Doris B. Strader

Determinants of metastatic rate and survival in patients with zollinger-ellison syndrome: A prospective long-term study

BACKGROUND/AIMS It is unclear whether tumor location, size, or the presence of multiple endocrine neoplasia type 1 (MEN-1) alters metastatic rate and survival in patients with pancreatic endocrine tumors. The purpose of this study was to determine the prognostic factors of survival and metastatic rate in patients with Zollinger-Ellison syndrome (ZES). METHODS Data were analyzed from 185 consecutive patients with ZES who were followed up prospectively. RESULTS Liver metastases were present in 24% of patients and correlated with the size of the primary tumor. Duodenal tumors were smaller than pancreatic tumors. Liver metastases occurred more often (P < 0.00001) with pancreatic than duodenal tumors, whereas the metastatic rate to lymph nodes was not different. Survival of patients with liver but not lymph node metastases was shortened. In patients with sporadic ZES, liver metastases were more common during the initial evaluation and survival was decreased compared with patients with MEN-1; however, during follow-up, an equal percentage of patients with and without MEN-1 developed liver metastases. CONCLUSIONS Survival was primarily determined by the presence of liver metastases. The frequency of liver metastases depends on the size and location of the primary tumor and on the presence of MEN-1 at the initial presentation. Metastases to the lymph nodes do not depend on these factors. A benign and malignant form of ZES exists.

Zollinger-Ellison syndrome can be the initial endocrine manifestation in patients with multiple endocrine neoplasia-type I

PURPOSE To determine whether patients with multiple endocrine neoplasia type I (MEN-I) can initially present with Zollinger-Ellison syndrome (ZES), and to learn whether ZES exhibits any distinguishing features when it occurs as a first manifestation of MEN-I. PATIENTS AND METHODS Sixty patients who had been referred to a clinical research center with ZES were examined by cohort analysis. Twenty-eight had MEN-I and 32 did not. In patients with MEN-I, we analyzed the temporal relationships between the clinical and biochemical manifestations of ZES and the other endocrinopathies associated with the neoplasia. To determine whether patients who had ZES as a first manifestation of MEN-I (n = 8) had any distinguishing clinical characteristics, we compared them to a cohort of patients with established sporadic ZES (n = 32) matched for age, sex, and time since the onset of symptoms consistent with ZES. RESULTS Of the 28 patients with ZES and MEN-I, 11 initially presented with ZES and hyperparathyroidism (HP) and 1 with evidence only for pituitary disease. Eight patients (29%) presented with features of ZES and developed clinical and biochemical evidence for HP later, while the same number developed these 2 endocrinopathies in the opposite order. In whichever order ZES and HP occurred, the time from the diagnosis of the first to the diagnosis of the second was similar. It ranged from 9 to 177 months in patients who presented with ZES first, and from 12 to 264 months in patients who presented with HP first. At the time of initial diagnosis, the patients who presented with ZES as a manifestation of MEN-I had no distinguishing ZES-related symptoms, biochemical assays, or tumor imaging results compared to the cohort of patients who had the syndrome sporadically. CONCLUSION Patients with MEN-I can initially present with a symptomatic pancreatic endocrine tumor syndrome without any other disease manifestations. In patients with ZES and MEN-I, up to one third may present with ZES without evidence of any other endocrinopathy. Consequently, patients with presumed sporadic ZES should undergo continual biochemical screening for other endocrinopathies characteristic of MEN-I and, in the future, genetic studies for the MEN-I gene.

Use of omeprazole in Zollinger-Ellison syndrome: a prospective nine-year study of efficacy and safety.

H+, K+‐ATPase inhibitors such as omeprazole are the antisecretory agents of choice for the management of gastric acid hypersecretory states, including the Zollinger‐Ellison syndrome. However, long‐term follow‐up data on the overall efficacy and safety of these agents in large numbers of patients are lacking. In the current study we examined the long‐term efficacy and safety of omeprazole in 116 patients with Zollinger‐Ellison syndrome treated with oral omeprazole at a single centre for up to 114 months (mean ± S.E.M. = 38 ± 3 months). The initial omeprazole maintenance dose was established according to the acute upward dose titration method in 89/116 patients (77%). Gastric acid output was effectively controlled using 60 mg of omeprazole once daily in 41/89 patients (46%) and 22/89 patients (25 %) required twice daily omeprazole therapy. The mean ranitidine equivalent dose for patients who required 60 mg omeprazole once daily (2.5 ± 0.2 g/day) was significantly lower than the mean ranitidine equivalent dose for patients who required more than 60 mg omeprazole once daily (4.3 ± 0.3 g/day). Long‐term omeprazole maintenance therapy was discontinued in 36/116 patients (31%) but in no cases was discontinuation due either to drug‐induced side‐effects or uncontrolled gastric acid output. Fasting serum gastrin levels were significantly elevated above pre‐treatment levels at only one time point during follow‐up and were likely due to tumour growth rather than a drug effect. The final long‐term omeprazole maintenance doses were lower than the initial doses but correlated closely with the preomeprazole basal acid output (r= 0.41, P < 0.001) and ranitidine equivalent dose requirements (r= 0.49, P < 0.001). We conclude that omeprazole effectively and safely controls gastric acid hypersecretion in all patients with Zollinger‐Ellison syndrome for up to nine years without evidence by tachyphylaxis.

An evaluation of human recombinant α interferon in patients with metastatic gastrinoma

Abstract Background: Metastatic gastrinoma is becoming increasingly recognized in patients with Zollinger-Ellison Syndrome. The mean 5-year survival of these patients is Methods: The efficacy and toxicity of interferon was assessed in 13 consecutive Zollinger-Ellison syndrome patients with liver metastases. Patients were treated with human recombinant α interferon (5 million IU, subcutaneously [SC]) daily and followed up at 3-month intervals with multiple imaging studies. At each follow-up, toxicity of therapy was assessed and fasting serum gastrin concentrations were obtained. Results: No patient showed a reduction in tumor size at any follow-up. One patient died after 2 months. At 6 months, six patients (46%) had stable tumor size in the liver, although new bone metastases developed in one patient. Three patients showed stable disease for up to 21 months. Changes in serum gastrin correlated with tumor response at 6 months. All patients developed some side effects of therapy. Thirty-one percent required dose reduction, and one patient (8%) had to have interferon therapy interrupted briefly. Conclusions: These results fail to define a therapeutic role for interferon in the treatment of metastatic gastrinoma.

Esophageal Function and Occurrence of Barrett’s Esophagus in Zollinger-Ellison Syndrome

Manifestations of esophageal disease are present in up to 60% of patients with Zollinger-Ellison syndrome (ZES), although esophageal function has been studied in only a few patients and the prevalence of Barretts mucosa is unknown in these patients. It is unclear whether the high prevalence of esophageal disease is related to gastric acid hypersecretion alone or to abnormalities of esophageal motility or lower esophageal sphincter (LES) function in addition. To address these issues in the present study esophageal function was evaluated prospectively in 92 consecutive patients with ZES (66 with active disease, 26 disease-free after curative resection) seen during a 1-year period after controlling acid hypersecretion. In the patients with active disease the mean basal acid output (BAO) was 33 +/- 3.0 mEq/h, the maximal acid output (MAO) was 56 +/- 4.0 mEg/h, fasting serum gastrin was 8,736 +/- 4,813 pg/ml and duration of disease prior to study was 12.5 +/- 2.0 years. At the time of manometry, gastric acid secretion was controlled in all patients and no patient had evidence of gastroesophageal reflux disease at upper gastrointestinal endoscopy. Esophageal manometry revealed normal motility in 85% of patients. Eleven percent had low LES pressures, and only 1% of patients had an elevated LES pressure. The frequency of Barretts mucosa (3%) was similar to that found in the general population but much less than that reported in patients with idiopathic GERD. No correlation was noted between LES pressures or manometric abnormalities and the fasting serum gastrin, BAO, MAO or the presence or absence of multiple endocrine neoplasia type I or previous vagotomy. Esophageal manometric results and LES pressure were similar in disease-free patients and those with active ZES. In conclusion, these results suggest that hypergastrinemia or other disease-specific abnormalities are not contributing to the high incidence of esophageal disease in patients with ZES because esophageal function in patients with ZES is similar to normals. Specifically, motility disorders in patients with ZES occur in similar frequency to normals, and LES pressure is normal in most patients. Despite the high levels of acid secretion and prominence of symptoms, the occurrence of Barretts mucosa was uncommon (3%) raising the possibility of additional protective mechanisms in patients with ZES.

Prospective study of the need for long-term antisecretory therapy in patients with Zollinger—Ellison syndrome following successful curative gastrinoma resection

A long‐term cure is now possible in more than 30% of selected patients with Zollinger–Ellison syndrome who undergo gastrinoma resection. The need, however, for continued gastric acid antisecretory therapy in these patients remains controversial. The current study was designed to determine whether post‐operative antisecretory therapy is needed in patients who have undergone successful gastrinoma resection and, if so, to attempt to define criteria with which to identify patients who require therapy. Twenty‐eight consecutive patients who had previously undergone curative gastrinoma resection were prospectively studied. When antisecretory therapy was discontinued, 43% (12/28) of these patients developed gastro‐oesophageal reflux, diarrhoea, acid–peptic symptoms or endoscopic evidence of acid‐peptic disease within 2 weeks and were deemed to have failed a trial of antisecretory drug withdrawal. The remaining 57% (16/28) of patients who successfully discontinued antisecretory therapy were followed for a mean time of 31 months after withdrawal of therapy. Analysis of acid output studies pre‐operatively, as well as at the time of drug withdrawal, demonstrated that patients who were unable to discontinue antisecretory therapy exhibited higher pre‐operative maximal acid output values and higher basal acid output values at the time of attempted drug withdrawal than patients who were able to discontinue therapy. Despite these findings, there was significant overlap in acid output values between groups so that it was not possible to define specific acid output criteria for successful drug withdrawal. Pre‐operative clinical characteristics, such as the presence or absence of gastro‐esophageal reflux or acid‐peptic disease, or post‐operative laboratory values, such as the fasting serum gastrin level, did not correlate with the ability to discontinue antisecretory therapy. We conclude that following successful curative gastrinoma resection, 40% of patients still require antisecretory therapy and that both symptom evaluation as well as upper endoscopy should be used to guide attempted drug withdrawal. Although patients who are not able to discontinue therapy have significantly higher acid output measurements than those who are able to discontinue therapy, neither acid output criteria nor any other laboratory or clinical characteristics are able to predict the need for continued antisecretory therapy in these patients.

Helicobacter pylori infection

SummaryThe present report describes two patients with fasting hypergastrinemia, gastric acid hypersecretion, andHelicobacter pylori gastritis. Provocative testing for Zollinger-Ellison syndrome was negative and imaging studies did not demonstrate an intra-abdominal mass. Following eradication of theHelicobacter pylori infection, the fasting hypergastrinemia resolved in both patients and in one patient the gastric acid hypersecretion also resolved. The implications of this case on the differential diagnosis of Zollinger-Ellison syndrome are discussed.

Inhibitory cyclic analogues and chlorambucil derivatives of bombesin-like peptides

Analogues of the amphibian neuropeptide, bombesin, and of the mammalian homologue, gastrin-releasing peptide, have been synthesized and their biological activity studied in small cell lung carcinoma and rat pancreatic acinar cells. The compounds are truncated sequences of the active tetradecapeptide BN(1-14) or GRP(20-27). Peptides were cyclized between position 5 or 7 and the carboxyl end of the des-Met14 fragment with D and L Ala11 and Lys5 substitutions, as well as various N-terminal groups attached. The smallest cyclic peptide, BN(7-13), bound to SCLC membranes with microM potency and inhibited BN stimulation of intracellular Ca++ levels. The most potent inhibitor is N-chloroambucil-[His7,D-Ala11]BN(7-13)ethyl ester, which antagonized BN function in SCLC and acinar cells with nM potency and also inhibited clonal growth of carcinoma cell lines.