vasoactive-intestinal-peptide and Pancreatic-Neoplasms

Vasoactive intestinal peptide-secreting tumors (VIPomas) are a group of rare neuroendocrine tumors, which cause a typical syndrome of watery diarrhea. Most of these tumors are found in the pancreas and are usually detected at a later stage. Although curative resection is not possible in most of these tumors, both symptom and tumor control can be achieved by a multidimensional approach, to enable a long survival of most patients. There are no clear-cut guidelines for the management of VIPomas because of the rarity of this neoplasm and lack of prospective data. In this review, we discuss the available evidence on the clinical features and management of these rare tumors.

Topics: Diarrhea; Humans; Magnetic Resonance Imaging; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Survival Analysis; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal polypeptide-secreting tumors (VIPomas) are rare neuroendocrine tumors that often present as watery diarrhea, hypokalemia, and achlorhydria or hypochlorhydria. In this study, we present our institutional experience of diagnosis and treatment of VIPomas, along with a review of the Chinese literature since 1980. Patient #1, diagnosed in 1984 and with intact clinical records, shows the natural history of this disease. Patient #2, diagnosed in 2015, shows the results of evaluation by nuclear medicine techniques and the outcomes of standardized treatment. Comprehensive review of 41 cases allows evaluation of clinical characteristics, treatments and outcomes of pancreatic VIPoma patients. All patients presented with watery diarrhea. The average stool volume reached 3247 mL per day. Average serum VIP level was 839.3 ng/L. Twelve of the 41 cases were reported to have metastases at diagnosis. Somatostatin receptor scintigraphy and

Topics: China; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Topics: Aged; Diabetes Mellitus, Type 2; Glucagon; Humans; Male; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Treatment Outcome; Vasoactive Intestinal Peptide

A 53-year-old man presented with diarrhoea and hypokalaemia and was diagnosed with a neuroendocrine tumour of unknown origin with multiple liver metastases. Somatostatin analogues led to a reduction in the size of the tumours and improvement of his symptoms. However, after several years, the tumours grew in size, and the patient's clinical symptoms recurred. The patient underwent transcatheter arterial embolization (TAE) of the hepatic artery to treat the liver metastases. Immediately after embolization, the symptoms disappeared. Although the patient had an unresectable vasoactive intestinal polypeptide-producing neuroendocrine tumour, the endocrine symptoms were able to be controlled with chemotherapy and TAE, resulting in a long-term survival.

Topics: Combined Modality Therapy; Embolization, Therapeutic; Endosonography; Hepatic Artery; Humans; Liver Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

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

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

VIPomas are rare pancreatic endocrine tumors associated with a well-defined clinical syndrome characterized by watery diarrhea, hypokalemia, and metabolic acidosis. The objective of this study was to review a single institution's experience with VIPomas, as well as to review the English literature. A retrospective review of the Johns Hopkins pancreatic database revealed four cases of VIPoma, with three patients being male. All patients presented with watery diarrhea, hypokalemia, hypercalcemia, and acidosis. All patients had no family history of multiple endocrine neoplasia. Computed tomography revealed the primary pancreatic tumor in all patients, with three tumors located in the tail of the pancreas. One tumor involved the entire pancreas. Computed tomography and/or octreotide radionuclide scans identified hepatic metastasis in three patients. Mean serum vasoactive intestinal polypeptide levels were 683 pg/ml (range 293 to 1,500 pg/ml). All patients underwent resection of the pancreatic primary tumor. Two patients also had simultaneous liver resections. All patients had evidence of malignancy as defined by the presence of metastatic lymph nodes and/or hepatic metastases. Two patients had complete resolution of symptoms after surgical resection. One patient required radioablation of liver metastases and adjuvant octreotide therapy for control of symptoms. One patient died of progressive metastatic disease 96 months after surgery, whereas the other three remain alive. Extended, meaningful survival can be achieved for VIPoma patients, combining an aggressive surgical approach with additional strategies for treatment of unresected disease.

Topics: Algorithms; Diagnosis, Differential; Diarrhea; Humans; Liver Neoplasms; Pancreatectomy; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary cancer syndrome presented mostly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. It occurs in approximately one in 30,000 individuals. Two different forms, sporadic and familial, have been described. The sporadic form presents with two of the three principal MEN1-related endocrine tumours (parathyroid adenomas, entero-pancreatic tumours and pituitary tumours) within a single patient, while the familial form consists of a MEN1 case with at least one first degree relative showing one of the endocrine characterising tumours. Other endocrine and non-endocrine lesions, such as adrenal cortical tumours, carcinoids of the bronchi, gastrointestinal tract and thymus, lipomas, angiofibromas, collagenomas have been described. The responsible gene, MEN1, maps on chromosome 11q13 and encodes a 610 aminoacid nuclear protein, menin, with no sequence homology to other known human proteins. MEN1 syndrome is caused by inactivating mutations of the MEN1 tumour suppressor gene. This gene is probably involved in the regulation of several cell functions such as DNA replication and repair and transcriptional machinery. The combination of clinical and genetic investigations, together with the improving of molecular genetics knowledge of the syndrome, helps in the clinical management of patients. Treatment consists of surgery and/or drug therapy, often in association with radiotherapy or chemotherapy. Currently, DNA testing allows the early identification of germline mutations in asymptomatic gene carriers, to whom routine surveillance (regular biochemical and/or radiological screenings to detect the development of MEN1-associated tumours and lesions) is recommended.

Topics: Adolescent; Adrenal Cortex Neoplasms; Adult; Aged; Aged, 80 and over; Angiofibroma; Carcinoid Tumor; Child; Facial Neoplasms; Female; Gastrinoma; Genetic Testing; Humans; Insulinoma; Lipoma; Male; Meningioma; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Parathyroid Neoplasms; Pituitary Neoplasms; Prolactinoma; Proto-Oncogene Proteins; Thyroid Neoplasms; Vasoactive Intestinal Peptide; Young Adult

Topics: Humans; Pancreatic Neoplasms; Prognosis; Vasoactive Intestinal Peptide; Vipoma

To discuss the experience of diagnosis and treatment of VIPoma by summarizing clinical information of 31 patients with VIPoma in China.. To analyze clinical manifestations, laboratory examinations, imaging features, operation, pathologic findings, and follow-up survey of 31 patients, among them 1 case was from our hospital and the other 30 cases were reported in Chinese literature from 1977 to 2002.. Periodical backache, skin rash, and polyps of colon were never reported previously, all of which except polyps disappeared after operation. Partial resection of superior mesenteric vein was also never reported. The mean serum value of VIP which had been very high before operation, decreased markedly after the operation (963.2 pg/ml Versus 131.9 pg/ml),the immunohistochemical expression of many kinds of digestive hormone including VIP presented positive. Hepatic involvement was 29.0%,nodal metastasis was 9.7%.. VIPoma is rare. Typical symptoms and the serum value of VIP are keys to diagnosis before operation, Surgical resection is the most effective means for cure. surgical debulking of the tumor, somatostatin analogues can be used for good palliation.

Topics: China; Humans; Immunohistochemistry; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Pancreaticojejunostomy; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

To discuss the experiences of diagnosis and treatment for vasoactive intestinal peptide-secreting-tumors (VIPoma) by summarizing clinical informations of 15 patients with VIPoma.. To analyze Clinical manifestations, laboratory examinations, imaging features, operation, pathological findings and follow up survey of 15 patients, among them 1 case from our hospital and the other 14 cases were searched in chinese biological and medical literature database from Jan 1987 to Dec 2002.. The main clinical manifestation include periodical secretory watery diarrhea, hypokalemia, achlorhydria, in addition, periodical backache, skin rash, and polyps of colon were presented in the case in our hospital. The immunohistochemical expression of many kinds of digestive hormone including VIP presented positive; All clinical symptoms of which except polyps disappeared after operation, elevated VIP data in serum also markedly decreased. Part resection of superior mesenteric vein was performed in the same patient.. VIPoma is rare. Typical symptoms and the serum value of VIP were keys to diagnosis, the operation is the most effective means for treatment. Resection of tumor, Radiofrequency tissue ablation, liver transplantation can be selected for metastatic VIPoma in the liver.

Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

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

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

Vasoactive intestinal polypeptide (VIP)-secreting tumors of the pancreas represent a rare subtype of pancreatic islet cell tumors with an estimated incidence of 0.2 to 0.5 per million per year. We provide data on a relatively large series of patients with VIP-secreting tumors and review current literature regarding this specific entity.. A retrospective review was performed of all patients with VIP-secreting tumors of the pancreas treated from 1977 to 1992 at our institution. Presenting signs, symptoms, mode of diagnosis, extent of disease, surgical resectability, tumor size, treatments, hormone levels, and survival were assessed.. Eighteen patients were identified, 9 male and 9 female. Ages ranged from 23 to 74 years (mean 51 years). Secretory diarrhea was the most common symptom, occurring in 16 of 18 patients (89%). The most common tumor location was the tail of the pancreas (9 patients). Fourteen patients (78%) had liver metastasis at diagnosis. Curative resections were attempted in only 5 patients (28%). The mean survival was 3.6 years with the longest disease-free survival being 15 years and longest overall survival 15 years.. VIP-secreting tumors are extremely rare entities and usually metastatic at the time of diagnosis. Despite advanced disease, these patients can have extended survival.

Topics: Adenoma, Islet Cell; Adult; Aged; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pancreatic Neoplasms; Time Factors; Vasoactive Intestinal Peptide

VIP-secreting tumours are rare, but they produce a dramatic clinical picture, the most prominent feature being profuse, watery diarrhoea and hypokalaemia. VIPomas are malignant and require sophisticated diagnostic and localization techniques in order to identify their presence. Delays in diagnosis are the rule rather than the exception. Improvements in the diagnosis of VIPomas appear to result in an increase in resectability rates. A definitive diagnosis is aided by the determination of plasma VIP concentrations through the use of sensitive radioimmunoassays. With heightened awareness of this syndrome, increasing numbers of patients can be identified and more effective treatments developed for the refractory and recurrent tumours.

Topics: Diagnosis, Differential; Diagnostic Imaging; Humans; Pancreas; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Prognosis; Radioimmunoassay; Treatment Outcome; Vasoactive Intestinal Peptide; Vipoma

Topics: Aged; Humans; Liver Neoplasms; Male; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome is an unusual paraneoplastic condition caused by excess vasoactive intestinal polypeptide (VIP) secreted by certain tumors. The onset of the syndrome is insidious, and diagnosis is usually delayed by months to years. Morbidity and mortality from untreated WDHA syndrome are related to long-standing dehydration and electrolyte and acid-base disturbances resulting in chronic renal failure. Diagnosis requires documentation of large volumes of secretory diarrhea, elevated serum VIP levels, and localization of the VIP-secreting tumor. Treatment includes correction of volume, electrolyte, and metabolic abnormalities, pharmacotherapy to decrease gastrointestinal secretion and increase absorption, and ultimately surgical resection or debulking of the vipoma.

Topics: Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Two patients are reported who presented with symptoms characteristic of a pancreatic vipoma. The necessity to measure more than one plasma VIP level for diagnosis, and the delay between the onset of illness and diagnosis is illustrated by both cases. Evidence suggests that vipomas are still under reported. The evolution of sophisticated diagnostic and therapeutic modalities over the twenty-five years separating both presentations is discussed.

Topics: Combined Modality Therapy; Dactinomycin; Diagnosis, Differential; Female; Humans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Prednisolone; Vasoactive Intestinal Peptide; Vipoma

Topics: Achlorhydria; Diarrhea; Humans; Hypokalemia; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

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

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

A case report is presented of a man with Verner-Morrison syndrome of extreme severity, caused by an unresectable pancreatic VIPoma. The pathological role of vasoactive intestinal polypeptide (VIP) is discussed in the pathogenesis of Watery Diarrhoea, Hypokalaemia, Achlorhydria (WDHA) syndrome. The authors describe the typical symptoms of the syndrome and provide a diagnostic and therapeutic strategy. Plasma level of VIP was determined by the authors' own VIP RIA method. Administration of a long acting somatostatin analogue, octreotide (Sandostatin, Sandoz) at a dose of 100 micrograms daily, decreased the plasma level of VIP from about 55 to 38 fmol/ml, which was associated with complete regression of the diarrhoea. Due to the 'escape phenomenon' the dose of Sandostatin was gradually increased and finally completed with streptozotocin (Zanosar, Upjohn) administration, which was repeated every 8 weeks. The combination of Sandostatin and streptozotocin resulted in complete regression of diarrhoea and substantial diminution of the tumour mass. The patient displayed a weight gain and returned to normal life.

Topics: Humans; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Remission Induction; Streptozocin; Vasoactive Intestinal Peptide; Vipoma

Although neoplasms that produce gut regulatory peptides and amines can be found throughout the gastroenteropancreatic axis (excluding carcinoids), the vast majority of these lesions are found within the pancreas. Recognition of the various clinical syndromes produced by the secretions of these tumors, the development of sensitive and specific radioimmunoassays for the elaborated peptides, and development of more effective localization techniques have contributed to earlier diagnosis and marked improvement in patient care. Treatment is directed toward medical management to correct the metabolic disturbances produced by the excessive amounts of gut regulatory peptides, followed by localization and extirpation of tumor. In the presence of unresectable tumor or metastases, palliative treatment directed at reducing peptide secretion or preventing its effects by surgery, chemotherapy, hormonal therapy, and hepatic-artery embolization can produce long-term remission of symptoms. Because the majority of these tumors are malignant, the ultimate goal in successful patient management is the early detection and surgical excision of the islet cell tumor before metastases occur.

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

Somatostatin is a peptide synthesized in many tissues that can act as a neurotransmitter, a systemic hormone, or a local hormone, and inhibits the secretion of hormones or other cell products. A long-acting synthetic analogue of somatostatin (SMS 201-995) has been developed which when administered subcutaneously has a biologic half-life of 90 to 120 minutes and can be administered 2 or 3 times per day. SMS 201-995 can lower plasma concentrations of growth hormone and somatomedin-C in patients with pituitary acromegaly, but no controlled trials to assess symptomatic response or change in tumor size have been done. In patients with pituitary thyrotropin-producing pituitary tumors, SMS 201-995 has been remarkably effective in producing biochemical and clinical responses and is the drug of first choice in this syndrome when tumor resection is not possible. In patients with the carcinoid syndrome, SMS 201-995 effectively reduces diarrhea, is the best available drug for treatment of carcinoid flush (effective in approximately 90% of cases), and is useful in treating carcinoid crisis. Eighty-five percent of patients with pancreatic islet cell tumors that produce vasoactive intestinal peptide will respond to SMS 201-995 with a reduction in diarrhea that often has been resistant to all other therapy. SMS 201-995 may also be useful in treating the symptoms in some patients with glucagonomas, growth hormone releasing hormone-producing tumors and insulinomas. Whether SMS 201-995 has a significant effect on gut neuroendocrine tumor growth remains uncertain. Certain nonmalignant diseases of the gut respond to somatostatin, including secretory diarrhea and fistulas of unknown cause. In general, SMS 201-995 has proved safe with few significant side effects, but whether the long-term use of the drug will result in an iatrogenic form of the somatostatinoma syndrome is uncertain.

Topics: Acromegaly; Adenoma, Islet Cell; Diarrhea; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Gastrointestinal Neoplasms; Growth Hormone; Humans; Intestinal Fistula; Malignant Carcinoid Syndrome; Octreotide; Pancreatic Neoplasms; Pancreatitis; Pituitary Neoplasms; Thyrotropin; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Ganglioneuroma; Humans; Pancreatic Neoplasms; Peptide PHI; Protein Precursors; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Animals; Humans; Intestines; Pancreatic Neoplasms; Somatostatin; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Adult; Aged; Antineoplastic Agents; Child, Preschool; Diagnosis, Differential; Female; Humans; Infant; Male; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Since the description of the watery diarrhea syndrome by Verner and Morrison 29 years ago, clinical and experimental observations have elucidated the pathophysiology of this disease. Vasoactive intestinal polypeptide (VIP) is produced and released by a tumor of the pancreatic islets or by a tumor of neural crest origin such as a ganglioneuroma. Under normal conditions, current evidence suggests that VIP is a neurotransmitter in the central and peripheral nervous systems and particularly in the peptidergic nervous system. The low VIP plasma concentration observed in healthy subjects is viewed as a neuronal overflow since it has been impossible to ascertain any endocrine role for circulating VIP. Markedly elevated VIP plasma levels in the VIPoma syndrome lead to intestinal secretion with severe secretory diarrhea, resulting in hypovolemia, hypokalemia, and acidosis. These symptoms subside after successful tumor removal. Approximately 50 percent of patients have metastatic spread at the time of diagnosis. For these patients, a new and promising therapeutic modality is available in the form of a subcutaneously administered somatostatin analogue that relieves symptoms through potent inhibition of VIP release from tumor tissue.

Topics: Adenoma, Islet Cell; Animals; Diagnosis, Differential; Humans; Pancreatic Neoplasms; Radioimmunoassay; Syndrome; Vasoactive Intestinal Peptide; Vipoma

Topics: Amino Acid Sequence; Bronchodilator Agents; Cyclic AMP; Cystic Fibrosis; Female; Gastrointestinal Motility; Hormones; Hormones, Ectopic; Humans; Male; Mental Disorders; Muscle Relaxation; Muscle, Smooth; Neoplasms, Nerve Tissue; Nervous System; Neurotransmitter Agents; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Receptors, Cell Surface; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide; Vasodilation; Vasodilator Agents

Topics: Amino Acid Sequence; Animals; Base Sequence; Digestive System Physiological Phenomena; DNA; Glucagon; Growth Hormone-Releasing Hormone; Humans; Hypothalamus; Median Eminence; Pancreatic Neoplasms; Peptide PHI; Peptides; Pituitary Gland; Receptors, Cell Surface; Receptors, Vasoactive Intestinal Peptide; Secretin; Swine; Tissue Distribution; Vasoactive Intestinal Peptide

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

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

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

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

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

Gut peptide secreting tumours originate most commonly from the pancreatic Islets of Langerhans. Tumours at a variety of other sites have also been shown to synthesize and release these peptides, reflecting the wide distribution of the peptide secreting cells of the diffuse neuroendocrine system. Tumours such as the glucagonomas, insulinomas, VIPomas and gastrinomas are associated with characteristic clinical syndromes resulting from the effects of the peptide they secrete. The majority of the islet cell tumours in fact secrete a number of different peptides and many of these are present in several molecular forms, some of which may not be biologically active. This may explain the lack of clinical sequelae in association with tumours such as the somatostatinomas. The clinical features, methods of diagnosis, localisation and treatment of these tumours will be discussed.

Topics: Adenoma, Islet Cell; Bombesin; Bronchial Neoplasms; C-Peptide; Carcinoma, Small Cell; Diagnosis, Differential; Endocrine System Diseases; Erythema; Gastrointestinal Hormones; Glucagon; Glucagonoma; Humans; Insulin; Insulin Secretion; Insulinoma; Male; Neoplasms; Neurotensin; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatinoma; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

The three new endocrine pancreatic tumour syndromes dealt with in this chapter--glucagonomas, VIPomas and somatostatinomas--are not common. Nonetheless, the patients are potentially curable by tumour resection and therefore wider knowledge of the clinical picture is of considerable importance. It is possible that there are still further, presently unrecognized, clinical syndromes waiting in the wings and studies are currently under way to try to ascertain the effects of elevated PP. Early tumour diagnosis depends firstly on clinical acumen but the easy availability of a reliable radioimmunoassay service is of considerable importance as this allows the physician to screen likely patients and so detect cases at an early stage. Tumour localization is still a major problem and requires expert radiological assistance. The dramatic effectiveness of the cytotoxic agent streptozotocin illustrates the great potential of chemotherapy and it may be expected that further drugs of this nature will be discovered, especially as it is now possible to establish isolated tumour strains for mass drug screening. These tumours have shown the effect of long continued peptide elevation and given valuable insight into the physiological role of the respective regulatory peptides.

Topics: Adenoma, Islet Cell; Gastrointestinal Hormones; Glucagon; Humans; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Somatostatin; Vasoactive Intestinal Peptide

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Animals; Bicarbonates; Brain; Dehydration; Digestive System; Gastrointestinal Hormones; Hormones, Ectopic; Humans; Nerve Fibers; Neurotransmitter Agents; Pancreas; Pancreatic Neoplasms; Swine; Syndrome; Vasoactive Intestinal Peptide

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

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

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

Topics: Achlorhydria; Adenoma, Islet Cell; Adult; Aged; Diagnosis, Differential; Diarrhea; Female; Gastric Juice; Humans; Hypokalemia; Male; Middle Aged; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

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

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

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

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

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

Recently, we have shown that the expression of receptors for vasoactive intestinal peptide (VIP) on intestinal adenocarcinomas can be used for in vivo targeting of primary or metastatic tumor sites using 123I-labeled VIP. Several other receptors and antigens including the TAG-72 protein have also been implemented for in vivo localization purposes. In this study, we have compared the in vitro and in vivo binding of 123I-VIP and of the 111In-labeled monoclonal antibody (MAb) directed against TAG-72 (OncoScint; 111In-CR-103) in patients with intestinal adenocarcinomas in a single-blinded, prospectively randomized trial.. Twenty patients were administered either 123I-VIP (150-200 MBq; 1 microgram) or 111In-CYT-103 (150 MBq; 1 mg) for one imaging study. After interim analysis demonstrated superior imaging with 123I-VIP, the next 10 patients (accounting for a total of 50 patients) enrolled in this trial underwent both studies in random order to allow for a direct comparison.. In total, 123I-VIP scans were true-positive in 28 of 30 patients (93%) versus 17 of 30 patients administered 111In-CYT-103 (56%). In the subgroup of 10 patients enrolled in the second part of the study, primary intestinal adenocarcinomas were imaged in five of five patients with 123I-VIP and in only two of these patients with 111In-CYT-103. Liver metastases were visualized in five of six patients by 123I-VIP receptor scanning and in four of these patients with 111In-CYT-103. The in vitro results indicated significant binding of 123I-VIP to primary colorectal tumors as well as to HT29 and COLO320 adenocarcinoma cells. In vitro, adenocarcinoma cells also expressed abundant numbers of the TAG-72 antigen.. Intestinal adenocarcinomas co-express VIP receptors and the IAG-72 antigen. Despite significant in vitro binding of both agents, however, the VIP receptor scan is more sensitive in localizing intestinal adenocarcinomas and metastatic spread.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Female; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Iodine Radioisotopes; Liver Neoplasms; Male; Middle Aged; Oligopeptides; Pancreatic Neoplasms; Pentetic Acid; Prospective Studies; Radioimmunodetection; Receptors, Vasoactive Intestinal Peptide; Single-Blind Method; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Intestinal adenocarcinomas and various endocrine tumors express large numbers of high-affinity receptors for vasoactive intestinal peptide (VIP). We have evaluated the usefulness of scanning with VIP labeled with iodine-123 for tumor localization in patients with gastrointestinal tumors.. Radioiodinated VIP was purified by high-pressure liquid chromatography and administered as a single intravenous bolus injection (300 pmol [1 microgram]). Scanning with radiolabeled VIP was compared with computed tomography and scanning with somatostatin analogues in 79 patients with colorectal cancer, pancreatic carcinoma, gastric cancer, carcinoid tumor, or insulinoma.. Visualization of gastrointestinal tumors and metastases was obtained with radiolabeled VIP. Binding of the labeled peptide by primary tumors and metastases was visible shortly after the injection and was still demonstrable at 24 hours. In patients with colorectal adenocarcinomas, primary or recurrent tumors were visualized in 10 of 10, liver metastases in 15 of 18, lung metastases in 2 of 3, and lymph-node metastases in 4 of 4. Primary pancreatic adenocarcinomas were visualized by imaging in 10 of 12 patients, and liver metastases were seen in 7 of 7. Primary or recurrent gastric adenocarcinomas were visualized in 5 of 5 patients, and liver metastases were seen in 2 of 2 patients. VIP scans were positive in 9 of 10 patients with carcinoid tumors and in 4 of 4 patients with insulinomas. Some tumors with positive VIP scans were also visualized with somatostatin analogues (4 of 17 colorectal adenocarcinomas, 8 of 9 carcinoids, and 2 of 2 insulinomas). In vitro binding studies confirmed the presence of VIP receptors on gastrointestinal tumors.. Scanning with radiolabeled VIP can visualize intestinal tumors and metastases that express receptors for VIP.

Topics: Adenocarcinoma; Carcinoid Tumor; Colorectal Neoplasms; Female; Gastrointestinal Neoplasms; Humans; Insulinoma; Iodine Radioisotopes; Male; Octreotide; Pancreatic Neoplasms; Radionuclide Imaging; Receptors, Somatostatin; Receptors, Vasoactive Intestinal Peptide; Stomach Neoplasms; Vasoactive Intestinal Peptide

Monoclonal antibodies have not been evaluated in metastasizing endocrine tumors, even though these lesions may induce severe morbidity of hormone excess in absence of considerable tumor burden.. A murine monoclonal antibody of the IgG2a subtype was generated by immunization with dispersed tumor cells from an endocrine pancreatic carcinoma associated with liver and peritoneal metastases as well as a therapy-resistant Verner-Morrison's syndrome.. Immunohistochemical staining disclosed selective tissue reactivity of the antibody and conspicuous immunostaining on the surface of the tumor cells. Infusion of 100 mg antibody over 2 days into the common hepatic artery of the patient was accompanied by reduced diarrhea volume until death 6 weeks later and transient elevation of total plasma immunoreactivity for vasoactive intestinal peptide due to large molecular forms of the peptide. Postmortem examination demonstrated disappearance of peritoneal metastases as well as absence of immunostaining for the injected antibody and the transferrin receptor within residual hepatic tumors.. The results substantiate that symptomatic alleviation and perhaps interference with tumor cell mass may be obtained with monoclonal antibodies in patients with endocrine tumors and that the antiidiotypic immunoglobulin response may play a role herein.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Neoplasm; Humans; Immunohistochemistry; Immunotherapy; Infusions, Intra-Arterial; Liver Neoplasms; Male; Mice; Mice, Inbred DBA; Middle Aged; Pancreatic Neoplasms; Peritoneal Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare functional pancreatic neuroendocrine neoplasms (p-NENs) characterized by watery diarrhea, hypokalemia, and achlorhydria. Here, we report the case of a 51-year-old female patient with VIPoma that recurred after a long-term disease-free interval. This patient had been asymptomatic for approximately 15 years after the initial curative surgery for pancreatic VIPoma, with no metastasis. The patient underwent a second curative surgery for the locally recurrent VIPoma. Whole-exome sequencing of the resected tumor revealed a somatic mutation in MEN1, which is reportedly responsible not only for multiple endocrine neoplasia type 1 (MEN1) syndrome but also sporadic p-NENs. Symptoms were controlled with lanreotide before and after surgery. The patient is alive with no relapse following 14 months after surgery. This case demonstrates the importance of long-term observation of patients with VIPoma.

Topics: Diarrhea; Female; Humans; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Topics: Humans; Insulin; Multiple Endocrine Neoplasia Type 1; Mutation; Neuroendocrine Tumors; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

VIPomas are generally rare functioning pancreatic neuroendocrine tumors (PanNETs) that cause watery diarrhea, hypokalemia, and achlorhydria. Due to their extreme rarity, the clinicopathological features and outcomes of VIPomas have not been well reported. This study aimed to determine the diagnostic and therapeutic characteristics and prognosis of VIPomas and to compare them with other PanNETs at a Japanese reference hospital. Medical records of 293 patients with PanNETs were collected. Patient and tumor characteristics and outcomes were retrospectively reviewed. This cohort had only 1.4% (four patients) of patients with VIPomas, and three of these patients changed from non-functioning (NF-) PanNETs during their disease course. Recurrences of hormonal symptoms were observed in all patients despite the initial controls, and all of them died from their disease, more specifically mainly from hormonal symptoms. Compared to the other PanNETs, VIPomas were all located at the pancreatic tail, were larger, and had a higher Ki-67 index and more metastasis. The median survival time was significantly shorter for patients with VIPoma than for those with NF-PanNET (5.9 vs. 26.7 years, p < 0.0001), insulinoma (21.8 years, p < 0.0001), and gastrinoma (12.3 years, p = 0.0325). This study presents the possibility of shifting from non-symptomatic to symptomatic VIPomas as they grow or of transforming from NF-PanNETs to VIPomas. VIPomas should be considered in patients with relatively large NF-PanNETs, especially those located in the pancreatic tail, when diarrhea is continuously observed. As hormonal symptoms are an important cause of death in VIPomas, long-term symptomatic control, which is relatively difficult, is of great significance.

Topics: Diarrhea; Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Retrospective Studies; Vasoactive Intestinal Peptide; Vipoma

This case report addresses the management of a pregnant woman in the peripartum period with a VIPoma. This rare and highly malignant neuroendocrine tumour secretes vasoactive intestinal peptide (VIP), a substance that may cause potentially life-threatening disruption to physiology. A 36-year-old woman presented for induction of labour with a three-year history of chronic diarrhoea, hypophosphataemia, palpitations and skin flushing. Raised VIP levels indicated presence of a VIPoma, however despite extensive investigation prior to pregnancy by neuroendocrine specialists, the tumour location remained unidentified. The patient delivered a healthy boy with the aid of forceps in theatre following an epidural top-up. Key features of management were a multidisciplinary approach, avoidance of triggers for VIP secretion, strict management of electrolytes and avoidance of severe changes in sympathetic tone during labour with epidural analgesia.

Topics: Adult; Female; Humans; Male; Pancreatic Neoplasms; Pregnancy; Vasoactive Intestinal Peptide; Vipoma

A paucity of effector T cells within tumors renders pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint therapies. While several under-development approaches target immune-suppressive cells in the tumor microenvironment, there is less focus on improving T cell function. Here we show that inhibiting vasoactive intestinal peptide receptor (VIP-R) signaling enhances anti-tumor immunity in murine PDAC models. In silico data mining and immunohistochemistry analysis of primary tumors indicate overexpression of the neuropeptide vasoactive intestinal peptide (VIP) in human PDAC tumors. Elevated VIP levels are also present in PDAC patient plasma and supernatants of cultured PDAC cells. Furthermore, T cells up-regulate VIP receptors after activation, identifying the VIP signaling pathway as a potential target to enhance T cell function. In mouse PDAC models, VIP-R antagonist peptides synergize with anti-PD-1 antibody treatment in improving T cell recruitment into the tumors, activation of tumor-antigen-specific T cells, and inhibition of T cell exhaustion. In contrast to the limited single-agent activity of anti-PD1 antibodies or VIP-R antagonist peptides, combining both therapies eliminate tumors in up to 40% of animals. Furthermore, tumor-free mice resist tumor re-challenge, indicating anti-cancer immunological memory generation. VIP-R signaling thus represents a tumor-protective immune-modulatory pathway that is targetable in PDAC.

Topics: Animals; Carcinoma, Pancreatic Ductal; Humans; Mice; Pancreatic Neoplasms; Receptors, Vasoactive Intestinal Peptide; Signal Transduction; Tumor Microenvironment; Vasoactive Intestinal Peptide

VIPoma of the Pancreas

Topics: Humans; Hypokalemia; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Neuroendocrine tumors are rare, heterogeneous neoplasms that produce a wide variety of clinical symptoms. Diarrhea in neuroendocrine tumors is incredibly common and is usually benign in nature. We report two extreme cases of diarrhea in metastatic neuroendocrine tumors that threatened fatality and provide evidence for steroids as a novel agent in the management of vasoactive intestinal peptide tumors.. A 63-year-old Caucasian male with a grade 2 (Ki-67 17%) metastatic small bowel neuroendocrine tumor, and a 43-year-old female with a grade 2 (Ki-67 5%) metastatic pancreatic vasoactive intestinal peptide tumor. Both patients suffered life-threatening diarrhea despite extensive treatment modalities, including new systemic agents. This case explains how a lack of compliance and patient under-reporting of symptoms contributed to their challenging clinical course. Only steroids had a significant sustained effect on the diarrhea of the patient with vasoactive intestinal peptide tumor.. This report discusses two rare cases of life-threatening diarrhea in neuroendocrine tumors and stresses the importance of accurate clinical history taking, patient education, and compliance for symptom control. The report suggests steroids as a potential novel pharmaceutical option in the management of vasoactive intestinal peptide tumors; this is of great significance as it may provide a new approach to their management and potentially act as a life-saving agent in other oncology patients.

Topics: Adult; Diarrhea; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Topics: Cholangiopancreatography, Magnetic Resonance; Diarrhea; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Humans; Liver Neoplasms; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Topics: Humans; Liver Neoplasms; Male; Middle Aged; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Radiopharmaceuticals; Receptors, Peptide; Treatment Outcome; Vasoactive Intestinal Peptide; Vipoma

A 68-year-old woman with an 11-day history of sudden abdominal pain and severe watery diarrhea was transferred to our hospital due to an exacerbation of renal function despite hydration. After treatment for dehydration and acidemia was provided in our intensive care unit, patient's renal function improved. Contrast-enhanced abdominal computed tomography was finally performed, revealing a hypervascular pancreatic mass with multiple hepatic masses. This imaging finding along with her clinical symptoms indicated watery diarrhea hypokalemia achlorhydria (WDHA) syndrome caused by a pancreatic VIPoma. Somatostatin analog was administered immediately leading to the improvement of her diarrhea and her general condition. As a result, endoscopic ultrasonography-guided fine-needle aspiration could be performed. Consequently, she was diagnosed with a pancreatic neuroendocrine tumor. She then underwent surgical resection of the pancreatic tumor and liver metastasis. As revealed in the immunohistochemical analysis of the excised tumor tissue, VIP was highly expressed, resulting in the final diagnosis of pancreatic VIPoma. Therefore, the immediate use of a somatostatin analog is crucial for improving the patient's general condition and achieving a definitive diagnosis pathologically when a patient is suspected of having a pancreatic VIPoma.

Topics: Achlorhydria; Aged; Female; Hormones; Humans; Pancreatic Neoplasms; Somatostatin; Vasoactive Intestinal Peptide; Vipoma

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

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

We present a rare high-grade, functional, neuroendocrine carcinoma of the pancreas secreting vasoactive intestinal peptide. This case is unique, given the tumor's aggressive features and high Ki-67 index while also secreting functional hormones, which is unusual in high-grade neuroendocrine tumors (NETs). Our patient initially presented with diarrhea and was found to have a 4.7 × 3.1 × 3.3 cm pancreatic mass with diffuse hepatic metastasis staining positive for vasoactive intestinal peptide, chromogranin A and synaptophysin. She was initially underscored as grade 2 NET due to low mitosis, but subsequently restaged based on Ki-67 index as a grade 3 neuroendocrine carcinoma. She unfortunately was not a candidate for chemotherapy at that time. We conclude that high-grade NETs have the potential to secrete active peptide hormones. We therefore recommend that NETs with aggressive features be biopsied and assessed for Ki-67 activity and mitosis regardless if they are functional tumors, with goal for early initiation of chemotherapy.

Topics: Carcinoma, Neuroendocrine; Fatal Outcome; Female; Humans; Ki-67 Antigen; Liver; Middle Aged; Neoplasm Grading; Neoplasm Staging; Pancreas; Pancreatic Neoplasms; Patient Selection; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

The purpose of this study was to investigate the safety and efficacy of irreversible electroporation (IRE) for the management of unresectable pancreatic vasoactive intestinal peptide tumor (VIPoma) in a 34-year-old male patient. The initial symptom was watery diarrhea, which could not be stopped by fasting. Laboratory tests revealed high vasoactive intestinal peptide (VIP) hormone levels, hypokalemia, and metabolic acidosis. Computed tomography examination showed a 6.0 × 5.0-cm, contrast-enhanced lesion in the neck and body of the pancreas and obliteration of the portal vein. Pathological and immunohistochemical findings were indicative of pancreatic VIPoma. The patient was treated with octreotide and IRE, and had no obvious IRE-related complications, except for moderate pain at the puncture sites. The patient reported that the watery diarrhea had decreased gradually; moreover, the VIP hormone level was normalized 15 days after IRE. Computed tomography scans showed a large area of necrosis in the pancreatic lesion. The findings from this case indicated that IRE could be a feasible and safe technique in controlling pancreatic VIPoma; however, additional follow-up and findings from more cases are required to further confirm the efficacy of IRE ablation therapy for pancreatic VIPoma.

Topics: Adult; Antineoplastic Agents, Hormonal; Electroporation; Humans; Male; Octreotide; Pancreas; Pancreatic Neoplasms; Tomography, X-Ray Computed; Treatment Outcome; Vasoactive Intestinal Peptide; Vipoma

Gastro-entero-pancreatic neuroendocrine tumors (GEPNETs) are increasing in incidence, and accurate staging is important for selecting the appropriate treatment. (68)Ga-DOTATATE imaging is a promising approach for detecting GEPNETs and could help in selecting optimal therapeutic strategies. The aim of this study was to prospectively determine the clinical utility of (68)Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) in detecting unknown primary and metastatic GEPNETs.. One hundred thirty-one patients were enrolled in a prospective study of patients undergoing (68)Ga-DOTATATE PET/CT, (111)In-pentetreotide single-photon emission computed tomography (SPECT)/CT and multiphasic CT scan, and/or magnetic resonance imaging in a blinded fashion with comprehensive biochemical testing. The primary outcome measure was the detection of lesions by each imaging study.. (68)Ga-DOTATATE PET/CT imaging detected 95.1% of lesions (95% CI, 92.4% to 96.8%) with an average maximum standardized uptake value of 65.4 ± 47 (range, 6.9 to 244), anatomic imaging detected 45.3% of lesions (95% CI, 37.9% to 52.9%), and (111)In-pentetreotide SPECT/CT detected 30.9% of lesions (95% CI, 25.0% to 37.5%), with a significant difference between imaging modalities (P < .001). In four of 14 patients (28.6%), (68)Ga-DOTATATE PET/CT found a previously unknown primary tumor, and detected primary GEPNET, lymph node, and distant metastases correctly in 72 of 113 lesions (63.7%) when compared with histopathology, with 22.1% and 38.9% detected by using (111)In-pentetreotide SPECT/CT and anatomic imaging, respectively. On the basis of findings with (68)Ga-DOTATATE PET/CT, 43 of 131 patients (32.8%) had a change in management recommendation. In patients with carcinoid symptoms but negative biochemical testing, (68)Ga-DOTATATE PET/CT detected lesions in 65.2% of patients, 40% of which were detected neither by anatomic imaging nor by (111)In-pentetreotide SPECT/CT.. (68)Ga-DOTATATE PET/CT imaging provides important information for accurate staging of GEPNETs and selection of appropriate treatment interventions even in the absence of biochemical evidence of disease in symptomatic patients.

Topics: Adult; Aged; Aged, 80 and over; Chromogranin A; Female; Humans; Hydroxyindoleacetic Acid; Intestinal Neoplasms; Liver Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Neoplasms, Unknown Primary; Neuroendocrine Tumors; Organometallic Compounds; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Positron-Emission Tomography; Prospective Studies; Somatostatin; Stomach Neoplasms; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Young Adult

Topics: Aged; Carcinoma, Pancreatic Ductal; Humans; Immunohistochemistry; Male; Neoplasms, Multiple Primary; Neuroendocrine Tumors; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

The vasoactive intestinal peptide-secreting neuroendocrine tumor (VIPoma) is a very rare pancreatic tumor. We report the first case of a patient with VIPoma that co-secreted dopamine and had pulmonary emboli.. A 67-year-old woman presented with 2 months of watery diarrhea, severe generalized weakness,6.8 kg of weight loss, a facial rash, and hypokalemia. Colonoscopy did not reveal the cause of the chronic diarrhea. Initial biochemical testing showed markedly elevated serum vasoactive intestinal peptide (VIP) and pancreatic polypeptide. Computed tomography scan of the abdomen and pelvis revealed a 5.4-cm distal pancreatic mass. Octreoscan showed an intense uptake in the area of the pancreatic mass. Incidental pulmonary emboli were found and treated. Additional biochemical testing revealed a markedly elevated urinary dopamine level. The patient received preoperative α-blockade and octreotide. She underwent a successful laparoscopic distal pancreatectomy. Postoperative urinary dopamine and pancreatic polypeptide were within normal limits. Serum VIP decreased by half but remained elevated. Pathology confirmed a grade 1 pancreatic neuroendocrine tumor without lymph node metastasis. The patient's symptoms resolved and no longer required octreotide. Metastatic workup including computed tomography, F18-fluorodeoxglucose positron emission tomography, and Ga68-DOTATATE scans were negative during 4 years of follow-up.. VIPoma is a rare subtype of pancreatic neuroendocrine tumor that can secrete dopamine and can be associated with thromboembolism.

Topics: Aged; Dopamine; Female; Humans; Pancreatectomy; Pancreatic Neoplasms; Pulmonary Embolism; Vasoactive Intestinal Peptide; Vipoma

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

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

VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes vasoactive intestinal polypeptide (VIP). Its reported incidence is approximately 1 per 10 million individuals per year. Herein, we report the case of sporadic pancreatic VIPoma in a 47-year-old male who presented with a six-month history of chronic, plentiful, watery diarrhea. On physical examination, the patient looked sick, lethargic and had signs of dehydration. Laboratory investigations revealed high VIP hormone level (989pg/mL), hypokalemia, hypercalcemia, hyperglycemia, high blood urea nitrogen, high creatinine, and metabolic acidosis on arterial blood gas. Contrast-enhanced computed tomography (CT) scan showed a 3.1×3.3×4.7cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7×6.1×6.8cm metastatic hepatic lesion was identified. The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection. Histopathological and immunohistochemical examination of the pancreatic and hepatic lesions revealed neuroendocrine tumor (VIPoma). Postoperatively, the patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71pg/mL) and normalized electrolyte and acid-base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic liver lesion which was considered for hepatic artery embolization (HAE). The patient is still alive with a residual hepatic disease at 18months. We also present a brief literature review on VIPoma.

Topics: Humans; Liver; Liver Neoplasms; Male; Middle Aged; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal peptide (VIP) receptors are overexpressed in a broad variety of tumours. For the detection of these tumours, novel chemically modified and shortened VIP derivatives were designed.. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-derivatised VIP analogues were radiolabelled with (111)In and in vitro and in vivo behaviour was evaluated using stability and internalisation assays, as well as an initial biodistribution study.. Radiolabelling of the VIP analogues resulted in high radiochemical yields, without need for further purification steps. Stability of the VIP derivatives was variable and cell uptake studies in VIP receptor-positive cell lines revealed that only a limited number of derivatives were internalised. In the tumour mouse model, no specific tumour targeting was shown.. Since the tested VIP derivatives exhibited impaired in vitro and in vivo characteristics alternative modifications to increase their stability while retaining receptor affinity should be considered to enable the use of synthetic VIP analogues for tumour targeting.

Topics: Animals; Binding, Competitive; Carcinoma, Pancreatic Ductal; Cells, Cultured; CHO Cells; Cricetinae; Drug Design; Female; Heterocyclic Compounds, 1-Ring; Humans; Indium Radioisotopes; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Peptide Fragments; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Vasoactive Intestinal Peptide; Tissue Distribution; Vasoactive Intestinal Peptide

We report a successful treatment of a patient with heavily metastasized pancreatic vasoactive intestinal polypeptide-secreting tumor, which was unresponsive to high doses of octreotide analog using peptide receptor radionuclide therapy applying a radiolabeled somatostatin analog. After the peptide receptor radionuclide therapy, there was a decrease in vasoactive intestinal polypeptide levels, a significant reduction in somatostatin receptor expression and in molecular tumor volume on 68Ga DOTANOC PET/CT scan, and a complete long-term resolution of symptoms of the patient.

Topics: Dose-Response Relationship, Radiation; Female; Humans; Middle Aged; Neoplasm Metastasis; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Receptors, Somatostatin; Treatment Failure; Vasoactive Intestinal Peptide

Pancreatic neuroendocrine tumor (pNET) secretes various peptide hormones; however, calcitonin hypersecretion is rare. Its clinicopathological significance and treatment is still controversial.. A 43 year-old Japanese man presented severe watery diarrhea and a large mass in the pancreatic tail. Blood concentration of VIP was elevated to 649 pg/mL (reference range: 0-100 pg/mL), and calcitonin to 66,700 pg/mL (reference range: 15-86 pg/mL). There was no tumor in other endocrine organs. The resected tumor was composed of 80% calcitonin-positive cells and 10% VIP-positive cells. After the operation, the levels of VIP and calcitonin were decreased to 44 and 553 pg/mL, respectively, and diarrhea was improved. The mRNA of somatostatin receptor (SSTR) subtypes 2, 3 and 5 in the tumor tissue were increased 22.8, 25.1, and 37.0-fold of those of normal pancreas, respectively. At 19 months after the operation, blood calcitonin was again raised to 3,980 pg/mL, and metastatic tumors were found in the liver. With the treatment of long-acting somatostatin analogue, calcitonin was reduced to 803 pg/mL. The patient does not present endocrine symptom, and the size of the metastatic tumors appears stable.. From the world literature to date, co-secretion of VIP and calcitonin was documented in only 10 cases of pNET including the current case. Although VIP is a primary cause of diarrhea in these cases, high level of calcitonin may also influence on the clinical symptoms. Somatostatin analogue suppresses the levels of VIP and calcitonin, and the control proliferation is also expected when tumor cells express SSTRs.

Topics: Adult; Antineoplastic Agents, Hormonal; Calcitonin; Carcinoma, Neuroendocrine; Diarrhea; Humans; Male; Octreotide; Pancreas; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

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

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

Atrial natriuretic factor (ANF) prevents increases in intracellular levels of cAMP that are induced by secretin in the exocrine pancreas. We investigated the contribution of cyclic adenosine monophosphate (cAMP) efflux to ANF inhibition of secretin signaling.. Intracellular and extracellular cAMP were measured by radio-binding assays in isolated pancreatic acini exposed to secretin and other secretagogues, alone or with ANF. Levels of messenger RNA for multidrug resistance-associated protein (MRP)4, MRP5, and MRP8 were measured by real-time polymerase chain reaction. MRP4 was knocked down in AR42J cells by small interfering RNA. In vivo studies were performed in rats.. Pancreatic secretagogues increased levels of intracellular cAMP, but only secretin and vasoactive intestinal peptide promoted cAMP efflux; efflux was increased by ANF, through signaling via natriuretic peptide receptor-C and phospholipase C-protein kinase C. In time-course studies with active phosphodiesterases, levels of intracellular and extracellular cAMP increased earlier after the addition of secretin and ANF (1 min) than after the addition of secretin alone (3 min). Similar kinetic patterns occurred with a phosphodiesterase inhibitor. A probenecid-sensitive transporter mediated cAMP egression. The main cAMP transporter, MRP4, was expressed in AR42J cells and pancreas. cAMP egression occurred in AR42J cells exposed to secretin, but this response was reduced in cells that expressed MRP4 small interfering RNA. In rats, levels of cAMP in plasma and pancreatic juice increased after infusion with secretin alone or secretin plus ANF.. ANF signals via natriuretic peptide receptor-C coupled to the phospholipase C-protein kinase C pathway to increase secretin-induced efflux of cAMP, probably through MPR-4. Cyclic AMP extrusion might be a mechanism, in addition to phosphodiesterase action, to regulate intracellular cAMP levels in pancreatic acinar cells.

Topics: Animals; Atrial Natriuretic Factor; Calgranulin A; Cell Line, Tumor; Cyclic AMP; Multidrug Resistance-Associated Proteins; Pancreas, Exocrine; Pancreatic Neoplasms; Protein Kinase C; Rats; Rats, Sprague-Dawley; RNA, Messenger; RNA, Small Interfering; Secretin; Signal Transduction; Type C Phospholipases; Vasoactive Intestinal Peptide

Topics: Adult; Diarrhea; Female; Focal Nodular Hyperplasia; Humans; Pancreatic Neoplasms; Pancreaticoduodenectomy; Paresis; Remission Induction; Vasoactive Intestinal Peptide; Vipoma

VIPomas are rare neuroendocrine tumours, with metastases often confined to the liver. Orthotopic liver transplantation may be considered in patients with metastases confined to the liver, however the long term benefits have yet to be shown.. To discuss the role of orthotopic liver transplantation for neuroendocrine tumours including VIPomas.. We describe the case of a very rare pancreatic VIPoma, the therapeutic modalities employed, including orthotopic liver transplantation, and present the results of a relevant literature search.. This case is the longest (25 years) reported in the literature for survival from a VIPoma after initial diagnosis and long term survival after liver transplantation (9 years).. Liver transplantation for metastatic VIPomas confined to the liver may be justified in selected patients to provide symptomatic hormonal control and pain from tumour bulk, provided there is no extra hepatic disease and medical treatment has been exhausted.

Topics: Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal polypeptide secreting islet cell tumors (VIPomas) are neuroendocrine tumors that secrete excessive amounts of vasoactive intestinal polypeptide (VIP) that cause distinct syndromes characterized by large-volume diarrhea, hypokalemia, and dehydration. The annual incidence of these tumors is estimated to be about one per 10,000,000 individuals in the general population. We report a successful treatment of VIPoma with hepatic chemoembolization of a metastatic hepatic lesion evidenced by a reduction of VIP levels and resolutions of symptoms in a patient with pancreatic VIPoma unresponsive to increased doses of an octreotide analog.

Topics: Aged, 80 and over; Antineoplastic Agents, Hormonal; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Octreotide; Pancreatic Neoplasms; Treatment Outcome; Vasoactive Intestinal Peptide; Vipoma

Verner and Morrison described a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA) in 1958. VIPomas producing high amounts of vasoactive intestinal peptide (VIP) commonly originate from the pancreas. Typical symptoms play a momentous role in the diagnosis of VIPoma. Diarrhea may persist for years before the diagnosis. Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base metabolism disorders, which may cause chronic renal failure. Assessment of specific marker (VIP) offers high sensitivity in establishing the diagnosis. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogues. Treatment options include resection of the tumor, chemotherapy or the reduction of symptoms with somatostatin analogues. Early diagnosis and management may affect survival of patients favorably. VIPoma cases may be associated with multiple endocrine neoplasia type 1.

Topics: Achlorhydria; Aged; Biomarkers, Tumor; Diarrhea; Endosonography; Female; Humans; Hypokalemia; Immunohistochemistry; Magnetic Resonance Imaging; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Neuroendocrine tumors are uncommon, including VIPoma that produces vasoactive intestinal polypeptide. We report a 45-year-old female presenting with a history of diarrhea lasting three months. An abdominal CAT scan showed a solid tumor in the body of the pancreas. A fine needle aspiration biopsy of the tumor was compatible with a neuroendocrine tumor. The patient was subjected to a partial pancreatectomy, excising a 4 cm diameter tumor. The pathological study was compatible with a neuroendocrine carcinoma. There was no regional lymph node involvement. During the postoperative period the results of serum vasoactive intestinal polypeptide were received. These were 815.9 pg/ml before surgery and normalized after the operation.

Topics: Carcinoma, Neuroendocrine; Diagnosis, Differential; Diarrhea; Female; Humans; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

We report a case of VIPoma in a 72-year-old female patient who presented with excessive diarrhea, severe hypokalemia, and acidemia. She had been referred to our hospital three times because of severe diarrhea. No primary tumor site was found by conventional techniques, including contrast-enhanced CT and MRI, angiography, endoscopy, and positron emission tomography (PET), but a tumor was subsequently found in the head of the pancreas by octreotide scanning. Her diarrhea diminished dramatically after octreotide treatment, while her diarrhea has ceased without the therapy of octreotide at the first admission in the course of 2 years of her disease. Immunohistochemial analysis of the excised tumor tissue revealed the expression of both vasoactive intestinal peptide (VIP) and VIP and pituitary adenylate cyclase-activating peptide 1 (VPAC1) receptors. This is the first case report of a VIPoma that immunostains for VIP and VPAC1 receptors and indicates that abundant VIP produced by VIPoma might inhibit its growth and reduce VIP secretion via the VPAC1 receptor in vivo.

Topics: Achlorhydria; Aged; Diarrhea; Female; Gene Expression; Humans; Hypokalemia; Immunohistochemistry; Indium Radioisotopes; Isotope Labeling; Magnetic Resonance Imaging; Octreotide; Pancreatic Neoplasms; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Polypeptide, Type I; Syndrome; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Topics: Antineoplastic Agents, Hormonal; Diagnosis, Differential; Diarrhea; Female; Humans; Hypokalemia; Indium Radioisotopes; Irritable Bowel Syndrome; Liver; Liver Neoplasms; Middle Aged; Octreotide; Pancreatic Neoplasms; Radionuclide Imaging; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Mild hypokalemia is common and encountered in a multitude of diseases, but severe hypokalemia leading to rhabdomyolysis is relatively rare. The watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome caused by vasoactive intestinal polypeptide (VIP)-producing tumors, is an extremely rare cause of hypokalemic rhabdomyolysis and the literature is limited to one case report. We report a second case of an adult who presented with rhabdomyolysis due to severe hypokalemia. Further evaluation revealed that he had a VIP-producing pancreatic neuroendocrine tumor (NET), which was the cause of his hypokalemic rhabdomyolysis. Although rare in occurrence, a high index of suspicion is of paramount importance for establishing the correct diagnosis and treatment.

Topics: Achlorhydria; Adult; Diarrhea; Humans; Hypokalemia; Male; Pancreatic Neoplasms; Rhabdomyolysis; Syndrome; Vasoactive Intestinal Peptide; Vipoma

To discuss our experience in diagnosing and treating pancreatic vasoactive intestinal peptide-secreting tumors (VIPomas) by summarizing clinical information of 4 patients.. Clinical manifestations, laboratory examination, imaging features, surgical findings, and pathological findings of 4 patients with VIPoma admitted in our hospital from 1991 to the present are discussed.. Watery diarrhea and hypokalemia were the main clinical manifestations. Hepatic metastasis occurred in 2 patients. The pancreatic body and tail were the main locations of lesions. Two tumors were shown in the pancreatic body and tail in 1 patient. Two patients with hepatic metastases received a combination therapy of octreotide, surgery, and chemotherapy, which resulted in symptom improvement and normalization of the serum potassium values. Distal pancreatic resection and second resection of hepatic metastatic lesions were performed in 1 patient. Resection of the pancreatic body and tail was done in 1 patient, and pancreatoduodenectomy was performed in another patient. Laparotomy was done in 1 patient because of invasion of the superior mesenteric vein and duodenum.. Typical symptoms play an important role in the diagnosis of VIPoma. Octreotide therapy has advanced the preoperative electrolyte management, and the combination of octreotide, chemotherapy, and surgery may be helpful in metastatic disease.

Topics: Adult; Chromogranin A; Diagnosis, Differential; Fatal Outcome; Female; Humans; Immunohistochemistry; Male; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

We present an unusual case of a 52-year-old woman with severe, uncontrollable, refractory diarrhea attributable to pancreatic endocrine carcinoma (ECA) with markedly elevated serum vasoactive intestinal polypeptide (VIP) and calcitonin levels. After initial correction of fluid and electrolyte abnormalities, the patient was treated with high-dose octreotide. Shortly thereafter, due to the intractable nature of her diarrhea, she underwent cytoreductive hepatic surgery. The pancreatosplenectomy specimen showed a poorly differentiated ECA of the distal pancreas, immunoreactive for synaptophysin, CD56, and S100 protein, with morphologically similar hepatic and lymph node metastases. Postoperatively, her diarrhea improved, along with decline in serum VIP and calcitonin levels. Systemic chemotherapy with etoposide and cisplatin did not result in any radiographic and biochemical improvement. Having radiologically stable disease with depot-octreotide and short-acting octreotide (Sandostatin), she was subjected to peptide receptor radiotherapy with [177Lu-DOTA0,Tyr]octreotate (LuTate) that resulted in marked clinical and biochemical improvement, along with dramatic reduction in the number and size of hepatic metastases. In summary, this is a unique case of metastatic VIP- and calcitonin-secreting pancreatic ECA with dramatic sustained clinical, biochemical, and objective tumor response to peptide receptor radionuclide therapy.

Topics: Calcitonin; Combined Modality Therapy; Diarrhea; Female; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides, Cyclic; Radiopharmaceuticals; Vasoactive Intestinal Peptide

Topics: Adult; Female; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

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

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

Pancreatic polypeptide (PP) islet cell tumors are usually not associated with a distinct clinical syndrome, although some reports suggest that they can cause a watery diarrhea syndrome similar to vasoactive intestinal polypeptide (VIP) cell tumors. We report the case of a young woman with an unusual presentation of a pancreatic neuroendocrine tumor mainly secreting PP. The patient developed a reversible hypokalemic rhabdomyolysis very likely secondary to the presence of the tumor. The myopathy resolved following the restoration of normokaliemia using potassium supplementation and a partial laparoscopic pancreasectomy. Isolated cases of hypokalemic rhabdomyolysis induced by intestinal diseases have been described in literature but these did not include gastroenteropancreatic neoplasms. We suggest that pancreatic neuroendocrine tumors should be added to the list of intestinal diseases capable of producing hypokalemic myopathy.

Topics: Adult; Diagnosis, Differential; Diarrhea; Female; Humans; Hypokalemia; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Radionuclide Imaging; Rhabdomyolysis; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

Verner-Morrison syndrome, characterized by diarrhea, hypokalemia, and hypochlorhydria, is caused most commonly by vasoactive intestinal polypeptide-secreting islet cell tumors of the pancreas. Verner-Morrison syndrome has not been described as a paraneoplastic syndrome in non-small cell lung cancer. We describe a 38-year-old man with metastatic non-small cell lung cancer of large cell carcinoma with neuroendocrine differentiation who presented with bone metastasis and intractable secretory diarrhea that was unresponsive to pharmacological treatment, including octreotide. Laboratory evaluation indicated elevated serum calcitonin and vasoactive intestinal polypeptide levels. Chemotherapy resulted in a transient response in the patient's diarrhea and neuroendocrine markers. The patient did not respond to further therapy and died 5 months after onset of back pain. To our knowledge, this is the first published case of large cell carcinoma with neuroendocrine differentiation associated with treatment-responsive paraneoplastic Verner-Morrison syndrome.

Topics: Adult; Calcitonin; Carcinoma, Large Cell; Humans; Lung Neoplasms; Male; Octreotide; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Vasoactive Intestinal Peptide; Vipoma

Increased VIP plasma levels cause severe secretory diarrhea. Moreover, VIP is a major regulator of human intestinal motility. We hypothesized that VIP-mediated intestinal motility disturbances contribute to symptoms in elevated plasma VIP. Ten healthy volunteers were intubated twice with an orojejunal multilumen tube for duodenal manometry, jejunal perfusion of electrolyte and marker solution, and aspiration 10 and 40 cm more distally. All subjects randomly received intravenous infusion of saline and 300 pmol/kg x hr VIP for 5 hr. Results showed that VIP but not saline infusion induced netjejunal sodium secretion, watery diarrhea, and cardiovascular effects (P < 0.04). VIP did not alter intestinal motor activity or the mean duration of the interdigestive motility cycle or of phases I and II but nearly halved the duration of phase III (P = 0.0002). We conclude that increased plasma VIP markedly shortens human phase III activity without influencing other motility parameters. Hence, it is unlikely that VIP-mediated small intestinal motor disturbances cause symptoms in VIPOMA. Yet VIP may contribute to terminate phase III motility.

Topics: Gastrointestinal Motility; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Although pancreatic endocrine tumor can produce a variety of hormones, few pancreatic tumors produce a high systemic calcitonin concentration. Furthermore, calcitonin-producing pancreatic tumors rarely produce elevations of VIP in addition.. We evaluated and treated a 50-yr-old woman with the WDHA syndrome. Abdominal computed tomography (CT) detected a tumor in the tail of the pancreas. Peripheral plasma calcitonin and VIP concentrations were markedly increased to 2000 pg/mL (normal, <74 pg/mL) and 7200 pg/mL (normal, <100 pg/mL), respectively. We diagnosed a calcitonin- and VIP-producing pancreatic endocrine tumor, which was removed by distal pancreatectomy including splenectomy.. Plasma calcitonin and VIP were determined in blood from the vein draining the tumor and splenic vein, sampled at operation. These secreted concentrations were extremely high: 4640 and 3610 pg/mL for calcitonin; 24700 and 13500 pg/mL for VIP. Calcitonin and VIP were also highly elevated in the resected tumor. Plasma calcitonin and VIP rapidly decreased after tumor resection. The patient has been well without recurrence for over 20 yr.. An unusual pancreatic tumor secreting vasoactive intestinal peptide (VIP) caused WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria/hypochlorhydria) and also hypercalcemia. The latter was only partially offset by a large excess of calcitonin also secreted by the tumor.

Topics: Calcitonin; Female; Humans; Hypercalcemia; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

As case report we describe a rare cause of intractable "gastroenteritis" detected by ultrasonography. The 14 months-old boy was admitted to hospital because of intensive dehydration due to massive vomiting and diarrhoea. A salmonella enteritis with intractable hyponatraemia and hypokalaemia was thought to be the cause. After a dramatic relapse during oral treatment measures, further extensive laboratory tests finally disclosed an elevated serum level of vasoactive intestinal polypeptide ("VIP"). The VIP secreting tumor ("VIPoma") was detected ultrasonographically in a retroperitoneal localization mediocaudally of the right kidney. Diffuse distinct calcifications and an increased perfusion could be demonstrated. Intraspinal tumour spread was excluded by magnetic resonance imaging. After complete surgical removal of the tumour the clinical symptomatology normalized promptly and permanently. A VIP-excreting ganglioneuroblastoma with low grade growth fraction ("VIPoma") was diagnosed histologically. Common gastroenteritis in childhood represents no indication for ultrasound. In cases of unclear and therapy-resistant symptomatology, however, diagnostic work-up should include ultrasonography to search for retroperitoneal or pancreatic VIP-excreting tumours.

Topics: Gastroenteritis; Humans; Infant; Magnetic Resonance Imaging; Male; Pancreatic Neoplasms; Ultrasonography; Vasoactive Intestinal Peptide; Vipoma

Secretin receptors that are key for regulation of healthy pancreatic ductal epithelial cells have been reported to be functionally absent on ductal pancreatic adenocarcinomas. Here, we examine the possible presence and function of molecular forms of the secretin receptor in pancreatic cancer cell lines and in primary tumors. Surprisingly, reverse transcription-PCR and sequencing demonstrated wild-type secretin receptor mRNA in each of four cell lines and three primary tumors. Lack of biological response to nanomolar concentrations of secretin was best explained by the demonstrated coexpression of a second and predominant transcript in each of the cell lines and tumors. This represented a variant of the secretin receptor in which the third exon was spliced out to eliminate residues 44-79 from the NH(2)-terminal tail. This spliceoform has only recently been recognized in a rare gastrinoma, where it was incapable of binding secretin or signaling, and possessed dominant-negative activity to suppress hormone action at the wild-type secretin receptor (1). Overexpression of wild-type secretin receptor in Panc-1 cells driven by transfection of fully processed cDNA resulted in normal responsiveness to low concentrations of secretin, establishing the ability of these cells to produce a receptor capable of normal biosynthesis, trafficking, and signaling. Bioluminescence resonance energy transfer demonstrated that the variant receptor could form a heterodimer with wild-type receptor, providing a molecular mechanism for its dominant-negative activity. This suggests that missplicing is responsible for expression of a secretin receptor variant having the ability to suppress the function of wild-type receptor by a direct interaction. In 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays in receptor-bearing Chinese hamster ovary cells, the secretin receptor was shown to have growth-inhibitory effects. Suppression of this activity in pancreatic carcinoma might, therefore, facilitate tumor growth and progression of this aggressive neoplasm.

Topics: Alternative Splicing; Animals; Carcinoma, Pancreatic Ductal; Cell Division; CHO Cells; Cloning, Molecular; COS Cells; Cricetinae; Cyclic AMP; Dimerization; Humans; Pancreatic Neoplasms; Protein Isoforms; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Secretin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

MUC5AC mucin is not expressed in normal pancreas but is expressed in tumors. Little is known about the mechanisms that lead to this atypical expression. In this study, we demonstrate that stimulation of adenylyl cyclase and the protein kinase A (PKA) pathway by forskolin and vasoactive intestinal peptide (VIP) increased MUC5AC antigen expression and release from pancreatic cancer cells. Stimulation of the PKA pathway also increased MUC5AC mRNA. When SW1990 pancreatic cancer cells were grown on porous membranes they released MUC5AC mucins apically in response to VIP (10(-7) M) applied to their basolateral surfaces. SW1990 cells, as have been reported for other pancreatic cancer cells, have high affinity (<10(-7) M) VIP receptors and low affinity (>10(-6) M) secretin receptors. We also showed that four antibodies (CLH2, 21M1, 45M1, and Nd2) react with MUC5AC antigen in different cellular compartments of both tissues and cultured cells. In conclusion, the PKA pathway may contribute to the up-regulation of MUC5AC expression seen in pancreatic tumors.

Topics: Colforsin; Gastrointestinal Agents; Humans; Mucin 5AC; Mucins; Pancreatic Neoplasms; Protein Kinase C; Signal Transduction; Tumor Cells, Cultured; Up-Regulation; Vasoactive Intestinal Peptide

Tissue from a vasoactive intestinal peptide (VIP)-secreting human tumor has been used to establish and characterize human neuroendocrine primary cell cultures from which permanent, clone-derived cell lines have been established. Viable cells were obtained by enzymatic and mechanical dissociation of freshly resected pancreatic islet tumor and hepatic metastatic tumor tissues. Aliquots of tumor cells were established ex vivo under culture conditions including porous substrata coated with type IV collagen and laminin and a low serum, hormonally defined culture medium. The small (<10 microm) rounded, grape-like cells had a very slow growth rate of doubling times estimated at several weeks or more. After several passages, morphologically uniform cells were derived that strongly expressed neuroendocrine markers of synaptophysin and synaptobrevin. Although chromogranin A and VIP had somewhat weaker expression, both demonstrated phorbol ester-stimulated secretion. The morphologic and secretory properties were maintained by the cells for nearly 2 years in culture. The establishment of this novel VIP-secreting human neuroendocrine cell line (HuNET) makes available a culture model with which to study a transformed version of this pancreatic islet cell type and offers approaches by which to establish islet tumor cell lines.

Topics: Adult; Carcinoma, Islet Cell; Cell Separation; Chromogranin A; Chromogranins; Cryopreservation; Fluorescent Antibody Technique, Indirect; Humans; Immunoenzyme Techniques; Liver Neoplasms; Male; Pancreatic Neoplasms; Synaptophysin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

We evaluated the effects of GHRH antagonists on the proliferation of MiaPaCa-2 human pancreatic cancer cells and cAMP signaling in vitro. GHRH antagonists inhibited the proliferation of MiaPaCa-2 cells in vitro in a dose-dependent way and caused a significant elevation in cAMP production. In a superfusion system, short-term exposure of the cells to GHRH antagonists evoked an acute, dose-dependent release of cAMP into the medium. Native GHRH, which stimulates cAMP efflux from pituitary at nanomolar doses, did not influence cAMP release from cultured or superfused MiaPaCa-2 cells even at 10-30 microM. VIP, PACAP, secretin and glucagon also did not influence cell proliferation or cAMP production. Adenylate cyclase activator forskolin (FSK) caused a greater cAMP response, but a smaller antiproliferative effect than GHRH antagonists. Combined treatment with FSK and GHRH antagonist JV-1-38 potentiated the cAMP-inducing effect of FSK, but did not produce a greater inhibition of cell proliferation than JV-1-38 alone. A selective accumulation of radiolabeled GHRH antagonist [(125)I]JV-1-42 in vivo in MiaPaCa-2 carcinoma xenografted into nude mice was also observed. In conclusion, second messengers other than cAMP participate in the signal transduction pathways of GHRH analogs mediated by tumoral GHRH receptors.

Topics: Adenylyl Cyclases; Animals; Cell Division; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Glucagon; Growth Hormone-Releasing Hormone; Humans; Male; Mice; Mice, Nude; Muscles; Neoplasm Transplantation; Neuropeptides; Pancreatic Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Radioimmunoassay; Secretin; Signal Transduction; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The effects vasoactive intestinal peptide (VIP) antagonists were investigated on pancreatic cancer cell lines. (N-Stearyl, Norleucine17) VIP hybrid ((SN)VIPhyb) inhibited 125I-VIP binding to human Capan-2 cells with an IC50 value of 0.01 microM whereas VIP hybrid had an IC50 value of 0.2 microM. By RT-PCR and Northern blot, VPAC1 receptor mRNA was detected in CAPAN-2 cells. One microM (SN)VIPhyb and 10 microM VIPhyb inhibited the ability of 30 nM VIP to elevate cyclic AMP and increase c-fos mRNA. (SN)VIPhyb, 1 microM inhibited the clonal growth of CAPAN-2 cells in vitro. In vivo, (SN)VIPhyb (10 microg/day s.c.) inhibited CAPAN-2 xenograft growth in nude mice. These results indicate that (SN)VIPhyb is a pancreatic cancer VPAC receptor antagonist.

Topics: Amino Acid Sequence; Animals; Binding, Competitive; Cell Division; Cyclic AMP; Genes, fos; Humans; Inhibitory Concentration 50; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Pancreatic Neoplasms; Protein Binding; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Polypeptide, Type I; RNA, Messenger; Transplantation, Heterologous; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

A 42-year-old woman presented with a 4-year history of worsening diarrhoea that was watery, profuse and confirmed to be secretory in nature. She had tested positive for phenolphthalein on urinary laxative screening but continued to deny laxative usage. Her vasoactive intestinal polypeptide (VIP) level was subsequently found to be markedly elevated. Despite a normal abdominal ultrasound, a computed tomography scan revealed a 5-cm pancreatic tail mass. Octreotide scanning was used to exclude metastatic disease and she went on to have surgical removal of a localized pancreatic vasoactive intestinal polypeptide-oma which resulted in the complete resolution of her diarrhoea.

Topics: Adult; Diagnosis, Differential; Diarrhea; Female; Humans; Pancreatectomy; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Antagonists of GH-releasing hormone (GHRH) and vasoactive intestinal peptide (VIP) inhibit the proliferation of various tumors in vitro and in vivo, but a comparison of their antitumor effects and mechanisms of action has not been reported to date. We recently synthesized and characterized a series of analogs, some of which are primarily GHRH antagonists (JV-1-36, JV-1-38, and JV-1-42), whereas others are more selective for VIP receptors (VPAC-R; JV-1-50, JV-1-51, JV-1-52, and JV-1-53). LNCaP human prostatic cancer cells express VPAC-R, with predominant subtype 1 determined by RT-PCR. Our studies show that GHRH antagonists significantly inhibit the proliferation of both VPAC-R positive LNCaP cells (P < 0.001) and VPAC-R negative MiaPaCa-2 human pancreatic cancer cells cultured in vitro (P < 0.05 to P < 0.001). Growth inhibition of LNCaP cells is accompanied by a proportional reduction in prostate-specific antigen (PSA) secretion (P < 0.001). In a superfusion system, the inhibitory activities of the analogs on the rate of VIP and GHRH-induced PSA secretion correlate well with their VPAC-R binding affinities to LNCaP cell membranes. Antagonists more selective for VPAC-R display a stronger inhibition of inducible PSA release than GHRH antagonists, but have smaller effects or no effects on proliferation and PSA secretion in culture. Collectively, our findings demonstrate that the antiproliferative activity of the analogs on cancer cells is not correlated to their VPAC-R antagonistic potencies. Because GHRH antagonists inhibit the proliferation of LNCaP cells more powerfully than VPAC-R antagonists and also suppress the growth ofVPAC-R-negative MiaPaCa-2 cells, it can be concluded that their antiproliferative effect is exerted through a mechanism independent of VPAC-R.

Topics: Antineoplastic Agents; Cell Division; Growth Hormone-Releasing Hormone; Humans; Male; Pancreatic Neoplasms; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Neuropeptide; Receptors, Pituitary Hormone-Regulating Hormone; Receptors, Vasoactive Intestinal Peptide; RNA, Messenger; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide-secreting tumors (VIPomas) are extremely rare and difficult to diagnose. The authors describe a patient who was found to have a VIPoma after 3 years of symptoms. Somatostatin receptor scintigraphy using indium-labeled octreotide localized her tumor and prompted a surgical resection. This is the preferred imaging study for the earliest, most accurate, and cost-effective identification of VIPomas and their metastases.

Topics: Female; Humans; Liver Neoplasms; Magnetic Resonance Imaging; Middle Aged; Octreotide; Organotechnetium Compounds; Pancreatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

Human adenocarcinomas of the gastroenteropancreatic system overexpress vasoactive intestinal peptide (VIP) receptors and therefore represent logical diagnostic targets for receptor scintigraphy. Using iodine-123 labelled VIP, the newly employed diagnostic procedure termed VIP receptor scintigraphy (VIP-RS) appears to detect tumour tissue, especially pancreatic metastatic tumours, in almost all cases. So far, however, only a single centre has demonstrated convincing positive results. The aim of this study was to compare the sensitivity and specificity of VIP-RS with those of computer tomography (CT) and transabdominal ultrasound in patients with extensive pancreatic metastatic adenocarcinomas and neuroendocrine tumours. VIP was radiolabelled with carrier-free 123I using the chloramine T-method and preparative high-performance liquid chromatography for purification. Patients with metastatic pancreatic (n=12) and colorectal (n=3) carcinomas (adenocarcinoma: n=13, neuroendocrine tumour: n=2) were studied by VIP-RS, CT, ultrasound and, in one case, also by radioligand receptor autoradiography. Carrier-free radioiodinated VIP of maximum specific radioactivity maintained a high biological activity as determined by cAMP formation in receptor-expressing tumour cell lines. Intravenous injection of 123I-VIP did not cause any side-effects. Biodistribution, determined over 24 h, was high in the lungs and low in abdominal organs. Although all patients had extensive metastatic disease as evidenced by CT and ultrasound, VIP-RS was unable to detect either primaries or metastases in these patients. Only in two patients could a significant uptake of radiolabel be detected in organs directly infiltrated by the primary. To exclude false-negative findings, tumour tissue in one patient with a large primary, undetectable by VIP-RS, was analysed by radioligand receptor autoradiography and shown to be receptor positive. Moreover, in vitro receptor determinations showed that pancreatic carcinomas usually have fewer VIP receptors than the normal tissues to which they metastasize, like the liver. It is concluded that VIP can be radioactively labelled with maximum specific radioactivity while maintaining biological activity. Intravenous administration leads to a biodistribution almost identical to that reported previously. However, in contrast to these reports, very low sensitivity and specificity were observed for the detection of pancreatic cancers. In retrospect, these findings are

Topics: Adenocarcinoma; Adult; Aged; Colorectal Neoplasms; Female; Humans; Iodine Radioisotopes; Liver; Male; Middle Aged; Neuroendocrine Tumors; Pancreatic Neoplasms; Radionuclide Imaging; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Topics: Animals; Carbocyanines; Coloring Agents; Fluorescence; Gastrointestinal Neoplasms; In Vitro Techniques; Mice; Mice, Nude; Microscopy, Confocal; Octreotide; Optics and Photonics; Pancreatic Neoplasms; Receptors, Somatostatin; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Pancreatic vipoma is an unusual endocrine tumour, with only 5 cases reported in our country. We report a new case in a 41 year-old-male; the diagnosis was made on the basis of increased plasma levels of vasoactive intestinal peptide (VIP) and positive immunohistochemistry for VIP in the tumour. The peculiarities of this case were a strong steatorrhea which was managed with oral pancreatic enzymes and the findings of peritoneal carcinomatosis at the time of diagnosis.

Topics: Adult; Humans; Male; Pancreatic Neoplasms; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Vipoma

Antagonistic analogs of growth hormone-releasing hormone (GHRH) inhibit growth of various human cancers both in vivo and in vitro. GHRH, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide stimulate cyclic AMP (cAMP) release from various human cancer cell lines in vitro. Thus, in the present study, we investigated the effects of antagonistic analogs of GHRH on the GHRH- and VIP-induced cAMP release from cultured human cancer cells in a superfusion system. Various human cancer cell lines were exposed to human GHRH(1-29)NH2 (2-20 nM) or VIP (0.1-5 nM) repeatedly for 12 min or continuously for 96 min. GHRH antagonist MZ-5-156 at 100 to 200 nM concentration inhibited the GHRH- or VIP-induced cAMP release from mammary (MDA-MB-468), prostatic (PC-3), and pancreatic (SW-1990 and CAPAN-2) cancer cells. These results show that antagonistic analogs of GHRH suppress the stimulatory effects of GHRH and VIP on the cAMP production of various cancer cells. Because cAMP is a potent second messenger controlling many intracellular functions, including the stimulation of cell growth, an inhibition of autocrine/paracrine action of GHRH by the GHRH antagonists may provide the basis for the development of new methods for cancer treatment.

Topics: Animals; Breast Neoplasms; Cell Division; Cyclic AMP; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; In Vitro Techniques; Male; Neoplasms; Pancreatic Neoplasms; Pituitary Gland, Anterior; Prostatic Neoplasms; Rats; Second Messenger Systems; Sermorelin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Recent data demonstrated a high sensitivity (>90%) in the visualization of primary/recurrent pancreatic cancer as well as metastases by means of 123I-labeled vasoactive intestinal peptide (VIP). The aim of this study was to investigate the diagnostic value of radioiodinated VIP in patients suffering from adenocarcinoma of the exocrine pancreas.. Sixty consecutive patients (26 women, 34 men; mean age 59 yr) with histologically verified pancreatic cancer were investigated in this study. Twenty-one patients presented with organ-confined malignancy (19 at study entry and 2 during follow-up after initial surgery developed tumor recurrence), while 25 patients had distant metastases along with the local malignancy, and 7 patients had liver metastases after resection of the primary lesion (6 on study entry and 1 during follow-up showed tumor development). In 5 of these patients, abdominal lymph node metastases were present at the time of scanning. Of 10 patients, who had undergone potentially curative surgery for their cancer, 7 remained free of disease during follow-up until death or for at least 6 mo. Iodine-123-VIP (150-200 MBq; approximately 1 microg VIP) was administered to all patients. Scintigraphic results were evaluated as compared to conventional radiologic imaging methods and surgical exploration.. Primary pancreatic tumors were visualized by 123I-VIP in 19/21 patients (90%) with disease confined to the pancreas and in 8/25 patients (32%) suffering both from locoregional and disease metastatic to the liver. The overall 123I-VIP scan sensitivity for primary pancreatic adenocarcinomas was 58% (27/46 scans). Liver metastases were imaged in 29/32 patients (scan sensitivity 90%) and abdominal lymph node metastases in 4/5 patients. In 5 patients, the VIP receptor scan indicated the malignant lesion before CT. In vitro results confirmed specific binding of 123I-VIP to primary pancreatic tumor cells as well as to PANC1 adenocarcinoma cells.. Iodine-123-VIP receptor scanning has the potential to offer additional information to augment diagnostic standard methods and could influence the decision-making process in the treatment of pancreatic cancer.

Topics: Adenocarcinoma; Female; Humans; Iodine Radioisotopes; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Radionuclide Imaging; Receptors, Vasoactive Intestinal Peptide; Sensitivity and Specificity; Vasoactive Intestinal Peptide

A major problem in patients with small endocrine tumors is the difficulty in localizing the primary tumor site. Many endocrine tumors possess larger amounts of high affinity vasoactive intestinal peptide (VIP) binding sites compared with normal tissue or blood cells. We used radiolabeled VIP to localize the tumor site in a patient with Verner-Morrison syndrome (VMS). Under octreotide therapy, the VIP levels had declined in this patient, but a tumor site could not be detected by conventional techniques or by radiolabeled octreotide. However, using 123I-VIP, the tumor was detectable in the pancreatic tail. Surgical resection of the tumor was followed by complete remission of the VMS. Expression of VIP binding sites in the tumor was confirmed by a radioreceptor assay and showed cross-competition between VIP and octreotide. The identity of the VIP binding site in the tumor was analyzed by Northern blotting and revealed the expression of somatostatin receptor subtype 3, which binds both somatostatin-14 and VIP with higher affinity than octreotide. Iodine-123-VIP scintigraphy would be an effective tracer to identity the tumor site in VMS patients.

Topics: Adult; Humans; Indium Radioisotopes; Iodine Radioisotopes; Male; Pancreatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide; Vipoma

We report an optimized in situ hybridization (ISH) protocol with a rapid signal amplification procedure based on catalyzed reporter deposition (CARD) to increase the sensitivity of non-isotopic mRNA ISH on formaldehyde-fixed and paraffin-embedded tissue. The CARD method is based on the deposition of haptenized tyramide molecules in the vicinity of hybridized probes catalyzed by horseradish peroxidase. Commercially available and newly synthesized haptenized tyramides, including digoxigenin-, biotin-, di- and trinitrophenyl- as well as fluorescein-tyramide, were compared. The haptenized tyramides were visualized using peroxidase conjugated anti-hapten antibodies followed by the diaminobenzidine reaction. As a test system, we applied digoxigenin-labeled oligonucleotides to detect insulin and vasoactive intestinal polypeptide mRNA in pancreatic endocrine tumors and liver metastases. Our results indicate that specificity, sensitivity, and applicability of oligonucleotide mRNA ISH can be significantly improved by using chemically digoxigenin-labeled oligonucleotide probes and signal amplification by CARD. Furthermore, all tested tyramides provided approximately equal amplification efficiency. In conclusion, CARD signal amplification should further promote mRNA ISH studies on paraffin-embedded tissues and allow for multiple-target nucleic acid detection in situ.

Topics: Dinitrophenols; Formaldehyde; Gene Amplification; Haptens; Humans; In Situ Hybridization; Insulin; Liver; Liver Neoplasms; Oligonucleotide Probes; Pancreas; Pancreatic Neoplasms; Paraffin Embedding; RNA, Messenger; Sensitivity and Specificity; Tissue Fixation; Tyramine; Vasoactive Intestinal Peptide

A 30-year-old previously healthy woman was diagnosed as having a vasoactive intestinal polypeptide (VIP)-producing tumour of the pancreas. Her medical history was typical for neuroendocrine gastrointestinal tumours, presenting initially with non-specific symptoms but eventually she developed life-threatening manifestations requiring intensive care due to severe dehydration. She immediately recovered following surgical resection. The patient had elevated serum concentrations of VIP as well as pancreastatin, and post-operatively elevated concentrations of three growth factors, IGF-I, EGF and TGF-alpha, were seen. The importance of the alterations in plasma concentrations of the different peptides for her symptomatology are discussed.

Topics: Adult; Antidiarrheals; Dehydration; Female; Gastrointestinal Hormones; Growth Substances; Humans; Octreotide; Pancreatic Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal peptide (VIP) appears to be responsible for atropine-resistant, neurally mediated pancreatic ductal bicarbonate secretion and plays a role in both stimulation and inhibition of neoplastic growth in other organs. cDNAs encoding high affinity VIP-1 and VIP-2 receptors have been cloned, and these receptors may be differentiated based on the ability of VIP-1, but not VIP-2, receptors to couple to adenylyl cyclase in response to stimulation with micromolar concentrations of secretin. Recent data from our laboratory suggest expression of a low affinity secretin receptor in seven cell lines derived from human ductal pancreatic adenocarcinomas. In combination with the recent use of (123)I-labeled VIP to successfully image pancreatic adenocarcinomas in humans and the high affinity binding of both VIP and pituitary adenylate cyclase-activating peptides to sections from human pancreatic tumors, these findings suggest that VIP-1 receptors may be expressed on the majority of neoplastic pancreatic duct epithelial cells in vivo. To initially test the hypothesis that expression of VIP-1 receptors plays an important role in the pathophysiology of human ductal pancreatic adenocarcinomas, we used reverse transcription-PCR with Southern blot hybridization to confirm expression of VIP-1 and VIP-2 receptor mRNA in the vast majority of 28 human ductal pancreatic adenocarcinomas. Based on the cellular heterogeneity of these tumors, we also assessed VIP receptor subtype expression in seven well-characterized, secretin-responsive cell lines derived from human ductal pancreatic adenocarcinomas. Only VIP-1 receptor mRNA was detected in all seven secretin-responsive cell lines. A half-maximal increase in intracellular cyclic AMP was obtained with 0.5-5 nM VIP in each of these cell lines, consistent with expression of high affinity VIP receptors. The ability of 1 microM, but not 1 nM, secretin to stimulate intracellular cyclic AMP generation in these cells was consistent with VIP-1 receptor expression. Interestingly, 100 pM, but not 1 microM, VIP stimulated significant growth of VIP-1 receptor-bearing Capan-2 cells both in the absence and presence of serum. Because VIP-1 receptors appear to be expressed in the majority of neoplastic pancreatic duct cell lines and VIP stimulates growth of VIP-1 receptor-bearing Capan-2 cells in vitro, this peptide may well play an important role in the pathophysiology of tumors expressing these receptors in vivo.

Topics: Adenocarcinoma; Blotting, Southern; Cell Division; Cyclic AMP; Female; Humans; Male; Neoplasm Proteins; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; RNA, Messenger; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

To assess involvement of p53 mutations in development of pancreatic endocrine tumors.. Survey of sporadic pancreatic endocrine tumors.. Hospital referral centers, mainly in the Los Angeles, Calif, area.. We obtained fresh surgical specimens from 25 patients (convenience sample) with no family history of endocrine tumors and no evidence of multiple endocrine neoplasia 1 or von Hippel-Lindau disease. Preoperative tests included serum peptide analysis.. DNA was prepared from tumor specimens. We screened exons 5 through 8 of the p53 gene using single-strand conformation polymorphism analysis, followed by DNA sequencing when a variant was detected.. A three-base deletion mutation (codon 239) was found in one malignant tumor secreting vasoactive intestinal peptide.. p53 appears to have a limited role in development of pancreatic endocrine tumors. However, evidence from one of our patients suggests it may be involved in tumor progression in uncommon cases.

Topics: Codon; DNA, Neoplasm; Exons; Genes, p53; Humans; Male; Middle Aged; Mutation; Pancreatic Neoplasms; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Sequence Analysis, DNA; Vasoactive Intestinal Peptide

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

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

Topics: Duodenal Neoplasms; Female; Ganglioneuroma; Growth Hormone; Humans; Hyperplasia; Immunohistochemistry; Infant; Jejunal Neoplasms; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Vasoactive Intestinal Peptide

After surgical resection for rectosigmoid carcinoma a 63-year-old man had secretory diarrhea causing severe metabolic acidosis, hypokalemia, hypercalcemia and dehydration. Subsequent investigations revealed a mass measuring 4 x 5 cm in the uncinate process of the pancreas and an elevated vasoactive intestinal polypeptide concentration. The diarrhea responded to treatment with the somatostatin analogue. Sandostatin, and remained under control during a prolonged preoperative period. The patient underwent a Whipple procedure with immediate lessening of his diarrhea. This report illustrates a classic case of vipoma and demonstrates the need to consider this condition in the differential diagnosis of secretory diarrhea, even in the presence of other gastrointestinal lesions. The effectiveness of somatostatin analogues in stabilizing the diarrhea preoperatively is also well illustrated.

Topics: Diagnosis, Differential; Gastrointestinal Agents; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Octreotide; Pancreatic Neoplasms; Pancreaticoduodenectomy; Sigmoid Neoplasms; Vasoactive Intestinal Peptide; Vipoma

The response of confluent monolayers of normal and cystic fibrosis (CF) pancreatic epithelial cells to stimulation by extracellular ATP and ATP analogues was investigated in terms of mucin secretion. Mucin secretion was measured as release of M1 antigens by a direct sandwich enzyme immunoassay. Extracellular ATP provoked rapid (< or = 15 min) and strong mucin secretion (+ 480 +/- 35%) by the normal pancreatic cell lines but was not able to induce mucin secretion by the CF cell lines. The order of efficacy of nucleotide agonists with ATP > ADP > AMP > adenosine was that of typical P2-purinergic receptors. ATP induced a rapid and transient intracellular [Ca2+] mobilization in both normal and CF pancreatic epithelial cells. This work demonstrated that CFTR seemed to mediate ATP-dependent mucin secretion.

Topics: Adenocarcinoma; Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Adult; Antigens; Calcium; Carbachol; Cell Line; Colforsin; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelium; Humans; Immunoassay; Mucins; Pancreatic Neoplasms; Receptors, Purinergic P2; Transfection; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The growth of pancreatic cancers may be influenced by certain gut peptides. However, the alteration of gut peptide receptors in the progress of pancreatic carcinogenesis is largely unknown. With storage phosphor autoradiography, this study visualized and characterized receptors for cholecystokinin (CCK), somatostatin (SST), bombesin (BBS), secretin and vasoactive intestinal peptide (VIP) in pancreata of control hamsters (n = 7) and pancreatic preneoplastic lesions (n = 10) or adenocarcinomas (n = 10) of N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters. The specific CCK-A and secretin receptors expressed in normal pancreata were markedly reduced in pancreatic preneoplastic lesions and absent in adenocarcinomas. In the development of pancreatic tumours, the subgroup of SST receptors did not change, but both the affinity and binding capacity declined. In comparison with the binding of VIP to normal pancreata, specific VIP binding was significantly lower in preneoplastic lesions and almost absent in pancreatic adenocarcinomas. No specific binding for BBS was detected in normal pancreas or (pre)neoplastic lesions of hamster pancreas. The reduction or absence of receptors for CCK, secretin, SST and VIP in hamster pancreas with the progress of carcinogenesis suggests that in BOP-treated hamsters, pancreatic adenocarcinomas have, to a large extent, lost the hormone-dependent characteristics of the original tissue.

Topics: Adenocarcinoma; Animals; Carcinogens; Cholecystokinin; Cricetinae; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms; Precancerous Conditions; Receptors, Cholecystokinin; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Receptors, Somatostatin; Receptors, Vasoactive Intestinal Peptide; Secretin; Somatostatin; Vasoactive Intestinal Peptide

We present a case of a pancreatic islet cell tumor, demonstrating typical clinical and immunohistochemical characteristics of a VIPoma, but with the novel feature of massive stromal amyloid deposition. Amyloid deposition has been reported in association with insulinomas of the pancreas, but as far as the available literature suggests, it has not been reported in VIPomas. Islet associated polypeptide (IAPP) and calcitonin are both candidates for the amyloidogenic peptide in this case, based on observations in other tumors.

Topics: Aged; Amyloid; Female; Humans; Immunohistochemistry; Microscopy, Electron; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Authors report a case of Verner-Morrison syndrome which occurred in a 75-year-old man. The syndrome was caused by a pancreas VIP-oma with the histological structure of adenocarcinoma. Treatment with somatostatin analogous (octreotid) was effective, but the outcome was lethal due to subsequent pulmonary embolism.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Hormonal; Fatal Outcome; Humans; Male; Octreotide; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are structurally-related neuropeptides that function as trophic factors in addition to their more classical roles as neurotransmitters. Binding and molecular cloning studies have shown that their actions are mediated by receptors encoded by at least three different genes. VIP binding has been demonstrated on many tumor types, and radiolabeled VIP has recently been used as a novel method to localize intestinal tumors in humans and their sites of metastasis. To determine the receptor subtype and level of gene expression, we screened breast, intestinal, and pancreatic, cell lines by Northern blot analysis. Breast lines expressed VIP/PACAP1 receptor mRNA levels comparable to intestinal lines, in agreement with the studies showing particularly high VIP binding in these tumors and their derived cell lines. Pancreatic cell lines expressed mRNA for several receptor types. This extends the potential utility of VIP and PACAP in the localization of tumors, and because VIP and PACAP may regulate the growth rate of some tumors by autocrine or other mechanisms, the identification of receptor subtypes on these lines sets the stage for studies in which the activity of these individual receptors in growth and other processes can be investigated.

Topics: Animals; Breast Neoplasms; Cloning, Molecular; DNA Probes; Gene Expression; Humans; Intestinal Neoplasms; Mice; Pancreatic Neoplasms; Rats; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Hormone; Receptors, Vasoactive Intestinal Peptide; RNA, Messenger; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The effects of Vasoactive intestinal peptide (VIP) on mucin secretion in the pancreatic cancer Capan-1 cell line were studied by Enzyme-linked-immunosorbent-assay (ELISA), and by light and electron microscopy using immunocytological methods. During the exponential growth phase, mucins were accumulated in the cytoplasm of cells and slowly exocytosed. In contrast, there was enhanced exocytosis of mucins during the stationary phase when the cells were well-polarized. Moreover, during this phase, VIP induced a dose-dependent rise in mucin content in the extracellular medium. The reaction with anti-M1 monoclonal antibodies, which recognize specifically the peptide core of gastric mucins, showed an accumulation of secretion granules near the apex of well-polarized cells together with fusion of the granule and plasma membranes after VIP stimulation. Moreover, mucin exocytosis was stimulated by Pituitary adenylate cyclase activating polypeptide (PACAP) and secretin. It was also increased after forskolin treatment suggesting that this mechanism was cAMP-dependent. Our results suggested that exocytosis of mucins could be under the control of VIP in pancreatic duct cells of the Capan-1 cell line.

Topics: Cell Polarity; Colforsin; Cytoplasm; Cytoplasmic Granules; Enzyme-Linked Immunosorbent Assay; Exocytosis; Humans; Immunohistochemistry; Microscopy, Electron; Mucins; Neuropeptides; Pancreatic Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Secretin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Sixty-four kinds of cell lines were examined as to their ability to degrade glucagon using conditioned-media obtained from their protein-free cultures. Two human tumor cell lines were shown to produce this activity, and the cell line, HPC-YO, established from a human pancreatic carcinoma was shown to produce the highest level of activity. The glucagon-degrading enzyme (GDE) was purified from HPC-YO conditioned-medium by a combination of ion-exchange, gel filtration, and hydroxylapatite column chromatographies. The purified GDE also degraded vasoactive intestinal polypeptide (VIP) and secretin, however, it did not cleave EGF, gastrin, insulin, somatostatin, substance P, neurotensin, or growth hormone. The molecular weight of GDE is 83,000, as determined on SDS-polyacrylamide gel electrophoresis. The N-terminal amino acid sequence of GDE was blocked, and the five partial amino acid sequences obtained on lysyl-endopeptidase digestion were determined to be N-L-T-E-E-Y-D-V-S-D-G-E-I-E-L-L-Y-E-K, V-E-T-Y-Y-D-L-L-F-E-K, L-Y-W-F-L-D-E-A-K, S-N-S-T-S-Y-V-K, and Y-Y-A-S-T-S-Y-D-D-T-Y-K. The same or homologous amino acid sequences have not been found in known proteins, demonstrating that GDE is a novel peptidase that degrades the secretin family: glucagon, VIP, and secretin.

Topics: Amino Acid Sequence; Endopeptidases; Humans; Molecular Sequence Data; Pancreatic Neoplasms; Secretin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Pituitary adenylate cyclase activating polypeptide (PACAP) is a newly discovered neuropeptide which exists in two biologically active forms: PACAP-38 consisting of 38 amino acids and PACAP-27, a peptide corresponding to the N-terminal 27 amino acids of PACAP-38. Both PACAPs are derived from a 176 amino acid precursor (preproPACAP) which in addition gives rise to a 29 amino acid peptide, designated PACAP-related peptide (PRP). The presence of the three preproPACAP-derived peptides (PACAP-38, PACAP-27 and PRP) in tumour tissue from nine patients with VIP-producing tumours (pancreatic carcinoma, neuroblastoma, ganglioneuroma and pheochromocytoma) and eleven patients with non-VIP-secreting tumours (gastrinoma, glucagonoma, somatostatinoma, neuroblastoma) was examined by specific radioimmunoassays. In seven out of the nine VIP-secreting tumours elevated concentrations of all the three preproPACAP-derived peptides were found compared with normal tissue, while the concentrations in the non-VIP-secreting tumours were within the normal range. PACAP-38 was in all cases the dominating peptide, the concentration ranging from 41 to 3606 pmol/g. When tumour extracts were fractionated on Sephadex G50 column, tricine gel electrophoresis or reverse-phase HPLC immunoreactive components corresponding to synthetic PACAP-38, PACAP-27 and human PRP were identified, suggesting that preproPACAP was fully processed. Immunocytochemical examination showed PACAP-immunoreactive cells in the tumour tissue which also stained for VIP. This co-localization of PACAP and VIP was confirmed by double-staining experiments on the same sections, demonstrating PHM/VIP mRNA and PACAP-immunostaining in the same cells.

Topics: Adrenal Gland Neoplasms; Ganglioneuroma; Humans; Neoplasms; Neuroblastoma; Neuropeptides; Neurotransmitter Agents; Pancreatic Neoplasms; Pheochromocytoma; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Precursors; Vasoactive Intestinal Peptide

In the present study, the effects of VIP on the growth of two human pancreatic carcinoma cell lines PU-PAN-1 and PANC-1 were determined using tritiated thymidine incorporation. VIP receptors, intracellular cAMP and polyamines were investigated. The results indicated that VIP at a concentration of 10(-8) mol/L to 10(-7) mol/L can significantly stimulate the growth of PU-PAN-1 cells but not PANC-1 cells. This effect is dose-dependent and abolished by VIP receptor antagonist, [4-C1-Phe6, Leu17] VIP, suggesting VIP receptors in PU-PAN-1 cells may mediate this effect. VIP can markedly elevate the levels of intracellular cAMP and polyamines in PU-PAN-1 cells, indicating that the growth-promoting effect stimulated by VIP may be via a rapid increase in the biosyntheses of cAMP and polyamines. In addition, the VIP-antibody inhibited the growth of PU-PAN-1 cells in serum-free culture medium. The results above suggested that VIP has an autocrine regulatory effect on this pancreatic carcinoma cell line (PU-PAN-1).

Topics: Biogenic Polyamines; Cell Division; Cyclic AMP; Dose-Response Relationship, Drug; Humans; Immune Sera; Pancreatic Neoplasms; Receptors, Vasoactive Intestinal Peptide; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Human glucagonoma cells were isolated and maintained in vitro. Incubation experiments showed that carbachol (Cch) induced the simultaneous release of glucagon, VIP (vasoactive intestinal polypeptide), and pancreatic polypeptide (PP) at levels significantly higher than basal levels. Atropine abolished the stimulatory effect of Cch on glucagon, VIP, and PP release. An immunohistological study of the tumor tissues revealed that the cells contained glucagon, VIP, and PP. These findings demonstrate, for the first time, the in vitro release of glucagon from glucagonoma cells by Cch stimulation.

Topics: Carbachol; Glucagon; Glucagonoma; Humans; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Pancreatic endocrine tumors (PETs) may secrete a variety of peptide hormones, either alone or in combination, and intravenously administered provocative agents have been used to stimulate hormone release to aid in the diagnosis and localization in suspected cases. These features of PETs led us to perform detailed biochemical investigations and provocative testing in a 26-year-old man with a 5 cm vasoactive intestinal peptide (VIP)-secreting tumor of the head of the pancreas.. Plasma hormone radioimmunoassays and immunohistochemical studies were performed for a panel of peptide hormones, including VIP, neurotensin, and pancreatic polypeptide (PP). Acid alcohol extracts of tumor specimens were analyzed for these peptide hormones as well. Before operation, four provocative test regimens were administered intravenously after an overnight fast: pentagastrin (0.5 microgram/kg/5 sec); rapid calcium infusion (2 mg/kg/min); a combination of calcium (2 mg/kg/min) followed by pentagastrin (0.5 microgram/kg/min); and secretin (2 clinical units/kg bolus). Blood samples were collected before each test and 1, 2, 3, 5, and 10 minutes after the infusions.. Measurement of plasma hormone levels and tumor immunohistochemistry and hormonal extraction studies indicated secretion of VIP, neurotensin, and PP by the tumor. Coexpression of VIP and neurotensin was seen immunohistochemically within some individual tumor cells. Provocative testing resulted in maximal stimulation of VIP and neurotensin secretion with pentagastrin administration, which produced increases in plasma levels of VIP and neurotensin over basal levels of 81% and 87%, respectively. After operation, plasma levels of VIP, neurotensin, and PP were undetectable before and after administration of pentagastrin.. The results emphasize the importance of comprehensive biochemical evaluation in patients with VIPoma syndrome to detect the production of a range of peptide hormones. Administration of intravenous pentagastrin appears to stimulate release of VIP and NT and should be evaluated further as a provocative agent for the diagnosis and follow-up of patients with these tumors.

Topics: Adult; Calcium; Humans; Immunohistochemistry; Male; Neurotensin; Pancreatic Neoplasms; Pancreatic Polypeptide; Pentagastrin; Secretin; Stimulation, Chemical; Vasoactive Intestinal Peptide; Vipoma

The purpose of the present study was to determine whether vasoactive intestinal polypeptide (VIP) is released from the tumor cells of VIPoma and if so then to attempt to show how its release is regulated by cultured human VIPoma cells.. A resected specimen of a pancreatic tumor from a patient with watery diarrhea, hypokalemia, and achrohydria syndrome was examined. The dissociated cells were obtained by collagenase digestion of the tumor tissue and were cultured in vitro.. The extraction of tumor cells disclosed that the cells contained VIP and pancreatic polypeptide (PP). Neither insulin, glucagon, somatostatin nor pancreastatin was detected. Immunohistochemically, 40% to 60% of the cells in the tumor stained positively for VIP and 1% to 5% stained positively for PP. The dissociated cells became reaggregated in the culture (50 to 300 microns) and could be maintained in vitro. Incubation experiments revealed a simultaneous in vitro release of VIP and PP with a significant increase by either carbachol or phorbol myristate acetate but not by theophylline or caerulein. Atropine completely abolished the stimulatory effects of carbachol on VIP and PP release. Octreotide (somatostatin analogue [SMS 201-995]) significantly inhibited the carbachol and phorbol myristate acetate-stimulated VIP and PP release.. These findings show the in vitro release of VIP and PP from the VIPoma cells and also provide evidence for the direct inhibitory effect of somatostatin analogue on both the VIP and PP release from the tumor cells.

Topics: Adult; Atropine; Carbachol; Ceruletide; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Microscopy, Phase-Contrast; Octreotide; Pancreatic Neoplasms; Pancreatic Polypeptide; Tetradecanoylphorbol Acetate; Theophylline; Tumor Cells, Cultured; Vasoactive Intestinal Peptide; Vipoma

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

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

The binding and biological effect of pituitary adenylate cyclase activating polypeptide (PACAP), a novel hypothalamic peptide with high sequence homology to vasoactive intestinal polypeptide (VIP), were studied in rat AR 4-2 J pancreatic carcinoma cells and isolated rat pancreatic acini. PACAP(1-27) and analogue PACAP(1-23, VIP-24-28), but not VIP, displaced potently and reversibly 125I-PACAP(1-27) from binding to an abundantly expressed high affinity PACAP-preferring receptor on AR 4-2 J cells, referred to as "PACAP-1 receptor." High affinity binding was dependent on N-terminal and C-terminal residues of PACAP(1-27): PACAP(1-24,Cys-25) (7.3 +/- 1.6 microM), PACAP(1-23) (8.2 +/- 1.5 microM), VIP (> 30 microM), PACAP(3-27), PACAP(1-19), PACAP(3-19), PACAP(1-12), and PACAP(18-38) (all > 50 microM) showed low or no binding potency. In contrast, high and low affinity binding of 125I-VIP to AR 4-2 J cells was displaced equipotently by PACAP(1-27) and VIP, thus defining on these cells, in addition, two scarcely expressed binding sites, designated "VIP/PACAP-2 receptor," similar or identical to the previously described high and low affinity acinar VIP receptor. Binding of 125I-PACAP(1-27) to a high and low affinity binding site on rat pancreatic acini was inhibited equipotently by PACAP(1-27) and VIP, identifying these sites as VIP/PACAP-2 receptors. PACAP(1-23) recognized both type 2 binding sites with only slightly lower affinity. PACAP(1-27), PACAP(1-38), PACAP(1-23, VIP-24-28), and PACAP(1-23) equipotently stimulated acinar lipase release and cyclic AMP production in pancreatic acini. Co-incubation of PACAP(1-27) or VIP with cholecystokinin-8 or carbachol revealed additive effects on enzyme secretion. Our results suggest the predominant expression of VIP/PACAP-2 receptors on rat pancreatic acini, whereas AR 4-2 J cells express mainly PACAP-1 receptors. PACAP is a potent ligand for both receptor types and has to be regarded as a novel VIP-like pancreatic secretagogue.

Topics: Amino Acid Sequence; Animals; Carbachol; Cholecystokinin; In Vitro Techniques; Iodine Radioisotopes; Lipase; Molecular Sequence Data; Neuropeptides; Neurotransmitter Agents; Pancreas; Pancreatic Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Second Messenger Systems; Sequence Homology, Amino Acid; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

In the present work the effects of the novel neuropeptide Pituitary Adenylate Cyclase Activating Peptide (PACAP) on both AR4-2J cell growth and the modulation of ornithine decarboxylase activity were investigated. Both PACAP38 and the amidated form PACAP27 caused a concentration-dependent stimulation of AR4-2J cell growth; the maximal increase was seen at 1 nmol/L (30% above control, P less than 0.01) with a half-maximal effect at 0.01 nmol/L. Ornithine decarboxylase activity was also increased by PACAP in a dose-dependent manner, reaching half-maximal stimulation at 0.5 nmol/L. The addition of 1 nmol/L of somatostatin analog SMS 201-995 totally suppressed PACAP-stimulated AR4-2J cell growth. Vasoactive intestinal polypeptide (3 mumol/L) and 8-bromo-cyclic adenosine monophosphate (1 mmol/L) had no effect on cell proliferation. Treatment of cells by pertussis toxin (25 ng.mL-1.day-1) suppressed PACAP-stimulated AR4-2J cell growth but enhanced PACAP-induced stimulation of adenylate cyclase activity. It was concluded that PACAP stimulates AR4-2J cell proliferation by a mechanism that seems independent of cyclic adenosine monophosphate production. The mitogenic effect of PACAP depends on a pertussis toxin-sensitive G protein and is associated with an increase of ornithine decarboxylase activity.

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclases; Animals; Cell Count; Cell Division; Cyclic AMP; Dose-Response Relationship, Drug; Epidermal Growth Factor; Insulin; Neuropeptides; Octreotide; Ornithine Decarboxylase; Pancreatic Neoplasms; Pertussis Toxin; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Tumor Cells, Cultured; Vasoactive Intestinal Peptide; Virulence Factors, Bordetella

A patient with metastatic VIP-producing pancreatic tumor was successfully treated with subcutaneous octreotide, an analogue of somatostatin, for more than 4 years. The profuse diarrhea was rapidly controlled and the plasma concentrations of the hormones (VIP, neurotensin, gastrin, pancreatic polypeptide) fell to nearly normal within 2 months. Because of asymptomatic increase in tumor size, we added chemotherapy 2 years later. Since the drug is rapidly effective and well tolerated, it will probably become the therapy of choice in this syndrome.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Liver Neoplasms; Male; Neurotensin; Octreotide; Pancreatic Neoplasms; Streptozocin; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal polypeptide (VIP)-immunoreactive nerves have been demonstrated in close association with the islets of Langerhans, and VIP has been shown to stimulate insulin and somatostatin secretion. Using [125I]VIP and membranes prepared from rat insulinoma (RIN) cells, i.e., the subclones m5F (m5F; mainly insulin-secreting) and 14B (14B; mainly somatostatin-secreting), it was found that VIP (10(-10)-10(-7) M) competitively inhibited the binding of [125I]VIP. A single class of high affinity binding sites with Kd values of 0.40 +/- 0.06 nM and 0.36 +/- 0.08 nM for m5F and 14B, respectively, with a corresponding number of binding sites (Bmax) of 163 +/- 20 and 254 +/- 51 fmol/mg protein was observed. The rank order of potency in inhibiting [125I]VIP binding was in both cell lines: VIP greater than helodermin greater than pituitary adenylate cyclase activating polypeptide 1-27 (PACAP27) greater than peptide histidine isoleucine (PHI) greater than secretin. VIP caused a dose-dependent increase in cAMP-formation in both m5F and 14B cell membranes with EC50 values of 3.0 and 3.5 nM, respectively, but VIP (1.10(-9)-3.10(-6) M) had no effect on insulin secretion (over 2 h) from the m5F cells. Thus, the data suggest that the VIP-receptors in these neoplastic rat cell lines, despite an apparent coupling to adenylate cyclase activity, seem to be functionally uncoupled to an effect on insulin secretion following an acute exposure to VIP.

Topics: Adenylyl Cyclases; Animals; Cyclic AMP; Enzyme Activation; Insulin; Insulin Secretion; Insulinoma; Islets of Langerhans; Kinetics; Pancreatic Neoplasms; Radioligand Assay; Rats; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Hypercalcitoninemia in gastroenteropancreatic tumors associated with calcitonin immunoreactivity is rare.. We report here two patients in whom pancreatic neuroendocrine tumors both contained and secreted immunoreactive calcitonin. Both patients experienced elevated basal calcitonin immunoreactivity.. The peak responses of immunoreactive calcitonin occurred 5 minutes after pentagastrin administration in these two patients and were 30% and 180% above basal concentrations corresponding to peak increments of 0.39 and 8.78 ng/ml, respectively. The immunoreactive calcitonin response to pentagastrin in these two patients was not significantly different from that seen among five patients with medullary carcinoma of the thyroid gland.. It does not appear that immunoreactive calcitonin responses to pentagastrin stimulation will discriminate between patients with medullary carcinoma of the thyroid gland and those with nonfamilial, gastroenteropancreatic neuroendocrine tumors that express calcitonin immunoreactivity. In patients with secretory diarrhea and/or flushing, an elevated level of immunoreactive calcitonin, in the absence of a thyroid mass in the neck, may herald the presence of a gastroenteropancreatic neuroendocrine tumor.

Topics: Adenoma, Islet Cell; Aged; Calcitonin; Female; Humans; Liver Neoplasms; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Pentagastrin; Stomach Neoplasms; Thyroid Neoplasms; Vasoactive Intestinal Peptide

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

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

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

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

To elucidate the biosynthetic processing of the precursor for vasoactive intestinal peptide (prepro-VIP) in tumours producing VIP we have used newly developed radioimmunoassays directed against the five functional domains of the VIP precursor molecule: preproVIP 22-79, peptide histidine methionine (PHM), preproVIP 111-122, VIP and preproVIP 156-170 in combination with HPLC to identify and quantify the peptides in tumour specimen and plasma from patients with the watery diarrhoea syndrome. Elevated quantities of all the five peptides were found in the 13 tumours (nine neurogenic tumours, one pheochromocytoma, three pancreatic carcinomas) examined. The preproVIP derived peptides were expressed in non-equimolar amounts and the relative proportion of the various peptides differed markedly from tumour to tumour. The pheochromocytoma was the only tumour type which contained large amounts of preproVIP 156-170 in comparison with the other peptides. A proportion of the VIP precursor which varied from 7% to 73% followed a pathway in which the dibasic conversion site after PHM was uncleaved as evidenced by the presence of PHV, a C-terminally extended form of PHM. It was also found that unlike normal tissue a fraction of the C-terminal VIP precursor peptide, preproVIP 156-170, was having its C-terminal lysine residue removed during processing. The findings indicate that various post-translational processing pathways of preproVIP exist. All the peptide sequences produced in the tumour tissue were secreted as evidenced by their presence in plasma in elevated concentrations. The plasma levels of preproVIP 22-79, preproVIP 111-122 and PHV exceeded those of the remaining preproVIP-derived peptides suggesting that determination of these peptides in patients with VIP-secreting tumours may be better markers than VIP.

Topics: Adult; Aged; Amino Acid Sequence; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Molecular Sequence Data; Pancreatic Neoplasms; Peptide Fragments; Protein Precursors; Vasoactive Intestinal Peptide; Vipoma

PACAP (pituitary adenylate-cyclase-activating peptide)-binding receptors were investigated in membranes from the rat pancreatic acinar cell line, AR 4-2J, the rat hippocampus and the human neuroblastoma cell line NB-OK, by 125I-PACAP(1-27) (amino acid residues 1-27 of N-terminal amidated PACAP) binding and adenylate cyclase activation. The relative binding of 125I-PACAP(1-27) to the receptor, and ability to activate adenylate cyclase were PACAP greater than or equal to PACAP(1-27) greater than PACAP(2-38) greater than PACAP(1-9)-VIP(10-28)(PACAP-VIP) greater than PACAP(2-27) greater than [Ser9,Tyr13]VIP greater than [Tyr13]VIP greater than or equal to [Ser9]VIP greater than or equal to VIP(1-23)-PACAP(24-27)(VIP-PACAP) greater than VIP (vasoactive intestinal peptide). The N-terminal moiety of PACAP(1-27) was more important than the three amino acids at the C-terminus for 125I-PACAP(1-27)-binding site recognition. For rat pancreatic 125I-VIP-binding sites tested with 125I-VIP, the order of binding affinity was PACAP = PACAP(1-27) greater than or equal to VIP = [Ser9]VIP = [Tyr13]VIP = [Ser9,Try13]VIP greater than or equal to PACAP-VIP greater than or equal to VIP-PACAP greater than PACAP(2-38) = PACAP(2-27). Pancreatic 125I-VIP-binding sites, when compared to 125I-PACAP(1-27)-binding sites, showed little specificity and only weak coupling, so that PACAP and VIP-PACAP acted only as partial VIP agonists on adenylate cyclase.

Topics: Adenylyl Cyclases; Amino Acid Sequence; Animals; Binding Sites; Cell Membrane; Chimera; Enzyme Activation; Hippocampus; Humans; Molecular Sequence Data; Neuroblastoma; Neurons; Neuropeptides; Pancreatic Neoplasms; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

To examine the possible in vivo significance of the immunomodulatory effects of vasoactive intestinal polypeptide described in vitro, several parameters of peripheral blood lymphocyte function were studied in a patient with a pancreatic endocrine tumor and high circulating levels of vasoactive intestinal polypeptide. There was no imbalance of the circulating lymphocyte subpopulations, and the in vitro responses of the patient's lymphocytes to mitogens were normal. However, there was an increased number (32%) of peripheral lymphocytes expressing interleukin 2 receptor. Serum immunoglobulin M levels were higher than in controls, and the patient's lymphocytes exhibited a spontaneous in vitro immunoglobulin M production higher than normal. Comparable increases in both interleukin 2 receptor expression and immunoglobulin M production were induced in vitro in normal peripheral lymphocyte cultures by the addition of vasoactive intestinal polypeptide concentrations similar to that detected in the patient's plasma. These findings indicate that a modulatory effect of vasoactive intestinal polypeptide on lymphocyte activation and immunoglobulin synthesis may be operating in vivo. They also suggest that vasoactive intestinal polypeptide does not mediate major defects in peripheral blood lymphocyte function in vivo.

Topics: Adenoma, Islet Cell; Adjuvants, Immunologic; Epitopes; Female; Humans; Immunoglobulin M; Leukocyte Count; Lymphocytes; Middle Aged; Pancreatic Neoplasms; Protein Binding; Receptors, Interleukin-2; Vasoactive Intestinal Peptide; Vipoma

Topics: Humans; Pancreatic Neoplasms; Radioimmunoassay; Specimen Handling; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal peptide (VIP) receptors were identified in a human pancreatic carcinoma cell line by radioreceptor assay, including time course, dissociation study, competitive inhibition, and cross reactions with secretin and glucagon, both of which are hormones of the same family. Peak binding of 125I-VIP to the cells occurred at 20-30 min at 37 degrees C. Displacement curve showed an increasing inhibition of binding with increasing concentration of unlabeled VIP(inhibited by 95% at 1 microM of VIP). KD of VIP receptors was 1.68 x 10(-10)M, and the number of binding sites was 3.6 x 10(5)/cell. It was also shown that VIP was able to induce cAMP production in this cell line, indicating that the VIP receptors in this cell line were biologically active.

Topics: Carcinoma, Intraductal, Noninfiltrating; Humans; Pancreatic Neoplasms; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

A case of watery diarrhoea hypokalaemia achlorhydria (WDHA) syndrome due to a pancreatic tumour and identified by VIP plasma level, VIP immunocytochemistry, and ultrastructural analysis of tumour sections, is reported. Since VIP is the mediator of the syndrome and is biologically active under its amidated form, the enzymatic alpha-amidating activity was investigated and characterized in tumour extract; using the synthetic substrate D-Tyr-Val-Gly, the enzyme displayed an optimal activity at pH 7.0, under aerobic conditions and with 35 microM CuSO4 and 3 mM ascorbate as co-factors. The Kmax and Vmax values of the enzymatic activity were 133.7 microM and 26.9 pmol/h/micrograms protein respectively. Its molecular weight, determined by molecular sieving, was close to 36 kDa. Other tumours of the human endocrine pancreas were also investigated for the enzymatic activity. The clinical interest of studying the regulation of the alpha-amidating activity in such tumours is discussed.

Topics: Female; Humans; Immunohistochemistry; Middle Aged; Mixed Function Oxygenases; Molecular Weight; Multienzyme Complexes; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

The effect of a synthetic analogue of CCK (Thr4,Nle7CCK-9) on growth of SW-1990 human pancreatic cancer was examined in two experimental models. Nude mice bearing SW-1990 pancreatic cancer xenografts were injected with CCK (5, 15, or 25 micrograms/kg) or vehicle twice daily for 20 days. Animals were then sacrificed and tumor volume, weight, protein, and deoxyribonucleic acid (DNA) content were evaluated. SW-1990 cells were grown in vitro and the effects of CCK, secretin, vasoactive intestinal peptide (VIP), and proglumide (a CCK-receptor antagonist) on cell number and DNA synthesis were determined. The highest dose of CCK, 25 micrograms/kg, significantly increased tumor weight, protein content, and DNA content (P less than 0.005). In vitro, CCK caused significant increases in cell counts of up to 47% at six days and 66% at 12 days compared to control. Graded concentrations of CCK had a biphasic effect on DNA synthesis with significant increases of up to 65% (P less than 0.005). CCK-induced cell proliferation was inhibited by proglumide. Secretin slightly increased cancer cell growth, although not as potently as CCK, VIP or secretin in combination with CCK did not show potentiation. These results indicate that growth of some human pancreatic cancers may be influenced by gastrointestinal peptides, of which CCK is the most potent.

Topics: Adenocarcinoma; Animals; Cholecystokinin; DNA, Neoplasm; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Nude; Organ Size; Pancreas; Pancreatic Neoplasms; Proglumide; Secretin; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

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

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

We describe a case of a tumour of the sigmoid colon with hepatic metastases in a patient with previously documented ulcerative colitis. A diagnosis of metastatic vipoma was made on the basis of high plasma levels of vasoactive intestinal polypeptide (VIP). Profuse diarrhoea and profound metabolic upset were corrected by the use of a somatostatin analogue SMS 201-995, whilst conventional cytotoxic therapy produced a significant tumour response with return of the plasma VIP level to normal.

Topics: Adenoma, Islet Cell; Adult; Antineoplastic Combined Chemotherapy Protocols; Colitis, Ulcerative; Colostomy; Combined Modality Therapy; Female; Humans; Liver Neoplasms; Octreotide; Pancreatic Neoplasms; Sigmoid Neoplasms; Streptozocin; Vasoactive Intestinal Peptide; Vipoma

The molecular biological mechanism of the inhibition by VIP (vasoactive intestinal peptide) on proliferation of pancreatic cancer cells was studied by identifying hormone receptor and using tumor model in vivo. Inhibition appears only in those cells with VIP receptor. Cell-membrane receptors may change during carcinogenesis process. The inhibition of VIP (at certain concentration) on proliferation of tumor cells is remarkable, but, on the other hand, negligible on that of normal cells. These results suggested the feasibility of clinical application of VIP to the treatment of human pancreatic cancer.

Topics: Animals; Cricetinae; Female; Male; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

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

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

A 58-year-old Taiwanese woman was admitted to Mackay Memorial Hospital for evaluation profuse watery diarrhea. She presented with watery diarrhea, hypokalemia, and hypochlorhydria, and had experienced these problems for 2 years prior to admission. A pancreatic tumor with liver metastasis was noted by the ultrasound, abdominal CT scanning, and angiography studies. Surgical exploration disclosed an ill-defined ovoid tumor in the body and tail of the pancreas measuring 8 x 3 x 3 cm. The immunohistochemistry study of the tumor for VIP-immunoreactivity (VIP: vasoactive intestinal polypeptide) was markedly positive, and also stained slightly positive for other peptides, including pancreatic polypeptide (PP), calcitonin, glucagon, and neuron-specific enolase (NSE). Postoperatively, the patient recovered immediately from her symptoms and there has been no evidence of recurrence during the past 8 months of follow-up.

Topics: Adenoma, Islet Cell; Female; Humans; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal peptide-producing tumor tissue fragments obtained at surgery were maintained in short-term culture. Functional cellular integrity of vasoactive intestinal peptide-producing tumor tissue was reflected by progressive protein synthesis and the ability of tumor tissue to release vasoactive intestinal peptide when stimulated by the intracellular second messengers cyclic adenosine monophosphate and calcium. Studies with verapamil and ethyleneglycol-bis (beta-aminoethylether)-N,N'-tetraacetic acid suggest that cyclic nucleotide- and ionophore A23187-mediated vasoactive intestinal peptide release are dependent, at least in part, upon the availability and transmembrane transport of extracellular calcium.

Topics: 1-Methyl-3-isobutylxanthine; Adenoma, Islet Cell; Calcimycin; Calcium; Cells, Cultured; Cyclic AMP; Egtazic Acid; Female; Humans; Immunohistochemistry; Leucine; Middle Aged; Pancreatic Neoplasms; Radioimmunoassay; Vasoactive Intestinal Peptide; Verapamil; Vipoma

This case report describes a patient with pancreatic cholera caused by a vasoactive intestinal polypeptide-producing pancreatic tumor. The case presents several unusual characteristics of this disease. The primary tumor was a mucinous adenocarcinoma of the pancreas. The serum vasoactive intestinal polypeptide level of 2400 pmol/L is the highest reported. At this vasoactive intestinal polypeptide level, the somatostatin analogue SMS 201-995 at doses up to 2 mg/24 h did not control the 21 L/24 h stool output. Fecal incontinence due to a manometrically documented hypotonic internal anal sphincter occurred. Using surgically created stomas, the segmental gastrointestinal fluid and sodium losses were shown to be greatest from the jejunum, whereas potassium losses from the colon and small intestine were equal. The cellular mechanism for the small intestinal potassium secretion is not known.

Topics: Adenoma, Islet Cell; Adult; Anal Canal; Chlorine; Female; Humans; Intestine, Small; Pancreatic Neoplasms; Potassium; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Adult; Humans; Lymph Nodes; Male; Pancreas; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

A 35-yr-old woman presented with episodic secretory diarrhea. Plasma vasoactive intestinal peptide (VIP) and pancreatic polypeptide (PP) venous levels were elevated. An abdominal computerized tomographic scan showed an enlarged head of the pancreas but no discrete mass. Superselective abdominal arteriography also failed to localize the tumor. Transhepatic portal vein sampling for VIP and PP showed a large increase in VIP and PP in the veins draining the head of the pancreas, with the highest levels being found at the union of the posterior superior pancreaticoduodenal vein with the portal vein. Surgical exploration confirmed this tumor location and a 2 x 3 cm encapsulated benign tumor was enucleated from the posterior surface of the head of the pancreas. Postoperatively, VIP and PP levels decreased to normal and the diarrheal episodes ceased. This case report demonstrates the usefulness of transhepatic portal vein sampling in localization of VIPomas if other radiological modalities are not helpful.

Topics: Adenoma, Islet Cell; Adult; Blood Specimen Collection; Female; Humans; Pancreatic Neoplasms; Pancreatic Polypeptide; Portal Vein; Punctures; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Cardiovascular System; Hemodynamics; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

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

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

1. Vasoactive intestinal peptide (VIP) receptors were investigated in the tumoral acinar cell line AR 4-2 J derived from rat pancreas [125I]Iodo-VIP binding to cell membranes showed the following IC50 values for unlabeled peptides: VIP, 0.3 nM; peptide His-IleNH2, 2 nM; helodermin, 30 nM; secretin, 100 nM. After incubation with 20 nM dexamethasone, the binding capacity increased twofold but affinities were unchanged. External [125I]iodo-VIP binding to intact cells reached steady state after 5 min at 37 degrees C, while the sequestration-internalization of the [125I]iodo-VIP-receptor complex (tested by cold acid washing) increased progressively, reaching 75% of total binding after 1 h. This phenomenon was blocked at 4 degrees C. Further data with dexamethasone, tunicamycin, cycloheximide, low temperature, and/or phenylarsine oxide, suggested a half-life of 2 days for VIP receptors and the necessity of N-glycosylation for proper translocation. 2. For chemical [125I]iodo-VIP cross-linking bis[2-(succinimidooxycarbonyloxy)ethyl]sulfone gave the best yield when compared with five other bifunctional reagents. In membranes, the main specifically cross-linked peptide had Mr 66,000 under nonreducing conditions, and migrated with lower velocity (-5%) under reducing conditions. Cross-linking was suppressed by VIP, peptide His-IleNH2 and helodermin (competitively) and also by GTP. In intact cells, the Mr of [125I]iodo-VIP-cross-linked peptides depended on the mode of cell solubilization. After direct solubilization, the major cross-linked radioactivity migrated as a smear of Mr 130,000-180,000 but an Mr-66,000 peptide was also detectable. In contrast, the solubilization of cross-linked cells detached by mild trypsinisation gave mainly the Mr-66,000 labeled peptide. This suggests that most VIP receptors in intact, attached cells were in a high-Mr complex and that mild cell treatment was sufficient to disrupt this complex.

Topics: Animals; Autoradiography; Binding Sites; Cell Line; Cell Membrane; Cycloheximide; Dexamethasone; Electrophoresis; Pancreatic Neoplasms; Rats; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Temperature; Tunicamycin; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Adult; Female; Humans; Pancreatic Neoplasms; Tears; Vasoactive Intestinal Peptide; Vipoma

Specific binding sites for 125I-labelled rat peptide-histidine-isoleucine (PHI) were identified on rat insulinoma-derived RINm5F cells. The concentrations of peptides producing half-maximal displacement of label were rat PHI, 0.36 +/- 0.14 nM, vasoactive intestinal polypeptide (VIP), 0.38 +/- 0.13 nM and secretin, approximately 0.2 microM. Glucagon and glucagon-like peptide-1(7-36)amide were without effect on binding. PHI and VIP produced dose-dependent increases in cAMP production in the cells that were significantly (P less than 0.05) above unstimulated rates for ligand concentrations between 10(-8) and 10(-6) M. Both PHI and VIP produced a small but significant (P less than 0.05) enhancement in the rate of release of immunoreactive insulin from the cells but the effect was not dose dependent.

Topics: Adenoma, Islet Cell; Adenylyl Cyclases; Animals; Cyclic AMP; Enzyme Activation; Insulin; Insulin Secretion; Insulinoma; Iodine Radioisotopes; Pancreatic Neoplasms; Peptide PHI; Rats; Receptors, Cell Surface; Receptors, Peptide; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Antineoplastic Agents; Female; Humans; Middle Aged; Octreotide; Pancreatic Neoplasms; Somatostatin; Vasoactive Intestinal Peptide; Vipoma

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

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

We have previously shown that hamster H2T pancreatic ductal cancer has a receptor for vasoactive intestinal peptide (VIP) which is not present on a cell line of human pancreatic ductal cancer (MIA). The purpose of this study was to examine the effect of chronic administration of VIP on the growth of both H2T hamster pancreatic carcinoma and MIA human pancreatic carcinoma in vivo. The growth of H2T was studied in hamsters; a control group of six hamsters received 0.1% bovine serum albumin (BSA) in saline, and two treatment groups of six hamsters each received VIP (1 and 10 nmol/kg), all administered three times a day by i.p. injection for 35 days. Both doses of VIP inhibited the growth of H2T tumor (tumor area, weight, DNA, RNA, and protein content). The growth of MIA was studied in athymic Balb/c mice, one group of 10 received 0.1% BSA and the other 10 received VIP (1 nmol/kg), both three times a day by i.p. injection for 3 months. There was no difference in tumor growth rate between the two groups. Treatment with VIP did not have any effect on body weight or size of the normal pancreas in either the hamsters or the mice. We conclude that the differential response of hamster and human pancreatic cancer to VIP treatment may be due to the presence or absence of VIP receptors.

Topics: Adenocarcinoma; Animals; Body Weight; Cricetinae; Humans; Male; Mesocricetus; Mice; Mice, Inbred BALB C; Organ Size; Pancreatic Neoplasms; Species Specificity; Vasoactive Intestinal Peptide

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

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

Topics: Adenoma, Islet Cell; Adult; Female; Ganglioneuroma; Humans; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Retroperitoneal Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Two patients with severe secretory diarrhea due to metastatic vasoactive intestinal peptidoma were treated with a synthetic somatostatin analogue in an attempt to control the patients' vasoactive intestinal peptide-related symptoms. In both patients, a good initial response to this treatment could be demonstrated; not only did diarrhea subside but there was also a dramatic fall in vasoactive intestinal peptide plasma levels. However, after 11 and 4 days respectively, diarrhea recurred accompanied by a rise in vasoactive intestinal peptide plasma levels. In fact, under treatment with the somatostatin analogue and with natural somatostatin, a significant rebound state was observed regarding diarrhea as well as vasoactive intestinal peptide levels, which caused considerable difficulty in the clinical management in 1 patient. This patient had to undergo surgery. In the second patient, the responsiveness to somatostatin analogue returned a few days after discontinuation of the treatment, lasting, however, for a short period only. The possible mechanism of this escape and rebound with somatostatin treatment is discussed.

Topics: Adenoma, Islet Cell; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Somatostatin; Time Factors; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Humans; Octreotide; Pancreatic Neoplasms; Receptors, Neurotransmitter; Receptors, Somatostatin; Somatostatin; Vasoactive Intestinal Peptide; Vipoma

Peptide radioimmunoassay has become an important clinical and research tool in understanding the role of peptides in the pathophysiology of gut endocrine tumor syndromes. A gut peptide radioimmunoassay laboratory has been established for the diagnosis and clinical monitoring of endocrine tumors of the gastroenteropancreatic (GEP) system. Radioimmunoassay has enhanced our awareness that co-occurring peptide interactions may modify and ultimately influence the clinical expression of these tumors. Furthermore, it has helped develop a rationale for the use of prototype peptides such as somatostatin and its long-acting analogue Sandostatin (SMS 201-995) in the management of GEP tumors. This group's experience, as well as the experience of other investigators, is presented, and the clinical utility of peptide radioimmunoassay in the field of gut endocrinology is demonstrated.

Topics: Adult; Endocrine System Diseases; Female; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Humans; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Peptides; Radioimmunoassay; Somatostatin; Vasoactive Intestinal Peptide

A 20-yr-old black woman presented in 1969 with headache, amenorrhea, hyperprolactinemia, hypogonadotropism, hypogonadism, and hypercalcemia due to a chromophobe adenoma. She received 5000 rads to the sella. One year later she was found to have hyperparathyroidism due to parathyroid adenoma and three and a half glands were removed. Thirteen years later she presented with 3 months of profuse watery diarrhea, hypokalemia, hypercalcemia, hyperchloremic metabolic acidosis, and a normal anion gap. A vasoactive intestinal polypeptide-producing tumor of the pancreas was found and successfully removed, after which hypercalcemia resolved. This is an unusual case of the multiple endocrine neoplasia syndrome, type 1, being associated with a vasoactive intestinal polypeptide-oma and pancreatic cholera.

Topics: Adenoma, Islet Cell; Adult; Female; Humans; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Long-acting somatostatin analogues such as SMS 201-995 (Sandoz) are being evaluated in a wide range of clinical indications, including gut neuroendocrine tumours and acrogemaly. Long-term continuous SMS 201-995 treatment has achieved useful symptomatic improvement in diarrhoea in 4 patients with metastatic VIPomas who had relapsed following previous treatment. Clinical improvement has outlasted suppression of VIP secretion (suggesting an additional direct antisecretory action of SMS 201-995) and has occurred despite expansion of hepatic metastases. In 6 patients with tumours secreting gastrin and/or glucagon, secretion of these peptides was acutely inhibited by SMS 201-995. However, endocrine and clinical responses to chronic treatment have been less consistent. SMS 201-995 is active orally at doses of 4-8 mg and when given thrice-daily to 6 patients with active acromegaly, suppressed mean 24-h growth hormone levels by 51-88%. Despite significantly reduced plasma insulin concentrations, glucose tolerance did not deteriorate. SMS 201-995 was also effective in suppressing thyroid-stimulating hormone (TSH) and thyroid hormone secretion in a patient with mild thyrotoxicosis due to non-tumoural inappropriate TSH hypersecretion. In all cases SMS 201-995 treatment has been well tolerated and has few side-effects.

Topics: Acromegaly; Adenoma; Adult; Aged; Diarrhea; Female; Gastrointestinal Neoplasms; Glucagonoma; Growth Hormone; Humans; Hyperthyroidism; Liver Neoplasms; Male; Middle Aged; Neoplasms, Glandular and Epithelial; Octreotide; Pancreatic Neoplasms; Pituitary Neoplasms; Somatostatin; Streptozocin; Thyrotropin; Vasoactive Intestinal Peptide; Vipoma; Zollinger-Ellison Syndrome

The presence of peptide histidine-methionine (PHM)-like peptides has been determined in plasma and tumor specimens from patients with vasoactive intestinal peptide (VIP)-secreting tumors and the watery diarrhea syndrome. All patients had strikingly elevated plasma concentrations of PHM immunoreactivity (median, 1800; range, 500-6800 pmol/liter; n = 12), which were higher than those of VIP (median, 235; range, 50-580 pmol/liter). In patients with other endocrine and nonendocrine pancreatic tumors, plasma PHM concentrations were not significantly different from normal (median, 20; range, 5-60 pmol/liter; n = 28). Plasma samples from patients with diarrhea due to other illnesses also had PHM concentrations that were not significantly different from normal (median, 40; range, 10-80 pmol/liter; n = 23). The gel chromatographic profiles of plasma and tumor extracts from patients with VIP-secreting tumors revealed the presence of at least two molecular forms that reacted with an antiserum directed to the N-terminus of PHM (SY1). The later peak (Kav, 0.50-0.53) corresponded in position to synthetic PHM and also reacted with the PHM-specific antiserum (SY2). The earlier peak (Kav, 0.30-0.37), not reactive with antiserum SY2, corresponded to a large molecular form of PHM-like immunoreactivity previously identified as the predominant form in normal human stomach and plasma, though not in the rest of the intestinal tract. The neuroendocrine nature of the tumors was confirmed by the demonstration of immunostaining with a battery of antisera to neuroendocrine markers. Immunocytochemistry revealed the presence of both VIP and PHM in tumor cells. The presence of high circulating concentrations of PHM-like immunoreactivity in patients with VIP-secreting tumors, as measured with a PHM N-terminus-directed antiserum, SY1, suggests that use of this type of antiserum may provide valuable information in the diagnosis of such tumors. The contribution of the PHM-like peptides to the features of this syndrome is not known.

Topics: Adenoma, Islet Cell; Antibodies; Chromatography, Gel; Histocytochemistry; Humans; Immune Sera; Immunoenzyme Techniques; Pancreatic Neoplasms; Peptide PHI; Radioimmunoassay; Vasoactive Intestinal Peptide; Vipoma

Plasma vasoactive intestinal peptide (VIP) concentrations of normal individuals and patients with pancreatitis were studied using a VIP RIA kit. The inter-assay and intra-assay variation of this kit were between 2.1 and 9.4%. The VIP levels increased in the acute phase of acute pancreatitis and patients with chronic pancreatitis. The VIP concentration increased during the first 30 min of glucose tolerance test, but this increase was much smaller than that in insulin. These results suggest that this kit is useful for physiologic and pathologic changes in the VIP level.

Topics: Diabetes Mellitus; Glucose Tolerance Test; Humans; Insulin; Pancreatic Neoplasms; Pancreatitis; Radioimmunoassay; Vasoactive Intestinal Peptide

Using regional specific antisera the concentrations of vasoactive intestinal polypeptide (VIP) and the peptide with N-terminal histidine and C-terminal isoleucine (PHI) in various peripheral tissues and VIP producing tumours were compared with their immunohistochemical localization. In normal tissue the VIP levels were in general higher than the PHI levels, while the VIP/PHI ratio in tumour tissue varied considerably more than in normal tissue. By immunohistochemistry it was found that VIP and PHI immunoreactivity occurred in the same autonomic neurons. Gel chromatography revealed that VIP and PHI immunoreactivity in both normal and tumour tissue consisted of two larger molecular forms in addition to "authentic" peptides. These larger molecular forms which had overlapping elution positions probably represent VIP/PHI precursors. In tumour tissue the larger molecular forms constituted a larger proportion of the total immunoreactivity. Neurally induced relaxation of smooth muscle caused a simultaneous release of VIP and PHI which in combination with the observed relaxatory effect of the peptide suggest a role in the control of smooth muscle activity. Similarly VIP and PHI were co-secreted from tumour tissues as evidenced from elevated plasma levels in patients with VIP producing tumours. In conclusion VIP and PHI seem to co-exist and be co-secreted. Differences in posttranslational processing may create variable content and release of the two peptides.

Topics: Animals; Cats; Digestive System; Ganglioneuroma; Humans; Neuroblastoma; Pancreatic Neoplasms; Peptide PHI; Reference Values; Species Specificity; Swine; Tissue Distribution; Vasoactive Intestinal Peptide

Topics: Adult; Female; Gene Expression Regulation; Humans; Immunoenzyme Techniques; Nucleic Acid Hybridization; Pancreatic Neoplasms; RNA, Messenger; Vasoactive Intestinal Peptide

A pancreatic tumor associated with severe WDHA syndrome has been studied histologically and immunohistochemically. Light microscopy revealed that the growth pattern of the tumor varied greatly from zone to zone but with prevailing solid arrangement of the tumoral cells. The majority of the endocrine cells showed numerous eosinophilic, PTAH-positive, and argyrophilic secretory granules, that were ultrastructurally similar to those of normal and tumoral neurotensin-containing cells. A minority of the endocrine cells had secretory granules ultrastructurally different from the aforementioned ones, but these were not diagnostic on purely morphological grounds. Inside the tumor, immunohistochemistry demonstrated a majority of neurotensin-immunoreactive cells, sparse and small clusters of VIP-immunoreactive cells and few, dispersed pancreatic polypeptide-immunoreactive cells. Some structural and ultrastructural aspects of the tumoral stroma have also been reported. Ducts and solid masses of duct-like cells were also found, and small clusters and singly dispersed duct-like cells were seen invading the endocrine tissue and undergoing mitoses. Such features suggest that the tumor originated from precursors located in the medium-sized and small pancreatic ducts. Because of the multihormonal nature of the tumor, the role of neurotensin and VIP in producing the patient's symptoms is discussed and a synergistic action of the two hormones is suggested in causing the particularly severe WDHA syndrome.

Topics: Adult; Humans; Immunohistochemistry; Male; Neurotensin; Pancreatic Neoplasms; Pancreatic Polypeptide; Paraneoplastic Endocrine Syndromes; Vasoactive Intestinal Peptide; Vipoma

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

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

Five patients with metastatic pancreatic endocrine tumours injected a long acting somatostatin analogue (SMS 201-995) 50 micrograms subcutaneously every 12 hours and were followed up for three to six months. Treatment aimed at controlling excess secretion of hormone by the tumours thereby bringing symptomatic relief. Four patients showed a significant reduction in tumour related hormone concentrations but in none did values return to normal. All five patients, however, noted definite symptomatic improvement and in one this was dramatic (disappearance of life threatening diarrhoea and correction of metabolic acidosis and hypokalaemia within 48 hours). Mild worsening of symptoms and increasing fasting tumour related hormone concentrations after three to six months of treatment were reversed by doubling the 12 hourly dose. The treatment was well tolerated and had no deleterious effect on fasting blood glucose concentrations. This somatostatin analogue seems a promising non-invasive treatment for metastatic pancreatic endocrine tumours.

Topics: Adult; Aged; Blood Glucose; Female; Glucagon; Growth Hormone-Releasing Hormone; Humans; Male; Middle Aged; Neoplasm Metastasis; Octreotide; Pancreatic Neoplasms; Receptors, Opioid; Somatostatin; Vasoactive Intestinal Peptide

Topics: Diagnosis, Differential; Humans; Hyperparathyroidism; Insulinoma; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prolactin; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

The pathophysiological, biochemical, histological, ultrastructural, and immunohistochemical characters of a case of malignant pancreatic islet cell tumor with watery diarrhea syndrome were carefully investigated. Four hormones or mediators--somatostatin (SST), vasoactive intestinal peptide (VIP), serotonin, and prostaglandin E--were markedly elevated in the circulation. The diagnosis was further confirmed by exploratory laparotomy and autopsy. The contents of SST and VIP in tumor tissues were very high. Gel chromatography of tumor extract revealed single peaks for both SST and VIP. Immunohistochemical studies of tumor tissues showed numerous immunoreactive cells to anti-SST, moderate amount of VIP-positive cells, and a few hCG-, insulin-, and glucagon-positive cells. In conclusion, this is an unusual case of Verner-Morrison syndrome in which three kinds of bioactive hormones or mediators were simultaneously secreted; peptides, amine, and prostaglandin.

Topics: Adenoma, Islet Cell; Adult; Histocytochemistry; Hormones; Humans; Male; Pancreatic Neoplasms; Prostaglandins E; Serotonin; Somatostatin; Vasoactive Intestinal Peptide; Vipoma

Pancreatic islet cell tumors that secrete one or several polypeptide hormones have been suspected and diagnosed secondary to their systemic manifestations. This case report details the diagnosis and treatment of an 62-year-old man with a large pancreatic islet cell tumor without symptoms in whom the mass was found as a direct result of blunt trauma to the abdomen. The tumor contained high concentrations of both vasoactive intestinal polypeptide (VIP) and somatostatin. A discussion of VIP-containing tumors is included.

Topics: Achlorhydria; Adenoma, Islet Cell; Diarrhea; Humans; Hypokalemia; Male; Middle Aged; Pancreatic Neoplasms; Radiography; Vasoactive Intestinal Peptide

Topics: Achlorhydria; Adenoma, Islet Cell; Diarrhea; Female; Hormones, Ectopic; Humans; Hypokalemia; Middle Aged; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

VIP and secretin control the secretory function of the normal pancreas. We analysed their regulatory functions in a human pancreatic cancer cell line: Capan-1. Saturation binding experiments with 125I-VIP showed the existence of one class of binding sites of very high affinity: KD 6.4 +/- 3.0 X 10(-11) M and a low Bmax: 12 fmoles/10(6) cells, in both intact cells and membrane preparations. This site has not yet been described in normal or tumorous digestive cells. Competition binding experiments let us characterize two more binding sites, KD: 2.1 +/- 0.7 X 10(-9) M and 5.0 +/- 0.6 X 10(-8) M and the corresponding Bmax: 120 and 500 fmoles/10(6) cells. These sites are similar to those found on cells of the digestive tract. Competition binding experiments gave the following IC50: 3.0 +/- 0.9 X 10(-9) M for VIP; 2 +/- 0.6 X 10(-6) M for PHI; and 1 +/- 0.7 X 10(-5) M for secretin. VIP elicited a cAMP rise, the half maximal response being obtained at 1.2 X 10(-10) M. Secretin induced a cAMP response but only for concentrations higher than 10(-8) M. VIP receptors were found to be modulated by two factors: cell ageing and cell density. Cells chronically treated with VIP showed a slight decrease of their proliferation; insulin exerted an opposite effect. It is concluded that at the difference of normal pancreatic cells, the present cell line lacks secretin-preferring receptors and acquires some of the properties of intestinal cells.

Topics: Binding, Competitive; Cell Division; Cell Line; Cell Membrane; Cyclic AMP; Humans; Kinetics; Pancreatic Neoplasms; Peptide PHI; Peptides; Receptors, Cell Surface; Receptors, Vasoactive Intestinal Peptide; Secretin; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Cholecystokinin; Female; Humans; Pancreatic Neoplasms; Secretin; Vasoactive Intestinal Peptide; Vipoma

Vasoactive intestinal polypeptide (VIP), a basic polypeptide mainly found in neural tissue, has been associated with specific endocrine pancreatic tumors. In the present study, a sensitive and specific radioimmunoassay for VIP is described and its clinical application discussed.

Topics: Humans; Iodine Radioisotopes; Isotope Labeling; Pancreatic Neoplasms; Radioimmunoassay; Vasoactive Intestinal Peptide; Vipoma

Topics: Achlorhydria; Diarrhea; Humans; Hypokalemia; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Nine pancreatic endocrine tumours of patients with watery diarrhoea hypokalaemia achlorhydria (WDHA) syndrome were examined by immunohistochemistry and electron microscopy. All cases revealed neoplastic proliferation of VIP (vasoactive intestinal peptide)-immunoreactive (IR) cells. Immunoreactivity to a novel peptide hormone PHM-27, which is processed from a common big precursor peptide of VIP (prepro VIP/PHM-27), was identified in VIP-IR cells of 8 tumours. VIP-PHM-IR cells had secretory granules measuring about 130 to 220 nm in diameter. Radioimmunoassay of tumour tissue extracts showed high VIP and PHM contents in proportional amounts in most cases. According to the results of immunostaining, the 8 tumours fell into two large groups; 5 with PP (pancreatic polypeptide)-IR cells and 3 with CT (calcitonin)-IR cells. The former group demonstrated VIP cells and PP cells intermingled in various proportions, including one tumour in which coexistence of PP-IR and VIP-IR in the same cells was demonstrated. Cell heterogeneity of the tumours and possible relationships of VIP, PP and CT cells were discussed.

Topics: Adenoma, Islet Cell; Calcitonin; Histocytochemistry; Humans; Immunochemistry; Microscopy, Electron; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Peptide PHI; Protein Precursors; Radioimmunoassay; Staining and Labeling; Vasoactive Intestinal Peptide; Vipoma

A 43-yr-old-man with metastatic VIPoma in whom the conventional measures of surgery, chemotheraphy, and hepatic artery embolization ultimately failed to control his severe diarrhea, resulting from vasoactive intestinal polypeptide hypersecretion, was treated with a new long-acting somatostatin analogue, SMS 201-995, for 14 mo. SMS 201-995 not only controlled the diarrhea without side effects but appeared to have possibly induced a reduction in metastatic tumor size.

Topics: Adenoma, Islet Cell; Adult; Delayed-Action Preparations; Drug Evaluation; Humans; Liver Neoplasms; Male; Octreotide; Pancreatic Neoplasms; Somatostatin; Time Factors; Vasoactive Intestinal Peptide; Vipoma

Topics: Acidosis; Adenoma, Islet Cell; Aged; Diarrhea; Drug Resistance; Female; Humans; Hypokalemia; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Motilin; Neurotensin; Octreotide; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Vasoactive Intestinal Peptide

The pancreatic cholera syndrome is a serious and potentially fatal disease found in patients with endocrine pancreatic tumours and ganglioneuromas. Two patients with therapy-resistant pancreatic cholera syndrome were successfully treated with human leucocyte interferon given intramuscularly in a dose of 3 X 10(6)-6 X 10(6) IU per day. This produced a reduction in stool volume and plasma vasoactive intestinal polypeptide (VIP) within 3-5 days of the start of treatment. Tumour mass decreased in one of the patients after 3 months of treatment but some tumour tissue remained after 15 months' observation, although circulating concentrations of VIP are normal. The mechanisms of action of interferon are not known but a direct inhibition of tumour-cell hormone production and perhaps of tumour-cell proliferation might account for the rapid clinical response.

Topics: Adenoma, Islet Cell; Aged; Humans; Interferon Type I; Male; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

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

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

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

The effect of a synthetic somatostatin analog was studied in a patient with severe secretory diarrhea due to pancreatic cholera syndrome. Basal intestinal perfusion studies indicated an absence of water and sodium absorption, and active chloride secretion in the small bowel. Intravenous administration of the somatostatin analog (1 microgram/kg.h) changed zero net water movement to absorption (122 mL/30 cm of the jejunum per hour). Chloride secretion changed to absorption (5.0 to 7.9 meq/30 cm.h), and plasma vasoactive intestinal polypeptide concentration was reduced from 330 to 45 pmol/L (normal, less than 51). When the analog was given subcutaneously, 100 micrograms twice daily, stool weight decreased, and plasma vasoactive intestinal polypeptide concentration fell toward the normal range (67 pmol/L). Plasma concentration of pancreatic polypeptide was initially elevated and dropped during intravenous infusion of somatostatin analog but returned to baseline on maintenance therapy with the analog delivered subcutaneously. The patient has not had further diarrhea during 9 months of therapy.

Topics: Adenoma, Islet Cell; Aged; Feces; Female; Humans; Injections, Subcutaneous; Intestinal Absorption; Jejunum; Octreotide; Pancreatic Neoplasms; Pancreatic Polypeptide; Perfusion; Somatostatin; Vasoactive Intestinal Peptide; Vipoma; Water-Electrolyte Balance

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

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

Topics: Adenoma, Islet Cell; Adult; Aged; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Peptide PHI; Peptides; Protein Precursors; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Contrast Media; Diarrhea; Diatrizoate; Humans; Iodine; Iopanoic Acid; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Prednisone; Vasoactive Intestinal Peptide; Vipoma

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

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

Vipomas are tumours which secrete vasoactive intestinal peptide (VIP) and present with severe watery diarrhoea (the Verner and Morrison syndrome). The tumours are usually pancreatic in adults and originate in the sympathetic nervous system in children (neuroblastoma). The diagnosis is confirmed by the finding of raised plasma VIP. The treatment of choice is surgical excision of the tumour which leads to the regression of the watery diarrhoea.

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

Two patients with secretory diarrhea and signs and symptoms consistent with the Verner-Morrison syndrome and islet cell hyperplasia are described. Both patients responded well to subtotal pancreatectomies. The morphologic changes in the pancreata were characterized by proliferation of islets associated with periductal and interstitial fibrosis. Immunohistochemical stains demonstrated increased staining for serotonin in islet cells. A few islet cells also stained for vasoactive intestinal polypeptide. The significance of these results is discussed.

Topics: Adenoma, Islet Cell; Adult; Female; Histocytochemistry; Humans; Hyperplasia; Immunoenzyme Techniques; Islets of Langerhans; Male; Middle Aged; Pancreatic Neoplasms; Serotonin; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Alloxan; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; DNA Repair; Humans; Insulin; Islets of Langerhans; Molecular Weight; Pancreatic Neoplasms; Rats; Streptozocin; Vasoactive Intestinal Peptide

Topics: Diarrhea; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Growth hormone-releasing factors (GRF's) from two human pancreatic tumors (hpGRF's) that caused acromegaly and from the rat hypothalamus ( rhGRF ) were recently isolated and characterized. Although these peptides are potent growth hormone secretagogues, they have not until now been described to have actions outside the pituitary. These GRF's were shown to stimulate digestive enzyme secretion from an exocrine pancreatic preparation in vitro, rhGRF being more than 100 times as potent as hpGRF. Adenosine 3',5'-monophosphate mediates this action of the GRF's.

Topics: Amylases; Animals; Cyclic AMP; Growth Hormone-Releasing Hormone; Guinea Pigs; Humans; Pancreas; Pancreatic Neoplasms; Pituitary Gland; Rats; Vasoactive Intestinal Peptide

Topics: Gastrointestinal Hormones; Humans; Pancreatic Neoplasms; Somatostatin; Substance P; Vasoactive Intestinal Peptide; Vipoma

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

The biochemical characteristics of a pancreatic tumor from a patient with watery diarrhea, hypokalemia, hypochlorhydria, and steatorrhea is described Plasma concentrations of vasoactive intestinal peptide (VIP) were elevated 6-fold, those of neurotensin (NT) were elevated 10-fold, and those of pancreatic polypeptide (PP) were elevated 200-fold above the normal range. The pancreatic tumor removed was found to contain high concentrations of these peptides in a similar ratio to plasma. The tumor content of NT was 6 times higher than any previously reported, but no specific symptoms could be ascribed to NT. After removal of the tumor, plasma levels of VIP, NT, and PP returned to normal, and the diarrhea disappeared. Gel chromatography of plasma and tumor extracts indicated that all of the immunoreactive PP co-eluted with standard human PP. When the tumor extract was subjected to gel chromatography and high pressure liquid chromatography, two forms of VIP were detected, the major one resembling porcine VIP and a smaller more hydrophobic form detected by C- but not N-terminally directed VIP antisera. This smaller form was not present in normal ileum. Immunoreactive NT in plasma was predominantly an N-terminal fragment. High pressure liquid chromatography of the tumor extract revealed that approximately 75% of the NT immunoreactivity consisted of N-terminal fragments. In contrast, normal ileum contained only authentic NT-(1-13). Since N-terminal fragments of NT are thought to be biologically inactive, the nature of the immunoreactive NT should be determined before attempting to assign specific clinical symptoms to NT-secreting tumors.

Topics: Adenoma, Islet Cell; Chromatography, Gel; Chromatography, High Pressure Liquid; Fluorescent Antibody Technique; Humans; Ileum; Male; Middle Aged; Neurotensin; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Diarrhea; Humans; Hypokalemia; Male; Middle Aged; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Body Water; Diarrhea; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Topics: Female; Hormones, Ectopic; Humans; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Syndromes; Vasoactive Intestinal Peptide

Topics: Endocrine System Diseases; Enterochromaffin Cells; Female; Gastrointestinal Neoplasms; Glucagonoma; Humans; Insulinoma; Male; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Somatostatinoma; Stomach Neoplasms; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Peptide histidine isoleucine (PHI), first isolated from pig intestine, is distributed identically to vasoactive intestinal peptide (VIP) in all mammals. 42 patients with high plasma VIP secondary to VIPoma also had very high plasma PHI-like immunoreactivity, in a constant ratio to VIP. None of 125 patients with other endocrine tumours had high levels of either peptide. VIPoma tissue from 20 patients also contained PHI shown by immunocytochemistry to be produced by the same cell as VIP. Messenger RNA(mRNA) from one of these tumours contained the codes for VIP and a separate PHI-like sequence. Human PHI-like sequence differed from porcine PHI in only two aminoacid residues. A single cell thus produces two separate regulatory peptides with apparently similar potencies but different spectra of activity. In normal tissue the constant coproduction of two active neuropeptides by a single neuron provides further evidence against the doctrine of one neuron producing only one neurotransmitter.

Topics: Adenoma, Islet Cell; Base Sequence; Diarrhea; Genetic Code; Histocytochemistry; Humans; Intestinal Secretions; Intestine, Small; Pancreatic Neoplasms; Peptide PHI; Peptides; Radioimmunoassay; RNA, Messenger; RNA, Neoplasm; Vasoactive Intestinal Peptide; Vipoma

A typical pancreatic insulinoma is characterized by immunohistochemistry which reflects its histogenesis, morphology and hormonal activity.

Topics: Adenoma, Islet Cell; Glucagon; Humans; Insulin; Insulinoma; Microscopy, Electron; Pancreatic Neoplasms; Somatostatin; Vasoactive Intestinal Peptide

A patient with an islet cell tumor presented initially with a supra-renal mass that histologically had an extensive clear cell component. Electron microscopic and immunocytochemical findings were essential to prove that the extrapancreatic mass with clear cells was an unusual metastatic manifestation of an islet cell tumor. Both the pancreatic and extrapancreatic tumor cells contained neurosecretory granules and produced vasoactive intestinal polypeptide and substance P. The clear cell morphology was due to the accumulation of lipid and glycogen and cytoplasmic swelling.

Topics: Adenoma, Islet Cell; Cytoplasmic Granules; Histocytochemistry; Humans; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Substance P; Vasoactive Intestinal Peptide

It is known that the human exocrine pancreas responds to secretin stimulation more than does VIP, a structurally related peptide. We looked for the receptors for those polypeptides in a human pancreatic cancer cell line grown in culture and in nude mice. By analysing the cAMP responses and the 125I-VIP binding we found VIP receptors with a KD of 1.5 10(-9) M. Secretin stimulates the adenylate cyclase through the VIP receptor sites with a KD of 1.7. 10(-6) M. We noted also that during cell proliferation in culture there was about a 5 fold increase of the cAMP response to VIP.

Topics: Adenocarcinoma; Animals; Cell Division; Cell Line; Cyclic AMP; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Receptors, Cell Surface; Receptors, Vasoactive Intestinal Peptide; Secretin; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Child; Ganglioneuroma; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

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

Topics: Adenoma, Islet Cell; Humans; Insulinoma; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Adult; Diarrhea; Humans; Male; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

We attempted to reproduce the diarrhea of pancreatic cholera syndrome with prolonged (10-hour) administration of vasoactive intestinal polypeptide (VIP) in five healthy nonfasting subjects. The polypeptide was given as a continuous intravenous infusion at a rate of 400 pmol per kilogram of body weight per hour. By two hours the plasma VIP concentration had risen from a normal basal value of 15.3 +/- 0.2 (mean +/- S.E.M.) to 129 +/- 40 pmol per liter--within the range found in patients with pancreatic cholera syndrome. In each subject profuse watery diarrhea developed within 4.3 +/- 0.8 hours (range, 2.0 to 6.3), and the mean stool weight at 10 hours was 2441 +/- 600 g (normal 24-hour stool weight, less than 200 to 250 g). The results of stool analysis were consistent with secretory diarrhea. Between the first and last stool, there were significant increases in fecal sodium and bicarbonate concentrations and in pH. The large fecal bicarbonate loss induced hyperchloremic metabolic acidosis, which is characteristic in patients with pancreatic cholera syndrome. Our study suggests that VIP is not merely a marker of pancreatic cholera, but is the mediator of watery diarrhea in this syndrome.

Topics: Adenoma, Islet Cell; Adult; Diarrhea; Electrolytes; Feces; Flushing; Humans; Injections, Intravenous; Male; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Adult; Aged; Diabetes Mellitus; Diagnosis, Differential; Female; Glucagonoma; Humans; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Skin Diseases; Somatostatinoma; Vasoactive Intestinal Peptide

Synthetic human pancreatic growth hormone-releasing factor containing 40 amino acids ([hpGRF (1-40)]-OH) significantly stimulated plasma growth hormone (GH) levels in both sodium pentobarbital and urethane anesthetized rats. Synthetic secretin, gastric inhibitory polypeptide (GIP), and glucagon significantly decreased plasma GH levels while synthetic vasoactive intestinal peptide (VIP) had no effect. Secretin and GIP also altered the in vivo plasma GH response to [hpGRF(1-40)]-OH. Whether this effect is the result of an interaction at the pituitary level or is due to an extra-pituitary effect of secretin and GIP awaits further study.

Topics: Amino Acids; Animals; Dose-Response Relationship, Drug; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Pancreatic Neoplasms; Peptide Fragments; Rats; Secretin; Vasoactive Intestinal Peptide

Thirty-two tumors (31 pancreatic and one jejunal) all associated with severe watery diarrhea, increased VIP levels in blood and most with hypokalemia, were investigated. The VIP content of tumor tissue ranged from 23 to 15,000 pmol/g. VIP immunoreactive cells were detected histochemically in 24 of 28 tumors investigated, PP immunoreactive cells in 11 of 28 tumors, hCG (alpha chain) immunoreactive cells in 12 of 25 tumors, and neuron specific enolase (NSE) immunoreactive cells in 24 of 26 tumors (the 2 negative results were due to inadequate fixation). All cases showed light microscopic features of epithelial endocrine tumors. Electron microscopy demonstrated a prevalence of agranular, poorly granulated and a minority of well granulated cells. Most secretory granules were round, small (150+/- 30 nm diameter) and of moderate electron density, resembling those of the so-called D1 cells. By electron immunocytochemistry, PP was directly localized in a subpopulation of relatively larger granules (154 +/- 22 nm core diameter) showing closely applied membranes. VIP-storing granules, directly identified only in the jejunal tumor, appear to correspond to a subpopulation of slightly smaller P-type granules (126 +/- 37 nm core diameter) showing a narrow, clear halo. The origin, behavior, and diagnostic criteria of VIPomas are discussed.

Topics: Adult; Aged; Antibody Formation; Chorionic Gonadotropin; Cytoplasmic Granules; Female; Histocytochemistry; Humans; Liver Neoplasms; Male; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Potassium; Radioimmunoassay; Vasoactive Intestinal Peptide

Two patients have been studied with a two and a half and nine year history of metastatic pancreatic apudoma. In both patients the main feature was chronic watery diarrhoea with remissions after partial tumour resection and streptozotocin therapy. Plasma levels of circulating VIP and neurotensin were persistently raised in both patients. Chromatographic analysis of the plasma showed that a significant proportion of the raised immunoreactivity of both peptides eluted in an identical position to pure VIP and neurotensin. The extremely high concentrations of neurotensin did not appear to result in any feature which would allow distinction from the classical VIPoma syndrome.

Topics: Adult; Apudoma; Female; Gastrointestinal Hormones; Humans; Male; Middle Aged; Neurotensin; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

The effects of somatostatin on diarrhea and on small intestinal flow of water and electrolytes (slow-marker perfusion technique) in a patient with pancreatic cholera are reported. Continuous intravenous infusion of somatostatin (8 micrograms/kg/hr) suppressed the diarrhea, but a rebound was observed after somatostatin. Infusion of somatostatin at the same dosage decreased the ileal fluid flow rate to within control values. This effect was mainly due to a sharp reduction in the rate fluid entered the jejunum, but was also due to a suppression of the abnormal water and electrolyte secretion in the proximal jejunum. Secretion in the rest of the small bowel remained unchanged. Somatostatin did not noticeably alter the high preinfusion plasma level of prostaglandin E1, but decreased the initially high plasma concentration of vasoactive intestinal peptide to normal values. These results suggest that long-acting somatostatin analogs could be of value in the symptomatic treatment of diarrhea in pancreatic cholera.

Topics: Adenoma, Islet Cell; Adult; Humans; Infusions, Parenteral; Intestine, Small; Male; Pancreatic Neoplasms; Prostaglandins E; Somatostatin; Vasoactive Intestinal Peptide; Vipoma; Water-Electrolyte Balance

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

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

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

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

This syndrome, also known under the initials W.D.H.A., is due to a single or multiple pancreatic tumour or to micropolyadenomatosis consisting of non-beta islet cells. Malignancy is found in about two-thirds of the cases. The other endocrine glands are rarely involved. The syndrome is more frequent in women than in men. It is characterized by liquid diarrhoea, marked hypokalaemia and absence of gastric hyperacidity. The tumour is mainly diagnosed by echotomography, computerized tomography and arteriography. It can also be located by staged collections of blood along the portal system for hormonal assays. The nature of the tumour can only be ascertained by demonstrating the presence of the responsible hormone, usually the "vaso-intestinal peptide". Treatment is primarily surgical. Adjuvant treatments include streptozotocine and embolization by superselective catherization in cases of hepatic matastases. The prognosis is sombre since in spite of the various treatments cure can only be achieved in 50% of the patients.

Topics: Adenoma, Islet Cell; Adult; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Streptozocin; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Animals; Diarrhea; Humans; Male; Pancreatic Neoplasms; Rabbits; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Dactinomycin; Female; Humans; Indomethacin; Liver Neoplasms; Middle Aged; Pancreatic Neoplasms; Prednisolone; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Aged; Diabetes Mellitus, Type 1; Humans; Hypokalemia; Liver Neoplasms; Male; Pancreatic Neoplasms; Streptozocin; Syndrome; Vasoactive Intestinal Peptide; Vipoma

A 3 yr 11 mo-old girl showing classical symptoms of WDHA syndrome was transferred to our department of surgery. In preoperative examination, serum vasoactive intestinal peptide (VIP) was markedly elevated and pancreatic tumor was suspected. However, no tumor was found in the resected pancreas. Unfortunately, an unexpected adrenal tumor (ganglioneuroblastoma) was found in autopsy. The tumor was judged VIPO positive, immunohistochemically. This case was thought to be WDHA syndrome caused by VIPO-producing ganglioneuroblastoma (VIPoma).

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Child, Preschool; Female; Ganglioneuroma; Gastrointestinal Hormones; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

Topics: Adenoma, Islet Cell; Diarrhea; Gastrointestinal Hormones; Humans; Male; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

A case of pancreatic cholera (Verner-Morrison syndrome) associated with a pancreatic endocrine tumor and hepatic metastases is presented. VIP and HPP plasma levels, initially elevated, were accurately followed in various conditions: during corticosteroid therapy, after pancreatic tumor excision, during and after streptozotocin therapy (1.5 g/m2) by repeated intraarterial route). Only streptozotocin therapy resulted in a reduction of the stool volume with concomitant decrease in VIP plasma levels. However, the size of the hepatic metastases was unchanged and HPP plasma levels remained elevated. It is suggested that VIP represents the tumoral secretion and HPP a marker of the residual malignant tissue.

Topics: Adenoma, Islet Cell; Adult; Humans; Liver Neoplasms; Male; Outcome and Process Assessment, Health Care; Pancreatic Neoplasms; Streptozocin; Tissue Extracts; Vasoactive Intestinal Peptide; Vipoma

Topics: Achlorhydria; Adenoma, Islet Cell; Diarrhea; Female; Gastrointestinal Hormones; Humans; Hypokalemia; Middle Aged; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Glucagon; Humans; Hyperinsulinism; Immunoenzyme Techniques; Insulin; Islets of Langerhans; Pancreatic Neoplasms; Pancreatic Polypeptide; Vasoactive Intestinal Peptide

The Verner-Morrison syndrome has been described in 19 previous patients with ganglioneuroma and ganglioneuroblastoma but never neuroblastoma. Its occurrence following treatment of a neuroblastoma with chemotherapy with maturation of the tumor has only been reported on one previous occasion. Our case suggests that vasoactive intestinal polypeptide may be used not only as a diagnostic indicator for the presence of a neural crest tumor but also as a marker to monitor maturation of the tumor and indicate an improving prognosis.

Topics: Adenoma, Islet Cell; Female; Ganglioneuroma; Gastrointestinal Hormones; Hormones, Ectopic; Humans; Infant; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Vasoactive Intestinal Peptide; Vipoma; Vulvar Neoplasms

One hundred twenty-five pancreatic endocrine tumors were analyzed by immunocytochemistry using various antisera. Twenty-three of 27 insulinomas, 10 of 10 PP-omas (PP: pancreatic polypeptide) and 15 of 30 "nonsecreting" tumors were benign, whereas 8 of 13 glucagonomas, 16 of 24 gastrinomas, and 16 of 21 VIP-omas (VIP: vasoactive intestinal polypeptide) were malignant. As a rule, the hormone secreted by the tumor and causing clinical symptoms could be localized by immunocytochemistry. Fifty of 95 active tumors were found to contain cells immunoreactive to peptide(s) not causing clinical symptoms, and 54 of 30 "nonsecreting" tumors were shown to be multicellular. By electron microscopy more than one cell type could be identified in 12 tumors. Histologically, the growth pattern of the tumors was very variable and distribution of immunoreactive cells was distinctly patchy. Radioimmunoassay on extracts of 20 of 27 tumors confirmed the presence of peptides visualized by immunocytochemistry. In 17 of 22 specimens, groups of endocrine cells in close contact with ductules were found in the pancreatic parenchyma distant from the tumor. Pancreatic endocrine tumors probably arise from the pancreatic ductular epithelium. They are often multicellular, producing and sometimes secreting more than one hormone or hormone-like substance. They represent highly complex biologic systems in which the interrelationship of various gastrointestinal-pancreatic hormones can be studied.

Topics: Adolescent; Adult; Aged; Child; Endocrine System Diseases; Female; Glucagonoma; Humans; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Some physiological digestive processes thought to be under the control of VIP-ergic neurones are presented. The etiological role of the Vasoactive Intestinal Polypeptide in the Verner Morrison syndrome is discussed.

Topics: Adenoma, Islet Cell; Colon; Dilatation, Pathologic; Gastrointestinal Hormones; Humans; Intestinal Mucosa; Intestine, Small; Pancreatic Juice; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide; Vasodilation

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

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

Topics: Adenoma, Islet Cell; Angiography; Diagnosis, Differential; Diarrhea; Female; Gastrointestinal Hormones; Humans; Middle Aged; Pancreatic Neoplasms; Syndrome; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Water-Electrolyte Imbalance

Topics: Adenoma, Islet Cell; Aged; Female; Humans; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

A 51-year-old woman with a history of several years' watery diarrhoea caused by a vasoactive intestinal peptide (VIP) secreting tumour of the pancreas (VIPoma) is presented. Measured stool outputs ranged from 1000 to 2600 ml/24 h. S-K 2.5 mmol/I. The pancreatic VIPoma was localised by abdominal angiography and removed. The plasma concentration of vasoactive intestinal peptide was 80 pmol/l before and 5 pmol/I after the operation (normal under 30 pmol/I). The patient has been symptom-free for 15 months since surgery.

Topics: Adenoma, Islet Cell; Female; Gastrointestinal Hormones; Humans; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Vipoma

During a six-year period (1973-9) 52 patients with pancreatic tumours and 10 with ganglioneuroblastomas were found to have raised plasma vasoactive intestinal polypeptide (VIP) concentrations. All the patients had severe secretory diarrhoea, weight loss, dehydration, hypokalaemic acidosis, and a raised plasma urea concentration. Reduced gastric acid secretion was seen in 72% of patients. Plasma VIP concentrations were not raised in patients with diarrhoea due to other types of tumour or disease or in hormone-secreting tumours not associated with diarrhoea. Plasma VIP measurement may therefore give clinical guidance in a patient with persistent watery diarrhoea and hypokalaemic acidosis. Surgical excision was clearly the treatment of choice, but metastatic pancreatic tumours usually responded to streptozotocin.

Topics: Adult; Aged; Child; Child, Preschool; Diarrhea; Female; Ganglioneuroma; Gastrointestinal Hormones; Humans; Infant; Male; Middle Aged; Neural Crest; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

A case of non-beta islet cell tumor of the pancreas with elevated vasoactive intestinal polypeptide (VIP) levels and WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria) was studied. Angiography and radio isotope scanning showed profuse abnormal vascularity. Ultrasonography showed a solid mass with small- to medium-sized cystic spaces. Histologic examination with special staining (Sevier-Munger) showed carcinoid tumor.

Topics: Angiography; Apudoma; Female; Humans; Islets of Langerhans; Middle Aged; Pancreatic Hormones; Pancreatic Neoplasms; Ultrasonography; Vasoactive Intestinal Peptide

A female patient is described with a single pancreatic tumour producing vasoactive intestinal polypeptide (VIP), insulin, and pancreatic polypeptide. The initial presentation was with diarrhoea and hypokalaemia and a raised plasma VIP was demonstrated. Her symptoms improved with metoclopramide administration and absolute concentrations of 28 aminoacid (peak IV) VIP were found to have fallen. She then developed hypoglycaemia with hyperinsulinism. All symptoms resolved after surgical excision. This case emphasises the potential of these tumours to contain more than one endocrine cell type synthesising different biologically active peptides.

Topics: Apudoma; Diarrhea; Female; Gastrointestinal Hormones; Humans; Insulin; Insulin Secretion; Metoclopramide; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Vasoactive Intestinal Peptide

Topics: Diarrhea; Female; Gastrointestinal Hormones; Humans; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

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

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

Topics: Adenoma, Islet Cell; Carcinoid Tumor; Digestive System Neoplasms; Gastrointestinal Hormones; Hormones, Ectopic; Humans; Pancreatic Neoplasms; Somatostatin; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

In the Lausanne classification of islet cells which is based mainly on the ultrastructural characteristics of secretion granules, a total of nine different cell types have been described. By immunocytochemistry at least 12 different hormones or peptides have been either detected or postulated as being within cell types in the pancreatic islets. The cells responsible for the secretion of insulin, glucagon, GIP, pancreatic polypeptide and somatostatin have been firmly established. The identification of cells containing VIP, secretin, gastrin, biogenic amines and other peptides still remain tentative. The development of immunocytochemical techniques and their use at the light microscopic and ultrastructural level have been of immense value in the recognition of islet cell types and the peptides that they contain. Continued improvement in the purification of islet hormones and specific antibodies to these hormones together with correlative and immunocytochemical studies should lead to a better understanding of normal islet cell function, and thus hopefully, the cellular abnormalities encountered in tumors of the endocrine pancreas.

Topics: Animals; Antibodies; Cricetinae; Dogs; Glucagon; Histocytochemistry; Humans; Insulin; Langerhans Cells; Microscopy, Electron; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Rats; Somatostatin; Staining and Labeling; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Dehydration; Diagnosis, Differential; Diarrhea; Gastrointestinal Hormones; Humans; Hypokalemia; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Administration, Oral; Diarrhea; Female; Humans; Hypokalemia; Lithium; Middle Aged; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Topics: Acidosis; Adenoma, Islet Cell; Diarrhea; Female; Gastrointestinal Hormones; Humans; Hypokalemia; Middle Aged; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

A case of WDHA syndrome accompanied by a pancreatic tumor in a 44-year-old Japanese male is presented, the 6th case in Japan. Clinically, the patient suffered from unremitting watery diarrhea, hypokalemia and achlorhydria with marked anemia and jaundice. The patient died of emaciation, dehydration and bronchopenumonia, and an autopsy was performed. Autopsy examination revealed a hen's egg-sized tumor in the tail of the pancreas with metastases in liver, lungs and lymph nodes. In addition, bronchopneumonia and diabetic nephrosclerosis were present. Histologically, the tumor had the characteristics of an islet cell tumor, and histochemically the tumor cells were positive to Grimelius' stain which revealed non-B-islet cell features. Electron-microscopically, the tumor cells had electron dense round membrane-bounded granules resembling non-B-granules of pancreatic islet cells. With the immunoperoxidase procedure (PAP method), tumor cells nearly almost reacted to anti-vasoactive intestinal polypeptide (VIP) serum, which suggested that the tumor of the present case had the capability to produce VIP.

Topics: Achlorhydria; Adenoma, Islet Cell; Adult; Cytoplasmic Granules; Diarrhea; Humans; Hypokalemia; Male; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Aged; Diarrhea; Female; Humans; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

VIP has powerful stimulatory effects on both endocrine and exocrine pancreas but its localisation within the gland has not been established. In this study, human pancreas was obtained fresh at surgery (eleven) or within four hours of death (seven). The pancreas was also removed from rats (twenty-two). Immunocytochemical staining showed VIP to be present in fine nerve fibres in all areas of the pancreas. Many fibres were seen in the exocrine pancreas, running between the acini, and around ducts and blood vessels. In addition, dense networks of fibres were observed forming meshes around islets and occasional ganglia were found containing immunoreactive cell bodies. In general, there were fewer VIP fibres in the rat pancreas than in the human, but overall distribution was identical. The mean VIP content of whole human pancreatic tissue was 42 +/- 10 pmol/g wet weight (38 +/- 9 pmol/g in head, 49 +/- 6 pmol/g in body and 42 +/- 11 pmol/g in tail). Whole rat pancreatic tissue contained 28 +/- 7 pmol/g wet weight while preparations of isolated islets were found to contain 374 +/- 30 pmol/g. It is possible that the heavy VIP innervation of the islets described here indicates a role in the regulation of islet hormone release.

Topics: Animals; Female; Fluorescent Antibody Technique; Gastrointestinal Hormones; Humans; Islets of Langerhans; Male; Pancreas; Pancreatic Neoplasms; Radioimmunoassay; Rats; Species Specificity; Vasoactive Intestinal Peptide

A patient with water diarrhoea syndrome (WDS) is described. A pancreatic tumour was found containing many cells with immunoreactivity to enkephalin and neurotensin, a few with immunoreactivity to calcitonin but none to vasoactive intestinal peptide (VIP). High levels of calcitonin, neurotensin, VIP and pancreatic polypeptide (PP) were present in plasma as measured by radioimmunoassay. After removal of the tumour, the plasma levels of the first three peptides returned to normal and the WDS disappeared. On the other hand, plasma PP did not change. No specific symptoms could be attributed to the new spectrum of peptides found in the tumour. This is the first report of a pancreatic tumour containing high levels of neurotensin.

Topics: Aged; Calcitonin; Diarrhea; Endorphins; Enkephalins; Fluorescent Antibody Technique; Humans; Male; Neurotensin; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Vasoactive Intestinal Peptide

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

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

Topics: Brain Chemistry; Chromatography, Affinity; Chromatography, Gel; Colon; Diarrhea; Gastrointestinal Hormones; Humans; Molecular Weight; Pancreas; Pancreatic Neoplasms; Radioimmunoassay; Vasoactive Intestinal Peptide

A case of vasoactive intestinal peptide-producing adenoma of the tail of the pancreas (VIP) successfully managed by surgical resection is presented. Peripheral venous VIP levels correlated with the severity of the diarrhea. Intraoperatively, the VIP levels in the splenic and portal veins were 485 and 100 pg./ml., respectively. These data suggest that preoperative selective transhepatic venous catheterization for VIP sampling might be used to establish the site of VIP production and, thereby, direct surgical management. This technic requires further evaluation regarding its role in this clinical setting.

Topics: Adenoma; Gastrointestinal Hormones; Humans; Male; Middle Aged; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

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

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

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

With the advent of radioimmunoassay and immunocytochemical methods, the peptides of the gastrointestinal tract have been identified and measured. Gastrinoma and insulinoma syndromes have been wall characterized. The pancreatic cholera syndrome and some of the evidence that the major manifestations of this disease may be mediated by vasoactive intestinal peptide have been re-examined. Pancreatic polypeptide seems to be an ideal peptide for study of vagal-cholinergic mechanisms that regulate hormone release; it also appears to be a tumor marker for several types of pancreatic endocrine tumors, particularly those of pancreatic cholera. Secretin and cholecystokinin are important regulators of pancreatic exocrine secretion and have been used to test pancreatic function, but there is little evidence that they account for clinical disease. Glucagon-secreting tumors produce a clinical syndrome of diabetes mellitus and distinctive skin lesions, which can be cured by tumor resection. Hormone-secreting tumors may provide insight into normal gut physiology.

Topics: Adenoma, Islet Cell; Animals; Apudoma; Cholecystokinin; Diarrhea; Dogs; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon; Hormones; Humans; Intestines; Pancreas; Pancreatic Neoplasms; Pancreatic Polypeptide; Stomach; Stomach Neoplasms; Vasoactive Intestinal Peptide

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

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

The case of an infant who developed refractory watery diarrhea at the age of 2 weeks is described. Diarrhea was secretory in type, stool weight on no oral intake was 400 to 600 gm daily. A vasoactive intestinal peptide (VIP)-producing tumor was suspected. At the age of 7 1/2 months an exploratory laparotomy revealed nonbeta islet cell hyperplasia of the pancreas. VIP levels were elevated in plasma and pancreatic tissue. After 95% pancreatectomy, plasma VIP level dropped to normal. Hypokalemia, described in adult patients with VIP-producing pancreatic tumors and refractory watery diarrhea, was not a significant problem in this infant. This is the first report on the association of refractory watery diarrhea with elevated levels of plasma VIP and pancreatic islet nonbeta cell hyperplasia in the pediatric age group.

Topics: Adenoma, Islet Cell; Chronic Disease; Diagnosis, Differential; Diarrhea, Infantile; Humans; Hyperplasia; Infant, Newborn; Infant, Newborn, Diseases; Islets of Langerhans; Male; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

An early diagnosis of the Verner-Morrison syndrome will greatly enhance the chances of curative resection. There is a striking need for a simple diagnostic test. A number of suggestions have been made for the presumed hormone mediator of this syndrome. Numerous reports have led to a wide acceptance that vasoactive intestinal peptide (VIP) is the responsible mediator for the pharmacologic actions of this peptide are similar to the physiological characteristics noted in the watery diarrhea syndrome. A raised plasma VIP concentration, on the other hand, would suggest the presence of a tumour. These observations argue for the radioimmunoassay measurement of plasma VIP in a patient with the watery diarrhea syndrome.

Topics: Adenoma, Islet Cell; Diarrhea; Gastrointestinal Hormones; Humans; Hypokalemia; Pancreatic Neoplasms; Radioimmunoassay; Syndrome; Vasoactive Intestinal Peptide

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

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

The clinical features of the Verner-Morrison syndrome are surveyed. This rare clinical entity still needs to be more clearly defined. Especially in relation to the role of VIP and the clinical value of VIP measurements. A case with a good correlation between the activity of the disease and circulating VIP is presented.

Topics: Acute Kidney Injury; Adenoma, Islet Cell; Dehydration; Gastrointestinal Hormones; Humans; Pancreatic Neoplasms; Radioimmunoassay; Streptozocin; Syndrome; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Diarrhea; Gastrointestinal Hormones; Humans; Hypokalemia; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Syndrome; Ultrasonics; Vasoactive Intestinal Peptide

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

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

Topics: Adenoma, Islet Cell; Glucagon; Humans; Islets of Langerhans; Pancreatic Neoplasms; Somatostatin; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Evidence that VIP is the principal humoral mediator of the watery diarrhea syndrome includes: (a) actions of VIP in experimental anaimals parallel the clinical manifestations of the syndrome; (b) infusions of VIP induce watery diarrhea in intestinal loops of dogs and a picture resembling the clinical syndrome in pigs, at circulating levels of the peptide similar to those observed in human disease; (c) most patients with the watery diarrhea syndrome and underlying tumors have elevated plasma levels of VIP; (d) in those patients in whom pre- and postoperative measurements were made, plasma VIP levels fell to the normal range with removal of the tumor and relief of the diarrhea; and (e) extracts of such tumors are rich in VIP-immunoreactivity and VIP-like biologic activity. A few patients with the syndrome have been reported to have normal plasma VIP levels, and it is possible that other humoral agents (such as pancreatic polypeptide, prostaglandins) may contribute to the production of the diarrhea.

Topics: Adenocarcinoma; Adenoma; Adenoma, Islet Cell; Animals; Diarrhea; Dogs; Gastrointestinal Hormones; Humans; Neoplasms; Pancreatic Neoplasms; Swine; Syndrome; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenal Medulla; Aged; Diarrhea; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

The value of ultrasonic scanning in the localization of hormone producing gastrointestinal tumours was assessed in 16 patients. Fifteen patients had Zollinger-Ellison syndrome and one patient had a VIP tumour. In four patients with Zollinger-Ellison syndrome ultrasonic scanning demonstrated a solid mass lesion of the head of the pancreas of 2.2.4 and 8 cm respectively. One of these diagnoses was verified by autopsy, one was also found by subsequent CT-scanning and angiography. In one patient ultrasonic scanning demonstrated a 3 cm tumour of the tail of the pancreas. At ultrasonically guided percutaneous fine needle biopsy tumour cells were aspirated. Biochemistry confirmed a VIP tumour. In 11 patients ultrasonic scanning was normal. By laparotomy in nine of these tumours of 1--3 cm were found in three patients 5.9 and 15 months after scanning and in two patients multiple 0.5 cm tumours within the duodenal wall were demonstrated one half and 9 months after ultrasound. In four patients tumours were not demonstrated by surgery. Two of the 11 patients were not operated upon, and the tumours have not been localized. The advantages of the complete atraumatic, rapid and relatively cheap ultrasound technique and the ability of an ultrasonically guided biopsy for the demonstration of malignancy justify ultrasonic scanning to be an initial method of investigation in the localization of hormone producing gastrointestinal tumours.

Topics: Evaluation Studies as Topic; Gastrointestinal Neoplasms; Humans; Pancreatic Neoplasms; Ultrasonography; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

Topics: Gastrointestinal Hormones; Humans; Neoplasm Metastasis; Pancreatic Neoplasms; Preoperative Care; Vasoactive Intestinal Peptide

A patient with a vipoma of the pancreas and persistently elevated blood levels of vasoactive intestinal polypeptide (VIP) had watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). In the untreated state, the diarrhea was never profuse. Fecal volumes ranged from 0.16 to 1.24 L/day. Attempts to correct the dehydration by fluid and electrolyte loading resulted in a massive increase in fecal water and electrolyte loss. Prednisone cured the diarrhea and was associated with a decrease in plasma VIP levels. The patient had a marked circulatory disturbance with systemic arterial hypotension and cutaneous vasodilation that caused a subnormal body temperature. Removal of the tumor led to a dramatic change in the patient's circulation. Generalized vasodilation with systemic venous and arterial hypotension gave away to vasoconstriction with severe venous and arterial hypertension. Central venous pressure rose from -4.4 to +4.0 cm H2O and arterial pressure rose from 80/55 to 195/110 mm Hg. These changes might explain the unexpected and sometimes fatal heart failure that has complicated the removal of these tumors from some patients.

Topics: Achlorhydria; Diarrhea; Gastrointestinal Hormones; Humans; Hypokalemia; Hypotension; Male; Middle Aged; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

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

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

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

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

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

Topics: Adenoma, Islet Cell; Animals; APUD Cells; Biliary Tract; Cholera; Dehydration; Diarrhea; Gastric Juice; Gastrointestinal Hormones; Gastrointestinal Motility; Humans; Hypokalemia; In Vitro Techniques; Kidney Diseases; Metabolism; Neurotransmitter Agents; Pancreatic Neoplasms; Respiration; Vasoactive Intestinal Peptide

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

Topics: Adenoma, Islet Cell; Antigens; Calcitonin; Gastrointestinal Hormones; Hormones, Ectopic; Humans; Liver Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Vasoactive Intestinal Peptide

A sensitive and specific radioimmunoassay for the detection of vasoactive intestinal peptide has been used to study patients with the watery diarrhea syndrome. In eleven patients the syndrome was associated with tumors, and plasma levels of vasoactive intestinal peptide were elevated. VIP levels returned towards normal in five treated patients coincident with amelioration of symptoms. Normal values were obtained in patinets with chronic pancreatitis, sprue, medullary carcinoma, Zollinger-Ellison Syndrome and laxative abuse. In six other patients with indistinguishable syndrome and no findings of tumor at laparotomy and autopsy, vasoactive intestinal peptide levels were normal. The results suggest that VIP may be the causative agent in patients with the watery diarrhea syndrome and tumors, but that an indistinguishable syndrome exists for which VIP is not the cause.

Topics: Diarrhea; Female; Gastrointestinal Hormones; Humans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis; Streptozocin; Syndrome; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

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

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

Two unusual cases of the watery diarrhea syndrome are presented. In one patient an adrenal medullary tumor, a pheochromocytoma that produced vasoactive intestinal polypeptide (VIP) was excised with total relief of symptoms. The second patient a 65-year-old man with abrupt onset of massive watery diarrhea that led to acidosis and coma was symptomatically controlled for one year on 10 mg/day of prednisone. Elevated levels of VIP returned to normal after prednisone therapy was started. A benign islet cell tumor not localized by angiography was removed by distal pancreatic resection. Tissue levels of VIP were markedly elevated. VIP is a humoral mediator of the water diarrhea syndrome. Both benign and malignant pancreatic and extrapancreatic tumors may cause the watery diarrhea syndrome. Steroids may cause symptomatic relief of the diarrhea by lowering peptide levels to normal. The term watery diarrhea syndrome may be more accurate than the pancreatic cholera syndrome.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Aged; Diarrhea; Female; Gastrointestinal Hormones; Humans; Male; Middle Aged; Pancreatic Neoplasms; Pheochromocytoma; Prednisone; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Adult; Animals; Child; Diarrhea; Dogs; Gastrointestinal Hormones; Humans; Intestine, Small; Pancreatic Neoplasms; Streptozocin; Swine; Syndrome; Vasoactive Intestinal Peptide

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

Topics: Adenoma, Islet Cell; Animals; Diarrhea; Gastrointestinal Hormones; Humans; Neoplasm Metastasis; Pancreatic Neoplasms; Pancreatic Polypeptide; Swine; Syndrome; Vasoactive Intestinal Peptide

A patient is described who presented with the classical symptomatology and profound electrolyte disturbance of the Verner-Morrison syndrome due to a pancreatic apudoma secreting vasoactive intestinal polypeptide (VIP). Diagnosis was confirmed by plasma VIP as measured by a radio-immunoassay technique now available. It is suggested that the cyclical nature of the symptoms in this case was due to cyclical release of VIP from the tumour in response to an unknown stimulus. Perfusion studies confirmed the excess secretory state of water, sodium and chloride in the small intestine. Symptoms were completely abolished by surgery and the progress is being monitored by means of serial plasma VIP estimations to detect any early recurrence of metastatic disease.

Topics: Adenoma, Islet Cell; Aged; Apudoma; Female; Gastrointestinal Hormones; Humans; Pancreatic Neoplasms; Syndrome; Time Factors; Vasoactive Intestinal Peptide

In medical practice, diagnostic and therapeutic aspects of gastrointestinal hormones attract interest. Gastrin--in the form of pentagastrin--can be used for gastric secretory analysis and, in the analysis of exocrine pancreatic function, secretin and cholecystokinin-pancreozymin can be employed as stimulants. Diagnosis of hormone-producing tumors is possible by radioimmunological determination of serum levels of the hormone in question: so, dramatically high gastrin levels can be found in the Zollinger-Ellison syndrome while in the Verner-Morrison syndrome, VIP (vasoactive intestinal peptide) values are significantly elevated.--The therapeutic use of gastrointestinal hormones (gastrin, secretin) is waiting in the wings.

Topics: Cholecystokinin; Duodenal Ulcer; Gastrointestinal Diseases; Gastrointestinal Hormones; Humans; Pancreatic Diseases; Pancreatic Neoplasms; Pentagastrin; Secretin; Vasoactive Intestinal Peptide

Topics: Achlorhydria; Adult; Diarrhea; Female; Gastrointestinal Hormones; Humans; Hypokalemia; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Topics: Adenoma; Adrenal Cortex Hormones; Carcinoma, Bronchogenic; Diarrhea; Gastrointestinal Hormones; Humans; Lung Neoplasms; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Topics: Achlorhydria; Diarrhea; Gastrointestinal Hormones; Humans; Hypokalemia; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Vaso-active intestinal polypeptide (VIP) is a recently discovered polypeptide widely distributed throughout the gastro-intestinal tract and nervous system. Elevated plasma VIP levels are found in gut and neural endocrine tumours producing the watery diarrhoea syndrome. Fifty per cent of these tumours are intrinsically malignant and the mortality rate may be as high as 30% even from the bening growths owing to the serious metabolic sequelae of the syndrome. The plasma VIP level is not elevated in any other non-tumourous diarrhoeal condition. The biological action of VIP closely resembles the clinical features of the Verner-Morrison syndrome and experimental evidence strongly suggests that VIP is the causal agent. The measurement of plasma VIP is of exceptional diagnostic value, since detection of elevated levels enables early removal of the tumour and may be life-saving.

Topics: Adrenal Gland Neoplasms; Diagnosis, Differential; Diarrhea; Ganglioneuroma; Gastrointestinal Hormones; Humans; Hypokalemia; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Topics: Diarrhea; Gastrointestinal Hormones; Hormones, Ectopic; Humans; Male; Middle Aged; Pancreatic Neoplasms; Portal Vein; Vasoactive Intestinal Peptide

Topics: Achlorhydria; Adult; Diarrhea; Female; Gastrointestinal Hormones; Humans; Hypokalemia; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

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

A patient with the Watery-Diarrhoea syndrome and episodic hypercalcaemia is reported. Plasma levels of vasoactive intestinal peptide (VIP) were elevated, and an islet cell adenoma of the pancreas was removed following which VIP levels decreased and diarrhoea ceased. During a hypercalcaemic episode, serum parathyroid hormone (PTh) levels were suppressed indicating the hypercalcaemia was independent of PTh and probably due to a direct action of VIP on calcium turnover.

Topics: Adenoma, Islet Cell; Diarrhea; Female; Humans; Hypercalcemia; Middle Aged; Pancreatic Neoplasms; Parathyroid Hormone; Syndrome; Vasoactive Intestinal Peptide

Topics: Achlorhydria; Diarrhea; Gastrointestinal Hormones; Humans; Hypokalemia; Pancreatic Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Levels of vasoactive intestinal polypeptide (VIP) were measured by radioimmunoassay in plasma or tissue from thirty-five patients with watery diarrhoea, and in plasma of twenty-five normal controls. Plasma levels were between 0.6 and 11.0 ng/ml in thirty-one of the thirty-three patients in whom it was measured and too low to measure (less than 200 pg/ml) in the other two. Peptide levels were less than 200 pg/ml in twenty-three of the controls, but higher in the remaining two. All tissues from patients were "rich" in VIP (10 ng to 35 microgram per g). The aetiologic diagnoses included pancreatic islet-cell adenoma or adenocarcinoma, islet-cell hyperplasia, bronchogenic carcinoma, pheochromocytoma, ganglioneuroblastoma, medullary thyroid carcinoma, and retroperitoneal histiocytoma. The findings support the conclusions that: (1) VIP is a likely mediator of the water-diarrhoea syndrome; (2) the syndrome may result from a variety of tumours; (3) this or a related peptide hormone may be secreted by these tumours; and (4) these tumours may have a common embryonic origin.

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; APUD Cells; Diarrhea; Gastrointestinal Hormones; Humans; Lung Neoplasms; Pancreatic Neoplasms; Radioimmunoassay; Thyroid Neoplasms; Vasoactive Intestinal Peptide

A patient with watery diarrhea, hypokalemia, hypochlorhydria, and a non-beta islet cell carcinoma of the pancreas (Verner-Morrison syndrome) was found to have an elevated vasoactive intestinal peptide (VIP) concentration in the plasma as well as in the tumor. Treatment with streptozocin resulted in a dramatic subjective and objective tumor response in this patient. Plasma VIP concentration fell into the normal range after four courses of treatment, diarrhea ceased after the third course of therapy, and measurable tumor mass markedly decreased during that same period of time. The patient remains in clinical remission with no evidence of tumor regrowth 18 months after the beginning of treatment. In this patient, plasma VIP measurements were an excellent marker of tumor activity and correlated well with objective disease measurements and clinical response.

Topics: Adenoma, Islet Cell; Diarrhea; Female; Humans; Hypokalemia; Middle Aged; Pancreatic Neoplasms; Stomach Diseases; Streptozocin; Syndrome; Vasoactive Intestinal Peptide

1. Plasma VIP immunoreactivity is always diagnostically raised in patients with pancreatic tumour causing the Verner-Morrison syndrome. 2. Human tumour VIP is physico-chemically similar to porcine VIP. 3. The only other situation in which plasma VIP is very elevated is in patients with ganglioneuroblastomas associated with diarrhoea. 4. VIP is not elevated in patients with diarrhoea associated with pancreatic islet hyperplasia, designated the pseudo Verner-Morrison syndrome.

Topics: Adenoma, Islet Cell; Diagnosis, Differential; Diarrhea; Gastrointestinal Hormones; Humans; Ileum; Pancreatic Neoplasms; Radioimmunoassay; Syndrome; Tissue Extracts; Vasoactive Intestinal Peptide

Eighteen endocrine pancreatic tumors were examined for the occurrence of cells producing insulin, glucagon, gastrin, human pancreatic polypeptide (HPP), and vasoactive intestinal polypeptide (VIP) and for A1 cells. More than half of the tumors were mixed, i.e., they contained more than one type of hormone-producing cell. The clinical symptoms were attributable only to one of the hormones produced by the mixed tumors. Three of four tumors causing the watery diarrhea syndrome contained both VIP and HPP cells. In one such tumor there was a strong predominance of HPP cells; the serum HPP levels of this patient were a thousandfold elevated, whereas her VIP levels were within the normal range. Several lines of evidence point to HPP as a possible agent causing the watery diarrhea syndrome. In many of our patients, HPP cells hyperplasia was present in the extratumoral pancreas. Such hyperplasia may give rise to the raised serum HPP levels seen in many patients having endocrine pancreatic tumors.

Topics: Diarrhea; Humans; Pancreas; Pancreatic Neoplasms; Peptides; Vasoactive Intestinal Peptide