Jeffrey A. Norton, M.D., Douglas L. Fraker, M.D., H. Richard Alexander, M.D., David J. Venzon, Ph.D., John L. Doppman, M.D., Jose Serrano, M.D., Ph.D., Stephan U. Goebel, M.D., Paolo L. Peghini, M.D., Praveen K. Roy, M.D., Fathia Gibril, M.D., and Robert T. Jensen, M.D.
Background and Methods The role of surgery in patients withthe Zollinger–Ellison syndrome is controversial. To determinethe efficacy of surgery in patients with this syndrome, we followed151 consecutive patients who underwent laparotomy between 1981and 1998. Of these patients, 123 had sporadic gastrinomas and28 had multiple endocrine neoplasia type 1 with an imaged tumorof at least 3 cm in diameter. Tumor-localization studies andfunctional localization studies were performed routinely. Allpatients underwent surgery according to a similar operativeprotocol, and all patients who had surgery after 1986 underwentduodenotomy.
Results The 151 patients underwent 180 exploratory operations.The mean (±SD) follow-up after the first operation was8±4 years. Gastrinomas were found in 140 of the patients(93 percent), including all of the last 81 patients to undergosurgery. 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 werefree of disease at 10 years, as compared with none of the patientswith multiple endocrine neoplasia type 1. The overall 10-yearsurvival rate was 94 percent.
Conclusions All patients with the Zollinger–Ellison syndromewho do not have multiple endocrine neoplasia type 1 or metastaticdisease should be offered surgical exploration for possiblecure.
The Zollinger–Ellison syndrome is characterized by severepeptic ulcer disease that results from gastrin-secreting tumors(gastrinomas) of the gastrointestinal tract.1,2 In about 75percent of patients the tumors are sporadic, and 25 percentof patients have multiple endocrine neoplasia type 1 (MEN-1).1,2,3Patients with the Zollinger–Ellison syndrome have twoproblems that require treatment4 — the hypersecretionof gastric acid and the gastrinoma itself.1,2 Although mostgastrinomas grow slowly, 60 to 90 percent are malignant and25 percent show rapid growth.2,5,6
The hypersecretion of acid can now be controlled in almost everypatient by the administration of inhibitors of gastric H+/K+–ATPase.1,7Therefore, the natural history of the gastrinoma is becomingthe main determinant of long-term survival.1,5,8 Surgical excisionis the logical treatment; however, the role of surgery in patientswith sporadic gastrinomas1,9,10 and in patients with MEN-110,11,12,13is controversial. Because the tumors are uncommon, few studieshave involved enough patients to permit analysis of the variablesthat could affect surgical outcome. In studies undertaken beforeeffective medical treatment was available, many patients diedfrom acid-related complications, so the effects of resectionof the gastrinoma were often not clear. As a result, there isno agreement on whether no,9,10 some,9,10,14 or all15 patientswith the Zollinger–Ellison syndrome should undergo surgicalexploration. To address these issues, in 1981 the National Institutesof Health began a prospective study of the results of surgicalresection according to a fixed protocol in consecutive patientswith the Zollinger–Ellison syndrome. The study was designedto allow the incorporation of any advances in preoperative oroperative localization of tumors into the study so that theresults would reflect the best available surgical treatment.
Methods
All patients with a diagnosis of the Zollinger–Ellisonsyndrome who were referred to the National Institutes of Healthstarting in 1981 were considered for the surgical protocol.Previous reports have described the methods used (includingthe standard operative approach, duodenotomy, preoperative tumorlocalization, and postoperative assessment of cure), the immediatepostoperative and 3-to-6-month cure rate in 32 patients, theresults of adding routine duodenotomy to the protocol and the45-month cure rate in 73 patients with sporadic gastrinomas,and the immediate postoperative cure rate in 10 patients withMEN-1.16,17,18,19 The study was approved by the Clinical ResearchCommittee of the National Institute of Diabetes and Digestiveand Kidney Diseases, and all patients gave written informedconsent.
The diagnosis of MEN-1 in study patients with the Zollinger–Ellisonsyndrome was based on studies of acid secretion, measurementsof fasting serum gastrin, the results of secretin and calciumtests of gastrin secretion, the presence of a family historycompatible with the diagnosis of MEN-1, and the presence ofassociated endocrinopathies that occur in patients with MEN-1.20
Surgical Protocol for the Cure of Gastrinoma
We evaluated the location of the primary tumor (or in some patients,of the multiple primary tumors) and the location of metastaticgastrinomas in all patients, using conventional imaging studies(computed tomography, magnetic resonance imaging, transabdominalultrasonography, and selective abdominal angiography).18,21,22Starting in June 1994, all patients also underwent somatostatin-receptorscintigraphy.22 Functional localization of the gastrinoma wasperformed with the use of either transhepatic portal venoussampling (January 1980 to April 1992) or hepatic venous samplingafter the selective intraarterial injection of secretin to obtainblood samples for measurements of serum gastrin (January 1988to the present).23,24
We enrolled patients in the surgical protocol for possible cure,on the basis of criteria described previously,16,17,18,19,25if they had not undergone previous resection of the gastrinomaor if they had undergone an unsuccessful laparotomy and werelater found on imaging studies to have a localized extrahepaticgastrinoma and if they did not have MEN-1. Patients with MEN-1underwent exploration if a tumor of 3 cm or larger was detectedby imaging.19 Patients with liver metastases thought to be completelyresectable were included. We used two surgical protocols.17Before 1987, an extensive search for the gastrinoma was performedthrough palpation, intraoperative ultrasonography,18 and anextended Kocher maneuver,16,17 which involves elevating theduodenum and pancreatic head by dividing the ligamentous attachmentsto the retroperitoneum. In 1987, additional procedures wereadded for localizing duodenal gastrinomas.17,18 These includedendoscopic transillumination of the duodenum at surgery anda longitudinal incision of 3 cm in the descending duodenum.18
Tumors in the head of the pancreas were enucleated. Tumors inthe body and tail of the pancreas were enucleated if possible;otherwise, they were resected. Before the patients were dischargedfrom the hospital, serum gastrin was measured before and afterthe administration of secretin.17,26 The patients were reevaluatedwith imaging studies and the same serum gastrin measurementsthree to six months after resection and at yearly intervalsthereafter.17,26,27 Patients were considered to be free of diseaseif fasting serum gastrin concentrations were normal, the secretintest was negative,27 and imaging studies were negative.26 Agastrinoma of the lymph node was termed a primary tumor if itoccurred in a patient who was free of disease after resectionof a gastrinoma that was only in a lymph node. For the secretintest, 2 units of secretin (Ferring Laboratories, Suffern, N.Y.)per kilogram of body weight were given by intravenous bolusinjection after temporary discontinuation of antisecretory-drugtherapy, and serum gastrin was measured 2, 5, 10, and 20 minuteslater. A normal response was defined as an increase in the serumgastrin concentration of less than 200 pg per milliliter (95.4pmol per liter) above the preinjection value; a greater increasewas interpreted as indicating a gastrinoma.
Preoperative hypersecretion of gastric acid was controlled medicallyin all patients.28 Control of acid secretion was reevaluatedthree to six months after surgery, and antisecretory-drug therapywas then discontinued or the dose decreased if possible.29
Statistical Analysis
We used Fisher's exact test or the chi-square test to comparecategorical variables and the Mann–Whitney U test to comparecontinuous variables. The probabilities of survival and disease-freesurvival were calculated and plotted according to the methodof Kaplan and Meier.30 We compared the probabilities of survivalat predetermined times using Greenwood's formula for the standarderror of the survival estimates and the standard large-sampleformula for the difference between two independent proportions.The disease-free rate was calculated as the percentage of patientswho were free of disease during a specific follow-up period.The disease-free rates are estimates of the frequency of recurrenceamong patients who had long-term follow-up; these rates differfrom the disease-free survival rates calculated from the Kaplan–Meierestimates of the survival probabilities in the entire cohort.
Results
Between December 1981 and August 1998, we enrolled 151 patientswith the Zollinger–Ellison syndrome, of whom 123 had sporadicgastrinomas and 28 had gastrinomas with MEN-1 (Table 1). Thepatients with MEN-1 were younger and had higher preoperativeserum gastrin concentrations while fasting than the patientswith sporadic gastrinomas, but the groups were otherwise similar.
Table 1. Characteristics of the 151 Patients with the Zollinger–Ellison Syndrome before Initial Surgical Exploration.
Before the surgery, conventional imaging studies were positivein 24 to 48 percent of the patients with sporadic gastrinomas(Figure 1). Somatostatin-receptor scintigraphy was positivein 79 percent of the 54 patients with sporadic gastrinomas whounderwent testing and was equal in sensitivity to the resultswith all conventional imaging studies combined (P=0.07) (Figure 1).In patients with sporadic gastrinomas, functional localizationby measurement of gradients in serum gastrin concentrationshad greater sensitivity than any conventional imaging study(P<0.001), but the sensitivity was not greater than thatof somatostatin-receptor scintigraphy (Figure 1). More patientswith MEN-1 than with sporadic gastrinomas had positive resultson conventional imaging studies, as a result of the admissioncriterion of an imaged mass of 3 cm or greater.
Figure 1. A Comparison of the Results of Preoperative Imaging Studies in All Patients with the Zollinger–Ellison Syndrome (Left-Hand Panel) and a Comparison of the Results of Preoperative Imaging Studies Performed before Initial and Subsequent Operations and before Only the Initial Operation in Patients with Sporadic Gastrinomas (Right-Hand Panel).
The results are expressed as the percentage of operations performed in patients for whom the indicated localization study was performed preoperatively. In the left-hand panel, the 28 patients with multiple endocrine neoplasia type 1 (MEN-1) had a total of 32 operations, and the 123 patients with sporadic gastrinomas had a total of 148 operations. Somatostatin-receptor scintigraphy was performed before the last 54 surgical explorations (43 in patients with sporadic gastrinomas and 11 in patients with MEN-1), of which 27 were initial explorations. Portal venous sampling for measurement of serum gastrin was performed before 97 operations, 85 of which were in patients with sporadic gastrinomas. Intraarterial secretin injection with measurement of serum gastrin in hepatic venous blood was performed before 103 operations, 92 of which were in patients with sporadic gastrinomas. In the right-hand panel, there were a total of 148 operations (in 123 patients), of which 123 were initial operations (in 123 patients). The P values for all comparisons other than those shown were >0.05. CT denotes computed tomography, and MRI magnetic resonance imaging.
Operative Findings
The 151 patients underwent 180 operations; 23 patients had 2operations, and 2 had 3 or more operations (Table 2). Gastrinomaswere found in 88 percent of the initial surgical explorationsand 100 percent of subsequent explorations, with no significantdifferences between patients with sporadic gastrinomas and patientswith MEN-1. Gastrinomas were found during subsequent operationsin seven patients who had negative results on the initial operations.Gastrinomas were found in 96 percent of all surgical explorationsperformed beginning in 1987, when additional procedures wereincluded to localize duodenal gastrinomas at surgery. Beforethese procedures were used, gastrinomas were found in only 68percent of operations. This difference was due almost entirelyto the difference in results for patients with sporadic gastrinomas.Starting in March 1991, gastrinomas were found in 81 consecutivepatients who underwent 87 operations.
Table 2. Location of Primary Tumor, Extent and Size of Tumor, and Type of Operation in 151 Patients with the Zollinger–Ellison Syndrome.
A primary tumor was found in 93 percent of all patients —93 percent of the patients with sporadic gastrinomas and 96percent of the patients with MEN-1 (Table 2). In the patientswith sporadic gastrinomas, the primary tumor was the gastrinoma,but not all of the tumors in patients with MEN-1 were gastrinomas.Two of the 5 tumors (40 percent) resected in patients with MEN-1before 1987 were gastrinomas; thereafter, 17 of the 26 tumorsresected in patients with MEN-1 after 1986 were gastrinomas.
The most frequent location of the gastrinoma was the duodenum(Table 2). In patients with sporadic gastrinomas, duodenal gastrinomaswere 3.4 times as common as pancreatic gastrinomas (47 percentof patients vs. 14 percent of patients), and in patients withMEN-1, duodenal gastrinomas were 2.7 times as common as pancreaticgastrinomas (including only tumors that stained positive forgastrin; 16 of 28 patients vs. 6 of 28 patients) (Table 2).Eleven percent of all patients, primarily the patients withsporadic gastrinomas, had gastrinomas classified as primarylymph-node gastrinomas,31,32 and 9 percent had primary gastrinomasin sites other than the duodenum, pancreas, or lymph nodes.A larger percentage of patients with MEN-1 had pancreatic tumors(68 percent, vs. 14 percent among patients with sporadic gastrinomas;P=0.002); however, when only patients who had positive stainingfor gastrin were considered, only one third of the pancreatictumors in the patients with MEN-1 were gastrinomas.
In terms of the extent of the tumor, only a primary tumor wasfound in 48 percent of the 151 patients, mainly in patientswith sporadic gastrinomas. For all patients, metastases occurredmost commonly to lymph nodes, and duodenal gastrinomas weremore frequently associated with lymph-node metastases than wereprimary tumors in other sites.
The gastrinomas were resectable in almost all patients; onlya biopsy was performed in 2 percent of the surgical explorations(Table 2). Tumor resection or enucleation was possible in 76percent of the patients. A distal pancreatectomy was requiredin 14 percent of the patients, and a hepatic resection in 8percent.
Follow-Up
Forty-five percent of the patients were free of disease immediatelyafter the resection of their gastrinomas, mostly patients withsporadic gastrinomas (Table 3 and Figure 2). Of the patientswith MEN-1, all but one patient relapsed by 3 years, and allhad relapsed by 10 years, whereas of the patients with sporadicgastrinomas, 45 percent and 34 percent of the patients remainedfree of disease at 3 and 10 years, respectively (Figure 2A).
Figure 2. Disease-free Survival (Panel A) and Disease-Specific Survival (Panel B) among Patients with the Zollinger–Ellison Syndrome.
Panel A shows a Kaplan–Meier plot of disease-free survival. The data on disease-free survival are presented as percentages plotted as a function of the number of operations rather than the number of patients. Five of the 28 patients with multiple endocrine neoplasia type 1 (MEN-1) who underwent 32 surgical explorations of the abdomen and 74 of the 123 patients with sporadic gastrinomas who underwent 144 surgical explorations were free of disease immediately after surgery. The results are expressed as the percentage of the total number of surgical patients in each group who were free of disease at the indicated postoperative time. Panel B shows a Kaplan–Meier plot of survival with respect to the Zollinger–Ellison syndrome. There were four deaths from the Zollinger–Ellison syndrome: three from progressive metastatic disease and one from a paradoxical cerebral embolus through a patent foramen ovale. The results reflect only deaths that resulted from manifestations of the Zollinger–Ellison syndrome or malignant gastrinomas. Tick marks indicate the end of follow-up in individual patients.
In patients with sporadic gastrinomas, the disease-free rateat five years was not influenced by the results of preoperativelocalization studies, the presence of limited liver metastases,or the location of the primary gastrinoma (Table 3). Among patientswho were followed for an average of seven years, 17 of the 74patients with sporadic gastrinomas who were free of diseaseimmediately after surgery relapsed (23 percent), as comparedwith 5 of 5 patients with MEN-1 (100 percent) (Table 3).
The rate of disease-free survival among patients with sporadicgastrinomas was 40 percent at 5 years and 34 percent at 10 years(Figure 2A). In contrast, in patients with MEN-1, the rate ofdisease-free survival was 4 percent at 5 years and 0 percentat 10 years (Figure 2A). The rates of disease-free survivalat 5 and 10 years were not significantly different for patientswith primary tumors in different locations (Figure 3).
Figure 3. Kaplan–Meier Plot of Disease-free Survival According to Location of the Primary Tumor in Patients with Sporadic Gastrinomas.
The results are expressed as the percentage of patients with a primary tumor in the indicated location who were free of disease immediately after resection who were still free of disease at the indicated postoperative times. Tick marks indicate the end of follow-up in individual patients. The numbers below the figure show the numbers of patients with a primary tumor in each location who remained in the analysis.
When only deaths due to manifestations of the Zollinger–Ellisonsyndrome or malignant gastrinoma were included, the 5- and 10-yearrates of survival among the patients with sporadic gastrinomaswere 100 percent and 95 percent, respectively (Figure 2B). Thecorresponding rates among the patients with MEN-1 were 100 percentand 86 percent (Figure 2B). Only 4 of the 151 patients (3 percent)died from a cause related to the Zollinger–Ellison syndrome,and none of these deaths were related to gastric acid hypersecretion.Overall, 21 patients (14 percent) died from any cause, and therate did not differ significantly between the two groups.
Discussion
The value of surgical exploration as a means of cure in patientswith the Zollinger–Ellison syndrome is even more controversialtoday than when this study was started in 1981.9,10,13 The reasonsfor the controversy include the slow growth of many gastrinomas,the variable rate of cure, and the lack of information on thelong-term results of potentially curative resections. Untilrecently, many patients died from complications of gastric acidhypersecretion, surgical series included relatively few patients,follow-up after resection was often short, and there was nostandard operative approach that incorporated methods that improveintraoperative detection of gastrinomas. In the current study,a large number of patients were enrolled, advances in the preoperativeand intraoperative detection of tumors were incorporated intothe protocol, follow-up was long, and all patients receiveddrugs to control gastric-acid hypersecretion.
Our results support the conclusion that exploratory laparotomyshould be performed routinely in patients with sporadic gastrinomasif diffuse hepatic metastases are not present. Gastrinomas werefound in 93 percent of the patients in our study. In approximatelyone third of patients with sporadic gastrinomas, the resultsof imaging studies are negative. Surgical exploration almostalways detects gastrinomas in patients whose imaging studiesare negative, however, so negative results should not be a reasonfor not performing laparotomy.9,10 In our study, the disease-freerate immediately after resection was 51 percent, and it wassustained in the majority of patients during follow-up. Theseresults demonstrate that a substantial proportion of patientswith sporadic gastrinomas have long-term disease-free survival.
If routine surgery is to be advocated for patients with sporadicgastrinomas, careful preoperative imaging is essential, so asto exclude patients with more extensive disease who might notbenefit from surgery and to identify the primary tumor. Somatostatin-receptorscintigraphy, which images the entire body at one time, is moresensitive for detecting gastrinomas than any conventional imagingstudy.22 Since this test became available, all liver metastasesdetected at exploration have been detected by the test.
Most gastrinomas are found in the pancreas, duodenum, or lymphnodes near the head of the pancreas, but they have also beenfound in the heart, liver, bile ducts, ovary, kidney, mesentery,and other sites.1,33,34,35 They were found in such sites in9 percent of our patients, a finding that highlights the importanceof whole-body imaging by procedures such as somatostatin-receptorscintigraphy. Extensive exploration of the head of the pancreasand especially the duodenum must be carried out at surgery ifgastrinomas are to be found. In earlier studies, duodenal gastrinomaswere less common than pancreatic gastrinomas,1 whereas in thepresent study, duodenal tumors were more common, undoubtedlyas a result of the institution in 1987 of surgical proceduresto detect duodenal gastrinomas. These procedures are essentialif duodenal tumors are to be detected, because most duodenaltumors are not identified by any imaging study.17,18 Whetherendoscopic ultrasonography will make possible the preoperativeidentification of these small duodenal gastrinomas was not addressedin our study and is not yet clear.
Lymph nodes in the region of the head of the pancreas and duodenumshould be routinely removed at surgery even if they appear normal,because they may contain microscopic gastrinoma.17 The existenceof primary lymph-node gastrinomas is controversial.31 The presentstudy suggests that they may exist. Of the 15 patients withsporadic gastrinomas in whom only a resected lymph node containeda tumor and who were free of disease after resection and werefollowed for at least five years, only 3 patients relapsed.Aggressive resections, including pancreatoduodenectomies, arebeing recommended increasingly for patients with gastrinomas.1,12However, in the present study, in which few patients underwentaggressive surgery, the 10-year disease-specific rate of survivalwas 94 percent.
The question of whether surgery can be curative in patientswith MEN-1 is also controversial.1,11,13,19,36 Many, but notall, gastrinomas in patients with MEN-1 occur in the duodenum;in this study, 57 percent of such patients had gastrinomas locatedin the duodenum. However, even with the institution of proceduresto identify duodenal gastrinomas, only 16 percent of these patientswere free of disease immediately after surgery, and only 6 percentat five years. Proximal pancreatoduodenectomy has been foundto result in cure in some patients with MEN-112; however, fewpatients have been treated with this procedure. Larger gastrinomasare more likely to metastasize,5,37 but it is not known whetherearlier surgery — when the tumors are smaller than 3 cm— would result in an increased rate of cure.
Almost half of our patients with sporadic gastrinomas were notfree of disease after surgery. Somatostatin-receptor scintigraphyis not likely to improve this rate.38 Therefore, more sensitivemethods for intraoperative tumor localization, such as intraoperativescintigraphy,39 will have to be developed, or more aggressivesurgery, such as proximal pancreatoduodenectomy, will need tobe performed. More aggressive surgery might be justified insome patients through the use of intraoperative measurementsof serum gastrin to determine whether the gastrinoma has beencompletely resected40 or through the identification (by methodsnot yet described) of subgroups of patients with a poor prognosis.
In conclusion, we found that half of our patients with sporadicgastrinomas were free of disease immediately after surgery andthat long-term cure was possible in the majority of these patients.These results support the recommendation that patients withsporadic gastrinomas should undergo routine surgical explorationfor possible curative resection. Conversely, patients with MEN-1rarely become free of disease, even after extensive duodenalexploration; therefore, surgical exploration for cure of thegastrinoma is not routinely recommended in these patients.
Source Information
From the Department of Surgery, University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center, San Francisco (J.A.N.); the Surgical Metabolism Section, Surgery Branch, National Cancer Institute, Bethesda, Md. (D.L.F., H.R.A.); the Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Md. (D.J.V.); the Diagnostic Radiology Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Md. (J.L.D.); and the Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md. (J.S., S.U.G., P.L.P., P.K.R., F.G., R.T.J.).
Address reprint requests to Dr. Jensen at NIH/NIDDK/DDB, Bldg. 10, Rm. 9C-103, 10 Center Dr., MSC 1804, Bethesda, MD 20892-1804, or at robertj{at}bdg10.niddk.nih.gov.
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(2009). Neuroendocrine Tumors of the Pancreas. The Oncologist
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(2008). Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer
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Lodish, M. B., Powell, A. C., Abu-Asab, M., Cochran, C., Lenz, P., Libutti, S. K., Pingpank, J. F., Tsokos, M., Gorden, P.
(2008). Insulinoma and Gastrinoma Syndromes from a Single Intrapancreatic Neuroendocrine Tumor. J. Clin. Endocrinol. Metab.
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Anlauf, M, Perren, A, Henopp, T, Rudolf, T, Garbrecht, N, Schmitt, A, Raffel, A, Gimm, O, Weihe, E, Knoefel, W T, Dralle, H, Heitz, P. U, Komminoth, P, Kloppel, G
(2007). Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions. Gut
56: 637-644
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Hoffmann, K. M., Gibril, F., Entsuah, L. K., Serrano, J., Jensen, R. T.
(2006). 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. J. Clin. Endocrinol. Metab.
91: 204-212
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Marx, S. J., Simonds, W. F.
(2005). Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes. Endocr. Rev.
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Ramage, J K, Davies, A H G, Ardill, J, Bax, N, Caplin, M, Grossman, A, Hawkins, R, McNicol, A M, Reed, N, Sutton, R, Thakker, R, Aylwin, S, Breen, D, Britton, K, Buchanan, K, Corrie, P, Gillams, A, Lewington, V, McCance, D, Meeran, K, Watkinson, A, on behalf of UKNETwork for neuroendocrine tumours,
(2005). Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut
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Furukawa, M., Raffeld, M., Mateo, C., Sakamoto, A., Moody, T. W., Ito, T., Venzon, D. J., Serrano, J., Jensen, R. T.
(2005). Increased Expression of Insulin-Like Growth Factor I and/or Its Receptor in Gastrinomas Is Associated with Low Curability, Increased Growth, and Development of Metastases. Clin. Cancer Res.
11: 3233-3242
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Asgharian, B., Turner, M. L., Gibril, F., Entsuah, L. K., Serrano, J., Jensen, R. T.
(2004). 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. J. Clin. Endocrinol. Metab.
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Kaltsas, G. A., Besser, G. M., Grossman, A. B.
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Norton, J. A., Kivlen, M., Li, M., Schneider, D., Chuter, T., Jensen, R. T.
(2003). Morbidity and Mortality of Aggressive Resection in Patients With Advanced Neuroendocrine Tumors. Arch Surg
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(2003). Image of the Month--Diagnosis. Arch Surg
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Gibril, F., Chen, Y.-J., Schrump, D. S., Vortmeyer, A., Zhuang, Z., Lubensky, I. A., Reynolds, J. C., Louie, A., Entsuah, L. K., Huang, K., Asgharian, B., Jensen, R. T.
(2003). Prospective Study of Thymic Carcinoids in Patients with Multiple Endocrine Neoplasia Type 1. J. Clin. Endocrinol. Metab.
88: 1066-1081
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Chen, Y.-J., Vortmeyer, A., Zhuang, Z., Huang, S., Jensen, R. T.
(2003). Loss of Heterozygosity of Chromosome 1q in Gastrinomas: Occurrence and Prognostic Significance. Cancer Res.
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Goebel, S. U., Iwamoto, M., Raffeld, M., Gibril, F., Hou, W., Serrano, J., Jensen, R. T.
(2002). HER-2/neu Expression and Gene Amplification in Gastrinomas: Correlations with Tumor Biology, Growth, and Aggressiveness. Cancer Res.
62: 3702-3710
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Peghini, P. L., Iwamoto, M., Raffeld, M., Chen, Y.-J., Goebel, S. U., Serrano, J., Jensen, R. T.
(2002). Overexpression of Epidermal Growth Factor and Hepatocyte Growth Factor Receptors in a Proportion of Gastrinomas Correlates with Aggressive Growth and Lower Curability. Clin. Cancer Res.
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Marx, S. J., Nieman, L. K.
(2002). Aggressive Pituitary Tumors in MEN1: Do They Refute the Two-Hit Model of Tumorigenesis?. J. Clin. Endocrinol. Metab.
87: 453-456
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Gibril, F., Venzon, D. J., Ojeaburu, J. V., Bashir, S., Jensen, R. T.
(2001). Prospective Study of the Natural History of Gastrinoma in Patients with MEN1: Definition of an Aggressive and a Nonaggressive Form. J. Clin. Endocrinol. Metab.
86: 5282-5293
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Berger, A. C., Gibril, F., Venzon, D. J., Doppman, J. L., Norton, J. A., Bartlett, D. L., Libutti, S. K., Jensen, R. T., Alexander, H. R.
(2001). Prognostic Value of Initial Fasting Serum Gastrin Levels in Patients With Zollinger-Ellison Syndrome. JCO
19: 3051-3057
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Bordi, C., Corleto, V. D., Azzoni, C., Pizzi, S., Ferraro, G., Gibril, F., Delle Fave, G., Jensen, R. T.
(2001). The Antral Mucosa as a New Site for Endocrine Tumors in Multiple Endocrine Neoplasia Type 1 and Zollinger-Ellison Syndromes. J. Clin. Endocrinol. Metab.
86: 2236-2242
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Serrano, J., Goebel, S. U., Peghini, P. L., Lubensky, I. A., Gibril, F., Jensen, R. T.
(2000). Alterations in the p16INK4a/CDKN2A Tumor Suppressor Gene in Gastrinomas. J. Clin. Endocrinol. Metab.
85: 4146-4156
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Yu, F., Jensen, R. T., Lubensky, I. A., Mahlamaki, E. H., Zheng, Y.-L., Herr, A. M., Ferrin, L. J.
(2000). Survey of Genetic Alterations in Gastrinomas. Cancer Res.
60: 5536-5542
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Gibril, F., Reynolds, J. C., Lubensky, I. A., Roy, P. K., Peghini, P. L., Doppman, J. L., Jensen, R. T.
(2000). Ability of Somatostatin Receptor Scintigraphy to Identify Patients with Gastric Carcinoids: A Prospective Study. JNM
41: 1646-1656
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Goebel, S. U., Vortmeyer, A. O., Zhuang, Z., Serrano, J., Jensen, R. T., Lubensky, I. A.
(2000). Identical Clonality of Sporadic Gastrinomas at Multiple Sites. Cancer Res.
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Hirschowitz, B. I., Norton, J. A., Gibril, F., Jensen, R. T.
(1999). Surgery to Cure the Zollinger-Ellison Syndrome. NEJM
341: 2096-2097
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Wells, S. A.
(1999). Surgery for the Zollinger-Ellison Syndrome. NEJM
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