Expression of the calcium-sensing receptor in gastrinomas.

Extracellular calcium levels are able to influence the secretion of gastrin by gastrinomas and possibly affect the growth pattern. The molecular mechanisms of these functions are not known. The purpose of the present study was to investigate the presence of the calcium-sensing receptor (CaR) in 10 gastrinomas and determine the extent of expression in the tumors. The amounts of CaR messenger ribonucleic acid in eight tumors were determined by quantitative RT-PCR. Protein expression was analyzed by Western blot and immunohistochemistry using a monoclonal antibody (ADD). CaR messenger ribonucleic acid was detected in all gastrinomas with levels ranging from 0.04-3.16 times the amount of beta-actin transcripts. The Western blot showed a major immunoreactive band at 250 kDa and a minor at 140 kDa, corresponding to the receptor dimer and monomer, respectively. Immunohistochemistry demonstrated variable membranous staining in all gastrinomas and normal pancreatic islets. No staining was observed in the normal liver, lymph node, or exocrine pancreas. We conclude that the CaR is present in all gastrinomas, with expression varying by 80-fold. It probably contributes to the calcium-stimulated gastrin release by gastrinomas. Whether the density of the CaR is a determining factor of the magnitude of this gastrin release or plays a role in regulating the growth pattern of the gastrinoma, as it does in other cells, remains unclear at present.

Alterations in the p16INK4a/CDKN2A tumor suppressor gene in gastrinomas.

The p16INK4a/CDKN2A gene (p16INK4a) is frequently altered by homozygous deletion, mutation, or methylation in many nonendocrine tumors, and these alterations may be predictive of recurrence, tumor growth, or aggressiveness. Whether this is true of neuroendocrine tumors such as gastrinomas is unclear. To address this question we analyzed the gastrinomas from 44 patients for p16INK4a gene mutations and correlated the results to the tumor's biological behavior, growth pattern, and aggressiveness. No gastrinomas had mutations of exon 1 or exon 2 of the p16INK4a gene, although polymorphisms were found in 54%. No homozygous deletions were found. In 52% of the gastrinomas, hypermethylation of a 5'-CpG island of the p16INK4a gene promoter was found. To assess the growth behavior of the gastrinomas, all patients were assessed yearly with at least three conventional imaging studies (computed tomography scan, magnetic resonance imaging, and ultrasound), and since 1994 have been assessed with radionuclide scanning using [111In-diethylenetriamine pentaacetic acid,DPhe1]octreotide. The mean follow-up was 5.1+/-0.4 yr (range, 1.2-11.7). The presence or absence of methylation of the p16INK4a gene did not correlate with clinical characteristics of the gastrinoma, biological behavior (gastrin release and basal or maximal acid output), the presence or absence of known prognostic factors (tumor size, gastrinoma location, lymph node metastases, liver metastases, and curability), or growth pattern of the gastrinoma postresection. These results indicate that methylation of the p16INK4a gene is the most common gene alteration described to date in gastrinomas. Furthermore, because it is independent of disease stage it is probably an early event in the pathogenesis and because it is independent of the primary gastrinoma location, which is now thought to have different origins, methylation of the p16INK4a gene is probably a central process in the molecular pathogenesis of these tumors.

Ability of somatostatin receptor scintigraphy to identify patients with gastric carcinoids: a prospective study.

UNLABELLED: Gastric carcinoids are of increasing clinical concern because they may develop in hypergastrinemic states, especially with the increased chronic use of potent acid suppressants that can cause hypergastrinemia. However, gastric carcinoids are difficult to diagnose. Somatostatin receptor scintigraphy (SRS) has a high sensitivity and specificity for localizing carcinoids in other locations. The purpose of this study was to determine whether SRS could localize gastric carcinoids. METHODS: Two groups of patients with Zollinger-Ellison syndrome (ZES) with hypergastrinemia, each having a different increased risk of developing gastric carcinoids, were studied. One hundred sixty-two consecutive patients with ZES were studied prospectively, with 39 having multiple endocrine neoplasia, type 1 (MEN-1) (high increased risk), and 123 not having MEN-1 (low increased risk). Patients were admitted to the hospital initially and then yearly, undergoing SRS with SPECT, upper gastrointestinal endoscopy, and Jumbo Cup biopsies of any gastric abnormalities, as well as random biopsies of the gastric body. Tumor localization studies were also performed. Both the results of the routine SRS interpretation and the results of a masked review, with particular attention to the stomach of high risk MEN-1 patients, were correlated with the gastric biopsy results. RESULTS: Gastric SRS localization was positive in 19 (12%) of 162 patients. Sixteen patients had a gastric carcinoid, and 12 of these patients had SRS localization. The sensitivity of SRS in localizing a gastric carcinoid was 75%, with a specificity of 95%. Positive and negative predictive values were 63% and 97%, respectively. CONCLUSION: SRS is a noninvasive method that can identify patients with gastric carcinoids with a reasonable sensitivity and a high specificity. SRS should prove useful in the treatment of patients with hypergastrinemic states that have an increased incidence of gastric carcinoids. In patients with MEN-1, one must realize that localization in the upper abdomen on SRS may be caused by a gastric carcinoid and not a pancreatic endocrine tumor.

Prior sensitization of esophageal mucosa by acid reflux predisposes to reflux-induced chest pain.

Esophageal acid exposure is believed to be a major source of unexplained chest pain; but, individual episodes of reflux in pH study are not consistently associated with chest pain. Our aim was to discover whether prior sensitization of esophageal mucosa by acid reflux predisposes to reflux-induced chest pain. Ambulatory pH studies of patients referred to our laboratory from January 1991 to November 1996 with noncardiac chest pain was reviewed. We compared the frequency of esophageal acid exposure in the 30 minutes preceding chest pain episodes with a positive symptom/reflux association (+SRA) to reflux with the frequency of acid exposure in the 30 minutes preceding those chest pain episodes that were not associated with reflux negative symptom/reflux association (-SRA). We analyzed the time esophageal pH <4, symptom index (SI) defined as percentage of chest pain episodes associated with reflux in the preceding 5 minutes, and amount of reflux in the 30 minutes preceding each chest pain episode. Of 104 patients, 52 had chest pain during their pH study, 10 had high SI (> or =50%), and 42 had low SI (<50%). Those with a high SI were significantly more likely to have an abnormal pH study (p = 0.015). Chest pain associated with reflux in proceeding 5 minutes (+SRA) was strongly associated (p < 0.002) with additional reflux episodes in the preceding 25-minute period. Chest pain related to reflux is associated with sensitization of the esophageal mucosa by prior reflux events.

Surgery to cure the Zollinger-Ellison syndrome.

BACKGROUND AND METHODS: The role of surgery in patients with the Zollinger-Ellison syndrome is controversial. To determine the efficacy of surgery in patients with this syndrome, we followed 151 consecutive patients who underwent laparotomy between 1981 and 1998. Of these patients, 123 had sporadic gastrinomas and 28 had multiple endocrine neoplasia type 1 with an imaged tumor of at least 3 cm in diameter. Tumor-localization studies and functional localization studies were performed routinely. All patients underwent surgery according to a similar operative protocol, and all patients who had surgery after 1986 underwent duodenotomy. RESULTS: The 151 patients underwent 180 exploratory operations. The mean (+/-SD) follow-up after the first operation was 8+/-4 years. Gastrinomas were found in 141 of the patients (93 percent), including all of the last 81 patients to undergo surgery. The tumors were located in the duodenum in 74 patients (49 percent) and in the pancreas in 36 patients (24 percent); however, primary tumors were found in lymph nodes in 17 patients (11 percent) and in another location in 13 patients (9 percent). The primary location was unknown in 24 patients (16 percent). Among the patients with sporadic gastrinomas, 34 percent were free of disease at 10 years, as compared with none of the patients with multiple endocrine neoplasia type 1. The overall 10-year survival rate was 94 percent. CONCLUSIONS: All patients with the Zollinger-Ellison syndrome who do not have multiple endocrine neoplasia type 1 or metastatic disease should be offered surgical exploration for possible cure.

Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects.

BACKGROUND & AIMS: Proton pump inhibitors administered twice daily do not provide complete nocturnal acid suppression. Acid breakthrough, or decrease in intragastric pH to <4 for an hour or longer, occurs in three quarters of normal subjects and patients at night. We compared the effect of a third dose of omeprazole at bedtime with that of a dose of ranitidine at bedtime on residual nocturnal acid secretion in patients receiving omeprazole twice daily. METHODS: Twelve volunteers underwent overnight intragastric pH monitoring after 7 days of treatment with omeprazole, 20 mg twice daily, followed by different treatment supplements at bedtime: placebo; additional omeprazole, 20 mg; ranitidine, 150 mg; and ranitidine, 300 mg. RESULTS: Additional omeprazole at bedtime reduced the percentage of time with intragastric pH of <4 from 48% to 31% (P < 0.005) compared with omeprazole twice daily with placebo at bedtime. Ranitidine at bedtime reduced this parameter more, 5% with 150 mg and 6% with 300 mg (P <0.01 vs. omeprazole twice daily plus bedtime). Results for percentage of time with intragastric pH <3 were similar. Eleven subjects had acid breakthrough with placebo at bedtime; 7 with omeprazole at bedtime (P = NS); 4 with ranitidine, 150 mg at bedtime; and 3 with ranitidine, 300 mg at bedtime (P < 0. 05, ranitidine vs. placebo). CONCLUSIONS: Bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion in patients receiving omeprazole twice daily. This finding suggests that fasting breakthrough nocturnal acid secretion in patients receiving omeprazole twice daily is most likely histamine related.

Imipramine decreases oesophageal pain perception in human male volunteers.

BACKGROUND: Visceral hyperalgesia is a hallmark of functional gastrointestinal disorders. Antidepressants improve symptoms in these patients, although their mode of action is unclear. Antidepressant, anticholinergic, and analgesic mechanisms have been proposed. AIMS: To investigate whether imipramine, which has a visceral analgesic effect, increases pain thresholds to experimental visceral pain. METHODS: Visceral perception for first sensation and pain was measured with intraoesophageal balloon distension in 15 male volunteers. The effect of imipramine was studied in a double blind, placebo controlled, crossover study. Imipramine was given in ascending doses for 12 days (25 mg days 1-3, 50 mg days 4-6, 75 mg days 7-12), with oesophageal perception studied on day 13. RESULTS: Inflation volumes and intraballoon pressures at first sensation were not different between placebo and imipramine. Balloon inflation volume at pain threshold was higher on imipramine (p = 0.015). Median intraballoon pressures were not different at pain threshold for placebo and imipramine. Oesophageal wall compliance was not affected by imipramine. CONCLUSION: Increased pain thresholds on imipramine in this group of normal male volunteers in the absence of changes in oesophageal tone imply the presence of a visceral analgesic effect.

Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors.

OBJECTIVES: It is our experience that many patients treated with proton pump inhibitors (PPI) b.i.d. recover acid secretion during the night. Our aim was to assess the efficacy of omeprazole and lansoprazole b.i.d. on nocturnal gastric acidity. METHODS: Three groups were studied with intragastric pH monitoring. Group 1 consisted of 17 patients with gastroesophageal reflux disease (GERD) taking omeprazole 20 mg b.i.d. Group 2 was 16 male volunteers taking omeprazole 20 mg b.i.d. and Group 3 comprised 12 volunteers taking lansoprazole 30 mg b.i.d. RESULTS: The percentages of time that subjects had pH < 4 were lower during supine than upright periods in Groups 1 and 3 (P < 0.01). Recovery of nocturnal acid secretion lasting > 1 h, termed acid breakthrough, occurred in three-fourths of all individuals within 12 h from intake of the evening dose of PPI. Median time to acid breakthrough for the whole group was 7.5 h. CONCLUSION: Nocturnal acid breakthrough occurs in a majority of patients and normal volunteers taking PPI b.i.d.

Proximal and distal esophageal contractions have similar manometric features.

The human esophagus is composed of striated muscle proximally and of smooth muscle distally with a transition zone between the two. Striated muscle contracts much faster than smooth muscle. The change in pressure over time (dP/dt) of the contraction amplitude should therefore be higher in proximal than in distal esophagus, reflecting the presence of striated muscle proximally. There were 34 normal esophageal manometries of patients analyzed for swallow amplitude and dP/dt in the pharynx and esophagus. An additional 11 healthy controls were similarly studied. Amplitudes in pharynx and proximal and distal esophagus were not different. The mid-esophagus had a pressure trough (P < 0.001). The dP/dt in the pharynx was much higher than that in the esophagus (P < 0.001). The dP/dt of proximal and distal esophagus were of the same order of magnitude. The manometric behavior of the striated muscle portion of the proximal esophagus differs from that seen in the pharynx and shows similar characteristics to distal esophageal smooth muscle.

Mucosal acid exposure sensitizes a subset of normal subjects to intra-oesophageal balloon distension.

OBJECT: To assess the effect of acid infusion on the response of normal subjects to progressive intra-oesophageal balloon distension (IOBD). METHODS: Twenty-one volunteers underwent slow IOBD. Subjects were asked to indicate the first perception of sensation (S1) and the onset of pain (S2), balloon volumes being recorded at both points. A 15-min infusion of 0.1 M HCl (8 ml/min) was then instilled proximal to the balloon. Subjects were designated as acid-sensitive if they reported chest pain or heartburn during the acid infusion. Thereafter S1 and S2 were assessed again in the same manner. RESULTS: Nine subjects were acid-sensitive, 12 were acid-insensitive. The subgroup of 12 acid-insensitive subjects had an increase of pain threshold after acid infusion (P < 0.05), whereas the nine acid-sensitive subjects showed a decrease of pain threshold after acid infusion (P < 0.05). No change of the threshold for sensation occurred in either of these groups after acid infusion. CONCLUSION: Individuals showing mucosal acid sensitivity have a lower threshold for mechanoreceptor stimulation after acid exposure.