Chemoprevention with Somatuline© Delays the Progression of Pancreatic Neuroendocrine Neoplasms in a Mouse Model of Multiple Endocrine Neoplasia Type 1 (MEN1).

OBJECTIVE: Long-acting synthetic somatostatin analogues (SSA) are an essential part of the treatment of neuroendocrine neoplasms. We evaluated the chemopreventive effects of a long-acting somatostatin analogue on the development of pancreatic neuroendocrine neoplasms (pNENs) in a genetically engineered MEN1 knockout mouse model. MATERIALS AND METHODS: Heterozygote MEN1 knockout mice were injected every 28 days subcutaneously with the somatostatin analogue lanreotide (Somatuline Autogel©; Ipsen Pharma) or a placebo starting at day 35 after birth. Mice were euthanized after 6, 9, 12, 15 and 18 months, and the size and number of pNENs were measured due histological analysis and compared to the placebo group. RESULTS: The median tumor size of pNENs was statistically significantly smaller after 9 (control group vs. SSA group; 706.476 µm2 vs. 195.271 µm2; p = 0.0012), 12 (placebo group vs. SSA group 822.022 vs. 255.482; p ≤ 0.001), 15 (placebo group vs. SSA group 1192.568 vs. 273.533; p ≤ 0.001) and after 18 months (placebo group vs. SSA group 1328.299 vs. 864.587; p ≤ 0.001) in the SSA group. Comparing the amount of tumors in both groups, a significant reduction was achieved in treated Men1(+/-) mice (41%, p = 0.002). Immunostaining showed, however, no significant difference in the expression of the apoptosis marker caspase-3, but a significant difference in Ki67 index as a marker for tumor cell proliferation (p ≤ 0.005). CONCLUSION: Long-acting somatostatin analogues may be an effective chemopreventive approach to delay the progression of MEN1-associated pNENs. After our preclinical results, we would recommend to evaluate the effects of long-acting SSA in a prospective clinical trial.

Chemoprevention with Enalapril and Aspirin in Men1(+/T) Knockout Mouse Model.

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.

Is Routine Screening of Young Asymptomatic MEN1 Patients Necessary?

BACKGROUND: Recent clinical practice guidelines recommend that routine screening of MEN1 mutation carriers should start at the age of 5 years. The occurrence of clinically relevant MEN1 organ manifestations in children (≤18 years) was evaluated. METHODS: Two prospective collected databases of MEN1 patients (n = 166) who underwent annual screening were retrospectively analyzed for organ manifestations in MEN1 patients ≤18 years. The follow-up was based on the most recent screening examination until December 2015. RESULTS: Twenty [11 females, 9 males, (12%)] of 166 MEN1 patients were diagnosed with at least one organ manifestation at age ≤18 years. The most frequent manifestation was mild asymptomatic pHPT (n = 9, 45%, age range 8-18 years). Eight (40%) young patients had pNENs (three non-functioning pNENs, five insulinomas, age range 9-18 years). All five insulinomas were diagnosed based on hypoglycemic symptoms. The other organ manifestations were asymptomatic pituitary adenomas in six patients (30%, age range 15-18 years) and a bronchial carcinoid in one 15-year-old patient. Only six (30%) patients ≤18 years had clinically relevant organ manifestations. CONCLUSION: Symptomatic or severe manifestations in MEN1 patients rarely occur below the age of 16 years. With regard to psychological burden and cost-effectiveness, routine screening of asymptomatic MEN1 patients should be postponed at least until the age of 16 years.

Limited Value of Ga-68-DOTATOC-PET-CT in Routine Screening of Patients with Multiple Endocrine Neoplasia Type 1.

BACKGROUND: Routine screening is recommended for patients with multiple endocrine neoplasia type 1 (MEN1) to enable early detection and treatment of associated neuroendocrine neoplasms (NEN). Gallium68-DOTATOC-Positron emission tomography combined with computed tomography (Ga-68-DOTATOC-PET-CT) is a very sensitive and specific imaging technique for the detection of sporadic neuroendocrine tumors. The present study evaluated the value of Ga-68-DOTATOC-PET-CT in routine screening of patients with MEN1. METHODS: Between January 2014 and March 2016, all MEN1 patients underwent Ga-68-DOTATOC-PET-CT in addition to conventional imaging (computed tomography of the thorax, magnetic resonance imaging of the abdomen and pituitary, endoscopic ultrasonography). The diagnostic yield of conventional imaging and Ga-68-DOTATOC-PET-CT was prospectively documented and compared, and treatment changes caused by the addition of Ga-68-DOTATOC-PET-CT were recorded. RESULTS: Conventional imaging detected 145 NENs, mainly pancreaticoduodenal NENs (n = 117, 81%), in 31 of 33 MEN1 patients. Ga-68-DOTATOC-PET-CT detected 55 NENs in 23 of the 33 patients (p = 0.0001). Ninety (62%) NENs detected by conventional imaging were missed by DOTATOC-PET-CT. The majority of missed lesions were pNEN (n = 68; 74%). The sensitivity of Ga-68-DOTATOC-PET-CT for NENs <5, 5-9, 10-19 and ≥20 mm was 0, 29, 81 and 100%, respectively. However, Ga-68-DOTATOC-PET-CT detected more liver and lymph node metastases in patients with known metastatic disease, which did not lead to a change of patients' management. In one patient (3%), Ga-68-DOTATOC-PET-CT was the only imaging modality that detected a small intestine NEN and led to potentially curative surgery. CONCLUSION: Ga-68-DOTATOC-PET-CT cannot be recommended for routine screening of MEN1 patients. It might provide important additional information in patients with suspected or known metastatic disease.

An unusual phenotype of MEN1 syndrome with a SI-NEN associated with a deletion of the MEN1 gene.

UNLABELLED: We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation. LEARNING POINTS: Our patient presents an extraordinary course of disease.Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.

Minimally Invasive Versus Open Pancreatic Surgery in Patients with Multiple Endocrine Neoplasia Type 1.

OBJECTIVE: The role of minimally invasive pancreatic surgery for pancreatic neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1) is not well defined. The aim of this study was to compare the outcome of minimally invasive versus open pancreatic resections in patients with MEN1. MATERIALS AND METHODS: Prospectively collected data of MEN1 patients who underwent a primary distal pancreatic resection and/or enucleation for non-functioning pNENs or insulinoma were retrospectively analyzed regarding the outcome of minimally invasive or open pancreatic resections. RESULTS: Thirty-three patients underwent primary pancreatic resection for either organic hyperinsulinism (n = 9, 27 %) or non-functioning pNENs >1 cm in size (n = 24, 73 %) between 1987 and 2015. 21 (64 %) patients underwent an open surgical (group 1) and 12 patients (36 %) a minimally invasive approach, either laparoscopic (n = 8) or robotic assisted (n = 4) (group 2). Both groups were comparable regarding age, gender, number, and size of pancreatic tumors. In both groups, the hyperinsulinism of all patients (9/9,100 %) could be cured and all NF-pNENs >1 cm could be resected. Group 2 had a significant shorter operative time (200 vs. 260 min; p = 0.036), less intraoperative blood loss (120 vs. 280 ml; p < 0.001), and a shorter hospital stay (11 vs. 15.5 days; p = 0.034). The rate of patients with postoperative complications, especially postoperative pancreatic fistulas, was not different between groups (62 % group 1 vs. 67 % group 2, p = 0.74). CONCLUSION: Minimally invasive distal pancreatic resections and enucleations are feasible and safe in MEN1 patients with insulinoma or non-functioning pNENs.

Bronchopulmonary Neuroendocrine Neoplasms and Their Precursor Lesions in Multiple Endocrine Neoplasia Type 1.

OBJECTIVE: The prevalence and clinical behavior of bronchopulmonary neuroendocrine tumors (bNET) associated with multiple endocrine neoplasia type 1 (MEN1) are not well defined. This study aimed to determine the prevalence, potential precursor lesions and prognosis of bNET in patients with MEN1. METHODS: A database of 75 prospectively collected MEN1 cases was retrospectively analyzed for bNET. Patient characteristics, imaging and treatment were evaluated. Resection specimens of operated patients were reassessed by two specialized pathologists. Available CT scans of the whole cohort were reviewed to determine the prevalence of bronchopulmonary nodules. RESULTS: Five of the 75 MEN1 patients (6.6%; 2 male, 3 female) developed histologically confirmed bNET after a median follow-up of 134 months. The median age at diagnosis of bNET was 47 years (range 31-67), and all patients were asymptomatic. Four patients underwent anatomic lung resections with lymphadenectomy; the remaining patient with multiple lesions had only a wedge resection of the largest bNET. Tumor sizes ranged from 7 to 32 mm in diameter, and all bNET were well differentiated. Two patients had lymph node metastases. Two of 4 reevaluated resection specimens revealed multifocal bNET, and 3 specimens showed tumorlets (up to 3) associated with multifocal areas of a neuroendocrine cell hyperplasia within the subsegmental bronchi. One bNET-related death (1.3%) occurred during long-term follow-up. Review of the available CT scans of the patients without proven bNET revealed small bronchopulmonary lesions (≥3 mm) in 16 of 53 cases (30.2%). CONCLUSIONS: bNET in MEN1 might be more common than previously recognized. Their natural course seems to be rather benign. Multifocal tumorlets and multifocal neuroendocrine cell hyperplasia might represent their precursor lesions.

Radiologic diagnostic procedures in severely injured patients - is only whole-body multislice computed tomography the answer?

BACKGROUND: Whole-body multislice computed tomography (WB-MSCT) has become an important diagnostic tool in the early treatment phase of severely injured patients. The optimal moment of WB-MSCT's use during this treatment phase remains unclear. Many trauma centers use WB-MSCT in addition to conventional radiographs, while some trauma centers use WB-MSCT as the only radiological tool. The aim of this study was to determine the differences between these two protocols and to answer the question of whether conventional radiographs can still be used in the safe treatment of polytrauma patients. METHODS: Patients from the TraumaRegister DGU® with an injury severity score (ISS) of ≥16 were included. Group I received conventional radiographs and focused assessment with sonography in trauma (FAST) prior to a WB-MSCT, and group II received an initial WB-MSCT and FAST. Both groups were compared concerning treatment time and outcome. RESULTS: A total of 3,995 patients in group I were compared to 4,025 patients in group II. There were no differences in ISS (29.97 vs. 29.94), gender (male: 73.5% vs. 72.8%), age (45.47 vs. 45.12 years), or calculated mortality (21.41% vs. 21.44%). Time needed in the resuscitation room was slightly longer in group I (72 vs. 64 min); the durations until admittance to the ICU and arrival to the OR were not significantly different between the groups. There was no difference in mortality (18.2% vs. 18.4%) or the standardized mortality ratio (SMR) (0.85 vs. 0.86). CONCLUSIONS: WB-MSCT plays an inherent role in the treatment of multiple-injured patients. However, the use of WB-MSCT as the only diagnostic method in the resuscitation room is not needed. Conventional radiographs and FAST followed by WB-MSCT can be performed in the early resuscitation phase without impairing patient outcomes. This approach enables the emergency room team to perform life-saving procedures - chest-tube insertion, laparotomy, cardiopulmonary resuscitation -immediately and simultaneous. Nevertheless, randomized multi-center trials are needed to determine the comparability and effectiveness of these algorithms.

[In-hospital trauma management - damage control]. / Innerklinisches Traumamanagement - Damage Control - Die Mutter vieler Strategien.

Damage Control is a strategy for the initial treatment phase in severely injured patients. The aim is to avoid time consuming surgical procedures thereby reducing secondary damage and to improve patients' outcome. Once the patient is haemodynamically stabilized on the intensive care unit, definitive therapy - i. e. osteosynthesis, bowel/urinary tract reconstruction etc. - can be performed after a time interval of 5-10 days. Thus Damage Control is a quick and focused but preliminary treatment strategy in the initial emergency phase in critically injured patients.

[In-hospital trauma management - beyond routine in trauma resuscitation]. / Innerklinisches Traumamanagement - Seltenes ist selten: Zeugen Jehovas, Patienten mit Infektionskrankheiten, Schwangere und Kinder im Schockraum.

Trauma resuscitation in children, pregnant women, Jehovah's witnesses or in patients with infectious diseases like HIV is obviously beyond routine. This may result in uncertainty how to manage these patients appropriately. Preparation for such situations is essential. Therefore this article focuses on the specific problems associated with these kinds of patients.

Higher risk of aggressive pancreatic neuroendocrine tumors in MEN1 patients with MEN1 mutations affecting the CHES1 interacting MENIN domain.

CONTEXT: Sixty to 80% of multiple endocrine neoplasia type 1 (MEN1) patients develop pancreatic neuroendocrine neoplasias (pNENs), which reveal an aggressive behavior in 10%-20% of patients. Causative MEN1 mutations in the interacting domains of the encoded Menin protein directly alter its regulation abilities and may influence the phenotype. OBJECTIVE: The objective of the study was the evaluation of an association between MEN1 mutations in different interacting domains of Menin and the phenotype of pNENs. DESIGN: This was a retrospective analysis of a prospectively collected cohort of 71 genetically confirmed MEN1 patients at a tertiary referral center. MAIN OUTCOME MEASURES: Analysis of patients' characteristics and clinical phenotype of pNENs regarding the mutation type and its location in Menin interacting domains was measured. RESULTS: Sixty-seven patients (93%) developed pNENs after a median follow-up of 134 months. Patients with mutations leading to loss of interaction (LOI) with the checkpoint kinase 1 (CHES1) interacting domain codons (428-610) compared with patients with mutations resulting in LOI with other domains (eg, JunD, Smad3) had significantly higher rates of functioning pNENs (70% vs 34%), malignant pNENs (59% vs 16%), and aggressive pNENs (37% vs 9%), respectively. Patients with CHES1-LOI also had an increased pNEN-related mortality (20% vs 4.5%). Neither gender, age, nor the ABO blood types were associated with the phenotype of pNENs. CONCLUSIONS: MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.

Shortness: an unknown phenotype of multiple endocrine neoplasia type 1.

OBJECTIVE: An observation of shortness among the female participants of a regular screening program in multiple endocrine neoplasia type 1 (MEN1) patients has raised the question as to whether shortness represents a phenotype characteristic of the disease. METHODS: The body height (cm) of genetically confirmed MEN1 patients at the time of diagnosis was compared with the body height of their unaffected relatives (parents, siblings, and children), the midparental body height, and the body height of the age-matched German population. Univariate analysis of the clinical variables was performed using the t-test, Mann­Whitney U test, and ANOVA as appropriate, and multivariate analysis was performed as a logistic regression analysis. P values <0.05 were considered statistically significant. RESULTS: The mean body height of 22 female MEN1 patients (mean age 33.5 years) was 161 +/- 5 cm and thus significantly lesser than the body heights of their unaffected female relatives (mean 165.5 +/- 7.3 cm, P=0.027) and the age-matched German female population (mean 167 cm, P=0.0001) and mid-parental height (177.5 cm, P<0.0001). The mean body height of 24 male MEN1 patients (mean age 34.8 years) was also lesser (177 +/- 6.5 cm) than the average body height of German males in this age group (180 cm, P=0.031) and tended to be lesser than that of their unaffected male relatives (178.5 +/- 5.8 cm, P=0.0915) and the mid-parental body height (177.5 cm, P=0.124). CONCLUSIONS: Small body height is a yet unrecognized phenotype characteristic of MEN1 patients, especially in women. The mechanisms behind this phenotypical characteristic warrant further investigation.

Partial pancreaticoduodenectomy can provide cure for duodenal gastrinoma associated with multiple endocrine neoplasia type 1.

OBJECTIVE: To evaluate the outcome of pancreaticoduodenectomy (PD) versus non-PD resections for the treatment of gastrinoma in multiple endocrine neoplasia type 1. BACKGROUND: Gastrinoma in MEN1 is considered a rarely curable disease and its management is highly controversial both for timing and extent of surgery. METHODS: Clinical characteristics, complications and outcomes of 27 prospectively collected MEN1 patients with biochemically proven gastrinoma, who underwent surgery, were analyzed with special regard to the gastrinoma type and the initial operative procedure. RESULTS: Twenty-two (81%) patients with gastrinoma in MEN1 had duodenal gastrinomas and 5 patients (19%) had pancreatic gastrinomas. At the time of diagnosis, 21 (77%) gastrinomas were malignant (18 duodenal, 3 pancreatic), but distant metastases were only present in 4 (15%) patients. Patients with pancreatic gastrinomas underwent either distal pancreatic resections or gastrinoma enucleation with lymphadenectomy, 2 patients also had synchronous resections of liver metastases. One of these patients was biochemically cured after a median of 136 (77-312) months. Thirteen patients with duodenal gastrinomas underwent PD resections (group 1, partial PD [n = 11], total PD [n = 2]), whereas 9 patients had no-PD resections (group 2) as initial operative procedure. Perioperative morbidity and mortality, including postoperative diabetes, differed not significantly between groups (P > 0.5). All patients of group 1 and 5 of 9 (55%) patients of group 2 had a negative secretin test at hospital discharge. However, after a median follow-up of 136 (3-276) months, 12 (92%) patients of group 1 were still normogastrinemic compared to only 3 of 9 (33%) patients of group 2 (P = 0.023). Three (33%) patients of group 2 had to undergo up to 3 reoperations for recurrent or metastatic disease compared to none of group 1. CONCLUSIONS: Duodenal gastrinoma in MEN1 should be considered a surgically curable disease. PD seems to be the adequate approach to this disease, providing a high cure rate and acceptable morbidity compared to non-PD resections.

Long-term results of surgery for pancreatic neuroendocrine neoplasms in patients with MEN1.

PURPOSE: This study was made to evaluate long-term results of an aggressive surgical approach for pancreaticoduodenal neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1). METHODS: MEN1 patients with either biochemical evidence of functioning or non-functioning pNENs larger than 1 cm in size on imaging underwent duodenopancreatic surgery. Since 1997, patients were followed annually by biochemical testing and imaging studies. RESULTS: Thirty-eight genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 22) or non-functioning (n = 16) pNENs, nine patients were yet not operated. Malignant disease occurred in 12 (35%) patients defined by either lymph node (12 patients) and/or distant metastases (2 patients). Six patients with Zollinger-Ellison syndrome (ZES) required pylorus-preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure and 32 patients underwent other duodenopancreatic resections. Ten (26%) patients underwent up to four reoperations for either recurrent or metastatic disease that resulted in completion pancreatectomy in four patients. After median 109 months, 44 patients were alive and three patients died, one due to thymic carcinoid and two of unrelated causes. All eight patients with organic hyperinsulinism and 7 of 13 patients with ZES were biochemically cured. However, 24 of 38 (78%) patients developed new pNENs in the pancreatic remnant, but none developed distant metastases. CONCLUSIONS: Early resection of pNENs in MEN1 may prevent the development of distant metastases. However, the majority of patients develop new pNENs in the duodenopancreatic remnant which may require completion pancreatectomy in the long term.