Outcomes of 68Ga-NODAGA-Exendin-4 PET/CT Guided Surgical Management of Insulinomas in MEN1: A Preliminary Study.

The data on the use of 68Ga-NODAGA-exendin-4 PET/CT in localizing multiple endocrine neoplasia type 1 (MEN1)-related insulinomas is evolving; however, surgical outcomes data are not available. We describe our cohort of patients with MEN1-related endogenous hyperinsulinemic hypoglycemia (EHH), where 68Ga-NODAGA-exendin-4 PET/CT was used to guide conservative surgery. A retrospective record review of MEN1-related EHH cases managed between 2000 and 2024 was performed for clinical features, imaging, and management. Outcomes were assessed for patients whose surgical extent was determined by 68Ga-NODAGA-exendin-4 PET/CT versus conventional imaging (CECT and 68Ga-DOTATATE PET/CT). Five patients with a median age of 17 (15.5-18.5 years) with EHH underwent laparoscopic, single lesion enucleation based on 68Ga-NODAGA-exendin-4 PET/CT. On preoperative imaging, CT identified culprit lesion in four, while 68Ga-DOTATATE PET/CT localized in one, and had one false positive uptake in non-functioning NET. The median duration of hospital stay was 6 (5.5-9) days. Over a median follow-up of 48 (3.5-84.5) months, none had EHH recurrence or exocrine/endocrine pancreatic insufficiency. On follow-up, one patient had an uneventful pregnancy and delivery. In the remaining 15, who underwent surgery based on conventional imaging, 12 (80%) required extensive surgery beyond enucleation, of which two needed intraoperative ultrasound localization. This group had a postoperative hospital stay of 11 (8-23) days, one recurrence after 84 months, and pancreatic insufficiency in 5 (33%). Our center observation suggests that GLP1R-based PET/CT-guided conservative insulinoma surgery in MEN1 patients is effective and safe and needs further validation.

Disclosure: Y. Hwang: None. K. Kim: None. M. Yu: None. N. Hong: None. Y. Rhee: None. Objective: Multiple Endocrine Neoplasia Type 2 (MEN2) is a rare, inherited disorder that most commonly presents as medullary thyroid carcinoma (MTC). This genetic condition is associated with mutations in the RET proto-oncogene, activating RET tyrosine kinase. With MTC being the most life-threatening aspect, the mortality rates for MEN2 patients can vary depending on the type and timing of intervention. However, data on the mortality and morbidities of MEN2 in South Korea is limited. This study aims to utilize data from the National Health Insurance Service (NHIS) to examine the prevalence of comorbidities and mortality of MEN2 patients with MTC in South Korea. Methods: This study analyzed likely MEN2 patients using data from the Korean NHIS database spanning 2003 to 2020. The operational definition of MEN2 included individuals either 1) diagnosed with MTC and having an ICD-10 code for MEN (D44.8), or 2) diagnosed with MTC and presenting with at least one associated condition, such as primary hyperparathyroidism, pheochromocytoma and paraganglioma (PPGL), Hirschsprung's disease, cutaneous amyloidosis, or neuroma. Hirschsprung's disease, cutaneous amyloidosis, or neuroma were defined using ICD-10 code. Cases were matched in a 1:10 ratio by age, sex, and index year with controls who did not have any MEN2-associated diseases. Results: Our study evaluated 116 patients with likely MEN2 accompanied by MTC (mean age 43.0 ± 17.0 years; 33.6% male) and compared them to an age- and sex-matched control group of 1,160 individuals. The average age at diagnosis of MTC among the MEN2 patients was 43.6 years. A total of 86.2% of these patients (n=100) underwent total thyroidectomy, and 14.7% also received radioactive iodine ablation. Among 116 patients, 21 (18.1%) were diagnosed with primary hyperparathyroidism and underwent parathyroidectomy. Additionally, 25 out of 116 patients (21.6%) was diagnosed as PPGL. The analysis revealed a higher prevalence of comorbidities among the MEN2 patients, including diabetes mellitus (9.5% vs 5.1%, p=0.047), hypertension (46.6% vs 19.0%, p<0.001), and osteoporosis (3.5% vs 0.1%, p<0.001). Moreover, cancers other than thyroid cancer (C73.0) were more common in MEN2 patients than in controls (24.1% vs 0.7%, p<0.001). The MEN2 group also had a higher mortality risk, with an incidence rate of 10.1 per 1000 person-years and a hazard ratio of 2.12 (95% CI 1.07-4.19). Conclusions: This study revealed an increase in comorbidities and a higher prevalence of non-thyroid cancer, along with a higher mortality rate, in MEN2 patients with MTC. Our rigorous diagnostic criteria for MEN2, crucial for precise data analysis, led to a smaller patient cohort, reflecting the inherent complexities of rare disease epidemiology. These findings emphasize the need for a nationwide approach to effectively detect, monitor, and manage MEN2 patients and their associated conditions. Presentation: 6/2/2024

Disclosure: Y. Hwang: None. K. Kim: None. M. Yu: None. N. Hong: None. Y. Rhee: None. Objective: Multiple Endocrine Neoplasia Type 2 (MEN2) is a rare, inherited disorder that most commonly presents as medullary thyroid carcinoma (MTC). This genetic condition is associated with mutations in the RET proto-oncogene, activating RET tyrosine kinase. With MTC being the most life-threatening aspect, the mortality rates for MEN2 patients can vary depending on the type and timing of intervention. However, data on the mortality and morbidities of MEN2 in South Korea is limited. This study aims to utilize data from the National Health Insurance Service (NHIS) to examine the prevalence of comorbidities and mortality of MEN2 patients with MTC in South Korea. Methods: This study analyzed likely MEN2 patients using data from the Korean NHIS database spanning 2003 to 2020. The operational definition of MEN2 included individuals either 1) diagnosed with MTC and having an ICD-10 code for MEN (D44.8), or 2) diagnosed with MTC and presenting with at least one associated condition, such as primary hyperparathyroidism, pheochromocytoma and paraganglioma (PPGL), Hirschsprung's disease, cutaneous amyloidosis, or neuroma. Hirschsprung's disease, cutaneous amyloidosis, or neuroma were defined using ICD-10 code. Cases were matched in a 1:10 ratio by age, sex, and index year with controls who did not have any MEN2-associated diseases. Results: Our study evaluated 116 patients with likely MEN2 accompanied by MTC (mean age 43.0 ± 17.0 years; 33.6% male) and compared them to an age- and sex-matched control group of 1,160 individuals. The average age at diagnosis of MTC among the MEN2 patients was 43.6 years. A total of 86.2% of these patients (n=100) underwent total thyroidectomy, and 14.7% also received radioactive iodine ablation. Among 116 patients, 21 (18.1%) were diagnosed with primary hyperparathyroidism and underwent parathyroidectomy. Additionally, 25 out of 116 patients (21.6%) was diagnosed as PPGL. The analysis revealed a higher prevalence of comorbidities among the MEN2 patients, including diabetes mellitus (9.5% vs 5.1%, p=0.047), hypertension (46.6% vs 19.0%, p<0.001), and osteoporosis (3.5% vs 0.1%, p<0.001). Moreover, cancers other than thyroid cancer (C73.0) were more common in MEN2 patients than in controls (24.1% vs 0.7%, p<0.001). The MEN2 group also had a higher mortality risk, with an incidence rate of 10.1 per 1000 person-years and a hazard ratio of 2.12 (95% CI 1.07-4.19). Conclusions: This study revealed an increase in comorbidities and a higher prevalence of non-thyroid cancer, along with a higher mortality rate, in MEN2 patients with MTC. Our rigorous diagnostic criteria for MEN2, crucial for precise data analysis, led to a smaller patient cohort, reflecting the inherent complexities of rare disease epidemiology. These findings emphasize the need for a nationwide approach to effectively detect, monitor, and manage MEN2 patients and their associated conditions. Presentation: 6/2/2024

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by parathyroid, gastroenteropancreatic, pituitary and adrenal tumours. Cardiovascular disease has been identified as an important cause of death in MEN1 patients. Menin, the product of the MEN1 gene, is a co-activator for peroxisome proliferator-activated receptor-γ and the vitamin D receptor, which are involved in glucose metabolism. We aimed to compare insulin sensitivity and prevalence of impaired fasting glucose and diabetes mellitus between MEN1 patients and controls. Cross-sectional study. Sixty-three MEN1 gene mutation carriers (44% men, mean age 41 years) from 22 kindreds and 126 unrelated controls matched for gender, age and BMI. Fasting glucose levels were categorized and compared using WHO criteria. Homeostasis model assessment (HOMA) was used as a measure of insulin resistance. Homeostasis model assessment was significantly increased in MEN1 patients compared with controls (3·0 ± 2·0 vs 2·0 ± 1·0, P < 0·05). In MEN1 patients, HOMA was associated with BMI, but not with age, calcium and gastrin levels. Using logistic regression analysis, the presence of hyperparathyroidism, pancreatic lesions and various other manifestations was not associated with HOMA. Impaired fasting glucose was more prevalent in MEN1 compared with controls (17%vs 6%, P < 0·05). Three MEN1 patients (5%) compared with four controls (3%) were diabetic (not significant). Multiple endocrine neoplasia type 1 patients had decreased insulin sensitivity and higher prevalence of impaired fasting glucose compared with controls, which was unrelated to MEN1 manifestations. Impaired glucose metabolism may result in increased risk of cardiovascular disease in MEN1 patients.

Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the occurrence of tumors of parathyroids, neuroendocrine cells of the gastro-enteropancreatic tract and anterior pituitary. MEN1 gene encodes menin-oncosuppressor protein. Loss of heterozygosity at 11q13 is typical of MEN1 tumors. We have analyzed the MEN1 mRNA and menin expression in fibroblasts from normal skin biopsies and from MEN1 patients (two with a frameshift 738del4 (exon 3) mutation, introducing a premature stop codon, and an individual with an R460X (exon 10) nonsense mutation). The expression of full-length menin protein did not differ between MEN1 and normal fibroblasts. Wild-type alleles mRNAs were expressed in MEN1 patients, whereas mutant alleles were partially degraded by nonsense-mediated mRNA decay pathway, suggesting a mechanism of compensation for allelic loss by the up-regulation of wild-type menin expression at a post-transcriptional level. Small-interfering RNA silencing of the wild-type mRNA allele abolished menin compensation, whereas the ribozyme silencing of the MEN1-mutated mRNA allele resulted in strongly enhanced wild-type menin expression. Gel-retardation analysis showed that in vitro-specific RNA-protein complexes bound to MEN1 mRNA. These findings contribute to the understanding of tumorigenesis in MEN1, offering the basis for the development of RNA-based therapies in MEN1 gene mutation carriers.

Disclosure: K. Kim: None. Y. Hwang: None. M. Yu: None. S. Moon: None. N. Hong: None. Y. Rhee: None. Multiple Endocrine Neoplasia Type 1 (MEN1) is one of the rarest endocrine disorders, with a scarcity of comprehensive epidemiological data globally. This deficiency in data is even more pronounced in Asian populations, where MEN1 remains an under-researched area. Therefore, our aim is to identity the prevalence, demographic characteristics, and patterns of comorbidities associated with MEN1.This nationwide cohort study assessed likely MEN1 cases from the Korean National Health Insurance Service database (2003-2020), selected via two operational definitions: one requiring an ICD-10 code for MEN1 (D44.8) and the other mandating at least two related procedures for MEN1-associated conditions (Primary Hyperparathyroidism, Pituitary Adenomas, and Duodenopancreatic Neuroendocrine Tumors). Cases were 1:10 matched by age, sex, and index year with controls who did not have any MEN-1 associated tumors. Our study evaluated 412 patients with likely MEN1 (mean age 43.6 ± 15.8 years; 35.4% male) against an age-sex matched control group of 4,120. Baseline characteristics showed a higher prevalence of comorbidities in MEN1 patients, including diabetes mellitus (22.6% vs 4.8%), hypertension (38.1% vs 16.4%), and dyslipidemia (20.6% vs 11.2%), all with p&amp;lt;0.001. Cancer prevalence was markedly elevated in MEN1 patients across most types, compared to controls. Adrenal involvements were observed in 34.7% of MEN1 patients, with adrenal adenoma being the most common (31.6%). Parathyroid, pituitary, and duodenopancreatic involvements were identified in 58.6%, 22.3%, and 19.9% of MEN1 patients, respectively. Mortality analysis revealed MEN1 patients had a higher mortality rate (16.0 per 1000 person-years) and a younger mean age at death (60.1 years) compared to controls (68.0 years), with an adjusted mortality hazard ratio of 3.1. Additionally, mortality risk varied with organ involvement; parathyroid involvement showed an adjusted HR of 2.7, pituitary involvement 4.7, and duodenopancreas involvement 4.0. The risk increased significantly with multi-organ involvement, where patients affected in more than two organs had HRs from 2.8 to 7.3. Our findings indicate that MEN1 significantly impacts patient morbidity and mortality, necessitating improved surveillance and tailored management to enhance early detection and optimize care for this vulnerable patient group. These insights underscore the pressing need for further research into MEN1 and other rare diseases to advance patient care and outcomes. Presentation: 6/2/2024

Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components. Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA. A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors. Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1.

Disclosure: K. Kim: None. Y. Hwang: None. M. Yu: None. S. Moon: None. N. Hong: None. Y. Rhee: None. Multiple Endocrine Neoplasia Type 1 (MEN1) is one of the rarest endocrine disorders, with a scarcity of comprehensive epidemiological data globally. This deficiency in data is even more pronounced in Asian populations, where MEN1 remains an under-researched area. Therefore, our aim is to identity the prevalence, demographic characteristics, and patterns of comorbidities associated with MEN1.This nationwide cohort study assessed likely MEN1 cases from the Korean National Health Insurance Service database (2003-2020), selected via two operational definitions: one requiring an ICD-10 code for MEN1 (D44.8) and the other mandating at least two related procedures for MEN1-associated conditions (Primary Hyperparathyroidism, Pituitary Adenomas, and Duodenopancreatic Neuroendocrine Tumors). Cases were 1:10 matched by age, sex, and index year with controls who did not have any MEN-1 associated tumors. Our study evaluated 412 patients with likely MEN1 (mean age 43.6 ± 15.8 years; 35.4% male) against an age-sex matched control group of 4,120. Baseline characteristics showed a higher prevalence of comorbidities in MEN1 patients, including diabetes mellitus (22.6% vs 4.8%), hypertension (38.1% vs 16.4%), and dyslipidemia (20.6% vs 11.2%), all with p&amp;lt;0.001. Cancer prevalence was markedly elevated in MEN1 patients across most types, compared to controls. Adrenal involvements were observed in 34.7% of MEN1 patients, with adrenal adenoma being the most common (31.6%). Parathyroid, pituitary, and duodenopancreatic involvements were identified in 58.6%, 22.3%, and 19.9% of MEN1 patients, respectively. Mortality analysis revealed MEN1 patients had a higher mortality rate (16.0 per 1000 person-years) and a younger mean age at death (60.1 years) compared to controls (68.0 years), with an adjusted mortality hazard ratio of 3.1. Additionally, mortality risk varied with organ involvement; parathyroid involvement showed an adjusted HR of 2.7, pituitary involvement 4.7, and duodenopancreas involvement 4.0. The risk increased significantly with multi-organ involvement, where patients affected in more than two organs had HRs from 2.8 to 7.3. Our findings indicate that MEN1 significantly impacts patient morbidity and mortality, necessitating improved surveillance and tailored management to enhance early detection and optimize care for this vulnerable patient group. These insights underscore the pressing need for further research into MEN1 and other rare diseases to advance patient care and outcomes. Presentation: 6/2/2024

Rationale:Multiple endocrine neoplasia type 1 (MEN1) syndrome is a rare and complicated disease that is associated with several endocrine tumors. Here, we report a case of MEN1 associated with insulinoma, parathyroid, and pituitary tumors by 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT).Patient concerns:A 49-year-old woman presented with intermittent hypoglycemia for more than a year and developed indistinct consciousness without an apparent trigger.Diagnoses:Biochemical results showed abnormally high serum insulin and parathyroid hormone levels. She underwent an Abdominal magnetic resonance imaging revealed a small nodule in the uncinate process of the pancreas, but it did not clarify the nature of the small nodule. Pituitary magnetic resonance imaging scan revealed a micropituitary tumor, and parathyroid imaging showed no abnormalities. 18F-FDG PET/CT showed no apparent abnormal 18F-FDG uptake in the whole body. In contrast, 68Ga-DOTATATE PET/CT imaging showed pathological radiotracer uptake in the pancreatic uncinate process, accompanied by mild radiotracer uptake in the pituitary gland, and no apparent abnormal radiotracer uptake in the parathyroid area.Interventions:The patient underwent echoendoscopy for pancreatic uncinate process lesions and surgical resection.Outcomes:Histological analysis was suggested of insulinoma of pancreatic neuroendocrine tumor, the Ki-67 index was low (only 1% being positive).Lessons:This case demonstrates that 68Ga-DOTATATE can be used for the detection of MEN1-related tumors and preoperative localization of small and low-grade insulinomas by PET/CT.

AimTo assess postoperative complications and control of hormone secretions following pancreatoduodenectomy (PD) performed on multiple endocrine neoplasia type 1 (MEN1) patients with duodenopancreatic neuroendocrine tumors (DP-NETs).BackgroundThe use of PD to treat MEN1 remains controversial, and evaluating the right place of PD in MEN1 disease makes sense.MethodsThirty-one MEN1 patients from the Groupe d’étude des Tumeurs Endocrines MEN1 cohort who underwent PD for DP-NETs between 1971 and 2013 were included. Early and late postoperative complications, secretory control and overall survival were analyzed.ResultsIndication for surgery was: Zollinger–Ellison syndrome (n = 18; 58%), nonfunctioning tumor (n = 9; 29%), insulinoma (n = 2; 7%), VIPoma (n = 1; 3%) and glucagonoma (n = 1; 3%). Mean follow-up was 141 months (range 0–433). Pancreatic fistulas occurred in 5 patients (16.1%), distant metastases in 6 (mean onset of 43 months; range 13–110 months), postoperative diabetes mellitus in 7 (22%), and pancreatic exocrine insufficiency in 6 (19%). Five-year overall survival was 93.3% [CI 75.8–98.3] and ten-year overall survival was 89.1% [CI 69.6–96.4]. After a mean follow-up of 151 months (range 0–433), the biochemical cure rate for MEN-1 related gastrinomas was 61%.ConclusionIn MEN1 patients, pancreatoduodenectomy can be used to control hormone secretions (gastrin, glucagon, VIP) and to remove large NETs. PD was found to control gastrin secretions in about 60% of cases.

The multiple endocrine neoplasia type 1 (MEN1) locus has been previously localised to 11q13 by combined tumour deletion mapping and linkage studies and a 3.8-cM region flanked by PYGM and D11S97 has been defined. The zinc finger in the MEN1 locus (ZFM1) gene, which has also been mapped to this region, represents a candidate gene for MEN1. The ZFM1 gene, which consists of 14 exons, encodes a 623-amino acid protein and exons 2, 8 and 12 encode the putative nuclear localisation signal, a zinc finger motif, and a proline-rich region, respectively. We have investigated these potentially functional regions for germ-line mutations by single-stranded conformational polymorphism (SSCP) analysis in 64 unrelated MEN1 patients. In addition, we performed DNA sequence analysis of all the 14 exons and 13 of the 26 exon-intron boundaries in four unrelated MEN1 patients. A 6-bp deletion that resulted in the loss of two proline residues at codons 479 and 480 in exon 12 was found in one MEN1 patient. However, this did not co-segregate with MEN1 in the family and represented a rare polymorphism. Analysis by SSCP, DNA sequencing, northern blotting, Southern blotting and pulsed field gel electrophoresis revealed no additional genetic abnormalities of ZFM1 in the other MEN1 patients. Thus, our results indicate that ZFM1 is excluded as a candidate gene for MEN1.

Surgical intervention is advised in patients with multiple endocrine neoplasia type-1 (MEN-1) and nonfunctioning pancreatic neuroendocrine tumors (PanNETs) with a size ≥20 mm. Functioning PanNETs, such as in patients with endogenous hyperinsulinemic hypoglycemia (EHH) due to (one or multiple) insulinomas, should be treated surgically independent of size. Preoperative localization of insulinomas is critical for surgery. To evaluate the feasibility and sensitivity of 68Ga-DOTA-exendin-4 positron emission tomography (PET)/CT in the detection of clinically relevant lesions in patients with MEN-1 and EHH in combination with MRI. Post hoc subgroup analysis of a larger prospective imaging study with 52 patients with EHH. Six of 52 consecutive patients with EHH and genetically proven MEN-1 mutation were included. All patients received one 68Ga-DOTA-exendin-4 PET/CT and one MRI scan within 3 to 4 days. Thereafter, surgery was performed based on all imaging results. Lesion-based sensitivity of PET/CT and MRI for detection of clinically relevant lesions was calculated. Readers were unaware of other results. The reference standard was surgery with histology and treatment outcome. True positive (i.e., clinically relevant lesions) was defined as PanNETs ≥20 mm or insulinoma. In six patients, 37 PanNETs were confirmed by histopathology. Sensitivity (95% CI) in the detection of clinically relevant lesions for combined PET/CT plus MRI, MRI, and PET/CT was 92.3% (64% to 99.8%), 38.5% (13.9% to 68.4%), and 84.6% (54.6% to 98.1%), respectively (P = 0.014 for the comparison of PET/CT plus MRI vs MRI). Postsurgery, EHH resolved in all patients. 68Ga-DOTA-exendin-4 PET/CT is feasible in patients with MEN-1 and EHH. The combination with MRI is superior to MRI alone in the detection of insulinomas and may guide the surgical strategy.

Combined characterization of a pituitary adenoma and a subcutaneous lipoma in a MEN1 patient with a whole gene deletion

Introduction: Multiple endocrine neoplasia type 1 (MEN-1) is the most common inherited syndrome associated with NET development and gender-specific differences are emerging in neuroendocrine tumors (NETs). This study aimed to analyze gender difference in a single cohort of MEN-1 patients focusing on duodeno-pancreatic (DP)-NET and survival rates. Methods: MEN-1 patients referred to the Endocrinology Unit of the “Federico II” University of Naples, ENETS CoE, were retrospectively evaluated. Results: Among 100 MEN-1 patients enrolled, 59 (59%) were female and 41 (41%) male, and mean age at diagnosis was 39.4 years (range 5–86). No statistically significant association was identified between MEN-1 clinical manifestations and gender (primary hyperparathyroidism [PHPT] p: 1.0, DP-NET p: 0.83, pituitary adenoma [PA] p: 0.84, lung NET p: 0.64, and thymic NET p: 0.10), and similarly, age at diagnosis of MEN-1 and its individual manifestations was similar between genders. Survival analysis revealed no statistically significant difference between genders in DP-NET patients regarding progression disease p: 1.0 and death p: 1.0. Mean progression-free survival (PFS) of patients with DP-NET was 98.6 months (range 3–288), and mean overall survival (OS) was 130.1 months (range 3–444 months), without differences between genders (PFS p: 0.67 and OS p: 0.60). The Kaplan-Meier survival curves for PFS and OS showed no differences between genders (PFS p: 0.92; OS p: 0.87). Conclusion: In this MEN-1 cohort, no gender differences in the occurrence of PHPT, PA, DP-NET, lung NET, and thymic NET, nor in survival outcomes including PFS and OS within the DP-NET subcohort, emerged. Therefore, this study supports similar screening and follow-up for both male and female MEN-1 patients.

In patients with multiple endocrine neoplasia type 1 (MEN1), Cushing's syndrome (CS) from endogenous hypercortisolism can result from pituitary, adrenal or other endocrine tumours. The purpose of this study was to characterize the range of presentations of CS in a large series of MEN1 patients. Retrospective review of NIH Clinical Center inpatient records over an approximately 40-year period. Nineteen patients (eight males, 11 females) with CS and MEN1. Biochemical, imaging, surgical and pathological findings. An aetiology was determined for 14 of the 19 patients with CS and MEN1: 11 (79%) had Cushing's disease (CD) and three (21%) had ACTH-independent CS owing to adrenal tumours, frequencies indistinguishable from sporadic CS. Three of 11 MEN1 patients with CD (27%) had additional non-ACTH-secreting pituitary microadenomas identified at surgery, an incidence 10-fold higher than in sporadic CD. Ninety-one per cent of MEN1 patients with CD were cured after surgery. Two of three MEN1 patients with ACTH-independent CS (67%) had adrenocortical carcinoma. One patient with adrenal cancer and another with adrenal adenoma were cured by unilateral adrenalectomy. No case of ectopic ACTH secretion was identified in our patient cohort. The aetiology of CS could not be defined in five patients; in three of these, hypercortisolism appeared to resolve spontaneously. The tumour multiplicity of MEN1 can be reflected in the anterior pituitary, MEN1-associated ACTH-independent CS may be associated with aggressive adrenocortical disease and an aetiology for CS in MEN1 may be elusive in a substantial minority of patients.