up to 23% of labeled EGF. Thus CR2093 has potent inhibitory effects on the basal growth of AR42J which can be reversed by G17. It can also inhibit type 1 growth factor-stimulated growth, but although this action may in part be related to the antagonist's ability to inhibit binding to the EGF receptor, other mechanisms may be involved.

Topics: Amino Acids; Animals; Cell Division; Coloring Agents; Epidermal Growth Factor; Gastrins; Growth Inhibitors; Growth Substances; Humans; Iodine Radioisotopes; Pancreatic Neoplasms; Rats; Receptors, Cholecystokinin; Tetrazolium Salts; Thiazoles; Transforming Growth Factor alpha; Tumor Cells, Cultured

Topics: Carcinoma, Islet Cell; Fatal Outcome; Female; Gastrins; Gastrointestinal Hemorrhage; Humans; Liver Neoplasms; Middle Aged; Pancreatic Neoplasms

Gastrin and cholecystokinin (CCK) have proven trophic effects on the gut. We have previously demonstrated that these peptides stimulate an early event in cellular proliferation, namely ornithine decarboxylase activity (ODC), in a rat exocrine pancreatic cell line AR4-2J. Furthermore, this effect is mediated through a G/CCKB receptor. Thus, in the present study we sought to examine the signal transduction mechanisms linked to the G/CCKB receptor occupancy. Both gastrin and CCK induced a rapid (maximum at 40 s) increase in inositol triphosphates (InsP3) and diacylglycerol (DAG) formation in a dose-dependent manner (EC50 = 5.6 nM) that quickly returned to baseline. Although InsP3 levels remained at baseline, DAG levels demonstrated a second gradual increase that was maximal at 15 min. CCK/gastrin efficiency to stimulate DAG and InsP3 formation (EC50 = 5.6 nM) could be correlated to the G/CCKB receptor occupancy, suggesting a coupling of this receptor to phospholipase C. To examine the involvement of protein kinase C (PKC) activation in the increase in ODC activity, we stimulated the AR4-2J cells with the phorbol ester TPA and observed an increase in ODC activity with a maximal effect at 100 nM. TPA stimulation of ODC activity was completely abolished by the PKC inhibitor staurosporine (50 nM). However, 50 nM staurosporine inhibited only 65% of the gastrin and CCK induced increase in ODC activity suggesting that a portion of the G/CCKB receptor-mediated increase in ODC activity is PKC independent.

Topics: Alkaloids; Animals; Binding Sites; Cholecystokinin; Diglycerides; Dose-Response Relationship, Drug; Enzyme Activation; Gastrins; Inositol 1,4,5-Trisphosphate; Inositol Phosphates; Ornithine Decarboxylase; Pancreas; Pancreatic Neoplasms; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Protein Kinase C; Rats; Receptors, Cholecystokinin; Signal Transduction; Staurosporine; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured; Type C Phospholipases

Interactions between growth factor receptor systems may be important in the regulation of cell growth. The proliferation of pancreatic tumor AR42J cells has been shown to be stimulated by Epidermal growth factor (EGF) and gastrin and inhibited by somatostatin. To analyze the interaction between these different peptides, we explored the influence of EGF and gastrin on the somatostatin receptors. Treatment of AR42J cells with 10 nM EGF or gastrin for 24 hr increased specific binding of [125I] Tyr3SMS to 131 and 147% of that in control cells, respectively. The effect of peptides on [125I]Tyr3SMS binding was time- and dose-dependent, with half-maximal effect at 0.2 +/- 0.03 nM EGF and 0.3 +/- 0.15 nM gastrin. Scatchard plots revealed an increase in somatostatin receptor number of 27 and 80% after 48 hr of treatment with EGF and gastrin, respectively, without any change in receptor affinity. The increase in somatostatin receptor density was accompanied by the enhancement of biological responses to somatostatin. In cells pretreated with EGF or gastrin, the potency of somatostatin for inhibiting vasoactive intestinal peptide-stimulated cAMP content was increased 2-fold as that of somatostatin analog, SMS, for inhibiting cell proliferation. Furthermore, the efficiency of SMS as antiproliferative agent was greatly increased. Vasoactive intestinal peptide or forskolin did not modify [125I]Tyr3SMS binding of control or treated cells. The phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) did not affect [125I]Tyr3SMS binding. On the other hand, cycloheximide completely blocked the increase in [125I]Tyr3SMS binding induced by EGF and gastrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Base Sequence; Cell Division; Cyclic AMP; Cycloheximide; DNA Primers; Epidermal Growth Factor; Gastrins; Molecular Sequence Data; Octreotide; Pancreatic Neoplasms; Protein Kinase C; Receptors, Somatostatin; RNA, Messenger; Tumor Cells, Cultured; Up-Regulation

Gastrin gene expression in the pancreatic islets is developmentally regulated and occurs largely during fetal life. Deletional analysis of transiently transfected rat insulinoma cells with gastrin 5'-flanking sequences in luciferase reporter genes demonstrated that the gastrin promoter sequence proximal to -111 base pairs (bp) contains the cis-regulatory elements necessary for maximal transcription. Mutational analysis identified the sequence CCCCACCCCA (-109 to -100 bp) as a positive cis-regulatory element (CACC) located 5' to a previously described negative element (-100 to -90 bp) and E-box positive element at -82 bp. Multimers of the CACC element in a heterologous promoter activated transcription independent of the other cis-regulatory elements. CACC binding proteins were purified from insulinoma cell nuclear extracts by cation exchange and affinity chromatography. Southwestern blot of nuclear extracts identified a 70-kDa CACC-binding protein. Mutational analysis of the CACC element showed a close correlation between DNA binding of this protein and transcriptional activation. Transcriptional activation by multimers of the CACC element in a heterologous promoter was detected in a variety of cell lines but was strongest in those of islet lineage. Likewise, the presence of the 70-kDa CACC-binding protein was found in many cell lines but was most abundant in the insulinoma cells. The CACC-binding protein has not been previously identified among the known pancreatic regulatory factors and may have an important role in the developmental expression of gastrin.

Topics: 3T3 Cells; Animals; Base Sequence; Cell Line; DNA Mutational Analysis; DNA-Binding Proteins; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Insulinoma; Islets of Langerhans; Mice; Molecular Sequence Data; Molecular Weight; Nuclear Proteins; Pancreatic Neoplasms; Polymerase Chain Reaction; Promoter Regions, Genetic; Rats; Regulatory Sequences, Nucleic Acid; Sequence Deletion; Substrate Specificity; Transcription, Genetic; Transfection; Tumor Cells, Cultured

Transgenic mice bearing the elastase I promoter--SV40 T-antigen fusion gene (ELSV) develop pancreatic acinar cell carcinomas by 3 to 6 months of age. The purpose of the study was to determine if pancreatic carcinomas and dysplastic pancreas from the Tg (Ela-1, SV40E + Ela-1, neo) Bri19 strain of ELSV transgenic mice express gastrin (CCK-B) receptors. To accomplish this, we utilized iodine 125 (125I)-gastrin binding studies, reverse transcription-polymerase chain reaction (RT-PCR), and Southern blot analysis to examine pancreatic carcinomas from 26-week-old male ELSV transgenic mice, dysplastic pancreas from 8-week-old male ELSV transgenic mice, and normal pancreas from 30-week-old nontransgenic male mice (SJL/J) and from 8-week-old nontransgenic male mice (B6SJLF1/J). No saturable gastrin binding to normal nontransgenic mouse pancreas was found. In contrast, saturable gastrin binding was detected at pH 6.5, 22 degrees C, in 9 of 13 pancreatic carcinomas and all 5 dysplastic pancreata. Competitive inhibition 125I-gastrin binding assays showed gastrin bound to a single class of high-affinity receptors (receptor binding affinity [Kd] 0.11 +/- 0.02 nM, binding capacities ranging from 1 to 60 fmol/mg protein for pancreatic carcinomas; Kd: 0.15 +/- 0.04 nM, binding capacities ranging from 1 to 9 fmol/mg protein for dysplastic pancreas). RT-PCR and Southern blot analysis confirmed 125I-gastrin binding studies by demonstrating gastrin (CCK-B) receptor mRNA expression in pancreatic carcinomas and dysplastic pancreas but an absence of mRNA expression in normal nontransgenic mouse pancreas. In conclusion, pancreatic carcinomas and dysplastic pancreas in ELSV transgenic mice novelly express gastrin (CCK-B) receptors. This expression may provide a growth advantage to acinar cells as part of the multistage process of carcinogenesis.

Topics: Animals; Blotting, Southern; Carcinoma, Acinar Cell; Gastrins; Gene Expression Regulation, Neoplastic; Male; Mice; Mice, Transgenic; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; RNA, Messenger

Detection of subjects from a multiple endocrine neoplasia type 1 family must rest on clinical, biochemical and radiological data, since study of the genome is unable to detect these subjects. In the new family described here, 6 out of the 14 subjects explored were affected. One had a confirmed pancreatic endocrine tumour and in 3 others a pancreatic endocrine tumour was highly probable, since insulin and glucagon levels, as well as ultrasonic exploration of the pancreas were pathological. Measurements of gastrointestinal hormones gave normal results in all cases. We conclude that to detect this endocrine neoplasia in subjects at risk it seems necessary to measure plasma insulin levels and perform an abdominal ultrasonography.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Child; Female; Gastrins; Glucagon; Humans; Insulin; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Pituitary Neoplasms; Risk Factors; Substance P; Ultrasonography; Vasoactive Intestinal Peptide

Between 1987 and 1991, 16 patients (13 females, three males; mean age 52.4 [33-73] years) with Zollinger-Ellison syndrome (ZES) were treated according to a standardized surgical concept. The diagnostic work-up consisted of measuring serum gastrin levels, pre-operative localization by ultrasound and abdominal computed tomography, as well as extensive staging by laparotomy. As complete a tumour resection as possible was the aim of treatment in 15 patients, while in one patient it was to reduce the tumour mass. In six patients who had resection of a solitary tumour there was no evidence of recurrence after 6-42 months of follow-up. Exploration of the duodenum made it possible to identify and then remove a small gastrinoma of the duodenal wall in three patients. No gastrinoma was found in one patient despite extensive exploration. In a further four patients the laparotomy was purely exploratory, because diffuse metastasization was found. In four patients the primary tumour and, where present, the regional lymph nodes were removed, but the signs of ZES persisted, i.e. the intervention was merely palliative. In one female patient, reduction of tumour mass was necessary because the symptoms could not be controlled by conservative measures: she died postoperatively from toxic hepatitis. This experience indicates that standardized surgical intervention achieves potentially curative results in nearly 40% of patients. Including the duodenum in the surgical exploration allows the identification of even small gastrinomas of the duodenal wall. It is concluded that all patients with ZES but no evidence of diffuse metastases should undergo surgical treatment.

Topics: Adult; Aged; Algorithms; Clinical Protocols; Diagnostic Imaging; Duodenal Neoplasms; Female; Gastrins; Humans; Laparotomy; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Palliative Care; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

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-releasing peptide (GRP) has previously been shown to be an autocrine growth factor for small cell lung cancer, and our objective in the study presented here was to determine whether GRP has a similar role in pancreatic cancer. Using 125I-GRP, we demonstrated binding to specific, saturable, high-affinity sites (Kd = 1 nM; Bmax = 245 fmol/mg protein) in membrane preparations from the pancreatic tumor cell line Capan. The receptors were found to be biologically active. In whole cells, a GRP analogue bound to these receptors and stimulated rapid transfer of tritium from the tritiated lipid inositol pool to inositol triphosphates. Exogenous GRP addition stimulated incorporation of [3H]thymidine into DNA 20-60%. This stimulatory effect was blocked by the addition of a monoclonal antibody that complexed specifically with the receptor-binding portion of the peptide. In addition, the monoclonal antibody inhibited the growth of Capan cells in an in vitro growth assay without exogenous peptide. Bombesin receptor-specific antagonists also inhibited growth in a similar fashion. These data suggest that paracrine production of GRP may be important in pancreatic tumor growth, or that low-levels of a GRP-like peptide may play an autocrine role in this tumor.

Topics: Amino Acid Sequence; Antibodies, Monoclonal; Binding Sites; Bombesin; Cell Division; Cell Membrane; DNA, Neoplasm; Gastrin-Releasing Peptide; Gastrins; Humans; Inositol; Iodine Radioisotopes; Molecular Sequence Data; Pancreatic Neoplasms; Peptides; Stimulation, Chemical; Tumor Cells, Cultured

Cholecystokinin (CCK-A) and gastrin (CCK-B) receptors have been demonstrated in the azaserine-induced rat pancreatic carcinoma DSL-6. In order to determine at what stage in azaserine-induced pancreatic carcinogenesis gastrin (CCK-B) receptors are first expressed, we examined the binding of [125I]gastrin-I to normal rat pancreas, azaserine-induced premalignant pancreatic nodules, grossly normal internodular pancreas, and DSL-6 carcinoma. We observed that specific gastrin binding was absent in normal pancreas, premalignant nodules, and internodular pancreas, and also reconfirmed our previous report of marked overexpression of gastrin (CCK-B) receptors in the DSL-6 carcinoma. Specific cholecystokinin (CCK) binding was present in all pancreatic tissue types tested. Therefore, we conclude that the presence of gastrin (CCK-B) receptors in the azaserine-induced pancreatic carcinoma DSL-6, in contrast to their absence in premalignant nodules, suggests that the expression of the gastrin (CCK-B) receptor may be important in the transformation from premalignant nodules to pancreatic cancer.

Topics: Animals; Azaserine; Cell Transformation, Neoplastic; Gastrins; Male; Pancreas; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; Sincalide

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

Female Syrian golden hamsters with N-nitroso-bis (2-oxopropyl) amine (BOP)-induced pancreatic cancers were treated for 2 months with bombesin/gastrin-releasing peptide (GRP) antagonist D-Tpi6,Leu13 psi(CH2NH)Leu14 bombesin(6-14) (RC-3095). Bombesin and GRP(14-27) were also administered alone and in combination with the antagonist RC-3095. RC-3095 exerted a dose-dependent inhibitory effect on growth of pancreatic cancers. The number of animals with pancreatic cancers was significantly lower in the group treated with 60 micrograms/day of RC-3095 and the weight of tumorous pancreata was reduced. Administration of bombesin or GRP alone did not stimulate the growth of pancreatic tumors and, in fact, had a slightly suppressive effect on cancers which was significant only in Experiment I. Bombesin and GRP (14-27) given together with RC-3095 did not nullify the inhibitory effect of the antagonist on pancreatic cancer growth. Actually, a greater inhibition of pancreatic tumors was observed after administration of RC-3095 together with bombesin or GRP, than with RC-3095 alone. The mechanism of action of bombesin, GRP, and bombesin antagonists on pancreatic cancers appears to be complex. The inhibitory effect of bombesin antagonists on pancreatic cancer growth was accompanied by a decrease in the binding capacity of EGF receptors in tumor membranes. Administration of bombesin also caused a down-regulation of EGF receptors and the greatest decrease in binding capacity of EGF receptors was observed after treatment with RC-3095 in combination with GRP. Inhibition of pancreatic cancer can thus be tentatively explained by some common pathways in the action of bombesin, GRP and their antagonists, that could be mediated by interference with EGF-receptor mechanisms.

Topics: Animals; Body Weight; Bombesin; Carcinoma; Cricetinae; Dose-Response Relationship, Drug; Down-Regulation; Epidermal Growth Factor; ErbB Receptors; Female; Gastrin-Releasing Peptide; Gastrins; Growth Hormone; Insulin-Like Growth Factor I; Mesocricetus; Nitrosamines; Pancreatic Neoplasms; Peptide Fragments; Peptides; Receptors, Bombesin; Receptors, Neurotransmitter

We previously established pluripotent transformed rat islet cell lines, MSL-cells, of which certain clones have been used to study processes of islet beta-cell maturation, including the transcriptional activation of the insulin gene induced by in vivo passage. Thus, successive sc transplantation in NEDH rats resulted in stable hypoglycemic insulinoma tumor lines, such as MSL-G2-IN. Occasionally, hypoglycemia as well as severe weight loss were observed in the early tumor passages of MSL-G and the subclone, NHI-5B, which carry the transfected neomycin and human insulin genes as unique clonal markers. By selective transplantation, it was possible to segregate stable anorectic normoglycemic tumor lines, MSL-G-AN and NHI-5B-AN, from both clones. These tumors cause an abrupt onset of anorexia when they reach a size of 400-500 mg (< 0.3% of total body weight), and the observed weight loss parallels that of starved rats until death results from cachexia. After tumor resection, animals immediately resume normal feeding behavior. Comparative studies of hormone release and mRNA content in anorectic lines, MSL-G-AN and NHI-5B-AN, vs. those in the insulinoma line, MSL-G2-IN, revealed selective glucagon gene expression in both of the anorectic tumors, whereas insulin and islet amyloid polypeptide gene expression were confined to the insulinoma. Both tumor phenotypes produced cholecystokinin and gastrin in variable small amounts, making it unlikely that these hormones contribute to the anorectic phenotype. Tumor necrosis factor (cachectin) was not produced by any of the tumors. Proglucagon was processed as in the fetal islet to products representative of both pancreatic alpha-cell and intestinal L-cell phenotypes, with glucagon and Glp-1 (7-36)amide as the major extractable products. In contrast to the administration of cholecystokinin, neither glucagon, Glp-1 (7-36)amide, nor their combination, affected feeding behavior in fasted mice, suggesting the presence of a hitherto unidentified anorectic substance released from the glucagonoma. We conclude 1) that glucagonomas and insulinomas can be derived from a common clonal origin of pluripotent MSL cells, thus supporting the existence of a cell lineage relationship between islet alpha- and beta-cell during ontogeny; and 2) that our glucagonomas release an anorexigenic substance(s) of unknown nature that causes a severe weight loss comparable to that reported in animals carrying tumor necrosis factor-producing experimental

Topics: Adenoma, Islet Cell; Animals; Anorexia; Base Sequence; Blotting, Northern; Cholecystokinin; Eating; Gastrins; Gene Expression; Glucagon; Hormones; Hypoglycemia; Molecular Sequence Data; Neoplasm Transplantation; Pancreatic Neoplasms; Protein Precursors; Rats; Tumor Cells, Cultured; Weight Loss

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

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

Several bombesin-receptor antagonists are available that inhibit secretory and growth effects of bombesin, in vitro. In the present study, we examined the effects of a new class of bombesin receptor antagonists (modified GRP(15-27) peptides, with D-Pro26 and D-Ala24 moieties), on bombesin mediated effects, in vivo and in vitro. Of the 10 different compounds tested, BW-10 or 2258U89 ([de-NH2)Phe19,D-Ala24,D-Pro26 psi(CH2NH)Phe27]-GRP(19-27)) was most potent towards inhibiting bombesin binding to rat pancreatic acinar cancer cells with an ID50 of 0.5 nM. BW-10 (1 and 10 nM) significantly inhibited the gastrin response to 1 nM bombesin, from isolated rat stomach, in vitro, in a dose-dependent fashion. BW-10 (10-100 nmol/kg) was equally effective at significantly inhibiting bombesin evoked gastrin release in anesthetized rats, in vivo. [D-Phe6]Bombesin(6-13)-propylamide (BIM), a member of another class of antagonists, reported previously to be the most potent antagonist, in vitro, on the other hand, enhanced bombesin provoked gastrin release in rats. The antagonistic effects of BIM, in vivo, may thus be more selective. Intravenous infusion of BW-10 (10 nmol/kg/h) partially depressed gastrin and pancreatic polypeptide and completely abolished insulin released in response to bombesin, in conscious dogs. These results suggest that BW-10 functions as one of the most potent bombesin receptor antagonists, in vitro and in vivo, which could potentially be used as a therapeutic compound in treatment of some human diseases.

Topics: Animals; Bombesin; Dogs; Female; Gastrins; Gastrointestinal Hormones; In Vitro Techniques; Insulin; Kinetics; Male; Oligopeptides; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioligand Assay; Rats; Receptors, Bombesin; Receptors, Neurotransmitter; Tumor Cells, Cultured

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

Fifty exocrine pancreatic adenocarcinomas and 57 benign tumors induced in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) were examined for the presence of argyrophil cells antiinsulin, -glucagon, -somatostatin, -pancreatic polypeptide (PP), -gastrin/CCK, -vasoactive intestinal polypeptide (VIP), and - neuron-specific enolase (NSE) reactive cells. Argyrophil - and antihormone-reactive cells were found in the normal pancreatic ducts and in the acini, as well as in hyperplastic and atypical ducts/ductules, tubular complexes, benign lesions, and in 80% of ductal adenocarcinomas. Insulin and antiNSE-reactive cells were the most common, followed in decreasing frequency by glucagon, somatostatin, and PP cells. Antigastrin-/CCK-and -VIP-reactive cells were found in two cases. Argyrophil cells were present in about 60% of the tumors with Grimelius staining and in 55% of those with Churukian-Schenk staining. Insulin cells were seen in ductal cancer that had grown into a lymph node and in the lymph node metastases of another cancer. A novel finding was the presence of argyrophil and insulin cells within the lumen of some malignant glandular structures. Coexistence of several peptide cells was found in 52% of the cancers. The presence of argyrophil and hormone-producing cells in induced pancreatic ductal/ductular lesions further strengthens the existence of a close developmental relationship between exocrine and endocrine cells of the pancreas.

Topics: Adenocarcinoma; Animals; Cricetinae; Female; Gastrins; Glucagon; Immunohistochemistry; Insulin; Islets of Langerhans; Male; Mesocricetus; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Silver Staining; Somatostatin; Vasoactive Intestinal Peptide

The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Surgery for peptic ulcer disease may increase the risk of pancreatic cancer. The effect of duodenogastric reflux on pancreatic carcinogenesis was tested, and changes in the circulating levels of cholecystokinin (CCK) and gastrin were measured. Male Wistar rats (n = 40) weighing 250-300 g were randomized to undergo gastrotomy (control) or split gastrojejunostomy (to produce complete duodenogastric reflux) and then to receive azaserine (30 mg/kg/week intraperitoneally) or saline injections for 3 weeks. At 6 months, blood CCK was assayed and the pancreas was excised for quantitative estimation of atypical acinar cell foci (AACF), the precursor lesions of carcinoma. Rats that had undergone split gastrojejunostomy weighed 15-19 per cent less than controls (P < 0.05), but their relative pancreatic weight (mg pancreas per 100 g body-weight) was 52-60 per cent greater (P < 0.001). Acidophilic AACF occurred only in azaserine-treated rats with duodenogastric reflux. Although plasma CCK concentrations were unchanged, split gastrojejunostomy increased basal and postprandial gastrin levels by 98-175 per cent (P < 0.05). Duodenogastric reflux produces sustained hypergastrinaemia and promotes experimental pancreatic carcinogenesis.

Topics: Anastomosis, Surgical; Animals; Cholecystokinin; Duodenogastric Reflux; Gastrins; Jejunum; Male; Pancreatic Neoplasms; Postoperative Complications; Rats; Rats, Inbred Strains; Stomach

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

Many reports have emphasized the role of gastrin as a growth factor for normal gastrointestinal mucosa and gastrointestinal cancers. Recent studies have pointed out that this peptide acts also as a growth factor for the pancreatic cancer cell line AR42J. This effect is mediated by gastrin [cholecystokinin (CCK)-B] receptors. In the present study, we investigated gastrin (CCK-B) receptor expression in the azaserine-induced rat pancreatic carcinoma DSL-6, comparing it to normal rat pancreas, and we also characterized CCK receptor subtypes in this tumor. The results showed that there is extensive gastrin binding to the DSL-6 pancreatic carcinoma. No evidence of specific gastrin binding to normal pancreas was found. Analysis of the ability of gastrin-17-I to inhibit 125I-gastrin-I binding demonstrated that gastrin bound to a single class of receptors with a Kd of 0.21 +/- 0.04 nM and a binding capacity of 184 +/- 29 fmol/mg protein. 125I-Gastrin-I binding was inhibited by the specific CCK-B receptor antagonist L365,260 approximately 40 times more effectively than by the specific CCK-A receptor antagonist L364,718. Analysis of the ability of cholecystokinin octapeptide (CCK-8) to inhibit 125I-Bolton-Hunter-CCK-8 binding revealed two CCK binding sites, i.e., a high affinity site and a low affinity site. The observed binding affinities of CCK-8 were then introduced into the computer analysis of the dose-inhibition curve of the ability of gastrin-17-I to inhibit binding of 125I-Bolton-Hunter-CCK-8, which was significantly better fit by a three-site model than by a two-site model. The three sites meet the criteria for CCK-B, high affinity CCK-A, and low affinity CCK-A receptors. The binding capacity of CCK-B receptors constitutes 34% of the total high affinity CCK binding sites. This study demonstrated that DSL-6 pancreatic carcinoma expresses three subtypes of CCK receptors. Gastrin (CCK-B) receptors, which were not detected in normal rat pancreas, constitute about one third of the total high affinity CCK receptors. We suggest that novel expression of gastrin (CCK-B) receptors may be generated by gene mutation or amplification during carcinogenesis and may play an important role in promoting tumor growth.

Topics: Animals; Azaserine; Gastrins; Male; Pancreatic Neoplasms; Rats; Rats, Inbred Lew; Receptors, Cholecystokinin; Sincalide

Eighteen pancreatic neuroendocrine (NE) tumours were analysed for nuclear DNA content by image cytometry (ICM) and flow cytometry (FCM). The DNA indices (DIs) obtained by ICM were somewhat higher than those obtained by FCM, but a major disagreement was present only in 1 case. Thirteen patients had been followed up at least for 6 years after the diagnosis or until death. At 6 years of follow-up all 4 patients with a tumour with a DI greater than or equal to 1.8 by ICM had died from their NE tumour or had metastatic disease, whereas all 9 patients with a smaller DI had no evidence of the disease (P = 0.001). The DIs calculated from the FCM data also correlated well with the final outcome (P = 0.01). A high incidence of DNA aneuploidy was found by both methods in histologically and clinically benign NE tumours; 12 (67%) were DNA aneuploid by FCM and 16 (89%) by ICM. It is concluded that pancreatic NE tumours are frequently DNA aneuploid, and both cytometric DNA methods give prognostic information in these tumours. The presence of DNA aneuploidy should not be considered as a sign of malignant behaviour in pancreatic NE tumours, whereas a large DI is associated with poor prognosis.

Topics: Adult; Aged; Aneuploidy; DNA, Neoplasm; Female; Flow Cytometry; Gastrins; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Ploidies

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

The control of cell proliferation by gastrin has been investigated in a rat pancreatic tumour cell line, AR4-2J. Exogenous gastrin, 10(-12) to 10(-8) M, stimulated cell growth of thymidine-synchronised AR4-2J cells cultured over 48 h in serum-free medium. Cell lysates of AR4-2J cells contained an average of 4.5 and 3.5 pg gastrin per 10(6) cells, when grown in serum-supplemented or serum-free media, respectively, as revealed by radioimmunoassay. In serum-free medium, AR4-2J secrete 34 ng 1(-1) 10(-6) cells of gastrin over 48 h. Addition of an anti-gastrin immunoglobulin preparation, but not control immunoglobulins, caused a maximum 52% reduction in cell growth. These data are consistent with an autocrine role for gastrin in the control of AR4-2J cell growth. These results were supported by studies with gastrin/CCK receptor antagonists. Six non-peptide gastrin/CCK receptor antagonists inhibited AR4-2J cell growth in a concentration-related manner. The concentration required for 50% inhibition (IC50) of cell growth by the amino acid-derived antagonists proglumide (3.5 x 10(-3) M), benzotript (1.8 x 10(-3) M), loxiglumide (1.1 x 10(-4) M) and lorglumide (6.7 x 10(-5) M) were of the same order and significantly correlated with their IC50 for inhibition of 125I-gastrin binding to AR4-2J cells. Inhibition of cell growth by these antagonists was partially reversed by the addition of exogenous gastrin. In contrast, the IC50 for inhibition of cell growth with two benzodiazepine-derived antagonists, the CCK-B receptor antagonist L-365,260 (4.6 x 10(-5) M) and the CCK-A receptor antagonist devazepide (1.7 x 10(-5) M) were two-three orders of magnitude greater than those required to inhibit gastrin binding (10(-8)-10(-7) M). The growth inhibitory effects of L-365,260 and devazepide were not reversed by exogenous gastrin suggesting these benzodiazepine-derived antagonists do not inhibit cell growth by interaction with gastrin receptors. The results are consistent with gastrin being an autocrine growth factor in AR4-2J cells, and that stimulation of cell growth is due to stimulation of the gastrin, rather than CCK-B, receptor sub-type. This study highlights that gastrin receptor antagonists warrant further investigation as agents to control growth of tumours, such as those from the gastrointestinal tract, which express gastrin receptors.

Topics: Animals; Binding, Competitive; Cell Division; Cell Line; Culture Media; DNA Replication; Gastrins; Kinetics; Pancreatic Neoplasms; Rats; Receptors, Cholecystokinin; Thymidine; Tumor Cells, Cultured

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

Female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 months with new pseudononapeptide bombesin receptor antagonist [D-Tpi6,Leu13 psi (CH2NH)-Leu14]bombesin(6-14)(RC-3095), administered s.c. with implanted osmotic minipumps releasing 20 micrograms/day of the analogue. The results were compared to those obtained by treatment with somatostatin analogue RC-160 (35 micrograms/day and 150 micrograms/day) or [D-Trp6]luteinizing hormone-releasing hormone (25 micrograms/day), which inhibited the growth of pancreatic cancers in our previous studies. A new acetylated somatostatin analogue [formula: see text] (30 micrograms/day) also was used for comparison of therapeutic response. All peptide analogues induced tumor inhibition by at least one of the measured parameters. Bombesin antagonist RC-3095 and high dose of RC-160 (150 micrograms/day) had the greatest inhibitory effect on pancreatic cancers: A significant decrease in the number of animals with tumors, reduced pancreatic weight, 87-89% inhibition of tumorous pancreas weight, and a significant diminution in the number of tumor nodules and argyrophilic nucleolar organizer region count in tumor cell nuclei were observed in the groups treated with these regimens. We were able to detect receptors for bombesin in membranes of N-nitrosobis(2-oxopropyl)amine-induced pancreatic tumors and these receptors were not down-regulated after treatment with the bombesin antagonist. In hamsters treated with bombesin antagonists, tumor inhibition might be explained by a significant decrease in the binding capacity of epidermal growth factor receptors in pancreatic cancers. The acetylated somatostatin analogue RC-160-II had a similar inhibitory effect on the tumors as the original analogue RC-160. Our results suggest that the increase in the dose of RC-160 improves the therapeutic response, and this finding should be taken into account in clinical use of this somatostatin analogue. In view of its strong inhibitory effect on experimental pancreatic tumors, the bombesin antagonist RC-3095 might be considered as a possible new agent for the therapy of human exocrine pancreatic cancer.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Antineoplastic Agents; Bombesin; Carcinogens; Cell Membrane; Cricetinae; ErbB Receptors; Female; Gastrins; Mesocricetus; Molecular Sequence Data; Nitrosamines; Organ Size; Pancreatic Neoplasms; Peptide Fragments; Receptors, Bombesin; Receptors, Neurotransmitter; Somatostatin

The authors have established a long-term tissue culture cell line (BON) derived from a metastatic human carcinoid tumor of the pancreas. The cells have been in continuous passage for 46 months. Tissue culture cells produce tumors in a dose-dependent fashion after SC inoculation of cell suspensions in athymic nude mice. BON tumors, grown in nude mice, are histologically identical to the original tumor; they possess gastrin and somatostatin receptors, synthesize serotonin and chromogranin A, and have a doubling time of approximately 13 days. The antiproliferative effects of the long-acting somatostatin analogue, SMS 201-995 (300 micrograms/kg, t.i.d.), and 2% alpha-difluoromethylornithine on BON xenografts in nude mice were examined. Tumor size was significantly decreased by day 14 of treatment with either agent and at all points of analysis thereafter until the animals were killed (day 33). In addition, tumor weight, DNA, RNA, and protein contents were significantly decreased in treated mice compared with controls. Establishment of this human carcinoid xenograft line, BON, provides an excellent model to study further the biological behavior of carcinoid tumors and the in vivo effect of chemotherapeutic agents on tumor growth.

Topics: Animals; Binding Sites; Carcinoid Tumor; Cell Division; Cell Line; DNA; Eflornithine; Gastrins; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Octreotide; Pancreatic Neoplasms; Proteins; Receptors, Somatotropin; RNA; Tumor Cells, Cultured

Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas, only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas, however, there were nine partial regressions and three complete regressions, an overall regression rate of 67%. For anaplastic disease, the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site, endocrine hyperfunction, or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity, which was severe for most patients, consisted primarily of vomiting, leukopenia, thrombocytopenia, anemia, alopecia, and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas, originating in typical neuroendocrine tumor sites (small and large bowel, pancreas, and stomach) or of unknown origin, who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.

Topics: Adenoma, Islet Cell; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Carcinoma; Cisplatin; Etoposide; Female; Gastrins; Glucagon; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Remission Induction; Survival Rate

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

We studied the effects of hormonal manipulation by orchiectomy, alone or in combination with the aromatase inhibitor aminoglutethimide (AGT), and by luteinizing hormone-releasing hormone agonist (LH-RH-A) (goserelin) treatment on the development of early putative (pre)neoplastic lesions induced in the pancreas of rats and hamsters by azaserine and N-nitrosobis(2-oxopropyl)amine respectively. Treatment of the animals started 1 week after the last injection with carcinogen and continued for 4 months. Orchiectomy caused a significant inhibition of growth of acidophilic atypical acinar cell nodules in the rat model, whereas surgical castration did not show an effect in the hamster model. In rats, but not in hamsters, orchiectomy resulted in a significant decrease in body weight and in absolute, but not relative pancreatic weight. Treatment of the animals with AGT or goserelin did not cause a significant effect on the development of either putative preneoplastic acinar lesions in rat pancreas or early ductular lesions in hamster pancreas. Hamsters showed clearly higher plasma epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) concentrations than rats, while plasma testosterone levels were significantly lower. Plasma EGF and IGF-1 levels decreased with increasing age in both control and treatment groups. Compared to controls there were no clear unequivocal effects of treatment on EGF, IGF-1 and gastrin levels. Plasma testosterone levels decreased by orchiectomy and LH-RH-A treatment. In rats hormone-induced effects on food intake and altered nutritional status might be important with respect to the development of carcinogen-induced preneoplastic pancreatic lesions.

Topics: Aminoglutethimide; Animals; Azaserine; Body Weight; Buserelin; Carcinogens; Cricetinae; Epidermal Growth Factor; Gastrins; Goserelin; Male; Mesocricetus; Nitrosamines; Orchiectomy; Organ Size; Pancreatic Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains; Somatomedins; Testosterone

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

It has been found by immunohistochemical staining that antigens normally found in gastric and/or intestinal epithelial cells are expressed in most differentiated duct cell carcinomas of the pancreas. Among 88 such tumors, 93% and 92%, respectively, expressed M1 and cathepsin E, markers of gastric surface-foveolar epithelial cells, 51% expressed pepsinogen II, a marker of gastroduodenal mucopeptic cells, 48% expressed CAR-5, a marker of colorectal epithelial cells, and 35% expressed M3SI, a marker of small intestinal goblet cells. Most of the tumors also expressed normal pancreatic duct antigens; 97% expressed DU-PAN-2, and 59% expressed N-terminus gastrin-releasing peptide. In agreement with these findings, electron microscopy revealed malignant cells with fine structural features of gastric foveolar cells, gastric mucopeptic cells, intestinal goblet cells, intestinal columnar cells, pancreatic duct epithelial cells, and cells with features of more than one cell type. Normal pancreatic duct epithelium did not express any marker of gastrointestinal epithelial cells, whereas such benign lesions as mucinous cell hypertrophy and papillary hyperplasia commonly expressed gut-type antigens but rarely expressed pancreatic duct cell markers. By contrast, lesions characterized by atypical papillary hyperplasia commonly expressed both gastric and pancreatic duct cell markers. Metaplastic pyloric-type glands expressed pepsinogen II and, except for their expression of cathepsin E, were indistinguishable from normal pyloric glands. In marked contrast, the immunohistochemical and ultrastructural features of 14 ductuloacinar cell tumors were those of cells lining terminal ductules, centroacinar cells, and/or acinar cells; none expressed any gut-type antigen. The results indicate that gastrointestinal differentiation is common in both benign and malignant lesions of pancreatic duct epithelium and suggest that duct cell carcinomas are histogenetically related to gastric- and intestinal-type metaplastic changes of epithelial cells lining the main and interlobular ducts of the pancreas.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Antigens, Surface; Aspartic Acid Endopeptidases; Biomarkers, Tumor; Bombesin; Cathepsin E; Cathepsins; Endopeptidases; Epithelial Cells; Epithelium; Gastrin-Releasing Peptide; Gastrins; Humans; Immunoenzyme Techniques; Intestines; Pancreas; Pancreatic Neoplasms; Pepsinogens; Peptides; Staining and Labeling; Stomach

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

Topics: Animals; Carnivora; Female; Ferrets; Gastrins; Glucagon; Immunoenzyme Techniques; Insulin; Male; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin

The effect of tetragastrin on pancreatic tumors induced by azaserine was investigated in Wistar rats. Rats were given 25 weekly injections of 10 mg/kg body weight of azaserine and 1 mg/kg body weight of tetragastrin as a suspension in olive oil every other day. Carcinogen-induced pancreatic lesions were examined by histochemical techniques, and were classified as ATPase-positive or ATPase-negative. In week 62, quantitative histological analysis showed that prolonged administration of tetragastrin had little or no influence on the number and size of the carcinogen-induced pancreatic lesions, although it caused significantly increased cell proliferation, indicated by a greater labelling index of the pancreatic acinar cells.

Topics: Adenosine Triphosphatases; Animals; Azaserine; Body Weight; Cell Division; Gastrins; Male; Mitotic Index; Organ Size; Pancreatic Neoplasms; Rats; Rats, Inbred Strains; Tetragastrin

In 98 patients with histologically proved pancreatic islet cell carcinoma who were studied between 1950 and 1987, 55 had functioning tumors and 43 had nonfunctioning tumors. Both patient groups were compared in regard to age at presentation, metastases, and survival. Mean age at diagnosis was 51.1 years for the 55 men and 47 years for the 43 women. At diagnosis, 51 of the patients had regional disease and 47 had distant metastases. When matched for age, sex, and extent of disease, survival did not differ significantly in cases of functioning and nonfunctioning tumors. The patients' ages and the extent of disease at presentation were the most significant factors in prognosis and survival.

Topics: Adenoma, Islet Cell; Adult; Female; Gastrins; Hormones; Humans; Immunohistochemistry; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis

The insulinoma is the most common pancreas tumour with endocrine activity, with more than 2,000 cases being described in the literature worldwide. The first successful extirpation was performed by Graham in 1928. Clinical appearance is characterized by severe paroxysmal hypoglycaemia together with inadequately increased serum insulin levels. Surgery is indicated in such situations because of limited effectiveness of medicamentous therapy. Surgical approach and long-time results are discussed in this paper, with reference being made to 13 cases of the authors.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Follow-Up Studies; Gastrins; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Reoperation

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

The gastrin gene is expressed in fetal pancreatic islet cells, but after birth expression is selectively repressed as the islets terminally differentiate. DNA transfection studies identified a cis regulatory domain between -108 and -76 in the gastrin promoter which controls gastrin transcription in islet cells. This cis regulatory domain comprises adjacent positive and negative elements. The negative element (-108 to -82) contains the sequence ATTCCTCT, which is also found in the negative element of the beta-interferon promoter. Gel retardation assays and DNase footprinting studies demonstrated that specific islet nuclear protein(s) bind to the gastrin negative element. In vivo competition studies demonstrated that the trans-acting factors which bind to this element specifically repress gastrin promoter activity in islet cells. Immediately downstream of the negative element lies a positive element (-82 CATATGG -76), which activates gastrin transcription in islet cells. The sequence of the positive element resembles the islet-specific enhancer elements of the insulin gene (CATCTGG/C). Gel mobility shift assays and in vivo competition studies indicate that this positive element activates the gastrin promoter by binding to the same islet cell transcription factor which binds enhancer elements in the rat insulin gene. The tandem organization of the negative and positive elements suggests that this regulatory domain may act as a switch controlling the transient transcription of the gastrin gene during fetal islet development.

Topics: Animals; Base Sequence; Cell Line; Cells, Cultured; Exons; Fetus; Gastrins; Genes, Regulator; Insulinoma; Islets of Langerhans; Molecular Sequence Data; Oligonucleotide Probes; Pancreatic Neoplasms; Plasmids; Promoter Regions, Genetic; Rats; Restriction Mapping; Transfection

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

The authors demonstrate three patients--two with a nesidioma of the B-cells with insulin production, the third had a nesidioma made up of non-B cells with clinical manifestations of gastrin hypersecretion. The surgical solution was successful in the patients with B-cell nesiodiomas.

Topics: Adolescent; Adult; Epilepsy; Female; Gastrins; Humans; Insulin; Insulin Secretion; Insulinoma; Male; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Cholecystokinin (CCK) receptors were investigated in the tumoral acinar cell line AR 4-2 J derived from rat pancreas, after preincubation with 20 nM dexamethasone. At steady state binding at 37 degrees C (i.e., after a 5 min incubation), less than 10% of the radioactivity of [125I]BH-CCK-9 (3-(4-hydroxy-[125I]iodophenyl)propionyl (Thr34, Nle37) CCK(31-39)) could be washed away from intact cells with an ice-cold acidic medium, suggesting high and rapid internalization-sequestration of tracer. By contrast, more than 85% of the tracer dissociated rapidly after a similar acid wash from cell membranes prelabelled at steady state. In intact AR 4-2 J cells, internalization required neither energy nor the cytoskeleton framework. Tracer internalization was reversed partly but rapidly at 37 degrees C but slowly at 4 degrees C. In addition, two degradation pathways of the tracer were demonstrated, one intracellular and one extracellular. Intracellular degradation occurred at 37 degrees C but not at 20 degrees C and resulted in progressive intracellular accumulation of [125I]BH-Arg that corresponded, after 1 h at 37 degrees C, to 35% of the radioactivity specifically bound. This phenomenon was not inhibited by serine proteinase inhibitors and modestly only by monensin and chloroquine. Besides, tracer degradation at the external cell surface was still observable at 20 degrees C and yielded a peptide (probably [125I]BH-Arg-Asp-Tyr(SO3H)-Thr-Gly). This degradation pathway was partly inhibited by bacitracin and phosphoramidon while thiorphan, an inhibitor of endopeptidase EC 3.4.24.11, was without effect.

Topics: Animals; Arsenicals; Binding, Competitive; Cell Membrane; Chloroquine; Cholecystokinin; Cytochalasin D; Dinitrophenols; Endocytosis; Gastrins; Hydrogen-Ion Concentration; Iodine Radioisotopes; Kinetics; Pancreas; Pancreatic Neoplasms; Rats; Sincalide; Succinimides; Temperature; Tumor Cells, Cultured

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

Ten patients with various metastatic pancreatic tumours have received Sandostatin (octreotide) for up to 5 years, initially 50 micrograms t.i.d. subcutaneously but increased over 6-12 months to 500 micrograms t.i.d. Three patients showed no biochemical or clinical response to Sandostatin. In the remaining patients, treatment was extremely effective: tumour secretions fell by nearly 60% and clinical symptoms improved or resolved in all. At 5-6 months, all patients showed worsening symptoms and rising hormonal concentrations. Although relapses were initially responsive to Sandostatin (at 500 micrograms t.i.d.), patients eventually became unresponsive to all therapies, and all died within 6 months of the development of this resistive phase. Side effects were minimal and long-term therapy was well tolerated. Steatorrhoea and the development of gallstones were not observed.

Topics: Gastrins; Glucagon; Humans; Injections, Subcutaneous; London; Octreotide; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

7 gastrinomes and 1 gastrin-producer complex carcinoma-carcinoid tumor were examined by light and electron microscopical-method and by immunohistochemical method. In six cases, the tumor was in the pancreas or in the wall of duodenum; in two cases its localisation was of extra-gastroenteropancreatic (liver, lymph node). All patients developed Zollinger-Ellison syndrome, three patients bled and one had diarrhea. One patient had other tumors, besides gastrinome, which were characteristic of MEN-I syndrome. By immunohistochemical methods all tumors proved to be gastrin and neuron-specific-enolase positive. In four cases somatostatin positivity, in some cases glucagon, pancreatic polypeptide, S-100 protein, keratin and carcinoembryonal antigen positivity were detected. Relation could not be detected between other polypeptide hormones, produced besides gastrin, and biological behaviour of tumor and clinical symptoms.

Topics: Carcinoid Tumor; Carcinoma; Duodenal Neoplasms; Gastrins; Humans; Pancreatic Neoplasms; Stomach Neoplasms; Zollinger-Ellison Syndrome

Many reports emphasized the role of gastrin as growth factor on normal gastrointestinal mucosa and pancreas. In the present study, we analyzed the proliferative effects of cholecystokinin (CCK) and gastrin peptides on a rat tumoral pancreatic cell line, AR42J, which possesses both CCKA and CCKB receptor subtypes. The results showed a good correlation between the binding of gastrin to CCKB receptor [Kd 1.125 +/- 0.3 (SD) nM] and its ability to either induce ornithine decarboxylase activity [50% effective concentration, 0.6 +/- 0.3 nM] and [3H]-thymidine incorporation [50% effective concentration, 2 +/- 0.4 nM]. Furthermore, the ability of different cholecystokinin and gastrin antagonists such as proglumide and asperlicin derivatives (respectively, CR1409, CR1505, and L364,718) were tested. We found that all antagonists displaced 125I-labeled gastrin binding, with the following order of potencies: L364,718 greater than CR1409 greater than CR1505 greater than proglumide. Furthermore, the 50% inhibitory concentration of CR1409 and CR1505 to inhibit gastrin stimulated ornithine decarboxylase activity (an early event involved in cell proliferation) and [3H]thymidine incorporation were in agreement with their constants of inhibition (Ki) on gastrin binding. The L364,718 compound, at a concentration which fully occupied the CCKA without affecting the CCKB, had no effect on gastrin stimulated ornithine decarboxylase activity and [3H]thymidine incorporation. In addition, this compound appeared to be a full agonist on CCKB receptor. These results confirm the implication of the CCKB receptor in the proliferative response of AR42J cells to gastrin.

Topics: Animals; DNA, Neoplasm; Gastrins; Glutamine; Ornithine Decarboxylase; Pancreatic Neoplasms; Proglumide; Rats; Receptors, Cholecystokinin; Thymidine; Tumor Cells, Cultured

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 occurrence of transthyretin (TTR) in 25 endocrine pancreatic tumors was investigated by immunohistochemical methods using both polyclonal and monoclonal antibodies. All malignant insulinomas were strongly TTR immunoreactive, more so than their benign counterparts, which in some cases were TTR negative. All glucagonomas and nonfunctioning tumors were TTR immunoreactive, whereas gastrinomas and VIPomas were TTR negative. TTR, chromogranin A, and the argyrophil reaction (Grimelius' silver technique) had similar distributions among the cells in many, but not all, tumors. Coexistence of TTR with glucagon, insulin, or pancreatic polypeptide in tumor cells was demonstrated. TTR was also quantitated in preoperative serum samples by electroimmuno assay in some cases. Although one patient with a glucagonoma had a markedly increased serum TTR level, five other patients with endocrine tumors, including two patients with glucagonoma, had TTR levels in serum that were within or below the reference range.

Topics: Adenoma, Islet Cell; Gastrins; Glucagon; Humans; Immunohistochemistry; Immunologic Techniques; Insulin; Pancreatic Neoplasms; Prealbumin; Staining and Labeling; Tissue Distribution

The clinical, microscopic, immunohistochemical and ultrastructural features of 7 gastrinomas and 1 combined carcinoma-carcinoid tumor were evaluated. The tumors were located in the pancreas or duodenal wall in 6 cases, and on extragastro-enteropancreatic sites in 2 (liver or peripancreatic lymph node). All patients had the Zollinger-Ellison syndrome, 3 of them with additional bleeding and 1 with diarrhea. One patient with gastrinoma had additional tumors characteristic of the MEN-I syndrome. Immunohistochemistry showed gastrin and neuron-specific enolase-positivity in all of the tumors. Somatostatin was found in 4 cases, and single cell glucagon, pancreatic polypeptide. S-100 protein, keratin as well as carcino-embryonic antigen positivity in another few. Additional hormone production did not appear to be connected with biological behaviour of the tumors or with the clinical symptoms.

Topics: Adolescent; Adult; Aged; Carcinoembryonic Antigen; Carcinoid Tumor; Duodenal Neoplasms; Female; Gastrins; Glucagon; Humans; Immunohistochemistry; Keratins; Male; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; S100 Proteins; Somatostatin; Zollinger-Ellison Syndrome

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 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

Topics: ACTH Syndrome, Ectopic; Adenoma, Islet Cell; Adrenocorticotropic Hormone; Combined Modality Therapy; Female; Gastrins; Humans; Hydrocortisone; Middle Aged; Neoplasm Metastasis; Pancreas; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes

Although part of pancreatic endocrine tumors may be multihormonal by immunohistochemical study, the clinical manifestations are often related to hypersecretion of only one type of peptide hormone. Only a few cases have shown two or more syndromes simultaneously or transition of one type of syndrome to another with the passage of time. The case reported here is an islet cell carcinoma with liver metastases. The clinical manifestations changed from Zollinger-Ellison syndrome to hypoglycemic syndrome with the secretion of gastrin, insulin and serotonin. The immunohistochemical study confirmed multihormonal production. The elevation of growth hormone with acromegaly was also noted in this case. It remains to be seen if the excessive production of growth hormone was due to growth hormone-releasing hormone secreted by the endocrine pancreatic tumor or to the possible presence of a pituitary microadenoma as a component of the multiple endocrine neoplasia type I syndrome.

Topics: Adenoma, Islet Cell; Gastrins; Growth Hormone; Hormones; Humans; Male; Middle Aged; Pancreatic Neoplasms

Ten patients with metastatic pancreatic endocrine tumours were treated with the long-acting somatostatin analogue octreotide (SMS 201-995). Three patients showed no response, clinically or biochemically, and treatment was therefore withdrawn. The seven remaining patients continued treatment for a median period of 28 months (range 13-54 months). Treatment was initially effective, symptoms improved and the concentrations of tumour-related hormones were reduced. Worsening of symptoms and rising levels of tumour-related hormone concentrations occurred a median of 5 months (range 1-6 months) after the start of therapy and were initially reversed by increasing the dose of octreotide over a median of 10 months (range 6-16 months). However, after a median of 13 months (range 5-34 months) at the maximum dosage, symptoms recurred and were no longer responsive to a further increase in dosage of octreotide or other therapeutic measures. All patients died within a period of 5 months once this resistant phase of their illness had been reached.

Topics: Adenoma, Islet Cell; Gastrins; Glucagon; Humans; Liver Neoplasms; Octreotide; Pancreatic Neoplasms; Time Factors; Vasoactive Intestinal Peptide

Prealbumin, one of the main thyroxine transport proteins, has recently been shown to be a valuable immunohistochemical marker of neuroendocrine tumours. We report the case of a multisecretory pancreatic endocrine tumour whose prealbumin secretion was so high that it produced a peak on routine serum protein electrophoresis and induced a euthyroid hyperthyroxinemia. The maximal binding capacity of prealbumin for thyroxine was indeed markedly increased, whereas its affinity for this hormone was normal. The tumour was associated with gastric hyperacidity and hypergastrinemia thereby evoking a Zollinger-Ellison syndrome. The secretin stimulation test and gastrin tumoural immunohistochemistry were, however, negative. We suggest that the concomitant tumoural production of gastrin-releasing peptide was responsible for the gastric hyperacidity and hypergastrinemia. This hormone probably also accounted for a moderate hypercorticism.

Topics: Adrenocortical Hyperfunction; Gastrins; Humans; Hyperthyroxinemia; Immunoenzyme Techniques; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prealbumin; Thyroxine-Binding Proteins; Zollinger-Ellison Syndrome

The long-acting somatostatin analog (octreotide) was administered to a 37-yr-old woman with the ectopic ACTH syndrome. The patient had diffuse metastatic spread of a nonpituitary tumor, presumably of pancreatic origin, and severe and rapidly progressive hypercortisolism with extreme myopathy, hypokalemia, and diabetes mellitus. Plasma ACTH and lipotropin levels and 24-h urinary cortisol excretion were greatly elevated [218 pg/mL (48 pmol/L), 1340 pg/mL (220 pmol/L), and up to 830 micrograms/24 h (2290 nmol/day), respectively]. Urinary cortisol excretion decreased to normal within 3 days after the initiation of octreotide therapy (150, 300, and 600 micrograms/day), and plasma ACTH and lipotropin levels also decreased. Urinary cortisol excretion remained normal for 2 months during chronic octreotide therapy, and her general condition improved dramatically. The only side-effect was a slight increase in the number of bowel movements. Tumor progression, however, was not controlled, and she eventually died of hepatic insufficiency. These data indicate that octreotide can be a highly effective treatment for patients with the ectopic ACTH syndrome.

Topics: ACTH Syndrome, Ectopic; Adrenocorticotropic Hormone; Adult; beta-Lipotropin; Female; Gastrins; Humans; Hydrocortisone; Neoplasms, Unknown Primary; Octreotide; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Saliva; Somatostatin

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

The 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

As part of a study to manage islet cell tumors in patients with multiple endocrine neoplasia (MEN), patients with MEN I and Zollinger-Ellison syndrome (ZES) underwent surgery if a pancreatic islet cell tumor was identified on imaging studies. Patients with MEN I and either insulinoma or vasoactive intestinal polypeptide tumor (VIPoma) underwent surgery whether or not a tumor was identified. Each patient underwent preoperative portal venous sampling (PVS). Nine patients with MEN I and one with MEN II underwent surgery; seven had ZES, one had insulinoma, one had VIPoma, and one had both insulinoma and ZES. Eight of the nine patients with MEN I had an identifiable hormone gradient on PVS. Islet cell tumors were removed from the pancreas of each patient; two patients also had duodenal wall tumors, and three patients had malignant islet cell tumors. No patient with ZES and MEN I was cured of ZES despite the fact that islet cell tumor was removed from the region of the gastrin gradient in five of six patients. The single patient with MEN II and ZES and the three additional patients with MEN I and either insulinoma or VIPoma were cured by islet cell tumor resection. The results indicate that islet cell tumors in patients with MEN I can be both extrapancreatic and malignant. In patients with MEN I and ZES, ZES cannot be cured by tumor resection, and PVS cannot be used to select patients for curative surgery. It appears that gastrinoma in patients with MEN II, as well as either insulinoma or VIPoma in patients with MEN I, can be cured by islet cell tumor resection.

Topics: Adenoma, Islet Cell; Adult; Biomarkers, Tumor; Fasting; Female; Follow-Up Studies; Gastrins; Humans; Insulin; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prospective Studies

In view of the trophic action of gastrointestinal hormones on the exocrine pancreas, the effects of secretin, octapeptide of cholecystokinin (CCK-8), and desglugastrin on the growth of hamster pancreatic well differentiated adenocarcinoma were investigated in vitro. Desglugastrin exhibited the greatest effect on thymidine incorporation into these cells after a lag period of 96 h. Doses of desglugastrin in the range from 30 to 270 ng/mL caused a significant and dose-dependent increase in thymidine incorporation. Higher doses of this peptide led to a decreased response. Secretin also increased thymidine incorporation, but the response was less than that induced by gastrin. Prolonged incubation with secretin for 96 h increased tritiated thymidine incorporation in a log-dose fashion in the range of 30 to 270 ng/mL. Doses of CCK-8 in the range of 90 to 810 ng/mL significantly increased thymidine incorporation after 48 h of incubation. Following 72 h of incubation, only the dose of 270 ng/mL continued to exhibit a significant stimulation. Our study suggests that the gastrointestinal hormones could directly increase the growth of pancreatic carcinoma cells, act synergistically with endogenous growth factors, or stimulate the local production of these factors. In any event, our results that gastrin, secretin, and CCK can stimulate the growth of pancreatic ductal tumor cells in tissue cultures, support earlier findings on normal and malignant pancreatic parenchyma.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Cell Cycle; Cell Line; Cricetinae; DNA Replication; DNA, Neoplasm; Gastrins; Kinetics; Molecular Sequence Data; Pancreatic Neoplasms; Secretin; Sincalide; Thymidine; Tritium

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

Over a five-year period, we measured concentrations of gut hormones in plasma samples from 353 patients in whom diagnoses of pancreatic endocrine tumors were subsequently confirmed. A median of 19 months (range, 7 to 120) after the initial diagnosis, 24 of these patients (6.8 percent) had elevated concentrations of other hormones in association with new clinical symptoms. In 13 of these patients (8 with glucagonomas, 3 with tumors secreting vasoactive intestinal polypeptide, and 2 with insulinomas), hypergastrinemia developed along with the clinical features of a gastrinoma; 5 patients died of gastrointestinal perforation or bleeding, apparently caused by this second tumor. We conclude that patients with pancreatic endocrine tumors, regardless of their initial clinical picture, require continued surveillance for new elevations of hormones.

Topics: Adenoma, Islet Cell; Adult; Aged; Gastrins; Gastrointestinal Hemorrhage; Glucagon; Glucagonoma; Hormones; Humans; Insulinoma; Middle Aged; Pancreatic Neoplasms; Time Factors; Vasoactive Intestinal Peptide; Vipoma; Zollinger-Ellison Syndrome

Signs and symptoms of Cushing's syndrome developed rapidly after total gastrectomy in a 37-yr-old man with a metastatic gastrin-secreting islet cell carcinoma. Argyrophilic tumor cells in a lymph node removed during operation immunostained for gastrin and ACTH. Treatment for more than 6 months with the somatostatin analog SMS 201-995 (300 micrograms/day) greatly reduced serum gastrin levels and normalized plasma ACTH and cortisol levels and urinary cortisol excretion, and the signs and symptoms of Cushing's syndrome disappeared. The size of the primary tumor in the head of the pancreas, which had grown rapidly before SMS 201-995 therapy, stabilized after 6 months of treatment with the analog. We conclude that SMS 201-995 can reduce ACTH as well as gastrin secretion from islet cell carcinomas as well as control tumor growth.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Gastrins; Hormones, Ectopic; Humans; Hydrocortisone; Male; Neoplasm Metastasis; Octreotide; Pancreatic Neoplasms

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

Acute effects of somatostatin analog (SMS 201-995) on pancreatic hormones were studied in two patients with malignant islet-cell carcinoma. Before and after subcutaneous injection of somatostatin with a doses of 50 micrograms, blood glucose (BG), serum growth hormone (hGH), C-peptide immunoreactivity (CPR), plasma immunoreactive glucagon (IRG) and gastrin were assayed, and changes in elution patterns of IRG and gastrin were also analyzed on Bio-Gel P-30 column chromatography. In Patient 1 with glucagonoma syndrome and hypergastrinemia, a prompt and remarkable decrease in plasma IRG and gastrin was observed after the injection of SMS 201-995 in association with a decrease in blood glucose, and then IRG and gastrin increased gradually. The suppressive effect continued for at least 6 hours. On gel filtration of the plasma obtained before the injection of the analog, three major peaks, greater than 20000, 9000 and 3500 molecular-weight (mol wt) fractions, were seen in IRG fraction. The decrease in plasma IRG observed at 1 hour after the injection was mainly due to a marked decrease in the 3500 molecular weight fraction. In addition, a slight decrease in the 9000 mol wt fraction was seen. At 4 hours after the injection, the 3500 mol wt peak returned to the previous level, while the 9000 mol wt peak decreased further. On the other hand, the gastrin elution pattern of plasma obtained before the injection revealed three major gastrin peaks, greater than 20000, 7000 and 5000 mol wt fraction. The changes in the gastrin elution pattern after the injection were similar to those of the IRG elution pattern. In Patient 2 with Zollinger-Ellison's syndrome, the plasma gastrin level decreased gradually for 5 hours after the injection. On gel filtration of the plasma obtained before the injection, two major gastrin peaks, 7000 and 5000 mol wt fraction, of which the large-molecular fraction was more prominent than the small-molecular fraction, were observed. After the injection, a marked decrease in the small-molecular fraction and a gradual decrease in the large-molecular fraction were observed for 4 hours, accompanied by a decrease in plasma gastrin. At 7 hours after the injection, the smaller fraction was augmented again. The serum CPR and hGH was slightly suppressed after the injection in both patients. The adverse effects of slight nausea and vomiting were noticed only in Patient 1.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Depression, Chemical; Female; Gastrins; Glucagon; Growth Hormone; Humans; Middle Aged; Octreotide; Pancreatic Hormones; Pancreatic Neoplasms

The symptoms resulting from the hyperinsulinemia of severe refractory metastatic insulinoma were palliated using self-administered divided doses of a long-acting minisomatostatin analog, octreotide. The substance was well tolerated and the attributable side effects were minimal (primarily gastrointestinal complaints). There were significant improvements in peripheral edema, ascites, and serum electrolytes throughout therapy. Serum insulin and glucagon levels were largely unchanged. Computed tomography scans performed during therapy showed stabilization of pancreatic and hepatic disease. Severe, recurrent hypoglycemic episodes due to hyperinsulinemia were reduced both in number and severity for almost a three-month period. This allowed the elimination or reduction of other chronic, supportive medications and improved quality of life.

Topics: Adenoma, Islet Cell; Antineoplastic Agents; Drug Resistance; Female; Gastrins; Glucagon; Humans; Insulin; Insulinoma; Middle Aged; Neoplasm Metastasis; Octreotide; Pancreatic Neoplasms; Somatostatin

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

A case of multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I (MEN I) is reported. The patient was a 41-year-old woman who had a past history of thyroid cancer (papillary carcinoma) and hyperparathyroidism due to parathyroid adenoma. Later, a nonfunctional pituitary tumor and five nonfunctional pancreatic tumors were found simultaneously and the patient was finally diagnosed as having MEN I. Following surgical enucleation, the pancreatic tumors were histopathologically diagnosed as benign islet cell tumors. One of them (tumor 3) exhibited a solid nodular pattern while the others showed gyriform patterns. They were divided histochemically and immunohistochemically into three types: two (tumors 1 and 2) produced a single hormone (glucagon), one (tumor 3) produced five (insulin, glucagon, somatostatin, gastrin and pancreatic polypeptide) and the remaining two (tumors 4 and 5) produced two (glucagon and pancreatic polypeptide). Electron microscopically, three types of endosecretory granules were found in the tumor cells of tumor 3 but only one type was found in tumor 4. However, in the tumor 4 extract, glucagon, pancreatic polypeptide, C-peptide, somatostatin, vasoactive intestinal peptide and growth hormone releasing factor were detected by radioimmunoassay. These findings suggest that these pancreatic tumors were both multicellular and multihormonal.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Gastrins; Glucagon; Growth Hormone-Releasing Hormone; Humans; Immunohistochemistry; Insulin; Microscopy, Electron; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Somatostatin; Vasoactive Intestinal Peptide

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

(Thr28,Nle31)CCK(23-33) (CCK-9) and gastrin(1-17)I (gastrin) inhibited adenylate cyclase activity in membranes from the tumoral rat pancreatic acinar cell line AR 4-2J through a Bordetella pertussis toxin-sensitive mechanism. This contrasted with the stimulatory effect exerted by CCK-9 on adenylate cyclase activity in membranes from normal rat pancreas. The relative potency of CCK-9, gastrin, and related peptides in inhibiting adenylate cyclase, when confronted with previous evidence, suggests that 'non-selective CCK-gastrin CCK-B receptors' predominating over 'selective CCK-A receptors' in the AR 4-2J cell line, favored the coupling of the first receptors to adenylate cyclase through Gi, while CCK-A receptors capable of stimulating the enzyme through Gs were detected only after Bordetella pertussis toxin pretreatment.

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclase Inhibitors; Animals; Cell Membrane; Cholecystokinin; Gastrins; Guanosine Triphosphate; Pancreas; Pancreatic Neoplasms; Pentagastrin; Peptide Fragments; Pertussis Toxin; Rats; Secretin; Tetragastrin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide; Virulence Factors, Bordetella

Nine patients with pancreatic apudomas (seven gastrinomas, one glucagonoma, one tumor secreting a substance P-like component) and nine with metastasized carcinoid tumors were treated with a somatostatin analogue (SMS 201-995), administered subcutaneously twice daily for 3 days. Treatment was pursued for 2 to 12 months in nine patients in whom SMS was clinically and/or biologically beneficial. In gastrinomas, SMS decreased plasma gastrin in all but one patient, inhibited the residual gastric acid secretion under H2-blockers and improved diarrhea; in the glucagonoma patient, glucagonemia decreased and skin lesions disappeared. In carcinoid syndrome, clinical efficacy was partial and inconstant; daily 5-hydroxyindole acetic acid (5-HIAA) output was slightly decreased. Plasma substance P levels decreased in six patients with initially high concentrations. No antitumoral activity or side effects have been so far evidenced. SMS 201-995 is a useful, well-tolerated agent in secreting pancreatic apudomas and to a lesser extent in carcinoid syndrome, where high-dosage regimens may be required.

Topics: Adult; Aged; Carcinoid Tumor; Female; Gastric Juice; Gastrins; Glucagonoma; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Somatostatin; Substance P; Zollinger-Ellison Syndrome

Topics: Adult; Carcinoid Tumor; Female; Gastrins; Glucagon; Glucagonoma; Humans; Hydroxyindoleacetic Acid; Male; Middle Aged; Pancreatic Neoplasms; Serotonin; Somatostatin; Zollinger-Ellison Syndrome

A tissue specimen taken from the pancreatic tumor of a patient suffering from Zollinger-Ellison syndrome associated with a concurrent Cushing's syndrome was investigated both morphologically and immunohistochemically. Histologically, the tumor cells were found to be arranged in a cord or ribbon pattern. An immunohistochemical study revealed that the tumor nodule contained both gastrin and ACTH. Further, double stainings of the same section disclosed that the same tumor nodule possessed both hormones simultaneously, thus confirming the concurrent presence of Zollinger-Ellison syndrome and Cushing's syndrome. An electron micrograph of the tumor cell showed the presence of numerous endocrine-type granules in the cytoplasm. These findings substantiate the concurrent presence of the two characteristic clinical syndromes.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Gastrins; Humans; Male; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Immunocytochemical studies of the distribution of glucagon, gastrin, insulin, and somatostatin in normal canine pancreatic islets and 20 canine islet cell tumors were done using the peroxidase-anti-peroxidase (PAP) technique. In the normal adult canine pancreas, islets typically consisted of clusters of 20-30 cells, but smaller foci and even individual cells were identified. Alpha cells (glucagon) were often peripherally located, beta cells (insulin) were centrally located and most numerous, and delta cells (somatostatin) were the least numerous and randomly located. Both juvenile and adult canine pancreases did not stain for gastrin. Of the 20 tumors examined, 18 had positive immunoreactivity for insulin, nine for glucagon, 14 for somatostatin, and one for gastrin. Two tumors were uninterpretable due to autolysis. Three tumors were pure insulinomas, but no pure somatostatinomas, glucagonomas, or gastrinomas were identified. Most tumors and metastases had mixed positive immunoreactivity; one neoplastic cell type predominated with lesser numbers of other cell types. Metastatic sites (liver and lymph node) stained for insulin and somatostatin, only. Foci of non-neoplastic islet cell tissue (nesidioblastosis), often located at the pancreatic-mesenteric junction, stained strongly positive for insulin, glucagon, and somatostatin but not for gastrin. The tumor staining pattern did not consistently correlate with tumor function, as determined by blood glucose and serum insulin assays. The PAP technique works well on paraffin-embedded, formalin-fixed tissue using rabbit or guinea pig antisera as the primary antibody. Staining occurred on sections of paraffin blocks stored for up to 7 years.

Topics: Adenoma, Islet Cell; Animals; Dog Diseases; Dogs; Female; Gastrins; Glucagon; Immunoenzyme Techniques; Insulin; Islets of Langerhans; Male; Pancreatic Neoplasms; Retrospective Studies; Somatostatin

Medical treatment of the Zollinger-Ellison syndrome has been generally accepted because of the proven efficacy of the histamine (H2)-receptor antagonists in achieving symptomatic relief, and because of early reports indicating that few, if any, gastrinomas were resectable for cure. Gastrin radioimmunoassay (RIA) has made earlier and more certain diagnosis possible, and therefore reevaluation of the surgical management of gastrinomas is necessary. Experience with 60 gastrinoma patients is reported. Comparison between the pregastrin RIA years (before 1970) and post-gastrin RIA years was made to determine whether there was evidence to support the continuation of medical treatment without attempts to resect the gastrinoma. Twenty-five cases were diagnosed in the pre-RIA years. Age at diagnosis ranged from 17 to 68 years (median, 45 years). All patients were operated on. Metastases were found in 56 percent. No tumor was identified in 8 percent. Tumor was resected for "cure" (normal fasting gastrin levels for two years postoperatively) in one patient. Seventeen patients have died, and tumor was the cause of death in 70 percent. The five-year survival rate was 44 percent; the 10-year survival rate was 40 percent. Thirty-five cases were diagnosed after 1970. Age at diagnosis ranged from 39 to 61 years (median, 46 years). Thirty patients were operated on. Metastases were identified in 23 percent and no tumor was found in 17 percent. Tumor was resected for "cure" in 30 percent of patients. Seven patients have died and tumor caused death in 42 percent. The five-year survival rate was 82 percent; the 10-year rate was 64 percent. Advances in diagnosis and surgical technique since 1970 have made early operative treatment applicable in patients with gastrinoma. Because death in most cases is caused by progression of the tumor, an aggressive surgical approach to resect the tumor is advised soon after the diagnosis of Zollinger-Ellison syndrome is established.

Topics: Duodenal Neoplasms; Follow-Up Studies; Gastrins; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prognosis; Radioimmunoassay; Zollinger-Ellison Syndrome

Topics: Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Radionuclide Imaging; Somatostatin; Zollinger-Ellison Syndrome

Thirty-one primary canine pancreatic endocrine tumors and their metastases were studied histologically and immunohistochemically for the presence of insulin, glucagon, somatostatin, pancreatic polypeptide (PP), gastrin, and adrenocorticotrophic hormone (ACTH). Tumors were also evaluated for the presence of amyloid. The cytoarchitectural pattern of 25 of 31 primary tumors was predominantly solid, whereas three tumors were mostly glandular, two were unclassified, and one had a gyriform pattern. Cells with insulin immunoreactivity were found in 30 of 31 tumors and were found in all cases in which there was clinical evidence of inappropriate insulin secretion. Insulin was the only hormone demonstrable in three of the 30 tumors, but cells immunoreactive for other hormones were also present in various combinations in most tumors [i.e., glucagon (13 of 30), somatostatin (17 of 30), PP (25 of 30), and gastrin (2 of 30)]. One tumor contained only cells with glucagon and PP immunoreactivity. Amyloid was found in ten of 31 primary tumors but was not detected in metastases. Cells with insulin immunoreactivity were the only cell type consistently present in tumors containing amyloid. Amyloid deposits did not immunoreact with any of the antisera. Seventeen of 31 dogs had metastasis of the pancreatic endocrine tumor to regional lymph nodes, liver, or both. All metastases available for study (15 of 17) contained cells with insulin immunoreactivity and some contained cells with PP or somatostatin immunoreactivity. No statistically significant (P greater than 0.05) differences in tendency to metastasize were found when pancreatic endocrine tumors were compared by region of origin, cytoarchitectural pattern, presence of amyloid, or by number of hormones contained within the tumor.

Topics: Adrenocorticotropic Hormone; Amyloid; Animals; Dog Diseases; Dogs; Female; Gastrins; Glucagon; Histocytochemistry; Immunoenzyme Techniques; Insulin; Male; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Retrospective Studies; Somatostatin

A patient with metastatic islet cell carcinoma demonstrated multiple clinical syndromes simultaneously with secretion of ACTH, gastrin, glucagon, and serotonin. Hepatic arterial embolization resulted in an initial decrease in all secretory products, which was sustained for glucagon and serotonin. Recrudescence of the Cushings and Zollinger-Ellison syndrome was managed by surgical extirpation of the primary tumor and regional metastases as well as bilateral adrenalectomy. Electron microscopy and immunocytochemistry of the primary tumor and the metastatic lesions revealed the presence of multiple types of granules within single cells and, different patterns of secretory profiles in different tumor sites.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Female; Gastrins; Glucagon; Humans; Liver Neoplasms; Microscopy, Electron; Neoplasm Metastasis; Pancreatic Neoplasms; Tomography, X-Ray Computed

Topics: Adult; Gastrins; Hormones, Ectopic; Humans; Insulin; Liver Neoplasms; Male; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

A pancreatic tumor that displayed bihormonal activity is described: the tumor elaborated insulin, resulting in a hyperinsulinism syndrome (spontaneous hypoglycemia) as well as a second hormone, apparently gastrin or a gastrin-like polypeptide, which led to the development of Zollinger-Ellison syndrome. The presence of these two syndromes complicated both the diagnosis and treatment of the disease. A histologic examination using an argyrophilic (Grimelius) reaction confirmed that the tumor had originated from endocrine cells of the gastrointestinal tract and was a bihormonal apudoma of the pancreas.

Topics: Apudoma; Female; Gastrins; Insulin; Insulin Secretion; Pancreatic Neoplasms

Secretin was injected into a feeding or nonfeeding artery of a gastrinoma and blood samples were taken from the hepatic vein (HV) or a peripheral artery (PA) to measure the changes of serum immunoreactive gastrin concentration (IRG). The IRG in the HV rose within 40 seconds and in the PA rose within 60 seconds after the injection of secretin into a feeding artery, but not after secretin was injected into a nonfeeder. These results indicated that secretin directly stimulates a gastrinoma to release gastrin in vivo. The selective arterial secretin injection test (SASI test) was applied in three patients in whom gastrinomas could not be located by computed tomography, ultrasonography, or arteriography, and functioning gastrinomas were located in all three patients. In one patient, malignant gastrinomas in the head of the pancreas and in the duodenum could be resected radically with the help of this test.

Topics: Adult; Aged; Angiography; Duodenal Neoplasms; Female; Gastrins; Histocytochemistry; Humans; Insulin; Laparotomy; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

The role of endogenous gastrin in the pathogenesis of "idiopathic" ulcer disease is difficult to determine; however, gastrin is probably only of limited importance besides various probable more important factors. In conditions associated with uncontrolled gastrin production by a gastrin secreting tumor or in cases in which the feedback regulation between gastrin release and intragastric pH is disturbed severe and recurrent ulcers may develop. Radioimmunological determination of serum gastrin levels enable to identify such cases of ulcer disease due to an excess of circulating gastrin.

Topics: Gastric Acid; Gastrins; Humans; Pancreatic Neoplasms; Peptic Ulcer; Recurrence; Zollinger-Ellison Syndrome

Pancreatic specimens of nine patients suffering from multiple endocrine neoplasia type I (MEN I) were investigated with regard to tumor frequency and growth pattern, islet hyperplasia and endocrine cell neoformation, immunocytochemical hormone profile of the tumors, and correlation to clinical symptoms. The majority of the 201 tumors were microadenomas (diameter less than 0.5 cm), which frequently displayed a trabecular growth pattern. Microadenomatosis was considered the most distinct feature of the MEN I pancreas. Additional larger tumors (diameter greater than 1.0 cm) were found in five patients. Whereas islet hyperplasia appears not to belong to the spectrum of the pancreatic lesions in MEN I, nesidioblastosis was occasionally observed. Immunocytochemical screening revealed that among hormone-positive tumors (approximately 80% of the tumors), pancreatic polypeptide tumors (PPomas), glucagonomas, and insulinomas were the most frequent. The high incidence of PPomas in these pancreases probably accounts for the elevated serum PP levels found in many MEN I patients. Somatostatinomas, gastrinomas, vasoactive intestinal polypeptide tumors (VIPomas), and neurotensinomas were rare. Clinically overt hyperinsulinism, observed in two patients and associated with a large insulinoma, was cured by tumor resection. Eight of nine patients presented a Zollinger-Ellison's syndrome (ZES), but only in two patients were gastrin-producing tumors found. The source of gastrin in MEN I patients with a ZES, in whom no gastrinoma could be detected, remains unclear.

Topics: Adult; Aged; Female; Gastrins; Glucagon; Histocytochemistry; Hormones; Humans; Immunoenzyme Techniques; Insulin; Male; Middle Aged; Multiple Endocrine Neoplasia; Neurotensin; Pancreatectomy; Pancreatic Neoplasms; Pancreatic Polypeptide; Pancreatitis; Somatostatin; Staining and Labeling

Determination of gastrointestinal hormones by radioimmunoassay in plasma is important for detection of endocrine-active tumours in the gut. Since in most cases multiple endocrine tumours occur, a variety of hormones such as gastrin, vasoactive intestinal polypeptide, glucagon, somatostatin, pancreatic polypeptide and neurotensin should be measured. Gastrin is helpful as a diagnostic tool in differentiating between Zollinger-Ellison syndrome and antral G-cell hyperplasia or hyperfunction. Autonomic neuropathy of the gut (as in diabetics) can be detected by measurements of plasma pancreatic polypeptide. The diagnostic value of measurements of plasma cholecystokinin, secretin and other gut peptide hormones is not yet defined.

Topics: Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Somatostatin; Vasoactive Intestinal Peptide

Between 1971 and 1983, 31 males and 13 females were found to have peptic ulceration associated with hypergastrinaemia. An antral G-cell lesion was present in 11 (25 per cent) and a gastrinoma in 14 (32 per cent). There were 11 patients with multiple endocrine adenomatosis (MEA) (25 per cent) and 4 (9 per cent) with primary hyperparathyroidism. Four patients (9 per cent) were unclassified. Length of history and level of gastrin did not differentiate between the groups and an average of 2.5 operations was performed per patient, while the overall mortality was 27.3 per cent. The patients with G-cell lesions were significantly younger than all the other groups (P less than 0.01). Partial gastrectomy adequately treated G-cell hyperplasia. Total gastrectomy was required to treat pancreatic gastrinomata but additional pancreatic resection did not improve the outcome. In MEA, parathyroidectomy did not influence the treatment of a gastrinoma. This is the first recorded experience of surgery for hypergastrinaemia in the United Kingdom and the outcome of such a retrospective study may be a guide to the future management of these conditions.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Female; Gastrectomy; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatectomy; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Blood Glucose; Female; Gastrins; Humans; Insulinoma; Male; Octreotide; Pancreatic Neoplasms; Somatostatin; Vipoma; Zollinger-Ellison Syndrome

Acromegaly is rarely caused by the ectopic secretion of growth hormone releasing factor (GRF) from peripheral neuroendocrine tumours. We evaluated the ability of a recently developed somatostatin analogue (SMS 201-995, Sandoz) to reduce hormone levels and pituitary size in a young woman with acromegaly and Zollinger-Ellison syndrome secondary to a metastatic pancreatic islet cell tumour secreting GRF and gastrin. Gastrin, GRF, and growth hormone (GH) levels declined dramatically following the initiation of therapy with the analogue by continuous iv infusion. Although intermittent sc therapy was not effective in suppressing hormone levels, continuous sc infusion of SMS 201-995 has provided good control of both GRF and GH levels for nine months. Moreover, treatment with SMS 201-995 was associated with a substantial reduction in pituitary enlargement and an improvement in her gastric symptoms. Continuous sc infusion of SMS 201-995 may be useful in treating enlarged pituitaries resistant to other modes of therapy.

Topics: Acromegaly; Adenoma, Islet Cell; Adult; Female; Gastrins; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Octreotide; Pancreatic Neoplasms; Somatostatin; Zollinger-Ellison Syndrome

Topics: Animals; Carcinoma; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Humans; Neoplasms, Hormone-Dependent; Pancreatic Neoplasms; Pentagastrin; Receptors, Cell Surface

Topics: Adenoma, Islet Cell; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Insulinoma; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The effects of coffee on exocrine pancreatic secretion are unknown but may be important, because a link between chronic stimulation of pancreatic secretion and experimental chemical carcinogenesis and an association between coffee drinking and human pancreatic adenocarcinoma have been reported. We measured exocrine pancreatic trypsin and gastric acid secretions collected through orogastroduodenal tubes and serum gastrin in eight non-coffee drinkers and eight coffee drinkers. During fasting, after one interdigestive cycle control period, one of four 250-ml samples [plain water, water plus caffeine (4.6 mg/kg), decaffeinated coffee (127.9 mg/kg), caffeinated coffee (127.9 mg/kg)] was administered through the orogastric tube. Caffeinated and decaffeinated coffee (p = 0.008), caffeine (p = 0.03), and an unidentified substance(s) in coffee other than caffeine (p = 0.008) were associated with increased interdigestive exocrine pancreatic trypsin secretion. In addition, we also confirmed that coffee and caffeine stimulated gastric acid secretion (p = 0.02) and decaffeinated coffee raised serum gastrin concentrations (p = 0.005). If an association between coffee and pancreatic carcinogenesis exists, chronic stimulation of the exocrine pancreas by secretagogues could result in a gland susceptible to carcinogenesis.

Topics: Adenocarcinoma; Adult; Caffeine; Coffee; Fasting; Female; Gastric Acid; Gastrins; Humans; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Trypsin

A patient with documented metastatic islet cell carcinoma of the pancreas and Zollinger-Ellison syndrome, with regression of tumor after total gastrectomy is described. Pertinent similar cases are summarized further suggesting that gastrectomy may have a role in the management of the tumorous as well as the acid-secretory features of this disease.

Topics: Aged; Female; Gastrectomy; Gastrins; Humans; Pancreatic Neoplasms; Postoperative Period; Zollinger-Ellison Syndrome

Acid and gastrin production after pyloric-preserving pancreaticoduodenectomy was evaluated in six patients. Five patients had low-normal basal and stimulated acid output; the sixth patient was achlorhydric. Fasting gastrin levels were less than 90 to 105 pg/mL (normal range) in five patients, three of whom had stimulated gastrin levels that remained below this range. Two patients had stimulated gastrin levels of 510 pg/mL and 205 pg/mL, respectively, within 15 minutes of eating; however, both levels returned to normal by 120 minutes' time. The sixth patient had mildly elevated fasting (105 pg/mL) and stimulated gastrin levels (160 to 200 pg/mL) throughout the test period. The results suggest that pyloric-preserving pancreaticoduodenectomy does not lead to either gastric hyperacidity or persistent hypergastrinemia.

Topics: Achlorhydria; Duodenum; Female; Gastric Acidity Determination; Gastrins; Humans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis; Pylorus; Radioimmunoassay

Topics: Diagnosis, Differential; Duodenal Ulcer; Gastrectomy; Gastrins; Humans; Male; Microscopy, Electron; Middle Aged; Pancreas; Pancreatic Neoplasms; Postoperative Complications; Zollinger-Ellison Syndrome

Topics: Animals; Cholecystokinin; Gastric Mucosa; Gastrin-Releasing Peptide; Gastrins; Gastrointestinal Neoplasms; Humans; Neurotransmitter Agents; Pancreas; Pancreatic Neoplasms; Peptides; Protein Conformation; Pyloric Antrum; Somatostatin; Vasoactive Intestinal Peptide

The largest-known family tree of a kindred with multiple endocrine neoplasia type I, dating back to 1840, has been constructed in Tasmania. There are over 600 descendants of one English migrant and his spouse living today. Preliminary data suggests that overall, one-quarter of all family members, and one-half of those above the age of 40 manifest one or more endocrine tumours. In the majority of cases, the diagnosis was not suspected until the general practitioner was informed of the family history, as the symptoms are vague, sometimes bizarre, and overlap with those of common disorders.

Topics: Adult; Aged; Child; Female; Gastrins; Humans; Hypercalcemia; Hypertension; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms; Prolactin

Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy.

Topics: Adult; Aged; Diarrhea; Female; Gastrins; Glucagon; Humans; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptide PHI; Peptides; Somatostatin; Vasoactive Intestinal Peptide

Examples of mucinous tumors from retroperitoneum (2) and pancreas (1) were studied. These tumors share many morphological similarities with ovarian mucinous tumour and adenoma malignum of uterine cervix. They have a similar spectrum of endocrine cells; serotonin, somatostatin, gastrin and pancreatic polypeptide cells were characterized. In nonproliferative areas was found a well-differentiated mucinous columnar epithelium with scarce endocrine cell. In more proliferative areas were found either a mucinous columnar lining with infolds and secondary glands or a less well-differentiated intestinal-type epithelium with papillary formations; both linings were well supplied in endocrine cells.

Topics: Adenocarcinoma; Adult; Endocrine Glands; Epithelium; Female; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Humans; Ovarian Neoplasms; Pancreatic Neoplasms; Pancreatic Polypeptide; Retroperitoneal Neoplasms; Serotonin; Somatostatin; Uterine Cervical Neoplasms

A patient presenting clinically with the glucagonoma syndrome had high plasma glucagon levels (1920 ng/l) and at laparotomy, a pancreatic islet cell tumour was removed. The tumour was dispersed and placed in culture where it remained viable for 63 days. The tumour cells secreted immunoreactive (IR) glucagon at levels up to 2400 ng/l as detected by a C-terminal glucagon specific antibody and 85 400 ngequiv./l as measured by an N-terminal glucagon specific antibody. The difference between these two levels was attributed to the presence of different molecular forms of glucagon measured with the N-terminal specific antibody. IR insulin (up to 302 mU/l) and IR somatostatin (up to 2500 ng/l) were also detected. There was no direct or inverse correlation between different hormone levels. Small but significant levels of N-terminal and C-terminal vasoactive intestinal peptide (VIP) were detected in some cultures but there was no evidence of gastrin or ACTH. Glucagon and somatostatin secretion persisted for the duration of the culture (63 days) but insulin concentrations declined. Incubation of cultures with somatostatin (1 ng/ml) caused a 75% decrease in glucagon levels, while insulin (1000 mU/l) produced a 70% inhibition of somatostatin.

Topics: Adenoma, Islet Cell; Cells, Cultured; Female; Fluorescent Antibody Technique; Gastrins; Glucagon; Glucagonoma; Humans; Immunoenzyme Techniques; Insulin; Insulin Secretion; Kinetics; Middle Aged; Neurotensin; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide

We studied a patient with a very small somatostatinoma that arose from the prominence of the orifice of the duct of Santorini. The patient presented clinically with epigastric discomfort, marked loss of weight, diarrhea, exertional dyspnea, and chest pain. He flushed intermittently and had occasional tachycardia and hypertension. Levels of serum serotonin and urinary 5-hydroxyindoleacetic acid were normal. A small ampullary tumor was resected and identified by immunohistochemical staining to be a somatostatinoma. The patient had gained 6.75 kg and was essentially free of symptoms 16 months after surgery.

Topics: Adenoma, Islet Cell; Gastrins; Humans; Male; Middle Aged; Neoplastic Stem Cells; Pancreatic Ducts; Pancreatic Neoplasms; Serotonin; Somatostatin; Somatostatinoma

A patient with a calcifying chronic pancreatitis was found to have a neuroendocrine islet cell tumour (a previously unreported association). The tumour secreted both gastrin and ACTH leading to clinical manifestations of both the Zollinger-Ellison syndrome and Cushing's syndrome.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Aged; Calcinosis; Chronic Disease; Gastrins; Humans; Male; Pancreatic Neoplasms; Pancreatitis; Zollinger-Ellison Syndrome

One hundred twenty-seven insulinomas from 95 cases (1 malignant and 94 benign) were studied pathologically. Thirty-six tumors (35 cases) were examined by electron microscopy. Typical beta-cell secretory granules of crystalloid-form cores and/or atypical secretory granules were discerned in all tumors examined. A new type of secretory granule, with high electron-dense crystalloid-form cores and moderate electron-dense granular substance filling the space between the core and the limiting membrane, were observed in two cases. Among 68 insulinomas (67 cases) subjected to immunocytochemical investigations with ten peptide hormones (insulin, glucagon, somatostatin, pancreatic polypeptide (PP), gastrin, motilin, secretin, vasoactive intestinal polypeptide (VIP), gastric inhibitory polypeptide (GIP), and neurotensin), 42 were found to be multihormonal, varying from two to four peptides secreted. The hormones contained were insulin, glucagon, PP, somatostatin, and gastrin in different combinations. One patient had hyperinsulinemia and hypergastrinemia concurrently, and two islet tumors were excised at an interval of 10 months. Both electron microscopy and immunocytochemistry confirmed the presence of beta- and alpha-cells in the first tumor, whereas the second tumor revealed only G-cells by electron microscopy, and G- and beta-cells on immunocytochemical staining. The morphologic and immunocytochemical characteristics of the insulinomas in this series are discussed.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Cytoplasmic Granules; Female; Gastrins; Hormones; Humans; Immunoenzyme Techniques; Insulin; Insulinoma; Male; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms

The case history of a patient with an islet cell carcinoma, which produced both gastrin and vasoactive intestinal polypeptide (VIP), is presented. Although several examples have been observed of the combined production of these hormones by pancreatic endocrine tumors, few reports have related the clinical details of such cases. Resolution of diarrhea occurred in our patient after institution of nasogastric suction and cimetidine therapy, suggesting that gastric hypersecretion, rather than VIP activity, accounted for this problem. Chemotherapy with streptozotocin and 5-fluorouracil was highly effective in ameliorating clinical symptoms, diminishing serum levels of gastrin and VIP, and greatly reducing the bulk of metastatic disease in this case.

Topics: Adenoma, Islet Cell; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Gastrins; Humans; Middle Aged; Pancreatic Neoplasms; Streptozocin; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Dacarbazine; Gastrins; Glucagon; Humans; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

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

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

Dispersed single-cell suspensions of human gastrinoma tissue were incubated for 15, 60, and 120 min in a calcium-containing medium, (0.1, 2, 10 mM) in calcium-free medium and in calcium-free medium containing the calcium ionophore A23187 (0.01, 1, and 100 micrograms/ml). Supernatant and pellet (intracellular) gastrin levels were determined by radioimmunoassay. Supernatant gastrin levels remained stable over 120 min in calcium chloride or calcium gluconate containing medium, while intracellular pellet gastrin approximately tripled during the same incubation period. Total gastrin (supernatant plus pellet) approximately doubled during the 2-hr incubation in calcium. However, calcium (0.1, 2, or 10 mM) failed to produce a dose-dependent rise in supernatant, pellet, or total gastrin when compared to calcium-free incubates. Contrary to the expected gastrin response to calcium, supernatant and pellet gastrin levels were higher in incubates in calcium-free medium than in calcium-containing incubates. A23187 (0.01 or 1 mcg/ml) in a calcium-free medium decrease supernatant gastrin while high dose ionophore (100 mcg/ml) increased supernatant gastrin. All doses of ionophore stimulated pellet and total gastrin levels. Thus, it appears that the clinical augmentation of gastrin levels, seen with calcium challenge in vivo may not be solely due to changes in serum calcium.

Topics: Adult; Calcimycin; Calcium; Cytological Techniques; Gastrins; Humans; Male; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

In vitro studies have demonstrated that secretin can stimulate the release of parathyroid hormone (PTH), but reports concerning its effects on PTH and calcium in vivo are contradictory. To examine this question further, a bolus injection of secretin (75 IU) was given to 12 normal subjects and 10 patients with primary hyperparathyroidism (HPT). Six of the patients had multiple endocrine neoplasia and five had endocrine pancreatic tumours (EPT). Three normocalcaemic patients with EPT were also included in the study. The mean serum gastrin level rose significantly (from 19 to 40 pmol/l, p less than 0.01) within 15 min of secretin injection in the normal subjects. HPT patients without EPT had a somewhat higher mean basal level of gastrin (39 pmol/l, p less than 0.05 compared with controls), but it did not increase significantly after the secretin bolus. In six EPT patients the gastrin concentrations rose by more than 300 pmol/l. Although secretin had a biological capacity to release gastrin, it had no discernible effects on either serum PTH or serum calcium in any of the groups studied. Nor were any changes in PTH or calcium observed when secretin was given as a continuous infusion (3 IU/kg/h) over 90 min. Thus, our data do not support the concept that secretin, in vivo, is a secretagogue of PTH.

Topics: Adult; Aged; Calcium; Female; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Parathyroid Glands; Parathyroid Hormone; Secretin; Zollinger-Ellison Syndrome

Topics: Adult; Gastrins; Humans; Male; Neoplasms, Multiple Primary; Pancreas; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

A young woman with acromegaly and Zollinger-Ellison syndrome associated with a GH-releasing factor (GRF)- and gastrin-secreting metastatic islet cell carcinoma was studied by means of specific antisera which recognize various regions of the GRF molecule. Using specific immunohistochemical techniques, the tumor cells were shown to contain GRF, gastrin, and gastrin-releasing peptide, but not GH. During a 4-h period, plasma GRF levels averaged 5.6 +/- 1.4 ng/ml (+/- SD), while GH levels averaged 148 +/- 71 ng/ml. GH secretion was pulsatile and increased after TRH administration. GRF RIAs may be useful in establishing the diagnosis of acromegaly secondary to the ectopic secretion of GRF.

Topics: Acromegaly; Adenoma, Islet Cell; Adult; Female; Gastrins; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Zollinger-Ellison Syndrome

37 patients suffering from apudomas of the pancreas are reported (18 insulinomas, 6 isletcell-hyperplasias, 9 Zollinger-Ellison syndroms, 1 glucagonoma, 3 without hormone production). In preoperative localization computerized tomography and angiography were the best with 65% positive findings. Insulinomas were enucleated, all free of recidives. 50% of operated isletcell hyperplasias had a postoperative resisting hyperinsulinism. Either gastrectomy or tumour enucleation was performed in the Zollinger-Ellison syndrome. The five-years survival rate was 43%.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Child; Female; Follow-Up Studies; Gastrectomy; Gastrins; Glucagon; Humans; Hyperplasia; Insulin; Insulinoma; Islets of Langerhans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Stomach Neoplasms; Zollinger-Ellison Syndrome

Four cases involving cystic endocrine neoplasms of the pancreas and liver are reported. Because of their rich collateral blood supply, islet cell tumors of the pancreas, even if large in size, rarely undergo central or cystic degeneration. However, failure to appreciate that a small percentage of these neoplasms may mimic benign pancreatic pseudocysts by their clinical and radiological appearance can lead to inappropriate surgical therapy. Ultrasound, computerized tomography, and/or angiography are rarely helpful in distinguishing between benign and neoplastic cysts. The definitive diagnosis can be made with assurance only by obtaining a generous biopsy of the cyst wall or any intracystic excrescences for histologic examination. Functional cystic tumors of the pancreas or liver should be excised totally whenever possible, and efforts should be made to remove as much of the tumor mass as possible even when a curative resection cannot be accomplished. Internal drainage may be acceptable as palliation for large, unresectable tumors.

Topics: Adenoma, Islet Cell; Adult; Cysts; Diagnosis, Differential; Female; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Cyst; Pancreatic Neoplasms; Tomography, X-Ray Computed

A case of somatostatin and pancreatic polypeptide (PP) producing tumor of the pancreas is presented. A 65-year-old woman was admitted for the evaluation of the tumor in the right upper quadrant of the abdomen. Clinical abnormalities included diabetic glucose intolerance, pancreatic insufficiency and marked dilatation of gallbladder. Marked high concentration of plasma PP and low levels of plasma insulin and glucagon were observed before operation. Plasma insulin concentrations in response to oral glucose tolerance test and arginine infusion were markedly low. A large quantity of somatostatin (4,300 ng/g ww) as well as PP (1,340 ng/g ww) was detected in the tumor, and somatostatin cells and PP cells were determined by immunofluorescence studies. After operation, pancreatic insufficiency and glucose intolerance were improved, and the patient made a favorable progress.

Topics: Aged; Female; Gastrins; Glucagon; Growth Hormone; Hormones; Humans; Insulin; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin

Topics: Adenoma, Islet Cell; Adult; Female; Gastrins; Glucagon; Humans; Hyperplasia; Islets of Langerhans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Serotonin; Somatostatin; Staining and Labeling; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

The role of radioimmunoassay (RIA) in the diagnosis and management of endocrine tumors, such as pituitary tumors, insulinomas, and gastrinomas, has long been well established. A variety of nonendocrine tumors are capable of elaborating one or more humoral substances that resemble immunologically well-known, well-characterized biologically active hormones or their prohormone precursors or metabolic products. The possible value of mass screening for carcinoma of the lung by the detection of precursor adrenocorticotropic hormone (ACTH) in plasma was tested. However, the usefulness was limited by the potential for false-positive, i.e., elevation of marker concentration in the plasma of heavy smokers even in the absence of invasive carcinoma. Although on occasion a dramatic decrease of plasma ACTH after surgical resection or on some chemotherapeutic schedules has been observed, this does not occur with sufficient regularity to serve definitely as an objective measure of efficacy of therapy. The limitations of nonhormonal tumor markers, such as carcinoembryonic antigen (CEA), are also considered.

Topics: Adrenocorticotropic Hormone; Animals; Diagnosis, Differential; Endocrine System Diseases; Gastrins; Humans; Insulin; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Pituitary Neoplasms; Radioimmunoassay; Zollinger-Ellison Syndrome

Histochemical, chemical and clinical features of two malignant endocrine pancreatic tumors were studied. Both tumors contained pancreatic polypeptide (PP)-immunoreactivity in the majority of tumor cells. In addition, one tumor contained a few scattered serotonin-fluorescent cells and the other scattered gastrin-immunoreactive cells. Pancreatic polypeptide hypersecretion was established from both tumors. Serotonin was produced by one tumor and gastrin was secreted by the other. No PP-associated endocrine symptoms were present, whereas the hypergastrinemia may have caused a bleeding duodenal ulcer in one patient. Although both tumors were highly malignant the clinical courses in the two patients were very different; one patient died within a few months whereas the other is alive 2 years after the diagnosis.

Topics: Adult; Female; Fluorescent Antibody Technique; Gastrins; Humans; Immunoenzyme Techniques; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Serotonin

A method for measurement of gastrin in human antral mucosa or in extragastric tissue has been developed and validated. Tissue gastrin was extracted by boiling followed by homogenization at neutral pH. Extractable gastrin immunoreactivity was measured by radioimmunoassay using an antiserum with equal affinity towards G-17 I, G-17 II, G-34 I and G-34 II molecular forms. Almost all extractable gastrin immunoreactivity was recovered after a single extraction and no significant interference by other peptides and/or substances present in tissue was found. The mean gastrin concentration in antral mucosa of healthy subjects was similar to that observed in duodenal ulcer patients, while patients with type A chronic atrophic gastritis or with antral gastrin cell hyperplasia had mean values significantly higher. Gastrin concentration in all specimens from gastrinoma or its metastases was above the upper limit of the range of control tissue. Measurement of tissue gastrin seems to be a valuable tool in the diagnosis of antral gastrin cell hyperplasia and Zollinger-Ellison syndrome.

Topics: Adolescent; Adult; Aged; Cholecystitis; Chronic Disease; Duodenal Ulcer; Female; Gastric Mucosa; Gastrins; Gastritis; Humans; Hyperplasia; Male; Middle Aged; Pancreatic Neoplasms; Pyloric Antrum; Zollinger-Ellison Syndrome

Operative experience with 45 gastrinoma patients has led to the identification of an anatomic area where occult tumors can be discovered and where excision of these tumors had led to apparent cure. Of 36 patients with histologically confirmed gastrinomas, 27 patients (75 percent) had obvious and 9 patients (25 percent) had occult tumors. All nine occult lesions were found within an anatomic triangle defined by the junction of the cystic and common bile ducts superiorly, the junction of the second and third portions of the duodenum inferiorly, and the junction of the neck and body of the pancreas medially. Although occult tumors from three patients (in the lymph nodes in two patients and in the duodenum in one patient) were removed primarily for histologic diagnosis, postoperative serum gastrin levels have remained within the normal range (follow-up of 86 to 99 months). Two patients had excision of the tumor with intent to cure. One patient with a solitary duodenal tumor was apparently cured but committed suicide 3 months postoperatively. The other patient had both obvious primary and occult metastatic tumors within the triangle and was eugastrinemic 9 months after excision. In all patients in whom tumor was found, it was locally excised, and no patient was subjected to radical pancreatic resection. There were no postoperative complications related to tumor removal. An aggressive approach towards curative tumor excision is now advocated for all gastrinoma patients who are suitable operative risks and have no evidence preoperatively of liver metastases or the multiple endocrine neoplasm-type I syndrome.

Topics: Biopsy; Duodenal Neoplasms; Follow-Up Studies; Gastrins; Humans; Liver Neoplasms; Lymphatic Metastasis; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The kinetics of secretion of gastrin and secretin before and after pancreaticoduodenectomy were studied. Prior to pancreaticoduodenectomy, gastrin secretory function was within the normal range; it was significantly reduced postoperatively. Preoperatively, patients had elevated basal levels of secretin with depressed reactivity. During pancreaticoduodenectomy, the upper part of the jejunum should be preserved as far as possible. Ulcers occurring after pancreaticoduodenectomy are more probably due to vagus nerve activity and other factors rather than to an imbalance between gastrin and secretin.

Topics: Adult; Aged; Arginine; Duodenum; Gastrectomy; Gastrins; Humans; Jejunum; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Postoperative Period; Secretin

Exploratory laparotomy and a search for gastrinomas was performed in 52 patients with the Zollinger-Ellison syndrome (ZES). Gastrinoma tissue was resected in 11 patients (21%), 6 (12%) of whom appear to have been cured. After surgery, serum gastrin levels in these six patients have remained normal from 10 months to 10 years. In the 46 other patients, tumor was unresectable because of metastases or multiple primary tumors (21 patients; 40%) or inability to find the tumor at laparotomy (21 patients; 40%). Multiple pancreatic islet cell adenomata were found in six of seven patients with multiple endocrine neoplasia (MEN), indicating that patients with this condition usually have diffuse involvement of the pancreas. The results of CT scans correlated with findings at laparotomy in 13 of 16 patients. The smallest tumor detected by CT scans was 1 cm in diameter. CT technology is more accurate in finding gastrinomas now than in the past and has a useful role in preoperative evaluation. The possibility of resection should be seriously considered in every patient with Zollinger-Ellison syndrome. Abdominal CT scans, transhepatic portal venous sampling, and laparotomy should be used to find the tumor and to determine whether it is resectable. Using presently available methods, it should be possible to cure about 25% of patients with gastrinomas who do not have MEN and over 70% of those without MEN who appear to have a solitary tumor. Total pancreatectomy may be necessary to cure some patients with MEN, but that operation is rarely justified. The morbidity and mortality of surgical attempts at curing this disease have become minimal; we have had no deaths or serious complications following such operations in over 10 yrs. Total gastrectomy and indefinite use of H2-receptor blocking agents are the therapeutic options for patients with unresectable gastrinomas. Because H2-receptor blocking agents fail to control acid secretion in many patients after several yrs of therapy, total gastrectomy is indicated in a large proportion of patients whose tumors cannot be resected. Total gastrectomy in patients with ZES is also safe using current techniques; our last death following this operation for ZES occurred 15 yrs ago.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Female; Gastrectomy; Gastrins; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Postoperative Complications; Tomography, X-Ray Computed; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Gastrins; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Topics: Animals; Cat Diseases; Cats; Duodenal Ulcer; Female; Gastrins; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

A patient is described who presented with a 10 year history of intermittent peptic ulcer symptoms and a 3 year history of an undiagnosed skin rash. Investigations indicated raised plasma levels of gastrin, glucagon and pancreatic polypeptide. A single tumour was localised to the pancreas and resected. The tumour had the typical histology of an apudoma, and contained cells which stained for gastrin, glucagon, pancreatic polypeptide and neurotensin.

Topics: Aged; Apudoma; Gastrins; Glucagon; Humans; Male; Pancreatic Neoplasms; Pancreatic Polypeptide; Syndrome

Topics: APUD Cells; Apudoma; Gastric Inhibitory Polypeptide; Gastrins; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Insulinoma; Motilin; Pancreatic Neoplasms; Secretin

Use of commercial immunoperoxidase kits for the study of gastrin, glucagon, insulin, and somatostatin production in 13 islet-cell tumors was assessed. Kits save time in preparation and technic, are convenient and easy to use, and are economical for occasional tests. Results are reproducible, with crisp immunostain, minimal background staining, and high sensitivity so that interpretation is easy. The relevant hormone was specifically identified in seven symptomatic tumors. Of six asymptomatic tumors, five showed strongly positive glucagon immunostain and one somatostatin. Nine tumors, in addition, contained somatostatin. Three tumors produced a third hormone. Use of kits can prove expensive for large numbers of tests. Reagents supplied were of unknown dilution and usually insufficient to run negative controls concurrently. Fading of immunostain was noticed after six months of storage.

Topics: Adenoma, Islet Cell; Gastrins; Glucagon; Humans; Immunoenzyme Techniques; Insulin; Pancreatic Neoplasms; Reagent Kits, Diagnostic; Retrospective Studies; Somatostatin

Immunocytochemical stains for various pancreatic hormones were performed on 77 pancreatic endocrine tumors from 59 patients [17 with hypoglycemia, three with glucagonoma syndrome, 18 were Zollinger-Ellison syndrome, six with WDHA (watery, diarrhea, hypokalemia, and achlorhydria) syndrome and 15 without endocrine symptoms]. In all tumors that caused either hypoglycemia or glucagonoma syndrome, insulin and glucagon were respectively identified. On the other hand, only 10 tumors from 18 patients with Zollinger-Ellison syndrome were positive for gastrin, and only four of six patients with WDHA syndrome had a vasoactive intestinal peptides-positive tumor. Ten of 15 clinically silent tumors contained hormone-producing cells but without a consistent pattern. Ten neoplasms were negative for all hormones tested. Twenty-six tumors showed positively for more than one hormone and usually one cell type predominated. Four patients had multiple tumors which showed variation in the architecture and cellular composition. The tumors were classified into three major histopathologic groups: solid, gyriform, and glandular. The correlation between the pattern of growth and the hormonal production was generally poor. However, a pure gyriform pattern was often associated with insulin production, and glandular differentiation was commonly seen in tumors associated with Zollinger-Ellison syndrome. This study demonstrates the reliability of the immunocytochemical method for the specific identification of cell types in pancreatic endocrine tumors.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Child; Female; Gastrins; Glucagon; Hormones; Humans; Immunoenzyme Techniques; Insulin; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Somatostatin; Vasoactive Intestinal Peptide

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

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

Topics: Blood Specimen Collection; Gastrins; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Veins; Zollinger-Ellison Syndrome

A 60-year-old patient developed signs and symptoms of glucagonoma syndrome (dermatitis, weight loss, anemia and hypoaminoacidemia). However, diabetes mellitus was absent. Glucagonoma was suspected because of markedly elevated plasma glucagon levels and the tumor was subsequently removed by surgery. Acidethanol extraction of the tumor and immunohistochemistry provided evidence of the presence of all four islet hormones, particularly that of glucagon and pancreatic polypeptide and to a lesser extent of somatostatin and insulin. Immunohistochemistry of the tumor (but not plasma) also showed the presence of alpha-HCG. Plasma glucagon immunoreactivity consisted to a large extent (approx. 90%) of a high molecular form of glucagon, probably proglucagon. In spite of the presence of alpha-HCG - which is assumed to be a marker of malignancy - the patient has been free of recurrence for the 2 1/2 years since surgery. The increasing number of cases reported during the past few years demonstrates that the syndrome is more common than previously suspected. Glucagon secretion and its typical clinical picture may be a valuable marker of a multihormonal pancreatic tumor. In a case of suspected glucagonoma, diagnosis can be established simply by obtaining a plasma glucagon level measurement.

Topics: Adenoma, Islet Cell; Anemia; Body Weight; Dermatitis; Gastrins; Glucagon; Glucagonoma; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Secretin; Syndrome

Topics: Aged; Coronary Disease; Gastrins; Glucagon; Humans; Liver Neoplasms; Male; Pancreatic Neoplasms; Pancreatic Polypeptide

Patients with the Zollinger-Ellison syndrome have been managed by total gastrectomy and more recently, by the use of H2-receptor antagonists. An alternative approach has been to identify those who might be cured by excision of a pancreatic islet-cell tumor without removal of the stomach. The course of such a patient is reported. A 40-yr-old man with massive gastric hypersecretion, acid-peptic disease, diarrhea, and elevated serum gastrin was treated by excising a pancreatic gastrinoma. Serum gastrin and gastric secretion became and have remained normal for 7 yr. Symptoms ceased and provocative tests with secretin and calcium have remained normal. Three additional patients with Zollinger-Ellison syndrome in whom pancreatic islet-cell tumor resection alone has resulted in long-term cures have been identified. All were middle-aged men with severe diarrhea. These successes, the availability of techniques that permit early identification and localization of gastrinomas, and the advent of H2-receptor antagonists that can control gastric hypersecretion without gastrectomy must be considered in managing patients with gastrinomas.

Topics: Adult; Follow-Up Studies; Gastrectomy; Gastrins; Humans; Male; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

In 10 out of 27 patients with a Zollinger-Ellison syndrome a gastrin-producing tumor was removed, in 5 localized with phlebography. In the remaining 12 patients the diagnosis of a gastrinoma was based on clinical data only. The 10 patients with surgically proven gastrinoma did not differ in their fasting blood-glucose levels, rise of gastrin serum levels after administration of secretin and calcium, in acid production patterns nor in survival time from those 12 patients in whom no gastric-producing tumor had been found. 5 of the 27 patients died, 4 just after surgery. One patient died from advanced malignant disease. In three of our patients localizing diagnostic procedures and consecutive tumor-removal were feasible with the protection of H2-receptor antagonists. The trend in the treatment of ZES goes away from elective total gastrectomy towards conservative treatment with H2-receptor antagonists in view of the low morbidity and the attempt of curative treatment by tumor-removal.

Topics: Adult; Aged; Cimetidine; Female; Gastrectomy; Gastrins; Histamine H2 Antagonists; Humans; Male; Middle Aged; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Topics: Adolescent; Adult; Aged; Child; Diagnosis, Differential; Female; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

The secretin injection test has been proved to be useful in the diagnosis of gastrinoma in vivo. Fresh gastrinoma cells were cultured for a short time in vitro and then stimulated with secretin. A rise in the gastrin concentration in the culture medium was observed within 10 min after the addition of secretin. This fact may be evidence that gastrinoma cells have receptors which bind with secretin resulting in the release of gastrin.

Topics: Cells, Cultured; Female; Gastrins; Humans; In Vitro Techniques; Injections, Intravenous; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Radioimmunoassay; Secretin; Zollinger-Ellison Syndrome

An endocrine pancreatic tumour that had not caused any endocrine symptoms was examined by histological, immunocytochemical and electron microscopic techniques. The majority of the tumour cells were argentaffin and contained secretory granules of the enterochromaffin cell type. Immunocytochemically a minority of tumour cells reacted to antisera against beta-endorphin, met- and leu-enkephalin, gastrin, somatostatin and ACTH. The tumour was thus multihormonal, and appeared to be more closely related to the classic Carcinoid tumours of the mid-gut than to most pancreatic endocrine tumours.

Topics: Adrenocorticotropic Hormone; Aged; Carcinoid Tumor; Endorphins; Enkephalins; Female; Gastrins; Humans; Microscopy, Electron; Pancreatic Neoplasms; Somatostatin

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

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

A 61-year-old man with a malignant endocrine pancreatic tumour, so-called "non-functioning" islet cell tumour, is described. The tumour consisted of enterochromaffin-like cells with positive immunocytochemistry for gastrin, glucagon and VIP, but neither of these or other peptides were elevated in the circulation. Elevated serum levels of HCG-alpha and HCG-beta subunits were found. They seemed to be valuable tumour markers during cytotoxic therapy.

Topics: Adenoma, Islet Cell; Antineoplastic Agents; Chorionic Gonadotropin; Female; Gastrins; Glucagon; Humans; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

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

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

Insulinoma, glucagonoma, gastrinoma (Zollinger-Ellison syndrome), vipoma, somatostatinoma and a tumor that secretes human pancreatic polypeptide are the primary endocrine-secreting tumors of the pancreas. hormones are produced by specific tumor cell types and cause a variety of dramatic clinical pictures. Diagnosis often requires hormone assays. Computerized tomography may be helpful. Definitive surgical treatment is possible, but metastases may be present.

Topics: Adenoma, Islet Cell; Apudoma; Gastrins; Glucagon; Humans; Insulin; Insulin Secretion; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

An islet cell carcinoma of the pancreas is described in a 68-year old woman which clinically produced Zollinger-Ellison syndrome and, later in its course, Cushing syndrome. The tumor was found to contain gastrin, ACTH, alpha-endorphin, somatostatin and calcitonin, by the immunoperoxidase technic. Electron microscopy revealed a single tumor cell type containing secretory granules of variable size, morphology and electron density. It appears that a single tumor cell population produced all five hormones and caused a transition in clinical symptomatology, while undergoing no change in morphology.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Aged; Calcitonin; Cushing Syndrome; Endorphins; Female; Gastrins; Hormones, Ectopic; Humans; Immunoenzyme Techniques; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Somatostatin; Zollinger-Ellison Syndrome

The main clinical signs of three dogs with Zollinger-Ellison syndrome were vomiting, diarrhoea, poor appetite and weight loss. The diagnosis was confirmed by histological examination and by gastrin immunocytochemistry. Gastrin was extracted from pancreatic tumours of two dogs. Gastrin-component III predominated in one dog while gastrin-component II and gastrin-component III were demonstrated in almost equal amounts in the other dog. In one dog serum gastrin concentration was high. Postmortem examination revealed pancreatic tumours in all three dogs and metastases in the regional lymph nodes and liver in two. The pancreatic tumours contained three patterns of growth: solid, trabecular and acinar. Electron microscopy of liver metastases showed cells with secretory granules. In all three dogs there was an erosive oesophagitis and thick gastric mucosa caused mainly by glandular proliferation. Two dogs had erosions and ulcers in the duodenum, one also in the first part of the jejunum. Villous atrophy and cellular infiltration of the duodenal mucosa were found in all dogs.

Topics: Adenoma, Islet Cell; Animals; Dog Diseases; Dogs; Esophagus; Female; Gastrins; Intestines; Male; Pancreatic Neoplasms; Stomach; Zollinger-Ellison Syndrome

A review of 42 patients with gastrinoma, who either survived five years or longer or who died during this period of evaluation, was carried out to define the surgical principles which might be combined with the recent trend toward cimetidine therapy. Thirty-four (80%) of the patients had total gastrectomy with an operative mortality rate of 2.3%, and eight patients (20%) had less than total gastrectomy. No tumor was found in six patients with hypergastrinemia and an abnormal secretin bolus whose five-year survival rate was 100%. Of the thirty-six patients having tissue proof of gastrinoma, twenty-two (61%) had complete resection of all gross tumor resulting in a 76% five-year survival rate. Fourteen patients had unresectable tumor or partial resection with a five-year survival rate of 21%. Complete gross tumor resection increased mean survival by six years (p < 0.01), but resulted in persistent eugastrinemia in only two patients. Long-term survival was possible with a combination of vagotomy, lesser gastric procedures, tumor resection, and cimetidine, seven of eight patients living more than five years. Surgical management of gastrinoma should be directed toward aggressive tumor resection and vagotomy, with reliance on cimetidine therapy postoperatively to control the gastric hypersecretion. Total gastrectomy should be reserved for cimetidine failures and those who do not wish to take cimetidine for the rest of their lives.

Topics: Adenoma, Islet Cell; Cimetidine; Follow-Up Studies; Gastrectomy; Gastrins; Humans; Jejunal Diseases; Pancreatectomy; Pancreatic Neoplasms; Peptic Ulcer; Vagotomy

The effect of intravenous secretin on plasma immunoreactive gastrin is presumed to improve diagnostic accuracy in patients with a gastrinoma. To investigate this further, the secretin provocation test was performed in control patients (n = 10), patients with a primary duodenal ulcer (n = 10), patients who had previously had surgery for a duodenal ulcer (n = 20), patients with symptomatic recurrent peptic ulceration (n = 50) and 2 patients with a histologically proved gastrinoma. It was found that the secretin test gave a false positive result in 3 out of 10 symptomatic duodenal ulcer patients, 2 out of 20 patients who had had previous duodenal ulcer surgery and were now asymptomatic and 15 out of 50 patients with recurrent peptic ulceration. Both gastrinoma patients had positive secretin tests but there were no obvious criteria that separated the gastrin response of a gastrinoma patient from those with primary or recurrent peptic ulceration. It is concluded that the secretin test is probably of little value in both the screening and the diagnosis of a gastrinoma.

Topics: Adenoma, Islet Cell; Diagnosis, Differential; Duodenal Ulcer; Gastrins; Humans; Pancreatic Neoplasms; Peptic Ulcer; Recurrence; Secretin

As part of a prospective diagnostic protocol, patients suspected of having pancreatic cancer had systemic and portal venous blood samples assayed, in coded batches, for peptide hormones and enzymes thought to be of potential value as tumor markers. An average of 111 patients were tested for each candidate marker. Results were analyzed by dividing patients into three groups according to the definitive diagnoses. These were pancreatic cancer (32% of patients), other cancers (27%), and benign diseases (41%). Although elevated mean levels of fasting plasma glucose and serum alkaline phosphatase were found in the pancreatic cancer group, there were no significant differences in the mean levels of any of the candidate markers studied in the three groups. The diagnostic values of normal and elevated levels of each candidate marker studied have been calculated. None has proven to be as useful as the serum level of pancreatic oncofetal antigen, fasting plasma glucose, or serum alkaline phosphatase in the diagnosis or exclusion of pancreatic cancer.

Topics: Alkaline Phosphatase; C-Peptide; Calcitonin; Chorionic Gonadotropin; Clinical Enzyme Tests; Clinical Laboratory Techniques; Evaluation Studies as Topic; Gastrins; Glucagon; Hormones; Humans; Insulin; Neoplasms; Pancreatic Neoplasms; Parathyroid Hormone; Prospective Studies; Ribonucleases

Three patients with the watery diarrhea-hypokalemia-achlorhydria (WDHA) syndrome were studied. All had watery diarrhea, hypokalemia and hypercalcemia. Plasma vasoactive intestinal polypeptide (VIP) levels determined by radioimmunoassay were markedly elevated in these patients, indicating that they had VIP-producing tumors. Plasma VIP levels determined serially after the operation indicate that its determination is useful in estimating the effect of a treatment. As for multiple endocrine neoplasia type 1 (MEN1), two out of the three cases belonged to this category. Patient 1 had a brother with insulinoma, and in case 2, even though there was no family history, the autopsy revealed not only multiple tumors of the pancreas but also pituitary adenomas, chief cell hyperplasia of the parathyroid glands, thyroid adenomas and adrenocortical adenomas. VIP and other hormones in the tumors as well as in the plasma were examined extensively in these cases. In case 1, VIP, gastrin and calcitonin were produced in the tumor and only plasma VIP levels were elevated. In case 2, with multiple tumors, tumor 1 produced VIP, glucagon pancreatic polypeptide, gastrin and calcitonin, and tumor 2, VIP, pancreatic polypeptide, gastrin and beta-melanocyte stimulating hormone. In this case, plasma VIP, pancreatic polypeptide and glucagon levels were elevated. In case 3, VIP and calcitonin were produced in the tumor, and plasma VIP and calcitonin levels were elevated. These results indicate that (1) VIP is a good tumor marker for the WDHA syndrome due to VIP-producing tumors; (2) patients with the WDHA syndrome are sometimes associated with MEN1; and (3) VIP-producing tumors are multiple hormone-producing tumors, and VIP predominantly elevated in the plasma results in the WDHA syndrome, although other hormones such as pancreatic polypeptide, glucagon and calcitonin are sometimes found to be elevated in plasma without contributing to the clinical features.

Topics: Achlorhydria; Adult; Calcitonin; Diarrhea; Female; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Hypokalemia; Insulin; Male; Middle Aged; Pancreatic Neoplasms; Parathyroid Hormone; Syndrome; Vasoactive Intestinal Peptide

Topics: Amino Acid Sequence; Animals; Cholecystokinin; Gastrins; Humans; Immune Sera; Intestinal Mucosa; Jejunum; Pancreatic Neoplasms; Radioimmunoassay; Swine; Trypsin

Topics: Amino Acid Sequence; Animals; Cross Reactions; Gastric Mucosa; Gastrins; Humans; Liver Neoplasms; Pancreatic Neoplasms; Peptide Fragments; Radioimmunoassay; Swine

Topics: Apudoma; Gastrins; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms; Radioimmunoassay; Secretin; Spain

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

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

The authors present a brief report on a familial case of Wermer's syndrome, and review the principal characteristics of this "multiple endocrine neoplasm" which usually affects the parathyroids, pancreas, and anterior pituitary.

Topics: Adult; Female; Gastrins; Glucagon; Humans; Insulin; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms; Pituitary Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Adult; Female; Gastrins; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Somatostatin; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

A new long-acting octapeptide analogue of somatostatin, Des AA1,2,4,5,12,13 D Try8 somatostatin, has been tested in 8 patients with pancreatic endocrine tumours. The analogue given subcutaneously suppressed the tumour-derived hormones in patients with insulinomas, glucagonomas, and gastrinomas for up to 24 h. The prolonged action appeared to be the result of slow release from the injection site. No side-effects were observed. Studies of long-term administration of this new peptide are now warranted.

Topics: Adult; Aged; Delayed-Action Preparations; Depression, Chemical; Female; Gastrins; Glucagon; Hormones, Ectopic; Humans; Insulin; Insulin Antagonists; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Pancreatic Neoplasms; Somatostatin

Topics: Brain; Celiac Disease; Digestive System Physiological Phenomena; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Obesity; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Secretin; Somatostatin; Substance P

Topics: Adenoma, Islet Cell; Gastrins; Glucagon; Humans; Hypoglycemia; Pancreatic Neoplasms; Skin Manifestations; Zollinger-Ellison Syndrome

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

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

A case of adrenocortical hyperfunction due to ectopic production of ACTH by a gastrin-producing tumor of the pancreas is described. Cushing's syndrome preceded the appearance of the overt Zollinger-Ellison syndrome by 2 years and was treated by bilateral adrenalectomy. The Zollinger-Ellison syndrome was initially treated with cimetidine, which successfully reduced the secretion of gastric acid. Because the pancreatic gastrinoma continued to grow, causing obstruction of the common bile duct, biliary diversion and total gastrectomy were performed. There is evidence that the pancreatic gastrinoma was the source of the ectopic production of ACTH and possibly secretion. The role of Histamine-2 blocking agents as therapy in the Zollinger-Ellison syndrome is discussed.

Topics: Adrenocorticotropic Hormone; Adult; Biliary Tract Diseases; Cholestasis; Common Bile Duct; Constriction, Pathologic; Gastrins; Hormones, Ectopic; Humans; Male; Pancreatic Neoplasms

Conventional or electron microscopy can contribute significantly to the diagnosis of pancreatic endocrine tumours. These techniques, however, are of limited value for the classification of the tumours, which should take both clinical and morphological findings into account. In this paper a classification based on both the clinical features and on the content of peptide hormone-producing cells in the tumours is presented.

Topics: Adenoma, Islet Cell; Cushing Syndrome; Gastrins; Glucagon; Humans; Malignant Carcinoid Syndrome; Pancreatic Neoplasms; Somatostatin; Zollinger-Ellison Syndrome

Pancreas and gut hormones are involved in many endocrine and gastrointestinal diseases. Radioimmunoassays for these hormones have proved particularly valuable in diagnosis, localisation and control of treatment of endocrine tumours, of which many are mixed. An estimate based on ten years experience in a homogenous population of 5 million inhabitants (Denmark) suggests, that endocrine gut tumour-syndromes on an average appear with an incidence of 1 patient per year/syndrome/million. At present six different syndromes are known: 1) The insulinoma syndrome, 2) The Zollinger-Ellison syndrome.3) The Verner-Morrison syndrome. 4) The glucagonoma syndrome. 5) The somatostatinoma syndrome, and 6) the carcinoid syndrome. Accordingly diagnostically valuable RIAs for pancreas and gut hormones include those for insulin, gastrin, VIP, HPP, glucagon, somatostatin, and presumably also substance P. It is probably safe to predict that the need for gut and pancreas hormone RIAs within the next decade will increase greatly in order to assure proper management of tumours producing gastroentero-pancreatic hormones.

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Cholecystokinin; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Intestinal Neoplasms; Motilin; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Secretin; Somatostatin; Substance P; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

The role of human pancreatic-polypeptide in endocrine tumours of the pancreas is reviewed. Pancreatic-polypeptide may be involved in 3 different ways: 1. In cases with pure PP producing tumours. 2. In mixed endocrine tumours containing PP cells. 3. In cases with PP cell hyperplasia in normal pancreatic tissue associated with endocrine pancreatic tumours as VIP-omas, insulinomas, and glucagonomas. PP does not seem to serve as a general marker for endocrine tumours of the pancreas, but PP determinations are useful in patients wbith watery diarrhoea syndromes, because such syndromes may be associated with tumours that contain PP cells. Large molecular forms of PP occur in plasma from patients with endocrine tumours and high PP concentrations, but may also be found in other groups of patients. It is suggested that an atropin-suppression test could be of diagnostic value in revealing patients with increased serum concentrations of PP from other causes than vagal stimulation of normal PP cells.

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Gastrins; Glucagon; Humans; Hyperplasia; Molecular Weight; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Syndrome; Zollinger-Ellison Syndrome

Gastro-entero-pancreatic (GEP) and bronchial endocrine tumours have been studied by immunohistochemistry using specific antisera against a variety of hormonal and neuronal peptides. In gastrinomas numerous tumour cells were found to contain GH-like immunoreactivity. These cells were identical with those storing gastrin. Gastrinomas as a rule were extremely heterogeneous containing a variety of minority cell populations, including CCK immunoreactive cells and neurotensin immunoreactive cells. Glucagonoma cells were found to store GIP-like material in addition to glucagon. In some insulinomas calcitonin-like material was encountered in the insulin producing tumour cells. In both glucagonomas and insulinomas other pancreatic endocrine cell types constituted minority cell populations. One intestinal somatostatinoma contained gastrin cells as a minority cell population. Bronchial endocrine tumours contained scattered cells displaying ACTH-like or enkephalin-like immunoreactivity. Two such tumours in addition contained cells displaying neurophysin immunoreactivity.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Bronchial Neoplasms; Cholecystokinin; Enkephalins; Fluorescent Antibody Technique; Gastrins; Glucagon; Growth Hormone; Humans; Insulin; Insulin Secretion; Neurophysins; Pancreatic Neoplasms; Serotonin; Somatostatin; Stomach Neoplasms; Zollinger-Ellison Syndrome

A 57-year-old male patient with metastasizing non-beta islet cell carcinoma of the pancreas is described. Both gastrin and VIP levels were elevated and the patient suffered from a syndrome of pancreatic cholera and hyperacidity. The tumour contained gastrin and VIP as demonstrated by immunofluorescence. The patient also had a history of familial renal stone formation and parathyroid nodular hyperplasia. Resection of pancreatic tumour in 1973 resulted in four years without symptoms. In 1977 definite signs of multiple hepatic metastases appeared. These signs disappeared after streptozotocin given in a dosage of 2 g three times at weekly intervals. The patient had remained well for 20 months after this treatment. The causative agents for the clinical syndrome in this case are discussed in view of circulating hormone levels.

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Gastrins; Gastrointestinal Hormones; Humans; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Streptozocin; Syndrome; Vasoactive Intestinal Peptide

Growth hormone (GH)-immunoreactive material was found to occur in the antral gastrin cells and in scattered cells of the pancreatic islets in several mammalian species, including man. Examination of gastrinomas revealed the majority of tumour cells to display GH-like immunoreactivity.

Topics: Animals; Fluorescent Antibody Technique; Gastrins; Growth Hormone; Humans; Intestines; Islets of Langerhans; Pancreatic Neoplasms; Pyloric Antrum; Species Specificity; Stomach Neoplasms

Topics: Child; Female; Gastrins; Hormones, Ectopic; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Relationships between hormonal secretions from the GI tract and gastric functional and/or pathological abnormalities could be studied according to 2 main lines : 1) gastric secretory changes could be the main symptom of hormonal secretory tumors, i.e. acid hypersecretion in the Zollinger Ellison syndrome, acid hyposecretion in pancreatic cholera and in somatostatinoma. In these cases, hormonal hypersecretion is directly responsible for the functional disturbances and the related symptoms; 2) gastric pathological conditions are sometimes accompanied by changes in hormonal secretion, but the level of interdependence is variable : high blood gastrin is directly depending upon the atrophic gastritis in pernicious anemia; this mechanism was also suggested in case of gastric carcinoma. Concerning ulcer disease, numerous problems are unsolved in respect to blood gastrin (basal and stimulated) abnormalities, as well as somatostatin and GIP secretions.

Topics: Aged; Anemia, Pernicious; Cholera; Duodenal Ulcer; Gastric Inhibitory Polypeptide; Gastric Juice; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Humans; Pancreatic Diseases; Pancreatic Neoplasms; Somatostatin; Stomach Diseases; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Pancreatic apudomas are not common but are frequently curable. Thus, it is important for every clinician to be fully aware of the varied clinical syndromes that suggest their presence. The availability of specific radioimmunoassays has made confirmation of the diagnosis relatively simple. Advances in the techniques for staining the different cell types have led to the recognition that many of these tumors are mixed, and that the general term "pancreatic apudoma" is appropriate. Pancreatic endocrine tumors, as examples to "nature's experiments," have yielded considerable insight into the possible physiologic effects of the various peptides they produce. It is to be hoped that further study of tumors such as the somatostatinoma and PPoma may yield further information about these enigmatic compounds.

Topics: Animals; Anura; Apudoma; Dogs; Gastrins; Gastrointestinal Hormones; Glucagon; Humans; Insulin; Insulin Secretion; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide

Several gastrointestinal peptides with proven or suggested endocrine or paracrine functions influence gastric acid secretion, gastrointestinal motility, and mucosal blood flow. Increased or decreased release of such factors could participate in the pathogenesis of duodenal ulcer disease by inducing increased gastric acid concentration in the duodenal bulb. To date, increased stimulation of parietal cells by gastrin has been demonstrated only in patients with gastrinoma, G-cell hyperplasia, gastric outlet obstruction, hyperparathyroidism, excluded antrum, and short bowel syndrome, but not in the usual duodenal ulcer disease. Also, a defective inhibition of parietal cell function by endocrine or paracrine factors, such as gastric inhibitory polypeptide, secretin, somatostatin and vasoactive intestinal polypeptide, seems not to exist in patients with duodenal ulcer disease. However, as long as the physiology of gastrointestinal peptides in gastric secretion and motility is not understood, a possible role of these factors in the pathogenesis of simple duodenal ulcer disease cannot be excluded.

Topics: Duodenal Neoplasms; Duodenal Ulcer; Gastric Juice; Gastrins; Gastrointestinal Hormones; Gastrointestinal Motility; Humans; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Within a ten-year scan (1967-1976) 207 insulinomas, 50 gastrinomas, 8 Verner-Morrison tumors, 5 glucagonomas and 12 endocrine pancreatic tumours with associated MEA syndrome (multiple endocrine adenomatosis) were treated surgically at various university hospitals (information obtained by questionnaire). Half of the insulinomas were treated by enucleation, one third by resection of the tail of the pancreas. Total gastrectomy was the procedure of choice in 80% of patients with gastrinoma, but sometimes pancreatic resection to remove the tumour was added. An new therapeutic concept of using histamine-H2 receptor antagonists for treating patients with Zollinger-Ellison syndrome is discussed. In the eight patients with a Verner-Morrison syndrome removal of the tumour or distal pancreatic resection was the procedure of choice.

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Gastrectomy; Gastrins; Glucagon; Histamine H2 Antagonists; Humans; Neoplasm Metastasis; Pancreatectomy; Pancreatic Neoplasms; Statistics as Topic; Syndrome; Zollinger-Ellison Syndrome

Topics: Apudoma; Carcinoid Tumor; Female; Gastrins; Gastrointestinal Neoplasms; Glucagon; Humans; Insulin; Insulin Secretion; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide

A case with the clinical appearance of WDHA syndrome is described in which serum concentrations of the newly recognized hormonal principle pancreatic polypeptide (PP) were highly elevated, while plasma levels of vasoactive intestinal peptide were within the normal range. The symptoms of the patient seem to be derived from the high levels of circulating PP, as illustrated by an improvement after resection of liver metastases accompanied by a marked decrease of serum PP concentration. Streptozotocin treatment was without effect upon the watery diarrhoea, and PP levels also remained unchanged during medical treatment. The appearance of a PP-secreting tumour leading to a clinical WDHA syndrome widens the spectrum of hormone assays that have to be performed in these patients.

Topics: Adult; Body Water; Diarrhea; Female; Gastrins; Humans; Pancreatic Neoplasms; Pancreatic Polypeptide; Streptozocin; Syndrome; Vasoactive Intestinal Peptide

A patient is described who had a malignant pancreatic islet cell apudoma secreting corticotrophin (ACTH) and melanocyte-stimulating hormone (MSH), both of which were clinically active, and very large quantities of immunoreactive gastrins, which were biologically active but clinically silent (normal gastric acid secretion and no peptic ulceration). The presence of parietal cell antibodies, with no increase in the plasma concentrations of hormones which can inhibit gastric acid secretion (secretin, GIP and VIP), suggests that many of the of the parietal cells may have been blocked by the autoantibodies.

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Adult; Apudoma; Gastrins; Humans; Male; Melanocyte-Stimulating Hormones; Pancreatic Neoplasms

Topics: Adenoma, Islet Cell; Gastrins; Glucagon; Hormones, Ectopic; Humans; Pancreatic Neoplasms; Somatostatin; Vasoactive Intestinal Peptide

Traditionally it is taught that hypoglycaemia may cause a clinical picture which mimics a variety of neurological and psychiatric disorders. Yet patients with insulinoma continue to baffle many medical specialists, who presumably are not sufficiently aware of the clinical features of hypoglycaemia. After examining medical records of seventeen patients, diagnosed as suffering from "insulinoma" in major Melbourne hospitals from 1971 to 1976, it was evident that these patients frequently undergo extensive investigations for supposed neurological disorders, the correct diagnosis being missed until they develop catastrophic symptoms. Of these seventeen patients, the diagnosis was made with reasonable speed in only six cases, while eight patients were initially discharged from hospital with a completely erroneous diagnosis. It seems likely that a number of patients with insulinoma, whose symptoms are less dramatic than those reported here, are being mistakenly treated as having epileptiform or psychiatric disorders.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Diagnostic Errors; Female; Gastrins; Humans; Hypoglycemia; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin; Time Factors

Topics: Adenoma, Islet Cell; Adult; Aged; Female; Gastrins; Glucagon; Humans; Infant; Insulin; Insulin Secretion; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Somatostatin

Topics: Adenoma, Islet Cell; Gastrins; Humans; Pancreatic Neoplasms; Secretin

Thirty pancreatic islet cell tumours were histologically classified and analysed for their possible peptide hormone content using the immunohistoperoxidase method. Seven tumours contained insulin, six tumours contained gastrin and eight tumours contained glucagon. One tumour contained all three hormones. In the insulin and gastrin-containing tumours, the cells were usually arranged in solid nests of cells, with tubular and acinar formations in about half the cases. In the glucagon-containing tumours the cells were mainly arranged in anastomosing ribbons consisting of one of two layers of small cells. Most of the hormone-containing tumours were argyrophilic using Grimelius' silver reaction. All but one of the glucagon-containing tumours were incidental findings at autopsy. About half of the other tumours had metastasized. It is concluded that a relation exists between the histological pattern of growth and immunohistochemically defined endocrine function of pancreatic islet cell tumours.

Topics: Adenoma, Islet Cell; Gastrins; Glucagon; Humans; Immunoenzyme Techniques; Insulin; Neoplasm Metastasis; Pancreatic Neoplasms

Within a ten-year scan (1967-1976) 207 insulinomas, 50 gastrinomas, 8 Verner-Morrison tumours, 5 glucagonomas and 12 endocrine pancreatic tumours with associated MEA syndrome (multiple endocrine adenomatosis) were treated surgically at various university hospitals (information obtained by questionnaire). Half of the insulinomas were treated by enucleation, one third by resection of the tail of the pancreas. Total gastrectomy was the procedure of choice in 80% of patients with gastrinoma, but sometimes pancreatic resection to remove the tumour was added. An new therapeutic concept of using histamine-H2 receptor antagonists for treating patients with Zollinger-Ellison syndrome is discussed. In the eight patients with a Verner-Morrison syndrome removal of the tumour or distal pancreatic resection was the procedure of choice.

Topics: Adenoma, Islet Cell; Gastrins; Germany, West; Glucagon; Insulin; Pancreatic Neoplasms

To evaluate its potential as an alternative to angiography in the diagnosis of pancreatic tumors, we performed selective vein catheterization for hormone assay on 11 patients with islet cell tumors and islet cell hyperplasias. In all patients, the abnormal pancreatic tissue was correctly localized preoperatively by this method.

Topics: Adenoma, Islet Cell; Aged; Catheterization; Female; Gastrins; Glucagon; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Phlebography

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

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

Topics: Gastrins; Humans; Pancreatic Neoplasms

Topics: Diagnosis, Differential; Diagnostic Errors; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Peptic Ulcer; Recurrence; Zollinger-Ellison Syndrome

Topics: Gastrins; Glucagon; Growth Hormone-Releasing Hormone; Humans; Hyperplasia; Insulin; Islets of Langerhans; Pancreatic Neoplasms; Peptides

A 61-year-old woman had watery diarrhea, hypochlorhydria, hypokalemia, and elevated serum gastrin levels. She had islet cell carcinoma of the body of the pancreas with multiple metastases to the liver. Radioimmunoassay and immunofluorescence demonstrated both vasoactive intestinal polypeptide (VIP) and gastrin in the surgically removed carcinoma and in a metastatic focus. Electron microscopical findings confirmed the presence of two cell types whose secretory granules had characteristics ascribed to these two hormones. Plasma prostaglandin E levels were also elevated above normal. Serum VIP levels became elevated to the Verner-Morrison range prior to her death of a bleeding duodenal ulcer two years after initial symptoms.

Topics: Adenoma, Islet Cell; Female; Gastrins; Gastrointestinal Hormones; Humans; Liver Neoplasms; Middle Aged; Neoplasm Metastasis; Pancreas; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Up to seven endocrine cell types have been identified ultrastructurally in the pancreas, including glucagon A cells, insulin B cells, somatostatin D cells, pancreatic peptide F cells and 5-hydroxytryptamine EC cells. In addition, D1 cells, which have been proposed as the cell type producing VIP and possible P cells of unknown function are seen. Various patterns of endocrine cell differentiation have been found in 20 endocrine pancreatic tumours. Well and poorly differentiated B cells have been identified in 6 insulinomas, diagnostic G cells in 3 out of 7 gastrinomas, D1 and/or F cells in 7 diarrheogenic tumours. Moreover, cells apparently unrelated to the prevalent clinical syndrome have been noted in 8 of the 20 tumours. Granular non diagnostic cells (poorly diagnostic gastrin cells? D1 cells?) were particularly frequent in gastrinomas; agranular or poorly granular cells, either by "active" or "Stem cell" type, were present in nearly all tumours, particularly in diarrheogenic tumours, gastrinomas and malignant insulinomas. A cytological classification of pancreatic endocrine tumours is proposed.

Topics: Adenoma, Islet Cell; Animals; Cats; Cell Differentiation; Dogs; Gastrins; Glucagon; Guinea Pigs; Humans; Insulin; Islets of Langerhans; Microscopy, Electron; Pancreatic Neoplasms; Serotonin; Somatostatin; Swine

A patient is presented with Zollinger-Ellison syndrome, in whom spontaneous disappearance of gastric hypersecretion and peptic ulcer disease occurred subsequent to an intercurrent illness causing acute nonspecific inflammation of the gastric mucosal lining. The dramatic clinical improvement after subsiding of the intercurrent illness was obviously linked to pronounced failure of the parietal cell mass for acid secretion and not to infarction of the gastrinoma because gastrin secretion by the tumor was unchanged.

Topics: Adenoma, Islet Cell; Adult; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Humans; Male; Pancreatic Neoplasms; Remission, Spontaneous; Secretory Rate; Zollinger-Ellison Syndrome

1) In electively immuno-induced carcinomas of the exocrine pancrease in Mice, where A (glucagon) and B (insulin) endocrine cells persist, cells with a pancreatic polypeptide immunoreactivity are also detected, even in late evolution stages. These cells, like D cells, containing somatostatin, are localized only in the pancreatic remains surrounding the anaplasic carcinomatous tissue: islets, adenomatous parenchyma, and ductular epithelium. Ultrastructure of these cells shows their active elaboration of numerous chracteristic secretion granules. (2) Immunocytoenzymatic detection of gastrin is negative in the exocrine and endocrine pancreatic tissues. However one of the anti-gastrin sera used gives a positive reaction, in some carinomatous cells only. Does this immunoreactivity characterize a polypeptide specific to the pancreatic carcinomatous cell?

Topics: Animals; Gastrins; Immunoenzyme Techniques; Mice; Neoplasms, Experimental; Pancreas; Pancreatic Neoplasms; Peptides

Topics: Adult; Aorta; Catheterization; Female; Gastrectomy; Gastrins; Humans; Lymphatic Metastasis; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Portal Vein; Vena Cava, Inferior; Zollinger-Ellison Syndrome

In 33 patients studied with endocrine neoplasms of the pancreas more than half the tumours contained pancreatic polypeptide (P.P.) producing cells, and a high radioimmunoassayable concentration of P.P. was found in the tumour extracts. Plasma was available from 28 patients, and very high circulating P.P. concentrations were found in 18. The presence of P.P. in hepatic and lymphnode metastases indicates that its production by the primary neoplasm cannot be ascribed to incidental adherence of normal P.P. cells. Measurements of plasma P.P. levels should be a new aid to diagnosis of pancreatic tumours.

Topics: Adenoma, Islet Cell; Gastrins; Gastrointestinal Hormones; Glucagon; Histocytochemistry; Humans; Insulin; Insulin Secretion; Pancreas; Pancreatic Hormones; Pancreatic Neoplasms; Peptides; Radioimmunoassay; Tissue Extracts

Topics: Diagnosis, Differential; Diarrhea; Gastrectomy; Gastrins; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Radiography; Stomach Neoplasms; Zollinger-Ellison Syndrome

As streptozocin has a toxic effect on gastrin producing cells in some patients with gastrinomas, the action of the drug upon normal gastrin release was evaluated in patients with carcinoid tumours (n=6) and malignant insulinomas (n=2). No acute effects were recorded in 22 instances where gastrin levels were followed during the first 24 hours after infusion of streptozocin. When gastrin levels were compared throughout a course of repeated infusions during months a significant increase was noted. Concentrations were doubled after 6 g streptozocin given during a four months period, and tripled after 10 g in nine months period. One patients developed bleeding duodenal ulcer after a total dose of 6 g. It is concluded that streptozocin does not damage normal G cells, but by some action seems to stimulate gastrin relase. Peptic ulceration may be an important side effect during a long term treatment.

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Female; Gastrins; Humans; Male; Neoplasm Metastasis; Pancreatic Neoplasms; Stomach Neoplasms; Streptozocin

Topics: Adenoma, Islet Cell; Animals; Dog Diseases; Dogs; Gastrins; Male; Pancreatic Neoplasms; Peptic Ulcer

Angiographic findings in one giant cell carcinoma, one cystadenocarcinoma, one poorly vascularized mucinous cystadenocarcinoma, as well as in two avascular (gastrin- and glucagon-producing) islet-cell tumors of the pancreas are described. Two hypervascularized islet-cell tumors are presented for comparison and a case of tumorous chronic pancreatitis in a child is reported because ot its rarity. The aggressiveness of the giant cell carcinoma of the pancreas was demonstrated by its expansive growth. In the case of cystadenocarcinoma angiography revealed the tumor with hepatic metastases not diagnosed at explorative laparotomy. The relative hypovascularity in the case of mucinous cystadenocarcinoma was unusual. Both avascular islet-cell tumors simulated a pancreatic pseudocyst and the final diagnosis was made only by immunoassay. Chronic pancreatitis in a child presented with marked hypervascularization.

Topics: Adenoma, Islet Cell; Adult; Aged; Angiography; Carcinoma; Celiac Artery; Chronic Disease; Contrast Media; Cystadenoma; Diagnosis, Differential; Female; Gastrins; Glucagon; Hepatic Artery; Humans; Male; Middle Aged; Pancreatic Cyst; Pancreatic Neoplasms; Pancreatitis; Zollinger-Ellison Syndrome

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

Recent technics, e.g. radio-immunoassay of gastrin (MacGuigan 1968), cellular immuno-fluroescence (Polak and Pearse 1972) have modified our concepts of the physiopathology of the Zollinger-Ellison syndrome hypergastrinemia of pancreatic origin. 1. Pollak and Pearse, (1972) Ganguli, Pollak and Pearse (1974) have shown that apart from the Zollinger-Ellison syndrome of pancreatic origin (ZE type II) there are cases where the hypergastrinemia is due to hyperplasia of the antral "G" cells which secrete gastrin (ZE Tye I). Thus is raised the problem of the relationship between common peptic ulcer, "G" cell antral hyperplasia and pancreatic hypergastrinemia. 2. There exists, in the anterior part of the intestine (pancreas, duodenum, stomach, ileum) a system of neuro-humoral cells derived embryologically from the neural crest (Weichert 1967, Gorin and Leger 1969). These pluripotent cells may be the origin of digestive endocrine, or carcinoid tumours, islet cell adenomas, or gastrinomas. Thus may be explained among others the multihormonal secretion of some of these tumours and the frequently multiple sites. 3. Gastrin is secreted by the duodenal "G" cells (Watson 1974). Their physiopathological role is still unknown.

Topics: Gastrins; Humans; Intestines; Pancreas; Pancreatic Neoplasms; Stomach; Zollinger-Ellison Syndrome

Topics: Cholecystokinin; Gastrins; Humans; Pancreas; Pancreatic Diseases; Pancreatic Hormones; Pancreatic Neoplasms; Secretin

The clinical symptomatology of the Zollinger-Ellison syndrome and the pathologic anatomy of gastrinomas are reviewed. Experience with 17 patients with the Zollinger-Ellison syndrome is presented with special reference to stimulation tests (secretin, glucagon, calcium infusion, test meal) and to localization and immunohistologic, ultrastructural, and biochemical findings in gastrinomas. Multiple hormone production by the tumors is frequent. The ultrastructure and the Sephadex G-50 gel filtration patterns of immunoreactive gastrin in sera and tumors are not uniform and are not related to localization of the tumors in the pancreas or duodenum or to the gastrin concentration. Hyperplasia of the pancreatic islets is a frequent finding in gastrinoma patients, suggesting that hypergastrinemia may stimulate islet growth.

Topics: Antigens, Neoplasm; Calcium; Chromatography, Gel; Duodenal Neoplasms; Eating; Gastrins; Glucagon; Humans; Immune Sera; Insulin; Intestinal Mucosa; Islets of Langerhans; Lymphatic Metastasis; Microscopy, Electron; Neoplasm Metastasis; Pancreatic Neoplasms; Radioimmunoassay; Secretin; Staining and Labeling; Zollinger-Ellison Syndrome

After removal of two large pancreactic insulinomas, although the presenting spontaneous hypoglycaemia was eliminated, severe and persisting haematemesis and melaena supervened with a rise in serum gastrin. The patient had multiple endocrine adenopathy (pituitary, parathyroids and islet cells), but no evidence of a pancreatic gastrin-producing tumour. After emergency gastric operation for the bleeding, the serum gastrin remained high until the hypercalcaemia and hyperparathyroidism had been corrected by subtotal parathyroidectomy. Immunofluorescence studies showed gastrin in the parathyroid tissue.

Topics: Adenoma, Islet Cell; Endocrine System Diseases; Fluorescent Antibody Technique; Gastrins; Glucose Tolerance Test; Hormones, Ectopic; Humans; Hyperparathyroidism; Hypoglycemia; Male; Middle Aged; Pancreatic Neoplasms; Parathyroid Glands

Topics: Adenoma, Islet Cell; Depression, Chemical; Female; Gastrins; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Middle Aged; Pancreatic Neoplasms; Somatostatin

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Adult; Dehydration; Female; Gastrins; Glucagon; Hormones, Ectopic; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Syndrome; Zollinger-Ellison Syndrome

Twenty-four endocrine pancreatic tumors were examined immunohistochemically for insulin, glucagon, gastrin and ACTH. In seven of these tumors, more than one peptide-hormone-containing cell type was observed. These seven tumors were also examined with conventional staining methods for the presence of A1, A2, and B cells. The results showed that these staining methods do not always distinguish between the different hormone-producing cell types of endocrine pancreatic tumors. In spite of the fact that several types of hormone-secreting cells were found in the tumors, the case histories described symptoms characteristic of hypersecretion of only one of the hormones. The hormone of the predominating cell type could not always explain the clinical symptoms. Our results indicate the endocrine pancreatic tumors often are multihormonal. Therefore, it would seem advisable to screen serum from all insuloma patients for a variety of peptide hormones.

Topics: Adrenocorticotropic Hormone; Adult; Female; Fluorescent Antibody Technique; Gastrins; Glucagon; Hormones, Ectopic; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Spectrometry, Fluorescence

Results of light and electron-microscopic studies of primary pancreatic tumor and of metastasis in a new case of Pancreatic Cholera (P.C.) are reported. The primary tumor but not the metastases, contained unusual, large cystic glandular formations, lined both by pancreatic-duct- and small-intestine-like epithelia and closely connected with the endocrine proliferation. A part from a few D-cells, the endocrine tumoral cells could not be identified by histochemical stainings. Their ultrastructural pattern, with small secretory granules (diameter less than 300 nm) and numerous cytoplasmic bunches of filaments, was very similar to that of gastric and duodenal D1-cells. Normal duodenal D1-cells have been said to produce gastric inhibitory peptide, a substance structurally and biologically similar to the vasoactive intestinal peptide actually secreted by the tumor. The normal histological appearance of gastric, gallbladder, jejunal, ileal, right and left colonic mucosae is consistent with the responsibility of the tumoral secretion in the impairment of gut functions in P.C.

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Adult; Cell Transformation, Neoplastic; Cytoplasmic Granules; Dehydration; Female; Gastric Mucosa; Gastrins; Histocytochemistry; Humans; Intestines; Liver Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Peptides; Syndrome

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Child; Diarrhea; Female; Gastric Juice; Gastrins; Glucose; Humans; Hypercalcemia; Male; Middle Aged; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

L-asparaginase (140,000 units) infused into the hepatic artery resulted in a remission from disabling hypoglycaemia for nine months in a man with islet cell carcinoma of the pancreas and hepatic metastases. The tumour produced insulin and gastrin with resulting hypoglycaemia and recurrent peptic ulceration which were unresponsive to other drugs. Following L-asparaginase there was a fall in both plasma and insulin and gastrin.

Topics: Adenoma, Islet Cell; Asparaginase; Gastrins; Humans; Hypoglycemia; Insulin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms

Topics: Adenoma, Islet Cell; Adult; Gastrins; Humans; Male; Pancreatic Neoplasms; Time Factors; Zollinger-Ellison Syndrome

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

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

Material from eight peptide hormone-secreting tumours, extirpated from the pancreas or from the antrum-duodenum region, was examined. Four of the patients had the clinical manifestations of the Zollinger-Ellison syndrome, two showed the features of an insulin-secreting tumour and one had a glucagonoma. Gastrin-producing cells, identified by immunohistochemistry, were found in five of the tumours. These cells displayed a varying degree of formaldehyde-ozone-induced fluorescence. This agrees with previous observations on the gastrin cell of human antral and duodenal mucosa. From model experiments, formaldehyde-ozone-induced fluorescence is thought to reflect the presence of peptides having tryptophan in the NH2-terminal position. The nature of this peptide in gastrin-producing cells is unknown.

Topics: Adult; Aged; Duodenal Neoplasms; Female; Fluorescence; Formaldehyde; Gastrins; Gastrointestinal Neoplasms; Glucagon; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Ozone; Pancreatic Neoplasms; Stomach Neoplasms; Tryptophan; Zollinger-Ellison Syndrome

With better methods of diagnosis, patients will be identified earlier in the course of their disease and will often have atypical and borderline manifestations of the syndrome. Serum gastrin measurements with calcium and especially with secretin challenge will be the most important method of diagnosis. Any patient with acid hypersecretion who has a high serum gastrin level that does higher on secretin infusion should be considered to have the Zollinger-Ellison syndrome. A firm diagnosis of the Zollinger-Ellison syndrome should be made, if at all possible, prior to operation. At operation, a thorough search of the pancreas, duodenum, stomach, greater and lesser omentum and liver should be made for primary and secondary gastrinomas. If the preoperative data firmly establish the diagnosis of the Zollinger-Ellison syndrome, a total gastrectomy should be carried out even if no primary tumor is found. Similarly, a total gastrectomy should be done even if there are massive hepatic metastases. If total gastrectomy is not performed, the patient is apt to die of complications of acid hypersecretion. The only possible exceptions to the rule of always performing a total gastrectomy are in asymptomatic patients with easily excisable tumors or patients with tumors of the duodenum that are easily excisable, providing that in both instances after the excision of the tumor the output of gastric acid as measured at operation is immediately halted. All possible metastatic tumor tissue should be removed. The more tumor tissue removed, the longer the patient will survive. Metastases should be treated aggressively. They do not disappear after total gastrectomy in our experience, and they may kill patients. Patients should be followed after operation with serial measurements of serum gastrin concentrations and by hepatic scintillation scans and hepatic angiography. If hepatic metastases develop, intrahepatic artery infusions of 5-fluorouracil may slow tumor growth.

Topics: Adenocarcinoma; Adult; Aged; Angiography; Calcium; Endoscopy; Female; Gastrectomy; Gastrins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Peptic Ulcer; Postoperative Complications; Preoperative Care; Radioimmunoassay; Secretin; Zollinger-Ellison Syndrome

Topics: Alcoholism; Amylases; Anemia, Pernicious; Atrophy; Bicarbonates; Gastrins; Gastritis; Humans; Pancreas; Pancreatic Juice; Pancreatic Neoplasms; Pancreatitis; Secretin; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adult; Aged; Dehydration; Diagnosis, Differential; Diarrhea; Female; Fluorescent Antibody Technique; Gastrins; Humans; Hypokalemia; Islets of Langerhans; Male; Microscopy, Electron; Middle Aged; Neoplasm Metastasis; Pancreas; Pancreatic Neoplasms; Radioimmunoassay; Staining and Labeling; Syndrome; Zollinger-Ellison Syndrome

Topics: Adult; Aged; Carcinoid Tumor; Cholinesterases; Esterases; Female; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Hormones; Humans; Immunochemistry; Kidney Neoplasms; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Peptide Biosynthesis; Staining and Labeling

Topics: Adenoma, Islet Cell; Adolescent; Adult; Age Factors; Calcium; Child; Fasting; Female; Gastric Acidity Determination; Gastric Juice; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Diarrhea; Gastrins; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Secretin; Syndrome; Zollinger-Ellison Syndrome

Topics: Alkaline Phosphatase; Amylases; Bilirubin; Duodenal Neoplasms; Duodenum; gamma-Glutamyltransferase; Gastrins; Humans; Intestinal Absorption; Iron; Leucyl Aminopeptidase; Lipase; Pancreas; Pancreatic Neoplasms; Pancreatitis; Postoperative Complications

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

Topics: 5-Hydroxytryptophan; Adrenocorticotropic Hormone; Aldosterone; Carcinoid Tumor; Carcinoma, Adenoid Cystic; Chromaffin System; Cortisone; Female; Gastrins; Humans; Hydroxyindoleacetic Acid; Inclusion Bodies; Insulin; Lymphatic Metastasis; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Serotonin

Topics: Adenoma, Islet Cell; Antibodies; Gastrins; Humans; Molecular Weight; Pancreatic Neoplasms

Topics: Adenoma, Islet Cell; Adult; Aged; Carcinoid Tumor; Diarrhea; Female; Gastrins; Humans; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Neoplasm Metastasis; Pancreas; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Adenocarcinoma; Adenoma, Islet Cell; Calcium; Child; Duodenal Diseases; Gastric Juice; Gastrins; Humans; Lymphatic Metastasis; Male; Pancreatic Neoplasms; Radiography; Zollinger-Ellison Syndrome

The effect of total gastrectomy on the biologic behavior of malignant gastrinomas was studied from patient data collected in the ZE tumor registry. A total of 267 patients with documented metastatic tumor had definitive gastric operations. In the 137 patients who had total gastrectomy, survival was 75% at one year, 55% at five years and 42% at ten years. In the 130 patients who had lesser gastric operations, survival was 51% at one year, 27% at five years and 18% at ten years. Deaths from progressive tumor growth occurred in 17% of the patients at risk after total gastrectomy and 30% of the patients at risk after lesser gastric operations. A subgroup of 127 patients with documented liver metastasis had definitive gastric operations. Seventythree patients with liver metastasis had total gastrectomy with survival of 68% at one year, 42% at five years and 30% at ten years. Fifty-four patients with liver metastasis had lesser gastric operations with survival of 44% at one year, 7% at five years and none at ten years. Deaths from progressive tumor growth occurred in 25% of the patients at risk after total gastrectomy and 50% of the patients at risk after lesser gastric operations. Regression of metastatic ZE tumor was clearly documented in only four patients; all had total gastrectomy. Presumptive regression of primary tumor occurred in seven patients, five had total gastrectomy. The study clearly demonstrated that total gastrectomy was the procedure of choice for malignant ZE tumors, even in the presence of widespread metastasis. The results provided indirect evidence to support a gastric feedback effect which influences growth of gastrinomas; however, the results also show that total gastrectomy furnished neither predictable nor permanent protection from subsequent tumor growth and metastasis.

Topics: Adolescent; Adult; Female; Gastrectomy; Gastrins; Humans; Liver Neoplasms; Male; Neoplasm Metastasis; Neoplasm Regression, Spontaneous; Pancreatic Neoplasms; Prognosis; Zollinger-Ellison Syndrome

In both normal volunteers and in patients with primary hyperparathyroidism, the induction of a metabolic alkalosis by infusion of sodium bicarbonate results in a decrease in serum calcium ion and in an increase of circulating parathyroid hormone concentrations. Bicarbonate infusion may serve in man as a new provocative test for release of parathyroid hormone. Furthermore, we speculate that the metabolic alkalosis which is found at times in patients with the Zollinger-Ellison syndrome and severe peptic ulcer disease may result in parathyroid gland stimulation.

Topics: Adult; Aged; Alkalosis; Bicarbonates; Calcium; Female; Gastric Juice; Gastrins; Humans; Hypercalcemia; Hyperparathyroidism; Male; Metabolic Clearance Rate; Middle Aged; Pancreatic Neoplasms; Parathyroid Hormone; Peptic Ulcer; Sodium Chloride; Zollinger-Ellison Syndrome

Topics: Achlorhydria; Diagnosis, Differential; Duodenal Ulcer; Fasting; Gastrectomy; Gastrins; Humans; Hyperplasia; Malabsorption Syndromes; Male; Middle Aged; Pancreatic Neoplasms; Peptic Ulcer; Stomach Diseases; Zollinger-Ellison Syndrome

Topics: Achlorhydria; Gastrectomy; Gastric Juice; Gastrins; Humans; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

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

Topics: Acromegaly; Anemia, Pernicious; Duodenal Neoplasms; Gastric Mucosa; Gastrins; Humans; Hyperparathyroidism; Pancreatic Neoplasms; Peptic Ulcer; Pyloric Antrum; Time Factors; Zollinger-Ellison Syndrome

Topics: Adolescent; Adult; Age Factors; Aged; Child; Diagnosis, Differential; Female; Gastric Juice; Gastrins; Histamine; Humans; Hyperinsulinism; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Hormones; Pancreatic Neoplasms; Secretory Rate; Sex Factors; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Asparaginase; Child; Child, Preschool; Cushing Syndrome; Female; Gastrins; Glucagon; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Phenytoin; Secretin; Streptozocin; Zollinger-Ellison Syndrome

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

Topics: Adult; Blood Glucose; Calcitonin; Calcium; Circadian Rhythm; Duodenal Ulcer; Female; Follicle Stimulating Hormone; Gastrectomy; Gastrins; Glucagon; Growth Hormone; Hormones; Humans; Hydrocortisone; Insulin; Luteinizing Hormone; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Parathyroid Neoplasms; Pedigree; Phosphorus; Prolactin; Thyrotropin

Topics: Adult; Animals; Autopsy; Fluorescent Antibody Technique; Gastrins; Histocytochemistry; Humans; Immune Sera; Lymph Nodes; Lymphatic Metastasis; Male; Microscopy, Electron; Pancreatic Neoplasms; Rabbits; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Duodenal Neoplasms; Follow-Up Studies; Gastrectomy; Gastric Acidity Determination; Gastrins; Humans; Hyperplasia; Lymph Node Excision; Lymphatic Metastasis; Male; Methods; Pancreatic Neoplasms; Vagotomy; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Calcium; Chlorides; Diarrhea; Follow-Up Studies; Gastric Juice; Gastrins; Humans; Lymph Nodes; Male; Middle Aged; Neoplasm Metastasis; Pancreas; Pancreatic Neoplasms; Potassium; Sodium; Stimulation, Chemical; Syndrome; Time Factors

Topics: Adenoma, Islet Cell; Adult; Aged; Angiography; Carcinoid Tumor; Celiac Artery; Cytoplasmic Granules; Duodenal Neoplasms; Female; Gastrins; Humans; Insulin; Insulin Secretion; Male; Mesenteric Arteries; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Serotonin; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Calcium; Endocrine Glands; Gastric Acidity Determination; Gastrins; Humans; Hyperparathyroidism, Secondary; Pancreatic Neoplasms; Secretory Rate; Thyroid Neoplasms; Zollinger-Ellison Syndrome

Topics: Adult; Autopsy; Bone Neoplasms; Calcinosis; Gastrins; Humans; Hypoglycemia; Liver; Liver Neoplasms; Male; Neoplasm Metastasis; Pancreatic Neoplasms; Radiography; Stomach; Zollinger-Ellison Syndrome

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

Topics: Carcinoid Tumor; Gastric Acidity Determination; Gastric Juice; Gastrins; Hormones, Ectopic; Humans; Intestinal Mucosa; Intestine, Small; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptic Ulcer; Stomach; Zollinger-Ellison Syndrome

Topics: Gastrins; Histocytochemistry; Humans; Islets of Langerhans; Microscopy, Electron; Pancreatic Neoplasms; Staining and Labeling; Zollinger-Ellison Syndrome

Topics: Acidosis; Adenoma, Islet Cell; Adult; Autopsy; Diarrhea; Female; Fluorescent Antibody Technique; Gastric Juice; Gastrins; Gastrointestinal Hormones; Humans; Hypokalemia; Liver Neoplasms; Male; Neoplasm Metastasis; Pancreatic Neoplasms; Peptides; Radioimmunoassay; Secretin; Syndrome

Topics: Adenoma, Islet Cell; Diarrhea; Fluorouracil; Follow-Up Studies; Gastrectomy; Gastrins; Glucagon; Humans; Immunoassay; Insulin; Insulin Secretion; Neoplasm Metastasis; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Streptozocin

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Diarrhea; Female; Gastrins; Humans; Hyperglycemia; Hyperinsulinism; Hypokalemia; Insulin; Insulin Secretion; Kidney Diseases; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Zollinger-Ellison Syndrome

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

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

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

The clinical data are presented of two women with profound metabolic upset from exceptional water and electrolyte losses in diarrhoea. One had an islet-cell adenoma of the pancreas and the other abnormal islets. Gastric and pancreatic function were abnormal in both, consistent with the subsequent demonstration of a pancreatic and choleretic secretagogue in the tumour tissue and pancreatic and gastric secretagogues in circulating blood (Cleator, Thomson, Sircus, and Coombes, 1970).

Topics: Adenoma, Islet Cell; Adult; Diarrhea; Female; Gastrins; Humans; Hypercalcemia; Hypokalemia; Hyponatremia; Islets of Langerhans; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Peptides; Radionuclide Imaging; Water-Electrolyte Balance

Methods for bio-assay of secretin-like humoral agents in both cat and dog are described. Bio-assay of tumour extracts and of plasma from patients with the pancreatic choleraic syndrome are described. The first patient was found to have choleretic and secretinlike activity in an extract of her pancreatic islet cell tumour and gastrin-like activity in her plasma. The second patient was found to have both secretin and gastrin-like activity in her plasma, as well as choleretic activity. It is concluded that at least part of the profuse, watery electrolyte diarrhoea of the ;pancreatic cholera' syndrome associated with peptide-secreting adenoma of the pancreas is likely to be a reflection of the excessive production of secretin, as well as of gastrin, and possibly also of a choleretic agent.

Topics: Adenoma, Islet Cell; Animals; Bicarbonates; Biological Assay; Cats; Diarrhea; Dogs; Gastrins; Humans; Pancreas; Pancreatic Neoplasms; Rats; Secretin; Water-Electrolyte Balance

Topics: Adenoma, Islet Cell; Diarrhea; Gastrins; Humans; Hypokalemia; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Secretin; Zollinger-Ellison Syndrome

Topics: Adult; Aged; Diarrhea; Female; Gastric Juice; Gastrins; Glucocorticoids; Glucose Tolerance Test; Humans; Hypercalcemia; Islets of Langerhans; Male; Middle Aged; Pancreatic Neoplasms; Preoperative Care; Radiography; Secretin

Topics: Aged; Animals; Biological Assay; Dogs; Female; Gastrins; Humans; Neoplasm Metastasis; Pancreatic Neoplasms; Skin Neoplasms; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adult; Animals; Dogs; Female; Gastric Juice; Gastrins; Humans; Male; Pancreatic Neoplasms; Peptic Ulcer; Rats; Swine; Zollinger-Ellison Syndrome

Topics: Adrenal Gland Neoplasms; Adult; Child; Gastrins; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Multiple Endocrine Neoplasia; Pancreatic Diseases; Pancreatic Neoplasms; Parathyroid Neoplasms; Tolbutamide

Topics: Animals; Dogs; Gastrins; Histamine; Humans; Pancreatic Neoplasms; Vagus Nerve

Topics: Adenoma, Islet Cell; Antibiotics, Antineoplastic; Blood Glucose; Female; Gastrins; Glucagon; Hormones, Ectopic; Humans; Hypoglycemia; Insulin; Insulin Secretion; Liver Neoplasms; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Radionuclide Imaging

Topics: Adenoma, Islet Cell; Adult; Calcium; Gastric Acidity Determination; Gastric Juice; Gastrins; Glucagon; Humans; Hypercalcemia; Insulin; Magnesium; Male; Pancreatic Neoplasms; Stimulation, Chemical; Vagotomy; Zollinger-Ellison Syndrome

Topics: Adult; Angiography; Celiac Artery; Female; Gastrins; Humans; Insulin; Laparotomy; Mesenteric Arteries; Neoplasm Metastasis; Pancreatic Neoplasms; Radionuclide Imaging; Selenium; Technetium

Topics: Adult; Aged; Duodenal Ulcer; Female; Gastric Acidity Determination; Gastric Juice; Gastrins; Histamine; Humans; Male; Middle Aged; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Topics: Adult; Aged; Animals; Biological Assay; Diarrhea; Female; Gastric Acidity Determination; Gastric Juice; Gastrins; Humans; Male; Middle Aged; Pancreatic Neoplasms; Peptic Ulcer; Rats; Secretory Rate; Urine; Zollinger-Ellison Syndrome

Topics: ACTH Syndrome, Ectopic; Adenoma, Islet Cell; Adrenocorticotropic Hormone; Adult; Fatal Outcome; Female; Gastrins; Humans; Islets of Langerhans; Melanocyte-Stimulating Hormones; Neoplasms; Neuroendocrine Tumors; Pancreatic Neoplasms

The production of ACTH-like material by tumours arising in non-endocrine tissue may initiate severe adrenocortical hyperfunction. The pathogenesis and clinical and laboratory features of Cushing's syndrome associated with such tumours are characteristic. The autonomous production by the tumour of ACTH-like material cannot be suppressed by exogenous corticoids. The onset of clinical symptoms is rapid; muscle wasting, general weakness, thirst and peripheral edema predominate, and the classical signs of Cushing's syndrome may be absent. High levels of plasma 17-hydroxycorticosteroids and urinary 17-hydroxycorticosteroids and 17-ketosteroids, usually with normal levels of urinary aldosterone, commonly occur. Hypokalemic alkalosis unresponsive to replacement therapy may cause death. In the case reported herein, the intriguing possibility exists that two hormone-like substances were produced by the primary growth and its metastases: one, ACTH-like, to account for the adrenal hyperplasia and Cushing's syndrome; and another, gastrin-like, giving rise to the ulcerogenic diathesis.

Topics: 17-Hydroxycorticosteroids; 17-Ketosteroids; Adenoma, Islet Cell; Adrenalectomy; Adrenocortical Hyperfunction; Autopsy; Carcinoma, Islet Cell; Chloramphenicol; Cushing Syndrome; Drug Therapy; Gastrins; Humans; Hypokalemia; Neoplasm Metastasis; Neoplasms; Pancreatic Neoplasms; Pathology; Spironolactone; Zollinger-Ellison Syndrome

It is suggested that there are two hormonal syndromes associated with noninsulin-secreting islet cell tumours and this case is an example of the non-gastrin-secreting type with watery diarrhoea and hypokalaemia. The patient had histamine-fast achlorhydria and a normal gastric biopsy and no gastrin was recovered from the tumour tissue. The watery diarrhoea was isosmotic with plasma and was increased by an intravenous saline load. There was a dramatic response to steroids.

Topics: Achlorhydria; Adenoma, Islet Cell; Aldosterone; Cortisone; Dexamethasone; Diarrhea; Feces; Gastrins; Humans; Hypocalcemia; Hypokalemia; Neoplasms; Pancreatic Neoplasms; Potassium; Prednisone; Sodium; Surgical Procedures, Operative; Urine; Water-Electrolyte Balance; Zollinger-Ellison Syndrome

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

Topics: Child; Gastrins; Humans; Liver Neoplasms; Neoplasms; Pancreatic Neoplasms; Pathology; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Carcinoma, Islet Cell; Gastrins; Humans; Pancreatic Neoplasms; Peptic Ulcer; Stomach; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Gastric Juice; Gastrins; Gastrointestinal Hormones; Humans; Neoplasms; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Black People; Gastric Juice; Gastrins; Gastrointestinal Hormones; Humans; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Endocrine Glands; Endocrine System Diseases; Gastrins; Gastrointestinal Hormones; Humans; Pancreatic Neoplasms; Peptic Ulcer; Ulcer

Topics: Adenoma, Islet Cell; Gastric Juice; Gastrins; Gastrointestinal Hormones; Humans; Pancreatic Neoplasms; Peptic Ulcer; Zollinger-Ellison Syndrome