Causes of Death and Prognostic Factors in Multiple Endocrine Neoplasia Type 1: A Prospective Study

Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking. To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%Y14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature series, the main causes of MEN1-related deaths were due to the malignant nature of the PETs, followed by the malignant nature of thymic carcinoid tumors. These results differ from the results of a number of the literature series, especially those reported before the 1990s. The causes of non-MEN1-related death for the 2 series, in decreasing frequency, were cardiovascular disease, other nonendocrine tumors 9 lung diseases, cerebrovascular diseases. The most frequent non-MEN1-related tumor deaths were colorectal, renal 9 lung 9 breast, oropharyngeal. Although both overall and diseaserelated survival are better than in the past (30-yr survival of NIH series: 82% overall, 88% disease-related), the mean age at death was 55 years, which is younger than expected for the general population. Detailed analysis of causes of death correlated with clinical, laboratory, and tumor characteristics of patients in the 2 series allowed identification of a number of prognostic factors. Poor prognostic factors included higher fasting gastrin levels, presence of other functional hormonal syndromes, need for 93 parathyroidectomies, presence of liver metastases or distant metastases, aggressive PET growth, large PETs, or the development of new lesions. The results of this study have helped define the causes of death of MEN1 patients at present, and have enabled us to identify a number of prognostic factors that should be helpful in tailoring treatment for these patients for both shortand long-term management, as well as in directing research efforts to better define the natural history of the disease and the most important factors determining long-term survival at present. (Medicine 2013;92: 135Y181) Abbreviations: BAO = basal acid output, CI = confidence interval, CNS = central nervous system, CT = computed tomography, DRS = disease-related survival, GERD = gastroesophageal reflux disease, GRFoma = growth hormone-releasing factor-secreting tumor, GTE = Groupe d’etude des Tumeurs Endocrines, HPT = hyperparathyroidism, HR = hazard ratio, MAO = maximal acid output, MEN1 = multiple endocrine neoplasia type 1, MEN1/PET = patients with MEN1 with pancreatic endocrine tumors, MEN1/ZES = patients with MEN1 and Zollinger-Ellison syndrome, MRI = magnetic resonance imaging, NET = neuroendocrine tumor, NIH = National Institutes of Health, non-MEN1 related = not related to MEN1, OS = overall survival, PET = pancreatic endocrine tumor, PTH = parathormone, SRS = somatostatin receptor scintigraphy, VIPoma = vasoactive intestinal peptide secreting tumor, ZES = Zollinger-Ellison syndrome. INTRODUCTION T he autosomal dominant disorder, multiple endocrine neoplasia type 1 (MEN1) has an incidence of 0.22%Y0.25% in postmortem studies. MEN1 is caused by alterations in the 10 exonMenin gene located on chromosome 11q13, which result in abnormalities (mutations, deletions, truncations, primarily) in the 610 amino acid nuclear protein, menin. Although the exact mechanisms by which altered or absent menin causes the clinicopathologic changes characteristic of MEN1 are not known, numerous studies have demonstrated Medicine & Volume 92, Number 3, May 2013 www.md-journal.com 135 From the Department of Medicine and Bioregulatory Science (TI, HI), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Digestive Diseases Branch (TI, HI, HU, MJB, RTJ), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and Hôpital Kirchberg (MJB), Luxembourg, Luxembourg. Financial support and conflicts of interest: This research was supported in part by funding from the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health. The authors have no conflicts of interest to disclose. Reprints: Dr. Robert T. Jensen, NIH/NIDDK/DDB, Bldg. 10, Rm. 9C-103, 10 Center Drive, MSC 1804, Bethesda, MD 20892-1804 (e-mail: [email protected]). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0b013e3182954af1 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. that menin is involved in many important cellular processes such as cell cycle regulation, transcriptional control, cell division, and genomic stability. Patients with MEN1 classically develop adenomas or hyperplasia of multiple endocrine glands, with parathyroid hyperplasia resulting in hyperparathyroidism (HPT) being the most frequent clinical abnormality (90%Y100%), followed by pancreatic endocrine tumors (PETs) (functional E20%Y70%^ or nonfunctional E80%Y100%^), pituitary adenomas (functional/ nonfunctional E20%Y65%^), adrenal tumors (occasionally functional E10%Y73%^), and thyroid adenomas (primarily nonfunctional E0Y10%^). It has been recognized recently that MEN1 patients have an increased occurrence of other endocrine and nonendocrine tumors including carcinoid tumors (thymic E0Y8%^, gastric E7%Y35%^, bronchial E0Y8%^, and rarely intestinal); skin tumors (angiofibromas E88%^, collagenomas E72%^, lipomas E34%^, and melanomas); central nervous system (CNS) tumors (meningiomas, ependymomas, schwannomas E0Y8%^); and smooth muscle tumors (leiomyomas, leiomyosarcomas E1%Y7%^). 354,388,393,413,465 In other reports, small numbers of other tumors have also been described, although it is unclear if they are increased in frequency or aggressiveness in MEN1 patients (lymphoma, renal cancer, hematologic disorders Ethrombotic thrombocytopenic purpura, myeloma^, ovarian tumors, gastrointestinal stromal tumors, seminomas, chondrosarcoma, mesothelioma, thymomas). Whereas there have been many advances in a number of aspects related to MEN1 including molecular understanding, development of molecular screening methods, and treatment of various MEN1-related disorders, the late course of the disease remains unclear, particularly the current causes of death. An understanding of the late course of disease could allow treatments to be tailored to the most significant disorders found to occur (for example, treatment of PETs), and could allow the possible identification of risk factors and prognostic factors that could alter treatment approaches. This is important because the disease has a long course in many cases, and thus there are often opportunities to institute treatments early in the course. There is a lack of prospective studies evaluating the longterm course and causes of death of MEN1 patients at present. This lack of information is a particular problem at present because there have been numerous widespread treatment changes over the last few years that have altered the late course of MEN1, and have likely altered the causes of death. These changes include the increased ability to control various hormone excess states that were a frequent cause of death in early studies of MEN1 patients, 399,438,444,458,461,465,466 accounting for up to 73%Y91% of all deaths in some early series. These include particularly the ability to treat the gastric acid hypersecretion in Zollinger-Ellison syndrome (ZES), earlier diagnosis and better treatment of insulinomas, and the increased use of somatostatin analogues or other treatments for other hypersecretory states (vasoactive intestinal peptide secreting tumors EVIPomas^, etc). This also includes an understanding of the diffuse nature of the parathyroid disease in these patients resulting in HPT, which almost all patients develop early in the disease course, and the development of effective treatment with multigland parathyroidectomies, which prevents the development of nephrolithiases, and renal failure, which not infrequently occurred in earlier series. Similarly, the recognition of the pituitary disease and more aggressive treatments have made this a rare cause of morbidity and death at present compared to in earlier studies. Lastly, it is now recognized that MEN1 patients develop neoplasms other than those classically described, such as various carcinoid tumors, CNS tumors, skin tumors, and soft tissue tumors. Of these the carcinoid tumors can be of concern because they can be aggressive and develop later in the disease course.34,40,94,131,150,151,253,326,360,465 The thymic carcinoids, which are rarely reported before 1990, are of particular concern, especially in males, because as a group they are the most aggressive tumors that MEN1 patients develop and are an increasing cause of death, later in the disease course.111,130,131,151, 408,413,414,465 With the effective treatment of hormone excess states, they are becoming increasingly important. We conducted this study to describe the current course of MEN1 patients late in the disease history, as well as the causes of death at present, and to identify prognostic factors for different causes of death. Unfortunately, to our knowledge there are no reports in the literature of prospective studies of MEN1 patients containing sufficient deaths to allow a direct comparison to the patients in the present study. To allow comparison to existing data in the literature, we compared our results to outcomes reported in 2 other groups of MEN1 patients, as described in the Methods section below. From these comparisons we were able to draw a number of conclusions and to identify a number of prognostic factors that could affect clinical management. PATIENTS AND METHODS NIH MEN1/ZES Patients All patients admitted to the National Institutes of Health (NIH) Digestive Diseases Branch with a diagnosis of a PET with ZES with MEN1 over a 32-year period were evaluated for eligibility for this study. Eligibility requirements included the presence of MEN1 with a PETwith ZES and an agreement to participate prospectively in the initial and follow-up evaluations. The present study is part of a prospective study of patients with MEN1 with MEN1/ZES at the NIH approved by the Clinical Research Committee of the National Institute of Diabetes and Digestive and Kidney Diseases. Diagnostic Criteria Diagnostic criteria for a PET included functional, pathologic, or imaging evidence for the presence of a PET. Diagnostic criteria for ZES were as previously described and included 1) elevated fasting serum gastrin (9100 pg/mL until 1994, 9200 pg/mL since 1994); 2) elevated basal acid output (BAO 915 mEq in unoperated patients, 95 mEq in patients with previous acid reducing surgery; 3) positive provocative testing with secretin (an increase of 9120 pg/mL postinjection) or with calcium (an increase of 9395 pg/mL); 4) positive histologic confirmation of gastrinoma; or 5) a combination of these criteria. Secretin testing and the calcium provocative test were performed as described previously. With the calcium test, an increase of 9395 pg/mL over the average of the pre-injection values was considered a positive response. The calcium infusion test was not performed if the patient was hypercalcemic prior to starting the test. Diagnostic criteria for MEN1 with MEN1/ZES included ZES plus either a family history of MEN1 or evidence of HPT or pituitary disease as previously described. Serum gastrin levels were determined by Bioscience Laboratories (New York, NY) until 1994 and subsequently by Mayo Clinic Laboratories (Rochester, MN). BAO and maximal acid output (MAO) were measured when off all antisecretory Ito et al Medicine & Volume 92, Number 3, May 2013 136 www.md-journal.com * 2013 Lippincott Williams & Wilkins Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. medications as described previously. Briefly, patients were not treated with anticholinergic agents for 3 days, oral histamine H2-receptor antagonists for at least 30 hours, proton pump inhibitors for 1 week, and all intravenous infusions of H2-receptor antagonists for at least 12 hours. MAO was assessed whenever possible if either pentagastrin or histalog was available by administering either histolog (1.5 mg/kg intramuscularly, Eli Lilly, Indianapolis, IN) or pentagastrin (6 Kg/kg subcutaneously, Ayerst Laboratories, NewYork, NY) as described previously. All results were expressed as mEq/h. Evaluations and Definitions On the initial evaluation, a family and personal history for endocrinopathies or other illness was obtained as described previously. Using a questionnaire, outside records, and correspondence from referring physicians, we thoroughly reviewed the MEN1-related disease. We obtained a detailed record of the diagnosis and treatment of all endocrinopathies, with particular attention to parathyroid, pituitary, and pancreatic disorders. For parathyroid disorders the time of first determination of hypercalcemia, history of renal colic, parathyroidectomy history (time, number, type of operation, result, and time of last calcium and/ or parathormone EPTH^ assessment) were obtained. The time of first onset of renal colic or determination that hypercalcemia or HPT was present was taken as the time of establishment of HPT and was used in the study as the time of diagnosis of HPT as described previously. Each patient underwent extensive questioning regarding symptoms compatible with gastric acid hypersecretion including abdominal pain, heartburn, nausea, vomiting, weight loss, diarrhea, and gastrointestinal bleeding. We conducted a complete review of past medical history for other diseases including other gastrointestinal and hepatic disorders present at the time of the initial admission. The time of onset of ZES and time of diagnosis of ZES were determined as described previously. The duration of ZES from onset to diagnosis was calculated as the interval from the time of onset to the time of diagnosis of ZES. The time of onset of MEN1 was the time of the first clinical manifestation of MEN1 (renal colic, pituitary disease, symptomatic PET) or the time the disease was first detected by biochemical screening. Most of the study period preceded the widespread use of genetic testing, and no patients were initially identified by genetic testing. The time of diagnosis and onset of MEN1 or pituitary disease was determined as described previously. To establish the presence of lipomas, melanomas, smooth muscle tumors, thyroid disease, or other PETs prior to evaluation at the NIH, we reviewed the hospital pathology and physician records from pre-NIH evaluations. Family history of MEN1 was considered positive if any sibling, parent, or grandparent had any of the principal manifestations compatible with MEN1 (parathyroid, pituitary, PET). Patients were admitted for the initial evaluation and then yearly as described previously, except for patients with advanced disease who were admitted more frequently depending on the antitumor treatment protocol (every 3Y6 months). 382,450,476 On the initial admission and subsequent admissions, all patients had laboratory evaluations including complete blood count, urinalysis, at least 3 fasting serum gastrin levels, tumor imaging studies, biochemistry studies including liver function tests and an upper gastrointestinal endoscopy. Cross-sectional imaging studies (ultrasound, computed tomography scan ECT^with contrast, and magnetic resonance imaging EMRI^) were performed to assess tumor location and extent as described previously. If the tumor localization or extent was unclear, selective abdominal angiography was performed. Since 1994, all patients underwent initially and then yearly somatostatin receptor scintigraphy (SRS) using 6 mCi of EIn-DTPA-DPhe^octreotide with spot views and single photon emission CT imaging at 4 hours and 24 hours postinjection performed as previously described. Liver metastases were established by biopsy in all patients as described previously. Bonemetastaseswere assessed using bone scanning, SRS, and MRI of the spine as described. 138,476 If imaging results remained uncertain, bone biopsy was performed. Gastric acid hypersecretion was controlled in all patients using either histamine receptor antagonists (cimetidine, ranitidine, famotidine) alone or with an anticholinergic agent until 1983, then primarily using proton pump inhibitors (omeprazole, lansoprazole) as described previously. 200,266,281,282,283,284,294,350,417 Sufficient antisecretory drug was given to reduce acid secretion to G10 mEq/h in the hour before the next dose of medication or to G5 mEq/h (or to the absence of symptoms) in patients with prior partial gastrectomy or severe gastroesophageal reflux disease (GERD). At the initial NIH evaluation and on subsequent NIH admission all patients underwent detailed clinical, biochemical, and imaging studies to assess the possible presence of MEN1 and, if present, additional studies to assess the extent of MEN1 involvement. To assess parathyroid function all patients were evaluated for total serum calcium, albumin, plasma, PTH determination using an assay that identified the midportion of PTH (performed at the NIH from 1974 to 1983 and by Bioscience Laboratories from 1983 to 1991). Since 1988 an assay measuring the intact PTH molecule (Nichols Institute, San Juan Capistrano, CA) was performed. Plasma ionized calcium levels were performed in the last 10 years. To assess pituitary disease, serum prolactin, adrenocorticotropin, thyroid stimulating hormone, growth hormone, luteinizing hormone, follicle stimulating hormone, thyroid function studies (T4, T3) and urinary cortisol excretion were assessed, as were sella turcica size and pituitary imaging abnormalities using CT and/or MRI of the sella turcica. To assess for the presence of a functional PET in addition to fasting gastrin levels, plasma insulin, proinsulin, glucose, adrenocorticotropin, glucagon, pancreatic polypeptide, serotonin, calcitonin and urinary 5-hydroxyindolacetic acid, N-methyl histamine excretion and cortisol excretion were determined. Prior to surgery in patients with insulinomas and selected patients with gastrinomas, functional localization studies were performed assessing hormonal gradients using either selective venous sampling or hepatic vein sampling after intraarterial injections of either calcium or secretin as described previously. The presence of a PET was also assessed by tumor imaging studies using cross-sectional imaging (ultrasound, CT scan, MRI, and, if results were unclear, angiography) and SRS as described above. Thymic carcinoids were assessed by chest CT scanning, SRS and, since 2000, MRI of the chest as described. Lung/bronchial carcinoids were assessed by chest CT and chest X-ray and, since 2000, by MRI of the chest, and were confirmed by thoracotomy. The presence of gastric carcinoids was assessed by upper gastrointestinal endoscopy using a videoscope GIF 100 endoscope (Olympus America, Inc., Melville, NY) with a 3.7 mm biopsy channel. Skin lesions associated with MEN1 (collagenoma, angiofibromas, lipomas, melanomas) were investigated in all patients since 2000 as described previously. Other tumors that are found in MEN1 patients (smooth muscle tumors Eleiomyomas, leiomyosarcomas, etc^, CNS tumors Emeningiomas, ependymomas, schwannomas^) were sought for using cross-sectional Medicine & Volume 92, Number 3, May 2013 MEN1 and Death * 2013 Lippincott Williams & Wilkins www.md-journal.com 137 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. imaging studies as well as upper and lower gastrointestinal endoscopy as described previously. Exploratory laparotomy was performed in patients with MEN1 with PET/ZES with an imageable lesion 92.5 cm, who did not have diffuse liver metastases or an intercurrent illness limiting life expectancy. At exploration all patients had a standard operation consisting of an extensive search for a PET/gastrinoma as described previously. 314,315,316 Because of the frequent occurrence of gastrinomas in the duodenum, which are frequently small and multiple in MEN1, particular attention was paid preoperatively and intraoperatively to the duodenum by performing an extended Kocher maneuver, intraoperative endoscopic transillumination of the duodenum, intraoperative ultrasound with a 10-MHz real time transducer and a 3-cm longitudinal duodenotomy. Parathyroidectomy was performed in all patients with renal colic, nephrolithiases, reduced bone density, or symptoms due to HPT. Initially, either a 3.5 gland resection or 4 glands with an implant was performed. All lung carcinoids and thymic carcinoids were treated with surgical resection as described previously. Gastric carcinoids were treated by endoscopic resection, except in 3 patients who underwent total gastrectomy because of the extensiveness of the disease and the growth as described previously. In patients with liver metastases, after histologic confirmation no anticancer treatment was given initially, and the growth of the liver metastases was evaluated by repeated imaging studies in 3Y6 months as described previously. If on recent imaging, no growth was seen, growth was reassessed at 3Y6 month intervals. If growth was seen, patients were treated with interferon (5 10 units/d), chemotherapy (streptozotocin, fluorouracil, and doxorubicin), or octreotidelong-acting release (octreotide-LAR) preparation. Patients who initially had metastases that were limited to 1 lobe of liver or that were considered potentially resectable were considered for exploratory laparotomy and partial hepatic resection as described previously. For each patient the number and size of each measurable tumor were determined in transverse sections of an imaging modality and the rate of growth on serial imaging studies was calculated as described previously. The rate of change of the most rapidly growing hepatic or extrahepatic tumor was used to determine the growth category. Patients were stratified in 2 groups based on their tumor growth rate: patients were classified as having an aggressive form of MEN1 if there was 925% increase in tumor volume per month or appearance of new lesion(s) at any follow-up evaluation. Patients were classified as developing liver metastases or any new lesion(s) if during follow-up evaluations a new lesion(s) appeared either in the liver or in other sites. Causes of Death Any deaths during follow-up were classified as either MEN1 related or not. MEN1-related deaths were deaths due to an MEN1-associated feature, including endocrinopathy, metastatic neuroendocrine tumor (NET), and MEN1 treatment. MEN1-related deaths were also classified as being ZES related or not. ZES-related deaths were defined as deaths due to the tumor because of metastatic spread of the gastrinoma, tumorrelated complications, or acute effects of gastric acid hypersecretion (n = 0) as described previously. The causes of MEN1-related deaths (including all ZES-related deaths) were further categorized into the following 5 subgroups: 1) death due to ZES/PET with progressive liver metastases causing progressive inanition or sepsis; 2) death due to the development of a progressive thymic carcinoid tumor; 3) death due to the development of a non-ZES functional PET; 4) death due to the development of another (nongastrinoma, nonthymic carcinoid tumor) MEN1-associated malignant tumor, and 5) death due to tumor-related embolism. The causes of non-MEN1-related deaths were further categorized into the following 5 subgroups: 1) death due to cardiac causes including myocardial infarction, arrhythmia, or cardiac arrest; 2) death due to the development of an additional non-MEN1-associated malignancy; 3) death due to a cerebrovascular accident; 4) death due to a drug-related cause not related to treatment of advanced metastatic disease; and 5) death due to progressive aplastic anemia. Genetic Analysis Sequence analysis of the MEN1 gene was performed since 1998 through our laboratory, the Molecular Diagnosis program of the Children’s Research Institute (Children’s National Medical Center, Washington, DC), or through GeneDx Inc. (Gaithersburg, MD). The polymerase chain reaction conditions and primers were as previously described. Literature Review of Causes of Death in MEN1 Patients With or Without PETs Unfortunately, to our knowledge there are no series in the literature comparable to the current study in which a large number of MEN1/ZES patients have been prospectively followed, so a direct comparison is not possible. Furthermore, there are insufficient patients reported in the literature with MEN1/ZES described with causes of death defined not due to acid hypersecretion. Therefore, in an attempt to allow comparisons between our data and data from the existing literature, we used 2 specific groups from the literature for comparison, realizing that these groups of patients are not completely comparable in all aspects to our population. First, we compared our results to the results of a pooled summary of a literature search for any case report or small series of MEN1 patients (G7 deaths) where the patients had a PET of any kind, the cause of death was reported, and the cause of death was not peptic ulcer related. This group was similar to our NIH population in that all had MEN1, all had PETs, and 67% had ZES; however, not all patients had ZES. The search for these patients included primarily reports since 1980, when effective medical/surgical treatments for the gastric acid hypersecretion of MEN1 patients with ZES became widely available and in general use. Specifically, we excluded patients in a series or report where the long-term survival was limited due to death from the complications of uncontrolled acid peptic disease. Especially in many early series of patients treated before 1980, this was the major cause of death, and thus few patients had long-term follow-up, which is not the case at present. In the mid-1970s adequate medical antisecretory treatments with either H2-histamine receptor antagonists or proton pump inhibitors became generally available, and this, in addition to the use of total gastrectomy in selected patients, has led to the current situation where few patients die of acid peptic-related disease. Because the current natural history and causes of death are thought to differ markedly from these early reports, 367,378,379,448,465 we did not include patients from the early reports. Second, we compared our results with results of larger MEN1 series in the literature that reported the cause of death of Q10 patients who died from any cause other than a peptic ulcer-related cause. These patients were similar to our NIH patients in that all had MEN1; however, they were different in that not all had PETs or ZES: 60% had a PET and 54% had ZES. This group resembled the general population of Ito et al Medicine & Volume 92, Number 3, May 2013 138 www.md-journal.com * 2013 Lippincott Williams & Wilkins Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. MEN1 patients reported in large series with or without ZES. Comparing our results with this group allowed identification of similarities and differences from series more typical of a general population of MEN1 patients with advanced disease. To accomplish these comparisons, we searched MEDLINE (National Library of Medicine, Bethesda, MD) using the key words MEN1 or multiple endocrine neoplasia combined with gastrinoma, pancreatic endocrine tumor, glucagonoma, ZollingerEllison syndrome, thymic carcinoid, HPT, death, survival, and pituitary tumor, either alone or in combination. We reviewed the bibliographies of all papers to identify papers, book chapters, and other reports not referenced in MEDLINE. All papers were reviewed and relevant data entered into an Excel spreadsheet (Microsoft, Redmond, WA) that was used for all analyses and comparisons. The Japanese literature was also carefully reviewed, both using MEDLINE and reviewing symposium proceedings, books, and abstracts of scientific meetings. We found 10 reports that appeared only in Japanese; for these, the titles and data were translated into English. For the first comparison with small series or case reports of patients with MEN1 with PETs (MEN1/PET patients) with at least 1 reported death not peptic ulcer disease related, we identified 108 separate reports containing 227 patients; 62 reports contained a single case 156,162,165,202,206,207,213,216,229,236,249,264,296,297,300,301,304Y306,311, 313,333,334,358,359,361,369,381,386,387,391,393,396,398,409,411,414,426,430, 438,449,460,462,464,467,468 and 40 contained 91 case (mean, 4.3 cases/ report). 247,303,346,353,362,372,375,389,398,406,407,413,425,427,431,440,443,458,461,466,475 For the second comparison we found 18 series that reported the non-peptic cause of death in Q7 MEN1 patients with or without a PET. Statistical Analysis All data were entered into Excel spreadsheets and analyzed using Statistica MAC (Statsoft, Tulsa, OK) and Statview (SAS Institute, Inc., Cary, NC). Statistical analysis was performed using the Student t test for paired and unpaired values, the Mann-Whitney U test, the Fisher exact test, the chi-square test, and ANOVA. For a post hoc test the Bonferroni/Dunn test was used. P values G 0.05 were considered significant. All continuous variables are reported as mean T SEM. Survival curves were plotted in the form of Kaplan-Meier, and 95% confidence intervals (CI) were calculated using Statview (SAS Institute, Inc., Cary, NC).