gastrins and Neoplasm-Metastasis

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

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

G17DT or Gastrimmune, as it was formally known, is an antigastrin 17 immunogen producing neutralising high affinity antibodies directed against gastrin-17 (G17). Preclinical studies, initiated to identify biological functionality of G17DT-induced antibodies, confirmed that the antibodies both reduced G17 stimulated gastric acid secretion and inhibited gastrin from interacting with the CCK-2 receptor. Therapeutic efficacy of both passive and active immunisation with G17DT has been established in a number of tumour systems including both primary and metastatic disease. Furthermore, additive effects with 5-fluorouracil (5-FU)/leucovorin have been confirmed in both colon and gastric tumour models. Phase I/II studies in advanced gastrointestinal (GI) malignancies have shown no systemic or autoimmune reactions to active immunisation with G17DT. Use of an optimised dose has yielded a high proportion of responders (> 80%), with minimal side effects and antibody titres measurable within 2-4 weeks. Taken together these results suggest that the G17DT immunogen is a promising agent for the treatment of GI cancer and Phase III trials, currently underway, will definitively evaluate this early promise.

Topics: Adenocarcinoma; Animals; Antibodies; Antigens; Cancer Vaccines; Clinical Trials as Topic; Colonic Neoplasms; Diphtheria Toxoid; Gastrins; Gastrointestinal Neoplasms; Humans; Immunotherapy; Multicenter Studies as Topic; Neoplasm Metastasis; Stomach Neoplasms

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

An assessment of treatment methods for the Zollinger-Ellison syndrome over 25 years suggests that the dual surgical approach of excision of resectable tumor and total gastrectomy provides the greatest possibility of attaining tumor and serum gastrin control. Normal serum gastrin levels and reduction of tumor status, not observed with nonoperative management, were attained by surgical treatment, particularly when the tumor (or hyperplasia) was limited to the pancreas, stomach, duodenum and regional lymph nodes. Eleven of 16 such operations resulted in tumor control, and 10 of these patients developed normal serum gastrin concentrations. In elective clinical situations combined medical and surgical therapy is a rational approach allowing confirmation of diagnosis and safe, definitive surgical control of the syndrome before metastases occur.

Topics: Cimetidine; Gastrectomy; Gastrins; Guanidines; Humans; Neoplasm Metastasis; Retrospective Studies; Streptozocin; Zollinger-Ellison Syndrome

Topics: Cimetidine; Gastrectomy; Gastric Juice; Gastrins; Humans; Hyperplasia; Neoplasm Metastasis; Postoperative Complications; Pyloric Antrum; Vagotomy; 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

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

Topics: Adult; Duodenal Ulcer; Female; Gastrectomy; Gastric Juice; Gastric Mucosa; Gastrins; Humans; Intestine, Small; Jejunum; Male; Middle Aged; Neoplasm Metastasis; Radiography; Radioimmunoassay; Ulcer; Zollinger-Ellison Syndrome

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

Somatostatin and gastrin receptors are overexpressed in medullary thyroid carcinoma (MTC) cells; hence, both of them are potential targets for peptide receptor scintigraphy and radiotherapy. Therefore, the aim of our study was to assess the clinical value of two technetium-99m-labeled peptides, a new gastrin analog, the EDDA/HYNIC-(D)Glu-octagastrin and a somatostatin analog, EDDA/HYNIC-Tyr(3)-octreotide (EDDA/HYNIC-TOC) for scintigraphy in patients with MTC to detect recurrences and metastases and select patients for peptide receptor radiotherapy.. Thirty (30) patients, 20 females and 10 males, 22-83 years of age (mean, 52.7) with the diagnosis of MTC in different stages of the disease (preoperative, postsurgery, remission, recurrence, or metastatic disease) were included in this study. Before surgery, in all patients serum calcitonin concentrations were elevated. The diagnosis of MTC was confirmed in all cases by histopathology of the removed tumor and immunohistochemical staining giving positive reactions for calcitonin and chromogranin A. Imaging studies using (99m)Tc-EDDA/HYNIC-TOC and a new minigastrin analog, (99m)Tc-EDDA/HYNIC-(D)Glu-octagastrin, were performed in each patient and the results compared with each other and with other imaging methods. Scans of the whole body, head, neck, and chest were performed 2 and 4 hours after injections of the tracer, 500-600 MBq in each case, using a double-head Varicam (Elscint, Israel) gamma camera.. (99m)Tc-EDDA/HYNIC-TOC detected somatostatin receptor-positive lesions in 20 patients with MTC, whereas (99m)Tc-EDDA/HYNIC-(D)Glu-octagastrin displayed gastrin receptors in 11 patients. In 9 cases, the scans were positive in both methods, although in 2 cases different pathologic foci were visualized. In 12 cases, only (99m)Tc-EDDA/HYNIC-TOC scintigraphy was positive, whereas in 3 other cases only (99m)Tc-EDDA/HYNIC-(D)Glu-octagastrin revealed pathologic lesions.. Scintigraphy using (99m)Tc-HYNIC-TOC permits the visualization of somatostatin receptor-positive MTC in the majority of cases. The new gastrin analog, (99m)Tc-HYNIC-(D)Glu-octagastrin, is well tolerated, shows no renal retention, and in some cases of MTC, provides additional information on the expression of gastrin receptors. However, inferior quality of octagastrin scans indicates the need for further improvement of this radiopeptide.

Topics: Adult; Aged; Aged, 80 and over; Animals; Carcinoma, Medullary; Edetic Acid; Female; Gastrins; Humans; Hydrazines; Indium Radioisotopes; Male; Mice; Mice, Inbred BALB C; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Nicotinic Acids; Organotechnetium Compounds; Radionuclide Imaging; Sensitivity and Specificity; Thyroid Gland; Thyroid Neoplasms

Proton pump inhibitors (PPIs) are administered commonly to aged people; however, their effect on colorectal cancer (CRC) has still not been fully elucidated. Here, we examined the effect of PPIs and consequent alkalization on CRC cells. PPI administration alkalized the fecal pH and increased serum gastrin concentration. PPI and pH8 treatment (alkalization) of CMT93 mouse colon cancer cells inhibited cell growth and invasion, increased oxidative stress and apoptosis, and decreased mitochondrial volume and protein levels of cyclin D1 and phosphorylated extracellular signal-regulated kinase (pERK) 1/2. In contrast, gastrin treatment enhanced growth and invasion, decreased oxidative stress and apoptosis, and increased mitochondrial volume and cyclin D1 and pERK1/2 levels. Concurrent treatment with a PPI, pH8, and gastrin increased aldehyde dehydrogenase activity and also enhanced liver metastasis in the BALB/c strain of mice. PPI administration was associated with

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Clostridium perfringens; Colorectal Neoplasms; Cyclin D1; Enterotoxins; Extracellular Signal-Regulated MAP Kinases; Feces; Gastrins; Hydrogen-Ion Concentration; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mitochondria; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Oxidative Stress; Proton Pump Inhibitors

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

Peritoneal metastasis is a major cause of recurrence of gastric cancer and integrins are key molecules involved in gastric cancer cells attachment to the peritoneum. The peptide hormone, gastrin, initially identified for its role in gastric acid secretion is also a growth factor for gastric mucosa. Gastrin has also been shown to contribute to gastric cancers progression. Here, we provide the first evidence that gastrin increases the adhesion of gastric cancer cells. Gastrin treatment induces the expression of α2 integrin subunit through a mechanism that involves the ERK pathway. We also observed in response to gastrin an increase in the amount of α2 integrin associated with β1subunit. In addition, gastrin-stimulated cell adhesion was blocked with an anti-α2β1 integrin neutralizing antibody. We also show that gastrin activates the integrin pathway via the phosphorylation of β1 integrin by a Src family kinase. This mechanism may contribute to the enhancement of cell adhesion observed in response to gastrin since we found an inhibition of gastrin-mediated cell adhesion when cells were treated with a Src inhibitor. By regulating one of the key step of the metastatic process gastrin might contribute to increase the aggressive behaviour of human gastric tumours.

Topics: Cell Adhesion; Cell Line, Tumor; Gastrins; Humans; Integrin alpha2beta1; MAP Kinase Signaling System; Neoplasm Metastasis; Peritoneal Neoplasms; Peritoneum; Phosphorylation; Signal Transduction; Stomach Neoplasms

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

To review the presentation, treatment and outcome of patients with type 1 gastric carcinoid tumours.. We retrospectively reviewed medical records and re-evaluated histopathological specimens of 26 patients with type 1 gastric carcinoids treated at a single tertiary referral centre from 1993 to 2013, with median time of follow-up 52.5 months (IQR 90.8).. Seven patients (27%) had single tumours and 19 patients (73%) multiple tumours at the time of diagnosis. The median number of tumours and median diameter of largest tumour were 2.5 (IQR 3.2) and 6.0 mm (IQR 9.5) respectively. Median serum gastrin was 321.0 pmol/l (IQR 604.0) and median serum chromogranin A 7.7 nmol/l (IQR 5.3). Three patients had metastatic disease at the time of diagnosis and two developed metastases during follow-up. Patients with metastatic disease had larger primary tumours than the others (20.0 mm (IQR 28.5) vs. 5.0 mm (IQR 5.5), p = 0.04). There was a positive correlation between age and tumour size (r = 0.44, p = 0.03) and between serum chromogranin A and serum gastrin at diagnosis (r = 0.76, p = 0.001). Patients were either treated with surgery (n = 8 (31%)), a long-acting somatostatin analogue and/or gastrin receptor antagonist (n = 10 (39%)) for a period of time, or were observed without treatment (n = 8 (31%) with close endoscopic follow up.. Although gastric carcinoids have an overall good prognosis, a significant proportion develops metastatic disease. As partial and total gastrectomy is associated with major side effects, treatment with long-acting a somatostatin analogue or gastrin antagonist should be considered.

Topics: Aged; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Chromogranin A; Comorbidity; Enterochromaffin-like Cells; Female; Follow-Up Studies; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Norway; Octreotide; Receptor, Cholecystokinin B; Retrospective Studies; Somatostatin; Stomach Neoplasms; Tertiary Care Centers; Tomography, X-Ray Computed; Treatment Outcome

Gastric cancer is the most common epithelial malignancy and the second leading cause of cancer-related death worldwide; metastasis is a crucial factor in the progression of gastric cancer. The present study applied gastrin-17 amide (G-17) in SGC7901 cells. The results showed that G-17 promoted the cell cycle by accelerating the G0/G1 phase and by increasing the cell proliferation rate by binding to the gastrin receptor. The migratory and invasive abilities of the SGC7901 cells were increased by G-17. The expression levels of matrix metalloproteinase (MMP)-7, MMP-9 and vascular endothelial growth factor (VEGF) were enhanced by G-17 as well. Moreover, G-17 caused the overexpression of β-catenin and TCF-4. G-17 also caused a preferential cytoplasmic and nuclear localization of β-catenin with a high TOP-FLASH activity. Finally, axin reduced the migratory and invasive abilities of the SGC7901 cells, and inhibited the expression of β-catenin, TCF-4, MMP-7, MMP-9 and VEGF; these effects were counteracted by adding G-17. In summary, the present study confirmed the proliferation and metastasis-promoting role of G-17 via binding to the gastrin receptor, and the β-catenin/TCF-4 pathway was found to be essential for mediating G-17-induced metastasis in gastric cancer. These results may provide a novel gene target for the treatment of gastric cancer.

Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; beta Catenin; Cell Line, Tumor; Cell Movement; Cell Proliferation; G1 Phase; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 7; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Receptor, Cholecystokinin B; Signal Transduction; Stomach Neoplasms; Transcription Factor 4; Transcription Factors; Vascular Endothelial Growth Factor A

We recently reported that overexpression of progastrin (PG) in embryonic epithelial cells (HEKmGAS cells) increased proliferation of the cells compared to that of control HEKC cells. Here, we report the novel finding that tumorigenic and metastatic potential of HEKmGAS cells is also increased significantly compared to that of HEKC cells. Cell surface-associated annexinA2 (CS-ANXA2) binds PG and is overexpressed on cancer cells, allowing us to successfully use fluorescently labeled PG peptide for enumerating metastatic lesions of transformed/cancer cells in vivo. Next, we examined the hypothesis that increased tumorigenic/metastatic potential of isogenic HEKmGAS versus HEKC cells maybe due to transformed phenotype of stem cells. FACSorting/FACScanning of cells demonstrated significant increases in percent doublecortin-CAM-kinase-like1 (DCLK1)/Lgr5-positive stem cells, coexpressing cluster of differentiation44 (CD44)/CS-ANXA2, in HEKmGAS versus HEKC cells. Distinct differences were noted in the morphology of HEKC versus HEKmGAS spheroidal growths on nonadherent cultures (selective for stem cells). HEKC spheroids were rounded with distinct perimeters (e.g., basement membranes), whereas HEKmGAS spheroids were amorphous with no perimeters. Relative levels of DCLK1/Lgr5/CD44 and ANXA2/β-catenin/pNFκBp65/metalloproteinases were significantly increased in HEKmGAS versus HEKC cells, growing as monolayer cultures, 3D spheroids (in vitro), or xenografts (in vivo). Interestingly, HEKC cells enriched for CS-ANXA2 developed amorphous spheroids, whereas downregulation of ANXA2 in HEKmGAS clones resulted in loss of matrixmetalloproteinases (MMPs) and re-formation of rounded spheroids, suggesting that high levels of CS-ANXA2/MMPs may impact spheroid morphology. Downregulation of DCLK1 significantly attenuated activation of β-catenin, with loss of proliferation of HEKmGAS and HEKC cells, suggesting that DCLK1 is required for maintaining proliferation of cells. Our results suggest the novel possibility that transformed stem cells, unlike nontransformed stem cells, coexpress stem cell markers DCLK1 and CD44 with CS-ANXA2.

Topics: Animals; Annexin A2; beta Catenin; Biomarkers; Cell Line; Cell Transformation, Neoplastic; Doublecortin-Like Kinases; Epithelial Cells; Gastrins; Gene Expression; Gene Expression Regulation; Humans; Hyaluronan Receptors; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Mice, Nude; Mice, SCID; Neoplasm Metastasis; Phenotype; Protein Precursors; Protein Serine-Threonine Kinases; Spheroids, Cellular; Stem Cells

Topics: Blood-Brain Barrier; Brain Neoplasms; Breast Neoplasms; Carcinoma; Cytokines; Gastrins; Gastrointestinal Neoplasms; Helicobacter Infections; Humans; Lung Neoplasms; Mast Cells; Neoplasm Metastasis; Stress, Physiological

Gastrointestinal (GI) hormones regulate several GI functions, including the proliferation and repair of normal mucosa, and hormone receptors may therefore be implicated in the growth, invasion, and metastasis of cancers of the GI tract. The aim of this study was to determine the cellular distribution of gastrin in intestinal-type gastric cancers, and to determine its relationship to outcomes after R0 gastrectomy.. Eighty-six consecutive patients undergoing R0 gastrectomy for adenocarcinoma were studied. Normal gastric mucosa and tumor were stained for gastrin and their specific cellular distribution was determined.. The duration of survival of patients whose tumors exhibited well-differentiated gastrin-positive tumor (GPT) cells (n = 12) was significantly poorer than that of patients whose tumors were GPT-negative (5-year survival, 30% vs 54%; P = 0.037). Patients with GPT-positive intestinal-type gastric cancer (5 of 47 patients) had the poorest survival of all (median, 14 months; 5-year survival, 0%; P = 0.006). In a multivariate analysis, only lymph node metastases (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.2 to 3.79; P = 0.01) and the presence of GPT cells (HR, 6.61; 95% CI, 1.74 to 25.09; P = 0.01) were independently and significantly associated with durations of survival in patients with intestinal-type gastric cancer.. The presence of GPT cells in patients with gastric adenocarcinoma is a significant and independent prognostic indicator.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Confidence Intervals; Female; Gastrectomy; Gastrins; Gene Expression; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Multivariate Analysis; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Stomach Neoplasms; Survival Rate

Ghrelin is a potent orexigenic peptide principally produced in the stomach by a distinct population of neuroendocrine cells in the oxyntic mucosa of the fundus. Exogenous ghrelin given as an intravenous infusion has been shown to increase caloric intake in patients with cancer cachexia. In this study, we hypothesized that elevated endogenous ghrelin, produced by increased neuroendocrine cell tumor burden, also exerts an orexigenic effect helping to maintain body mass index. To evaluate the effect of elevated endogenous ghrelin, 35 patients with neuroendocrine tumors were enrolled, assigning them to one of two groups depending on the presence of hepatic metastases. Following an overnight fast, serum was collected and sent for ghrelin measurement by an outside laboratory. The two groups were well matched for all other relevant clinical variables including subtype of tumor, primary location of tumor and tumor treatment history. Nearly all patients with hepatic metastases had elevated levels of ghrelin compared to the standard reference range given for matched controls. The presence of hepatic metastases was associated with significantly elevated ghrelin levels (p<0.05) and a greater mean body mass index. In addition, we report a positive correlation between serum ghrelin and total tumor surface area and between serum ghrelin and body mass index, suggesting that elevated endogenous ghrelin may be sufficient to overcome any partial ghrelin resistance typically seen in cancer cachexia. These results support the possibility that ghrelin is co-released from neuroendocrine tumors and exerts an orexigenic effect in these patients, helping to maintain their body mass index despite widely disseminated disease.

Topics: Adult; Aged; Appetite; Biomarkers; Body Mass Index; Cachexia; Chromogranin A; Female; Gastrins; Ghrelin; Humans; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Prospective Studies

Little is known about the natural course of multiple gastric carcinoids associated with type A gastritis. Between 1993 and 2003, we enrolled eight patients, diagnosed as having multiple gastric carcinoids associated with type A gastritis, in a follow-up program without surgical resection. In these patients, endoscopy showed multiple small polyps on the gastric body, with nonantral atrophic gastritis. Histologically, biopsy specimens obtained from the polyps revealed carcinoid tumors. The serum gastrin level was found to be very high in all patients, and testing for anti-parietal cell antibody was positive in seven. The mean follow-up was 5.8 years (range, 1.5-10.8 years). The levels of serum gastrin increased in all patients, but, endoscopically, the carcinoid tumors did not change in size. Neither hepatic nor lymphatic metastasis was detected on abdominal computed tomography (CT). These patients were free of the development or metastasis of carcinoids, in spite of their continuous hypergastrinemia. It was concluded that multiple gastric carcinoids associated with type A gastritis may be indolent.

Topics: Aged; Biopsy; Carcinoid Tumor; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Gastrins; Gastritis; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Stomach Neoplasms

Adhesion between neighbouring epithelial cells is a crucial and tightly controlled process. In the gastrointestinal tract, the integrity of cell-cell contacts is essential for the regulation of electrolyte absorption and for the prevention of tumour metastasis. We recently showed that migration of the gastric epithelial cell line IMGE-5 is stimulated by the nonamidated form of the hormone gastrin(17). Here, we examine the effect on cell-cell adhesion of the prohormone progastrin, the concentration of which is increased in the plasma of patients with colorectal carcinoma. Progastrin induced the dissociation of both tight junction (TJ) and adherens junction (AJ) complexes in IMGE-5 cells. In progastrin-secreting DLD-1 human colorectal carcinoma cells, expression of an antisense gastrin construct restored membrane localisation of zonula occludens-1 (ZO-1), occludin, beta-catenin and E-cadherin. This restoration was reversed by treatment with exogenous progastrin. Endogenous or exogenous progastrin also increased the paracellular flux of mannitol, and induced cell migration of several gastrointestinal cell lines. In addition, progastrin enhanced Src tyrosine kinase activity and induced a spatial delocalisation of protein kinase C alpha. Using dominant-negative mutants and pharmacological inhibitors, we showed that the stimulation of Src kinase activity was essential for the regulation of TJs. By contrast, the dissociation of AJs involved phosphatidylinositol 3-kinase, partly through the formation of a complex with protein kinase C alpha. We conclude that separate pathways mediate the disruption of AJs and TJs by progastrin. Either pathway may contribute to the co-carcinogenic role of this prohormone in colorectal carcinoma.

Topics: Adherens Junctions; Animals; Antisense Elements (Genetics); beta Catenin; Cadherins; Cell Adhesion; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Cytoskeletal Proteins; Epithelial Cells; Gastrins; Humans; Intestinal Mucosa; Mannitol; Membrane Proteins; Mice; Neoplasm Metastasis; Occludin; Phosphatidylinositol 3-Kinases; Phosphoproteins; Protein Kinase C; Protein Kinase C-alpha; Protein Precursors; Signal Transduction; src-Family Kinases; Tight Junctions; Trans-Activators; Zonula Occludens-1 Protein

In our inbred strain of cotton rats (Sigmodon hispidus) 50% of the females develop spontaneous ECL cell-derived tumors in the acid-producing part of the stomach due to hypergastrinemia secondary to gastric hypoacidity. Although the mechanism behind the hypoacidity is unknown, the female cotton rat is an excellent model for studying ECL cell-related tumorigenesis. In this study we wanted to explore the malignancy potential of these tumors and the ability of a gastrin receptor antagonist (YF476) to prevent their development. First, nine hypergastrinemic female cotton rats (10 months of age) were diagnosed by laparotomy as having gastric tumors. They were killed 6 months later. Second, 18 female cotton rats (2 months of age) were dosed monthly for 6 months with YF476 (500 micro mol/kg body wt) by s.c. injection, while 21 age-matched animals received vehicle. Samples from each stomach were collected for histology, immunohistochemistry and northern blot analysis. The gastric tumors harbored cells with immunohistochemical features of ECL cells. The tumors were found at times to invade and penetrate the stomach wall and to metastasize to perigastric sites. ECL-derived tumor cells were discovered in peritoneal fluid. At death only 1 out of 18 animals given YF476 displayed carcinomas (invasive growth), compared with 7 out of 21 in the vehicle dosed control group (P = 0.048). The spontaneous gastric tumors in cotton rats derived from ECL cells. The tumors were able to penetrate the stomach wall and to metastasize by intracavital seeding. Gastrin receptor blockade lowered the incidence of such tumors. We propose that the tumors are ECL cell carcinomas and that gastrin is the driving force behind the transformation from normal to malignant ECL cells.

Topics: Animals; Blotting, Northern; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Enterochromaffin-like Cells; Female; Gastrins; Immunohistochemistry; Liver; Mucous Membrane; Neoplasm Metastasis; Rats; Receptor, Cholecystokinin B; RNA, Messenger; Sigmodontinae; Time Factors

Increases in neuroendocrine phenotype and secretory products are closely correlated with tumor progression and androgen independence in prostate cancer. In this study, we explored this correlation using serum progastrin-releasing peptide (ProGRP), a carboxy-terminal region common to three subtypes of precursors for gastrin-releasing peptide (GRP), which is released from the neuroendocrine phenotype to act as a growth factor.. In 60 patients with benign prostatic hyperplasia (BPH) and 200 with prostate cancer, serum ProGRP levels were determined with an enzyme-linked immunosorbent assay (ELISA) kit and evaluated in relation to clinical stage, hormonal treatment, and prostate-specific antigen (PSA) values. Fourteen randomly selected patients were entered in the follow-up study. Additionally, expression of ProGRP as determined by immunohistochemical analysis was compared to that of chromogranin-A (CgA) in tissue samples from several subjects.. We found a positive correlation between PSA and ProGRP in patients with untreated prostate cancer; no correlation was found in the treated groups. The increases in the ProGRP value and in the percentage of patients with higher than normal values were significant (P < 0.0001), especially in the androgen-independent group (P < 0.0001). A longitudinal study showed that, in a subset of patients, the ProGRP values tended to increase transiently when the cancer became androgen independent, but remained unchanged or decreased at the androgen-dependent stage. Positive staining for ProGRP occurred in a different distribution in neuroendocrine tissues than that of staining for CgA.. The clinical results demonstrated the existence of a regulatory mechanism for GRP, which to date had only been observed in cell lines. These findings suggest that GRP is a growth factor potentially upregulated by androgen but that does not rely principally on androgen modulation. The large overlap in levels of ProGRP among the groups limits the use of this value as a monitoring tool. Measurement of ProGRP, however, does have potential as an independent parameter to evaluate androgen-independent progression and to facilitate a new therapeutic strategy that may compensate for current limitations of diagnosis based on PSA alone.

Topics: Adult; Aged; Androgens; Biomarkers, Tumor; Disease Progression; Enzyme-Linked Immunosorbent Assay; Gastrin-Releasing Peptide; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Longitudinal Studies; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Peptide Fragments; Peptides; Phenotype; Prostate-Specific Antigen; Prostatic Neoplasms; Protein Precursors; Recombinant Proteins; Up-Regulation

The high sensitivity of pentagastrin stimulation in detecting primary or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type on human MTC. Indeed, autoradiographic studies have demonstrated cholecystokinin (CCK)-B/gastrin receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, some ovarian cancers, astrocytomas and potentially a variety of adenocarcinomas. The aim of this study was to systematically screen and optimize, in a preclinical model and a pilot clinical study, suitable radioligands for targeting CCK-B receptors in vivo.. A variety of CCK/gastrin-related peptides, all bearing the C-terminal CCK receptor-binding tetrapeptide sequence Trp-Met-Asp-PheNH2 or derivatives thereof, were studied. They were radioiodinated by the lodogen or Bolton-Hunter procedures. The peptides were members of the gastrin or CCK families, which differ by the intramolecular position of a tyrosyl moiety. Their stability and affinity were studied in vitro and in vivo; their biodistribution and therapeutic efficacy were tested in nude mice bearing subcutaneous human MTC xenografts. Diethylenetriamine pentaacetic acid (DTPA) derivatives of suitable peptides were synthesized successfully, and their preclinical and initial clinical evaluations were performed, labeled with 111In.. All members of the CCK or gastrin families were stable in serum (with half-lives of several hours at 37 degrees C); nevertheless, the stability of those peptides bearing N-terminal pGlu residues or D-amino acids was significantly higher. In accordance with their comparably low affinity, nonsulfated members of the CCK family showed fairly low uptake in the tumor and other CCK-B receptor-expressing tissues. Sulfated CCK derivatives performed significantly better but also displayed a comparably high uptake in normal CCK-A receptor-expressing tissues. This effect was probably due to their similar affinity for both CCK-A and CCK-B receptors. Best tumor uptake and tumor-to-nontumor ratios were obtained with members of the gastrin family because of their selectivity and affinity for the CCK-B receptor subtype. Pilot therapy experiments in MTC-bearing animals showed significant antitumor efficacy compared with untreated controls. DTPA derivatives of minigastrin were successfully developed. In a pilot clinical study, radioiodinated and 111In-labeled derivatives showed excellent targeting of physiological CCK-B receptor-expressing organs, as well as all known tumor sites.. CCK/gastrin analogs may be a useful new class of receptor-binding peptides for diagnosis and therapy of CCK-B receptor-expressing tumors, such as MTC or small cell lung cancer. Nonsulfated gastrin derivatives may be preferable because of their CCK-B receptor selectivity, hence lower accretion in normal CCK-A receptor-expressing organs.

Topics: Adult; Aged; Amino Acid Sequence; Animals; Carcinoma, Medullary; Carcinoma, Small Cell; Cholecystokinin; Data Interpretation, Statistical; Female; Gastrins; Humans; Indium Radioisotopes; Iodine Radioisotopes; Isotope Labeling; Lung Neoplasms; Lymphatic Metastasis; Male; Mice; Mice, Nude; Middle Aged; Molecular Sequence Data; Neoplasm Metastasis; Neoplasms, Experimental; Peptides; Radioisotopes; Radionuclide Imaging; Receptors, Cholecystokinin; Thyroid Neoplasms

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

We attempted to clarify whether serum levels of a carboxy-terminal fragment of ProGRP, ProGRP(31-98), could serve as a more accurate tumour marker in patients with SCLC than neuron-specific enolase (NSE). ProGRP(31-98) and NSE were measured retrospectively in 101 newly diagnosed untreated patients with SCLC, 111 with non-small-cell lung cancer (NSCLC) and 114 patients with non-malignant lung diseases. ProGRP(31-98) and NSE levels were determined using a sandwich enzyme-linked immunosorbent assay. Sensitivity in SCLC patients was 72.3% for ProGRP(31-98) and 62.4% for NSE. Comparing the area under curve (AUC) of 'receiver operator characteristics' of ProGRP(31-98) with that of NSE, ProGRP(31-98) was the more powerful marker in the diagnosis of SCLC (P = 0.0001). Serum levels of ProGRP(31-98) were higher in the 40 patients with extensive disease than in the 61 patients with limited disease (P = 0.0082). ProGRP(31-98) was significantly higher in patients with pure small-cell carcinoma than in patients with mixed small-cell/large-cell carcinoma (P = 0.02). In serial measurement in 16 patients responding to treatment, a high degree of correlation was noted between the decrease in serum ProGRP(31-98) levels and clinical response during the second week after treatment (P = 0.0045). These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.

Topics: Biomarkers, Tumor; Carcinoma, Small Cell; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Peptides; Phosphopyruvate Hydratase; Protein Precursors

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

The effects of combined administration of bombesin (40 micrograms/kg body weight) and the ornithine decarboxylase (ODC) inhibitor, 1,3-diaminopropane (DAP), on the development of large and small intestinal tumors and the incidence of their metastasis to the peritoneum induced by azoxymethane (AOM, 7.4 mg/kg body weight), the ODC activity of the intestinal wall, and the labeling index of the intestinal mucosa and tumor were investigated in inbred Wistar rats. Rats received weekly s.c. injections of AOM for 10 weeks, s.c. injections of bombesin every other day, and drinking water containing DAP (2.5 g/l) until the end of the experiment at week 40. Administration of bombesin significantly increased the incidence of intestinal tumors at week 40. It had no influence on the location, size, histological features or depth of involvement of intestinal adenocarcinomas, but significantly increased the incidence of their metastasis to the peritoneum. It also resulted in a significant increase in the intestinal ODC activity and labeling index. Administration of DAP with bombesin significantly reduced the enhancement of intestinal carcinogenesis by bombesin. Although the combined use of DAP with bombesin had little or no influence on the location, size, histological features, or depth of involvement of intestinal cancers, the incidence of their metastasis was significantly reduced. DAP significantly attenuated bombesin enhancement of the intestinal ODC activity and labeling index. These findings indicate that ODC inhibition attenuated the enhancement of intestinal carcinogenesis and metastasis to the peritoneum.

Topics: Adenocarcinoma; Animals; Azoxymethane; Body Weight; Bombesin; Cell Division; Diamines; Drug Synergism; Gastrins; Intestinal Mucosa; Intestinal Neoplasms; Male; Neoplasm Metastasis; Ornithine Decarboxylase Inhibitors; Peritoneal Neoplasms; Rats; Rats, Wistar

Enterochromaffinlike (ECL) cell carcinoids recently observed in rats stimulated new interest in gastric endocrine tumors arising in humans.. Paraffin-embedded sections of 55 endocrine tumor cases were stained with H&E, mucin tests were performed, and immunoperoxidase was used for detecting endocrine markers; 23 cases were also investigated ultrastructurally.. Forty-five argyrophil carcinoids, 9 neuroendocrine carcinomas, and 1 gastrinoma were identified. Three clinicopathologic subtypes of carcinoids were characterized: (1) twenty-eight cases, none metastatic, arose in a background of body-fundus atrophic gastritis and hypergastrinemia; (2) seven cases, 2 locally metastatic, were associated with hypertrophic gastropathy and hypergastrinemia due to multiple endocrine neoplasia/Zollinger-Ellison syndrome; and (3) ten were sporadic cases, 7 of which were deeply invasive, 6 metastatic, and 5 histologically atypical. All carcinoids showed histochemical and ultrastructural patterns of ECL cells. The 9 neuroendocrine carcinomas, all deeply invasive and metastatic, were composed of anaplastic, small- to intermediate-sized cells with high mitotic index and focal necrosis.. Gastrin-promoted carcinoids represent a benign or low grade tumor disease, whereas sporadic carcinoids and neuroendocrine carcinomas are life-threatening neoplasms, independent of gastrin promotion.

Topics: Adult; Aged; Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; Carcinoid Tumor; Chromogranin A; Chromogranins; Female; Gastrins; Glycoprotein Hormones, alpha Subunit; Humans; Immunoenzyme Techniques; Immunohistochemistry; Male; Membrane Glycoproteins; Microscopy, Electron; Middle Aged; Mucin-1; Multiple Endocrine Neoplasia; Neoplasm Invasiveness; Neoplasm Metastasis; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Serotonin; Somatostatin; Stomach Neoplasms; Thiolester Hydrolases; Ubiquitin Thiolesterase

There have been no reports on the relationship between serum gastrin level and liver metastasis in human colorectal cancer. One hundred forty patients who underwent surgery for colorectal cancer (T2 or more) were enrolled in this study. Fasting serum gastrin level was determined prior to the surgery. Incidence of liver metastasis was significantly (P < 0.01) higher in patients with a serum gastrin level of > or = 150 pg/ml (37 percent; 14/38) than in those with a serum gastrin level of < 150 pg/ml (12 percent; 12/102). As for the tumors with venous invasion, liver metastasis was detected in 11 of 55 patients (20 percent) with a serum gastrin level of < 150 pg/ml; however, it was detected in 11 of 19 patients (58 percent) with a serum gastrin level of > or = 150 pg/ml (P < 0.01). These results suggest that serum gastrin serves as a useful predictor of liver metastasis from colorectal cancer and that the predictability of liver metastasis can be improved when both serum gastrin level and venous invasion are considered.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Colorectal Neoplasms; Female; Gastrins; Humans; Incidence; Liver Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Prognosis; Veins

The effects of bombesin on the incidence, number and histology of colon tumors induced by azoxymethane (AOM), and on their metastases to the peritoneum and/or lymph nodes, were investigated in Wistar rats. Rats received weekly s.c. injections of AOM for 10 weeks, and s.c. injections of bombesin in depot form every other day until the end of the experiment in week 30. Administration of bombesin significantly increased the incidence of colon tumors in week 30. It had no influence on the histological features or depths of involvement of colon adenocarcinomas, but significantly increased the incidence of cancer metastasis to the peritoneum and/or lymph nodes. It also caused a significant increase in the labeling index of the colon epithelial cells. Our findings indicate that bombesin enhances the development and metastasis of colon tumors, and that this effect may be related to its effect in increasing proliferation of epithelial cells of the colon.

Topics: Adenocarcinoma; Animals; Azoxymethane; Bombesin; Colon; Colonic Neoplasms; Gastrins; Male; Neoplasm Metastasis; Norepinephrine; Rats; Rats, Inbred Strains

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

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

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

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

The effects of prolonged administration of tetragastrin from the beginning of intrarectal instillation of 1 ml of 0.25% N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and after MNNG-treatment on the incidence and histology of colonic tumors were compared in inbred Wistar rats. In week 35 prolonged administration of testragastrin in depot form from the beginning of MNNG-treatment resulted in a significant reduction in the incidence of colonic tumors and a significant increase in the incidence of mucinous adenocarcinoma, unlike the well-differentiated adenocarcinoma produced in controls without gastrin. In contrast, prolonged administration of tetragastrin after MNNG-treatment had little or no influence on the incidence, size or histology of colonic tumors. Thus tetragastrin had no promoting effect on colonic tumors.

Topics: Adenocarcinoma; Animals; Cocarcinogenesis; Colonic Neoplasms; Drug Administration Schedule; Gastrins; Male; Methylnitronitrosoguanidine; Neoplasm Metastasis; Rats; Rats, Inbred Strains; Tetragastrin

In a patient with Zollinger-Ellison syndrome, control of the peptic ulcer diathesis was attempted by excision of a small duodenal gastrinoma and removal of three lymph nodes containing metastases. The patient has been asymptomatic for 2.5 years with basal achlorhydria, a normal serum gastrin level and a negative gastrin response to secretin. Our experience with this patient emphasizes the fact that the presence of metastatic disease does not preclude the possibility of long-term control of hypergastrinemia by resection of the tumor. Attempts to cure the Zollinger-Ellison syndrome by tumor resection alone, however, should only be made in patients whose hypersecretion is adequately controlled by antisecretory drugs.

Topics: Antacids; Female; Gastrins; Humans; Middle Aged; Neoplasm Metastasis; Zollinger-Ellison Syndrome

Gut endocrine cells in a total of 122 intestinal-tract adenocarcinomas induced in inbred Wistar rats by 1,2-dimethylhydrazine dihydrochloride were examined histologically, ultrastructurally, and immunohistochemically for gastrin, somatostatin, vasoactive-intestinal polypeptide (VIP), and glicentin (enteroglucagon). Of the 122 tumors, argyrophil cells were detected in 42 tumors (34.3%) comprising 15 tumors of the well differentiated type and 27 tumors of the poorly differentiated type, including signet-ring-cell carcinomas. Of the 27 tumors of the poorly differentiated type, 12 were regarded as endocrine-cell carcinomas composed of numerous argyrophil or argentaffin cells and mucus-containing cells. Immunohistochemically, 7 of the 12 tumors had glicentin and two of these seven tumors also had gastrin and argentaffin cells synchronously. None of the tumors showed immunoreactivity for somatostatin and VIP. Nine of the 12 tumors metastasized to the lung, pancreas, liver, mesenterium, omentum, and lymph nodes. The metastatic foci of these tumors were also shown to have glicentin and argentaffin cells. Ultrastructurally, four types of endocrine granule were found in the tumor cells and amphicrine cells containing endocrine granules and mucous granules were noted. These endocrine-cell tumors were assumed to develop from totipotent immature cells of endodermal origin.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Carcinogens; Chromaffin System; Dimethylhydrazines; Enterochromaffin Cells; Female; Gastrins; Glucagon-Like Peptides; Intestinal Neoplasms; Male; Microscopy, Electron; Neoplasm Metastasis; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Somatostatin; Vasoactive Intestinal Peptide

Sulfated gastrins were quantitated in sera from 15 patients with the Zollinger--Ellison syndrome (ZES) by specific radioimmunoassays. The total concentration of gastrin varied from 174 to 285 000 pmol/l. Sulfated gastrins constituted 44.8 +/- 5.5% (mean +/- S.E.M.) of the gastrins in ZES sera compared with 37.7 +/- 1.9% in sera from 100 control subjects (P greater than 0.1). There was no correlation between gastrin concentration and sulfation (r = 0.40). Gel and ion-exchange chromatography showed that up to 90% of the gastrins could be in the sulfated form. The highest degree of sulfation was found in sera where the small gastrin components dominated. Thus, the percentage of small gastrins (G-17 and G-14) correlated with the degree of sulfation (N = 15, r = 0.75, P less than 0.01). We suggest therefore that proteolytic processing of the gastrin precursor and sulfation of tyrosyl are associated.

Topics: Female; Gastrins; Humans; Male; Middle Aged; Molecular Weight; Neoplasm Metastasis; Radioimmunoassay; Sulfuric Acid Esters; Sulfuric Acids; Zollinger-Ellison Syndrome

We determined the relative concentrations of gastrin molecular species in serum samples from 21 patients with Zollinger-Ellison syndrome with localized gastrinoma (n = 11) or gastrinoma with hepatic metastases (n = 10). Gastrin molecular species were separated by gel-filtration chromatography and quantitated by radioimmunoassay with a gastrin antiserum produced in our laboratory. The percentage gastrin-17 of the total gastrin in the two groups differed significantly (nonparametric Wilcoxon rank test; p less than 0.01). Patients with the Zollinger-Ellison syndrome with apparently localized gastrinoma had a lower percentage of G- 17 (7.6%, SEM 1.6%) than did patients with gastrinoma with hepatic metastases (31.1%, SEM 6.1%). This procedure may be useful in the early classification of tumors in patients with Zollinger-Ellison syndrome.

Topics: Gastrins; Humans; Liver Neoplasms; Neoplasm Metastasis; Stomach Neoplasms; Zollinger-Ellison Syndrome

A 35-year-old man with the Zollinger-Ellison syndrome who is alive and well 20 years following diagnosis at age 15, is represented. At the initial operation for a bleeding duodenal ulcer a ZE tumor of the pancreas also was excised. After two additional ineffective ulcer operations, total gastrectomy was performed. At that time, retroperitoneal and peripancreatic metastases were noted, and several were removed. Three years later at laparotomy, extensive hepatic metastases were biopsied as well. Spontaneous remission occurred and when re-explored at age 34, after 14 years, no metastases were identifiable in any area. The serum gastrin level has remained elevated, casting doubt upon its value as a criterion for evaluation of tumor recurrence or activity. Other additional interesting aspects are discussed. The importance of elimination of the acid-secreting cells by total gastrectomy is emphasized. The patient remains well.

Topics: Abdominal Neoplasms; Adolescent; Adult; Gastrectomy; Gastrins; Humans; Male; Neoplasm Metastasis; Remission, Spontaneous; Time Factors; 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

Mean fasting levels of pancreatic polypeptide (PP) in 24 patients with Zollinger-Ellison syndrome (ZES) and in 12 patients with hyperparathyroidism originating from families with multiple endocrine adenomatosis type I (MEAI-HPT) were significantly higher than in 72 normal controls. The overlap between the 3 groups, however, was large. In patients with ZES, increased PP levels were not related to the presence of MEAI or metastases; nor was there a correlation between serum PP and gastrin concentrations. The post-prandial PP release in 10 ZES patients and in 10 patients with MEAI-HPT was lower than in 9 normal controls. The physiological significance of the present findings is unclear.

Topics: Adolescent; Adult; Aged; Fasting; Female; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Multiple Endocrine Neoplasia; Neoplasm Metastasis; Pancreatic Polypeptide; Zollinger-Ellison Syndrome

A case of malignant endocrine tumour of the jejunum, associated with severe duodenal ulcer is described. The tumour and a local metastasis were examined by immunohistochemistry and found to contain abundant somatostatin-immunoreactive cells together with less numerous cells displaying gastrin immunoreactivity. This is to our knowledge the first case of intestinal somatostatinoma. The presence of gastrin cells in the tumour may explain the ulcer diathesis.

Topics: Duodenal Ulcer; Female; Gastrins; Humans; Intestinal Neoplasms; Jejunum; Middle Aged; Neoplasm Metastasis; Somatostatin

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

Topics: Gastrectomy; Gastric Juice; Gastrins; Humans; Male; Middle Aged; Neoplasm Metastasis; Werner Syndrome; Zollinger-Ellison Syndrome

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

Topics: Adult; Diagnosis, Differential; Diarrhea; Female; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Hypercalcemia; Liver Neoplasms; Multiple Endocrine Neoplasia; Neoplasm Metastasis; Zollinger-Ellison Syndrome

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

Over a period of 21 years 39 patients with gastrinoma were surgically treated. Thirty-three patients had total gastrectomy with two postoperative deaths, and 6 patients had a lesser procedure. The postoperative fasting gastrin levels remained elevated and did not always indicate the extent of tumor involvement. Further mobilization of tumor gastrin by provocative infusion of calcium gluceptate, 15 mg/kg of body weight, should be carried out routinely. A hepatic angiogram should be considered when the gastrin levels exceed 1,000 picograms per ml. Chemotherapy consisting of Tubercidin, Streptozotocin and 5-Fluorouracil was given to 5 patients with extensive gastrinoma. All patients felt better and gained from three to 35 pounds in weight. Since 60% of the patients died or have definite evidence of tumor activity it is assumed that the tumor growth was not inhibited and that it is malignant. Approximately 40% of the patients seem to do well despite modest elevations in gastrin levels suggesting that the retained tumor could be considered benign.

Topics: Adenoma, Islet Cell; Fasting; Fluorouracil; Gastrins; Humans; Liver Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Postgastrectomy Syndromes; Prognosis; Stomach Neoplasms; Streptozocin; Tubercidin

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

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

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

50 cases of interposition of jejunal loop (32 for gastric cancer and 18 for ulcerous pathology) carried out over the last 3 years are reported. From a technical point of view and as an alternative to degastroenteroanastomosis, interposition of the loop is preferred in partial oral end-to-end on the stomach. In neoplastic lesions, Mouchet-Camey type reconstruction was adopted as a routine measure. After describing the complications of the operation and analyzing the causes, the long-term results are evaluated using absorption curves with 131-I labelled oleic acid. The excellent weight increase in the inflammatory forms, and the lack of reflow and dumping in patients subjected to total gastrectomy for cancer, confirm the value of the technique.

Topics: Adult; Aged; Dumping Syndrome; Duodenal Ulcer; Gastrectomy; Gastrins; Humans; Iodine Radioisotopes; Jejunum; Middle Aged; Neoplasm Metastasis; Oleic Acids; Peptic Ulcer; Postoperative Complications; Radioimmunoassay; Stomach Neoplasms; Stomach Ulcer; 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: Adolescent; Adult; Aged; Female; Gastrins; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Zollinger-Ellison Syndrome

Topics: Adult; Female; Gastrins; Humans; Liver Neoplasms; Neoplasm Metastasis; 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: Adult; Calcium; Follow-Up Studies; Gastrectomy; Gastrins; Hepatic Artery; Humans; Ligation; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Mesentery; Middle Aged; Neoplasm Metastasis; Peritoneal Neoplasms; Radiography; Radionuclide Imaging; Streptozocin; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Administration, Oral; Aged; Gastrectomy; Gastrins; Glucagon; Glucose; Glucose Tolerance Test; Humans; Injections, Intravenous; Insulin; Insulin Secretion; Liver; Liver Neoplasms; Male; Neoplasm Metastasis; Zollinger-Ellison Syndrome

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

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

A pair of gastrin tridecapeptides (;minigastrins') have been isolated from Zollinger-Ellison tumour tissue; they correspond to the fragment 5-17 of the heptadecapeptides isolated from the same source. In one (type II) the tyrosine residue present is sulphated, in the other (type I) it is not. The proportion of types I and II is approximately 2:1 similar to that for the ;big' gastrins and the heptadecapeptides isolated from the same source and from human antral mucosa. Both minigastrins are potent stimulants of gastric acid secretion. Immunological evidence exists to indicate that both are present as circulating forms of the hormone gastrin in patients with the Zollinger-Ellison syndrome and in fed normal subjects.

Topics: Amino Acids; Chromatography; Chromatography, Gel; Gastrins; Humans; Liver Neoplasms; Molecular Weight; Neoplasm Metastasis; Neoplasm Proteins; Peptide Fragments; Peptides; Zollinger-Ellison Syndrome

Topics: Adult; Celiac Disease; Diarrhea; Esophagitis; Female; Gastrins; Humans; Hyperparathyroidism; Male; Middle Aged; Neoplasm Metastasis; Radiography; 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: 5-Hydroxytryptophan; Adrenocorticotropic Hormone; Breast Neoplasms; Calcitonin; Chorionic Gonadotropin; Erythropoietin; Estradiol; Female; Gastrins; Hormones, Ectopic; Humans; Hyperkalemia; Middle Aged; Neoplasm Metastasis; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Progesterone

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; Adolescent; Adult; Aged; Female; Gastrectomy; Gastric Juice; Gastrins; Humans; Hyperparathyroidism; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Radioimmunoassay; Secretory Rate; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adrenocorticotropic Hormone; Adult; Aminoglutethimide; Gastrins; Glucagon; Hormones, Ectopic; Humans; Male; Metyrapone; Microscopy, Electron; Neoplasm Metastasis; Radioimmunoassay; Streptozocin

Topics: Angiography; Calcium; Female; Gastrectomy; Gastrins; Humans; Lymphatic Metastasis; Male; Neoplasm Metastasis; Pancreatectomy; Prognosis; Radioimmunoassay; Spectrophotometry, Atomic; 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: 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; Adult; Calcium; Duodenal Ulcer; Gastric Juice; Gastrins; Humans; Hypercalcemia; Hyperparathyroidism; Hyperplasia; Male; Neoplasm Metastasis; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adult; Aged; Duodenal Ulcer; Female; Gastrins; Humans; Liver Neoplasms; Male; Neoplasm Metastasis; Zollinger-Ellison 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: Adult; Aged; Carcinoid Tumor; Cholestasis; Duodenal Neoplasms; Duodenal Obstruction; Duodenal Ulcer; Female; Gastrins; Gastrointestinal Hemorrhage; Histamine Release; History, 19th Century; History, 20th Century; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Neoplasm Metastasis; Peptic Ulcer Perforation; Peptides; Prognosis; Serotonin

A patient with a multiple-hormone-producing islet cell carcinoma, who had previously been successfully treated with streptozotocin, was given three further infusions of this drug because of the redevelopment of gastric hypersecretion. Although some evidence of damage to the gastrinsecreting cells was obtained, the fasting plasma gastrin was not significantly altered and the patient died from a perforated duodenal ulcer. Serum insulin levels were considerably reduced and the patient became mildly diabetic but the main complication of treatment was a severe though reversible renal tubular defect. At necropsy considerable quantities of gastrin, but low levels of insulin and glucagon were extracted from a tumour metastasis.

Topics: Acetoacetates; Adenoma, Islet Cell; Antibiotics, Antineoplastic; Autopsy; Blood Glucose; Diabetes Insipidus; Duodenal Ulcer; Female; Gastric Juice; Gastrins; Glucagon; Glucosamine; Humans; Insulin; Kidney Tubules; Lactates; Liver Neoplasms; Middle Aged; Mutagens; Neoplasm Metastasis; Nitroso Compounds; Nitrosourea Compounds; Peptic Ulcer Perforation; Pyruvates; Urea

Topics: Adolescent; Child; Female; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Male; Methods; Neoplasm Metastasis; Prognosis; Radioimmunoassay; Zollinger-Ellison Syndrome

Topics: Adult; Calcium; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Neoplasm Metastasis; Vagotomy; Zollinger-Ellison Syndrome

Topics: Adolescent; Adult; Female; Follow-Up Studies; Gastrectomy; Gastrins; Humans; Hypophysectomy; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Zollinger-Ellison Syndrome

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

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

Two peptides which are potent stimulants of gastric acid secretion are isolated from Zollinger-Ellison tumour tissue. They have aminoacid constitutions identical with those of human gastrin types I and II as isolated from human antral mucosa, and they are present in similar proportions. Their electrophoretic and chromatographic behaviour corresponds to that of human gastrins. Evidence is presented in respect of the one isolated in greater amount that its aminoacid sequence is probably identical with that of human gastrin type I.

Topics: Amino Acid Sequence; Amino Acids; Animals; Cats; Chromatography, Thin Layer; Dogs; Electrophoresis; Gastric Juice; Gastrins; Humans; Neoplasm Metastasis; Pancreas; Peptides; Zollinger-Ellison Syndrome

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; Adrenal Gland Diseases; Gastrins; Glucagon; Glucose Tolerance Test; Humans; Hypercalcemia; Hyperinsulinism; Immunoassay; Insulin; Insulin Antibodies; Insulin Secretion; Multiple Endocrine Neoplasia; Neoplasm Metastasis; Parathyroid Diseases; Tolbutamide; 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; Biological Assay; Diarrhea; Female; Gastrectomy; Gastric Acidity Determination; Gastric Juice; Gastrins; Histamine; Humans; Male; Middle Aged; Neoplasm Metastasis; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Diarrhea; Duodenal Ulcer; Endoplasmic Reticulum; Gastrins; Humans; Hypokalemia; Liver; Microscopy, Electron; Neoplasm Metastasis

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

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