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Background: Neuroendocrine tumors of the gastroenteropancreatic (GEP) tract are encountered either as a sporadic type or as part of multiple endocrine neoplasia type 1 (MEN-1) syndrome. Inactivating MEN1 gene mutations have been found to be responsible for this syndrome and have also been described in sporadic cases. The aim of the present study was to evaluate the presence of mutations in the MEN1 gene in a series of 10 well-differentiated neuroendocrine tumors: five of the foregut and five of the midgut tract. Methods: Retrospective screening for MEN1 gene mutations was carried out in 10 archived, paraffin-embedded neuroendocrine tumors. Polymerase chain reaction amplification and automated sequence analysis of the DNA extracted from the tumors were performed. Results: One mutation (359 del 4) in exon 2 of the MEN1 gene was identified in a neuroendocrine tumor of the foregut (VIPoma of the pancreas). No mutation was identified in midgut neuroendocrine tumors. Conclusions: Our data confirm that retrospective genetic analysis can be used to identify mutations in the MEN1 gene and indicate that somatic MEN1 gene mutations are a rare event in sporadic neuroendocrine GEP tumors. The frequency of these mutations was 10% in our series, which may differ from that in other studies, due to the small number of cases analyzed.

The aim of the present study was to investigate ECLomas and enterochromaffin-like (ECL) cell hyperplasia in gastric human mucosa regarding the immunohistochemical expression of chromogranin A (CgA) epitopes and to measure the same CgA epitopes in plasma samples. Eight gastric biopsies from ECLomas, seven of type I and one of type III, and biopsies from one patient showing only ECL cell hyperplasia were included in the study. Our results revealed a varying expression of region-specific CgA epitopes in the ECLomas regarding both the frequency of immunoreactive cells and intensity of immunoreactivity. CgA284-301 (pancreastatin) was not revealed in any neoplasm, whereas CgA361-372 (catestatin) was expressed in all ECLomas. However, the number of immunoreactive cells to vesicular monoamino transporter 2 (VMAT 2) or the commercial monoclonal CgA (CgA250-284) antibodies were generally higher. The plasma concentrations of the region-specific CgA radioimmunoassays differed considerably, with highest concentrations of CgA1-17 and CgA116-130 epitopes and the lowest with the CgA17-37, CgA63-76, CgA238-247 and CgA441-424 epitopes. No relationship was found between tissue expression and plasma concentration of CgA epitopes. In conclusion, this study shows that VMAT 2 and the commercial CgA antibodies seem more useful for histopathological diagnosis of ECLomas than the antibodies to the other CgA regions.

Gastrinomas of the stomach are extremely rare endocrine tumors producing Zollinger-Ellison syndrome. We report here the case of a patient with gastrinoma of the stomach who presented regional and hepatic metastases at the time of diagnosis. The endocrine tumor was discovered incidentally 8 yr after the onset of symptoms related to peptic ulcer, which responded to medical treatment with a proton pump inhibitor. Surgery did not cure the patient, as demonstrated by provocative tests showing serum gastrin responses indicative of residual disease. A long-term treatment with the somatostatin analog lanreotide induced a biochemical response and was associated with a substantially stable disease.

Functioning gastroenteropancreatic endocrine tumors produce and secrete different substances that can be detected in the plasma and cause hormone-related syndromes. Symptoms such as diarrhea associated either with typical skin rash or peptic ulcer disease may be suggestive of the presence of intestinal carcinoid or gastrinoma. Other clinical manifestations such as severe hypoglycemia, diabetes, necrolytic erythema and gallbladder disease may also indicate an endocrine tumor. Sometimes, patients present no, or just vague, symptoms such as dyspepsia or abdominal pain and nonfunctioning endocrine tumors in these patients can be found incidentally during diagnostic imaging procedures or at operation. Usually, the diagnosis is established by the measurement of the specific tumor marker in the plasma and, sometimes, in the urine. In some cases, normal basal hormone levels are observed even in the presence of typical symptoms. Therefore, stimulatory tests such as the secretin test for gastrinomas are required to establish the diagnosis. General markers for the diagnosis of gastroenteropancreatic endocrine tumors are also available. Among these, chromogranin A has proved to be of great value for diagnosing nonfunctioning tumors and is considered the most sensitive general marker. The availability of both specific and general markers as well as stimulatory tests may enable the clinician to diagnose functioning gastroenteropancreatic endocrine tumors at an early stage and to recognize nonfunctioning tumors.

Elevated plasma levels of vasoactive intestinal polypeptide (VIP) (as assessed by a radio-immunoassay), were found in 7/11 patients with AIDS or AIDS-related Complex (ARC), evaluated because of prolonged intractable diarrhea with either an infectious (6 cases) or a non-infectious (5 cases) etiology. Six subjects have been treated with the somatostatin analogue octreotide, which gave both a favourable clinical response and a significant reduction in plasma VIP concentrations. Evaluation of plasma VIP levels may provide a pathophysiological basis for explaining the efficacy of octreotide therapy in HIV-infected patients suffering from both infectious and non-infectious refractory diarrhea.

A case of pancreatic somatostatinoma in a patient with long-standing symptoms of intestinal pseudo-obstruction is reported. Diagnosis was made incidentally following an exploratory laparotomy for an episode of acute intestinal obstruction. After surgical excision of the endocrine neoplastic tissue there was a decrease in plasma somatostatin levels, associated with a striking improvement of symptoms related to gut motility dysfunction. Delayed intestinal transit and gastric emptying and impaired gallbladder contraction persisted after surgery during a follow-up of 9 years in association with a positive calcium-pentagastrin test, suggestive of residual tumoral somatostatin secretion. This case report shows that a chronic intestinal pseudo-obstruction syndrome can be associated with a somatostatin-producing endocrine neoplasm and confirms the clinical heterogeneity of somatostatinoma patients.

Calcium infusion has been advocated as a provocative test for the diagnosis of some endocrine tumors of the pancreas and gastrointestinal tract (gastrinoma, insulinoma, intestinal carcinoids). The release of gastrin from gastrinoma tissue is very sensitive to alterations in the serum calcium level, and the calcium infusion test is recommended in Zollinger-Ellison syndrome when the results of secretin stimulation are equivocal. The calcium provocative test in the detection of insulinoma and carcinoid tumors is less reliable than other safer and simpler procedures. Intravenous injection of calcium followed by pentagastrin stimulates the release of somatostatin in patients with somatostatinoma and offers a reliable means for establishing the diagnosis of this tumor. Calcium administration has not proven to be useful in the diagnosis of other endocrine tumors of the digestive system.

This case report describes a 27-year-old man with von Recklinghausen's neurofibromatosis, manifested as cutaneous cafè au lait spots and neurofibromas, associated with duodenal somatostatinoma. The patient presented with ultrasonographic evidence of dilatation of the biliary and pancreatic ducts, in absence of clinical symptoms. The reason for the performance of ultrasonography was to identify the cause of an increase of hepatic enzymes during the last two years. Diagnostic ERCP showed an ulcerated tumor in the papillary region and pathological findings were compatible with somatostatinoma. Endoscopic sphincterotomy with placement of endoprostheses was successful in achieving biliary and pancreatic drainage. Subsequently a curative resection of the tumor was performed by the Whipple procedure and provocative tests demonstrated normal plasma somatostatin concentrations.

We have recently reported that hypothyroidism increases immunoreactive (IR)-vasoactive intestinal polypeptide (VIP) and VIP mRNA content in both parvocellular and magnocellular neurons of the rat, hypothalamic paraventricular nucleus (PVN). As VIP can stimulate vasopressin (AVP) secretion, we conducted an anatomical investigation to determine whether VIP-containing neurons in other regions of the brain that are involved with homeostatic mechanisms of water and salt conservation are also affected by hypothyroidism. The distribution and intensity of VIP immunostaining in neurons and fibers of the magnocellular-neurohypophysial system, including the hypothalamic PVN, supraoptic nucleus (SON) and accessory magnocellular cell groups, circumventricular subfornical organ (SFO), preoptic and anterior hypothalamus, midline thalamus, subthalamic zona incerta and posterior septal nuclei were studied using a highly sensitive immunocytochemical technique and unbiased neuronal counting methods, based on the optical dissector principle. Hypothyroidism increased the intensity of VIP immunostaining and/or the number/section, percentage and numerical density of IR-VIP neurons in the PVN, SON, nucleus circularis, periventricular preoptic nucleus of the hypothalamus and SFO. In addition, IR-VIP perikarya and/or fibers in the hypothalamic medial preoptic area and anterior periventricular nucleus, nucleus reuniens of the thalamus and dorsal fornix-triangular septal nucleus complex were also apparent in the hypothyroid animals while no immunostaining was seen in these areas in control animals. No quantitative and/or qualitative modifications in IR-VIP neurons and fibers were noted in the anterior hypothalamic area, suprachiasmatic nucleus, thalamic paraventricular nucles an subthalamic zona incerta between hypothyroid and control animals. These findings suggest an inverse relationship between thyroid hormone and VIP content and/or distribution of IR-VIP neurons in specific forebrain regions involved in the control of AVP release, extracellular fluid volume, thirst, blood pressure and anterior pituitary secretion. This raises the possibility that changes in fluid homeostasis and cardiovascular function occurring in hypothyroidism may be mediated, at least in part, by VIP-producing neurons in diverse regions of the brain.

OBJECTIVE To evaluate plasma levels of vasoactive intestinal peptide (VIP) in AIDS patients with refractory idiopathic diarrhoea, and to assess the role of treatment with octreotide. PATIENTS Three AIDS patients were evaluated for severe watery diarrhoea of 2-6 months' duration, which was complicated by weight loss, weakness, and fluid and electrolyte abnormalities. They had not shown a significant response to several regimens of empirical antimicrobial chemotherapy, or symptomatic antidiarrhoeal treatment. METHODS A complete diagnostic examination, including repeated microbiological evaluation and radiological, ultrasonographic, endoscopic and histological examination, was performed. Plasma levels of VIP were determined by radioimmunoassay and compared with concentrations in a group of healthy subjects. RESULTS Since no clinically significant results were obtained from standard diagnostic evaluation and empirical therapeutical attempts, idiopathic refractory diarrhoea was diagnosed. Plasma concentrations of VIP were moderately elevated in all three subjects examined, with levels of 11.5, 17.5 and 9.5 pmol/l (values < 8.8 pmol/l in the control group). One patient received 50-100 micrograms octreotide three times daily subcutaneously for 6 months, resulting in complete resolution of diarrhoea and significant improvement in body weight and quality of life, together with a reduction in VIP concentration to within normal values. CONCLUSIONS Although the somatostatin analogue octreotide has been used successfully in the management of both infectious and non-infectious AIDS-related diarrhoea, gastrointestinal neuroendocrine function and circulating humoral mediators of diarrhoea have not hitherto been investigated extensively in HIV-infected subjects. Our data on the association of idiopathic secretory diarrhoea and elevated plasma VIP levels provide a possible pathophysiological rationale for identifying AIDS patients whose refractory diarrhoea may be more responsive to octreotide treatment.

One hundred and eight patients with an endoscopically documented healed duodenal ulcer (DU) participated to a multicentre, randomized, double-blind, long-term study. The study was planned with the aim to compare the efficacy of nizatidine 150 mg with ranitidine 150 mg in preventing relapse during the 2 years following the DU healing. Fifty four patients were assigned to each treatment. Endoscopic examinations were scheduled at 6, 12 and 24 months. Clinical evaluations were performed every two months. Routine laboratory tests were investigated at the beginning of the study and at each of the scheduled endoscopies.chi-squared test with Yate's correction, Student's t test for unpaired data, Wilcoxon Rank Sum test and Logrank test. Twenty five patients dropped-out: 15 in the nizatidine and 10 in the ranitidine group. The cumulative relapse rate was 18% for nizatidine and 21% for ranitidine treatment (p:ns). Both drugs resulted safe, as only minor side effects were registered.nizatidine is as effective and safe as ranitidine in the long-term (2 year) treatment of DU.

One hundred and one active gastric ulcer patients concluded an 8-week, randomized, double-blind multicentre study, planned with the aim to compare the effectiveness of a new H2 blocker, nizatidine, with ranitidine. Thirty-three patients received 300 mg nizatidine at bedtime, 34,150 mg nizatidine b.i.d. and 34,150 mg ranitidine b.i.d. The three groups were well matched for the common clinical parameters. After 4 weeks, healing rates were 51.5% (confidence intervals 95%: 34.1-68.9%), 61.8% (41.2-82.4%), 76.5% (51-102%), respectively. At this check point ranitidine showed a significantly better outcome than did 300 mg nizatidine at bedtime (p less than 0.05). After 8 weeks, healing rates were 81.8% (54.1-109.5%), 88.2% (58.7-117.7%) and 88.2% (58.7-117.7%); these differences were not statistically significant. Age, sex, ulcer symptoms, alcohol and cigarette consumption, concomitant treatments, ulcer size and site and length of ulcer history were all found not to influence ulcer healing. Pain relief and antacid consumption were comparable in the three treatment groups. No clinically significant unwanted effects were recorded throughout the study. Nizatidine can, in our opinion, be successfully used in the treatment of active gastric ulcer.

4154 Background: Somatostatin analogues represent the treatment of choice for inoperable well-differentiated NETs, mainly for symptomatic patients (pts). Methods: Sixty pts with histologically proven well-differentiated NETs (accordingly to the WHO classification) were randomized to receive lanreotide prolonged release (PR) 60 mg every 3 weeks or the new drug formulation Autogel (ATG) 120 mg every 6 weeks, Primary end point was to show the equivalence between the PR and the ATG formulations in terms of clinical, symptomatic and biochemical responses. Secondary endpoints were the evaluation of tolerability, progression-free and overall survival. The estimated accrual of 30 pts for each randomization arm was achieved, accordingly to the test of Dunnet and Gent for proving the non-inferiority of the lanreotide ATG formulation. Pts were treated until progression. Globally, 40 males and 20 females were studied (median age 61, range 29–81). Primary tumour site: small bowel 37%, pancreas 27%, lung 13%, unknown 1...

The interdigestive gastroduodenal motor activity and serum motilin levels were studied in 22 dyspeptic patients with markedly delayed gastric emptying not due to diseases known to impair gastroduodenal motility and in 7 control subjects with normal gastric emptying. Motor activity was recorded using a manometric probe positioned in the gastric antrum and in the proximal duodenum, and blood samples for radioimmunoassay of motilin were taken every 15 min during the recording period. The control subjects showed gastroduodenal activity fronts of the migrating motor complex associated with motilin peaks. Almost all patients with delayed gastric emptying showed no activity fronts in the stomach, and only half of them showed activity fronts starting in the duodenum. In these patients a significant reduction in the number of motilin peaks and in the integrated motilin output during the identified peaks was also observed. The results of this study indicate that most dyspeptic patients with idiopathic delay in gastric emptying may also have an alteration in interdigestive gastroduodenal motility, mainly characterized by a lack of gastric activity fronts, associated with an impaired motilin release.