Vitaly A. Fishbeyn

A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas

ObjectiveThis study determined, prospectively, whether duodenotomy (DX) should be routinely performed in explorations for patients with Zollinger-Ellison syndrome (ZES). Summary Background DataDuodenal gastrinomas are now being found with increasing frequency in patients with Zollinger-Ellison syndrome. The surgical approach used to detect these tumors is controversial. Some recommend intraoperative endoscopy with transillumination (IOE) at surgery, while others recommend routine DX. MethodsBeginning in 1989, the authors prospectively compared the ability of palpation, intraoperative ultrasound (IOUS), IOE, and DX (in that sequence) to detect gastrinomas in 35 consecutive patients with ZES. Each patient also underwent preoperative localization studies. ResultsThirty-three of 35 patients (94%) had tumor detected and excised; duodenal gastrinomas were excised in 27 patients (77%). The average size of the duodenal tumors was 0.8 cm, significantly smaller (p < 0.005) than the pancreatic and lymph node tumors in this series. Standard palpation after a Kocher maneuver identified 19 of the 31 duodenal tumors (61 %) in the 27 patients. IOUS revealed only eight duodenal tumors (26%) and no new lesions. IOE identified 20 duodenal gastrinomas (64%) and 6 new lesions. DX identified 31 duodenal tumors (100%) and 5 additional tumors. The morbidity rate was 17%. One patient had a duodenal fistula after operation (2.8%) and subsequently recovered. No patient died. ConclusionsThese results demonstrate that the duodenum is the most common location for gastrinoma in patients with ZES (77%) and that DX to detect and remove duodenal gastrinomas should be routinely performed in all explorations for patients with ZES.

Assessment and Prediction of Long-term Cure in Patients with the Zollinger-Ellison Syndrome: The Best Approach

Gastrinoma is the most common functional pancreatic endocrine tumor [1-3]. Because of autonomous gastrin release by the gastrinoma, patients develop gastric acid hypersecretion as part of the Zollinger-Ellison syndrome [1, 4]. In recent years, effective medical therapies have been developed to control gastric acid hypersecretion, which previously was the leading cause of death in patients with the Zollinger-Ellison syndrome [5-7]. Increasingly, the malignant nature of the tumor is becoming the primary determinant of long-term survival [2, 8], and therefore patients with the Zollinger-Ellison syndrome are increasingly being considered for possible gastrinoma resection [1, 2, 9, 10]. However, considerable disagreement has arisen about the possible benefit of resection to the patient [11]. This difference in opinion has occurred primarily because of widely ranging disease-free rates (4% to 90%) in different series [1, 12-14]. Further, even without surgery, many patients have an excellent long-term prognosis because of the slow growth of the gastrinoma [15, 16]. Also, many patients experience complications from peptic ulcer disease (for example, perforation) before diagnosis of the syndrome; such complications increase the surgical risk. Thus, the possible long-term benefit of surgery in terms of disease-free survival must be studied to determine whether it outweighs the risk. Disease-free rates have varied markedly among studies for several reasons, including differences in sample size, follow-up, selection criteria for surgery, and operative approach. For example, surgery in these studies has ranged from a detailed exploration with removal of only gastrinomas identified at surgery to blind proximal pancreaticoduodenectomy in cases in which no tumor was found but selective venous sampling showed gastrin positivity in this area [1, 12, 14, 17-21]. However, the primary reason for the variation in the disease-free rate in different series is the lack of agreement on what evaluations should be routinely done after operation to establish disease-free status. Many studies only determined fasting serum gastrin levels [10, 17, 22-24]; however, fasting hypergastrinemia can be caused by achlorhydria, which is frequently seen in patients receiving gastric acid antisecretory drugs, and thus hypergastrinemia may not always represent a disease recurrence or a failure to render the patient disease free [25]. Further, some patients with the Zollinger-Ellison syndrome have a normal fasting serum gastrin level but a positive secretin or calcium provocative test result [26]; other patients have been described who only had a positive calcium provocative test or only abnormal imaging studies [27, 28]. To address this problem, we did a study to determine the best method to assess disease-free status after surgery and to predict long-term disease-free status during follow-up. Methods Our investigation included 81 consecutive patients who underwent surgical exploration for possible curative gastrinoma resection between December 1980 and December 1991 as part of the ongoing National Institutes of Health prospective study of patients with the Zollinger-Ellison syndrome. Thus, many of these patients have been described previously [4, 18, 19, 28-39]. Patients were considered to have a confirmed diagnosis of the Zollinger-Ellison syndrome if they met at least two of the following criteria: an elevated fasting serum gastrin level; a basal acid output of more than 15 mEq/h if the patient had not undergone previous gastric surgery or of more than 5 mEq/h if the patient had undergone previous gastric surgery; an increase in the serum gastrin level of 200 pg/mL after the intravenous administration of secretin; and an increase in the serum gastrin level of 395 pg/mL after an intravenous calcium infusion. The secretin provocative test was done as described previously [28], with Secretin-Kabi (Ferring AB, Malmo, Sweden) given by intravenous bolus injection (2 U/kg body weight). The calcium provocative test was done as described previously [28], with calcium gluconate (10%) (54 mg/kg per hour [5 mg calcium/kg per hour]) given by continuous intravenous infusion for 3 hours. Serum gastrin levels were determined by Bioscience Laboratories (New York, New York). All samples were diluted as necessary to give values that fell on the midportion of the standard curve as described previously [28]. Patients with elevated gastrin levels had repeated determinations. All patients had upper gastrointestinal endoscopy, computed tomography [29], ultrasonography [30], and selective angiography [31] that included selective injections of the hepatic, gastroduodenal, splenic, and superior mesenteric arteries before operation. In addition, patients evaluated after 1987 also underwent magnetic resonance imaging [32]. Before surgery, basal and maximal acid outputs were measured as described previously [33, 34]. Maximal acid output was measured after pentagastrin stimulation (6 g/kg subcutaneously). Sufficient oral antisecretory medication was given to reduce gastric acid output to less than 10 mEq/h before the next dose of medication for patients without previous gastric surgery and to less than 5 mEq/h for those who had previous gastric surgery [4, 33]. The minimal dose of cimetidine or ranitidine given by continuous infusion or of omeprazole given by intermittent intravenous bolus injection to reduce gastric acid secretion to 10 mEq/h or less was determined in all patients as described previously [35, 36, 39], and this dose was administered at surgery and during the postoperative period to control gastric acid secretion. At surgery, an extensive exploration, including mobilization of the duodenum, was done as described previously [18, 19]. In addition, patients who had surgery after 1986 also underwent transduodenal endoscopic transillumination [37] and duodenotomy [19] to localize duodenal gastrinomas and intraoperative ultrasonography as described previously [19, 38]. Specific Protocol After surgery, before discharge from the hospital, fasting serum gastrin concentrations were determined on at least 3 separate days and a secretin provocative test was done. Each patient was discharged on the same dose of oral antisecretory drug that he or she was taking before operation, as described previously [18, 19]. If tumor was resected, patients were reevaluated 3 to 6 months after surgery to determine disease-free status and to assess control of gastric acid hypersecretion. Thereafter, patients who had had tumor resection were reassessed yearly. Patients who did not undergo resection were evaluated yearly. Tumor recurrence after resection was assessed by noninvasive imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) functional studies, which included determination of fasting serum gastrin levels on 3 different days, and provocative tests with secretin and calcium. Gastric acid antisecretory drugs were withdrawn and gastric acid output was determined to ensure that fasting serum gastrin determinations and secretin provocative tests were done on days when patients were not achlorhydric to avoid physiologic hypergastrinemia. As shown in Figure 1, elevation of the fasting serum gastrin level may be secondary to drug-induced achlorhydria. Therefore, to adequately assess the importance of either an elevated fasting serum gastrin level or a positive secretin or calcium provocative test, all gastric acid antisecretory agents had to be withdrawn before these studies. Figure 1. Relation between the fasting serum gastrin concentration and basal acid output in a patient assessed for recurrence 6 months after resection of a gastrinoma. Disease-free status was defined by amelioration of all symptoms of the Zollinger-Ellison syndrome after operation; a significant reduction in gastric acid output at follow-up, no significant increase in basal acid output (that is, <50% increase) at follow-up, and no significant increase in gastric acid antisecretory drug requirements after operation as described previously [34]; a normal fasting serum gastrin concentration (<110 pg/mL) [19, 34]; negative results on provocative testing with secretin (an increase of less than 200 pg/mL in gastrin level) and calcium (an increase of less than 395 pg/mL in gastrin level) [27]; and no evidence of tumor on imaging studies. Further, these criteria were used at all follow-up times so that the persistence of these findings further established disease-free status. In patients who were considered disease-free at any postoperative visit, recurrence was defined by the development of an elevated fasting serum gastrin level (>110 pg/mL) when achlorhydria was not present, a positive result on a calcium or secretin provocative test, abnormal imaging studies, or a significant increase in basal acid output during follow-up, increased drug requirements, or clinical symptoms of Zollinger-Ellison syndrome that persisted during subsequent visits. Patients who had a recurrence (n = 11) were divided into two groups: One group included eight patients who had a recurrence within 36 months after surgery (early recurrence), and the other group included three patients who had a recurrence 36 to 72 months after surgery (late recurrence). Statistics The proportion of patients remaining disease free after surgery was plotted using the Kaplan-Meier method [40], and this curve was used to estimate the probability that a patient would remain disease free [41]. The sensitivity, specificity, and predictive values [42] for the fasting serum gastrin determination and the secretin provocative test were calculated using the results at 3-year follow-up for the 46 patients who remained in the study to that point. To compare differences in recurrence rates, the McNemar test was used [40]. We used Rothmans method [41] to calculate 95% CIs for the probability of being disease free at 3 years and Brown and Hollanders [42

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.

Currently used doses of omeprazole in Zollinger-Ellison syndrome are too high

The efficacy of omeprazole increases during the first few days of administration, suggesting that long-term maintenance dose requirements in patients with Zollinger-Ellison syndrome may be lower than those initially established by upward titration. Long-term maintenance doses of omeprazole were prospectively reduced in 37 patients who had been taking omeprazole for 22 +/- 4 months. Successful reduction was defined as reduction to 20 mg once or twice daily with an absence of symptoms, endoscopy without evidence of active acid-peptic disease, and a gastric acid output of < 10 mEq/h. Sixty-eight percent of patients (25/37) were successfully reduced to 20 mg of omeprazole once (18/24) or twice daily (7/13). Ninety-five percent of patients (20/21) without multiple endocrine neoplasia type I, severe gastroesophageal reflux disease, or previous partial gastrectomy had safe reductions of doses. It is concluded that the currently used omeprazole maintenance doses in patients with Zollinger-Ellison syndrome are too high and advocated that the initial dose still be established by acute daily upward titration followed by gradual reduction once control of acid output has been achieved.

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.

Synthesis and Biological Activity of Cholecystokinin Antagonists

Cholecystokinin (CCK) is a gastrointestinal hormone1 that stimulates satiety2 and pancreatic enzyme secretions in digestion. The active portion of the hormone is the carboxyl terminal octapeptide sequence. CCK is present as a neuropeptide in the CNS3 with the octapeptide being the active released species from neurons. CCK8 is present in vagal afferents and in the brain, it is co-localized with dopamine4. Thus, besides a role in mediation of gastrointestinal functions, a CNS role for CCK in satiety and in modulation of dopamine release or function is investigated.