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Background: Multiple endocrine neoplasia type 1 (MEN1)-associated duodenopancreatic neuroendocrine neoplasms (dpNEN) represent the most frequent syndrome-associated cause of death, but the adequate treatment is sometimes considered controversial. Objective: Presentation of possible diagnostic and therapeutic options for MEN1-associated dpNENs. Material and methods: In this review article retrospective case studies, expert recommendations, national and international guidelines as well as personal experiences were analyzed and evaluated. Results: Due to early detection programs and the use of the most modern imaging techniques, dpNEN are nowadays diagnosed much earlier. Nonfunctional pNENs currently represent the most frequent dpNENs with about 70%, followed by gastrinomas and insulinomas. Regardless of their functional activity, dpNENs with a size of > 2 cm are generally an indication for surgery. The choice of the optimal treatment strategy, however, in most cases remains the subject of controversial discussions, although nowadays surgery should always be performed in an organ-preserving and minimally invasive way when feasible. Recurrences or new dpNENs are expected in more than 60% of cases, necessitating a reoperation in up to 40% of these cases. Duodenopancreatic resections and reoperations can be carried out safely by experienced practitioners and with an acceptable level of risk. Conclusion: The planning of treatment requires careful consideration of the suitable timing, the extent of the operation, the risk of recurrence and potential morbidities. Furthermore, preserving pancreatic function and the quality of life is of utmost importance. In view of the complexity of the disease, MEN1 patients should be treated in specialized centers. [ABSTRACT FROM AUTHOR]

Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary condition manifesting as an autosomal dominant genetic pattern. This genetic anomaly is marked by the formation of tumors in diverse endocrine glands, leading to a complex array of clinical manifestations. The correlation between colorectal cancer (CRC) and MEN1 mutations remains unknown. This study aimed to report an Iranian female CRC patient with a MEN1 genetic mutation. Material and method: A 37-year-old female presented to a physician complaining of rectal lesions, tubular adenoma, and rectal adenocarcinoma, suggesting moderately differentiated colorectal adenocarcinoma symptoms. HLA typing was tested for her. Finally, whole exome sequencing (WES) was performed using the patient's DNA. Based on a standard pipeline, the variant was identified and interpreted. Results: The findings demonstrated a known heterozygous missense mutation in the exon 2 of the MEN1 gene, g.64577373T-G, c.209A>C, p.Asp70Ala in the patients which has a variant uncertain significant (VUS) pathogenicity. She also had no celiac disease (HLA-DQ2/DQ8 genotypes are negative). Conclusion: The correlation between the identified genotype and the anatomical phenotype of the patient suggested that the identified variant can lead to colorectal abnormalities in the patient, contributing to the distinctive features of MEN1 disease. Understanding the underlying genetic mechanisms is important for diagnosing and treating this condition. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the predictive role of specific clinical factors for the diagnosis of Multiple Endocrine Neoplasia type-1 (MEN1) and type-4 (MEN4) in patients with an initial diagnosis of gastrointestinal, bronchial, or thymic neuroendocrine tumor (NET). Methods: Patients referred to the NET Unit between June 2021 and December 2022 with a diagnosis of NET and at least one clinical criterion of suspicion for MEN1 and MEN4 underwent molecular analysis of the MEN1 and CDKN1B genes. Phenotypic criteria were: (1) age ≤ 40 years; (2) NET multifocality; (3) MEN1/4-associated manifestations other than NETs; and (4) endocrine syndrome related to NETs or pituitary/adrenal tumors. Results: A total of 22 patients were studied. In 18 patients (81.8%), the first-level genetic test was negative (Group A), while four patients (25%) were positive for MEN1 (Group B). No patient was positive for MEN4. In Group A, 10 cases had only one clinical criterion, and three patients met three criteria. In Group B, three patients had three criteria, and one met all criteria. Conclusion: These preliminary data show that a diagnosis of NET in patients with a negative family history is suggestive of MEN1 in the presence of ≥three positive phenotypic criteria, including early age, multifocality, multiple MEN-associated manifestations, and endocrine syndromes. This indication may allow optimization of the diagnosis of MEN in patients with NET. [ABSTRACT FROM AUTHOR]

Guidelines for multiple endocrine neoplasia type 1 (MEN1) recommend intensive imaging surveillance without specifying a superior regimen, including the role of somatostatin receptor imaging (SRI) with positron emission tomography (PET). The primary outcomes were to: (1) Assess change in treatment of duodenal‐pancreatic neuroendocrine neoplasms (DP‐NENs), bronchopulmonary NENs, and thymic tumors attributed to use of SRI PET/computed tomography (CT) and (2) estimate radiation from imaging and risk of cancer death attributed to imaging radiation. This was a retrospective single center study, including all MEN1 patients, who had had at least one SRI PET/CT. A total of 60 patients, median age 42 (range 21–54) years, median follow‐up 6 (range 1–10) years were included. Of 470 cross sectional scans (MRI, CT, SRI PET/CT), 209 were SRI PET/CT. The additional information from SRI PET had implications in 1/14 surgical interventions and 2/12 medical interventions. The estimated median radiation dose per patient was 104 (range 51–468) mSv of which PET contributed with 13 (range 5–55) mSv and CT with 91 mSv (range 46–413 mSv), corresponding to an estimated increased median risk of cancer death of 0.5% during 6 years follow‐up. SRI PET had a significant impact on 3/26 decisions to intervene in 60 MEN1 patients followed for a median of 6 years with SRI PET/CT as the most frequently used modality. The surveillance program showed a high radiation dose. Multi‐modality imaging strategies designed to minimize radiation exposure should be considered. Based on our findings, SRI‐PET combined with CT cannot be recommended for routine surveillance in MEN1 patients. [ABSTRACT FROM AUTHOR]

Background: Malignant thymic carcinoids are uncommon tumours among patients with multiple endocrine neoplasia type 1 (MEN-1). Current guidelines advise performance of a preventative, routine transcervical thymectomy (TCT) during parathyroidectomy, although data on the yield is scarce. In this review, we aimed to revisit available literature to investigate and summarize the efficacy of routine TCT for the prevention of thymic carcinoid tumours among MEN-1 patients after searching four databases (PubMed, Embase, Medline, and Cochrane Library). Summary: Seven eligible studies were identified: retrospective observational studies: 3 and case reports describing one or more patients: 4. A total of 122 patients were included, 56 males (45.9%) and a pooled mean age of 40 years (±10). All underwent a routine TCT as part of parathyroidectomy; no details on the extent of TCT were available. Overall, only one (0.9%) incidental carcinoid was found. However, although all other patients underwent prophylactic TCT at the time of parathyroidectomy, an additional nine (7.4%) developed a thymic carcinoid during follow-up, after a median time of 36 months (range: 8–226). Key Messages: There is currently not enough evidence to support the efficacy of a routine TCT to prevent the development of thymic carcinoid among MEN-1 patients. As this is a rare but potentially highly aggressive tumour, attention should be shifted towards improving follow-up programs and developing specific imaging-screening protocols. This enables early detection of thymic carcinoids in a timely manner and improves outcomes, even after performance of a routine TCT. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by the occurrence of two or more endocrine gland tumors. Here, we show a case of a 52-year-old man diagnosed with MEN1 through gastrinoma, parathyroid adenoma and gene detection. The MEN1 patient's case was complicated with relapsed primary hyperparathyroidism (PHPT), and they received ultrasound-guided radiofrequency ablation (RFA). The patient had a remarkable recovery after RFA treatment for the relapsed PHPT. It might be an alternative treatment for MEN1 patients with poor conditions such as high surgical risk, unwillingness to choose parathyroid surgery or those unable to tolerate surgery. Individualized therapy significantly benefits the prognosis of MEN1 patients. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene encoding menin, is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (NETs). Development of these tumours is associated with wide variations in their severity, order and ages (from <5 to >80 years), requiring life-long scre ening. To improve tumour surveillance and quality of life, better circulating biomarkers, particularly for pancreatic NETs that are associated with higher mortality, are required. We, therefore, examined the expression of circulating miRNA in the serum of MEN1 patien ts. Initial profiling analysis followed by qRT-PCR validation studies identified miR-3156-5p to be significantly downregulated (-1.3 to 5.8-fold, P < 0.05-0.0005) in nine MEN1 patients, compared to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human pancreatic NET cells resulted in reduced MEN1 (49%, P < 0.05), menin (54%, P < 0.05) and miR-3156-5p expression (20%, P < 0.005), compared to control-treated cells, suggesting that miR-3156-5p downregulation is a consequence of loss of MEN1 expression. In silico analysis identified mortality factor 4-like 2 (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, P < 0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 expression (1.5-fold, P < 0.05), compared to control-treated cells, thereby confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse relationship between miR-3156-5p and MORF4L2 expression represents a potential serum biomarker that could facilitate the detection of NET occurrence in MEN1 patients. [ABSTRACT FROM AUTHOR]

This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis: Mutation‐negative patients with 2/3 main manifestations have a different clinical course compared to mutation‐positive patients. As for primary hyperparathyroidism: subtotal parathyroidectomy is the initial procedure of choice. Current debate centres around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumours (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1‐related tumours. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and nonfunctioning microadenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the paediatric age and initiating screening in the second decade is advisable. MEN1 has a significant impact on quality of life and US data show a significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumour behaviour and effects of more individualized interventions. [ABSTRACT FROM AUTHOR]

Parathyroid cancer is a rare malignancy originating from the parathyroid glands, which regulate calcium levels in the body. This review article aims to provide a comprehensive overview of parathyroid cancer, including its epidemiology, etiology, clinical presentation, diagnostic methods, treatment options, and prognosis. The article also highlights recent advancements in research and potential future directions for improving the management of this challenging disease. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical characteristics of patients with multiple endocrine neoplasia type 1 (MEN1)-related insulinoma and their relationship with specific biochemical changes and to summarize the features of treatment options for the Chinese population with this disease and the impact on long-term prognosis.Methods: "MEN1" and "insulinoma" were used when searching the Peking Union Medical College Hospital (PUMCH) medical record retrieval system to obtain clinical information about patients. We identified patients diagnosed with MEN1-associated insulinoma based on endocrinological, radiological, and pathological examinations, and subsequently analyzed their clinical data.Results: A total of 55 patients with MEN1-associated insulinoma were included, including 29 (52.7%) men and 26 (47.3%) women. The parathyroid gland was the most commonly affected (78.2%), followed by the pituitary gland (69.1%) and adrenal gland (16.4%). Insulinoma was the first manifestation of MEN1 in at least 23.6% (13/55) of patients. Nineteen (34.5%) patients presented with initial symptoms of hypoglycemia before the age of 22 years. Among the 24 Patients with high serum calcium (Ca) had significantly lower serum insulin levels than those with normal serum Ca levels (p < 0.001) during hypoglycemic episodes. However, serum C-peptide level at 0.5 h and serum insulin level at 1 h was higher in patients with hypercalcemia than in patients with normal serum Ca levels in the oral glucose tolerance test (OGTT), although the differences were not statistically significant. Multifocal pancreatic neuroendocrine tumors (pNETs) were present in 38 (69.1%) patients; most of them (55.6%, 20/36) underwent multiple enucleations, and 45% (9/20) had a postoperative recurrence. Five patients (10%) who underwent distal pancreatectomy developed pancreatic insufficiency after an average of seven years. patients who underwent genetic testing, 23 (95.8%) were positive for MEN1 mutation, with mutations most commonly found in exons 2 (21.7%) and 3 (13%).Conclusions: In our study, the rates of postoperative recurrence and long-term complications in patients with MEN1 with multifocal pNETs were significantly different from those in other international centers and might be related to the choice of surgical method. In addition, elevated serum Ca levels in patients with primary hyperparathyroidism may affect insulin secretion. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant tumor syndrome with a high degree of heterogeneity in clinical phenotypes, generally involving the parathyroid, anterior pituitary, and enteropancreas. In recent years, several new insights into the clinical features of MEN1 have been reported in the literature. However, it is not clear whether MEN1-associated primary tumors can occur in the liver. Case presentation: We report the case of a 52-year-old man with multiple endocrine neoplasia type 1 diagnosed by genetic sequencing. After uniportal thoracoscopic right middle lobectomy, laparoscopic radical resection of the liver tumors, and radiofrequency ablation of the parathyroid space, the parathyroid hormone level decreased from 177 pg/ml to a normal level (20 pg/ml). No local tumor recurrence was observed during a follow-up of 5 months. Conclusion: We report the first case of MEN1 with simultaneous liver and lung involvement in which the patient underwent radical resection of the tumors, and we propose the possibility that the liver and other nonendocrine organs may also develop diseases associated with MEN1; although, this view needs further verification. Gene detection has crucial clinical significance for guiding diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN 1) syndrome is a rare, complex genetic disorder characterized by increased predisposition to tumorigenesis in multiple endocrine and non-endocrine tissues. Diagnosis and management of MEN 1 syndrome is challenging due to its vast heterogeneity in clinical presentation. Case presentation: A 23-year-old female, previously diagnosed with Polycystic Ovarian Syndrome (PCOS) and pituitary microprolactinoma presented with drowsiness,confusion and profuse sweating developing over a period of one day. It was preceded by fluctuating, hallucinatory behavior for two weeks duration. There was recent increase in appetite with significant weight gain. There was no fever, seizures or symptoms suggestive of meningism. Her Body mass index(BMI) was 32 kg/m2.She had signs of hyperandrogenism. Multiple cutaneous collagenomas were noted on anterior chest and abdominal wall. Her Glasgow Coma Scale was 9/15. Pupils were sluggishly reactive to light. Tendon reflexes were exaggerated with up going planter reflexes. Moderate hepatomegaly was present. Rest of the clinical examination was normal. Laboratory evaluation confirmed endogenous hyperinsulinaemic hypoglycaemia suggestive of an insulinoma. Hypercalcemia with elevated parathyroid hormone level suggested a parathyroid adenoma. Presence of insulinoma, primary hyperparathyroidism and pituitary microadenoma, in 3rd decade of life with characteristic cutaneous tumours was suggestive of a clinical diagnosis of MEN 1 syndrome. Recurrent, severe hypoglycaemia complicated with hypoglycaemic encephalopathy refractory to continuous, parenteral glucose supplementation and optimal pharmacotherapy complicated the clinical course. Insulinoma was localized with selective arterial calcium stimulation test. Distal pancreatectomy and four gland parathyroidectomy was performed leading to resolution of symptoms. Conclusions: Renal calculi or characteristic cutaneous lesions might be the only forewarning clinical manifestations of an undiagnosed MEN 1 syndrome impending a life-threatening presentation. Comprehensive management of MEN 1 syndrome requires multi-disciplinary approach with advanced imaging modalities, advanced surgical procedures and long-term follow up due to its heterogeneous presentation and the varying severity depending on the disease phenotype. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome caused by germline variants in the MEN1 gene located on chromosome 11q13. We found a Chinese woman who had a pancreatic tumor, parathyroid tumor, adrenal tumor, and suspicion of gastrinoma. Case presentation: The proband and her immediate family members underwent genetic detection. The results showed that two of the proband's six relatives had the same variants as the proband, and her sister also had the typical symptoms of MEN1. However, the first- and second-time genetic detection results showed that they were homozygous variants, which did not conform to Mendelian inheritance laws. Multiplex ligation-dependent probe amplification (MLPA) was used to rule out homozygous variants caused by a deletion of gene fragments in the proband and her immediate family members. The MLPA results showed that the gene deletion was absent in the MEN1. The results from the third genetic detection (redesigned the primer) showed that they had a heterozygous variant. A new MEN1 germline variant [c.201delC (p.Ala68Profs*51)], which could induce MEN1, was found in this study. Conclusions: This newly identified germline variant could improve the identification of clinical phenotypes and the early diagnosis of MEN1. Clinician should consider the present of situation that intron variant causing detection error. Re-designing the primers close to the variant site for gene detection could avoid this situation. [ABSTRACT FROM AUTHOR]

Insulinomas are uncommon neuroendocrine tumors and metastatic disease is extremely rare. We report a patient with metastatic insulinoma associated with multiple endocrine neoplasia type 1 presenting with hypoglycemia following sleeve gastrectomy. Potential causes of hypoglycemia include dumping syndrome, noninsulinoma pancreatogenous hypoglycemia syndrome, and rarely insulinoma. MEN1‐associated insulinomas have a higher recurrence rate. [ABSTRACT FROM AUTHOR]

Purpose: Neuroendocrine neoplasia (NEN) of the thymus is a very rare entity with a poor prognosis. None of the treatments was proofed by studies. Usually, therapy protocols for bronchopulmonary carcinoids are used. So far no data exist on the effect of mammalian target of rapamycin (mTOR) inhibitors. We describe our long‐term experience with everolimus and give a thorough review of the therapeutic strategies used so far. Patients and Methods: Four patients (mean age 46 years, range 37–55) with progressing thymic NEN (t‐NEN) (two well‐differentiated atypical carcinoids and two atypical carcinoids with large cell characteristics) were treated with everolimus 10 mg/day after the failure of at least one previous medical therapy. Everolimus was applied after a mean interval of 32.4 months (range 5–56) after the first diagnosis. The follow‐up included clinical examination, imaging and chromogranin A testing in 3 or 6 monthly intervals. Results: We observed stable disease for a mean of 20.8 months. Both patients with large cell characteristics t‐NEN (Ki‐67 of 20%) had rapid progress after 7 and 10 months and had more previous therapies (three and six) than the patients with well‐differentiated t‐NEN (Ki‐67 5% and 10%, progress after 24 and 42 months, one and two previous therapies). No severe side effects occurred. In three of four patients, everolimus led to stable disease for the longest compared to the other nonsurgical therapies used. Conclusion: Comparing the sparse data available everolimus is a promising treatment for t‐NEN at least in second‐line therapy. A low Ki‐67 index was associated with a better outcome. [ABSTRACT FROM AUTHOR]

Introduction: Multiple endocrine neoplasia type 1 (MEN 1) is an infrequent autosomal dominant hereditary syndrome. Common manifestations are related to hypercalcemia, which is caused by primary hyperparathyroidism (PHPT). Brown tumors are infrequent as initial presentation of PHPT associated with MEN 1. It occurs in less than 2% of MEN 1 population. Results: A 36-year-old woman started the disease 25 years ago in an insidious and progressive manner. She presented a soft tumor in the left malar region that progressively increased in volume. We treated recurrent multiple brown tumors in a patient with PHPT and pituitary adenoma. Conclusion: The follow-up was demanding and multidisciplinar^. The long-term prognosis is uncertain; therefore, close monitoring of the patient should be carried out through clinical, laboratory and imaging evaluation. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BS) is a genetic channelopathy syndrome that causes fatal cardiac dysrhythmias and sudden death. Fever and antiarrhythmics are aggravating factors of BS. There are many reports about BS preceded by fever but fewer reports on BS caused by hypercalcemia (HC). Here, we describe a unique case of BS preceded by concurrent fever and HC. A 46-year-old male visited the emergency department for malaise and fever. During admission, he suddenly developed cardiac arrest and ventricular fibrillation (VF). After resuscitation, electrocardiogram (ECG) showed "coved-type" ST elevation in V1 and V2, which led to the diagnosis of BS. This ST change declined after the fever subsided. He also had HC at the same time. After admission, he developed septic shock. We started treatment assuming that it was caused by the aggravation of ulcerative colitis, and liver abscess was revealed on contrast-enhanced computed tomography. After the infection was controlled, we implanted an implantable cardioverter defibrillator (ICD) and he was discharged. The cause of HC appeared to be an ectopic parathyroid adenoma, and calcium was normalized after tumor resection. In addition, this patient had nonfunctional pituitary adenoma and a nonfunctional adrenal tumor. His condition was indicative of multiple endocrine neoplasia type 1. This patient had BS presenting as VF induced by fever due to liver abscess and early repolarization, increasing the risk of arrhythmic events to carry out ICD implantation. HC can contribute to induce arrhythmia. [ABSTRACT FROM AUTHOR]

Background: Gastric enterochromaffin‐like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. Methods: Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014–2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin‐ and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. Results: Thirty‐eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5 mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n = 22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206 pg/ml vs. 30.5 pg/ml, p <.001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p =.302, chromogranin A: p =.464). Conclusion: Enterochromaffin‐like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported. [ABSTRACT FROM AUTHOR]

Background: Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor size is still regarded as the main prognostic factor and therefore used for surgical decision-making. We assessed reliability and agreement of radiological and pathological tumor size in a population-based cohort of patients with MEN1-related pNETs. Methods: Patients were selected from the Dutch MEN1 database if they had undergone a resection for a pNET between 2003 and 2018. Radiological (MRI, CT, and endoscopic ultrasonography [EUS]) and pathological tumor size were collected from patient records. Measures of agreement (Bland-Altman plots with limits of agreement [LoA] and absolute agreement) and reliability (intraclass correlation coefficients [ICC] and unweighted kappa) were calculated for continuous and categorized (< or ≥2 cm) pNET size. Results: In 73 included patients, the median radiological and pathological tumor sizes measured were 22 (3–160) and 21 (4–200) mm, respectively. Mean bias between radiological and pathological tumor size was −0.2 mm and LoA ranged from −12.9 to 12.6 mm. For the subgroups of MRI, CT, and EUS, LoA of radiological and pathological tumor size ranged from −9.6 to 10.9, −15.9 to 15.8, and −13.9 to 11.0, respectively. ICCs for the overall cohort, MRI, CT, and EUS were 0.80, 0.86, 0.75, and 0.76, respectively. Based on the 2 cm criterion, agreement was 81.5%; hence, 12 patients (18.5%) were classified differently between imaging and pathology. Absolute agreement and kappa values of MRI, CT, and EUS were 88.6, 85.7, and 75.0%, and 0.77, 0.71, and 0.50, respectively. Conclusion: Within a population-based cohort, MEN1-related pNET size was not systematically over- or underestimated on preoperative imaging. Based on agreement and reliability measures, MRI is the preferred imaging modality. [ABSTRACT FROM AUTHOR]

The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies. [ABSTRACT FROM AUTHOR]

Background: MRI is a useful imaging modality to assess the presence of pancreatic neuroendocrine tumors (PNETs), allowing repeat monitoring examinations in multiple endocrine neoplasia type 1 (MEN-1) patients. Objectives: We aimed to compare the diagnostic accuracy of conventional MRI sequences to identify which sequence better depicts the presence of PNETs in MEN-1 patients. Method: We performed a retrospective analysis of consecutive MEN-1 patients who underwent a conventional MRI protocol to monitor previously proven PNETs. MRI sequences T1-w chemical shift (CS), T2-w HASTE, fat-suppressed (FS) T2-w HASTE, diffusion-weighted imaging (DWI), and pre- and post-contrast FS T1-w sequences were independently analyzed by 2 experienced radiologists using a 3-grade score (no lesion, uncertain lesion, and certain lesion); lesion size and signal intensity were recorded. A Friedman ANOVA and a Wilcoxon pairwise test for the post hoc analysis were used. The sensitivity of each sequence was measured, and the results were analyzed with the χ2 test. Results: We included 21 patients with a total of 45 PNETs proven by histology, endoscopic ultrasonography-guided fine-needle aspiration, CT, and nuclear medicine studies. A statistically significant (p < 0.01) difference was observed in the detection performance of each MRI sequence, particularly between DWI (91%) and T2-w FS (85%) sequences in comparison to the others (T1-w CS, T2-w, and pre- and post-contrast FS T1-w, ≤56% for all); no significant (p = 0.5) difference was found between the detection performance of DWI and T2-w FS sequences. No correlation was observed between the qualitative score of each sequence and lesion tumor size. Conclusions: DWI and T2-w FS sequences proved to be the most accurate in the detection of PNETs, thus suggesting a role for an abbreviated MRI protocol without contrast medium administration for monitoring MEN-1 patients. [ABSTRACT FROM AUTHOR]

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine tumor syndrome characterized by the triad of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (pNETs), and pituitary tumors. Patients are confronted with substantial morbidity and are consequently at risk for an impaired quality of life (QOL). Meticulous assessment of QOL and associated factors in a representative population is needed to understand the full spectrum of the burden of the disease. Patients and Methods: A cross-sectional study was performed using the national Dutch MEN1 cohort. Patients with a confirmed MEN1 mutation received the SF-36 Health Related Quality of Life questionnaire and questions regarding sociodemographic and medical history. Results: A total of 227 of 285 (80%) eligible MEN1 patients returned the questionnaires. Health-related QOL scores (HRQOL) in MEN1 patients were significantly lower for the majority of subscales of the SF-36 in comparison with the general Dutch population. The most consistent predictor for HRQOL was employment status, followed by the presence of a pituitary tumor. 16% of patients harboring a pNET and 29% of patients with a pituitary tumor according to the medical records, reported that they were unaware of such a tumor. These subgroups of patients had several significant better QOL scores than patients who were aware of their pNET or pituitary tumors. Conclusion: Patients with MEN1 have an impaired QOL in comparison with the general Dutch population warranting special attention within routine care. For daily practice, physicians should be aware of their patients' impaired QOL and of the impact of unemployment on QOL. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 is a rare autosomal inherited syndrome that affects a variety of endocrine tissues such as the parathyroid, endocrine pancreas, and anterior pituitary. Osseous complications are often misdiagnosed. We presented a case of a 46-year-old woman with pathological fractures of the lower limb. She had a history of type 1 diabetes and galactorrhea. Laboratory examinations showed hypercalcemia and an increased level of parathyroid hormone related to hyperparathyroidism. Serum chromogranin A level was increased at 9369 ng/mL (N < 102). A somatostatin receptor scintigraphy (octreoscan) revealed pathological uptake in the gastric wall, later cave adenopathy, and liver. The diagnosis of multiple endocrine neoplasia type 1 was made based on radiological and histological findings. The patient underwent a subtotal parathyroidectomy associated with somatostatin analog treatment leading to significant improvement. A literature review was conducted by searching PubMed using these following terms: multiple endocrine neoplasia type 1, hyperparathyroidism, fracture, menin, osteoporosis. We emphasized bone involvement related to multiple endocrine neoplasia type 1 syndrome. This diagnosis should be considered when pathological fractures occur in young patients with a history of endocrine disorder. We highlighted the importance of imaging features in making the diagnosis of multiple endocrine neoplasia type 1. Early management of this disease is necessary. Treatment including parathyroidectomy and somatostatin analogs leads to bone preservation and functional improvement. [ABSTRACT FROM AUTHOR]

Background: MEN1 is a complex, rare, syndrome inherited in an autosomal dominant tract and characterized by the development of multiple neuroendocrine tumors, requiring lifelong surveillance and multiple medical and surgical therapies throughout the patient's life. For all these reasons, a diagnosis of MEN1 can be a psychological shock for the patient, as well as his/her relatives, more so than the diagnosis of a single tumor. In the last two decades, clinicians have started to consider the emotional, psychological, relational, and social aspects of their patients' lives. The data collected in the present analyses highlight the unique features of MEN1 syndrome, and aim to evaluate the Quality of Life in the patients and their relatives. In this study, a comprehensive survey of various aspects of Health-Related Quality of Life was performed in a large series of Italian MEN1 patients, by administering five of the most common targeted questionnaires.Results: The results of the study showed that our patients, despite having a complex multi-tumor syndrome, were moderately optimistic (50%), and this corresponds with a normal Quality of Life. This positive response is strictly correlated with the fact that the patients are cared for at a dedicated Referral Center, receiving personalized care and constant follow-up, which gives them reassurance regarding the high quality of management of the disorder.Conclusions: The possibility of having access to a clinical Referral Center for their complex rare disease, together with the support of a dedicated patient association, has been demonstrated to be the ideal model for the management of post-diagnosis shock, and contributes to the preservation of a good Health-Related Quality of Life for MEN1 patients. [ABSTRACT FROM AUTHOR]

Aims: Proton pump inhibitors (PPIs) are among the most widely used medications in the United States. Most PPI users have persistent hypergastrinaemia during treatment. However, gastric neuroendocrine tumours diagnosed in long‐term PPI users are rarely reported. Their clinicopathological features and prognosis are not characterised. It remains unclear whether or not they can be classified as Type III sporadic tumours. Methods and results: We retrospectively characterised 66 gastric neuroendocrine tumours from patients without atrophic gastritis and gastrinoma from two tertiary care medical centres, including 38 tumours in patients who had used PPIs for at least 1 year and 28 tumours from patients without long‐term PPI use (control group, Type III tumours). Compared to controls, tumours from long‐term PPI users tended to be in the pT1–2 category (98% versus 79%, P = 0.09) and less often invaded the serosa (3% versus 18%, P = 0.08) or lymphovascular spaces (11% versus 32%, P = 0.06). Using Kaplan–Meier analysis, long‐term PPI users had significantly longer overall survival than controls (P = 0.035). While three control patients developed distant metastasis and seven died, long‐term PPI users were without distant metastasis (P = 0.06) or death (P = 0.002) during follow‐up. However, five long‐term PPI users developed additional gastric neuroendocrine tumour(s), while none of the controls did (P = 0.07). Conclusions: Our results show that gastric neuroendocrine tumours of long‐term PPI users are probably less aggressive compared to Type III sporadic tumours and have an indolent disease course. Our findings support the classification of gastric neuroendocrine tumours in long‐term PPI users as a separate subtype. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disorder that is inherited in an autosomal dominant manner. The characteristics of the disease are the combined occurrence of tumors in glands of the endocrine system, such as the parathyroid glands, pituitary gland and endocrine pancreas. Germline mutations in the MEN1 gene are associated with the occurrence of MEN1 and genetic testing for this gene is generally used as a basis for diagnosis. In this paper, a case of MEN1 in a middle‑aged Japanese woman is reported. Direct sequencing analysis of the patient's DNA was performed and it revealed a MEN1 gene heterozygous germline (NM_130799.2:c.930delG) mutation in exon 5. This deletion/frameshift mutation produced a stop codon in the downstream sequence (NP_570711.1:p.Glu273LysfsTer7). To the best of our knowledge, this is the first report describing the NM_130799.2:c.930delG mutation as the basis for MEN1. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited endocrine tumor syndrome caused by inactivating variants of the MEN1 gene. The aim of this study is to explore the clinical and genetic characteristics of four MEN1 patients. We isolated genomic deoxyribonucleic acid from lymphocytes, parathyroid, and thymic tumoral tissue specimens from the MEN1 patients. All exons of the MEN1 and CDNK1B genes and adjacent exon-intron sequences were amplified by polymerase chain reaction and subsequently sequenced. Further, the splice alterations were studied by sequencing the amplified RT-PCR products for MEN1 cDNA. We identified four heterozygous MEN1 germline variants: c.564delC, c.1268G>A, IVS5+5delG, and c.1546_1547insC. Both c.564delC and IVS5+5delG were novel variants. The impact of the MEN1 splice variant, IVS5+5delG, was evaluated using bioinformatics and in vitro analyses. The analyses indicated that this variant resulted in skipping of the neighboring exon and was disease-causing. Two novel somatic variants, c.249_252delGTCT and c.313_314insC, were found. Additionally, loss of heterozygosity (LOH) for the MEN1 locus (IVS5+5delG and c.564delC) was found in tumor tissue samples from the MEN1 patients, consistent with Knudson's two-hit mechanism. We identified four MEN1 germline variants and two novel somatic variants. Early recognition of the phenotype coupled with variant screening of the MEN1 gene is the key to diagnosing and treating MEN1 effectively at an early stage. [ABSTRACT FROM AUTHOR]

Context: Multiple endocrine neoplasia type 1 (MEN 1) is characterized by multisystem neoplasia including primary hyperparathyroidism and pituitary adenoma. Despite the adolescent onset of endocrinopathies, information regarding the impact of maternal MEN 1 on pregnancy is limited to case reports. Objective: To explore pregnancy outcomes in MEN 1 positive women. Methods: Retrospective case series of maternofoetal outcomes MEN 1 positive mothers managed at the Royal Hobart Hospital between 1967 and 2018. Data were retrieved from medical records and Australian averages calculated based on the Australian Institute of Health and Welfare data. Results: Twenty‐six women with MEN 1 were identified accounting for 96 pregnancies and 76 live born infants. Hyperparathyroidism was evident in 16 pregnancies. A significant increase in serum calcium in the second trimester (β = 0.14, P <.001) occurred that was not mediated by parathyroid hormone. Hypercalcaemia was mild‐moderate with parathyroidectomy or medical management required in one and four pregnancies, respectively. Compared to the Australian average, women with MEN 1 were more likely to develop gestational diabetes (56% vs 8.9%, P =.001), hypertensive disorders (25.9% vs 7.6, P =.018), have shorter gestations (38.1 vs 38.7 weeks, P =.015) and have low birthweight infants (30.1% vs 6.5%, P =.001). However, emergency caesarean deliveries (63.2% vs 52.3%) and miscarriage rate (20.8% vs 20%) were not significantly different. Conclusion: Maternal MEN 1 is associated with an increased risk of gestational diabetes, hypertensive disorders and low neonatal birthweight, but not with an increased miscarriage rate. Whilst hypercalcaemia worsens during the second trimester, most pregnancies progressed without overt complications or requirement for intervention. [ABSTRACT FROM AUTHOR]

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27-29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet c linical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms. [ABSTRACT FROM AUTHOR]

The multiple endocrine neoplasia (MEN) workshops had their beginnings at Queen's University in Kingston, Ontario in June 1984. This initial meeting brought clinicians and scientists together to focus on mapping the gene for multiple e ndocrine neoplasia type 2 (MEN2). These efforts culminated in the identification of the RET protooncogene as the causative gene a decade later. Over the next 35 years th ere were a total of 16 international workshops focused on the several MEN syndromes. Importantly, these workshops were instrumental in efforts to define the molecular basis for multiple endocrine neoplasia type 1 (MEN1), MEN2, von Hippel-Lindau disease (VHL), Carney Complex, hereditary pheochromocytoma and hyperparathyroidism. In this same spirit some 150 scientists and clinicians met at MD Anderson Cancer Ce nter, 27-29 March 2019, for the 16th International Workshop on Multiple Endocrine Neoplasia (MEN2019). Appropriate to its location in a cancer centre, the workshop fo cused on important issues in the causation and treatment of malignant aspects of the MEN syndromes: medullary thyroid carcinoma, pancreatic neuroendocrine tumours, malignant pheochromocytoma and parathyroid carcinoma. Workshops at the meeting focused on a better understanding of how the identified molecular defects in these genetic syndromes lead to transformation, how to apply targeted kinase inhibitors and immunotherapy to treat these tumours and important clinical management issues. This issue of Endocrine-Related Cancer describes these discussions and recommendations. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 is a rare hereditary syndrome characterized by parathyroid, anterior pituitary and pancreatic tumors, that may also be associated with benign cutaneous neoplasms like angiofibromas and collagenomas, that can precede endocrine manifestations. We present the case of a 23-year-old female patient with primary hyperparathyroidism, Cushing disease and a pancreatic neuroendocrine tumor associated with multiple collagenomas that appeared before systemic symptoms. [ABSTRACT FROM AUTHOR]

Medullary thyroid cancer (MTC) is typically associated with multiple endocrine neoplasia type 2 syndrome (MEN 2), but not with multiple endocrine neoplasia type 1 (MEN 1). We report a very rare case of MTC in a patient with MEN 1 syndrome. A 60-year-old Caucasian woman with sporadic MEN 1 syndrome was admitted in October 2018 for recurrent hyperparathyroidism unresponsive to medical therapy. Her medical history included the diagnosis of a non-functioning pancreatic neuroendocrine tumor (NF-pNET) of the head of the pancreas 1.5 cm in size in 2001, and subtotal parathyroidectomy for uncontrolled hyperparathyroidism due to bilateral parathyroid hyperplasia in the same year. This history prompted genetic studies, and MEN 1 syndrome was confirmed. Family screening was performed in first-degree relatives, with negative results. Other typical clinical manifestations of MEN 1 syndrome were ruled out. In November 2018, the patient underwent excision of the residual left inferior parathyroid, extended to include the left thyroid lobe, for recurrent uncontrolled hyperparathyroidism. The pathologist identified MTC and adenoma of the parathyroid gland. Genetic tests were performed to identify any RET mutation, with negative results. The patient underwent total thyroidectomy about 6 months later, and the subsequent histological report showed only focal reactive C-cell hyperplasia of the thyroid. A literature review identified only three previously published cases of MTC coexisting with MEN 1 syndrome. This association may have two etiological hypotheses: either a sporadic MTC arising in a patient with MEN 1 syndrome, or a rare case of medullary cancer linked to a MEN 1 gene mutation. [ABSTRACT FROM AUTHOR]

Summary: This study evaluated bone features of PHPT using HR-pQCT. The results showed both cortical and trabecular bones were significantly impaired in PHPT patients. Male and female PHPT patients suffered similar damages in bone. HR-pQCT indices were not observed to differ in MEN1 and sporadic PHPT patients. Introduction: High-resolution peripheral quantitative CT is a novel imaging technique used to separately assess trabecular and cortical bone status of the radius and tibia in vivo. Using HR-pQCT, we aimed to evaluate bone features of primary hyperparathyroidism patients in a Chinese population and reveal similarities and differences in bone features in multiple endocrine neoplasia type 1–related PHPT and sporadic PHPT patients in the Chinese population. Methods: A case-control study was designed. In 58 PHPT patients and 58 sex- and age-matched healthy controls, the distal radius and tibia were scanned using HR-pQCT. Areal bone mineral density (aBMD) was also determined in PHPT patients using dual-energy X-ray absorptiometry (DXA). Results: In comparison with controls, PHPT patients were observed to exhibit reduced volumetric BMD at the cortical and trabecular compartments, thinner cortices, and more widely spaced trabeculae. Significant differences were still observed when comparing data of female and male patients with age-matched controls separately. MHPT patients (n = 11) were found to have lower aBMD Z-scores in the lumbar spine, trochanteric region, and total hip compared with sporadic PHPT patients (n = 47), while no differences were observed in HR-pQCT indices between the two groups. In multiple linear regression models, no significant correlations were identified between PTH and HR-pQCT indices. However, height was found to positively correlate with HR-pQCT-derived trabecular indices at both the radius and tibia. Conclusions: PHPT affects geometry, volumetric density, and microstructure in both the cortical and trabecular bones in both male and female Chinese patients. MHPT patients were observed to have reduced aBMD as determined by DXA in the lumbar spine and hip in comparison with sporadic PHPT patients. However, HR-pQCT indices were not observed to differ. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia Type 1 (MEN-1) is an inherited syndrome characterized by the development of endocrine tumors of the pancreas, parathyroid, and pituitary glands. Mesenchymal tumors and adrenal neoplasms might also accompany this syndrome. However, the syndrome is rarely associated with thyroid tumors in contrary to the multiple endocrine neoplasia Type 2 that includes medullary thyroid carcinoma. This case study presents a 44-year-old woman who was diagnosed with MEN-1 on the basis of her clinical characteristics, laboratory data, and the presence of endocrine tumors. Follicular thyroid carcinoma was detected in the patient when she was being operated for nodular goiter, 12 years ago. We report this rare case which is likely the third case in the available scientific literature. [ABSTRACT FROM AUTHOR]

Importance: Guidelines advocate subtotal parathyroidectomy (SPTX) or total parathyroidectomy with autotransplantation (TPTX) with bilateral cervical thymectomy for primary hyperparathyroidism (pHPT) associated with multiple endocrine neoplasia type 1 (MEN1). However, both procedures are associated with a significant risk of permanent hypoparathyroidism. Objective: The aim of the current study was to compare long‐term results of either single gland excision (SGE, 1‐2 glands), SPTX and TPTX for the treatment of MEN1‐associated pHPT. Design and setting: Data of genetically confirmed MEN1 patients who underwent surgery for pHPT between 1987 and 2017 were retrieved from a prospective database and were retrospectively analysed. Results: Eighty‐nine MEN1 patients underwent either TPTX (n = 38, 42.7%), SPTX (n = 23, 25.8%) or SGE (n = 28, 31.5%). The rate of disease persistence after initial surgery was 2.6%, 0% and 14.2% in the TPTX, SPTX and SGE groups, respectively. After median follow‐up of 112 (range 7‐411) months, the rate of recurrent pHPT was significantly higher in the SGE group (n = 19, 21.3%) compared with the TPTX (n = 4, 4.4%, P = .001) and the SPTX (n = 9, 10.1%, P = .03) groups. Analysis of the recurrence‐free time among the surgical groups revealed a significant difference (P = .036). The median time to recurrence was significantly shorter after SGE (101, range 3‐301 months) than after SPTX (139, range 28‐278 months, P = .018) and TPTX (204, range 75‐396 months, P = .049). Twelve (32%) patients who underwent TPTX developed permanent hypoparathyroidism compared with only 4 (17%, P = .06) in the SPTX and 0 in the SGE group (P = .001). Conclusion: Given the high rate of postoperative permanent hypoparathyroidism after TPTX and SPTX, SGE is a valid option for the treatment of MEN1‐associated pHPT. [ABSTRACT FROM AUTHOR]

Context: Multiple endocrine neoplasia 1 (MEN 1) is an autosomal dominant disease presenting as hyperplasia and neoplasia of parathyroid, pituitary and enteropancreatic tissues. Over 90% of gene carriers develop phenotypic disease by age 30 years, potentially with onset of asymptomatic disease during childhood and adolescence. Objective: To describe the paediatric and young adult manifestations of MEN 1. Design: Descriptive retrospective study of 180 patients with a common MEN1 genotype. The paediatric and young adult (age <22 years) manifestations were determined using hospital records and disease surveillance data. Results: Primary hyperparathyroidism (PHPT) was identified in 42 patients (mean age 17.2 ± 3.3 years). Parathyroidectomy was performed in 16 (38.1%; mean age 17.8 ± 3.2). Four patients experienced recurrent PHPT (25%), and six (37.5%) developed permanent hypoparathyroidism. Pituitary disease was identified in 13 patients. Prolactinoma was found in nine patients (mean age 16.6 ± 2.6 years) of whom four (44.4%) had macroprolactinoma. Two patients required surgical intervention; dopamine agonists showed efficacy in six patients. Two patients with Cushing's disease were successfully treated surgically. Three patients with nonfunctioning pituitary microadenoma managed conservatively. Pancreatic neuroendocrine neoplasms (pNENs) were diagnosed in 12 patients (mean age 17.0 ± 2.6 years): three patients with insulinoma successfully resected (two resected and one exhibiting perineural invasion) and nine patients with nonfunctioning adenomas (NFAs). Conclusion: Pituitary adenomas, PHPT and pNENs are encountered in the paediatric and young adult MEN 1 population. Successful outcomes are typically achieved using standard medical and surgical paradigms; however, parathyroidectomy was associated with a substantial complication rate. [ABSTRACT FROM AUTHOR]

Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen's kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean±SD: 2 mm/year±3.4 mm vs. 1.9 mm/year±3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs. [ABSTRACT FROM AUTHOR]

Despite recent advances in genomics and the discovery of numerous genes involved in carcinogenesis, the mechanisms of malignant transformation of different tissues remain poorly understood in most cases. This review presents the current knowledge on the role of the MEN1 gene and its protein product menin in the development of multiple endocrine neoplasia type 1 (MEN1), or Wermer's syndrome. Here, we discuss the putative molecular and genetic mechanisms of carcinogenesis associated with the MEN1 gene mutation, as well as available and promising in vivo and in vitro models for studying the molecular basis of the disease. The lack of clear data on the role of the MEN1 gene in tumor initiation and progression in patients with MEN1 syndrome allows us to suggest two models for occurrence of malignant transformation in endocrine tissues. [ABSTRACT FROM AUTHOR]

Summary: Objective: Literature concerning the impact of multiple endocrine neoplasia type 1 (MEN 1) on fertility is limited to case reports despite the early onset of endocrinopathies, such as primary hyperparathyroidism and prolactinoma, that may impact fertility. This study describes the impact of unrecognized and untreated MEN 1 on fertility and pregnancy outcomes in a multigenerational cohort of the Tasman 1 MEN 1 kindred. Methods: All MEN 1 positive (MEN 1+, n = 63) and MEN 1 negative (MEN 1−, n = 75) descendants born between 1825 and 1951 of a common founder. Review of birth, death, marriage and medical records provided data on date of birth and death, gender, MEN 1 status and the number of pregnancies and children per parent. Results: Compared to MEN 1− parents, MEN 1+ parents had more children (RR 1.30, 1.02‐1.66) and live births (RR 1.31, 1.02‐1.67) with no excess of stillbirths (RR 1.24, 0.24‐6.36). Compared to the era‐matched Tasmanian fertility rate, MEN 1+ parents had more children (4.87 ± 4.11 vs 3.40 ± 0.61, P = 0.048), whereas MEN 1− parents had similar numbers of children (3.67 ± 3.27 vs 3.36 ± 0.62, P = 0.55). MEN 1+ parents had a similar number of MEN 1+ and MEN 1− offspring (2.1 ± 1.9 vs 2.5 ± 2.3, P = 0.31). Indirectly assessed miscarriage rate was similar between MEN 1+ and MEN 1− mothers (P = 0.77). Clinically overt pituitary disease reduced MEN 1+ kindred member likelihood of parenthood (33% vs 97%). Conclusions: There was no adverse impact of MEN 1 on patient fertility overall; however, MEN 1‐related pathology may have impaired the reproductive potential of a subset of individuals with pituitary disease. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal domi nant disorder characterised by the combined occurrence of parathyroid, pituit ary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome st ability, transcription, cell division and proliferation, but its mechanistic roles in t umourigenesis remain to be fully elucidated. miRNAs are non-coding single-stranded RNAs th at post-transcriptionally regulate gene expression and have been associated with tumour d evelopment, although the contribution of miRNAs to MEN1-associated tumourigenesis an d their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative 'tumour suppressor' miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knockout of the Men1 gene (Men1+/- mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitar y tumours (by 2.3-fold, P < 0.05; 2.1-fold P < 0.01 and 1.6-fold P < 0.05, respectively) of Men1+/- mice, compared to normal WT pituitaries. miR-15a and miR-16-1 expression inver sely correlated with expression of cyclin D1, a known pro-tumourigenic target o f these miRNAs, and knockdown of menin in a human cancer cell line (HeLa), and AtT2 0 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (P < 0.05), indicating that the decrease in miR-15a may be a direct result of lost menin ex pression. [ABSTRACT FROM AUTHOR]

The aim of this report was to illustrate a case of parathyroid carcinoma (PC) in a patient with multiple endocrine neoplasia type 1 (MEN1) along with a comprehensive literature review. A 61-year-old man presented with 9-cm PC causing primary hyperparathyroidism (PHPT). His pre-operative corrected calcium and intact PTH serum levels were 2.92 mmol/L and 391.7 pg/mL, respectively. The neoplastic gland was removed in bloc with thyroid and central compartment lymph nodes. A literature review was run by searching PubMed MEDLINE from 1977 to 2018 for studies of all types, in the English language only, using the terms “Parathyroid, carcinoma, Multiple endocrine neoplasia, type 1, (MEN1).” Pathology confirmed PC. Post-operative calcium and PTH levels were normal. A diagnosis of MEN1 was established post-operatively. Seventeen cases of PC in patients with MEN1 have been reported in the literature. 59% of patients were men, and median age at diagnosis was 50 years, with median serum PTH of 379 pg/mL and median serum calcium level of 3.2 mmol/L. The occurrence of PC in the context of MEN1 is extremely rare. Diagnosis and treatment may represent a challenge, so opportune identification or suspicion of malignancy and adoption of correct surgical approach may offer affected patients the best outcome. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine neoplasias (pNEN) are the most common cause of death in adult patients with multiple endocrine neoplasia type 1 (MEN1). So far, only few chemopreventive strategies (e.g., with somatostatin analogues) have been evaluated for MEN1 associated pNENs. In this experimental study on 75 Men1(+/T) knockout mice, the effect of aspirin (n = 25) and an inhibitor of angiotensin-I converting enzyme (enalapril, n = 25) compared to controls (n = 25) were evaluated as single chemopreventive strategies for pNENs after 6, 9, 12, 15, and 18 months. After each study period, mice were sacrificed and the resected pancreata were evaluated by histopathological analysis, immunostaining, and real-time PCR. PNEN size and number was measured. Aspirin and enalapril lead to a pNEN size reduction of 80% (167,518 vs. 838,876 µm2, p < 0.001) and 79% (174,758 vs. 838,876 µm2, p < 0.001) compared to controls. Furthermore, aspirin and enalapril treatment resulted in a significant reduction of the number of pNENs by 33%, (p = 0.04) and 41% (p = 0.002) respectively. The apoptosis marker caspase 3 revealed a higher positive expression in pNEN of treated Men1(+/T) mice. Immunostaining of VEGF in pNEN detected a downregulation of its expression in treated Men1(+/T) mice compared to the control group. REL A transcript was significantly downregulated in 18-months treated enalapril Men1(+/T) mice, but not in aspirin-treated Men1(+/T) mice. There was no significant difference in the Ki-67 index. Using a transgenic mouse model that imitates human MEN1, this study provides first evidence that aspirin and enalapril are effective chemopreventive agents that aid in the progression of pNENs. [ABSTRACT FROM AUTHOR]

Background: The advantages of nanomedicines include preferential delivery of the payload directly to tumor tissues. CYT-21625 is the novel, first-in-class gold nanomedicine designed to target tumor vasculature and cancer cells by specifically delivering recombinant human tumor necrosis factor alpha (rhTNF) and a paclitaxel prodrug.Methods: We analyzed TNF receptor expression in publicly available gene expression profiling data and in thyroid tissue samples. Mice with metastatic FTC-133 and 8505C xenografts and the MEN1 conditional knock-out mice were treated weekly with CYT-21625 and gold nanoparticles with rhTNF only (CYT-6091); controls included mice treated with either paclitaxel or saline. In vivo luciferase activity was used to assess the effects on tumor growth. Computed tomography, magnetic resonance imaging, and 18F-Fludeoxyglucose positron emission tomography were used to study tumor selectivity in mice with insulin-secreting pancreatic neuroendocrine tumors (PNETs). All statistical tests were two-sided.Results: Anaplastic thyroid cancer (ATC) expressed statistically significantly higher levels of TNF receptor superfamily 1A and 1B messenger RNA (n = 11) and protein (n = 6) than control samples (n = 45 and 13, respectively). Mice (n = 5-7 per group) with metastatic ATC (P < .009) and FTC-133 xenografts (P = .03 at week 3, but not statistically significant in week 4 owing to reduced sample size from death in non-CYT-21625 groups) treated with CYT-21625 had a statistically significantly lower tumor burden. Treatment with CYT-21625 resulted in loss of CD34 expression in intratumoral vasculature, decreased proliferating cell nuclear antigen, and increased cleaved caspase-3. Intratumoral vascular leakage occurred only in mice with PNET and ATC treated with CYT-6091 and CYT-21625. CYT-6091 and CYT-21625 preferentially deposited in PNETs and statistically significantly decreased serum insulin levels (n = 3 per group, P < .001). There were no toxicities observed in mice treated with CYT-21625.Conclusions: CYT-21625 is effective in mice with PNETs and metastatic human thyroid cancer with no toxicities. Thus, CYT-21625 should be studied in patients with advanced PNETs and thyroid cancer. [ABSTRACT FROM AUTHOR]

Aim: Pancreatic neuroendocrine tumors (pNETs) can occur in patients with a familial syndrome either as multiple endocrine neoplasia type 1 (MEN-1) or as sporadic tumors. Endoscopic ultrasound (EUS) has become one of the first-line investigations for pNET characterization. The ultrasonographic features of pNETs may differ depending on the familial versus sporadic pathogenesis of the tumor. Therefore, the EUS findings could help and direct the definition of a pNET with an impact on the most appropriate diagnostic and therapeutic patient management. Methods: In this single-center retrospective study, we reviewed the EUS features of 94 pNETs from 37 MEN-1 patients and 15 pNETs from 11 sporadic disease patients at the time of their first EUS assessment. We analyzed the most relevant morphological and ultrasonographic characteristics of the tumors and compared the findings between the 2 patient groups. Results: Patients with MEN-1 more likely present with multiple pNETs than patients with sporadic disease. Sporadic pNETs are usually much bigger than those due to MEN-1. Moreover, pNETs are more heterogeneous in patients with sporadic disease than in those with MEN-1. No statistical difference with regard to definition of the margins, morphology, and vascularization of the pNETs appears between the 2 groups. Conclusions: Patients with sporadic disease usually present with bigger and more heterogeneous pNETs than patients with MEN-1, who tend to present with a higher number of lesions. EUS can facilitate the precise characterization of a pNET, and the ultrasonographic features of the lesion can help and distinguish MEN-1-related versus sporadic disease. [ABSTRACT FROM AUTHOR]

The MEN1 gene encodes MENIN, a tumor suppressor that plays a role in multiple cellular processes. Germline and somatic mutations in MEN1 have been identified in hereditary and sporadic tumors of neuroendocrine origins suggesting context-specific functions. In this review, we focus on the development of mutational Men1 in vivo models, the known cellular activities of MENIN and efforts to identify vulnerabilities in tumors with MENIN loss. [ABSTRACT FROM AUTHOR]

To report the clinical, hormonal, and genetic features of a female with multiple endocrine neoplasia type 1 (MEN1) with multiple uterine leiomyomas. The study was conducted at a tertiary care endocrinology unit. A 27-year-old female was diagnosed with prolactinoma, primary hyperparathyroidism (PHPT), and multiple uterine leiomyomas. In view of prolactinoma and PHPT, a clinical diagnosis of MEN1 syndrome was made. She also had multiple uterine leiomyomas for which myomectomy was done. Genetic analysis revealed a novel mutation c.1763C>T, p.S588L of MEN1 gene. The association of uterine leiomyomas with MEN1 is exceptionally rare. This is the first report of multiple uterine leiomyomas in a patient with MEN1 from our country and the first report of this mutation in the MEN1 gene in the world. We conclude that in the presence of multiple uterine leiomyomas and endocrine tumor, clinical examination and laboratory evaluation may uncover the diagnosis of MEN1 syndrome in these patients. [ABSTRACT FROM AUTHOR]

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal dominant inherited syndrome caused by mutations in the MEN1 tumor suppressor gene. The diagnosis is defined clinically by the presence of 2 or more primary MEN1 tumors (parathyroid, anterior pituitary, and pancreatic islet). We describe the case of a patient who presented with classic history and imaging findings for MEN1. Case Report: A male in his early thirties with a history of hyperparathyroidism and a transsphenoidal prolactinoma resection presented years later with abdominal symptoms concerning for Zollinger-Ellison syndrome: worsening epigastric abdominal pain, nausea, vomiting, and diarrhea. Contrast-enhanced computed tomography (CT) of the abdomen revealed hyperenhancing pancreatic lesions and duodenal inflammation, suggesting pancreatic neuroendocrine tumor (gastrinoma) with secondary duodenitis. Bilateral indeterminate hypoattenuating adrenal nodules were also seen on contrast-enhanced CT, and follow-up magnetic resonance imaging confirmed benign adrenal adenomas. Furthermore, thyroid ultrasound and sestamibi scintigraphy revealed a parathyroid adenoma. With confirmatory imaging findings, history, and presenting symptoms, the patient was clinically diagnosed with MEN1 syndrome and underwent surgical and medical management. Conclusion: This case exhibits the classic history with corresponding imaging findings of MEN1 syndrome, including pancreatic neuroendocrine tumors, parathyroid adenoma, and adrenal adenomas. High clinical suspicion for MEN1 should lead to endocrinology evaluation with appropriate laboratory workup and targeted imaging evaluation of the typical endocrine organs as described for this patient. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 1 (MEN1) is associated with a heterozygous inherited mutation of the menin 1 (MEN1) gene; however, the molecular pathogenesis remains to be fully elucidated. In the present study, whole exome sequencing was performed on two pancreatic neuroendocrine tumors (PNETs), termed T1 and T2, peri-tumoral tissue (PT) and a blood sample obtained from a patient with MEN1. The cells in T1 and T2, but not PT, showed loss of chromosome 11 where MEN1 was located, confirming that the loss of heterozygosity (LOH) of MEN1 was a crucial event in tumorigenesis. PT exhibited chromosome copy number variations (CNVs), suggesting that CNVs may occur ahead of MEN1-associated tumorigenesis. The ploidy, CNVs and somatic point mutations were completely different in T1 and T2, showing the first evidence that multiple PNETs in patients with MEN1 are heterogeneous and arise from polyclonal origins. With the except of one recurrent and possibly benign mutation, no other suspicious driver mutations were identified in the tumors. By contrast, accompanying several chromosome losses, germline heterozygous mutations in the tumor suppressor genes, mucin 6, oligomeric mucus/gel-forming (MUC6), and G protein-coupled receptor 17 (GPR17) showed loss of heterozygosity in the two tumors, or in T2, respectively. These data demonstrated that chromosome instability may aggravate inherited mutations other than MEN1, thus contributing to the tumorigenesis in MEN1-associated PNETs. [ABSTRACT FROM AUTHOR]

Summary: Context: Bronchopulmonary neuroendocrine tumours (bpNETs) and thymic carcinoid (ThC) are features of multiple endocrine neoplasia type 1 (MEN 1), and surveillance guidelines recommend periodic thoracic imaging. The optimal thoracic imaging modality and screening frequency remain uncertain as does the prognosis of small lung nodules when identified. Objectives: To evaluate fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) for identification and prognostic assessment of thoracic lesions in MEN 1. Design: Retrospective observational study. Setting and participants: Fifty consecutive MEN 1 patients undergoing screening with 18F‐FDG PET/CT at a tertiary referral hospital between July 2011 and December 2016. Interventions: 18F‐FDG PET/CT. Outcome measures: Pulmonary and thymic lesion prevalence, size, functional characteristics and behaviour. Results: Thirteen patients (26.0%) exhibited pulmonary nodules with multiple nodules identified in nine (18.0%). An asymptomatic 31 mm FDG‐avid ThC was identified in one patient (2%). Of the 13 patients with pulmonary nodules, four (8.0%) exhibited 13 FDG‐avid nodules (mean size 10.1 ± 9.1 mm), and nine (18.0%) demonstrated 26 FDG nonavid nodules (mean size 6.9 ± 5.8 mm). All FDG‐avid lesions increased in size vs 11 (42.3%) FDG nonavid lesions (P = .0004). For FDG‐avid and nonavid nodules, the median doubling time was 24.2 months (IQR 11.4‐40.7) and 48.6 months (IQR 37.0‐72.2), respectively. Nodule resection was undertaken in two patients, typical bronchial carcinoid diagnosed in one (FDG nonavid) and metastatic renal cell carcinoma in the second (FDG avid). Conclusion: Thoracic imaging with 18F‐FDG PET/CT effectively identifies pulmonary nodules and ThC. FDG‐avid pulmonary lesions are significantly more likely to progress than nonavid lesions. [ABSTRACT FROM AUTHOR]