Patients with multiple endocrine neoplasia type 1 with gastrinomas have an increased risk of severe esophageal disease including stricture and the premalignant condition, Barrett's esophagus.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (MEN1/ZES). Although esophageal reflux symptoms are common in these patients, little is known about long-term occurrence of severe peptic esophageal disease including strictures and Barrett's esophagus (BE). OBJECTIVE: The objective of the study was to prospectively analyze the frequency of severe peptic esophageal disease in ZES patients with and without MEN1. SETTING: The study was conducted at a tertiary care research center. PATIENTS: Two hundred ninety-five patients (80 = MEN1/ZES, 215 = sporadic ZES) participated in a prospective study. INTERVENTIONS AND OUTCOME MEASURES: Assessment of MEN1, acid hypersecretion, upper gastrointestinal endoscopy/biopsies, and tumor status were measured initially and at each follow-up. Esophageal manometry was performed in 89 patients. Frequency and type of esophageal disease were correlated with clinical/laboratory/tumoral features of ZES/MEN1. RESULTS: In MEN1/ZES patients, esophageal stricture was 3-fold higher, BE 5-fold higher, and dysplasia 8-fold higher, and one patient died of esophageal adenocarcinoma. Esophageal symptoms were more frequent or severe in MEN1/ZES, but known risk factors for severe esophageal disease and ZES-specific features did not differ between MEN1/ZES and sporadic ZES. In MEN1/ZES, the onset of ZES was 10 yr earlier, and H2-antagonists were used longer and at lower doses. MEN1/ZES patients with esophageal disease differed from those without in that ZES diagnosis was delayed longer, esophageal symptoms were more frequent or severe, hiatal hernias were more frequent, esophagitis or pyloric scarring was more common, basal acid output was higher, and hyperparathyroidism was underdiagnosed. CONCLUSIONS: This study shows that MEN1/ZES patients have a higher incidence of severe esophageal disease including the premalignant condition BE and identifies factors important for their pathogenesis that need to be incorporated into their long-term treatment.

Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1.

Multiple endocrine neoplasm type 1 (MEN1) is associated with parathyroid, pancreatic, and pituitary tumors. Although most patients present with hyperparathyroidism, the diagnosis can be difficult, because a significant proportion present with other endocrinopathies or may lack a family history, and other MEN1 manifestations may be mild. Recently, multiple cutaneous lesions (angiofibromas and collagenomas) were reported to be frequent in MEN1 patients, and it was proposed that their discovery suggested the diagnosis of MEN1. The purpose of this study was to prospectively assess the frequency and sensitivity/specificity of various cutaneous criteria for MEN1 in 110 consecutive patients with gastrinomas with or without MEN1. All patients had hormonal and functional studies to determine MEN1 status (48 with MEN1, 62 without MEN1), dermatological evaluation, and tumor imaging studies. Angiofibromas and collagenomas were more frequent in MEN1 patients (64% vs. 8% and 62% vs. 5%; P < 0.00001) and were multiple in 77-81% of the MEN1 patients. Lipomas occurred in 17%. The presence of these skin lesions did not correlate with age, disease duration, or other MEN1 features. Angiofibromas or collagenomas (single or multiple) had 50-65% sensitivity for MEN1 and 92-100% specificity. The combination criterion of multiple angiofibromas (more than three) and any collagenomas had the highest sensitivity (75%) and specificity (95%). This criterion has greater sensitivity than pituitary or adrenal disease and is comparable to hyperparathyroidism in some studies of patients with MEN1 with gastrinoma. This criterion should have sufficient sensitivity/specificity to be clinically useful.

Development of bombesin analogs with conformationally restricted amino acid substitutions with enhanced selectivity for the orphan receptor human bombesin receptor subtype 3.

The human bombesin receptor subtype 3 (hBRS-3) orphan receptor, which has a high homology to bombesin (Bn) receptors [gastrin-releasing peptide (GRP) and neuromedin B (NMB) receptors], is widely distributed in the rat central nervous system. Its natural ligand or role in physiology is unknown due to lack of selective ligands. Its target disruption leads to obesity, diabetes, and hypertension. A synthetic high-affinity agonist, [D-Tyr6,beta-Ala11,Phe13,Nle14]Bn(6-14), has been described, but it is nonselective for hBRS-3 over other Bn receptors; however, substitution of (R)- or (S)-amino-3-phenylpropionic acid (Apa) for beta-Ala11 resulted in a modestly selective ligand. In the present study, we have attempted to develop a more selective hBRS-3 ligand by using two strategies: substitutions on phenyl ring of Apa11 and the substitution of other conformationally restricted amino acids into position 11 of [D-Tyr6,beta-Ala11,Phe13,Nle14]Bn(6-14). Fifteen analogs were synthesized and affinities were determined for hBRS-3 and Bn receptors (hGRP-R and hNMB-R). Selective analogs were tested for their ability to activate each receptor by stimulating phospholipase C. One analog, [D-Tyr6,Apa-4Cl,Phe13,Nle14]Bn(6-14), retained high affinity for the hBRS-3 (Ki=8 nM) and had enhanced selectivity (>230-fold) for hBRS-3 over hGRP-R or hNMB-R. This analog specifically interacted with hBRS-3, fully activated hBRS-3 receptors, and was a potent agonist at the hBRS-3 receptor. This enhanced selectivity should allow this analog to be useful for investigating the possible role of hBRS-3 in physiological or pathological processes.

Prospective study of the ability of serial measurements of serum chromogranin A and gastrin to detect changes in tumor burden in patients with gastrinomas.

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

Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1.

Little is known of the natural history of thymic carcinoids in multiple endocrine neoplasia type 1 (MEN1). This is important because in 1993 they were identified as a frequent cause of death, yet only small retrospective studies and case reports exist. We report results of a prospective study of 85 patients with MEN1 evaluated for pancreatic endocrine tumors and followed over a mean of 8 yr with serial chest computed tomography, magnetic resonance imaging (MRI), chest x-ray, and, since 1994, octreoscans [somatostatin receptor scintigraphy (SRS)]. Seven patients (8%) developed thymic carcinoids. Patients with and without carcinoids did not differ in clinical, laboratory, or MEN1 tumor features, except for male gender and the presence of a gastric carcinoid. All thymic tumors were hormonally inactive. Four thymic carcinoids lacked 11q loss of heterozygosity, although it was found in three pancreatic endocrine tumors. Computed tomography and/or MRI were more sensitive than SRS or chest x-ray in detecting tumors initially or with recurrence. All patients underwent resection of the thymic carcinoid, and in all patients followed more than 1 yr, the tumor recurred. Bone metastases developed in two patients and were detected early only on MRI, not SRS. This study provides information on early thymic carcinoids and allows modifications of existing guidelines to be recommended for their diagnosis, surveillance, and treatment.